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0dc04e203d0103ba6c236935a8fed94bf6db119c	wikidoc	Genophore	Genophore A genophore is the DNA of a prokaryote. This is commonly referred to as a prokaryotic chromosome. The term chromosome is misleading for a genophore because the genophore lacks chromatin . The genophore is compacted through a mechanism known as supercoiling. Where a chromosome is compacted via chromatin. The genophore is circular in most prokaryotes, and linear in very few. The circular nature of the genophore allows replication to occur without telomeres. Genophores are generally of a much smaller size than Eukaryotic chromosomes. A genophore of a true organism can be as small as 580,073 base pairs (Mycoplasma genitalium). Many eukaryotes (such as plants and animals) carry genophores in organelles such as mitochondria and chloroplasts. These organelles are very similar to true prokaryotes.	Genophore Template:Mergeto A genophore is the DNA of a prokaryote. This is commonly referred to as a prokaryotic chromosome. The term chromosome is misleading for a genophore because the genophore lacks chromatin [1]. The genophore is compacted through a mechanism known as supercoiling[2]. Where a chromosome is compacted via chromatin. The genophore is circular in most prokaryotes, and linear in very few. The circular nature of the genophore allows replication to occur without telomeres.[3] Genophores are generally of a much smaller size than Eukaryotic chromosomes. A genophore of a true organism can be as small as 580,073 base pairs (Mycoplasma genitalium). Many eukaryotes (such as plants and animals) carry genophores in organelles such as mitochondria and chloroplasts. These organelles are very similar to true prokaryotes.[4]	https://www.wikidoc.org/index.php/Genophore
7903100c71c0c89affe3b10b4e628df55f69b568	wikidoc	Geobacter	Geobacter Geobacter is a genus of proteobacteria. Geobacter are an anaerobic respiration bacterial species which have capabilities that may make them useful in bioremediation. The geobacter was found to be the first organism with the ability to oxidize organic compounds and metals, including iron, radioactive metals and petroleum compounds into environmentally benign carbon dioxide while using iron oxide or other available metals as electron acceptor. The Geobacter is under continuing research for a variety of applications, discussed below. # History Geobacter metallireducens was first isolated by Derek Lovley in 1987 in sand sediment from the Potomac River in Washington D.C. The first strain was deemed strain GS-15. Geobacter have been found in anaerobic conditions in soils and aquatic sediment. # Potential and actual applications Research on the potential of the Geobacter is underway and on-going. The Geobacter's ability to consume oil-based pollutants and radioactive material with carbon dioxide as waste by-product has already been used in environmental clean-up for underground petroleum spills and for the precipitation of uranium out of groundwater. The Geobacter metabolizes the material by creating "pili," columns the width of a 3-5 nanometers that act as conduits to pass electrons between the food material and the Geobacter. This manner of consumption has also lead scientists to theorize that the Geobacter could act as a natural battery. This natural battery could use renewable biomass such as compost materials, or be used to convert human and animal solid waste into electricity. There are also potential applications in the field of nanotechnology for the creation of nanowires in very small circuits and electronic devices. The miniature wires could also be connected, creating a microscopic power grid. ## Biodegradation and Bioremediation Microbial biodegradation of recalcitrant organic pollutants is of great environmental significance and involves intriguing novel biochemical reactions. In particular, hydrocarbons and halogenated compounds have long been doubted to be degradable in the absence of oxygen, but the isolation of hitherto unknown anaerobic hydrocarbon-degrading and reductively dehalogenating bacteria during the last decades provided ultimate proof for these processes in nature. Many novel biochemical reactions were discovered enabling the respective metabolic pathways, but progress in the molecular understanding of these bacteria was rather slow, since genetic systems are not readily applicable for most of them. However, several complete genome sequences are now available for bacteria capable of anaerobic organic pollutant degradation. The genome of the hydrocarbon degrading and iron-reducing species Geobacter metallireducens (accession nr. NC_007517) was determined recently. The genome revealed the presence of genes for reductive dehalogenases, suggesting a wide dehalogenating spectrum of the organisms. Moreover, genome sequences provided unprecedented insights into the evolution of reductive dehalogenation and differing strategies for niche adaptation. Geobacter species are often the predominant organisms when extracellular electron transfer is an important bioremediation process in subsurface environments. Therefore, a systems biology approach to understanding and optimizing bioremediation with Geobacter species has been initiated with the ultimate goal of developing in silico models that can predict the growth and metabolism of Geobacter species under a diversity of subsurface conditions. To date, these studies have included sequencing the genomes of multiple Geobacter species and detailed functional genomic/physiological studies on one species, Geobacter sulfurreducens . Genome-based models of several Geobacter species that are able to predict physiological responses under different environmental conditions are now available. Quantitative analysis of gene transcript levels during in situ uranium bioremediation has demonstrated that it is possible to track in situ rates of metabolism and the in situ metabolic state of Geobacter in the subsurface. Initial attempts to link in silico Geobacter models with existing subsurface hydrological and geochemical models are underway. It is expected that this systems approach to bioremediation with Geobacter will provide the opportunity to evaluate multiple Geobacter -catalyzed bioremediation strategies in silico prior to field implementation, thus providing substantial savings when initiating large-scale in situ bioremediation projects for groundwater polluted with uranium and/or organic contaminants. # Popular culture Geobacter are used as a plot device in the first episode of the third season of ReGenesis.	Geobacter Geobacter is a genus of proteobacteria. Geobacter are an anaerobic respiration bacterial species which have capabilities that may make them useful in bioremediation. The geobacter was found to be the first organism with the ability to oxidize organic compounds and metals, including iron, radioactive metals and petroleum compounds into environmentally benign carbon dioxide while using iron oxide or other available metals as electron acceptor. The Geobacter is under continuing research for a variety of applications, discussed below. # History Geobacter metallireducens was first isolated by Derek Lovley in 1987 in sand sediment from the Potomac River in Washington D.C. The first strain was deemed strain GS-15. Geobacter have been found in anaerobic conditions in soils and aquatic sediment.[1] # Potential and actual applications Research on the potential of the Geobacter is underway and on-going. The Geobacter's ability to consume oil-based pollutants and radioactive material with carbon dioxide as waste by-product has already been used in environmental clean-up for underground petroleum spills and for the precipitation of uranium out of groundwater. The Geobacter metabolizes the material by creating "pili," columns the width of a 3-5 nanometers that act as conduits to pass electrons between the food material and the Geobacter. This manner of consumption has also lead scientists to theorize that the Geobacter could act as a natural battery. This natural battery could use renewable biomass such as compost materials, or be used to convert human and animal solid waste into electricity. There are also potential applications in the field of nanotechnology for the creation of nanowires in very small circuits and electronic devices. The miniature wires could also be connected, creating a microscopic power grid.[2] ## Biodegradation and Bioremediation Microbial biodegradation of recalcitrant organic pollutants is of great environmental significance and involves intriguing novel biochemical reactions. In particular, hydrocarbons and halogenated compounds have long been doubted to be degradable in the absence of oxygen, but the isolation of hitherto unknown anaerobic hydrocarbon-degrading and reductively dehalogenating bacteria during the last decades provided ultimate proof for these processes in nature. Many novel biochemical reactions were discovered enabling the respective metabolic pathways, but progress in the molecular understanding of these bacteria was rather slow, since genetic systems are not readily applicable for most of them. However, several complete genome sequences are now available for bacteria capable of anaerobic organic pollutant degradation. The genome of the hydrocarbon degrading and iron-reducing species Geobacter metallireducens (accession nr. NC_007517) was determined recently. The genome revealed the presence of genes for reductive dehalogenases, suggesting a wide dehalogenating spectrum of the organisms. Moreover, genome sequences provided unprecedented insights into the evolution of reductive dehalogenation and differing strategies for niche adaptation.[3] Geobacter species are often the predominant organisms when extracellular electron transfer is an important bioremediation process in subsurface environments. Therefore, a systems biology approach to understanding and optimizing bioremediation with Geobacter species has been initiated with the ultimate goal of developing in silico models that can predict the growth and metabolism of Geobacter species under a diversity of subsurface conditions. To date, these studies have included sequencing the genomes of multiple Geobacter species and detailed functional genomic/physiological studies on one species, Geobacter sulfurreducens . Genome-based models of several Geobacter species that are able to predict physiological responses under different environmental conditions are now available. Quantitative analysis of gene transcript levels during in situ uranium bioremediation has demonstrated that it is possible to track in situ rates of metabolism and the in situ metabolic state of Geobacter in the subsurface. Initial attempts to link in silico Geobacter models with existing subsurface hydrological and geochemical models are underway. It is expected that this systems approach to bioremediation with Geobacter will provide the opportunity to evaluate multiple Geobacter -catalyzed bioremediation strategies in silico prior to field implementation, thus providing substantial savings when initiating large-scale in situ bioremediation projects for groundwater polluted with uranium and/or organic contaminants.[4] # Popular culture Geobacter are used as a plot device in the first episode of the third season of ReGenesis.	https://www.wikidoc.org/index.php/Geobacter
27c40215dbd0414caa6111db416a38bf73d7aa20	wikidoc	Gerin oil	Gerin oil Gerin Oil or Geriniol is a fictional drug used as a device to criticize religion in articles written by Richard Dawkins. It is an anagram of religion. The first article, Gerin Oil, was published in an American secular humanism publication, Free Inquiry, in December 2003. It was popularised in an article titled Opiate of the masses. It describes a dangerous legal drug "Gerin Oil" or "Geriniol." Dawkins blames its effects as being responsible for historic acts of violence such as the September 11th attacks, massacres of native South Americans by conquistadors, and the Salem Witch Trials. According to Dawkins, users are often introduced to the drug at social gatherings such as weddings and funerals. In small amounts it is considered harmless, although its usage may increase over time. Medium usage of "Gerin Oil" is said to cause a disconnect with reality where users expect private wishes expressed to come true, often accompanied by spasmodic muscular movement or contraction. In large doses it is said to cause aural or visual hallucinations. Its use is also linked to child mutilation, sexual prohibition, and the tendency to smile when convicted of mass murder.	Gerin oil Gerin Oil or Geriniol is a fictional drug used as a device to criticize religion in articles written by Richard Dawkins. It is an anagram of religion. The first article, Gerin Oil,[1] was published in an American secular humanism publication, Free Inquiry, in December 2003. It was popularised in an article titled Opiate of the masses.[2] It describes a dangerous legal drug "Gerin Oil" or "Geriniol." Dawkins blames its effects as being responsible for historic acts of violence such as the September 11th attacks, massacres of native South Americans by conquistadors, and the Salem Witch Trials. According to Dawkins, users are often introduced to the drug at social gatherings such as weddings and funerals. In small amounts it is considered harmless, although its usage may increase over time. Medium usage of "Gerin Oil" is said to cause a disconnect with reality where users expect private wishes expressed to come true, often accompanied by spasmodic muscular movement or contraction. In large doses it is said to cause aural or visual hallucinations. Its use is also linked to child mutilation, sexual prohibition, and the tendency to smile when convicted of mass murder.	https://www.wikidoc.org/index.php/Gerin_oil
62d88bd1b57827f0bf649e47ad99a801aa305b59	wikidoc	Germ cell	Germ cell A germ cell is part of the germline and is involved in the reproduction of organisms. Germ cells should not be confused with "germs" (pathogens). For example, the germ cells in male and female humans are the sperm and the eggs respectively. Germ cells includes all stages of gametogenesis, i.e. gametogonia, gametocytes, gametids and gametes. By a narrower definition, the term germ cell can also just refer to gametes, which are produced by meiosis of the aforementioned germ cells, but this definition is less precise. Cells that are not part of the germline are somatic cells. # Ploidy Normal human somatic cells are diploid, which means they contain 23 pairs of chromosomes, including one pair of sex chromosomes; an X from the mother, and an X or a Y from the father. If the sex chromosomes are XX then the organism is female and if they are XY then the organism is male. Human germ cells are normally haploid, which means they contain half the chromosomes of somatic cells, or 23 chromosomes and one sex chromosome. Thus when the germ cells unite in fertilization, the cell becomes diploid, and commences embryogenesis. # Origin Primordial germ cells are predecessors of germ cells. They migrate to the gonadal ridge, where they form gametogonia, and thus start gametogenesis # In gene therapy Genetic therapy, where new genetic material is introduced into an organism, usually confers new, genetic instructions for a cell and it's daughter cells, and the new genetic information dies with the organism. When the genetic material is put into a germ cell, the new genetic information (for better or worse) may be transfered to biological offspring.	Germ cell Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] A germ cell is part of the germline and is involved in the reproduction of organisms. Germ cells should not be confused with "germs" (pathogens). For example, the germ cells in male and female humans are the sperm and the eggs respectively. Germ cells includes all stages of gametogenesis, i.e. gametogonia, gametocytes, gametids and gametes. By a narrower definition, the term germ cell can also just refer to gametes, which are produced by meiosis of the aforementioned germ cells, but this definition is less precise. Cells that are not part of the germline are somatic cells. # Ploidy Normal human somatic cells are diploid, which means they contain 23 pairs of chromosomes, including one pair of sex chromosomes; an X from the mother, and an X or a Y from the father. If the sex chromosomes are XX then the organism is female and if they are XY then the organism is male. Human germ cells are normally haploid, which means they contain half the chromosomes of somatic cells, or 23 chromosomes and one sex chromosome. Thus when the germ cells unite in fertilization, the cell becomes diploid, and commences embryogenesis. # Origin Primordial germ cells are predecessors of germ cells. They migrate to the gonadal ridge, where they form gametogonia, and thus start gametogenesis # In gene therapy Genetic therapy, where new genetic material is introduced into an organism, usually confers new, genetic instructions for a cell and it's daughter cells, and the new genetic information dies with the organism. When the genetic material is put into a germ cell, the new genetic information (for better or worse) may be transfered to biological offspring.[1]	https://www.wikidoc.org/index.php/Germ_cell
c1fda07450cb0af62f09a46bfb46cee4124bb0dd	wikidoc	Germander	Germander # Overview Teucrium is a genus of perennial plants in the family Lamiaceae. The name is believed to refer to King Teucer of Troy. Members of the genus are commonly known as germanders. These species are herbs, shrubs or subshrubs. They are most common in Mediterranean climates. An unusual feature of this genus compared with other members of Lamiaceae is that the flowers completely lack the upper lip of the corolla, although it is somewhat reduced also in other genera (Ajuga among them). Several species are used as food plants by the larvae of some Lepidoptera species including the Coleophora case-bearers Coleophora auricella and Coleophora chamaedriella. The latter is only known from Wall Germander (T. chamaedrys). Teucrium species are rich in essential oils. They are valued as ornamental plants and a pollen source, and some species have culinary and/or medical value. # Selected species ## Formerly placed here - Ajuga chamaepitys (L.) Schreb. (as T. chamaepitys L.)	Germander Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Teucrium is a genus of perennial plants in the family Lamiaceae. The name is believed to refer to King Teucer of Troy.[3] Members of the genus are commonly known as germanders. These species are herbs, shrubs or subshrubs. They are most common in Mediterranean climates. An unusual feature of this genus compared with other members of Lamiaceae is that the flowers completely lack the upper lip of the corolla, although it is somewhat reduced also in other genera (Ajuga among them). Several species are used as food plants by the larvae of some Lepidoptera species including the Coleophora case-bearers Coleophora auricella and Coleophora chamaedriella. The latter is only known from Wall Germander (T. chamaedrys). Teucrium species are rich in essential oils. They are valued as ornamental plants and a pollen source, and some species have culinary and/or medical value. # Selected species ## Formerly placed here - Ajuga chamaepitys (L.) Schreb. (as T. chamaepitys L.)[5]	https://www.wikidoc.org/index.php/Germander
39f102ce6b566e7d0b3c76a8967e06cffca87f2f	wikidoc	Germolene	Germolene Germolene is a brand name used on a range of antiseptic products produced by Bayer. Traditionally Germolene was a thick antiseptic ointment of a distinctive pink colour, but the name is now used not only on the traditional product but also on cream, gel and liquid antiseptics and a range of other products such as antispetic wipes. Germolene liquid is sometimes used in TV production, whereby it is injected into food props to stop the actors eating them. The BBC does this on the soap EastEnders after a spate of thefts from the sets.OR Germolene was invented by Sir William Henry Veno ( also invented Veno's cough cure ) who sold his company to the Beechams Company.	Germolene Germolene is a brand name used on a range of antiseptic products produced by Bayer. Traditionally Germolene was a thick antiseptic ointment of a distinctive pink colour, but the name is now used not only on the traditional product but also on cream, gel and liquid antiseptics and a range of other products such as antispetic wipes. Germolene liquid is sometimes used in TV production, whereby it is injected into food props to stop the actors eating them. The BBC does this on the soap EastEnders after a spate of thefts from the sets.OR Germolene was invented by Sir William Henry Veno ( also invented Veno's cough cure ) who sold his company to the Beechams Company. Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Germolene
9857f7d77f626a2103309a8405cdeac4bd119469	wikidoc	Gerovital	Gerovital Gerovital H3 (or procaine hydrochloride and products known as GH3, Aslavital, Vitacel, and other variants which may or may not be identical to Gerovital H3) is a controversial preparation developed during the 1950s and promoted by its advocates as an effective anti-aging treatment. During Gerovital's "jet-set" heyday, Gerovital treatments were reportedly administered to a stellar array of celebrities and dignitaries, including John F. Kennedy, Marlene Dietrich, Kirk Douglas and Salvador Dalí. Today, the mainstream medical view is that the preparation was seriously investigated in the 1960s and discredited, and that any promotion today is quackery. In the United States, the FDA bans Gerovital H3 from interstate commerce as an unapproved drug and, since 1982, has prohibited its importation. # Development and marketing It was developed in Romania by Dr. Ana Aslan (January 1, 1897 – May 20, 1988). The main active ingredient is the well-known local anesthetic Procaine hydrochloride, (often referred to by the old brand name, Novocaine). It also contains small amounts of benzoic acid, potassium metabisulfite and disodium phosphate which are said to be important in the formulation, rendering it more effective by "stabilizing" it. Some advocates acknowledge that despite the stabilizers, the procaine in Gerovital H3 breaks down rapidly into DMAE and PABA, but ascribe the beneficial effects to these breakdown products. From the 1950s until her death in 1988, Dr. Aslan promoted Gerovital H3 with great success. In the 1960s and 1970s her Romanian clinic, the Parhon Institute, became a mecca for celebrities seeking treatment, and an upscale tourist attraction. The New York Times referred to Gerovital's "jet-set aura," noting that Dr. Aslan had been covered in "society columns where such public figures as Nikita S. Khrushchev, Konrad Adenauer, and Ibn Saud have been listed among the multitudes said to have taken the drug." As late as 1988 an advertisement by the Romanian National Tourist Office lauded "the picturesque and exciting cities, scenic delights, famous resorts (including Gerovital H3 treatment centers), cultural and historic treasures that await the traveler to Romania." # Denouncement A 1973 New York Times article said "cold water was thrown on 's reputation years ago" by "three reports published simultaneously in British Medical Journal found no merit for procaine hydrochloride for any of the problems of aging." A flurry of clinical trials in the mid-to-late 1970s suggests that Gerovital H3 acts as a weak, competitive, reversible MAO inhibitor, and so may have some antidepressant value, but otherwise has negligible effect on disease (see Clinical Trials, below). In 1994, the U.S. FDA Consumer magazine said: "No health claims for Gerovital have been substantiated, and FDA considers it an unapproved new drug. It has caused low blood pressure, respiratory difficulties, and convulsions in some users." Suppliers assert that the product is safe, and one cites a brief quotation from a newspaper article that says "while as early as 1973 Elmer Gardner of the FDA's Bureau of Drugs stated 'There is no safety problem with Gerovital H-3.'" # Clinical Trials ## Anti-aging Efficacy - Zdichynec B. ZFA. 1977;32(3):267-9. German. PMID 337694. ## Lack of Efficacy - Zwerling I, Plutchik R, Hotz M, Kling R, Rubin L, Grossman J, Siegel B. Effects of a procaine preparation (Gerovital H3) in hospitalized geriatric patients: a double-blind study. J Am Geriatr Soc. 1975 Aug;23(8):355-9. PMID 1097490. - Olsen EJ, Bank L, Jarvik LF. Gerovital-H3: a clinical trial as an antidepressant. J Gerontol. 1978 Jul;33(4):514-20. PMID 376578. - Ostfeld A, Smith CM, Stotsky BA. The systemic use of procaine in the treatment of the elderly: a review. J Am Geriatr Soc. 1977 Jan;25(1):1-19. PMID 12204. - Rissanen V, Rissanen P, Tuomisto J. Procaine (Gerovital): no effect on the rehabilitation result in patients with back or hip disease. Ann Med. 1990 Jun;22(3):151-6. PMID 2203382. ## Cognitive Effects - Cruceanu A, Bucsa L. Age differences in the glucose-6-phosphate dehydrogenase activity of homogenates from the liver of rats. The effect of Gerovital H3 on the glucose-6-phosphate dehydrogenase activity. Physiologie. 1979 Jan-Mar;16(1):71-5. PMID 106418. - MacFarlane MD. Procaine HCl (Gerovital H3): a weak, reversible, fully competitive inhibitor of monoamine oxidase. Fed Proc. 1975 Jan;34(1):108-10. PMID 1109354. - Bhaskaran D, Radha E. Murine regional brain monoamine oxidase activity: time- and age-dependent response to inhibitors. Gerontology. 1984;30(2):87-93. PMID 6706127. - Pop M, Tarba C. Changes induced in the bioelectric activity of rat subcortical nervous structures by Gerovital H3 and Aslavital as compared to procaine. Physiologie. 1988 Jul-Sep;25(3):137-49. PMID 3144011. ## Risks - Forstrom L, Hannuksela M, Idanpaan-Heikkila J, Salo OP. Hypersensitivity reactions to Gerovital. Dermatologica. 1977;154(6):367-9. PMID 142033. - Somsen GA, Schut NH. Acute renal failure due to self-medication. Neth J Med. 1998 Jul;53(1):45-6. PMID 9718943. - Search Medline for more articles on Gerovital. # Drug or nutrient? Procaine itself is universally considered to be a drug. Earlier references by advocates of Gerovital H3 always refer to it as a drug. Hoffer and Walker (1980) call it a "youth drug." Mircea Dumitru, Dr. Aslan's colleague and personal physician, describes it as "a complex drug acting like the procaine molecule ... The addition of benzoic acid, potassium and disodium phosphate increase the effects of Gerovital-H3® biotrophic treatment." Web-based suppliers outside the United States that offer to ship the preparation to the U.S. generally characterize it as a "nutrient" or "vitamin," perhaps because of less strict legal treatment of nutritional supplements in the U. S. under the Dietary Supplement Health and Education Act of 1994. Some sites selling the preparation say that a federal court in decision June 17, 1994, US vs Rodger Sless/TMI classified GeroVital H3 as a dietary supplement. # Quality control It is notable that virtually every company claiming to supply Gerovital H3 to the U. S. warns of widespread distribution of fake formulations. Each company suggests that products supplied by its competitors are phony (while asserting that they and only they are the only supplier of the real Romanian formula). - One company says it sells "real" Gerovital H3 and warns that "the American market is flooded with fake GH3®." - Another says it has "the ONLY ORIGINAL FORMULA BEING IMPORTED TO USA." - A third says "Beware of the many phony GH3's... we are the only company willing and able to supply documented proof of our GH3's authenticity." One Gerovital advocate states that the only way for a U. S. consumer to get authentic Gerovital H3 is to have a compounding pharmacy in the U. S. prepare it from a doctor's prescription. He adds, "don't bother with a conventional doctor will have the usual American medical establishment brain wash attitude." # FDA Ban As of 2004, the FDA's 1982 automatic detention alert is still in effect and bans the import of Gerovital H3 into the U.S. as "a new drug within the meaning of 201(p), without an approved new drug application ." The ban covers: - Gerovital, GH3, KH3, Zell H3, GH3, GH3 Cream, etc. - finished injectable or oral Procaine Hydrochloride - bulk Procaine Hydrochloride # 2003 UK Trademark revocation In the UK the term "Gerovital H3" was formerly considered to be a trademark of Prof Dr. A. Aslan, registered to Gerovital Cosmetics SA, but the trademark was challenged in 2003 by Societatea Comercială “Farmec” SA and subsequently revoked.	Gerovital Gerovital H3 (or procaine hydrochloride and products known as GH3, Aslavital, Vitacel, and other variants which may or may not be identical to Gerovital H3) is a controversial preparation developed during the 1950s and promoted by its advocates as an effective anti-aging treatment. During Gerovital's "jet-set" heyday, Gerovital treatments were reportedly administered to a stellar array of celebrities and dignitaries, including John F. Kennedy, Marlene Dietrich, Kirk Douglas and Salvador Dalí. Today, the mainstream medical view is that the preparation was seriously investigated in the 1960s and discredited, and that any promotion today is quackery. In the United States, the FDA bans Gerovital H3 from interstate commerce as an unapproved drug and, since 1982, has prohibited its importation. # Development and marketing It was developed in Romania by Dr. Ana Aslan (January 1, 1897 – May 20, 1988). The main active ingredient is the well-known local anesthetic Procaine hydrochloride, (often referred to by the old brand name, Novocaine). It also contains small amounts of benzoic acid, potassium metabisulfite and disodium phosphate which are said to be important in the formulation, rendering it more effective by "stabilizing" it. Some advocates acknowledge that despite the stabilizers, the procaine in Gerovital H3 breaks down rapidly into DMAE and PABA, but ascribe the beneficial effects to these breakdown products. From the 1950s until her death in 1988, Dr. Aslan promoted Gerovital H3 with great success. In the 1960s and 1970s her Romanian clinic, the Parhon Institute, became a mecca for celebrities seeking treatment, and an upscale tourist attraction. The New York Times referred to Gerovital's "jet-set aura," noting that Dr. Aslan had been covered in "society columns where such public figures as Nikita S. Khrushchev, Konrad Adenauer, and Ibn Saud have been listed among the multitudes said to have taken the drug." As late as 1988 an advertisement by the Romanian National Tourist Office lauded "the picturesque and exciting cities, scenic delights, famous resorts (including Gerovital H3 treatment centers), cultural and historic treasures that await the traveler to Romania." [1] # Denouncement A 1973 New York Times article said "cold water was thrown on [Gerovital]'s reputation years ago" by "three reports published simultaneously in British Medical Journal [that] found no merit for procaine hydrochloride for any of the problems of aging."[2] A flurry of clinical trials in the mid-to-late 1970s suggests that Gerovital H3 acts as a weak, competitive, reversible MAO inhibitor, and so may have some antidepressant value, but otherwise has negligible effect on disease (see Clinical Trials, below). In 1994, the U.S. FDA Consumer magazine said: "No health claims for Gerovital have been substantiated, and FDA considers it an unapproved new drug. It has caused low blood pressure, respiratory difficulties, and convulsions in some users."[3] Suppliers assert that the product is safe, and one cites a brief quotation from a newspaper article that says "while as early as 1973 Elmer Gardner of the FDA's Bureau of Drugs stated 'There is no safety problem with Gerovital H-3.'"[4] # Clinical Trials ## Anti-aging Efficacy - Zdichynec B. [Successes in novocain therapy in the control of premature ageing (author's transl)] ZFA. 1977;32(3):267-9. German. PMID 337694. [PubMed - indexed for MEDLINE] ## Lack of Efficacy - Zwerling I, Plutchik R, Hotz M, Kling R, Rubin L, Grossman J, Siegel B. Effects of a procaine preparation (Gerovital H3) in hospitalized geriatric patients: a double-blind study. J Am Geriatr Soc. 1975 Aug;23(8):355-9. PMID 1097490. [PubMed - indexed for MEDLINE] - Olsen EJ, Bank L, Jarvik LF. Gerovital-H3: a clinical trial as an antidepressant. J Gerontol. 1978 Jul;33(4):514-20. PMID 376578. [PubMed - indexed for MEDLINE] - Ostfeld A, Smith CM, Stotsky BA. The systemic use of procaine in the treatment of the elderly: a review. J Am Geriatr Soc. 1977 Jan;25(1):1-19. PMID 12204. [PubMed - indexed for MEDLINE] - Rissanen V, Rissanen P, Tuomisto J. Procaine (Gerovital): no effect on the rehabilitation result in patients with back or hip disease. Ann Med. 1990 Jun;22(3):151-6. PMID 2203382. [PubMed - indexed for MEDLINE] ## Cognitive Effects - Cruceanu A, Bucsa L. Age differences in the glucose-6-phosphate dehydrogenase activity of homogenates from the liver of rats. The effect of Gerovital H3 on the glucose-6-phosphate dehydrogenase activity. Physiologie. 1979 Jan-Mar;16(1):71-5. PMID 106418. [PubMed - indexed for MEDLINE] - MacFarlane MD. Procaine HCl (Gerovital H3): a weak, reversible, fully competitive inhibitor of monoamine oxidase. Fed Proc. 1975 Jan;34(1):108-10. PMID 1109354. [PubMed - indexed for MEDLINE] - Bhaskaran D, Radha E. Murine regional brain monoamine oxidase activity: time- and age-dependent response to inhibitors. Gerontology. 1984;30(2):87-93. PMID 6706127. [PubMed - indexed for MEDLINE] - Pop M, Tarba C. Changes induced in the bioelectric activity of rat subcortical nervous structures by Gerovital H3 and Aslavital as compared to procaine. Physiologie. 1988 Jul-Sep;25(3):137-49. PMID 3144011. [PubMed - indexed for MEDLINE] ## Risks - Forstrom L, Hannuksela M, Idanpaan-Heikkila J, Salo OP. Hypersensitivity reactions to Gerovital. Dermatologica. 1977;154(6):367-9. PMID 142033. [PubMed - indexed for MEDLINE] - Somsen GA, Schut NH. Acute renal failure due to self-medication. Neth J Med. 1998 Jul;53(1):45-6. PMID 9718943. [PubMed - indexed for MEDLINE] - Search Medline for more articles on Gerovital. # Drug or nutrient? Procaine itself is universally considered to be a drug. Earlier references by advocates of Gerovital H3 always refer to it as a drug. Hoffer and Walker (1980) call it a "youth drug." Mircea Dumitru, Dr. Aslan's colleague and personal physician, describes it as "a complex drug acting like the procaine molecule ... The addition of benzoic acid, potassium and disodium phosphate increase the effects of Gerovital-H3® biotrophic treatment."[5] Web-based suppliers outside the United States that offer to ship the preparation to the U.S. generally characterize it as a "nutrient" or "vitamin," perhaps because of less strict legal treatment of nutritional supplements in the U. S. under the Dietary Supplement Health and Education Act of 1994. Some sites selling the preparation say that a federal court in decision June 17, 1994, US vs Rodger Sless/TMI classified GeroVital H3 as a dietary supplement. # Quality control It is notable that virtually every company claiming to supply Gerovital H3 to the U. S. warns of widespread distribution of fake formulations. Each company suggests that products supplied by its competitors are phony (while asserting that they and only they are the only supplier of the real Romanian formula). - One company says it sells "real" Gerovital H3 and warns that "the American market is flooded with fake GH3®." - Another says it has "the ONLY ORIGINAL FORMULA BEING IMPORTED TO USA." - A third says "Beware of the many phony GH3's... we are the only company willing and able to supply documented proof of our GH3's authenticity." One Gerovital advocate states that the only way for a U. S. consumer to get authentic Gerovital H3 is to have a compounding pharmacy in the U. S. prepare it from a doctor's prescription. He adds, "don't bother with a conventional doctor [who] will have the usual American medical establishment brain wash attitude."[6] # FDA Ban As of 2004, the FDA's 1982 automatic detention alert is still in effect and bans the import of Gerovital H3 into the U.S. as "a new drug within the meaning of 201(p), without an approved new drug application [Unapproved New Drug, Section 505(a)]."[7] The ban covers: - Gerovital, GH3, KH3, Zell H3, GH3, GH3 Cream, etc. - finished injectable or oral Procaine Hydrochloride - bulk Procaine Hydrochloride # 2003 UK Trademark revocation In the UK the term "Gerovital H3" was formerly considered to be a trademark of Prof Dr. A. Aslan, registered to Gerovital Cosmetics SA, but the trademark was challenged in 2003 by Societatea Comercială “Farmec” SA and subsequently revoked.[8]	https://www.wikidoc.org/index.php/Gerovital
32bc5abc81d26447b9f74f5c0004b35e724fa3fd	wikidoc	Gestation	Gestation Gestation is the carrying of an embryo or fetus inside a female viviparous animal. Mammals during pregnancy can have one or more gestations at the same time (multiple gestations). According to the National Center for Health and Statistics there were over 136,000 multiple human births documented in the United States in 2003(NCHS). The time interval of a gestation is called gestation period, and the length of time the offspring have spent developing in the uterus is called gestational age. # Humans Human pregnancy can be divided into three trimesters, each three months long. The third trimester begins at about 28 weeks. The 23rd week is the first week when a preterm fetus is considered viable. Before this age major developmental events that would allow the fetus to survive outside the womb have not yet occurred. This division is somewhat arbitrary as children born before this point have survived, but only with significant medical assistance. In humans, birth normally occurs at a gestational age of 37 to 42 weeks. Childbirth occurring before 37 weeks of gestation is considered preterm, childbirth after 25 weeks is usually considered "viable". Preterm and low birth weight babies make up the second leading cause of infant death at about 17%. Preterm births solely consist of 12% of infant deaths with an 84% majority within the 32-36 week period. It is estimated that two million babies worldwide die annually within 24 hours of birth. # Mammals In mammals, pregnancy begins when a fertilized zygote implants in the female's uterus; and ends once it leaves the uterus. Below are average and approximate values ordered by gestation period:	Gestation Gestation is the carrying of an embryo or fetus inside a female viviparous animal. Mammals during pregnancy can have one or more gestations at the same time (multiple gestations). According to the National Center for Health and Statistics there were over 136,000 multiple human births documented in the United States in 2003(NCHS). [1] The time interval of a gestation is called gestation period, and the length of time the offspring have spent developing in the uterus is called gestational age. # Humans Human pregnancy can be divided into three trimesters, each three months long. The third trimester begins at about 28 weeks. The 23rd week is the first week when a preterm fetus is considered viable. Before this age major developmental events that would allow the fetus to survive outside the womb have not yet occurred. This division is somewhat arbitrary as children born before this point have survived, but only with significant medical assistance. In humans, birth normally occurs at a gestational age of 37 to 42 weeks. Childbirth occurring before 37 weeks of gestation is considered preterm, childbirth after 25 weeks is usually considered "viable". [2] Preterm and low birth weight babies make up the second leading cause of infant death at about 17%.[citation needed] Preterm births solely consist of 12% of infant deaths with an 84% majority within the 32-36 week period. [3] It is estimated that two million babies worldwide die annually within 24 hours of birth. # Mammals In mammals, pregnancy begins when a fertilized zygote implants in the female's uterus; and ends once it leaves the uterus. Below are average and approximate values ordered by gestation period:	https://www.wikidoc.org/index.php/Gestation
3bebb21f0a7055de19fcefdfc7431b3cf8f60c30	wikidoc	Gestodene	Gestodene # Overview Gestodene is a progestogen hormonal contraceptive. Products containing gestodene include: - Melodene-15, Mirelle, and Minesse which contain 15 mcg of ethinylestradiol and 60 mcg of gestodene; - Meliane, Sunya, Femodette, and Millinette 20/75 which contain 20 mcg of ethinylestradiol and 75 mcg of gestodene; and - Gynera, Minulet, Femoden, Femodene, Katya and Millinette 30/75 which contain 30 mcg of ethinylestradiol and 75 mcg of gestodene. # Benefits Gestodene is androgenically neutral, meaning that contraceptive pills containing gestodene do not exhibit the androgenic side effects (e.g. acne, hirsutism, weight gain) often associated with second-generation contraceptive pills, such as those containing levonorgestrel. The synthetic estrogen dosage in third-generation contraceptive pills (including those containing gestodene) is lower than that in second-generation oral contraceptives, reducing the likelihood of weight gain, breast tenderness and migraine. Third-generation oral contraceptives are also suitable for use in patients with diabetes or lipid disorders because they have minimal impact on blood glucose levels and the lipid profile. # Adverse effects Women who take oral contraceptives containing gestodene are 5.6 times as likely to develop thromboembolism than women who do not take any contraceptive pill, and 1.6 times as likely to develop thromboembolism compared to women taking oral contraceptives containing levonorgestrel.	Gestodene Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Gestodene is a progestogen hormonal contraceptive. Products containing gestodene include: - Melodene-15, Mirelle, and Minesse which contain 15 mcg of ethinylestradiol and 60 mcg of gestodene; - Meliane, Sunya, Femodette, and Millinette 20/75 which contain 20 mcg of ethinylestradiol and 75 mcg of gestodene; and - Gynera, Minulet, Femoden, Femodene, Katya and Millinette 30/75 which contain 30 mcg of ethinylestradiol and 75 mcg of gestodene.[1] # Benefits Gestodene is androgenically neutral, meaning that contraceptive pills containing gestodene do not exhibit the androgenic side effects (e.g. acne, hirsutism, weight gain) often associated with second-generation contraceptive pills, such as those containing levonorgestrel.[2] The synthetic estrogen dosage in third-generation contraceptive pills (including those containing gestodene) is lower than that in second-generation oral contraceptives, reducing the likelihood of weight gain, breast tenderness and migraine.[3] Third-generation oral contraceptives are also suitable for use in patients with diabetes or lipid disorders because they have minimal impact on blood glucose levels and the lipid profile.[4] # Adverse effects Women who take oral contraceptives containing gestodene are 5.6 times as likely to develop thromboembolism than women who do not take any contraceptive pill, and 1.6 times as likely to develop thromboembolism compared to women taking oral contraceptives containing levonorgestrel.[5]	https://www.wikidoc.org/index.php/Gestodene
d534d24cedd9aa043b85467e55ca685a354f7f3c	wikidoc	Glasdegib	Glasdegib # 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 Glasdegib is a hedgehog pathway inhibitor indicated, in combination with low-dose cytarabine that is FDA approved for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adult patients who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anemia, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, thrombocytopenia, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### ULTOMIRIS is indicated for: DAURISMO is indicated, in combination with low-dose cytarabine, for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adult patients who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy. ### Dosage Forms And Strengths - DAURISMO 100 mg tablets: round, pale orange film-coated tablet debossed with "Pfizer" on one side and "GLS 100" on the other. - DAURISMO 25 mg tablets: round, yellow film-coated tablet debossed with "Pfizer" on one side and "GLS 25" on the other. - 100 mg orally once daily on days 1 to 28 in combination with cytarabine 20 mg subcutaneously twice daily on days 1 to 10 of each 28-day cycle in the absence of unacceptable toxicity or loss of disease control. For patients without unacceptable toxicity, treat for a minimum of 6 cycles to allow time for clinical response. - Administer DAURISMO with or without food. Do not split or crush DAURISMO tablets. Administer DAURISMO about the same time each day. If a dose of DAURISMO is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose of DAURISMO is missed or not taken at the usual time, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses of DAURISMO within 12 hours. - Assess complete blood counts, electrolytes, renal, and hepatic function prior to the initiation of DAURISMO and at least once weekly for the first month. - Monitor electrolytes and renal function once monthly for the duration of therapy. - Obtain serum creatine kinase levels prior to initiating DAURISMO and as indicated clinically thereafter (e.g., if muscle symptoms are reported). - Monitor electrocardiograms (ECGs) prior to the initiation of DAURISMO, approximately one week after initiation, and then once monthly for the next two months to assess for QTc prolongation. Repeat ECG if abnormal. Certain patients may require more frequent and ongoing ECG monitoring. - Certain patients may require more frequent and ongoing ECG monitoring. - Manage any abnormalities promptly ### Dosage Modification for Concomitant Use with Moderate CYP3A4 Inducers - Avoid concomitant use of DAURISMO with moderate CYP3A4 inducers. If concomitant use of moderate CYP3A4 inducers cannot be avoided, increase the DAURISMO dosage as tolerated as shown in Table 2. After the moderate CYP3A4 inducer has been discontinued for 7 days, resume the DAURISMO dose taken prior to initiating the moderate CYP3A4 inducer. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding DAURISMO Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding DAURISMO Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding DAURISMO FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding DAURISMO Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding DAURISMO Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None # Warnings ### Embryo-Fetal Toxicity - Based on its mechanism of action and findings from animal embryo-fetal developmental toxicity studies, DAURISMO can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. There are no clinical data on the use of DAURISMO in pregnant women. - In animal embryo-fetal developmental toxicity studies, glasdegib caused embryotoxicity, fetotoxicity and teratogenicity at maternal exposures that were less than the human exposure at the recommended human dose of 100 mg. Advise pregnant women of the potential risk to the fetus. ### Females of Reproductive Potential DAURISMO is not recommended for use during pregnancy. Conduct pregnancy testing in female patients of reproductive potential prior to initiating DAURISMO treatment. Advise females of reproductive potential to use effective contraception during treatment with DAURISMO and for at least 30 days after the last dose. Advise women not to breastfeed during treatment with DAURISMO and for at least 30 days after the last dose. ### Males Advise male patients with female partners of the potential risk of exposure through semen and to use effective contraception, including a condom, even after vasectomy, to avoid drug exposure to a pregnant partner or a female partner of reproductive potential during treatment with DAURISMO and for at least 30 days after the last dose. ### Blood Donation Advise patients not to donate blood or blood products while taking DAURISMO and for at least 30 days after the last dose of DAURISMO because their blood or blood products might be given to a female of reproductive potential. ### QTc Interval Prolongation - Patients treated with DAURISMO can develop QTc prolongation and ventricular arrhythmias, including ventricular fibrillation and ventricular tachycardia. Of the 98 evaluable patients treated with DAURISMO 100 mg in combination with low-dose cytarabine in the clinical trial, 5% were found to have a QTc interval greater than 500 ms and 4% of patients had an increase from baseline QTc greater than 60 ms. The clinical trial excluded patients with baseline QTc of greater than 470 ms or with a history of long QT syndrome or uncontrolled cardiovascular disease. - Of the 98 evaluable patients treated with DAURISMO 100 mg in combination with low-dose cytarabine in the clinical trial, 5% were found to have a QTc interval greater than 500 ms and 4% of patients had an increase from baseline QTc greater than 60 ms. The clinical trial excluded patients with baseline QTc of greater than 470 ms or with a history of long QT syndrome or uncontrolled cardiovascular disease. - Monitor electrocardiograms (ECGs) and electrolytes. Concomitant use of DAURISMO with drugs known to prolong the QTc interval and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. In patients with congenital long QT syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent ECG monitoring is recommended. - Interrupt DAURISMO if QTc increases to greater than 500 ms. Discontinue DAURISMO permanently for patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia. # Adverse Reactions ## Clinical Trials Experience - The safety profile of DAURISMO is based on experience in the BRIGHT AML 1003 study for 111 adults with newly-diagnosed AML and 14 adults with other conditions for which DAURISMO is not indicated. - Patients were treated with DAURISMO 100 mg daily in combination with low-dose cytarabine (N=84) or low-dose cytarabine alone (N=41). - The median duration of treatment in the DAURISMO with low-dose cytarabine arm was 83 days (range 3 to 972 days). - The median duration of treatment in the low-dose cytarabine alone arm was 47 days (range 6 to 239 days). - The median exposure to DAURISMO in the DAURISMO with low-dose cytarabine arm was 76 days (range 3 to 954 days). Thirty-two patients (38%) were treated with DAURISMO with low-dose cytarabine for at least 6 months and 14 patients (17%) were treated for at least 1 year. - Serious adverse reactions were reported in 79% of patients treated in the DAURISMO with low-dose cytarabine arm. The most common (≥5%) serious adverse reactions in patients receiving DAURISMO with low-dose cytarabine were febrile neutropenia (29%), pneumonia (23%), hemorrhage (12%), anemia (7%), and sepsis (7%). - The most common (≥5%) serious adverse reactions in patients receiving DAURISMO with low-dose cytarabine were febrile neutropenia (29%), pneumonia (23%), hemorrhage (12%), anemia (7%), and sepsis (7%). - Dose reductions associated with adverse reactions were reported in 26% of patients treated with DAURISMO with low-dose cytarabine, and the most common reasons (≥2%) for dose reductions due to adverse reactions were muscle spasms (5%), fatigue (4%), febrile neutropenia (4%), anemia (2%), thrombocytopenia (2%), and ECG QT prolonged (2%). - Adverse reactions leading to permanent discontinuation were reported in 36% of patients treated with DAURISMO with low-dose cytarabine, and the most common (≥2%) reasons for permanent discontinuation were pneumonia (6%), febrile neutropenia (4%), sepsis (4%), sudden death (2%), myocardial infarction (2%), nausea (2%), and renal insufficiency (2%). - The adverse reactions muscle spasms (4 in 12 patients) and decreased appetite (2 in 10 patients) worsened (i.e. progressed from Grades ≤ 2 to Grade 3 or higher) after the first 90 days of therapy in BRIGHT AML 1003. - Additional clinically-significant adverse reactions occurring in < 10% of patients treated with DAURISMO and low-dose cytarabine in BRIGHT AML 1003 include: Dental disorders: loose tooth and toothache Skin and subcutaneous tissue disorders: alopecia Cardiac disorders: QT interval prolonged - Dental disorders: loose tooth and toothache - Skin and subcutaneous tissue disorders: alopecia - Cardiac disorders: QT interval prolonged - The following laboratory abnormalities worsened (i.e. progressed from Grades ≤ 2 to Grade 3 or higher) after the first 90 days of therapy in BRIGHT AML 1003: hypophosphatemia (8 in 38 patients), creatinine increased (2 in 39 patients), and ALT increased (2 in 40 patients). - hypophosphatemia (8 in 38 patients), creatinine increased (2 in 39 patients), and ALT increased (2 in 40 patients). ## Postmarketing Experience There is limited information regarding Daurismo Postmarketing Experience in the drug label. # Drug Interactions # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Based on its mechanism of action and findings in animal embryo-fetal developmental toxicity studies, DAURISMO can cause fetal harm when administered to a pregnant woman. There are no clinical data on the use of DAURISMO in pregnant women to inform of a drug-associated risk of major birth defects and miscarriage. DAURISMO is not recommended for use during pregnancy. Conduct pregnancy testing in female patients of reproductive potential prior to initiating treatment with DAURISMO. Report pregnancy exposures to Pfizer at 1-800-438-1985. - The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glasdegib in women who are pregnant. ### Labor and Delivery The safety and effectiveness of DAURISMO during labor and delivery have not been evaluated. ### Nursing Mothers There are no data on the presence of glasdegib or its active metabolites in human milk, the effects of the drug on the breastfed child, or its effect on milk production. Because of the potential for serious adverse reactions in a breastfed child from DAURISMO, advise women who are taking DAURISMO not to breastfeed or provide breast milk to infants or children during treatment with DAURISMO and for at least 30 days after the last dose. ### Pediatric Use The safety and effectiveness of DAURISMO have not been established in pediatric patients. In repeat-dose toxicity studies in rats, oral administration of DAURISMO resulted in adverse changes in growing bone, teeth, and testis. Effects on bone consisted of partial to complete closure of the epiphyseal plate. Effects in growing incisor teeth included degeneration/necrosis of ameloblasts, and complete tooth loss with oral ulceration. Reproductive tissue toxicity was evidenced by testicular degeneration and hypospermatogenesis. These effects in bone, teeth and testis were observed after administration of DAURISMO for 26 weeks at greater than or equal to 50 mg/kg/day corresponding to approximately 6.6-times the steady state AUC in patients at the recommended human dose. ### Geriatic Use Of the total number of subjects in clinical studies of DAURISMO with low-dose cytarabine (N=88), 98% of the patients were age 65 years or older and 60% of the patients were age 75 years or older. There were insufficient patients younger than age 65 years to determine differences in adverse reactions reported from patients older than 65. ### Gender There is no FDA guidance on the use of DAURISMO with respect to specific gender populations. ### Race There is no FDA guidance on the use of DAURISMO with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of DAURISMO in patients with renal impairment. ### Hepatic Impairment No dosage modification is recommended for patients with mild to severe renal impairment (estimated glomerular filtration rate 15 to 89 mL/min). Monitor patients with severe renal impairment (eGFR 15 to 29 mL/min) for increased risk of adverse reactions, including QTc interval prolongation, due to increased glasdegib concentrations. ### Females of Reproductive Potential and Males Conduct pregnancy testing in females of reproductive potential within 7 days prior to initiating therapy with DAURISMO. ### Contraception - Females: Advise females of reproductive potential to use effective contraception during treatment with DAURISMO and at least 30 days after the last dose. - Males: It is not known if glasdegib is present in semen. Advise males of the potential risk of exposure through semen and to use effective contraception, including a condom, even after a vasectomy, to avoid drug exposure to a pregnant partner or a female partner of reproductive potential during treatment with DAURISMO and for at least 30 days after the last dose. Advise males to not donate semen during treatment with DAURISMO for at least 30 days after the last dose. ### Infertility Males: Based on findings in repeat-dose animal toxicity studies in rats, DAURISMO may impair fertility in males of reproductive potential. Some effects on male reproductive organs did not recover. Men should seek advice on effective fertility preservation before treatment. ### Immunocompromised Patients There is no FDA guidance one the use of DAURISMO in patients who are immunocompromised. # Administration and Monitoring ### Administration ### Recommended Dosage and Schedule Recommended dosage: 100 mg orally once daily on days 1 to 28 in combination with cytarabine 20 mg subcutaneously twice daily on days 1 to 10 of each 28-day cycle in the absence of unacceptable toxicity or loss of disease control. For patients without unacceptable toxicity, treat for a minimum of 6 cycles to allow time for clinical response. - Administer DAURISMO with or without food. - Do not split or crush DAURISMO tablets. - Administer DAURISMO about the same time each day. - If a dose of DAURISMO is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. - If a dose of DAURISMO is missed or not taken at the usual time, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. - Do not administer 2 doses of DAURISMO within 12 hours. ### Monitoring and Dosage Modifications - Assess complete blood counts, electrolytes, renal, and hepatic function prior to the initiation of DAURISMO and at least once weekly for the first month. - Monitor electrolytes and renal function once monthly for the duration of therapy. - Obtain serum creatine kinase levels prior to initiating DAURISMO and as indicated clinically thereafter (e.g., if muscle symptoms are reported). - Monitor electrocardiograms (ECGs) prior to the initiation of DAURISMO, approximately one week after initiation, and then once monthly for the next two months to assess for QTc prolongation. - Repeat ECG if abnormal. ### Dosage Modification for Concomitant Use with Moderate CYP3A4 Inducers - Avoid concomitant use of DAURISMO with moderate CYP3A4 inducers. - If concomitant use of moderate CYP3A4 inducers cannot be avoided, increase the DAURISMO dosage as tolerated. - After the moderate CYP3A4 inducer has been discontinued for 7 days, resume the DAURISMO dose taken prior to initiating the moderate CYP3A4 inducer. ### Monitoring There is limited information regarding Glasdegib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Glasdegib and IV administrations. # Overdosage There is no specific antidote for DAURISMO. Management of DAURISMO overdose should include symptomatic treatment and ECG monitoring. Glasdegib has been administered in clinical studies up to a dose of 640 mg/day. At the highest dosage, the adverse reactions that were dose limiting were nausea, vomiting, dehydration, hypotension, fatigue, and dizziness. # Pharmacology ## Mechanism of Action - Glasdegib is an inhibitor of the Hedgehog pathway. - Glasdegib binds to and inhibits Smoothened, a transmembrane protein involved in hedgehog signal transduction. - In a murine xenotransplant model of human AML, glasdegib in combination with low-dose cytarabine, inhibited increases in tumor size and reduced the percentage of CD45+/CD33+ blasts in the marrow to a greater extent than glasdegib or low-dose cytarabine alone. ## Structure There is limited information regarding DAURISMO Structure in the drug label. ## Pharmacodynamics ### Cardiac Electrophysiology - The effect of glasdegib administration on corrected QT interval (QTc) was evaluated in a randomized, single-dose, double-blind, 4-way crossover, placebo- and open-label moxifloxacin-controlled study in 36 healthy subjects. - At therapeutic plasma concentrations for the recommended dose, achieved with a single dose of 150 mg DAURISMO, the largest placebo and baseline-adjusted QTc interval change was 8 ms (90% CI: 6, 10 ms). - At a two-fold therapeutic plasma concentration, achieved with a single dose of 300 mg DAURISMO, the QTc change was 13 ms (90% CI: 11, 16 ms). Glasdegib is associated with concentration-dependent QTc prolongation. ## Pharmacokinetics - DAURISMO at 5 mg to 600 mg once daily (0.05 to 6 times the recommended dose) result in a dose proportional increase in glasdegib peak concentrations (Cmax) and area under the curve over the dosing interval (AUC0-Tau). - Steady-state plasma levels are reached by 8 days of daily dosing. - The median accumulation ratio of glasdegib ranged from 1.2 to 2.5 following once-daily dosing. - At DAURISMO 100 mg once daily, the geometric mean (geometric coefficient of variation, % CV) of glasdegib Cmax was 1252 ng/mL (44%) and AUC0-Tau was 17210 nghr/mL (54%) in patients with cancer. ### Absorption - The mean absolute bioavailability of DAURISMO is 77%. Following 100 mg once daily dosing, glasdegib median time to peak concentrations (Tmax) at steady-state ranged from 1.3 hours to 1.8 hours. - Effect of Food: A high-fat, high-calorie meal (total 800–1000 calories: 500–600 fat calories, 250 carbohydrate calories and 150 protein calories) reduced area under the curve over time to infinity (AUC0-INF) by 16% and Cmax by 31%. ### Distribution Glasdegib is 91% bound to human plasma proteins in vitro. The geometric mean (%CV) apparent volume of distribution (Vz/F) was 188 L (20%) in patients with hematologic malignancies. ### Elimination Glasdegib has a mean (± SD) half-life of 17.4 h (3.7) and geometric mean (%CV) apparent clearance of 6.45 L/h (25%) following 100 mg once daily dosing in patients with hematologic malignancies. - Metabolism Glasdegib is primarily metabolized by the CYP3A4 pathway, with minor contributions by CYP2C8 and UGT1A9. Glasdegib accounts for 69% of the total circulating drug related material in plasma. - Glasdegib is primarily metabolized by the CYP3A4 pathway, with minor contributions by CYP2C8 and UGT1A9. Glasdegib accounts for 69% of the total circulating drug related material in plasma. - Excretion Following a single oral dose of 100 mg radiolabeled glasdegib, 49% (17% unchanged) of the administered dose was eliminated in the urine and 42% (20% unchanged) of the administered dose was eliminated in the feces. - Following a single oral dose of 100 mg radiolabeled glasdegib, 49% (17% unchanged) of the administered dose was eliminated in the urine and 42% (20% unchanged) of the administered dose was eliminated in the feces. ### Specific Populations Age (25 to 92 years), sex, race (White, Black, Asian), body weight (43.5 to 145.6 kg), mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin 1–1.5 × ULN and any AST), and mild renal impairment (creatinine clearance 60–89 mL/min) did not have clinically meaningful effects on the pharmacokinetics of glasdegib. - Patients with Renal Impairment Following administration of a single dose of DAURISMO 100 mg, glasdegib AUC0-INF increased by 2.1-fold in subjects with moderate (eGFR 30 to 59 mL/min) and severe (eGFR 15 to 29 mL/min) renal impairment compared to subjects with normal renal function (eGFR ≥90 mL/min). The pharmacokinetics of glasdegib have not been studied in patients with end stage renal disease requiring hemodialysis. - Following administration of a single dose of DAURISMO 100 mg, glasdegib AUC0-INF increased by 2.1-fold in subjects with moderate (eGFR 30 to 59 mL/min) and severe (eGFR 15 to 29 mL/min) renal impairment compared to subjects with normal renal function (eGFR ≥90 mL/min). - The pharmacokinetics of glasdegib have not been studied in patients with end stage renal disease requiring hemodialysis. - Patients with Hepatic Impairment Following administration of a single dose of DAURISMO 100 mg, glasdegib AUC0-INF increased by 11% in subjects with moderate hepatic impairment (Child-Pugh B) and decreased by 24% in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function. - Following administration of a single dose of DAURISMO 100 mg, glasdegib AUC0-INF increased by 11% in subjects with moderate hepatic impairment (Child-Pugh B) and decreased by 24% in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function. ### Drug Interaction Studies - Clinical Studies and Model-Informed Approaches Effect of Strong CYP3A4 Inhibitors on Glasdegib: Co-administration of ketoconazole (a strong inhibitor of CYP3A4) with DAURISMO increased the glasdegib AUC0-INF by 2.4-fold and Cmax by 1.4-fold over glasdegib given alone. Effect of Strong and Moderate CYP3A4 Inducers on Glasdegib: Co-administration of rifampin (a strong inducer of CYP3A4) with DAURISMO decreased glasdegib AUC0-INF by 70% and Cmax by 35%. Co-administration of efavirenz (moderate CYP3A4 inducer) is predicted to decrease glasdegib AUC0-INF by 55% and Cmax by 25%. Effect of Gastric Acid Reducing Agents on Glasdegib: Co-administration of rabeprazole (a proton pump inhibitor) with DAURISMO did not alter glasdegib AUC0-INF but decreased Cmax by 20%. - Effect of Strong CYP3A4 Inhibitors on Glasdegib: Co-administration of ketoconazole (a strong inhibitor of CYP3A4) with DAURISMO increased the glasdegib AUC0-INF by 2.4-fold and Cmax by 1.4-fold over glasdegib given alone. - Effect of Strong and Moderate CYP3A4 Inducers on Glasdegib: Co-administration of rifampin (a strong inducer of CYP3A4) with DAURISMO decreased glasdegib AUC0-INF by 70% and Cmax by 35%. Co-administration of efavirenz (moderate CYP3A4 inducer) is predicted to decrease glasdegib AUC0-INF by 55% and Cmax by 25%. - Effect of Gastric Acid Reducing Agents on Glasdegib: Co-administration of rabeprazole (a proton pump inhibitor) with DAURISMO did not alter glasdegib AUC0-INF but decreased Cmax by 20%. - In Vitro Studies Effect of Glasdegib on Cytochrome P450 (CYP) Substrates: Glasdegib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A, and does not induce CYP1A2, CYP2B6, and CYP3A in vitro. Effect of Transporters on Glasdegib: Glasdegib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Effect of Glasdegib on Transporters: Glasdegib inhibits P-gp, BCRP, multidrug and toxin extrusion (MATE) protein 1, and MATE-2K, but not organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, and organic cation transporter (OCT)2 in vitro. - Effect of Glasdegib on Cytochrome P450 (CYP) Substrates: Glasdegib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A, and does not induce CYP1A2, CYP2B6, and CYP3A in vitro. - Effect of Transporters on Glasdegib: Glasdegib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). - Effect of Glasdegib on Transporters: Glasdegib inhibits P-gp, BCRP, multidrug and toxin extrusion (MATE) protein 1, and MATE-2K, but not organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, and organic cation transporter (OCT)2 in vitro. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenicity studies have not been performed with glasdegib. - Glasdegib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro chromosome aberration assay in human lymphocytes. Glasdegib was not clastogenic or aneugenic in the rat micronucleus assay. - Based on nonclinical safety findings, glasdegib has the potential to impair reproductive function in males. Men should seek advice on effective fertility preservation before treatment. In repeat-dose toxicity studies in rats, findings observed in the male reproductive tract included adverse testicular changes with glasdegib at doses ≥50 mg/kg/day, and consisted of minimal to severe hypospermatogenesis characterized by partial to complete loss of spermatogonia, spermatocytes and spermatids and testicular degeneration. Hypospermatogenesis did not recover whereas testicular degeneration did recover. The dose at which testicular effects were observed in male rats was identified as 50 mg/kg/day with corresponding systemic exposures that were approximately 6.6-times (based on AUC) those associated with the observed human exposure at the 100 mg once daily dose. - Men should seek advice on effective fertility preservation before treatment. - In repeat-dose toxicity studies in rats, findings observed in the male reproductive tract included adverse testicular changes with glasdegib at doses ≥50 mg/kg/day, and consisted of minimal to severe hypospermatogenesis characterized by partial to complete loss of spermatogonia, spermatocytes and spermatids and testicular degeneration. Hypospermatogenesis did not recover whereas testicular degeneration did recover. The dose at which testicular effects were observed in male rats was identified as 50 mg/kg/day with corresponding systemic exposures that were approximately 6.6-times (based on AUC) those associated with the observed human exposure at the 100 mg once daily dose. # Clinical Studies - The efficacy of DAURISMO in combination with low-dose cytarabine was evaluated in a multicenter, open-label, randomized study (Study BRIGHT AML 1003, NCT01546038) that included 115 patients age 55 years or older with newly-diagnosed AML who met at least one of the following criteria: a) age ≥75 years, b) severe cardiac disease, c) baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2, or d) baseline serum creatinine >1.3 mg/dL. - Patients were randomized 2:1 to receive DAURISMO at a 100 mg daily dose with low-dose cytarabine 20 mg subcutaneously twice daily on days 1 to 10 of a 28-day cycle (N=77) or low-dose cytarabine alone (N=38) in 28-day cycles until disease progression or unacceptable toxicity. - Patients were stratified by cytogenetic risk (good/intermediate or poor). The two treatment arms were generally balanced with respect to the baseline demographics and disease characteristics - Efficacy was established on the basis of overall survival (OS) from the date of randomization to death from any cause. - With a median follow-up of approximately 20 months, the DAURISMO with low-dose cytarabine arm was superior to low-dose cytarabine alone arm. - Improvement in OS was consistent across prespecified cytogenetic risk subgroups. # How Supplied ## Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (Medication Guide). ### Embryo-Fetal Toxicity Advise female patients of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy. Advise female patients and female partners of male patients to contact their healthcare provider with a known or suspected pregnancy. ### Females and Males of Reproductive Potential - Advise females of reproductive potential to use effective contraception during treatment with DAURISMO and for at least 30 days after the last dose. - Advise males of the potential risk of exposure through semen and to use effective contraception, including a condom, even after a vasectomy, to avoid drug exposure to a pregnant partner or a female partner of reproductive potential during treatment with DAURISMO and for at least 30 days after the last dose. ### Semen Donation Advise males not to donate semen during treatment with DAURISMO and for at least 30 days after the last dose of DAURISMO. ### Lactation Advise women not to breastfeed during treatment with DAURISMO and for at least 30 days after the last dose of DAURISMO. ### Blood Donation Advise patients not to donate blood or blood products during treatment with DAURISMO and for at least 30 days after the last dose of DAURISMO. ### Infertility Advise males of reproductive potential of the potential for impaired fertility from DAURISMO. Advise male patients to seek advice on effective fertility preservation before treatment. ### QT Interval Prolongation Inform patients of signs and symptoms that may be indicative of significant QT interval prolongation. Advise patients to contact their healthcare provider immediately in the event of syncope, pre-syncopal symptoms, and cardiac palpitations. # Precautions with Alcohol Alcohol-Glasdegib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Daurismo # Look-Alike Drug Names There is limited information regarding Daurismo Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	Glasdegib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Bhavya Bellannagari[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 Glasdegib is a hedgehog pathway inhibitor indicated, in combination with low-dose cytarabine that is FDA approved for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adult patients who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anemia, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, thrombocytopenia, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### ULTOMIRIS is indicated for: DAURISMO is indicated, in combination with low-dose cytarabine, for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adult patients who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy. ### Dosage Forms And Strengths - DAURISMO 100 mg tablets: round, pale orange film-coated tablet debossed with "Pfizer" on one side and "GLS 100" on the other. - DAURISMO 25 mg tablets: round, yellow film-coated tablet debossed with "Pfizer" on one side and "GLS 25" on the other. - 100 mg orally once daily on days 1 to 28 in combination with cytarabine 20 mg subcutaneously twice daily on days 1 to 10 of each 28-day cycle in the absence of unacceptable toxicity or loss of disease control. For patients without unacceptable toxicity, treat for a minimum of 6 cycles to allow time for clinical response. - Administer DAURISMO with or without food. Do not split or crush DAURISMO tablets. Administer DAURISMO about the same time each day. If a dose of DAURISMO is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose of DAURISMO is missed or not taken at the usual time, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses of DAURISMO within 12 hours. - Assess complete blood counts, electrolytes, renal, and hepatic function prior to the initiation of DAURISMO and at least once weekly for the first month. - Monitor electrolytes and renal function once monthly for the duration of therapy. - Obtain serum creatine kinase levels prior to initiating DAURISMO and as indicated clinically thereafter (e.g., if muscle symptoms are reported). - Monitor electrocardiograms (ECGs) prior to the initiation of DAURISMO, approximately one week after initiation, and then once monthly for the next two months to assess for QTc prolongation. Repeat ECG if abnormal. Certain patients may require more frequent and ongoing ECG monitoring. - Certain patients may require more frequent and ongoing ECG monitoring. - Manage any abnormalities promptly ### Dosage Modification for Concomitant Use with Moderate CYP3A4 Inducers - Avoid concomitant use of DAURISMO with moderate CYP3A4 inducers. If concomitant use of moderate CYP3A4 inducers cannot be avoided, increase the DAURISMO dosage as tolerated as shown in Table 2. After the moderate CYP3A4 inducer has been discontinued for 7 days, resume the DAURISMO dose taken prior to initiating the moderate CYP3A4 inducer. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding DAURISMO Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding DAURISMO Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding DAURISMO FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding DAURISMO Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding DAURISMO Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None # Warnings ### Embryo-Fetal Toxicity - Based on its mechanism of action and findings from animal embryo-fetal developmental toxicity studies, DAURISMO can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. There are no clinical data on the use of DAURISMO in pregnant women. - In animal embryo-fetal developmental toxicity studies, glasdegib caused embryotoxicity, fetotoxicity and teratogenicity at maternal exposures that were less than the human exposure at the recommended human dose of 100 mg. Advise pregnant women of the potential risk to the fetus. ### Females of Reproductive Potential DAURISMO is not recommended for use during pregnancy. Conduct pregnancy testing in female patients of reproductive potential prior to initiating DAURISMO treatment. Advise females of reproductive potential to use effective contraception during treatment with DAURISMO and for at least 30 days after the last dose. Advise women not to breastfeed during treatment with DAURISMO and for at least 30 days after the last dose. ### Males Advise male patients with female partners of the potential risk of exposure through semen and to use effective contraception, including a condom, even after vasectomy, to avoid drug exposure to a pregnant partner or a female partner of reproductive potential during treatment with DAURISMO and for at least 30 days after the last dose. ### Blood Donation Advise patients not to donate blood or blood products while taking DAURISMO and for at least 30 days after the last dose of DAURISMO because their blood or blood products might be given to a female of reproductive potential. ### QTc Interval Prolongation - Patients treated with DAURISMO can develop QTc prolongation and ventricular arrhythmias, including ventricular fibrillation and ventricular tachycardia. Of the 98 evaluable patients treated with DAURISMO 100 mg in combination with low-dose cytarabine in the clinical trial, 5% were found to have a QTc interval greater than 500 ms and 4% of patients had an increase from baseline QTc greater than 60 ms. The clinical trial excluded patients with baseline QTc of greater than 470 ms or with a history of long QT syndrome or uncontrolled cardiovascular disease. - Of the 98 evaluable patients treated with DAURISMO 100 mg in combination with low-dose cytarabine in the clinical trial, 5% were found to have a QTc interval greater than 500 ms and 4% of patients had an increase from baseline QTc greater than 60 ms. The clinical trial excluded patients with baseline QTc of greater than 470 ms or with a history of long QT syndrome or uncontrolled cardiovascular disease. - Monitor electrocardiograms (ECGs) and electrolytes. Concomitant use of DAURISMO with drugs known to prolong the QTc interval and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. In patients with congenital long QT syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent ECG monitoring is recommended. - Interrupt DAURISMO if QTc increases to greater than 500 ms. Discontinue DAURISMO permanently for patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia. # Adverse Reactions ## Clinical Trials Experience - The safety profile of DAURISMO is based on experience in the BRIGHT AML 1003 study for 111 adults with newly-diagnosed AML and 14 adults with other conditions for which DAURISMO is not indicated. - Patients were treated with DAURISMO 100 mg daily in combination with low-dose cytarabine (N=84) or low-dose cytarabine alone (N=41). - The median duration of treatment in the DAURISMO with low-dose cytarabine arm was 83 days (range 3 to 972 days). - The median duration of treatment in the low-dose cytarabine alone arm was 47 days (range 6 to 239 days). - The median exposure to DAURISMO in the DAURISMO with low-dose cytarabine arm was 76 days (range 3 to 954 days). Thirty-two patients (38%) were treated with DAURISMO with low-dose cytarabine for at least 6 months and 14 patients (17%) were treated for at least 1 year. - Serious adverse reactions were reported in 79% of patients treated in the DAURISMO with low-dose cytarabine arm. The most common (≥5%) serious adverse reactions in patients receiving DAURISMO with low-dose cytarabine were febrile neutropenia (29%), pneumonia (23%), hemorrhage (12%), anemia (7%), and sepsis (7%). - The most common (≥5%) serious adverse reactions in patients receiving DAURISMO with low-dose cytarabine were febrile neutropenia (29%), pneumonia (23%), hemorrhage (12%), anemia (7%), and sepsis (7%). - Dose reductions associated with adverse reactions were reported in 26% of patients treated with DAURISMO with low-dose cytarabine, and the most common reasons (≥2%) for dose reductions due to adverse reactions were muscle spasms (5%), fatigue (4%), febrile neutropenia (4%), anemia (2%), thrombocytopenia (2%), and ECG QT prolonged (2%). - Adverse reactions leading to permanent discontinuation were reported in 36% of patients treated with DAURISMO with low-dose cytarabine, and the most common (≥2%) reasons for permanent discontinuation were pneumonia (6%), febrile neutropenia (4%), sepsis (4%), sudden death (2%), myocardial infarction (2%), nausea (2%), and renal insufficiency (2%). - The adverse reactions muscle spasms (4 in 12 patients) and decreased appetite (2 in 10 patients) worsened (i.e. progressed from Grades ≤ 2 to Grade 3 or higher) after the first 90 days of therapy in BRIGHT AML 1003. - Additional clinically-significant adverse reactions occurring in < 10% of patients treated with DAURISMO and low-dose cytarabine in BRIGHT AML 1003 include: Dental disorders: loose tooth and toothache Skin and subcutaneous tissue disorders: alopecia Cardiac disorders: QT interval prolonged - Dental disorders: loose tooth and toothache - Skin and subcutaneous tissue disorders: alopecia - Cardiac disorders: QT interval prolonged - The following laboratory abnormalities worsened (i.e. progressed from Grades ≤ 2 to Grade 3 or higher) after the first 90 days of therapy in BRIGHT AML 1003: hypophosphatemia (8 in 38 patients), creatinine increased (2 in 39 patients), and ALT increased (2 in 40 patients). - hypophosphatemia (8 in 38 patients), creatinine increased (2 in 39 patients), and ALT increased (2 in 40 patients). ## Postmarketing Experience There is limited information regarding Daurismo Postmarketing Experience in the drug label. # Drug Interactions # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Based on its mechanism of action and findings in animal embryo-fetal developmental toxicity studies, DAURISMO can cause fetal harm when administered to a pregnant woman. There are no clinical data on the use of DAURISMO in pregnant women to inform of a drug-associated risk of major birth defects and miscarriage. DAURISMO is not recommended for use during pregnancy. Conduct pregnancy testing in female patients of reproductive potential prior to initiating treatment with DAURISMO. Report pregnancy exposures to Pfizer at 1-800-438-1985. - The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glasdegib in women who are pregnant. ### Labor and Delivery The safety and effectiveness of DAURISMO during labor and delivery have not been evaluated. ### Nursing Mothers There are no data on the presence of glasdegib or its active metabolites in human milk, the effects of the drug on the breastfed child, or its effect on milk production. Because of the potential for serious adverse reactions in a breastfed child from DAURISMO, advise women who are taking DAURISMO not to breastfeed or provide breast milk to infants or children during treatment with DAURISMO and for at least 30 days after the last dose. ### Pediatric Use The safety and effectiveness of DAURISMO have not been established in pediatric patients. In repeat-dose toxicity studies in rats, oral administration of DAURISMO resulted in adverse changes in growing bone, teeth, and testis. Effects on bone consisted of partial to complete closure of the epiphyseal plate. Effects in growing incisor teeth included degeneration/necrosis of ameloblasts, and complete tooth loss with oral ulceration. Reproductive tissue toxicity was evidenced by testicular degeneration and hypospermatogenesis. These effects in bone, teeth and testis were observed after administration of DAURISMO for 26 weeks at greater than or equal to 50 mg/kg/day corresponding to approximately 6.6-times the steady state AUC in patients at the recommended human dose. ### Geriatic Use Of the total number of subjects in clinical studies of DAURISMO with low-dose cytarabine (N=88), 98% of the patients were age 65 years or older and 60% of the patients were age 75 years or older. There were insufficient patients younger than age 65 years to determine differences in adverse reactions reported from patients older than 65. ### Gender There is no FDA guidance on the use of DAURISMO with respect to specific gender populations. ### Race There is no FDA guidance on the use of DAURISMO with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of DAURISMO in patients with renal impairment. ### Hepatic Impairment No dosage modification is recommended for patients with mild to severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 89 mL/min). Monitor patients with severe renal impairment (eGFR 15 to 29 mL/min) for increased risk of adverse reactions, including QTc interval prolongation, due to increased glasdegib concentrations. ### Females of Reproductive Potential and Males Conduct pregnancy testing in females of reproductive potential within 7 days prior to initiating therapy with DAURISMO. ### Contraception - Females: Advise females of reproductive potential to use effective contraception during treatment with DAURISMO and at least 30 days after the last dose. - Males: It is not known if glasdegib is present in semen. Advise males of the potential risk of exposure through semen and to use effective contraception, including a condom, even after a vasectomy, to avoid drug exposure to a pregnant partner or a female partner of reproductive potential during treatment with DAURISMO and for at least 30 days after the last dose. Advise males to not donate semen during treatment with DAURISMO for at least 30 days after the last dose. ### Infertility Males: Based on findings in repeat-dose animal toxicity studies in rats, DAURISMO may impair fertility in males of reproductive potential. Some effects on male reproductive organs did not recover. Men should seek advice on effective fertility preservation before treatment. ### Immunocompromised Patients There is no FDA guidance one the use of DAURISMO in patients who are immunocompromised. # Administration and Monitoring ### Administration ### Recommended Dosage and Schedule Recommended dosage: 100 mg orally once daily on days 1 to 28 in combination with cytarabine 20 mg subcutaneously twice daily on days 1 to 10 of each 28-day cycle in the absence of unacceptable toxicity or loss of disease control. For patients without unacceptable toxicity, treat for a minimum of 6 cycles to allow time for clinical response. - Administer DAURISMO with or without food. - Do not split or crush DAURISMO tablets. - Administer DAURISMO about the same time each day. - If a dose of DAURISMO is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. - If a dose of DAURISMO is missed or not taken at the usual time, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. - Do not administer 2 doses of DAURISMO within 12 hours. ### Monitoring and Dosage Modifications - Assess complete blood counts, electrolytes, renal, and hepatic function prior to the initiation of DAURISMO and at least once weekly for the first month. - Monitor electrolytes and renal function once monthly for the duration of therapy. - Obtain serum creatine kinase levels prior to initiating DAURISMO and as indicated clinically thereafter (e.g., if muscle symptoms are reported). - Monitor electrocardiograms (ECGs) prior to the initiation of DAURISMO, approximately one week after initiation, and then once monthly for the next two months to assess for QTc prolongation. - Repeat ECG if abnormal. ### Dosage Modification for Concomitant Use with Moderate CYP3A4 Inducers - Avoid concomitant use of DAURISMO with moderate CYP3A4 inducers. - If concomitant use of moderate CYP3A4 inducers cannot be avoided, increase the DAURISMO dosage as tolerated. - After the moderate CYP3A4 inducer has been discontinued for 7 days, resume the DAURISMO dose taken prior to initiating the moderate CYP3A4 inducer. ### Monitoring There is limited information regarding Glasdegib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Glasdegib and IV administrations. # Overdosage There is no specific antidote for DAURISMO. Management of DAURISMO overdose should include symptomatic treatment and ECG monitoring. Glasdegib has been administered in clinical studies up to a dose of 640 mg/day. At the highest dosage, the adverse reactions that were dose limiting were nausea, vomiting, dehydration, hypotension, fatigue, and dizziness. # Pharmacology ## Mechanism of Action - Glasdegib is an inhibitor of the Hedgehog pathway. - Glasdegib binds to and inhibits Smoothened, a transmembrane protein involved in hedgehog signal transduction. - In a murine xenotransplant model of human AML, glasdegib in combination with low-dose cytarabine, inhibited increases in tumor size and reduced the percentage of CD45+/CD33+ blasts in the marrow to a greater extent than glasdegib or low-dose cytarabine alone. ## Structure There is limited information regarding DAURISMO Structure in the drug label. ## Pharmacodynamics ### Cardiac Electrophysiology - The effect of glasdegib administration on corrected QT interval (QTc) was evaluated in a randomized, single-dose, double-blind, 4-way crossover, placebo- and open-label moxifloxacin-controlled study in 36 healthy subjects. - At therapeutic plasma concentrations for the recommended dose, achieved with a single dose of 150 mg DAURISMO, the largest placebo and baseline-adjusted QTc interval change was 8 ms (90% CI: 6, 10 ms). - At a two-fold therapeutic plasma concentration, achieved with a single dose of 300 mg DAURISMO, the QTc change was 13 ms (90% CI: 11, 16 ms). Glasdegib is associated with concentration-dependent QTc prolongation. ## Pharmacokinetics - DAURISMO at 5 mg to 600 mg once daily (0.05 to 6 times the recommended dose) result in a dose proportional increase in glasdegib peak concentrations (Cmax) and area under the curve over the dosing interval (AUC0-Tau). - Steady-state plasma levels are reached by 8 days of daily dosing. - The median accumulation ratio of glasdegib ranged from 1.2 to 2.5 following once-daily dosing. - At DAURISMO 100 mg once daily, the geometric mean (geometric coefficient of variation, % CV) of glasdegib Cmax was 1252 ng/mL (44%) and AUC0-Tau was 17210 nghr/mL (54%) in patients with cancer. ### Absorption - The mean absolute bioavailability of DAURISMO is 77%. Following 100 mg once daily dosing, glasdegib median time to peak concentrations (Tmax) at steady-state ranged from 1.3 hours to 1.8 hours. - Effect of Food: A high-fat, high-calorie meal (total 800–1000 calories: 500–600 fat calories, 250 carbohydrate calories and 150 protein calories) reduced area under the curve over time to infinity (AUC0-INF) by 16% and Cmax by 31%. ### Distribution Glasdegib is 91% bound to human plasma proteins in vitro. The geometric mean (%CV) apparent volume of distribution (Vz/F) was 188 L (20%) in patients with hematologic malignancies. ### Elimination Glasdegib has a mean (± SD) half-life of 17.4 h (3.7) and geometric mean (%CV) apparent clearance of 6.45 L/h (25%) following 100 mg once daily dosing in patients with hematologic malignancies. - Metabolism Glasdegib is primarily metabolized by the CYP3A4 pathway, with minor contributions by CYP2C8 and UGT1A9. Glasdegib accounts for 69% of the total circulating drug related material in plasma. - Glasdegib is primarily metabolized by the CYP3A4 pathway, with minor contributions by CYP2C8 and UGT1A9. Glasdegib accounts for 69% of the total circulating drug related material in plasma. - Excretion Following a single oral dose of 100 mg radiolabeled glasdegib, 49% (17% unchanged) of the administered dose was eliminated in the urine and 42% (20% unchanged) of the administered dose was eliminated in the feces. - Following a single oral dose of 100 mg radiolabeled glasdegib, 49% (17% unchanged) of the administered dose was eliminated in the urine and 42% (20% unchanged) of the administered dose was eliminated in the feces. ### Specific Populations Age (25 to 92 years), sex, race (White, Black, Asian), body weight (43.5 to 145.6 kg), mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin 1–1.5 × ULN and any AST), and mild renal impairment (creatinine clearance 60–89 mL/min) did not have clinically meaningful effects on the pharmacokinetics of glasdegib. - Patients with Renal Impairment Following administration of a single dose of DAURISMO 100 mg, glasdegib AUC0-INF increased by 2.1-fold in subjects with moderate (eGFR 30 to 59 mL/min) and severe (eGFR 15 to 29 mL/min) renal impairment compared to subjects with normal renal function (eGFR ≥90 mL/min). The pharmacokinetics of glasdegib have not been studied in patients with end stage renal disease requiring hemodialysis. - Following administration of a single dose of DAURISMO 100 mg, glasdegib AUC0-INF increased by 2.1-fold in subjects with moderate (eGFR 30 to 59 mL/min) and severe (eGFR 15 to 29 mL/min) renal impairment compared to subjects with normal renal function (eGFR ≥90 mL/min). - The pharmacokinetics of glasdegib have not been studied in patients with end stage renal disease requiring hemodialysis. - Patients with Hepatic Impairment Following administration of a single dose of DAURISMO 100 mg, glasdegib AUC0-INF increased by 11% in subjects with moderate hepatic impairment (Child-Pugh B) and decreased by 24% in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function. - Following administration of a single dose of DAURISMO 100 mg, glasdegib AUC0-INF increased by 11% in subjects with moderate hepatic impairment (Child-Pugh B) and decreased by 24% in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function. ### Drug Interaction Studies - Clinical Studies and Model-Informed Approaches Effect of Strong CYP3A4 Inhibitors on Glasdegib: Co-administration of ketoconazole (a strong inhibitor of CYP3A4) with DAURISMO increased the glasdegib AUC0-INF by 2.4-fold and Cmax by 1.4-fold over glasdegib given alone. Effect of Strong and Moderate CYP3A4 Inducers on Glasdegib: Co-administration of rifampin (a strong inducer of CYP3A4) with DAURISMO decreased glasdegib AUC0-INF by 70% and Cmax by 35%. Co-administration of efavirenz (moderate CYP3A4 inducer) is predicted to decrease glasdegib AUC0-INF by 55% and Cmax by 25%. Effect of Gastric Acid Reducing Agents on Glasdegib: Co-administration of rabeprazole (a proton pump inhibitor) with DAURISMO did not alter glasdegib AUC0-INF but decreased Cmax by 20%. - Effect of Strong CYP3A4 Inhibitors on Glasdegib: Co-administration of ketoconazole (a strong inhibitor of CYP3A4) with DAURISMO increased the glasdegib AUC0-INF by 2.4-fold and Cmax by 1.4-fold over glasdegib given alone. - Effect of Strong and Moderate CYP3A4 Inducers on Glasdegib: Co-administration of rifampin (a strong inducer of CYP3A4) with DAURISMO decreased glasdegib AUC0-INF by 70% and Cmax by 35%. Co-administration of efavirenz (moderate CYP3A4 inducer) is predicted to decrease glasdegib AUC0-INF by 55% and Cmax by 25%. - Effect of Gastric Acid Reducing Agents on Glasdegib: Co-administration of rabeprazole (a proton pump inhibitor) with DAURISMO did not alter glasdegib AUC0-INF but decreased Cmax by 20%. - In Vitro Studies Effect of Glasdegib on Cytochrome P450 (CYP) Substrates: Glasdegib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A, and does not induce CYP1A2, CYP2B6, and CYP3A in vitro. Effect of Transporters on Glasdegib: Glasdegib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Effect of Glasdegib on Transporters: Glasdegib inhibits P-gp, BCRP, multidrug and toxin extrusion (MATE) protein 1, and MATE-2K, but not organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, and organic cation transporter (OCT)2 in vitro. - Effect of Glasdegib on Cytochrome P450 (CYP) Substrates: Glasdegib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A, and does not induce CYP1A2, CYP2B6, and CYP3A in vitro. - Effect of Transporters on Glasdegib: Glasdegib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). - Effect of Glasdegib on Transporters: Glasdegib inhibits P-gp, BCRP, multidrug and toxin extrusion (MATE) protein 1, and MATE-2K, but not organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, and organic cation transporter (OCT)2 in vitro. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenicity studies have not been performed with glasdegib. - Glasdegib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro chromosome aberration assay in human lymphocytes. Glasdegib was not clastogenic or aneugenic in the rat micronucleus assay. - Based on nonclinical safety findings, glasdegib has the potential to impair reproductive function in males. Men should seek advice on effective fertility preservation before treatment. In repeat-dose toxicity studies in rats, findings observed in the male reproductive tract included adverse testicular changes with glasdegib at doses ≥50 mg/kg/day, and consisted of minimal to severe hypospermatogenesis characterized by partial to complete loss of spermatogonia, spermatocytes and spermatids and testicular degeneration. Hypospermatogenesis did not recover whereas testicular degeneration did recover. The dose at which testicular effects were observed in male rats was identified as 50 mg/kg/day with corresponding systemic exposures that were approximately 6.6-times (based on AUC) those associated with the observed human exposure at the 100 mg once daily dose. - Men should seek advice on effective fertility preservation before treatment. - In repeat-dose toxicity studies in rats, findings observed in the male reproductive tract included adverse testicular changes with glasdegib at doses ≥50 mg/kg/day, and consisted of minimal to severe hypospermatogenesis characterized by partial to complete loss of spermatogonia, spermatocytes and spermatids and testicular degeneration. Hypospermatogenesis did not recover whereas testicular degeneration did recover. The dose at which testicular effects were observed in male rats was identified as 50 mg/kg/day with corresponding systemic exposures that were approximately 6.6-times (based on AUC) those associated with the observed human exposure at the 100 mg once daily dose. # Clinical Studies - The efficacy of DAURISMO in combination with low-dose cytarabine was evaluated in a multicenter, open-label, randomized study (Study BRIGHT AML 1003, NCT01546038) that included 115 patients age 55 years or older with newly-diagnosed AML who met at least one of the following criteria: a) age ≥75 years, b) severe cardiac disease, c) baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2, or d) baseline serum creatinine >1.3 mg/dL. - Patients were randomized 2:1 to receive DAURISMO at a 100 mg daily dose with low-dose cytarabine 20 mg subcutaneously twice daily on days 1 to 10 of a 28-day cycle (N=77) or low-dose cytarabine alone (N=38) in 28-day cycles until disease progression or unacceptable toxicity. - Patients were stratified by cytogenetic risk (good/intermediate or poor). The two treatment arms were generally balanced with respect to the baseline demographics and disease characteristics - Efficacy was established on the basis of overall survival (OS) from the date of randomization to death from any cause. - With a median follow-up of approximately 20 months, the DAURISMO with low-dose cytarabine arm was superior to low-dose cytarabine alone arm. - Improvement in OS was consistent across prespecified cytogenetic risk subgroups. # How Supplied ## Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (Medication Guide). ### Embryo-Fetal Toxicity Advise female patients of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy. Advise female patients and female partners of male patients to contact their healthcare provider with a known or suspected pregnancy. ### Females and Males of Reproductive Potential - Advise females of reproductive potential to use effective contraception during treatment with DAURISMO and for at least 30 days after the last dose. - Advise males of the potential risk of exposure through semen and to use effective contraception, including a condom, even after a vasectomy, to avoid drug exposure to a pregnant partner or a female partner of reproductive potential during treatment with DAURISMO and for at least 30 days after the last dose. ### Semen Donation Advise males not to donate semen during treatment with DAURISMO and for at least 30 days after the last dose of DAURISMO. ### Lactation Advise women not to breastfeed during treatment with DAURISMO and for at least 30 days after the last dose of DAURISMO. ### Blood Donation Advise patients not to donate blood or blood products during treatment with DAURISMO and for at least 30 days after the last dose of DAURISMO. ### Infertility Advise males of reproductive potential of the potential for impaired fertility from DAURISMO. Advise male patients to seek advice on effective fertility preservation before treatment. ### QT Interval Prolongation Inform patients of signs and symptoms that may be indicative of significant QT interval prolongation. Advise patients to contact their healthcare provider immediately in the event of syncope, pre-syncopal symptoms, and cardiac palpitations. # Precautions with Alcohol Alcohol-Glasdegib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Daurismo # Look-Alike Drug Names There is limited information regarding Daurismo Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Glasdegib
f9f63b7d2089a10495033555abf2d0bab35c801e	wikidoc	Glyburide	Glyburide # 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 Glyburide is a hypoglycemic agent that is FDA approved for the treatment of type 2 diabetes mellitus. Common adverse reactions include epigastric fullness, heartburn, nausea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information: - Patients should be retitrated when transferred from glyburide (micronized) tablets or other oral hypoglycemic agents (see PRECAUTIONS). - There is no fixed dosage regimen for the management of diabetes mellitus with glyburide tablets or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient’s blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient’s response to therapy. - Short-term administration of glyburide tablets may be sufficient during periods of transient loss of control in patients usually controlled well on diet. - Usual Starting Dose: - The usual starting dose of glyburide tablets is 2.5 to 5 mg daily, administered with breakfast or the first main meal. Those patients who may be more sensitive to hypoglycemic drugs should be started at 1.25 mg daily. (See PRECAUTIONS section for patients at increased risk.) Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary and drug regimen are more prone to exhibit unsatisfactory response to therapy. - Transfer From Other Hypoglycemic Therapy Patients Receiving Other Oral Antidiabetic Therapy: - Transfer of patients from other oral antidiabetic regimens to glyburide tablets should be done conservatively and the initial daily dose should be 2.5 to 5 mg. When transferring patients from oral hypoglycemic agents other than chlorpropamide to glyburide tablets, no transition period and no initial or priming dose are necessary. When transferring patients from chlorpropamide, particular care should be exercised during the first two weeks because the prolonged retention of chlorpropamide in the body and subsequent overlapping drug effects may provoke hypoglycemia. - Patients Receiving Insulin: - Some Type II diabetic patients being treated with insulin may respond satisfactorily to glyburide tablets. If the insulin dose is less than 20 units daily, substitution of glyburide tablets 2.5 to 5 mg as a single daily dose may be tried. If the insulin dose is between 20 and 40 units daily, the patient may be placed directly on glyburide tablets 5 mg daily as a single dose. If the insulin dose is more than 40 units daily, a transition period is required for conversion to glyburide tablets. In these patients, insulin dosage is decreased by 50% and glyburide tablets 5 mg daily is started. Please refer to Titration to Maintenance Dose for further explanation. - Patients Receiving Colesevelam: - When colesevelam is coadministered with glyburide, maximum plasma concentration and total exposure to glyburide is reduced. Therefore, glyburide tablets should be administered at least 4 hours prior to colesevelam. - Titration to Maintenance Dose: - The usual maintenance dose is in the range of 1.25 to 20 mg daily, which may be given as a single dose or in divided doses (see Dosage Interval). Dosage increases should be made in increments of no more than 2.5 mg at weekly intervals based upon the patient’s blood glucose response. - No exact dosage relationship exists between glyburide tablets and the other oral hypoglycemic agents. Although patients may be transferred from the maximum dose of other sulfonylureas, the maximum starting dose of 5 mg of glyburide tablets should be observed. A maintenance dose of 5 mg of glyburide tablets provides approximately the same degree of blood glucose control as 250 to 375 mg chlorpropamide, 250 to 375 mg tolazamide, 500 to 750 mg acetohexamide, or 1000 to 1500 mg tolbutamide. - When transferring patients receiving more than 40 units of insulin daily, they may be started on a daily dose of glyburide tablets 5 mg concomitantly with a 50% reduction in insulin dose. Progressive withdrawal of insulin and increase of glyburide tablets in increments of 1.25 to 2.5 mg every 2 to 10 days is then carried out. During this conversion period when both insulin and glyburide tablets are being used, hypoglycemia may rarely occur. During insulin withdrawal, patients should test their urine for glucose and acetone at least three times daily and report results to their physician. The appearance of persistent acetonuria with glycosuria indicates that the patient is a Type I diabetic who requires insulin therapy. - Concomitant Glyburide and Metformin Therapy: - Glyburide tablets should be added gradually to the dosing regimen of patients who have not responded to the maximum dose of metformin monotherapy after four weeks (see Usual Starting Dose and Titration to Maintenance Dose). Refer to metformin package insert. - With concomitant glyburide and metformin therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. However, attempts should be made to identify the optimal dose of each drug needed to achieve this goal. With concomitant glyburide and metformin therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken (see PRECAUTIONS). - Maximum Dose: - Daily doses of more than 20 mg are not recommended. - Dosage Interval: - Once-a-day therapy is usually satisfactory. Some patients, particularly those receiving more than 10 mg daily, may have a more satisfactory response with twice-a-day dosage. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Glyburide in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Glyburide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Glyburide FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Glyburide in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Glyburide in pediatric patients. # Contraindications - Glyburide tablets are contraindicated in patients with: - Known hypersensitivity or allergy to the drug. - Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin. - Type I diabetes mellitus. - Concomitant administration of bosentan. # Warnings ### Special warning on increased risk of cardiovascular mortality - The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups. - UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glyburide and of alternative modes of therapy. - Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure. ### Precautions - Bioavailability studies have demonstrated that micronized glyburide tablets 3 mg provide serum glyburide concentrations that are not bioequivalent to those from nonmicronized glyburide tablets 5 mg. Therefore, patients should be retitrated when transferred from micronized glyburide tablets or other oral hypoglycemic agents. General Macrovascular Outcomes - There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glyburide or any other anti-diabetic drug. Hypoglycemia - All sulfonylureas are capable of producing severe hypoglycemia. Proper patient selection and dosage and instructions are important to avoid hypoglycemic episodes. Renal or hepatic insufficiency may cause elevated drug levels of glyburide and the latter may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency, are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose lowering drug is used. The risk of hypoglycemia may be increased with combination therapy. Loss of Control of Blood Glucose - When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection or surgery, a loss of control may occur. At such times it may be necessary to discontinue glyburide and administer insulin. - The effectiveness of any hypoglycemic drug, including glyburide, in lowering blood glucose to a desired level decreases in many patients over a period of time which may be due to progression of the severity of diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when glyburide is first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure. Hemolytic Anemia - Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because glyburide belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In postmarketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency. Laboratory Tests - Therapeutic response to glyburide tablets should be monitored by frequent urine glucose tests and periodic blood glucose tests. Measurement of glycosylated hemoglobin levels may be helpful in some patients. # Adverse Reactions ## Clinical Trials Experience Hypoglycemia: See PRECAUTIONS and OVERDOSAGE - Gastrointestinal Reactions: Cholestatic jaundice and hepatitis may occur rarely which may progress to liver failure; glyburide tablets should be discontinued if this occurs. - Liver function abnormalities, including isolated transaminase elevations, have been reported. - Gastrointestinal disturbances, e.g., nausea, epigastric fullness, and heartburn are the most common reactions, having occurred in 1.8% of treated patients during clinical trials. They tend to be dose related and may disappear when dosage is reduced. - Dermatologic Reactions: Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions occurred in 1.5% of treated patients during clinical trials. These may be transient and may disappear despite continued use of glyburide; if skin reactions persist, the drug should be discontinued. - Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas. - Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia (see PRECAUTIONS), aplastic anemia, and pancytopenia have been reported with sulfonylureas. - Metabolic Reactions: Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas; however, hepatic porphyria has not been reported with glyburide and disulfiram-like reactions have been reported very rarely. - Cases of hyponatremia have been reported with glyburide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH. - Other Reactions: Changes in accommodation and/or blurred vision have been reported with glyburide and other sulfonylureas. These are thought to be related to fluctuation in glucose levels. - In addition to dermatologic reactions, allergic reactions such as angioedema, arthralgia, myalgia and vasculitis have been reported. ## Postmarketing Experience There is limited information regarding Glyburide Postmarketing Experience in the drug label. # Drug Interactions - The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including non-steroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such drugs are administered to a patient receiving glyburide, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving glyburide, the patient should be observed closely for loss of control. - An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore concomitant administration of glyburide tablets and bosentan is contraindicated. - Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving glyburide, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving glyburide, the patient should be observed closely for hypoglycemia. - A possible interaction between glyburide and ciprofloxacin, a fluoroquinolone antibiotic, has been reported, resulting in a potentiation of the hypoglycemic action of glyburide. The mechanism for this interaction is not known. - A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical or vaginal preparations of miconazole is not known. Metformin - In a single-dose interaction study in NIDDM subjects, decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain. Coadministration of glyburide and metformin did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Colesevelam - Concomitant administration of colesevelam and glyburide resulted in reductions in glyburide AUC and Cmax of 32% and 47%, respectively. The reductions in glyburide AUC and Cmax were 20% and 15%, respectively when administered 1 hour before, and not significantly changed (-7% and 4%, respectively) when administered 4 hours before colesevelam. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B Pregnancy category B - Reproduction studies have been performed in rats and rabbits at doses up to 500 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to glyburide. 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. - Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose as close to normal as possible. Nonteratogenic Effects - Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If glyburide is used during pregnancy, it should be discontinued at least two weeks before the expected delivery date. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glyburide in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Glyburide during labor and delivery. ### Nursing Mothers - Although it is not known whether glyburide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, 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. If the drug is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Elderly patients are particularly susceptible to the hypoglycemic action of glucose lowering drugs. Hypoglycemia may be difficult to recognize in the elderly (see PRECAUTIONS). The initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see DOSAGE AND ADMINISTRATION). Elderly patients are prone to develop renal insufficiency, which may put them at risk of hypoglycemia. Dose selection should include assessment of renal function. ### Gender - There is no FDA guidance on the use of Glyburide with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Glyburide with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Glyburide in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Glyburide in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Glyburide in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Glyburide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Patients should be retitrated when transferred from glyburide (micronized) tablets or other oral hypoglycemic agents (see PRECAUTIONS). - There is no fixed dosage regimen for the management of diabetes mellitus with glyburide tablets or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient’s blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient’s response to therapy. - Short-term administration of glyburide tablets may be sufficient during periods of transient loss of control in patients usually controlled well on diet. Usual Starting Dose - The usual starting dose of glyburide tablets is 2.5 to 5 mg daily, administered with breakfast or the first main meal. Those patients who may be more sensitive to hypoglycemic drugs should be started at 1.25 mg daily. (See PRECAUTIONS section for patients at increased risk.) Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary and drug regimen are more prone to exhibit unsatisfactory response to therapy. Transfer From Other Hypoglycemic Therapy Patients Receiving Other Oral Antidiabetic Therapy - Transfer of patients from other oral antidiabetic regimens to glyburide tablets should be done conservatively and the initial daily dose should be 2.5 to 5 mg. When transferring patients from oral hypoglycemic agents other than chlorpropamide to glyburide tablets, no transition period and no initial or priming dose are necessary. When transferring patients from chlorpropamide, particular care should be exercised during the first two weeks because the prolonged retention of chlorpropamide in the body and subsequent overlapping drug effects may provoke hypoglycemia. Patients Receiving Insulin - Some Type II diabetic patients being treated with insulin may respond satisfactorily to glyburide tablets. If the insulin dose is less than 20 units daily, substitution of glyburide tablets 2.5 to 5 mg as a single daily dose may be tried. If the insulin dose is between 20 and 40 units daily, the patient may be placed directly on glyburide tablets 5 mg daily as a single dose. If the insulin dose is more than 40 units daily, a transition period is required for conversion to glyburide tablets. In these patients, insulin dosage is decreased by 50% and glyburide tablets 5 mg daily is started. Please refer to Titration to Maintenance Dose for further explanation. Patients Receiving Colesevelam - When colesevelam is coadministered with glyburide, maximum plasma concentration and total exposure to glyburide is reduced. Therefore, glyburide tablets should be administered at least 4 hours prior to colesevelam. Titration to Maintenance Dose - The usual maintenance dose is in the range of 1.25 to 20 mg daily, which may be given as a single dose or in divided doses (see Dosage Interval). Dosage increases should be made in increments of no more than 2.5 mg at weekly intervals based upon the patient’s blood glucose response. - No exact dosage relationship exists between glyburide tablets and the other oral hypoglycemic agents. Although patients may be transferred from the maximum dose of other sulfonylureas, the maximum starting dose of 5 mg of glyburide tablets should be observed. A maintenance dose of 5 mg of glyburide tablets provides approximately the same degree of blood glucose control as 250 to 375 mg chlorpropamide, 250 to 375 mg tolazamide, 500 to 750 mg acetohexamide, or 1000 to 1500 mg tolbutamide. - When transferring patients receiving more than 40 units of insulin daily, they may be started on a daily dose of glyburide tablets 5 mg concomitantly with a 50% reduction in insulin dose. Progressive withdrawal of insulin and increase of glyburide tablets in increments of 1.25 to 2.5 mg every 2 to 10 days is then carried out. During this conversion period when both insulin and glyburide tablets are being used, hypoglycemia may rarely occur. During insulin withdrawal, patients should test their urine for glucose and acetone at least three times daily and report results to their physician. The appearance of persistent acetonuria with glycosuria indicates that the patient is a Type I diabetic who requires insulin therapy. Concomitant Glyburide and Metformin Therapy - Glyburide tablets should be added gradually to the dosing regimen of patients who have not responded to the maximum dose of metformin monotherapy after four weeks (see Usual Starting Dose and Titration to Maintenance Dose). Refer to metformin package insert. - With concomitant glyburide and metformin therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. However, attempts should be made to identify the optimal dose of each drug needed to achieve this goal. With concomitant glyburide and metformin therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken (see PRECAUTIONS). Maximum Dose - Daily doses of more than 20 mg are not recommended. Dosage Interval - Once-a-day therapy is usually satisfactory. Some patients, particularly those receiving more than 10 mg daily, may have a more satisfactory response with twice-a-day dosage. Specific Patient Populations - Glyburide is not recommended for use in pregnancy or for use in pediatric patients. - In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see PRECAUTIONS). ### Monitoring - Therapeutic response to glyburide tablets should be monitored by frequent urine glucose tests and periodic blood glucose tests. Measurement of glycosylated hemoglobin levels may be helpful in some patients. - There is no fixed dosage regimen for the management of diabetes mellitus with glyburide tablets or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient’s blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient’s response to therapy. # IV Compatibility There is limited information regarding IV Compatibility of Glyburide in the drug label. # Overdosage - Overdosage of sulfonylureas, including glyburide tablets, can produce hypoglycemia. Mild hypoglycemic symptoms, without loss of consciousness or neurological findings, should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate which will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may recur after apparent clinical recovery. # Pharmacology ## Mechanism of Action - Glyburide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glyburide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs. The combination of glyburide and metformin may have a synergistic effect, since both agents act to improve glucose tolerance by different but complementary mechanisms. - Some patients who are initially responsive to oral hypoglycemic drugs, including glyburide, may become unresponsive or poorly responsive over time. Alternatively, glyburide tablets may be effective in some patients who have become unresponsive to one or more other sulfonylurea drugs. - In addition to its blood glucose lowering actions, glyburide produces a mild diuresis by enhancement of renal free water clearance. Disulfiram-like reactions have very rarely been reported in patients treated with glyburide tablets. ## Structure - Glyburide tablets USP contain glyburide, USP, which is an oral blood-glucose-lowering drug of the sulfonylurea class. Glyburide, USP is a white, crystalline compound. The chemical name for glyburide, USP is 1-((p-(2-(5-chloro-o-anisamido)ethyl)phenyl)-sulfonyl)-3-cyclohexylurea. It has the following structural formula: - C23H28ClN3O5S M.W. 493.99 - Each tablet, for oral administration, contains 1.25 mg, 2.5 mg or 5 mg of glyburide, USP. In addition, each tablet contains the following inactive ingredients: microcrystalline cellulose, pregelatinized corn starch, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate. In addition, the 2.5 mg contains FD&C yellow No. 6 aluminum lake and the 5 mg contains D&C yellow No. 10 aluminum lake, and FD&C blue No. 1 aluminum lake. ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Glyburide in the drug label. ## Pharmacokinetics - Single dose studies with glyburide tablets in normal subjects demonstrate significant absorption of glyburide within one hour, peak drug levels at about four hours, and low but detectable levels at twenty-four hours. Mean serum levels of glyburide, as reflected by areas under the serum concentration-time curve, increase in proportion to corresponding increases in dose. Multiple dose studies with glyburide in diabetic patients demonstrate drug level concentration-time curves similar to single dose studies, indicating no buildup of drug in tissue depots. The decrease of glyburide in the serum of normal healthy individuals is biphasic; the terminal half-life is about 10 hours. In single dose studies in fasting normal subjects, the degree and duration of blood glucose lowering is proportional to the dose administered and to the area under the drug level concentration-time curve. The blood glucose lowering effect persists for 24 hours following single morning doses in nonfasting diabetic patients. Under conditions of repeated administration in diabetic patients, however, there is no reliable correlation between blood drug levels and fasting blood glucose levels. A one year study of diabetic patients treated with glyburide showed no reliable correlation between administered dose and serum drug level. - The major metabolite of glyburide is the 4-trans-hydroxy derivative. A second metabolite, the 3-cis-hydroxy derivative, also occurs. These metabolites probably contribute no significant hypoglycemic action in humans since they are only weakly active (1/400th and 1/40th as active, respectively, as glyburide) in rabbits. - Glyburide is excreted as metabolites in the bile and urine, approximately 50% by each route. This dual excretory pathway is qualitatively different from that of other sulfonylureas, which are excreted primarily in the urine. - Sulfonylurea drugs are extensively bound to serum proteins. Displacement from protein binding sites by other drugs may lead to enhanced hypoglycemic action. In vitro, the protein binding exhibited by glyburide is predominantly non-ionic, whereas that of other sulfonylureas (chlorpropamide, tolbutamide, tolazamide) is predominantly ionic. Acidic drugs such as phenylbutazone, warfarin, and salicylates displace the ionic-binding sulfonylureas from serum proteins to a far greater extent than the non-ionic binding glyburide. It has not been shown that this difference in protein binding will result in fewer drug-drug interactions with glyburide tablets in clinical use. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, and Impairment of Fertility - Studies in rats at doses up to 300 mg/kg/day for 18 months showed no carcinogenic effects. Glyburide is nonmutagenic when studied in the Salmonella microsome test (Ames test) and in the DNA damage/alkaline elution assay. No drug related effects were noted in any of the criteria evaluated in the two year oncogenicity study of glyburide in mice. # Clinical Studies - There is limited information regarding Clinical Studies of Glyburide in the drug label. # How Supplied - Glyburide tablets USP, 1.25 mg are white, round, bi-convex, compressed tablets engraved with N horizontal bisect 342 on one side and 1.25 on the other side. They are supplied as follows: - Glyburide tablets USP, 2.5 mg are peach-colored, round, bi-convex, compressed tablets engraved with N horizontal bisect 343 on one side and 2.5 on the other side. They are supplied as follows: - NDC 42291-316-50 bottles of 500 - Glyburide tablets USP, 5 mg are light-green colored, round, bi-convex, compressed tablets engraved with N horizontal bisect 344 on one side and 5 on the other side. They are supplied as follows: - NDC 42291-317-10 bottles of 1000 ## Storage - Store at 20° to 25°C (68° to 77°F) . - Dispense in tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Keep container tightly closed. - KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be informed of the potential risks and advantages of glyburide and of alternative modes of therapy. They also should be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of urine and/or blood glucose. - The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Primary and secondary failure also should be explained. Physician Counseling Information for Patients - In initiating treatment for type 2 diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible. Use of glyburide or other antidiabetic medications must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitution or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of glyburide or other antidiabetic medications. Maintenance or discontinuation of glyburide or other antidiabetic medications should be based on clinical judgment using regular clinical and laboratory evaluations. # Precautions with Alcohol - Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose lowering drug is used. The risk of hypoglycemia may be increased with combination therapy. # Brand Names Diabeta, Micronase. # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Glyburide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Glyburide is a hypoglycemic agent that is FDA approved for the treatment of type 2 diabetes mellitus. Common adverse reactions include epigastric fullness, heartburn, nausea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information: - Patients should be retitrated when transferred from glyburide (micronized) tablets or other oral hypoglycemic agents (see PRECAUTIONS). - There is no fixed dosage regimen for the management of diabetes mellitus with glyburide tablets or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient’s blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient’s response to therapy. - Short-term administration of glyburide tablets may be sufficient during periods of transient loss of control in patients usually controlled well on diet. - Usual Starting Dose: - The usual starting dose of glyburide tablets is 2.5 to 5 mg daily, administered with breakfast or the first main meal. Those patients who may be more sensitive to hypoglycemic drugs should be started at 1.25 mg daily. (See PRECAUTIONS section for patients at increased risk.) Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary and drug regimen are more prone to exhibit unsatisfactory response to therapy. - Transfer From Other Hypoglycemic Therapy Patients Receiving Other Oral Antidiabetic Therapy: - Transfer of patients from other oral antidiabetic regimens to glyburide tablets should be done conservatively and the initial daily dose should be 2.5 to 5 mg. When transferring patients from oral hypoglycemic agents other than chlorpropamide to glyburide tablets, no transition period and no initial or priming dose are necessary. When transferring patients from chlorpropamide, particular care should be exercised during the first two weeks because the prolonged retention of chlorpropamide in the body and subsequent overlapping drug effects may provoke hypoglycemia. - Patients Receiving Insulin: - Some Type II diabetic patients being treated with insulin may respond satisfactorily to glyburide tablets. If the insulin dose is less than 20 units daily, substitution of glyburide tablets 2.5 to 5 mg as a single daily dose may be tried. If the insulin dose is between 20 and 40 units daily, the patient may be placed directly on glyburide tablets 5 mg daily as a single dose. If the insulin dose is more than 40 units daily, a transition period is required for conversion to glyburide tablets. In these patients, insulin dosage is decreased by 50% and glyburide tablets 5 mg daily is started. Please refer to Titration to Maintenance Dose for further explanation. - Patients Receiving Colesevelam: - When colesevelam is coadministered with glyburide, maximum plasma concentration and total exposure to glyburide is reduced. Therefore, glyburide tablets should be administered at least 4 hours prior to colesevelam. - Titration to Maintenance Dose: - The usual maintenance dose is in the range of 1.25 to 20 mg daily, which may be given as a single dose or in divided doses (see Dosage Interval). Dosage increases should be made in increments of no more than 2.5 mg at weekly intervals based upon the patient’s blood glucose response. - No exact dosage relationship exists between glyburide tablets and the other oral hypoglycemic agents. Although patients may be transferred from the maximum dose of other sulfonylureas, the maximum starting dose of 5 mg of glyburide tablets should be observed. A maintenance dose of 5 mg of glyburide tablets provides approximately the same degree of blood glucose control as 250 to 375 mg chlorpropamide, 250 to 375 mg tolazamide, 500 to 750 mg acetohexamide, or 1000 to 1500 mg tolbutamide. - When transferring patients receiving more than 40 units of insulin daily, they may be started on a daily dose of glyburide tablets 5 mg concomitantly with a 50% reduction in insulin dose. Progressive withdrawal of insulin and increase of glyburide tablets in increments of 1.25 to 2.5 mg every 2 to 10 days is then carried out. During this conversion period when both insulin and glyburide tablets are being used, hypoglycemia may rarely occur. During insulin withdrawal, patients should test their urine for glucose and acetone at least three times daily and report results to their physician. The appearance of persistent acetonuria with glycosuria indicates that the patient is a Type I diabetic who requires insulin therapy. - Concomitant Glyburide and Metformin Therapy: - Glyburide tablets should be added gradually to the dosing regimen of patients who have not responded to the maximum dose of metformin monotherapy after four weeks (see Usual Starting Dose and Titration to Maintenance Dose). Refer to metformin package insert. - With concomitant glyburide and metformin therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. However, attempts should be made to identify the optimal dose of each drug needed to achieve this goal. With concomitant glyburide and metformin therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken (see PRECAUTIONS). - Maximum Dose: - Daily doses of more than 20 mg are not recommended. - Dosage Interval: - Once-a-day therapy is usually satisfactory. Some patients, particularly those receiving more than 10 mg daily, may have a more satisfactory response with twice-a-day dosage. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Glyburide in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Glyburide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Glyburide FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Glyburide in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Glyburide in pediatric patients. # Contraindications - Glyburide tablets are contraindicated in patients with: - Known hypersensitivity or allergy to the drug. - Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin. - Type I diabetes mellitus. - Concomitant administration of bosentan. # Warnings ### Special warning on increased risk of cardiovascular mortality - The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups. - UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glyburide and of alternative modes of therapy. - Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure. ### Precautions - Bioavailability studies have demonstrated that micronized glyburide tablets 3 mg provide serum glyburide concentrations that are not bioequivalent to those from nonmicronized glyburide tablets 5 mg. Therefore, patients should be retitrated when transferred from micronized glyburide tablets or other oral hypoglycemic agents. General Macrovascular Outcomes - There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glyburide or any other anti-diabetic drug. Hypoglycemia - All sulfonylureas are capable of producing severe hypoglycemia. Proper patient selection and dosage and instructions are important to avoid hypoglycemic episodes. Renal or hepatic insufficiency may cause elevated drug levels of glyburide and the latter may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency, are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose lowering drug is used. The risk of hypoglycemia may be increased with combination therapy. Loss of Control of Blood Glucose - When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection or surgery, a loss of control may occur. At such times it may be necessary to discontinue glyburide and administer insulin. - The effectiveness of any hypoglycemic drug, including glyburide, in lowering blood glucose to a desired level decreases in many patients over a period of time which may be due to progression of the severity of diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when glyburide is first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure. Hemolytic Anemia - Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because glyburide belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In postmarketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency. Laboratory Tests - Therapeutic response to glyburide tablets should be monitored by frequent urine glucose tests and periodic blood glucose tests. Measurement of glycosylated hemoglobin levels may be helpful in some patients. # Adverse Reactions ## Clinical Trials Experience Hypoglycemia: See PRECAUTIONS and OVERDOSAGE - Gastrointestinal Reactions: Cholestatic jaundice and hepatitis may occur rarely which may progress to liver failure; glyburide tablets should be discontinued if this occurs. - Liver function abnormalities, including isolated transaminase elevations, have been reported. - Gastrointestinal disturbances, e.g., nausea, epigastric fullness, and heartburn are the most common reactions, having occurred in 1.8% of treated patients during clinical trials. They tend to be dose related and may disappear when dosage is reduced. - Dermatologic Reactions: Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions occurred in 1.5% of treated patients during clinical trials. These may be transient and may disappear despite continued use of glyburide; if skin reactions persist, the drug should be discontinued. - Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas. - Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia (see PRECAUTIONS), aplastic anemia, and pancytopenia have been reported with sulfonylureas. - Metabolic Reactions: Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas; however, hepatic porphyria has not been reported with glyburide and disulfiram-like reactions have been reported very rarely. - Cases of hyponatremia have been reported with glyburide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH. - Other Reactions: Changes in accommodation and/or blurred vision have been reported with glyburide and other sulfonylureas. These are thought to be related to fluctuation in glucose levels. - In addition to dermatologic reactions, allergic reactions such as angioedema, arthralgia, myalgia and vasculitis have been reported. ## Postmarketing Experience There is limited information regarding Glyburide Postmarketing Experience in the drug label. # Drug Interactions - The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including non-steroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such drugs are administered to a patient receiving glyburide, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving glyburide, the patient should be observed closely for loss of control. - An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore concomitant administration of glyburide tablets and bosentan is contraindicated. - Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving glyburide, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving glyburide, the patient should be observed closely for hypoglycemia. - A possible interaction between glyburide and ciprofloxacin, a fluoroquinolone antibiotic, has been reported, resulting in a potentiation of the hypoglycemic action of glyburide. The mechanism for this interaction is not known. - A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical or vaginal preparations of miconazole is not known. Metformin - In a single-dose interaction study in NIDDM subjects, decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain. Coadministration of glyburide and metformin did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Colesevelam - Concomitant administration of colesevelam and glyburide resulted in reductions in glyburide AUC and Cmax of 32% and 47%, respectively. The reductions in glyburide AUC and Cmax were 20% and 15%, respectively when administered 1 hour before, and not significantly changed (-7% and 4%, respectively) when administered 4 hours before colesevelam. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B Pregnancy category B - Reproduction studies have been performed in rats and rabbits at doses up to 500 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to glyburide. 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. - Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose as close to normal as possible. Nonteratogenic Effects - Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If glyburide is used during pregnancy, it should be discontinued at least two weeks before the expected delivery date. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glyburide in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Glyburide during labor and delivery. ### Nursing Mothers - Although it is not known whether glyburide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, 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. If the drug is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Elderly patients are particularly susceptible to the hypoglycemic action of glucose lowering drugs. Hypoglycemia may be difficult to recognize in the elderly (see PRECAUTIONS). The initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see DOSAGE AND ADMINISTRATION). Elderly patients are prone to develop renal insufficiency, which may put them at risk of hypoglycemia. Dose selection should include assessment of renal function. ### Gender - There is no FDA guidance on the use of Glyburide with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Glyburide with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Glyburide in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Glyburide in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Glyburide in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Glyburide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Patients should be retitrated when transferred from glyburide (micronized) tablets or other oral hypoglycemic agents (see PRECAUTIONS). - There is no fixed dosage regimen for the management of diabetes mellitus with glyburide tablets or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient’s blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient’s response to therapy. - Short-term administration of glyburide tablets may be sufficient during periods of transient loss of control in patients usually controlled well on diet. Usual Starting Dose - The usual starting dose of glyburide tablets is 2.5 to 5 mg daily, administered with breakfast or the first main meal. Those patients who may be more sensitive to hypoglycemic drugs should be started at 1.25 mg daily. (See PRECAUTIONS section for patients at increased risk.) Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary and drug regimen are more prone to exhibit unsatisfactory response to therapy. Transfer From Other Hypoglycemic Therapy Patients Receiving Other Oral Antidiabetic Therapy - Transfer of patients from other oral antidiabetic regimens to glyburide tablets should be done conservatively and the initial daily dose should be 2.5 to 5 mg. When transferring patients from oral hypoglycemic agents other than chlorpropamide to glyburide tablets, no transition period and no initial or priming dose are necessary. When transferring patients from chlorpropamide, particular care should be exercised during the first two weeks because the prolonged retention of chlorpropamide in the body and subsequent overlapping drug effects may provoke hypoglycemia. Patients Receiving Insulin - Some Type II diabetic patients being treated with insulin may respond satisfactorily to glyburide tablets. If the insulin dose is less than 20 units daily, substitution of glyburide tablets 2.5 to 5 mg as a single daily dose may be tried. If the insulin dose is between 20 and 40 units daily, the patient may be placed directly on glyburide tablets 5 mg daily as a single dose. If the insulin dose is more than 40 units daily, a transition period is required for conversion to glyburide tablets. In these patients, insulin dosage is decreased by 50% and glyburide tablets 5 mg daily is started. Please refer to Titration to Maintenance Dose for further explanation. Patients Receiving Colesevelam - When colesevelam is coadministered with glyburide, maximum plasma concentration and total exposure to glyburide is reduced. Therefore, glyburide tablets should be administered at least 4 hours prior to colesevelam. Titration to Maintenance Dose - The usual maintenance dose is in the range of 1.25 to 20 mg daily, which may be given as a single dose or in divided doses (see Dosage Interval). Dosage increases should be made in increments of no more than 2.5 mg at weekly intervals based upon the patient’s blood glucose response. - No exact dosage relationship exists between glyburide tablets and the other oral hypoglycemic agents. Although patients may be transferred from the maximum dose of other sulfonylureas, the maximum starting dose of 5 mg of glyburide tablets should be observed. A maintenance dose of 5 mg of glyburide tablets provides approximately the same degree of blood glucose control as 250 to 375 mg chlorpropamide, 250 to 375 mg tolazamide, 500 to 750 mg acetohexamide, or 1000 to 1500 mg tolbutamide. - When transferring patients receiving more than 40 units of insulin daily, they may be started on a daily dose of glyburide tablets 5 mg concomitantly with a 50% reduction in insulin dose. Progressive withdrawal of insulin and increase of glyburide tablets in increments of 1.25 to 2.5 mg every 2 to 10 days is then carried out. During this conversion period when both insulin and glyburide tablets are being used, hypoglycemia may rarely occur. During insulin withdrawal, patients should test their urine for glucose and acetone at least three times daily and report results to their physician. The appearance of persistent acetonuria with glycosuria indicates that the patient is a Type I diabetic who requires insulin therapy. Concomitant Glyburide and Metformin Therapy - Glyburide tablets should be added gradually to the dosing regimen of patients who have not responded to the maximum dose of metformin monotherapy after four weeks (see Usual Starting Dose and Titration to Maintenance Dose). Refer to metformin package insert. - With concomitant glyburide and metformin therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. However, attempts should be made to identify the optimal dose of each drug needed to achieve this goal. With concomitant glyburide and metformin therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken (see PRECAUTIONS). Maximum Dose - Daily doses of more than 20 mg are not recommended. Dosage Interval - Once-a-day therapy is usually satisfactory. Some patients, particularly those receiving more than 10 mg daily, may have a more satisfactory response with twice-a-day dosage. Specific Patient Populations - Glyburide is not recommended for use in pregnancy or for use in pediatric patients. - In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see PRECAUTIONS). ### Monitoring - Therapeutic response to glyburide tablets should be monitored by frequent urine glucose tests and periodic blood glucose tests. Measurement of glycosylated hemoglobin levels may be helpful in some patients. - There is no fixed dosage regimen for the management of diabetes mellitus with glyburide tablets or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient’s blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient’s response to therapy. # IV Compatibility There is limited information regarding IV Compatibility of Glyburide in the drug label. # Overdosage - Overdosage of sulfonylureas, including glyburide tablets, can produce hypoglycemia. Mild hypoglycemic symptoms, without loss of consciousness or neurological findings, should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate which will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may recur after apparent clinical recovery. # Pharmacology ## Mechanism of Action - Glyburide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glyburide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs. The combination of glyburide and metformin may have a synergistic effect, since both agents act to improve glucose tolerance by different but complementary mechanisms. - Some patients who are initially responsive to oral hypoglycemic drugs, including glyburide, may become unresponsive or poorly responsive over time. Alternatively, glyburide tablets may be effective in some patients who have become unresponsive to one or more other sulfonylurea drugs. - In addition to its blood glucose lowering actions, glyburide produces a mild diuresis by enhancement of renal free water clearance. Disulfiram-like reactions have very rarely been reported in patients treated with glyburide tablets. ## Structure - Glyburide tablets USP contain glyburide, USP, which is an oral blood-glucose-lowering drug of the sulfonylurea class. Glyburide, USP is a white, crystalline compound. The chemical name for glyburide, USP is 1-((p-(2-(5-chloro-o-anisamido)ethyl)phenyl)-sulfonyl)-3-cyclohexylurea. It has the following structural formula: - C23H28ClN3O5S M.W. 493.99 - Each tablet, for oral administration, contains 1.25 mg, 2.5 mg or 5 mg of glyburide, USP. In addition, each tablet contains the following inactive ingredients: microcrystalline cellulose, pregelatinized corn starch, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate. In addition, the 2.5 mg contains FD&C yellow No. 6 aluminum lake and the 5 mg contains D&C yellow No. 10 aluminum lake, and FD&C blue No. 1 aluminum lake. ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Glyburide in the drug label. ## Pharmacokinetics - Single dose studies with glyburide tablets in normal subjects demonstrate significant absorption of glyburide within one hour, peak drug levels at about four hours, and low but detectable levels at twenty-four hours. Mean serum levels of glyburide, as reflected by areas under the serum concentration-time curve, increase in proportion to corresponding increases in dose. Multiple dose studies with glyburide in diabetic patients demonstrate drug level concentration-time curves similar to single dose studies, indicating no buildup of drug in tissue depots. The decrease of glyburide in the serum of normal healthy individuals is biphasic; the terminal half-life is about 10 hours. In single dose studies in fasting normal subjects, the degree and duration of blood glucose lowering is proportional to the dose administered and to the area under the drug level concentration-time curve. The blood glucose lowering effect persists for 24 hours following single morning doses in nonfasting diabetic patients. Under conditions of repeated administration in diabetic patients, however, there is no reliable correlation between blood drug levels and fasting blood glucose levels. A one year study of diabetic patients treated with glyburide showed no reliable correlation between administered dose and serum drug level. - The major metabolite of glyburide is the 4-trans-hydroxy derivative. A second metabolite, the 3-cis-hydroxy derivative, also occurs. These metabolites probably contribute no significant hypoglycemic action in humans since they are only weakly active (1/400th and 1/40th as active, respectively, as glyburide) in rabbits. - Glyburide is excreted as metabolites in the bile and urine, approximately 50% by each route. This dual excretory pathway is qualitatively different from that of other sulfonylureas, which are excreted primarily in the urine. - Sulfonylurea drugs are extensively bound to serum proteins. Displacement from protein binding sites by other drugs may lead to enhanced hypoglycemic action. In vitro, the protein binding exhibited by glyburide is predominantly non-ionic, whereas that of other sulfonylureas (chlorpropamide, tolbutamide, tolazamide) is predominantly ionic. Acidic drugs such as phenylbutazone, warfarin, and salicylates displace the ionic-binding sulfonylureas from serum proteins to a far greater extent than the non-ionic binding glyburide. It has not been shown that this difference in protein binding will result in fewer drug-drug interactions with glyburide tablets in clinical use. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, and Impairment of Fertility - Studies in rats at doses up to 300 mg/kg/day for 18 months showed no carcinogenic effects. Glyburide is nonmutagenic when studied in the Salmonella microsome test (Ames test) and in the DNA damage/alkaline elution assay. No drug related effects were noted in any of the criteria evaluated in the two year oncogenicity study of glyburide in mice. # Clinical Studies - There is limited information regarding Clinical Studies of Glyburide in the drug label. # How Supplied - Glyburide tablets USP, 1.25 mg are white, round, bi-convex, compressed tablets engraved with N horizontal bisect 342 on one side and 1.25 on the other side. They are supplied as follows: - Glyburide tablets USP, 2.5 mg are peach-colored, round, bi-convex, compressed tablets engraved with N horizontal bisect 343 on one side and 2.5 on the other side. They are supplied as follows: - NDC 42291-316-50 bottles of 500 - Glyburide tablets USP, 5 mg are light-green colored, round, bi-convex, compressed tablets engraved with N horizontal bisect 344 on one side and 5 on the other side. They are supplied as follows: - NDC 42291-317-10 bottles of 1000 ## Storage - Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. - Dispense in tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Keep container tightly closed. - KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be informed of the potential risks and advantages of glyburide and of alternative modes of therapy. They also should be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of urine and/or blood glucose. - The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Primary and secondary failure also should be explained. Physician Counseling Information for Patients - In initiating treatment for type 2 diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible. Use of glyburide or other antidiabetic medications must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitution or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of glyburide or other antidiabetic medications. Maintenance or discontinuation of glyburide or other antidiabetic medications should be based on clinical judgment using regular clinical and laboratory evaluations. # Precautions with Alcohol - Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose lowering drug is used. The risk of hypoglycemia may be increased with combination therapy. # Brand Names Diabeta, Micronase. # Look-Alike Drug Names - A® — B®[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Glibenclamide
9b095cade4472ecee309078e34de81d87a0065f6	wikidoc	Glipizide	Glipizide # 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 Glipizide is a hypoglycemic agent that is FDA approved for the treatment of type 2 diabetes mellitus. Common adverse reactions include hypoglycemia, constipation, diarrhea, flatulence, nausea, asthenia, dizziness, feeling nervous, headache, tremor. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Glipizide tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. - Dosing Information - There is no fixed dosage regimen for the management of diabetes mellitus with glipizide or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient’s blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood-glucose-lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient’s response to therapy. - Short-term administration of glipizide may be sufficient during periods of transient loss of control in patients usually controlled well on diet. - In general, glipizide should be given approximately 30 minutes before a meal to achieve the greatest reduction in postprandial hyperglycemia. - Initial Dose - The recommended starting dose is 5 mg, given before breakfast. Geriatric patients or those with liver disease may be started on 2.5 mg. - Titration - Dosage adjustments should ordinarily be in increments of 2.5 to 5 mg, as determined by blood glucose response. At least several days should elapse between titration steps. If response to a single dose is not satisfactory, dividing that dose may prove effective. The maximum recommended once daily dose is 15 mg. Doses above 15 mg should ordinarily be divided and given before meals of adequate caloric content. The maximum recommended total daily dose is 40 mg. - Maintenance - Some patients may be effectively controlled on a once-a-day regimen, while others show better response with divided dosing. Total daily doses above 15 mg should ordinarily be divided. Total daily doses above 30 mg have been safely given on a b.i.d. basis to long-term patients. - In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see PRECAUTIONS section). - Patients Receiving Insulin - As with other sulfonylurea-class hypoglycemics, many stable non-insulin-dependent diabetic patients receiving insulin may be safely placed on glipizide. When transferring patients from insulin to glipizide, the following general guidelines should be considered: - For patients whose daily insulin requirement is 20 units or less, insulin may be discontinued and glipizide therapy may begin at usual dosages. Several days should elapse between glipizide titration steps. - For patients whose daily insulin requirement is greater than 20 units, the insulin dose should be reduced by 50% and glipizide therapy may begin at usual dosages. Subsequent reductions in insulin dosage should depend on individual patient response. Several days should elapse between glipizide titration steps. - During the insulin withdrawal period, the patient should test urine samples for sugar and ketone bodies at least three times daily. Patients should be instructed to contact the prescriber immediately if these tests are abnormal. In some cases, especially when patient has been receiving greater than 40 units of insulin daily, it may be advisable to consider hospitalization during the transition period. - Patients Receiving Other Oral Hypoglycemic Agents - As with other sulfonylurea-class hypoglycemics, no transition period is necessary when transferring patients to glipizide. Patients should be observed carefully (1 to 2 weeks) for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to glipizide due to potential overlapping of drug effect. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Glipizide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Glipizide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Glipizide FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Glipizide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Glipizide in pediatric patients. # Contraindications - Glipizide tablets are contraindicated in patients with: - Known hypersensitivity to the drug. - Type 1 diabetes mellitus, diabetic ketoacidosis, with or without coma. This condition should be treated with insulin. # Warnings SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY - The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes, 19, supp. 2: 747-830, 1970). - UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2-1/2 times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glipizide and of alternative modes of therapy. - Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure. ### Precautions General Macrovascular Outcomes - There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glipizide tablets or any other anti-diabetic drug. Renal and Hepatic Disease - The metabolism and excretion of glipizide may be slowed in patients with impaired renal and/or hepatic function. If hypoglycemia should occur in such patients, it may be prolonged and appropriate management should be instituted. Hypoglycemia - All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Renal or hepatic insufficiency may cause elevated blood levels of glipizide and the latter may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency, are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used. Loss of Control of Blood Glucose - When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. At such times, it may be necessary to discontinue glipizide and administer insulin. - The effectiveness of any oral hypoglycemic drug, including glipizide, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when first given. Hemolytic Anemia - Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because glipizide belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In postmarketing reports hemolytic anemia has also been reported in patients who did not have known G6PD deficiency. Laboratory Tests - Blood and urine glucose should be monitored periodically. Measurement of glycosylated hemoglobin may be useful. # Adverse Reactions ## Clinical Trials Experience - In U.S. and foreign controlled studies, the frequency of serious adverse reactions reported was very low. Of 702 patients, 11.8% reported adverse reactions and in only 1.5% was glipizide discontinued. Hypoglycemia - See PRECAUTIONS and OVERDOSAGE sections. Gastrointestinal - Gastrointestinal disturbances are the most common reactions. Gastrointestinal complaints were reported with the following approximate incidence: nausea and diarrhea, one in seventy; constipation and gastralgia, one in one hundred. They appear to be dose-related and may disappear on division or reduction of dosage. Cholestatic jaundice may occur rarely with sulfonylureas: glipizide should be discontinued if this occurs. Dermatologic - Allergic skin reactions including erythema, morbilliform or maculopapular eruptions, urticaria, pruritus, and eczema have been reported in about one in seventy patients. These may be transient and may disappear despite continued use of glipizide; if skin reactions persist, the drug should be discontinued. Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas. Hematologic - Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia (see PRECAUTIONS), aplastic anemia, and pancytopenia have been reported with sulfonylureas. Metabolic - Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas. In the mouse, glipizide pretreatment did not cause an accumulation of acetaldehyde after ethanol administration. Clinical experience to date has shown that glipizide has an extremely low incidence of disulfiram-like alcohol reactions. Endocrine Reactions - Cases of hyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion have been reported with this and other sulfonylureas. Miscellaneous - Dizziness, drowsiness, and headache have each been reported in about one in fifty patients treated with glipizide. They are usually transient and seldom require discontinuance of therapy. Laboratory Tests - The pattern of laboratory test abnormalities observed with glipizide was similar to that for other sulfonylureas. Occasional mild to moderate elevations of SGOT, LDH, alkaline phosphatase, BUN and creatinine were noted. One case of jaundice was reported. The relationship of these abnormalities to glipizide is uncertain, and they have rarely been associated with clinical symptoms. ## Postmarketing Experience - The following adverse events have been reported in post-marketing surveillance: Hepatobiliary - Cholestatic and hepatocellular forms of liver injury accompanied by jaundice have been reported rarely in association with glipizide; glipizide should be discontinued if this occurs. # Drug Interactions - The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents, some azoles, and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta-adrenergic blocking agents. When such drugs are administered to a patient receiving glipizide, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving glipizide, the patient should be observed closely for loss of control. In vitro binding studies with human serum proteins indicate that glipizide binds differently than tolbutamide and does not interact with salicylate or dicumarol. However, caution must be exercised in extrapolating these findings to the clinical situation and in the use of glipizide with these drugs. - Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving glipizide, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving glipizide, the patient should be observed closely for hypoglycemia. - A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known. The effect of concomitant administration of fluconazole and glipizide has been demonstrated in a placebo-controlled crossover study in normal volunteers. All subjects received glipizide alone and following treatment with 100 mg of fluconazole as a single daily oral dose for 7 days. The mean percentage increase in the glipizide AUC after fluconazole administration was 56.9% (range: 35 to 81). # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Glipizide was found to be mildly fetotoxic in rat reproductive studies at all dose levels (5 to 50 mg/kg). This fetotoxicity has been similarly noted with other sulfonylureas, such as tolbutamide and tolazamide. The effect is perinatal and believed to be directly related to the pharmacologic (hypoglycemic) action of glipizide. In studies in rats and rabbits no teratogenic effects were found. There are no adequate and well controlled studies in pregnant women. Glipizide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Nonteratogenic Effects - Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If glipizide is used during pregnancy, it should be discontinued at least one month before the expected delivery date. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glipizide in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Glipizide during labor and delivery. ### Nursing Mothers - Although it is not known whether glipizide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, 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. If the drug is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered. ### Pediatric Use - Safety and effectiveness in children have not been established. ### Geriatic Use - A determination has not been made whether controlled clinical studies of glipizide included sufficient numbers of subjects aged 65 and over to define a difference in response 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 Glipizide with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Glipizide with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Glipizide in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Glipizide in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Glipizide in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Glipizide in patients who are immunocompromised. # Administration and Monitoring ### Administration - There is no fixed dosage regimen for the management of diabetes mellitus with glipizide or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient’s blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood-glucose-lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient’s response to therapy. - Short-term administration of glipizide may be sufficient during periods of transient loss of control in patients usually controlled well on diet. - In general, glipizide should be given approximately 30 minutes before a meal to achieve the greatest reduction in postprandial hyperglycemia. Initial Dose - The recommended starting dose is 5 mg, given before breakfast. Geriatric patients or those with liver disease may be started on 2.5 mg. Titration - Dosage adjustments should ordinarily be in increments of 2.5 to 5 mg, as determined by blood glucose response. At least several days should elapse between titration steps. If response to a single dose is not satisfactory, dividing that dose may prove effective. The maximum recommended once daily dose is 15 mg. Doses above 15 mg should ordinarily be divided and given before meals of adequate caloric content. The maximum recommended total daily dose is 40 mg. Maintenance - Some patients may be effectively controlled on a once-a-day regimen, while others show better response with divided dosing. Total daily doses above 15 mg should ordinarily be divided. Total daily doses above 30 mg have been safely given on a b.i.d. basis to long-term patients. - In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see PRECAUTIONS section). Patients Receiving Insulin - As with other sulfonylurea-class hypoglycemics, many stable non-insulin-dependent diabetic patients receiving insulin may be safely placed on glipizide. When transferring patients from insulin to glipizide, the following general guidelines should be considered: - For patients whose daily insulin requirement is 20 units or less, insulin may be discontinued and glipizide therapy may begin at usual dosages. Several days should elapse between glipizide titration steps. - For patients whose daily insulin requirement is greater than 20 units, the insulin dose should be reduced by 50% and glipizide therapy may begin at usual dosages. Subsequent reductions in insulin dosage should depend on individual patient response. Several days should elapse between glipizide titration steps. - During the insulin withdrawal period, the patient should test urine samples for sugar and ketone bodies at least three times daily. Patients should be instructed to contact the prescriber immediately if these tests are abnormal. In some cases, especially when patient has been receiving greater than 40 units of insulin daily, it may be advisable to consider hospitalization during the transition period. Patients Receiving Other Oral Hypoglycemic Agents - As with other sulfonylurea-class hypoglycemics, no transition period is necessary when transferring patients to glipizide. Patients should be observed carefully (1 to 2 weeks) for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to glipizide due to potential overlapping of drug effect. ### Monitoring - Blood and urine glucose should be monitored periodically. Measurement of glycosylated hemoglobin may be useful. # IV Compatibility - There is limited information regarding IV Compatibility of Glipizide in the drug label. # Overdosage - There is no well documented experience with glipizide overdosage. The acute oral toxicity was extremely low in all species tested (LD50 greater than 4 g/kg). - Overdosage of sulfonylureas including glipizide can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery. Clearance of glipizide from plasma would be prolonged in persons with liver disease. Because of the extensive protein binding of glipizide, dialysis is unlikely to be of benefit. # Pharmacology ## Mechanism of Action - The primary mode of action of glipizide in experimental animals appears to be the stimulation of insulin secretion from the beta cells of pancreatic islet tissue and is thus dependent on functioning beta cells in the pancreatic islets. In humans glipizide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glipizide lowers blood glucose during long-term administration has not been clearly established. In man, stimulation of insulin secretion by glipizide in response to a meal is undoubtedly of major importance. Fasting insulin levels are not elevated even on long-term glipizide administration, but the postprandial insulin response continues to be enhanced after at least 6 months of treatment. The insulinotropic response to a meal occurs within 30 minutes after an oral dose of glipizide in diabetic patients, but elevated insulin levels do not persist beyond the time of the meal challenge. Extrapancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. - Blood sugar control persists in some patients for up to 24 hours after a single dose of glipizide, even though plasma levels have declined to a small fraction of peak levels by that time (see Pharmacokinetics below). - Some patients fail to respond initially, or gradually lose their responsiveness to sulfonylurea drugs, including glipizide. Alternatively, glipizide may be effective in some patients who have not responded or have ceased to respond to other sulfonylureas. Other Effects - It has been shown that glipizide therapy was effective in controlling blood sugar without deleterious changes in the plasma lipoprotein profiles of patients treated for NIDDM. - In a placebo-controlled, crossover study in normal volunteers, glipizide had no antidiuretic activity, and, in fact, led to a slight increase in free water clearance. ## Structure - Glipizide is an oral blood-glucose-lowering drug of the sulfonylurea class. - The Chemical Abstracts name of glipizide is 1-cyclohexyl-3-((p-(2-(5-methylpyrazine-carboxamido)ethyl)phenyl)sulfonyl)urea. It has the following structural formula: - Glipizide is a whitish, odorless powder with a pKa of 5.9. It is insoluble in water and alcohols, but soluble in 0.1 N NaOH; it is freely soluble in dimethylformamide. - Each tablet for oral administration contains 5 mg or 10 mg of glipizide. Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose (monohydrate), magnesium stearate, microcrystalline cellulose, and starch (corn). ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Glipizide in the drug label. ## Pharmacokinetics - Gastrointestinal absorption of glipizide in man is uniform, rapid, and essentially complete. Peak plasma concentrations occur 1 to 3 hours after a single oral dose. The half-life of elimination ranges from 2 to 4 hours in normal subjects, whether given intravenously or orally. The metabolic and excretory patterns are similar with the two routes of administration, indicating that first-pass metabolism is not significant. Glipizide does not accumulate in plasma on repeated oral administration. Total absorption and disposition of an oral dose was unaffected by food in normal volunteers, but absorption was delayed by about 40 minutes. Thus glipizide was more effective when administered about 30 minutes before, rather than with, a test meal in diabetic patients. Protein binding was studied in serum from volunteers who received either oral or intravenous glipizide and found to be 98 to 99% one hour after either route of administration. The apparent volume of distribution of glipizide after intravenous administration was 11 liters, indicative of localization within the extracellular fluid compartment. In mice no glipizide or metabolites were detectable autoradiographically in the brain or spinal cord of males or females, nor in the fetuses of pregnant females. In another study, however, very small amounts of radioactivity were detected in the fetuses of rats given labelled drug. - The metabolism of glipizide is extensive and occurs mainly in the liver. The primary metabolites are inactive hydroxylation products and polar conjugates and are excreted mainly in the urine. Less than 10% unchanged glipizide is found in the urine. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - A twenty month study in rats and an eighteen month study in mice at doses up to 75 times the maximum human dose revealed no evidence of drug-related carcinogenicity. Bacterial and in vivo mutagenicity tests were uniformly negative. Studies in rats of both sexes at doses up to 75 times the human dose showed no effects on fertility. # Clinical Studies - There is limited information regarding Clinical Studies of Glipizide in the drug label. # How Supplied - Glipizide tablets, USP for oral administration are available as: - 5 mg: round, white, scored tablets, debossed GG 771 on one side and plain on the reverse side, and supplied as: - NDC 0904-6124-61 blister pack of 100 - 10 mg: round, white, scored tablets, debossed GG 772 on one side and plain on the reverse side, and supplied as: - NDC 0904-6123-61 blister pack of 100 ## Storage - Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature). - Dispense in a tight, light-resistant container. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Information for Patients - Patients should be informed of the potential risks and advantages of glipizide and of alternative modes of therapy. They should also be informed about the importance of adhering to dietary instructions, of a regular exercise program, and of regular testing of urine and/or blood glucose. - The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Primary and secondary failure should also be explained. Physician Counseling Information for Patients - In initiating treatment for type 2 diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible. Use of glipizide tablets or other antidiabetic medications must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitution or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of glipizide tablets or other antidiabetic medications. Maintenance or discontinuation of glipizide tablets or other antidiabetic medications should be based on clinical judgment using regular clinical and laboratory evaluations. # Precautions with Alcohol - Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used. # Brand Names Glucotrol, Glucotrol XL. # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Glipizide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Glipizide is a hypoglycemic agent that is FDA approved for the treatment of type 2 diabetes mellitus. Common adverse reactions include hypoglycemia, constipation, diarrhea, flatulence, nausea, asthenia, dizziness, feeling nervous, headache, tremor. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Glipizide tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. - Dosing Information - There is no fixed dosage regimen for the management of diabetes mellitus with glipizide or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient’s blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood-glucose-lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient’s response to therapy. - Short-term administration of glipizide may be sufficient during periods of transient loss of control in patients usually controlled well on diet. - In general, glipizide should be given approximately 30 minutes before a meal to achieve the greatest reduction in postprandial hyperglycemia. - Initial Dose - The recommended starting dose is 5 mg, given before breakfast. Geriatric patients or those with liver disease may be started on 2.5 mg. - Titration - Dosage adjustments should ordinarily be in increments of 2.5 to 5 mg, as determined by blood glucose response. At least several days should elapse between titration steps. If response to a single dose is not satisfactory, dividing that dose may prove effective. The maximum recommended once daily dose is 15 mg. Doses above 15 mg should ordinarily be divided and given before meals of adequate caloric content. The maximum recommended total daily dose is 40 mg. - Maintenance - Some patients may be effectively controlled on a once-a-day regimen, while others show better response with divided dosing. Total daily doses above 15 mg should ordinarily be divided. Total daily doses above 30 mg have been safely given on a b.i.d. basis to long-term patients. - In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see PRECAUTIONS section). - Patients Receiving Insulin - As with other sulfonylurea-class hypoglycemics, many stable non-insulin-dependent diabetic patients receiving insulin may be safely placed on glipizide. When transferring patients from insulin to glipizide, the following general guidelines should be considered: - For patients whose daily insulin requirement is 20 units or less, insulin may be discontinued and glipizide therapy may begin at usual dosages. Several days should elapse between glipizide titration steps. - For patients whose daily insulin requirement is greater than 20 units, the insulin dose should be reduced by 50% and glipizide therapy may begin at usual dosages. Subsequent reductions in insulin dosage should depend on individual patient response. Several days should elapse between glipizide titration steps. - During the insulin withdrawal period, the patient should test urine samples for sugar and ketone bodies at least three times daily. Patients should be instructed to contact the prescriber immediately if these tests are abnormal. In some cases, especially when patient has been receiving greater than 40 units of insulin daily, it may be advisable to consider hospitalization during the transition period. - Patients Receiving Other Oral Hypoglycemic Agents - As with other sulfonylurea-class hypoglycemics, no transition period is necessary when transferring patients to glipizide. Patients should be observed carefully (1 to 2 weeks) for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to glipizide due to potential overlapping of drug effect. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Glipizide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Glipizide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Glipizide FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Glipizide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Glipizide in pediatric patients. # Contraindications - Glipizide tablets are contraindicated in patients with: - Known hypersensitivity to the drug. - Type 1 diabetes mellitus, diabetic ketoacidosis, with or without coma. This condition should be treated with insulin. # Warnings SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY - The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes, 19, supp. 2: 747-830, 1970). - UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2-1/2 times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glipizide and of alternative modes of therapy. - Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure. ### Precautions General Macrovascular Outcomes - There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glipizide tablets or any other anti-diabetic drug. Renal and Hepatic Disease - The metabolism and excretion of glipizide may be slowed in patients with impaired renal and/or hepatic function. If hypoglycemia should occur in such patients, it may be prolonged and appropriate management should be instituted. Hypoglycemia - All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Renal or hepatic insufficiency may cause elevated blood levels of glipizide and the latter may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency, are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used. Loss of Control of Blood Glucose - When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. At such times, it may be necessary to discontinue glipizide and administer insulin. - The effectiveness of any oral hypoglycemic drug, including glipizide, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when first given. Hemolytic Anemia - Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because glipizide belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In postmarketing reports hemolytic anemia has also been reported in patients who did not have known G6PD deficiency. Laboratory Tests - Blood and urine glucose should be monitored periodically. Measurement of glycosylated hemoglobin may be useful. # Adverse Reactions ## Clinical Trials Experience - In U.S. and foreign controlled studies, the frequency of serious adverse reactions reported was very low. Of 702 patients, 11.8% reported adverse reactions and in only 1.5% was glipizide discontinued. Hypoglycemia - See PRECAUTIONS and OVERDOSAGE sections. Gastrointestinal - Gastrointestinal disturbances are the most common reactions. Gastrointestinal complaints were reported with the following approximate incidence: nausea and diarrhea, one in seventy; constipation and gastralgia, one in one hundred. They appear to be dose-related and may disappear on division or reduction of dosage. Cholestatic jaundice may occur rarely with sulfonylureas: glipizide should be discontinued if this occurs. Dermatologic - Allergic skin reactions including erythema, morbilliform or maculopapular eruptions, urticaria, pruritus, and eczema have been reported in about one in seventy patients. These may be transient and may disappear despite continued use of glipizide; if skin reactions persist, the drug should be discontinued. Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas. Hematologic - Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia (see PRECAUTIONS), aplastic anemia, and pancytopenia have been reported with sulfonylureas. Metabolic - Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas. In the mouse, glipizide pretreatment did not cause an accumulation of acetaldehyde after ethanol administration. Clinical experience to date has shown that glipizide has an extremely low incidence of disulfiram-like alcohol reactions. Endocrine Reactions - Cases of hyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion have been reported with this and other sulfonylureas. Miscellaneous - Dizziness, drowsiness, and headache have each been reported in about one in fifty patients treated with glipizide. They are usually transient and seldom require discontinuance of therapy. Laboratory Tests - The pattern of laboratory test abnormalities observed with glipizide was similar to that for other sulfonylureas. Occasional mild to moderate elevations of SGOT, LDH, alkaline phosphatase, BUN and creatinine were noted. One case of jaundice was reported. The relationship of these abnormalities to glipizide is uncertain, and they have rarely been associated with clinical symptoms. ## Postmarketing Experience - The following adverse events have been reported in post-marketing surveillance: Hepatobiliary - Cholestatic and hepatocellular forms of liver injury accompanied by jaundice have been reported rarely in association with glipizide; glipizide should be discontinued if this occurs. # Drug Interactions - The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents, some azoles, and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta-adrenergic blocking agents. When such drugs are administered to a patient receiving glipizide, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving glipizide, the patient should be observed closely for loss of control. In vitro binding studies with human serum proteins indicate that glipizide binds differently than tolbutamide and does not interact with salicylate or dicumarol. However, caution must be exercised in extrapolating these findings to the clinical situation and in the use of glipizide with these drugs. - Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving glipizide, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving glipizide, the patient should be observed closely for hypoglycemia. - A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known. The effect of concomitant administration of fluconazole and glipizide has been demonstrated in a placebo-controlled crossover study in normal volunteers. All subjects received glipizide alone and following treatment with 100 mg of fluconazole as a single daily oral dose for 7 days. The mean percentage increase in the glipizide AUC after fluconazole administration was 56.9% (range: 35 to 81). # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Glipizide was found to be mildly fetotoxic in rat reproductive studies at all dose levels (5 to 50 mg/kg). This fetotoxicity has been similarly noted with other sulfonylureas, such as tolbutamide and tolazamide. The effect is perinatal and believed to be directly related to the pharmacologic (hypoglycemic) action of glipizide. In studies in rats and rabbits no teratogenic effects were found. There are no adequate and well controlled studies in pregnant women. Glipizide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Nonteratogenic Effects - Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If glipizide is used during pregnancy, it should be discontinued at least one month before the expected delivery date. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glipizide in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Glipizide during labor and delivery. ### Nursing Mothers - Although it is not known whether glipizide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, 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. If the drug is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered. ### Pediatric Use - Safety and effectiveness in children have not been established. ### Geriatic Use - A determination has not been made whether controlled clinical studies of glipizide included sufficient numbers of subjects aged 65 and over to define a difference in response 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 Glipizide with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Glipizide with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Glipizide in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Glipizide in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Glipizide in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Glipizide in patients who are immunocompromised. # Administration and Monitoring ### Administration - There is no fixed dosage regimen for the management of diabetes mellitus with glipizide or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient’s blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood-glucose-lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient’s response to therapy. - Short-term administration of glipizide may be sufficient during periods of transient loss of control in patients usually controlled well on diet. - In general, glipizide should be given approximately 30 minutes before a meal to achieve the greatest reduction in postprandial hyperglycemia. Initial Dose - The recommended starting dose is 5 mg, given before breakfast. Geriatric patients or those with liver disease may be started on 2.5 mg. Titration - Dosage adjustments should ordinarily be in increments of 2.5 to 5 mg, as determined by blood glucose response. At least several days should elapse between titration steps. If response to a single dose is not satisfactory, dividing that dose may prove effective. The maximum recommended once daily dose is 15 mg. Doses above 15 mg should ordinarily be divided and given before meals of adequate caloric content. The maximum recommended total daily dose is 40 mg. Maintenance - Some patients may be effectively controlled on a once-a-day regimen, while others show better response with divided dosing. Total daily doses above 15 mg should ordinarily be divided. Total daily doses above 30 mg have been safely given on a b.i.d. basis to long-term patients. - In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see PRECAUTIONS section). Patients Receiving Insulin - As with other sulfonylurea-class hypoglycemics, many stable non-insulin-dependent diabetic patients receiving insulin may be safely placed on glipizide. When transferring patients from insulin to glipizide, the following general guidelines should be considered: - For patients whose daily insulin requirement is 20 units or less, insulin may be discontinued and glipizide therapy may begin at usual dosages. Several days should elapse between glipizide titration steps. - For patients whose daily insulin requirement is greater than 20 units, the insulin dose should be reduced by 50% and glipizide therapy may begin at usual dosages. Subsequent reductions in insulin dosage should depend on individual patient response. Several days should elapse between glipizide titration steps. - During the insulin withdrawal period, the patient should test urine samples for sugar and ketone bodies at least three times daily. Patients should be instructed to contact the prescriber immediately if these tests are abnormal. In some cases, especially when patient has been receiving greater than 40 units of insulin daily, it may be advisable to consider hospitalization during the transition period. Patients Receiving Other Oral Hypoglycemic Agents - As with other sulfonylurea-class hypoglycemics, no transition period is necessary when transferring patients to glipizide. Patients should be observed carefully (1 to 2 weeks) for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to glipizide due to potential overlapping of drug effect. ### Monitoring - Blood and urine glucose should be monitored periodically. Measurement of glycosylated hemoglobin may be useful. - # IV Compatibility - There is limited information regarding IV Compatibility of Glipizide in the drug label. # Overdosage - There is no well documented experience with glipizide overdosage. The acute oral toxicity was extremely low in all species tested (LD50 greater than 4 g/kg). - Overdosage of sulfonylureas including glipizide can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery. Clearance of glipizide from plasma would be prolonged in persons with liver disease. Because of the extensive protein binding of glipizide, dialysis is unlikely to be of benefit. # Pharmacology ## Mechanism of Action - The primary mode of action of glipizide in experimental animals appears to be the stimulation of insulin secretion from the beta cells of pancreatic islet tissue and is thus dependent on functioning beta cells in the pancreatic islets. In humans glipizide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glipizide lowers blood glucose during long-term administration has not been clearly established. In man, stimulation of insulin secretion by glipizide in response to a meal is undoubtedly of major importance. Fasting insulin levels are not elevated even on long-term glipizide administration, but the postprandial insulin response continues to be enhanced after at least 6 months of treatment. The insulinotropic response to a meal occurs within 30 minutes after an oral dose of glipizide in diabetic patients, but elevated insulin levels do not persist beyond the time of the meal challenge. Extrapancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. - Blood sugar control persists in some patients for up to 24 hours after a single dose of glipizide, even though plasma levels have declined to a small fraction of peak levels by that time (see Pharmacokinetics below). - Some patients fail to respond initially, or gradually lose their responsiveness to sulfonylurea drugs, including glipizide. Alternatively, glipizide may be effective in some patients who have not responded or have ceased to respond to other sulfonylureas. Other Effects - It has been shown that glipizide therapy was effective in controlling blood sugar without deleterious changes in the plasma lipoprotein profiles of patients treated for NIDDM. - In a placebo-controlled, crossover study in normal volunteers, glipizide had no antidiuretic activity, and, in fact, led to a slight increase in free water clearance. ## Structure - Glipizide is an oral blood-glucose-lowering drug of the sulfonylurea class. - The Chemical Abstracts name of glipizide is 1-cyclohexyl-3-((p-(2-(5-methylpyrazine-carboxamido)ethyl)phenyl)sulfonyl)urea. It has the following structural formula: - Glipizide is a whitish, odorless powder with a pKa of 5.9. It is insoluble in water and alcohols, but soluble in 0.1 N NaOH; it is freely soluble in dimethylformamide. - Each tablet for oral administration contains 5 mg or 10 mg of glipizide. Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose (monohydrate), magnesium stearate, microcrystalline cellulose, and starch (corn). ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Glipizide in the drug label. ## Pharmacokinetics - Gastrointestinal absorption of glipizide in man is uniform, rapid, and essentially complete. Peak plasma concentrations occur 1 to 3 hours after a single oral dose. The half-life of elimination ranges from 2 to 4 hours in normal subjects, whether given intravenously or orally. The metabolic and excretory patterns are similar with the two routes of administration, indicating that first-pass metabolism is not significant. Glipizide does not accumulate in plasma on repeated oral administration. Total absorption and disposition of an oral dose was unaffected by food in normal volunteers, but absorption was delayed by about 40 minutes. Thus glipizide was more effective when administered about 30 minutes before, rather than with, a test meal in diabetic patients. Protein binding was studied in serum from volunteers who received either oral or intravenous glipizide and found to be 98 to 99% one hour after either route of administration. The apparent volume of distribution of glipizide after intravenous administration was 11 liters, indicative of localization within the extracellular fluid compartment. In mice no glipizide or metabolites were detectable autoradiographically in the brain or spinal cord of males or females, nor in the fetuses of pregnant females. In another study, however, very small amounts of radioactivity were detected in the fetuses of rats given labelled drug. - The metabolism of glipizide is extensive and occurs mainly in the liver. The primary metabolites are inactive hydroxylation products and polar conjugates and are excreted mainly in the urine. Less than 10% unchanged glipizide is found in the urine. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - A twenty month study in rats and an eighteen month study in mice at doses up to 75 times the maximum human dose revealed no evidence of drug-related carcinogenicity. Bacterial and in vivo mutagenicity tests were uniformly negative. Studies in rats of both sexes at doses up to 75 times the human dose showed no effects on fertility. # Clinical Studies - There is limited information regarding Clinical Studies of Glipizide in the drug label. # How Supplied - Glipizide tablets, USP for oral administration are available as: - 5 mg: round, white, scored tablets, debossed GG 771 on one side and plain on the reverse side, and supplied as: - NDC 0904-6124-61 blister pack of 100 - 10 mg: round, white, scored tablets, debossed GG 772 on one side and plain on the reverse side, and supplied as: - NDC 0904-6123-61 blister pack of 100 ## Storage - Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature). - Dispense in a tight, light-resistant container. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Information for Patients - Patients should be informed of the potential risks and advantages of glipizide and of alternative modes of therapy. They should also be informed about the importance of adhering to dietary instructions, of a regular exercise program, and of regular testing of urine and/or blood glucose. - The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Primary and secondary failure should also be explained. Physician Counseling Information for Patients - In initiating treatment for type 2 diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible. Use of glipizide tablets or other antidiabetic medications must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitution or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of glipizide tablets or other antidiabetic medications. Maintenance or discontinuation of glipizide tablets or other antidiabetic medications should be based on clinical judgment using regular clinical and laboratory evaluations. # Precautions with Alcohol - Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used. # Brand Names Glucotrol, Glucotrol XL. # Look-Alike Drug Names - A® — B®[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Glipizide
4aa3a0073188cd8931c3b38de32e628bcfda0a81	wikidoc	Glutamine	Glutamine # Overview Glutamine (abbreviated as Gln or Q; Glx or Z represents either glutamate or glutamic acid) is one of the 20 amino acids encoded by the standard genetic code. Its side chain is an amide formed by replacing the side-chain hydroxyl of glutamic acid with an amine functional group. It can therefore be considered the amide of the acidic amino acid glutamate. Its codons are CAA and CAG. # Nutrition ## Occurrences in nature Glutamine is the most abundant naturally occurring, non-essential amino acid in the human body. In the body it is found circulating in the blood as well as stored in the skeletal muscles. It becomes conditionally essential (requiring intake from food or supplements) in states of illness or injury. ### Dietary sources Food sources of glutamine include: - Animal sources: meat, fish, eggs, milk, yogurt, ricotta cheese, cottage cheese, - Plant sources: beans, spinach, parsley, cabbage. Small amounts of free L-glutamine are found in vegetable juices and fermented foods, such as miso ## Functions - A substrate for DNA synthesis. - Major role in protein synthesis. - Primary source of fuel for enterocytes (cells lining the inside of the small intestine). - Precursor for rapidly dividing immune cells, thus aiding in immune function. - Regulation of acid-base balance in the kidney. - Alternative source of fuel for the brain and helps to block cortisol-induced protein catabolism. - As a form of fixed nitogen by heterocysts, exchanged for photosynthate from undifferentiated cyanobacterial cells. Polar (uncharged) ## Use In catabolic states of injury and illness, GLN becomes conditionally-essential (requiring intake from food or supplements). Glutamine has been studied extensively over the past 10-15 years and has been shown to be useful in treatment of serious illnesses, injury, trauma, burns, cancer and its treatment related side-effects as well as in wound healing for postoperative patients (citation pending). That is why it is now also classified as a "nutraceutical". Glutamine is also marketed as a supplement used for muscle growth in weightlifting, bodybuilding, endurance and other sports. ## Aiding gastrointestinal function There have been several recent studies into the effects of glutamine and what properties it possesses, and, there is now a significant body of evidence that links glutamine-enriched diets with intestinal effects; aiding maintenance of gut barrier function, intestinal cell proliferation and differentiation, as well as generally reducing septic morbidity and the symptoms of Irritable Bowel Syndrome. The reason for such "cleansing" properties is thought to stem from the fact that the intestinal extraction rate of glutamine is higher than that for other amino acids, and is therefore thought to be the most viable option when attempting to alleviate conditions relating to the gastrointestinal tract. These conditions were discovered after comparing plasma concentration within the gut between glutamine-enriched and non glutamine-enriched diets. However, even though glutamine is thought to have "cleansing" properties and effects, it is unknown to what extent glutamine has clinical benefits, due to the varied concentrations of glutamine in varieties of food. ## Aiding recovery after surgery It is also known that glutamine has various effects in reducing healing time after operations. Hospital-stay times after abdominal surgery can be reduced by providing parenteral nutrition regimes containing high amounts of glutamine to patients. Clinical trials have revealed that patients on supplementation regimes containing glutamine have improved nitrogen balances, generation of cysteinyl-leukotrienes from polymorphonuclear neutrophil granulocytes and improved lymphocyte recovery and intestinal permeability (in postoperative patients) - in comparison to those who had no glutamine within their dietary regime; all without any side-effects.	Glutamine Template:NatOrganicBox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Glutamine (abbreviated as Gln or Q; Glx or Z represents either glutamate or glutamic acid) is one of the 20 amino acids encoded by the standard genetic code. Its side chain is an amide formed by replacing the side-chain hydroxyl of glutamic acid with an amine functional group. It can therefore be considered the amide of the acidic amino acid glutamate. Its codons are CAA and CAG. # Nutrition ## Occurrences in nature Glutamine is the most abundant naturally occurring, non-essential amino acid in the human body. In the body it is found circulating in the blood as well as stored in the skeletal muscles. It becomes conditionally essential (requiring intake from food or supplements) in states of illness or injury. ### Dietary sources Food sources of glutamine include: - Animal sources: meat, fish, eggs, milk, yogurt, ricotta cheese, cottage cheese, - Plant sources: beans, spinach, parsley, cabbage. Small amounts of free L-glutamine are found in vegetable juices and fermented foods, such as miso [1] ## Functions - A substrate for DNA synthesis. - Major role in protein synthesis. - Primary source of fuel for enterocytes (cells lining the inside of the small intestine). - Precursor for rapidly dividing immune cells, thus aiding in immune function. - Regulation of acid-base balance in the kidney. - Alternative source of fuel for the brain and helps to block cortisol-induced protein catabolism. - As a form of fixed nitogen by heterocysts, exchanged for photosynthate from undifferentiated cyanobacterial cells. Polar (uncharged) ## Use In catabolic states of injury and illness, GLN becomes conditionally-essential (requiring intake from food or supplements). Glutamine has been studied extensively over the past 10-15 years and has been shown to be useful in treatment of serious illnesses, injury, trauma, burns, cancer and its treatment related side-effects as well as in wound healing for postoperative patients (citation pending). That is why it is now also classified as a "nutraceutical". Glutamine is also marketed as a supplement used for muscle growth in weightlifting, bodybuilding, endurance and other sports. ## Aiding gastrointestinal function There have been several recent studies into the effects of glutamine and what properties it possesses, and, there is now a significant body of evidence that links glutamine-enriched diets with intestinal effects; aiding maintenance of gut barrier function, intestinal cell proliferation and differentiation, as well as generally reducing septic morbidity and the symptoms of Irritable Bowel Syndrome. The reason for such "cleansing" properties is thought to stem from the fact that the intestinal extraction rate of glutamine is higher than that for other amino acids, and is therefore thought to be the most viable option when attempting to alleviate conditions relating to the gastrointestinal tract. [2] These conditions were discovered after comparing plasma concentration within the gut between glutamine-enriched and non glutamine-enriched diets. However, even though glutamine is thought to have "cleansing" properties and effects, it is unknown to what extent glutamine has clinical benefits, due to the varied concentrations of glutamine in varieties of food. [2] ## Aiding recovery after surgery It is also known that glutamine has various effects in reducing healing time after operations. Hospital-stay times after abdominal surgery can be reduced by providing parenteral nutrition regimes containing high amounts of glutamine to patients. Clinical trials have revealed that patients on supplementation regimes containing glutamine have improved nitrogen balances, generation of cysteinyl-leukotrienes from polymorphonuclear neutrophil granulocytes and improved lymphocyte recovery and intestinal permeability (in postoperative patients) - in comparison to those who had no glutamine within their dietary regime; all without any side-effects. [3]	https://www.wikidoc.org/index.php/Glutamine
f0b11714798b0ca93fc13c1ac689c5c4a9cb48ad	wikidoc	Glyceride	Glyceride Glycerides, more correctly known as acylglycerols, are esters formed from glycerol and fatty acids. Glycerol has three hydroxyl functional groups, which can be esterified with one, two, or three fatty acids to form monoglycerides, diglycerides, and triglycerides. Vegetable oils and animal fats contain mostly triglycerides, but are broken down by natural enzymes (lipases) into mono- and diglycerides and free fatty acids. Soaps are formed from the reaction of glycerides with sodium hydroxide. Glycerol is a product that can soften dehydrated skin by absorbing moisture from the air. If pure glycerol were left exposed to normal air, in 10 to 12 hours it would become 80% glycerol and 20% water by absorbing 1/5 of its weight in water. da:Glycerid de:Acylglycerine eo:Glicerido ko:글리세라이드 it:Gliceridi he:גליצריד	Glyceride Glycerides, more correctly known as acylglycerols, are esters formed from glycerol and fatty acids. Glycerol has three hydroxyl functional groups, which can be esterified with one, two, or three fatty acids to form monoglycerides, diglycerides, and triglycerides. Vegetable oils and animal fats contain mostly triglycerides, but are broken down by natural enzymes (lipases) into mono- and diglycerides and free fatty acids. Soaps are formed from the reaction of glycerides with sodium hydroxide. Glycerol is a product that can soften dehydrated skin by absorbing moisture from the air. If pure glycerol were left exposed to normal air, in 10 to 12 hours it would become 80% glycerol and 20% water by absorbing 1/5 of its weight in water. Template:Glycerides da:Glycerid de:Acylglycerine eo:Glicerido ko:글리세라이드 it:Gliceridi he:גליצריד Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Glyceride
5f17f29a7cb07802ef85c6985aa0a2a099892d85	wikidoc	Glycomics	Glycomics Glycomics, an analogous term to genomics and proteomics, is the comprehensive study of glycomes (the entire complement of sugars, whether free or present in more complex molecules, of an organism), including genetic, physiologic, pathologic, and other aspects. Glycomics "is the systematic study of all glycan structures of a given cell type or organism" and is a subset of glycobiology. The term glycomics is derived from the chemical prefix for sweetness or a sugar, "glyco-", and was formed to follow the naming convention established by genomics (which deals with genes) and proteomics (which deals with proteins). The identity of the entirety of carbohydrates in an organism is thus collectively referred to as the glycome. This area of research has to deal with an inherent level of complexity not seen in other areas of applied biology. 68 building blocks (molecules for DNA, RNA and proteins; categories for lipids; types of sugar linkages for saccharides) provide the structural basis for the molecular choreography that constitutes the entire life of a cell. DNA and RNA have four building blocks each (the nucleosides or nucleotides). Lipids are divided into eight categories based on ketoacyl and isoprene. Proteins have 20 (the amino acids). Saccharides have 32 types of sugar linkages.. While these building blocks can be attached only linearly for proteins and genes, they can be arranged in a branched array for saccharides, further increasing the degree of compexity. Advances in glycomics are anticipated to be driven by improvements in molecular sequencing and bioinformatics, which is the computational organization and processing of sequence data.	Glycomics Glycomics, an analogous term to genomics and proteomics, is the comprehensive study of glycomes (the entire complement of sugars, whether free or present in more complex molecules, of an organism), including genetic, physiologic, pathologic, and other aspects.[1][2] Glycomics "is the systematic study of all glycan structures of a given cell type or organism" and is a subset of glycobiology.[3] The term glycomics is derived from the chemical prefix for sweetness or a sugar, "glyco-", and was formed to follow the naming convention established by genomics (which deals with genes) and proteomics (which deals with proteins). The identity of the entirety of carbohydrates in an organism is thus collectively referred to as the glycome. This area of research has to deal with an inherent level of complexity not seen in other areas of applied biology. 68 building blocks (molecules for DNA, RNA and proteins; categories for lipids; types of sugar linkages for saccharides) provide the structural basis for the molecular choreography that constitutes the entire life of a cell. DNA and RNA have four building blocks each (the nucleosides or nucleotides). Lipids are divided into eight categories based on ketoacyl and isoprene. Proteins have 20 (the amino acids). Saccharides have 32 types of sugar linkages.[4]. While these building blocks can be attached only linearly for proteins and genes, they can be arranged in a branched array for saccharides, further increasing the degree of compexity. Advances in glycomics are anticipated to be driven by improvements in molecular sequencing and bioinformatics, which is the computational organization and processing of sequence data.	https://www.wikidoc.org/index.php/Glycomics
d65ece1d819ffe7916df8d3056dd91fa6fb543f9	wikidoc	Liquorice	Liquorice Liquorice or licorice (see spelling differences) (Template:IPA2, ]], ]], or ]]) is the root of Glycyrrhiza glabra, from which a sweet flavour can be extracted. The liquorice plant is a legume (related to beans and peas) and native to southern Europe and parts of Asia. It is a herbaceous perennial, growing to 1 m in height, with pinnate leaves about 7–15 centimetres (3–6 inches) long, with 9–17 leaflets. The flowers are 0.8–1.2 cm (1/3 to 1/2 inch) long, purple to pale whitish blue, produced in a loose inflorescence. The fruit is an oblong pod, 2–3 centimetres (about 1 inch) long, containing several seeds. # Cultivation and uses Liquorice is grown as a root crop mainly in southern Europe. Historically, it is also linked with Pontefract in Yorkshire, England, which has an annual liquorice festival. Very little commercial liquorice is grown in North America, where it is replaced by a related native species, American Licorice (G. lepidota), which has similar uses. In northern China, the related Chinese Liquorice (G. uralensis) is cultivated for use in traditional Chinese medicine. Liquorice grows best in deep, fertile, well-drained soils, with full sun, and is harvested in the autumn two to three years after planting. Liquorice extract is produced by boiling liquorice root and subsequently evaporating most of the water (in fact, the word 'liquorice' is derived from the Ancient Greek words for 'sweet root'). Liquorice extract is traded both in solid and syrup form. Its active principle is glycyrrhizin, a sweetener more than 50 times as sweet as sucrose which also has pharmaceutical effects. G. uralensis contains this chemical in much greater concentration. ## Culinary use Liquorice flavour is found in a wide variety of liquorice candies. The most popular in the United Kingdom are Liquorice allsorts. In continental Europe, however, far stronger, saltier candies are preferred. It should be noted, though, that in most of these candies the taste is reinforced by aniseed oil, and the actual content of liquorice is quite low. In the Netherlands Liquorice candy is called "Drop", (and it is actually one of the most popular forms of candy) but only a few of the many forms that are sold contain aniseed, although mixing it with mint, menthol or with laurel is popular, and mixing it with Ammonium chloride creates the very popular salty liquorice. Liquorice is also found in some soft drinks (such as root beer), and is in some herbal teas where it provides a sweet aftertaste. The flavor is common in medicines to disguise unpleasant flavors. Liquorice is popular in Italy, particularly in the South, in its natural form. The root of the plant is simply dug up, washed and chewed as mouth-freshener. Throughout Italy unsweetened liquorice is consumed in the form of small black pieces made only from 100% pure liquorice extract; the taste is bitter and intense. Liquorice is also very popular in Syria where it is sold as a drink. Dried liquorice root can be chewed as a sweet. According to the US Department of Agriculture Food Database, black licorice contains approximately 100 calories per ounce (28g). Chinese cuisine uses liquorice as a culinary spice for savoury foods. It is often employed to flavour broths and foods simmered in soy sauce. Other herbs and spices of similar flavour include Anise, star anise, tarragon, and fennel. ## Medicinal use Powdered liquorice root is an effective expectorant, and has been used for this purpose since ancient times, especially in Ayurvedic medicine where it is also used in tooth powders. Modern cough syrups often include liquorice extract as an ingredient. Additionally, liquorice may be useful in conventional and naturopathic medicine for both mouth ulcers and peptic ulcers. Non-prescription aphthous ulcer treatment CankerMelts incorporates glycyrrhiza in a dissolving adherant troche. Liquorice is also a mild laxative and may be used as a topical antiviral agent for shingles, opthalmic, oral or genital herpes. Liquorice affects the body's endocrine system as it contains isoflavones (phytoestrogens). It can lower the amount of serum testosterone, but whether it affects the amount of free testosterone is unclear. Large doses of glycyrrhizinic acid and glycyrrhetinic acid in liquorice extract can lead to hypokalemia and serious increases in blood pressure, a syndrome known as apparent mineralocorticoid excess. These side effects stem from the inhibition of the enzyme 11β-hydroxysteroid dehydrogenase (type 2) and subsequent increase in activity of cortisol on the kidney. 11β-hydroxysteroid dehydrogenase normally inactivates cortisol in the kidney; thus, liquorice's inhibition of this enzyme makes the concentration of cortisol appear to increase. Cortisol acts at the same receptor as the hormone aldosterone in the kidney and the effects mimic aldosterone excess, although aldosterone remains low or normal during liquorice overdose. To decrease the chances of these serious side effects, deglycyrrhizinated liquorice preparations are available. The disabling of similar enzymes in the gut by glycyrrhizinic acid and glycyrrhetinic acid also causes increased mucus and decreased acid secretion. It inhibits Helicobacter pylori, is used as an aid for healing stomach and duodenal ulcers, and in moderate amounts may soothe an upset stomach. Liquorice can be used to treat ileitis, leaky gut syndrome, irritable bowel syndrome and Crohn's disease as it is antispasmodic in the bowels. Liquorice is an adaptogen which helps reregulate the Hypothalamic-pituitary-adrenal axis. It can also be used for auto-immune conditions including lupus, scleroderma, rheumatoid arthritis and animal dander allergies. In traditional Chinese medicine, liquorice is commonly used in herbal formulae to "harmonize" the other ingredients in the formula and to carry the formula into all 12 of the regular meridians and to relieve a spasmodic cough. Liquorice is used as an important ingredient in Fu zheng anti-cancer formulas where it is an anti-inflammatory compound . In traditional American herbalism it is used in the Hoxsey anti-cancer formula. ## Toxicity Excessive consumption of liquorice or liquorice candy is known to be toxic to the liver and cardiovascular system, and may produce hypertension and oedema. There have been occasional cases where blood pressure has increased with excessive consumption of liquorice tea, but such occasions are rare and reversible when the herb is withdrawn. Most cases of hypertension from licorice were caused by overeating concentrated liquorice candy. # Gallery - Sliver of licorice root Sliver of licorice root - Various licorice root slivers Various licorice root slivers # Notes - ↑ Jump up to: 1.0 1.1 Huxley, A., ed. (1992). New RHS Dictionary of Gardening. ISBN 0-333-47494-5 - ↑ Dutch website of Wageningen University with English information about "Drop" - ↑ Licorice Calories - ↑ Das, S.K. "Deglycyrrhizinated liquorice in aphthous ulcers". The Journal of the Association of Physicians of India. Association of Physicians of India. 37 (10): 647. Unknown parameter \|coauthors= ignored (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Krausse, R. (2004). "In vitro anti-Helicobacter pylori activity of Extractum liquiritiae, glycyrrhizin and its metabolites". The Journal of Antimicrobial Chemotherapy. Oxford University Press. 54 (1): 243–246. Unknown parameter \|coauthors= ignored (help) - ↑ Materia Medica, retrieved 24 May 2007 - ↑ Jump up to: 7.0 7.1 Winston, David (2007). Adaptogens: Herbs for Strength, Stamina, and Stress Relief. Healing Arts Press. Unknown parameter \|coauthors= ignored (help) - ↑ Bensky, Dan (2004). Chinese Herbal Medicine: Materia Medica, Third Edition. Eastland Press. ISBN 0939616424. Unknown parameter \|coauthors= ignored (help) - ↑ The Nurse's Guide To Herbal Remedies from Salisbury University - ↑ A Guide to Medicinal and Aromatic Plants from Purdue University - ↑ Subhuti Dharmananda, Ph.D., Safety Issues Affecting Herbs: Herbs that May Increase Blood Pressue, retrieved 24 May 2007	Liquorice Liquorice or licorice (see spelling differences) (Template:IPA2, [[[:Template:IPA]]], [[[:Template:IPA]]], or [[[:Template:IPA]]]) is the root of Glycyrrhiza glabra, from which a sweet flavour can be extracted. The liquorice plant is a legume (related to beans and peas) and native to southern Europe and parts of Asia. It is a herbaceous perennial, growing to 1 m in height, with pinnate leaves about 7–15 centimetres (3–6 inches) long, with 9–17 leaflets. The flowers are 0.8–1.2 cm (1/3 to 1/2 inch) long, purple to pale whitish blue, produced in a loose inflorescence. The fruit is an oblong pod, 2–3 centimetres (about 1 inch) long, containing several seeds.[1] # Cultivation and uses Liquorice is grown as a root crop mainly in southern Europe. Historically, it is also linked with Pontefract in Yorkshire, England, which has an annual liquorice festival. Very little commercial liquorice is grown in North America, where it is replaced by a related native species, American Licorice (G. lepidota), which has similar uses. In northern China, the related Chinese Liquorice (G. uralensis) is cultivated for use in traditional Chinese medicine. Liquorice grows best in deep, fertile, well-drained soils, with full sun, and is harvested in the autumn two to three years after planting.[1] Liquorice extract is produced by boiling liquorice root and subsequently evaporating most of the water (in fact, the word 'liquorice' is derived from the Ancient Greek words for 'sweet root'). Liquorice extract is traded both in solid and syrup form. Its active principle is glycyrrhizin, a sweetener more than 50 times as sweet as sucrose which also has pharmaceutical effects. G. uralensis contains this chemical in much greater concentration. ## Culinary use Template:Mainarticle Liquorice flavour is found in a wide variety of liquorice candies. The most popular in the United Kingdom are Liquorice allsorts. In continental Europe, however, far stronger, saltier candies are preferred. It should be noted, though, that in most of these candies the taste is reinforced by aniseed oil, and the actual content of liquorice is quite low. In the Netherlands Liquorice candy is called "Drop", (and it is actually one of the most popular forms of candy) but only a few of the many forms that are sold contain aniseed, although mixing it with mint, menthol or with laurel is popular, and mixing it with Ammonium chloride creates the very popular salty liquorice. [2] Liquorice is also found in some soft drinks (such as root beer), and is in some herbal teas where it provides a sweet aftertaste. The flavor is common in medicines to disguise unpleasant flavors. Liquorice is popular in Italy, particularly in the South, in its natural form. The root of the plant is simply dug up, washed and chewed as mouth-freshener. Throughout Italy unsweetened liquorice is consumed in the form of small black pieces made only from 100% pure liquorice extract; the taste is bitter and intense. Liquorice is also very popular in Syria where it is sold as a drink. Dried liquorice root can be chewed as a sweet. According to the US Department of Agriculture Food Database, black licorice contains approximately 100 calories per ounce (28g).[3] Chinese cuisine uses liquorice as a culinary spice for savoury foods. It is often employed to flavour broths and foods simmered in soy sauce. Other herbs and spices of similar flavour include Anise, star anise, tarragon, and fennel. ## Medicinal use Powdered liquorice root is an effective expectorant, and has been used for this purpose since ancient times, especially in Ayurvedic medicine where it is also used in tooth powders. Modern cough syrups often include liquorice extract as an ingredient. Additionally, liquorice may be useful in conventional and naturopathic medicine for both mouth ulcers[4] and peptic ulcers.[5] Non-prescription aphthous ulcer treatment CankerMelts incorporates glycyrrhiza in a dissolving adherant troche. Liquorice is also a mild laxative and may be used as a topical antiviral agent for shingles, opthalmic, oral or genital herpes. Liquorice affects the body's endocrine system as it contains isoflavones (phytoestrogens). It can lower the amount of serum testosterone,[6] but whether it affects the amount of free testosterone is unclear. Large doses of glycyrrhizinic acid and glycyrrhetinic acid in liquorice extract can lead to hypokalemia and serious increases in blood pressure, a syndrome known as apparent mineralocorticoid excess. These side effects stem from the inhibition of the enzyme 11β-hydroxysteroid dehydrogenase (type 2) and subsequent increase in activity of cortisol on the kidney. 11β-hydroxysteroid dehydrogenase normally inactivates cortisol in the kidney; thus, liquorice's inhibition of this enzyme makes the concentration of cortisol appear to increase. Cortisol acts at the same receptor as the hormone aldosterone in the kidney and the effects mimic aldosterone excess, although aldosterone remains low or normal during liquorice overdose. To decrease the chances of these serious side effects, deglycyrrhizinated liquorice preparations are available. The disabling of similar enzymes in the gut by glycyrrhizinic acid and glycyrrhetinic acid also causes increased mucus and decreased acid secretion. It inhibits Helicobacter pylori, is used as an aid for healing stomach and duodenal ulcers, and in moderate amounts may soothe an upset stomach. Liquorice can be used to treat ileitis, leaky gut syndrome, irritable bowel syndrome and Crohn's disease as it is antispasmodic in the bowels.[7] Liquorice is an adaptogen which helps reregulate the Hypothalamic-pituitary-adrenal axis. It can also be used for auto-immune conditions including lupus, scleroderma, rheumatoid arthritis and animal dander allergies.[7] In traditional Chinese medicine, liquorice is commonly used in herbal formulae to "harmonize" the other ingredients in the formula and to carry the formula into all 12 of the regular meridians[8] and to relieve a spasmodic cough. Liquorice is used as an important ingredient in Fu zheng anti-cancer formulas where it is an anti-inflammatory compound . In traditional American herbalism it is used in the Hoxsey anti-cancer formula. ## Toxicity Excessive consumption of liquorice or liquorice candy is known to be toxic to the liver[9] and cardiovascular system, and may produce hypertension and oedema.[10] There have been occasional cases where blood pressure has increased with excessive consumption of liquorice tea, but such occasions are rare and reversible when the herb is withdrawn.[11] Most cases of hypertension from licorice were caused by overeating concentrated liquorice candy. # Gallery - Sliver of licorice root Sliver of licorice root - Various licorice root slivers Various licorice root slivers # Notes - ↑ Jump up to: 1.0 1.1 Huxley, A., ed. (1992). New RHS Dictionary of Gardening. ISBN 0-333-47494-5 - ↑ [1] Dutch website of Wageningen University with English information about "Drop" - ↑ Licorice Calories - ↑ Das, S.K. "Deglycyrrhizinated liquorice in aphthous ulcers". The Journal of the Association of Physicians of India. Association of Physicians of India. 37 (10): 647. Unknown parameter \|coauthors= ignored (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Krausse, R. (2004). "In vitro anti-Helicobacter pylori activity of Extractum liquiritiae, glycyrrhizin and its metabolites". The Journal of Antimicrobial Chemotherapy. Oxford University Press. 54 (1): 243–246. Unknown parameter \|coauthors= ignored (help) - ↑ Materia Medica, retrieved 24 May 2007 - ↑ Jump up to: 7.0 7.1 Winston, David (2007). Adaptogens: Herbs for Strength, Stamina, and Stress Relief. Healing Arts Press. Unknown parameter \|coauthors= ignored (help) - ↑ Bensky, Dan (2004). Chinese Herbal Medicine: Materia Medica, Third Edition. Eastland Press. ISBN 0939616424. Unknown parameter \|coauthors= ignored (help) - ↑ The Nurse's Guide To Herbal Remedies from Salisbury University - ↑ A Guide to Medicinal and Aromatic Plants from Purdue University - ↑ Subhuti Dharmananda, Ph.D., Safety Issues Affecting Herbs: Herbs that May Increase Blood Pressue, retrieved 24 May 2007 # External links - National Institute of Health - Medline - PDRhealth.com - Profile of Deglycyrrhizinated Licorice (DGL) - Chemical & Engineering News article on Licorice - Non-profit dedicated to promoting licorice - Offers information and more than 160 licorice products from 13 countries - Pontefract Liquorice Festival Template:Herbs & spices ar:عرقسوس bg:Женско биле cs:Lékořice lysá da:Glat Lakrids de:Lakritze hsb:Słódnik hu:Édesgyökér it:Glycyrrhiza glabra lb:Séissholz lt:Paprastasis saldymedis nl:Zoethout no:Lakrisplante sr:Сладић fi:Lakritsikasvi sv:Lakritsrot th:ชะเอมเทศ vec:Glycyrrhiza glabra Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Glycyrrhiza_glabra
fbcbb1a3138f81cf0b0bf35ffc636973b67a24a6	wikidoc	Goitrogen	Goitrogen # Overview Goitrogens are substances that suppress the function of the thyroid gland by interfering with iodine uptake which can, as a result, cause an enlargement of the thyroid. # Goitrogenic drugs Chemicals that have been shown to have goitrogenic effects include: - Sulfadimethoxine, propylthiouracil, potassium perchlorate, and iopanoic acid. - Thiocyanate overload in Central Africa, especially if also in conjunction with selenium deficiency. Reliance on cassava as a carbohydrate provides a source of thiocyanate in some areas. # Goitrogenic foods Certain foods have been identified as goitrogenic. These foods include: - Soybeans (and soybean products such as tofu) - Pine nuts - Peanuts - Millet - Strawberries - Peaches - Spinach - Bamboo shoots - Radishes - Horseradish - Vegetables in the genus Brassica Bok choy Broccoli Broccolini (Asparations) Brussels sprouts Cabbage Cauliflower Chinese cabbage Choy sum Collard greens Kai-lan (Chinese broccoli) Kale Kohlrabi Mizuna Mustard greens Rapeseed (yu choy) Rapini Rutabagas Tatsoi Turnips - Bok choy - Broccoli - Broccolini (Asparations) - Brussels sprouts - Cabbage - Cauliflower - Chinese cabbage - Choy sum - Collard greens - Kai-lan (Chinese broccoli) - Kale - Kohlrabi - Mizuna - Mustard greens - Rapeseed (yu choy) - Rapini - Rutabagas - Tatsoi - Turnips # Foods stimulating thyroid tissue Some foods and drinks have an opposite effect on the thyroid gland--that is, they stimulate thyroid function rather than suppressing it; examples being avocado, coconut, and saturated fat.. Indeed some studies on rats suggest that excess caffeine in conjunction with a lack of iodine may promote the formation of thyroid cancers. Despite being generally a stimulant, caffeine, (examples: coffee, tea, cola, chocolate) acts on thyroid function as a suppressant. # Footnotes - ↑ Takizawa T, Imai T, Ueda M, Onodera H, Hirose M (2006). "Comparison of enhancing effects of different goitrogen treatments in combination with beta-estradiol-3-benzoate for establishing a rat two-stage thyroid carcinogenesis model to detect modifying effects of estrogenic compounds". Cancer Sci. 97 (1): 25–31. doi:10.1111/j.1349-7006.2005.00132.x. PMID 16367917.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Vanderpas J (2006). "Nutritional epidemiology and thyroid hormone metabolism". Annu. Rev. Nutr. 26: 293–322. doi:10.1146/annurev.nutr.26.010506.103810. PMID 16704348. - ↑ Akindahunsi AA, Grissom FE, Adewusi SR, Afolabi OA, Torimiro SE, Oke OL (1998). "Parameters of thyroid function in the endemic goitre of Akungba and Oke-Agbe villages of Akoko area of southwestern Nigeria". African journal of medicine and medical sciences. 27 (3–4): 239–42. PMID 10497657.CS1 maint: Multiple names: authors list (link) - ↑ Siddhanti SR, King MW, Tove SB (1990). "Influence of dietary fat on factors in serum that regulate thyroid cell metabolism" (PDF). J. Nutr. 120 (11): 1297–304. PMID 2172489.CS1 maint: Multiple names: authors list (link) Thyroid hyperplasia has been demonstrated in mice:*"Toxicology and carcinogenesis studies of coconut oil acid diethanolamine condensate (CAS No. 68603-42-9) in F344/N rats and B6C3F1 mice (dermal studies)". National Toxicology Program technical report series. 479: 5–226. 2001. PMID 12571684. - ↑ Denice Moffat. "Bad Foods for Thyroid". Retrieved 2007-10-12. - ↑ Son HY, Nishikawa A, Kanki K; et al. (2003). "Synergistic interaction between excess caffeine and deficient iodine on the promotion of thyroid carcinogenesis in rats pretreated with N-bis(2-hydroxypropyl)nitrosamine". Cancer Sci. 94 (4): 334–7. PMID 12824900.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)	Goitrogen # Overview Goitrogens are substances that suppress the function of the thyroid gland by interfering with iodine uptake which can, as a result, cause an enlargement of the thyroid. # Goitrogenic drugs Chemicals that have been shown to have goitrogenic effects include: - Sulfadimethoxine, propylthiouracil, potassium perchlorate, and iopanoic acid.[1] - Thiocyanate overload in Central Africa, especially if also in conjunction with selenium deficiency.[2] Reliance on cassava as a carbohydrate provides a source of thiocyanate in some areas.[3] # Goitrogenic foods Certain foods have been identified as goitrogenic. These foods include: - Soybeans (and soybean products such as tofu) - Pine nuts - Peanuts - Millet - Strawberries - Peaches - Spinach - Bamboo shoots - Radishes - Horseradish - Vegetables in the genus Brassica Bok choy Broccoli Broccolini (Asparations) Brussels sprouts Cabbage Cauliflower Chinese cabbage Choy sum Collard greens Kai-lan (Chinese broccoli) Kale Kohlrabi Mizuna Mustard greens Rapeseed (yu choy) Rapini Rutabagas Tatsoi Turnips - Bok choy - Broccoli - Broccolini (Asparations) - Brussels sprouts - Cabbage - Cauliflower - Chinese cabbage - Choy sum - Collard greens - Kai-lan (Chinese broccoli) - Kale - Kohlrabi - Mizuna - Mustard greens - Rapeseed (yu choy) - Rapini - Rutabagas - Tatsoi - Turnips # Foods stimulating thyroid tissue Some foods and drinks have an opposite effect on the thyroid gland--that is, they stimulate thyroid function rather than suppressing it; examples being avocado, coconut,[4] and saturated fat.[5]. Indeed some studies on rats suggest that excess caffeine in conjunction with a lack of iodine may promote the formation of thyroid cancers. [6]Despite being generally a stimulant, caffeine, (examples: coffee, tea, cola, chocolate) acts on thyroid function as a suppressant.[citation needed] # Footnotes - ↑ Takizawa T, Imai T, Ueda M, Onodera H, Hirose M (2006). "Comparison of enhancing effects of different goitrogen treatments in combination with beta-estradiol-3-benzoate for establishing a rat two-stage thyroid carcinogenesis model to detect modifying effects of estrogenic compounds". Cancer Sci. 97 (1): 25–31. doi:10.1111/j.1349-7006.2005.00132.x. PMID 16367917.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Vanderpas J (2006). "Nutritional epidemiology and thyroid hormone metabolism". Annu. Rev. Nutr. 26: 293–322. doi:10.1146/annurev.nutr.26.010506.103810. PMID 16704348. - ↑ Akindahunsi AA, Grissom FE, Adewusi SR, Afolabi OA, Torimiro SE, Oke OL (1998). "Parameters of thyroid function in the endemic goitre of Akungba and Oke-Agbe villages of Akoko area of southwestern Nigeria". African journal of medicine and medical sciences. 27 (3–4): 239–42. PMID 10497657.CS1 maint: Multiple names: authors list (link) - ↑ Siddhanti SR, King MW, Tove SB (1990). "Influence of dietary fat on factors in serum that regulate thyroid cell metabolism" (PDF). J. Nutr. 120 (11): 1297–304. PMID 2172489.CS1 maint: Multiple names: authors list (link) Thyroid hyperplasia has been demonstrated in mice:*"Toxicology and carcinogenesis studies of coconut oil acid diethanolamine condensate (CAS No. 68603-42-9) in F344/N rats and B6C3F1 mice (dermal studies)". National Toxicology Program technical report series. 479: 5–226. 2001. PMID 12571684. - ↑ Denice Moffat. "Bad Foods for Thyroid". Retrieved 2007-10-12. - ↑ Son HY, Nishikawa A, Kanki K; et al. (2003). "Synergistic interaction between excess caffeine and deficient iodine on the promotion of thyroid carcinogenesis in rats pretreated with N-bis(2-hydroxypropyl)nitrosamine". Cancer Sci. 94 (4): 334–7. PMID 12824900.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) # External links - Goitrogen page - Goitrogen page from The World's Healthiest Foods site	https://www.wikidoc.org/index.php/Goitrogen
030362aa97cb35e8674d535e041b9aeaf0f965a7	wikidoc	GoldenGem	GoldenGem GoldenGem is a neural network computer program. The default configuration is the standard one, a three level perceptron, which was shown simultaneously, but independently, to be a 'universal nonlinear function approximator' in two articles in the same journal in 1989. # Freeware but not open source status The program was supported by user registration, and was converted to freeware in 2006 and 2007, first at download.com and then at the main website. Some software websites continue to post information from an earlier pad file relating to a charge for the use of the program, but all links followed will eventually lead to the main site or download.com. The software is not open source because there is concern whether editors would have adequate technical expertise. # Operational modes While it can access the end-of-the-day daily stock, index, and bond information provided by Yahoo, MSN and Google; however a serious user would manage text files of his own data in one of two other formats, either a folder of .csv files or a single .txt file downloaded from other sources such as forexrate.com, or the Bank of England, or particular niche commodity prices. The article on Technical Analysis correctly describes the manner in which neural network software can act as a bridge between technical analysis and the more highly regarded fundamental analysis. # Sources of confusion Many users fail to understand the multi-variable nature of the software. A user must provide a set of share prices, indices, interest rates, or exchange rates which he already expects may be useful to predict the share price of interest. # Training and validation Training is accomplished by the use of a logarithmic sensitivity adjustment. Validation is by a pair of indicator lights. The first indicator light which becomes yellow if both the correlation coefficient and adjusted correlation coefficient -f predicted versus actual change is larger than 0.2 and green if it is larger than 0.5 while the second indicator light goes from red to yellow to green as the training input is removed by the user's control of the sensitivity adjustment. Secondly visual comparison of the graphs is needed to ensure the correlation coefficient is not large due to isolated coincidental similarities. Thirdly the user should run a validation data set on an interval in the past. # The adjusted correlation coefficient The adjusted correlation coefficient is needed because it is possible to obtain a falsely favourable correlation coefficient during backtesting by a strategy of returning to the known mean value of past data. A neural network will choose this strategy if it fails to find a relationship. Since the known mean value of past data includes time in the relative future during backtesting the use of the unadjusted correlation coefficient would incorrectly reward such a strategy, which would not necessarily be profitable to continue into the future. The adjusted correlation coefficient is the ordinary correlation coefficient multiplied by the variance of the actual changes and divided by the variance of the predicted changes. This becomes small if the neural network becomes unstable or if it converges upon a strategy of continual sudden return to the past mean value. The second indicator light shows the minimum of the adjusted and unadjusted correlation coefficients. # The transition function The transition function is arctan rather than the sometimes used hyperbolic tangent function. The reason is that the arctan function is suitable for an analog neural network. # Limitations The configuration of the program is limited to analyzing the values of a set of variables that change over time, with the aim of predicting the future value of one of those variables based only on the current value -f all the variables. Therefore it would not be useful for analyzing credit risk at a single point in time, for example. Also the displays and user interface assume that the data is daily and that no data is provided -n weekends. While this is not an essential feature it would make use of the program too confusing to be used for intraday data; for example if used for hourly data the tick marks at the bottom of the screen labelled 'weeks' would refer to five hour intervals, and the slider labelled 'days' being set to 21, in an attempt to exclude weekends, would set an interval of fifteen hours. Whereas the training takes into account the overall relation among the variables throughout the entire backtesting interval, there is no particular weight attached to, for example, yesterday's values, -r values from last week. A large coincidental change in the values of the variables on the final day of data would impact upon the prediction. A user can compensate by including what are known as 'stochastics' as input variables. The justification for not doing so is that the use of 'stochastics' would degrade the performance in cases when a change in today's values are genuinely meaningful, and that variability in performance due to the dependence on data from only one day should not affect the -verall average performance of the prediction. The algorithm is the most widely used and simplest algorithm. Improved algorithms such as conjugate gradient may possibly be superior.	GoldenGem GoldenGem is a neural network computer program. The default configuration is the standard one, a three level perceptron, which was shown simultaneously, but independently, to be a 'universal nonlinear function approximator' in two articles in the same journal in 1989.[1][2] # Freeware but not open source status The program was supported by user registration, and was converted to freeware in 2006 and 2007, first at download.com and then at the main website. Some software websites continue to post information from an earlier pad file relating to a charge for the use of the program, but all links followed will eventually lead to the main site or download.com. The software is not open source because there is concern whether editors would have adequate technical expertise. # Operational modes While it can access the end-of-the-day daily stock, index, and bond information provided by Yahoo, MSN and Google; however a serious user would manage text files of his own data in one of two other formats, either a folder of .csv files or a single .txt file downloaded from other sources such as forexrate.com, or the Bank of England, or particular niche commodity prices. The article on Technical Analysis correctly describes the manner in which neural network software can act as a bridge between technical analysis and the more highly regarded fundamental analysis. # Sources of confusion Many users fail to understand the multi-variable nature of the software. A user must provide a set of share prices, indices, interest rates, or exchange rates which he already expects may be useful to predict the share price of interest. # Training and validation Training is accomplished by the use of a logarithmic sensitivity adjustment. Validation is by a pair of indicator lights. The first indicator light which becomes yellow if both the correlation coefficient and adjusted correlation coefficient of predicted versus actual change is larger than 0.2 and green if it is larger than 0.5 while the second indicator light goes from red to yellow to green as the training input is removed by the user's control of the sensitivity adjustment. Secondly visual comparison of the graphs is needed to ensure the correlation coefficient is not large due to isolated coincidental similarities. Thirdly the user should run a validation data set on an interval in the past. # The adjusted correlation coefficient The adjusted correlation coefficient is needed because it is possible to obtain a falsely favourable correlation coefficient during backtesting by a strategy of returning to the known mean value of past data. A neural network will choose this strategy if it fails to find a relationship. Since the known mean value of past data includes time in the relative future during backtesting the use of the unadjusted correlation coefficient would incorrectly reward such a strategy, which would not necessarily be profitable to continue into the future. The adjusted correlation coefficient is the ordinary correlation coefficient multiplied by the variance of the actual changes and divided by the variance of the predicted changes. This becomes small if the neural network becomes unstable or if it converges upon a strategy of continual sudden return to the past mean value. The second indicator light shows the minimum of the adjusted and unadjusted correlation coefficients. # The transition function The transition function is arctan rather than the sometimes used hyperbolic tangent function. The reason is that the arctan function is suitable for an analog neural network. # Limitations The configuration of the program is limited to analyzing the values of a set of variables that change over time, with the aim of predicting the future value of one of those variables based only on the current value of all the variables. Therefore it would not be useful for analyzing credit risk at a single point in time, for example. Also the displays and user interface assume that the data is daily and that no data is provided on weekends. While this is not an essential feature it would make use of the program too confusing to be used for intraday data; for example if used for hourly data the tick marks at the bottom of the screen labelled 'weeks' would refer to five hour intervals, and the slider labelled 'days' being set to 21, in an attempt to exclude weekends, would set an interval of fifteen hours. Whereas the training takes into account the overall relation among the variables throughout the entire backtesting interval, there is no particular weight attached to, for example, yesterday's values, or values from last week. A large coincidental change in the values of the variables on the final day of data would impact upon the prediction. A user can compensate by including what are known as 'stochastics' as input variables. The justification for not doing so is that the use of 'stochastics' would degrade the performance in cases when a change in today's values are genuinely meaningful, and that variability in performance due to the dependence on data from only one day should not affect the overall average performance of the prediction. The algorithm is the most widely used and simplest algorithm. Improved algorithms such as conjugate gradient may possibly be superior. # External links - www.goldengem.co.uk # Notes - ↑ K. Funahashi, On the approximate realization of continuous mappings by neural networks, Neural Networks vol 2, 1989 - ↑ K. Hornik, Multilayer feed-forward networks are universal approximators, Neural Networks, vol 2, 1989 Template:WikiDoc Sources	https://www.wikidoc.org/index.php/GoldenGem
671f262b6a6e4d33731899497c4978aeb69fafb2	wikidoc	Goldenrod	Goldenrod The goldenrod is a yellow flowering plant in the Family Asteraceae. # Description About 80 perennial species make up the genus Solidago, most being found in the meadows and pastures, along roads, ditches and waste areas in North America, and a few from Europe that were introduced some 250 years ago. Many species are difficult to distinguish. Probably due to their bright, golden yellow flower heads blooming in late summer, the goldenrod is often unfairly blamed for causing hay fever in humans. The pollen causing these allergy problems is mainly produced by Ragweed (Ambrosia sp.), blooming at the same time as the goldenrod, but is wind-pollinated. Goldenrod pollen is too heavy and sticky to be blown far from the flowers, and is thus mainly pollinated by insects. Goldenrods are easily recognized by their golden inflorescence with hundreds of small capitula, but some are spike-like and other have auxiliary racemes. They have slender stems, usually hairless but S. canadensis shows hairs on the upper stem. They can grow to a length between 60 cm and 1.5 m. Their alternate leaves are linear to lanceolate. Their margins are usually finely to sharply serrated. Propagation is by wind-disseminated seed or by underground rhizomes. They form patches that are actually vegetative clones of a single plant. # Use and cultivation Goldenrod is used as a food plant by the larvae of some Lepidoptera species - see list of Lepidoptera that feed on goldenrods. The Goldenrod then forms a leathery bulb (called a gall) around the invading insect as a quarantine to keep it confined to a small part of the plant. Parasitoid wasps have evolved to find these galls, and lay eggs in the insect after penetrating the bulb. In a final nod to evolutionary complexity, woodpeckers have learned to blast open the gall and eat the wasp-infested insect holed up in the center. Goldenrods can be used for decoration and making tea. Goldenrods are, in some places, held as a sign of good luck or good fortune; but they are considered weeds by some. Goldenrods are mostly short-day plants and bloom in late summer and early fall and some species produce abundant nectar when moisture is plentiful before bloom, and the bloom period is relatively warm and sunny. Honey from goldenrods often is dark and strong due to admixtures of other nectars. However when there is a strong honey flow, a light (often water white), spicy-tasting honey is produced. While the bees are ripening the honey there is a rank odor and taste, but finished honey is much milder. ## Garden use British gardeners adopted goldenrod long before Americans. Goldenrod only began to gain some acceptance in American gardening (other than wildflower gardening) during the 1980s. A hybrid with aster, known as x Solidaster is less unruly, with pale yellow flowers, equally suitable for dried arrangements. Solidago canadensis was introduced as a garden plant in Central Europe, and is now common in the wild. In Germany, it is considered an invasive species that displaces native vegetation from its natural habitat. Goldenrod is a companion plant, playing host to some beneficial insects, repelling some pests ## Industrial use Inventor Thomas Edison experimented with goldenrod to produce rubber, which it contains naturally. Edison created a fertilization and cultivation process to maximize the rubber content in each plant. His experiments produced a 12 foot tall plant that yielded as much as 12 percent rubber. The rubber produced through Edison's process was resilient and long lasting. The tires on the Model T given to him by his friend Henry Ford were made from goldenrod. Examples of the rubber can still be found in his laboratory, elastic and rot free after more than 50 years. However, even though Edison turned his research over to the U.S. government a year before his death, goldenrod rubber never went beyond the experimental stage. ## Medicinal use The variety Solidago virgaurea is a traditional kidney tonic. It has aquaretic, anti-inflammatory, antispasmodic and antiseptic action and seems to increase kidney output. This makes it useful as an agent to counter inflammation and irritation of the kidneys when bacterial infection or stones are present. Such use is in combination with other herbs that create a synergistic therapeutic effect on the urinary system. As in other areas of herbalism, blending creates a therapy greater than the effect of a single herb alone. The aquaretic action is also useful in helping to dissolve kidney stones by diluting their components and preventing them from reoccuring. See herbal medicine Goldenrod has also been used as part of a tincture to aid in cleansing of the kidney/bladder during a healing fast, in conjunction with Potassium broth and specific juices. 'Solidago odora' is also sold as a medicinal, for these issues: mucus, kidney/bladder cleansing and stones, colds, digestion. Link here: for herbalist citation. # Cultural significance The goldenrod is the state flower of the U.S. states of Kentucky (adopted March 16, 1926) and Nebraska (adopted April 4, 1895). It used to be the state flower of Alabama, being adopted as such on September 6, 1927, but was later rejected in favour of the camellia. Goldenrod was recently named the state wildflower for South Carolina. In Midwestern states in the mid-twentieth century it was said that when the goldenrod bloomed, it would soon be time to go back to school--the blossoms appeared in mid- to late August, shortly before the traditional start of school on the day after Labor Day. In Sufjan Stevens' song, Casimir Pulaski Day, the narrator brings goldenrod to his girlfriend upon finding out that she has been diagnosed with bone cancer. Carrie Hamby's song, Solidago, tells the story of Thomas Edison's experiments with making goldenrod a domestic source of rubber during the 2nd world war. The Sweet Goldenrod (Solidago odora) is also the state herb of Delaware as of June 24, 1996. # Species - Solidago albopilosa E.L. Braun : Whitehair Goldenrod - Solidago altiplanities C.& J. Taylor : High Plains Goldenrod - Solidago arguta Ait. : Atlantic Goldenrod Solidago arguta. var. arguta : Atlantic Goldenrod Solidago arguta var. boottii (Hook.) Palmer & Steyermark : Boott's Goldenrod Solidago arguta var. caroliniana Gray : Atlantic Goldenrod Solidago arguta var. harrisii (Steele) Cronq. : Harris' Goldenrod Solidago arguta var. neurolepis (Fern.) Steyermark : Atlantic Goldenrod - Solidago arguta. var. arguta : Atlantic Goldenrod - Solidago arguta var. boottii (Hook.) Palmer & Steyermark : Boott's Goldenrod - Solidago arguta var. caroliniana Gray : Atlantic Goldenrod - Solidago arguta var. harrisii (Steele) Cronq. : Harris' Goldenrod - Solidago arguta var. neurolepis (Fern.) Steyermark : Atlantic Goldenrod - Solidago auriculata Shuttlw. ex Blake : Eared Goldenrod - Solidago bicolor L. : White Goldenrod - Solidago brachyphylla Chapman : Dixie Goldenrod - Solidago buckleyi Torr. & Gray : Buckley's Goldenrod (Template:StatusVulnerable) - Solidago caesia L. : Wreath Goldenrod Solidago caesia var. caesia : Wreath Goldenrod Solidago caesia var. curtisii (Torr. & Gray) Wood : Mountain Decumbent Goldenrod - Solidago caesia var. caesia : Wreath Goldenrod - Solidago caesia var. curtisii (Torr. & Gray) Wood : Mountain Decumbent Goldenrod - Solidago calcicola Fern. : Limestone Goldenrod - Solidago californica Nutt. : California Goldenrod - Solidago canadensis L. : Canada Goldenrod, Canadian Goldenrod Solidago canadensis var. canadensis : Canada Goldenrod Solidago canadensis var. gilvocanescens Rydb. : Shorthair Goldenrod Solidago canadensis var. hargeri Fern. : Harger's Goldenrod Solidago canadensis var. lepida (DC.) Cronq. : Canada Goldenrod Solidago canadensis var. salebrosa (Piper) M.E. Jones : Salebrosa Goldenrod Solidago canadensis var. scabra Torr. & Gray : Canada Goldenrod - Solidago canadensis var. canadensis : Canada Goldenrod - Solidago canadensis var. gilvocanescens Rydb. : Shorthair Goldenrod - Solidago canadensis var. hargeri Fern. : Harger's Goldenrod - Solidago canadensis var. lepida (DC.) Cronq. : Canada Goldenrod - Solidago canadensis var. salebrosa (Piper) M.E. Jones : Salebrosa Goldenrod - Solidago canadensis var. scabra Torr. & Gray : Canada Goldenrod - Solidago cutleri Fern. : Cutler's alpine Goldenrod - Solidago deamii Fern. : Deam's Goldenrod - Solidago discoidea Ell. : Rayless Mock Goldenrod - Solidago fistulosa P. Mill. : Pinebarren Goldenrod - Solidago flaccidifolia Small : Mountain Goldenrod - Solidago flexicaulis L. : Zigzag Goldenrod - Solidago gattingeri Chapman : Gattinger's Goldenrod - Solidago gigantea Ait. : Giant Goldenrod - Solidago glomerata Michx. : Clustered Goldenrod - Solidago gracillima Torr. & Gray : Virginia Goldenrod - Solidago guiradonis Gray : Guirado Goldenrod - Solidago hispida Muhl. ex Willd. : Hairy Goldenrod Solidago hispida var. arnoglossa Fern. : Hairy Goldenrod Solidago hispida var. hispida : Hairy Goldenrod Solidago hispida var. lanata (Hook.) Fern. : Hairy Goldenrod Solidago hispida var. tonsa Fern. : Hairy Goldenrod - Solidago hispida var. arnoglossa Fern. : Hairy Goldenrod - Solidago hispida var. hispida : Hairy Goldenrod - Solidago hispida var. lanata (Hook.) Fern. : Hairy Goldenrod - Solidago hispida var. tonsa Fern. : Hairy Goldenrod - Solidago juliae Nesom : Julia's Goldenrod - Solidago juncea Ait. : Early Goldenrod - Solidago latissimifolia P. Mill. : Elliott's Goldenrod - Solidago leavenworthii Torr. & Gray : Leavenworth's Goldenrod - Solidago ludoviciana (Gray) Small : Louisiana Goldenrod - Solidago macrophylla Pursh : Largeleaf Goldenrod - Solidago missouriensis Nutt. : Missouri Goldenrod Solidago missouriensis var. fasciculata Holz. : Missouri Goldenrod Solidago missouriensis var. missouriensis : Missouri Goldenrod Solidago missouriensis var. tenuissima (Woot. & Standl.) C.& J. Taylor : Missouri Goldenrod Solidago missouriensis Nutt. var. tolmieana (Gray) Cronq. : Tolmies' Goldenrod - Solidago missouriensis var. fasciculata Holz. : Missouri Goldenrod - Solidago missouriensis var. missouriensis : Missouri Goldenrod - Solidago missouriensis var. tenuissima (Woot. & Standl.) C.& J. Taylor : Missouri Goldenrod - Solidago missouriensis Nutt. var. tolmieana (Gray) Cronq. : Tolmies' Goldenrod - Solidago mollis Bartl. : Velvety Goldenrod Solidago mollis var. angustata Shinners : Velvety Goldenrod Solidago mollis var. mollis : Velvety Goldenrod - Solidago mollis var. angustata Shinners : Velvety Goldenrod - Solidago mollis var. mollis : Velvety Goldenrod - Solidago multiradiata Ait. : Rocky Mountain Goldenrod, Alpine Goldenrod Solidago multiradiata var. arctica (DC.) Fern. : Arctic Goldenrod Solidago multiradiata var. multiradiata : Rocky Mountain Goldenrod Solidago multiradiata var. scopulorum Gray : Manyray Goldenrod - Solidago multiradiata var. arctica (DC.) Fern. : Arctic Goldenrod - Solidago multiradiata var. multiradiata : Rocky Mountain Goldenrod - Solidago multiradiata var. scopulorum Gray : Manyray Goldenrod - Solidago nana Nutt. : Baby Goldenrod - Solidago nemoralis Ait. : Gray Goldenrod, American Western Goldenrod Solidago nemoralis var. longipetiolata (Mackenzie & Bush) Palmer & Steyermark : Gray Goldenrod Solidago nemoralis var. nemoralis : Gray Goldenrod - Solidago nemoralis var. longipetiolata (Mackenzie & Bush) Palmer & Steyermark : Gray Goldenrod - Solidago nemoralis var. nemoralis : Gray Goldenrod - Solidago odora Ait. : Anise-scented Goldenrod, Sweet Goldenrod Solidago odora var. chapmanii (Gray) Cronq. : Chapman's Goldenrod Solidago odora var. odora : Anise-scented Goldenrod - Solidago odora var. chapmanii (Gray) Cronq. : Chapman's Goldenrod - Solidago odora var. odora : Anise-scented Goldenrod - Solidago ouachitensis C.& J. Taylor : Ouachita Mountain Goldenrod - Solidago patula Muhl. ex Willd. : Roundleaf Goldenrod Solidago patula var. patula : Roundleaf Goldenrod Solidago patula var. strictula Torr. & Gray : Roundleaf Goldenrod - Solidago patula var. patula : Roundleaf Goldenrod - Solidago patula var. strictula Torr. & Gray : Roundleaf Goldenrod - Solidago petiolaris Ait. : Downy Ragged Goldenrod Solidago petiolaris var. angusta (Torr. & Gray) Gray : Downy Ragged Goldenrod Solidago petiolaris var. petiolaris : Downy Ragged Goldenrod - Solidago petiolaris var. angusta (Torr. & Gray) Gray : Downy Ragged Goldenrod - Solidago petiolaris var. petiolaris : Downy Ragged Goldenrod - Solidago pinetorum Small : Small's Goldenrod - Solidago plumosa Small : Plumed Goldenrod - Solidago porteri Small : Porter's Goldenrod - Solidago puberula Nutt. : Downy Goldenrod (Template:StatusVulnerable) Solidago puberula var. puberula : Downy Goldenrod Solidago puberula var. pulverulenta (Nutt.) Chapman : Downy Goldenrod - Solidago puberula var. puberula : Downy Goldenrod - Solidago puberula var. pulverulenta (Nutt.) Chapman : Downy Goldenrod - Solidago pulchra Small : Carolina Goldenrod - Solidago radula Nutt. : Western Rough Goldenrod Solidago radula var. laeta (Greene) Fern. : Western Rough Goldenrod Solidago radula var. radula : Western Rough Goldenrod Solidago radula var. stenolepis Fern. : Western Rough Goldenrod - Solidago radula var. laeta (Greene) Fern. : Western Rough Goldenrod - Solidago radula var. radula : Western Rough Goldenrod - Solidago radula var. stenolepis Fern. : Western Rough Goldenrod - Solidago roanensis Porter : Roan Mountain Goldenrod Template:StatusEndangered - Solidago rugosa P. Mill. : Wrinkleleaf Goldenrod, Rough-stemmed Goldenrod Solidago rugosa subsp. aspera (Ait.) Cronq. : Wrinkleleaf Goldenrod Solidago rugosa subsp. rugosa : Wrinkleleaf Goldenrod Solidago rugosa subsp. rugosa var. rugosa : Wrinkleleaf Goldenrod Solidago rugosa subsp. rugosa var. sphagnophila Graves : Wrinkleleaf Goldenrod Solidago rugosa subsp. rugosa var. villosa (Pursh) Fern. : Wrinkleleaf Goldenrod - Solidago rugosa subsp. aspera (Ait.) Cronq. : Wrinkleleaf Goldenrod - Solidago rugosa subsp. rugosa : Wrinkleleaf Goldenrod Solidago rugosa subsp. rugosa var. rugosa : Wrinkleleaf Goldenrod Solidago rugosa subsp. rugosa var. sphagnophila Graves : Wrinkleleaf Goldenrod Solidago rugosa subsp. rugosa var. villosa (Pursh) Fern. : Wrinkleleaf Goldenrod - Solidago rugosa subsp. rugosa var. rugosa : Wrinkleleaf Goldenrod - Solidago rugosa subsp. rugosa var. sphagnophila Graves : Wrinkleleaf Goldenrod - Solidago rugosa subsp. rugosa var. villosa (Pursh) Fern. : Wrinkleleaf Goldenrod - Solidago rupestris Raf. : Eock Goldenrod - Solidago sciaphila Steele : Shadowy Goldenrod - Solidago sempervirens L. : Seaside Goldenrod, Beach Goldenrod Solidago sempervirens var. mexicana (L.) Fern. : Seaside Goldenrod Solidago sempervirens var. sempervirens : Seaside Goldenrod - Solidago sempervirens var. mexicana (L.) Fern. : Seaside Goldenrod - Solidago sempervirens var. sempervirens : Seaside Goldenrod - Solidago shortii Torr. & Gray : Short's Goldenrod Template:StatusEndangered - Solidago simplex Kunth : Mt. Albert Goldenrod - Solidago simplex subsp. randii (Porter) Ringius : Rand's Goldenrod Solidago simplex subsp. randii var. gillmanii (Gray) Ringius : Rand's Goldenrod Solidago simplex subsp. randii var. monticola (Porter) Ringius : Rand's Goldenrod Solidago simplex subsp. randii var. ontarioensis (Ringius) Ringius : Ontario Goldenrod Solidago simplex subsp. randii var. racemosa (Greene) Ringius : Rand's Goldenrod Solidago simplex subsp. randii var. randii (Porter) Kartesz & Gandhi : Rand's Goldenrod Solidago simplex subsp. simplex : Mt. Albert Goldenrod Solidago simplex subsp. simplex var. nana (Gray) Ringius : Dwarf Goldenrod Solidago simplex subsp. simplex var. simplex : Mt. Albert Goldenrod Solidago simplex subsp. simplex var. spathulata (DC.) Cronq. : Mt. Albert Goldenrod - Solidago simplex subsp. randii var. gillmanii (Gray) Ringius : Rand's Goldenrod Solidago simplex subsp. randii var. monticola (Porter) Ringius : Rand's Goldenrod Solidago simplex subsp. randii var. ontarioensis (Ringius) Ringius : Ontario Goldenrod Solidago simplex subsp. randii var. racemosa (Greene) Ringius : Rand's Goldenrod Solidago simplex subsp. randii var. randii (Porter) Kartesz & Gandhi : Rand's Goldenrod - Solidago simplex subsp. randii var. monticola (Porter) Ringius : Rand's Goldenrod - Solidago simplex subsp. randii var. ontarioensis (Ringius) Ringius : Ontario Goldenrod - Solidago simplex subsp. randii var. racemosa (Greene) Ringius : Rand's Goldenrod - Solidago simplex subsp. randii var. randii (Porter) Kartesz & Gandhi : Rand's Goldenrod - Solidago simplex subsp. simplex : Mt. Albert Goldenrod Solidago simplex subsp. simplex var. nana (Gray) Ringius : Dwarf Goldenrod Solidago simplex subsp. simplex var. simplex : Mt. Albert Goldenrod Solidago simplex subsp. simplex var. spathulata (DC.) Cronq. : Mt. Albert Goldenrod - Solidago simplex subsp. simplex var. nana (Gray) Ringius : Dwarf Goldenrod - Solidago simplex subsp. simplex var. simplex : Mt. Albert Goldenrod - Solidago simplex subsp. simplex var. spathulata (DC.) Cronq. : Mt. Albert Goldenrod - Solidago simulans Fern. : Fall Goldenrod - Solidago speciosa Nutt. : Showy Goldenrod Solidago speciosa var. erecta (Pursh) MacM. : Showy Goldenrod Solidago speciosa var. jejunifolia (Steele) Cronq. : Showy Goldenrod Solidago speciosa var. pallida Porter :Showy Goldenrod Solidago speciosa var. rigidiuscula Torr. & Gray : Showy Goldenrod Solidago speciosa var. speciosa : Showy Goldenrod - Solidago speciosa var. erecta (Pursh) MacM. : Showy Goldenrod - Solidago speciosa var. jejunifolia (Steele) Cronq. : Showy Goldenrod - Solidago speciosa var. pallida Porter :Showy Goldenrod - Solidago speciosa var. rigidiuscula Torr. & Gray : Showy Goldenrod - Solidago speciosa var. speciosa : Showy Goldenrod - Solidago spectabilis (D.C. Eat.) Gray : Nevada Goldenrod Solidago spectabilis var. confinis (Gray) Cronq. : Nevada Goldenrod Solidago spectabilis var. spectabilis : Nevada Goldenrod - Solidago spectabilis var. confinis (Gray) Cronq. : Nevada Goldenrod - Solidago spectabilis var. spectabilis : Nevada Goldenrod - Solidago sphacelata Raf. : Autumn Goldenrod - Solidago spithamaea M.A. Curtis : Blue Ridge Goldenrod - Solidago squarrosa Nutt. : Stout Goldenrod, Big Goldenrod - Solidago stricta Ait. : Wand Goldenrod - Solidago tortifolia Ell. : Twistleaf Goldenrod - Solidago tenuifolia : Slender Goldenrod - Solidago uliginosa Nutt. : Bog Goldenrod Solidago uliginosa var. levipes (Fern.) Fern. : Bog Goldenrod Solidago uliginosa var. linoides (Torr. & Gray) Fern. : Bog Goldenrod Solidago uliginosa var. terrae-novae (Torr. & Gray) Fern. : Bog Goldenrod Solidago uliginosa. var. uliginosa : Bog Goldenrod - Solidago uliginosa var. levipes (Fern.) Fern. : Bog Goldenrod - Solidago uliginosa var. linoides (Torr. & Gray) Fern. : Bog Goldenrod - Solidago uliginosa var. terrae-novae (Torr. & Gray) Fern. : Bog Goldenrod - Solidago uliginosa. var. uliginosa : Bog Goldenrod - Solidago ulmifolia Muhl. ex Willd. : Elmleaf Goldenrod Solidago ulmifolia var. microphylla Gray : Elmleaf Goldenrod Solidago ulmifolia var. palmeri Cronq. : Palmer's Goldenrod Solidago ulmifolia var. ulmifolia : Elmleaf Goldenrod - Solidago ulmifolia var. microphylla Gray : Elmleaf Goldenrod - Solidago ulmifolia var. palmeri Cronq. : Palmer's Goldenrod - Solidago ulmifolia var. ulmifolia : Elmleaf Goldenrod - Solidago velutina DC. : Threenerve Goldenrod - Solidago verna M.A. Curtis : Springflowering Goldenrod - Solidago virgaurea : Goldenrod, Aaron’s Rod - Solidago wrightii Gray : Wright's Goldenrod Solidago wrightii var. adenophora Blake : Wright's Goldenrod Solidago wrightii var. wrightii : Wright's Goldenrod - Solidago wrightii var. adenophora Blake : Wright's Goldenrod - Solidago wrightii var. wrightii : Wright's Goldenrod # Natural hybrids - Solidago × asperula Desf. (S. rugosa × S. sempervirens) - Solidago × beaudryi Boivin (S. rugosa × S. uliginosa) - Solidago × erskinei Boivin (S. canadensis × S. sempervirens) - Solidago × ovata Friesner (S. sphacelata × S. ulmifolia) - Solidago × ulmicaesia Friesner (S. caesia × S. ulmifolia) # Note - ↑ D. A. SHEALER, J. P. SNYDER, V. C. DREISBACH, D. F. SUNDERLIN, and J. A. NOVAK (July 1999). "Foraging Patterns of Eastern Gray Squirrels (Sciurus carolinensis) on Goldenrod Gall Insects, a Potentially Important Winter Food Resource". The American Midland Naturalist. 142 (1): 102–109. doi:10.1674/0003-0031(1999)142%5B0102:FPOEGS%5D2.0.CO;2. Unknown parameter \|doilabel= ignored (help)CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ "Goldenrod Rubber". Time Magazine. December 16, 1929. - ↑ Jump up to: 3.0 3.1 Campion, Kitty. (1995). Holistic Woman's Herbal - How to Achieve Health and Well-Being at Any Age, ISBN 978-0760710302, "Basic Maintenance", Pg. 65, "Kidney/Bladder tincture" recipe (kidney cleansing); "Self-Monitoring: Genito-Urinary and Breast Health" Pg. 96, "Kidney/Bladder Tonic" tincture recipe (cystitis). Barnes & Noble, Inc. - ↑ Donna Cunningham (May 2001). "Goldenrod and Other Essences for School Transitions". Vibration Magazine: The Journal of Vibrational/Flower Essences. - ↑ STATE SEAL, SONG AND SYMBOLS of Delaware	Goldenrod The goldenrod is a yellow flowering plant in the Family Asteraceae. # Description About 80 perennial species make up the genus Solidago, most being found in the meadows and pastures, along roads, ditches and waste areas in North America, and a few from Europe that were introduced some 250 years ago. Many species are difficult to distinguish. Probably due to their bright, golden yellow flower heads blooming in late summer, the goldenrod is often unfairly blamed for causing hay fever in humans. The pollen causing these allergy problems is mainly produced by Ragweed (Ambrosia sp.), blooming at the same time as the goldenrod, but is wind-pollinated. Goldenrod pollen is too heavy and sticky to be blown far from the flowers, and is thus mainly pollinated by insects. Goldenrods are easily recognized by their golden inflorescence with hundreds of small capitula, but some are spike-like and other have auxiliary racemes. They have slender stems, usually hairless but S. canadensis shows hairs on the upper stem. They can grow to a length between 60 cm and 1.5 m. Their alternate leaves are linear to lanceolate. Their margins are usually finely to sharply serrated. Propagation is by wind-disseminated seed or by underground rhizomes. They form patches that are actually vegetative clones of a single plant. # Use and cultivation Goldenrod is used as a food plant by the larvae of some Lepidoptera species - see list of Lepidoptera that feed on goldenrods. The Goldenrod then forms a leathery bulb (called a gall) around the invading insect as a quarantine to keep it confined to a small part of the plant. Parasitoid wasps have evolved to find these galls, and lay eggs in the insect after penetrating the bulb. In a final nod to evolutionary complexity, woodpeckers have learned to blast open the gall and eat the wasp-infested insect holed up in the center.[1] Goldenrods can be used for decoration and making tea. Goldenrods are, in some places, held as a sign of good luck or good fortune; but they are considered weeds by some. Goldenrods are mostly short-day plants and bloom in late summer and early fall and some species produce abundant nectar when moisture is plentiful before bloom, and the bloom period is relatively warm and sunny. Honey from goldenrods often is dark and strong due to admixtures of other nectars. However when there is a strong honey flow, a light (often water white), spicy-tasting honey is produced. While the bees are ripening the honey there is a rank odor and taste, but finished honey is much milder. ## Garden use British gardeners adopted goldenrod long before Americans. Goldenrod only began to gain some acceptance in American gardening (other than wildflower gardening) during the 1980s. A hybrid with aster, known as x Solidaster is less unruly, with pale yellow flowers, equally suitable for dried arrangements. Solidago canadensis was introduced as a garden plant in Central Europe, and is now common in the wild. In Germany, it is considered an invasive species that displaces native vegetation from its natural habitat. Goldenrod is a companion plant, playing host to some beneficial insects, repelling some pests ## Industrial use Inventor Thomas Edison experimented with goldenrod to produce rubber, which it contains naturally.[2] Edison created a fertilization and cultivation process to maximize the rubber content in each plant. His experiments produced a 12 foot tall plant that yielded as much as 12 percent rubber. The rubber produced through Edison's process was resilient and long lasting. The tires on the Model T given to him by his friend Henry Ford were made from goldenrod. Examples of the rubber can still be found in his laboratory, elastic and rot free after more than 50 years. However, even though Edison turned his research over to the U.S. government a year before his death, goldenrod rubber never went beyond the experimental stage. ## Medicinal use The variety Solidago virgaurea is a traditional kidney tonic. It has aquaretic, anti-inflammatory, antispasmodic and antiseptic action and seems to increase kidney output.[citation needed] This makes it useful as an agent to counter inflammation and irritation of the kidneys when bacterial infection or stones are present.[3] Such use is in combination with other herbs that create a synergistic therapeutic effect on the urinary system. As in other areas of herbalism, blending creates a therapy greater than the effect of a single herb alone. The aquaretic action is also useful in helping to dissolve kidney stones by diluting their components and preventing them from reoccuring. See herbal medicine Goldenrod has also been used as part of a tincture to aid in cleansing of the kidney/bladder during a healing fast, in conjunction with Potassium broth and specific juices.[3] 'Solidago odora' is also sold as a medicinal, for these issues: mucus, kidney/bladder cleansing and stones, colds, digestion. Link here: http://www.pennherb.com/cgi-bin/herbstore.cgi/indexherbs for herbalist citation. # Cultural significance The goldenrod is the state flower of the U.S. states of Kentucky (adopted March 16, 1926) and Nebraska (adopted April 4, 1895). It used to be the state flower of Alabama, being adopted as such on September 6, 1927, but was later rejected in favour of the camellia. Goldenrod was recently named the state wildflower for South Carolina. In Midwestern states in the mid-twentieth century it was said that when the goldenrod bloomed, it would soon be time to go back to school--the blossoms appeared in mid- to late August, shortly before the traditional start of school on the day after Labor Day.[4] In Sufjan Stevens' song, Casimir Pulaski Day, the narrator brings goldenrod to his girlfriend upon finding out that she has been diagnosed with bone cancer. Carrie Hamby's song, Solidago, tells the story of Thomas Edison's experiments with making goldenrod a domestic source of rubber during the 2nd world war. The Sweet Goldenrod (Solidago odora) is also the state herb of Delaware as of June 24, 1996. [5] # Species - Solidago albopilosa E.L. Braun : Whitehair Goldenrod - Solidago altiplanities C.& J. Taylor : High Plains Goldenrod - Solidago arguta Ait. : Atlantic Goldenrod Solidago arguta. var. arguta : Atlantic Goldenrod Solidago arguta var. boottii (Hook.) Palmer & Steyermark : Boott's Goldenrod Solidago arguta var. caroliniana Gray : Atlantic Goldenrod Solidago arguta var. harrisii (Steele) Cronq. : Harris' Goldenrod Solidago arguta var. neurolepis (Fern.) Steyermark : Atlantic Goldenrod - Solidago arguta. var. arguta : Atlantic Goldenrod - Solidago arguta var. boottii (Hook.) Palmer & Steyermark : Boott's Goldenrod - Solidago arguta var. caroliniana Gray : Atlantic Goldenrod - Solidago arguta var. harrisii (Steele) Cronq. : Harris' Goldenrod - Solidago arguta var. neurolepis (Fern.) Steyermark : Atlantic Goldenrod - Solidago auriculata Shuttlw. ex Blake : Eared Goldenrod - Solidago bicolor L. : White Goldenrod - Solidago brachyphylla Chapman : Dixie Goldenrod - Solidago buckleyi Torr. & Gray : Buckley's Goldenrod (Template:StatusVulnerable) - Solidago caesia L. : Wreath Goldenrod Solidago caesia var. caesia : Wreath Goldenrod Solidago caesia var. curtisii (Torr. & Gray) Wood : Mountain Decumbent Goldenrod - Solidago caesia var. caesia : Wreath Goldenrod - Solidago caesia var. curtisii (Torr. & Gray) Wood : Mountain Decumbent Goldenrod - Solidago calcicola Fern. : Limestone Goldenrod - Solidago californica Nutt. : California Goldenrod - Solidago canadensis L. : Canada Goldenrod, Canadian Goldenrod Solidago canadensis var. canadensis : Canada Goldenrod Solidago canadensis var. gilvocanescens Rydb. : Shorthair Goldenrod Solidago canadensis var. hargeri Fern. : Harger's Goldenrod Solidago canadensis var. lepida (DC.) Cronq. : Canada Goldenrod Solidago canadensis var. salebrosa (Piper) M.E. Jones : Salebrosa Goldenrod Solidago canadensis var. scabra Torr. & Gray : Canada Goldenrod - Solidago canadensis var. canadensis : Canada Goldenrod - Solidago canadensis var. gilvocanescens Rydb. : Shorthair Goldenrod - Solidago canadensis var. hargeri Fern. : Harger's Goldenrod - Solidago canadensis var. lepida (DC.) Cronq. : Canada Goldenrod - Solidago canadensis var. salebrosa (Piper) M.E. Jones : Salebrosa Goldenrod - Solidago canadensis var. scabra Torr. & Gray : Canada Goldenrod - Solidago cutleri Fern. : Cutler's alpine Goldenrod - Solidago deamii Fern. : Deam's Goldenrod - Solidago discoidea Ell. : Rayless Mock Goldenrod - Solidago fistulosa P. Mill. : Pinebarren Goldenrod - Solidago flaccidifolia Small : Mountain Goldenrod - Solidago flexicaulis L. : Zigzag Goldenrod - Solidago gattingeri Chapman : Gattinger's Goldenrod - Solidago gigantea Ait. : Giant Goldenrod - Solidago glomerata Michx. : Clustered Goldenrod - Solidago gracillima Torr. & Gray : Virginia Goldenrod - Solidago guiradonis Gray : Guirado Goldenrod - Solidago hispida Muhl. ex Willd. : Hairy Goldenrod Solidago hispida var. arnoglossa Fern. : Hairy Goldenrod Solidago hispida var. hispida : Hairy Goldenrod Solidago hispida var. lanata (Hook.) Fern. : Hairy Goldenrod Solidago hispida var. tonsa Fern. : Hairy Goldenrod - Solidago hispida var. arnoglossa Fern. : Hairy Goldenrod - Solidago hispida var. hispida : Hairy Goldenrod - Solidago hispida var. lanata (Hook.) Fern. : Hairy Goldenrod - Solidago hispida var. tonsa Fern. : Hairy Goldenrod - Solidago juliae Nesom : Julia's Goldenrod - Solidago juncea Ait. : Early Goldenrod - Solidago latissimifolia P. Mill. : Elliott's Goldenrod - Solidago leavenworthii Torr. & Gray : Leavenworth's Goldenrod - Solidago ludoviciana (Gray) Small : Louisiana Goldenrod - Solidago macrophylla Pursh : Largeleaf Goldenrod - Solidago missouriensis Nutt. : Missouri Goldenrod Solidago missouriensis var. fasciculata Holz. : Missouri Goldenrod Solidago missouriensis var. missouriensis : Missouri Goldenrod Solidago missouriensis var. tenuissima (Woot. & Standl.) C.& J. Taylor : Missouri Goldenrod Solidago missouriensis Nutt. var. tolmieana (Gray) Cronq. : Tolmies' Goldenrod - Solidago missouriensis var. fasciculata Holz. : Missouri Goldenrod - Solidago missouriensis var. missouriensis : Missouri Goldenrod - Solidago missouriensis var. tenuissima (Woot. & Standl.) C.& J. Taylor : Missouri Goldenrod - Solidago missouriensis Nutt. var. tolmieana (Gray) Cronq. : Tolmies' Goldenrod - Solidago mollis Bartl. : Velvety Goldenrod Solidago mollis var. angustata Shinners : Velvety Goldenrod Solidago mollis var. mollis : Velvety Goldenrod - Solidago mollis var. angustata Shinners : Velvety Goldenrod - Solidago mollis var. mollis : Velvety Goldenrod - Solidago multiradiata Ait. : Rocky Mountain Goldenrod, Alpine Goldenrod Solidago multiradiata var. arctica (DC.) Fern. : Arctic Goldenrod Solidago multiradiata var. multiradiata : Rocky Mountain Goldenrod Solidago multiradiata var. scopulorum Gray : Manyray Goldenrod - Solidago multiradiata var. arctica (DC.) Fern. : Arctic Goldenrod - Solidago multiradiata var. multiradiata : Rocky Mountain Goldenrod - Solidago multiradiata var. scopulorum Gray : Manyray Goldenrod - Solidago nana Nutt. : Baby Goldenrod - Solidago nemoralis Ait. : Gray Goldenrod, American Western Goldenrod Solidago nemoralis var. longipetiolata (Mackenzie & Bush) Palmer & Steyermark : Gray Goldenrod Solidago nemoralis var. nemoralis : Gray Goldenrod - Solidago nemoralis var. longipetiolata (Mackenzie & Bush) Palmer & Steyermark : Gray Goldenrod - Solidago nemoralis var. nemoralis : Gray Goldenrod - Solidago odora Ait. : Anise-scented Goldenrod, Sweet Goldenrod Solidago odora var. chapmanii (Gray) Cronq. : Chapman's Goldenrod Solidago odora var. odora : Anise-scented Goldenrod - Solidago odora var. chapmanii (Gray) Cronq. : Chapman's Goldenrod - Solidago odora var. odora : Anise-scented Goldenrod - Solidago ouachitensis C.& J. Taylor : Ouachita Mountain Goldenrod - Solidago patula Muhl. ex Willd. : Roundleaf Goldenrod Solidago patula var. patula : Roundleaf Goldenrod Solidago patula var. strictula Torr. & Gray : Roundleaf Goldenrod - Solidago patula var. patula : Roundleaf Goldenrod - Solidago patula var. strictula Torr. & Gray : Roundleaf Goldenrod - Solidago petiolaris Ait. : Downy Ragged Goldenrod Solidago petiolaris var. angusta (Torr. & Gray) Gray : Downy Ragged Goldenrod Solidago petiolaris var. petiolaris : Downy Ragged Goldenrod - Solidago petiolaris var. angusta (Torr. & Gray) Gray : Downy Ragged Goldenrod - Solidago petiolaris var. petiolaris : Downy Ragged Goldenrod - Solidago pinetorum Small : Small's Goldenrod - Solidago plumosa Small : Plumed Goldenrod - Solidago porteri Small : Porter's Goldenrod - Solidago puberula Nutt. : Downy Goldenrod (Template:StatusVulnerable) Solidago puberula var. puberula : Downy Goldenrod Solidago puberula var. pulverulenta (Nutt.) Chapman : Downy Goldenrod - Solidago puberula var. puberula : Downy Goldenrod - Solidago puberula var. pulverulenta (Nutt.) Chapman : Downy Goldenrod - Solidago pulchra Small : Carolina Goldenrod - Solidago radula Nutt. : Western Rough Goldenrod Solidago radula var. laeta (Greene) Fern. : Western Rough Goldenrod Solidago radula var. radula : Western Rough Goldenrod Solidago radula var. stenolepis Fern. : Western Rough Goldenrod - Solidago radula var. laeta (Greene) Fern. : Western Rough Goldenrod - Solidago radula var. radula : Western Rough Goldenrod - Solidago radula var. stenolepis Fern. : Western Rough Goldenrod - Solidago roanensis Porter : Roan Mountain Goldenrod Template:StatusEndangered - Solidago rugosa P. Mill. : Wrinkleleaf Goldenrod, Rough-stemmed Goldenrod Solidago rugosa subsp. aspera (Ait.) Cronq. : Wrinkleleaf Goldenrod Solidago rugosa subsp. rugosa : Wrinkleleaf Goldenrod Solidago rugosa subsp. rugosa var. rugosa : Wrinkleleaf Goldenrod Solidago rugosa subsp. rugosa var. sphagnophila Graves : Wrinkleleaf Goldenrod Solidago rugosa subsp. rugosa var. villosa (Pursh) Fern. : Wrinkleleaf Goldenrod - Solidago rugosa subsp. aspera (Ait.) Cronq. : Wrinkleleaf Goldenrod - Solidago rugosa subsp. rugosa : Wrinkleleaf Goldenrod Solidago rugosa subsp. rugosa var. rugosa : Wrinkleleaf Goldenrod Solidago rugosa subsp. rugosa var. sphagnophila Graves : Wrinkleleaf Goldenrod Solidago rugosa subsp. rugosa var. villosa (Pursh) Fern. : Wrinkleleaf Goldenrod - Solidago rugosa subsp. rugosa var. rugosa : Wrinkleleaf Goldenrod - Solidago rugosa subsp. rugosa var. sphagnophila Graves : Wrinkleleaf Goldenrod - Solidago rugosa subsp. rugosa var. villosa (Pursh) Fern. : Wrinkleleaf Goldenrod - Solidago rupestris Raf. : Eock Goldenrod - Solidago sciaphila Steele : Shadowy Goldenrod - Solidago sempervirens L. : Seaside Goldenrod, Beach Goldenrod Solidago sempervirens var. mexicana (L.) Fern. : Seaside Goldenrod Solidago sempervirens var. sempervirens : Seaside Goldenrod - Solidago sempervirens var. mexicana (L.) Fern. : Seaside Goldenrod - Solidago sempervirens var. sempervirens : Seaside Goldenrod - Solidago shortii Torr. & Gray : Short's Goldenrod Template:StatusEndangered - Solidago simplex Kunth : Mt. Albert Goldenrod - Solidago simplex subsp. randii (Porter) Ringius : Rand's Goldenrod Solidago simplex subsp. randii var. gillmanii (Gray) Ringius : Rand's Goldenrod Solidago simplex subsp. randii var. monticola (Porter) Ringius : Rand's Goldenrod Solidago simplex subsp. randii var. ontarioensis (Ringius) Ringius : Ontario Goldenrod Solidago simplex subsp. randii var. racemosa (Greene) Ringius : Rand's Goldenrod Solidago simplex subsp. randii var. randii (Porter) Kartesz & Gandhi : Rand's Goldenrod Solidago simplex subsp. simplex : Mt. Albert Goldenrod Solidago simplex subsp. simplex var. nana (Gray) Ringius : Dwarf Goldenrod Solidago simplex subsp. simplex var. simplex : Mt. Albert Goldenrod Solidago simplex subsp. simplex var. spathulata (DC.) Cronq. : Mt. Albert Goldenrod - Solidago simplex subsp. randii var. gillmanii (Gray) Ringius : Rand's Goldenrod Solidago simplex subsp. randii var. monticola (Porter) Ringius : Rand's Goldenrod Solidago simplex subsp. randii var. ontarioensis (Ringius) Ringius : Ontario Goldenrod Solidago simplex subsp. randii var. racemosa (Greene) Ringius : Rand's Goldenrod Solidago simplex subsp. randii var. randii (Porter) Kartesz & Gandhi : Rand's Goldenrod - Solidago simplex subsp. randii var. monticola (Porter) Ringius : Rand's Goldenrod - Solidago simplex subsp. randii var. ontarioensis (Ringius) Ringius : Ontario Goldenrod - Solidago simplex subsp. randii var. racemosa (Greene) Ringius : Rand's Goldenrod - Solidago simplex subsp. randii var. randii (Porter) Kartesz & Gandhi : Rand's Goldenrod - Solidago simplex subsp. simplex : Mt. Albert Goldenrod Solidago simplex subsp. simplex var. nana (Gray) Ringius : Dwarf Goldenrod Solidago simplex subsp. simplex var. simplex : Mt. Albert Goldenrod Solidago simplex subsp. simplex var. spathulata (DC.) Cronq. : Mt. Albert Goldenrod - Solidago simplex subsp. simplex var. nana (Gray) Ringius : Dwarf Goldenrod - Solidago simplex subsp. simplex var. simplex : Mt. Albert Goldenrod - Solidago simplex subsp. simplex var. spathulata (DC.) Cronq. : Mt. Albert Goldenrod - Solidago simulans Fern. : Fall Goldenrod - Solidago speciosa Nutt. : Showy Goldenrod Solidago speciosa var. erecta (Pursh) MacM. : Showy Goldenrod Solidago speciosa var. jejunifolia (Steele) Cronq. : Showy Goldenrod Solidago speciosa var. pallida Porter :Showy Goldenrod Solidago speciosa var. rigidiuscula Torr. & Gray : Showy Goldenrod Solidago speciosa var. speciosa : Showy Goldenrod - Solidago speciosa var. erecta (Pursh) MacM. : Showy Goldenrod - Solidago speciosa var. jejunifolia (Steele) Cronq. : Showy Goldenrod - Solidago speciosa var. pallida Porter :Showy Goldenrod - Solidago speciosa var. rigidiuscula Torr. & Gray : Showy Goldenrod - Solidago speciosa var. speciosa : Showy Goldenrod - Solidago spectabilis (D.C. Eat.) Gray : Nevada Goldenrod Solidago spectabilis var. confinis (Gray) Cronq. : Nevada Goldenrod Solidago spectabilis var. spectabilis : Nevada Goldenrod - Solidago spectabilis var. confinis (Gray) Cronq. : Nevada Goldenrod - Solidago spectabilis var. spectabilis : Nevada Goldenrod - Solidago sphacelata Raf. : Autumn Goldenrod - Solidago spithamaea M.A. Curtis : Blue Ridge Goldenrod - Solidago squarrosa Nutt. : Stout Goldenrod, Big Goldenrod - Solidago stricta Ait. : Wand Goldenrod - Solidago tortifolia Ell. : Twistleaf Goldenrod - Solidago tenuifolia : Slender Goldenrod - Solidago uliginosa Nutt. : Bog Goldenrod Solidago uliginosa var. levipes (Fern.) Fern. : Bog Goldenrod Solidago uliginosa var. linoides (Torr. & Gray) Fern. : Bog Goldenrod Solidago uliginosa var. terrae-novae (Torr. & Gray) Fern. : Bog Goldenrod Solidago uliginosa. var. uliginosa : Bog Goldenrod - Solidago uliginosa var. levipes (Fern.) Fern. : Bog Goldenrod - Solidago uliginosa var. linoides (Torr. & Gray) Fern. : Bog Goldenrod - Solidago uliginosa var. terrae-novae (Torr. & Gray) Fern. : Bog Goldenrod - Solidago uliginosa. var. uliginosa : Bog Goldenrod - Solidago ulmifolia Muhl. ex Willd. : Elmleaf Goldenrod Solidago ulmifolia var. microphylla Gray : Elmleaf Goldenrod Solidago ulmifolia var. palmeri Cronq. : Palmer's Goldenrod Solidago ulmifolia var. ulmifolia : Elmleaf Goldenrod - Solidago ulmifolia var. microphylla Gray : Elmleaf Goldenrod - Solidago ulmifolia var. palmeri Cronq. : Palmer's Goldenrod - Solidago ulmifolia var. ulmifolia : Elmleaf Goldenrod - Solidago velutina DC. : Threenerve Goldenrod - Solidago verna M.A. Curtis : Springflowering Goldenrod - Solidago virgaurea : Goldenrod, Aaron’s Rod - Solidago wrightii Gray : Wright's Goldenrod Solidago wrightii var. adenophora Blake : Wright's Goldenrod Solidago wrightii var. wrightii : Wright's Goldenrod - Solidago wrightii var. adenophora Blake : Wright's Goldenrod - Solidago wrightii var. wrightii : Wright's Goldenrod # Natural hybrids - Solidago × asperula Desf. (S. rugosa × S. sempervirens) - Solidago × beaudryi Boivin (S. rugosa × S. uliginosa) - Solidago × erskinei Boivin (S. canadensis × S. sempervirens) - Solidago × ovata Friesner (S. sphacelata × S. ulmifolia) - Solidago × ulmicaesia Friesner (S. caesia × S. ulmifolia) # Note - ↑ D. A. SHEALER, J. P. SNYDER, V. C. DREISBACH, D. F. SUNDERLIN, and J. A. NOVAK (July 1999). "Foraging Patterns of Eastern Gray Squirrels (Sciurus carolinensis) on Goldenrod Gall Insects, a Potentially Important Winter Food Resource". The American Midland Naturalist. 142 (1): 102–109. doi:10.1674/0003-0031(1999)142%5B0102:FPOEGS%5D2.0.CO;2. Unknown parameter \|doilabel= ignored (help)CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ "Goldenrod Rubber". Time Magazine. December 16, 1929. - ↑ Jump up to: 3.0 3.1 Campion, Kitty. (1995). Holistic Woman's Herbal - How to Achieve Health and Well-Being at Any Age, ISBN 978-0760710302, "Basic Maintenance", Pg. 65, "Kidney/Bladder tincture" recipe (kidney cleansing); "Self-Monitoring: Genito-Urinary and Breast Health" Pg. 96, "Kidney/Bladder Tonic" tincture recipe (cystitis). Barnes & Noble, Inc. - ↑ Donna Cunningham (May 2001). "Goldenrod and Other Essences for School Transitions". Vibration Magazine: The Journal of Vibrational/Flower Essences. - ↑ STATE SEAL, SONG AND SYMBOLS of Delaware	https://www.wikidoc.org/index.php/Goldenrod
fac87b5fc230c7555dd7d7c3cca59c84c8daaec7	wikidoc	Golimumab	Golimumab # 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 Golimumab is a tumor necrosis factor inhibitor that is FDA approved for the treatment of moderately to severely active rheumatoid arthritis (RA), active psoriatic arthritis (PsA), active ankylosing spondylitis (AS); and moderate to severe Ulcerative colitis (UC) with an inadequate response or intolerant to prior treatment or requiring continuous steroid therapy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include upper respiratory tract infection, nasopharyngitis and injection site reactions. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Golimumab, in combination with methotrexate, is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis. - Dosage: 50 mg administered by subcutaneous injection once a month - Golimumab, alone or in combination with methotrexate, is indicated for the treatment of adult patients with active psoriatic arthritis. - Dosage: 50 mg administered by subcutaneous injection once a month - Golimumab is indicated for the treatment of adult patients with active ankylosing spondylitis. - Dosage: 50 mg administered by subcutaneous injection once a month - Golimumab is indicated in adult patients with moderately to severely active ulcerative colitis who have demonstrated corticosteroid dependence or who have had an inadequate response to or failed to tolerate oral aminosalicylates, oral corticosteroids, azathioprine, or 6-mercaptopurine for: - inducing and maintaining clinical response - improving endoscopic appearance of the mucosa during induction - inducing clinical remission - achieving and sustaining clinical remission in induction responders - Dosage: 200 mg subcutaneous injection at Week 0, followed by 100 mg at Week 2 and then maintenance therapy with 100 mg every 4 weeks. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Golimumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Golimumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness of golimumab have not been established in pediatric patients younger than 18 years ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Golimumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Golimumab in pediatric patients. # Contraindications None # Warnings ### Serious Infections Patients treated with golimumab are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, or parasitic organisms including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, and tuberculosis have been reported with TNF-blockers. Patients have frequently presented with disseminated rather than localized disease. The concomitant use of a TNF-blocker and abatacept or anakinra was associated with a higher risk of serious infections; therefore, the concomitant use of golimumab and these biologic products is not recommended. Treatment with golimumab should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants such as corticosteroids or methotrexate may be at greater risk of infection. Consider the risks and benefits of treatment prior to initiating golimumab in patients: - with chronic or recurrent infection; - who have been exposed to tuberculosis; - with a history of an opportunistic infection; - who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or - with underlying conditions that may predispose them to infection. In controlled Phase 3 trials through Week 16 in patients with RA, PsA, and AS, serious infections were observed in 1.4% of golimumab-treated patients and 1.3% of control-treated patients. In the controlled Phase 3 trials through Week 16 in patients with RA, PsA, and AS, the incidence of serious infections per 100 patient-years of follow-up was 5.7 (95% CI: 3.8, 8.2) for the golimumab group and 4.2 (95% CI: 1.8, 8.2) for the placebo group. In the controlled Phase 2/3 trial through Week 6 of golimumab induction in UC, the incidence of serious infections in golimumab 200/100 mg-treated patients was similar to the incidence of serious infections in placebo-treated patients. Through Week 60, the incidence of serious infections was similar in patients who received golimumab induction and 100 mg during maintenance compared with patients who received golimumab induction and placebo during the maintenance portion of the UC trial. Serious infections observed in golimumab-treated patients included sepsis, pneumonia, cellulitis, abscess, tuberculosis, invasive fungal infections, and hepatitis B infection. Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving TNF-blockers, including patients who have previously received treatment for latent or active tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating golimumab and periodically during therapy. Treatment of latent tuberculosis infection prior to therapy with TNF-blockers has been shown to reduce the risk of tuberculosis reactivation during therapy. Prior to initiating golimumab, assess if treatment for latent tuberculosis is needed; an induration of 5 mm or greater is a positive tuberculin skin test, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG). Consider anti-tuberculosis therapy prior to initiation of golimumab in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Cases of active tuberculosis have occurred in patients treated with golimumab during and after treatment for latent tuberculosis. Monitor patients for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy, patients who are on treatment for latent tuberculosis, or patients who were previously treated for tuberculosis infection. Consider tuberculosis in the differential diagnosis in patients who develop a new infection during golimumab treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis. In the controlled and uncontrolled portions of the Phase 2 RA and Phase 3 RA, PsA, and AS trials, the incidence of active TB was 0.23 and 0 per 100 patient-years in 2347 golimumab-treated patients and 674 placebo-treated patients, respectively. Cases of TB included pulmonary and extra pulmonary TB. The overwhelming majority of the TB cases occurred in countries with a high incidence rate of TB. In the controlled Phase 2/3 trial of golimumab induction through Week 6 in UC, no cases of TB were observed in golimumab 200/100 mg-treated patients or in placebo-treated patients. Through Week 60, the incidence per 100 patient-years of TB in patients who received golimumab induction and 100 mg during the maintenance portion of the UC trial was 0.52 (95% CI: 0.11, 1.53). One case of TB was observed in the placebo maintenance group in a patient who received golimumab intravenous (IV) induction. If patients develop a serious systemic illness and they reside or travel in regions where mycoses are endemic, consider invasive fungal infection in the differential diagnosis. Consider appropriate empiric antifungal therapy and take into account both the risk for severe fungal infection and the risks of antifungal therapy while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. To aid in the management of such patients, consider consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections. The use of TNF-blockers including golimumab has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers (i.e., surface antigen positive). In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients who received concomitant immunosuppressants. All patients should be tested for HBV infection before initiating TNF-blocker therapy. For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended before initiating TNF-blocker therapy. The risks and benefits of treatment should be considered prior to prescribing TNF-blockers, including golimumab, to patients who are carriers of HBV. Adequate data are not available on whether anti-viral therapy can reduce the risk of HBV reactivation in HBV carriers who are treated with TNF-blockers. Patients who are carriers of HBV and require treatment with TNF-blockers should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, TNF-blockers should be stopped and antiviral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF-blockers after HBV reactivation has been controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF-blockers in this situation and monitor patients closely. ### Malignancies Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation of therapy ≤ 18 years of age), of which golimumab is a member. Approximately half the cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression, and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (range 1 to 84 months) after the first dose of TNF blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports. The risks and benefits of TNF-blocker treatment including golimumab should be considered prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF-blocker in patients who develop a malignancy. In the controlled portions of clinical trials of TNF-blockers including golimumab, more cases of lymphoma have been observed among patients receiving anti-TNF treatment compared with patients in the control groups. During the controlled portions of the Phase 2 trials in RA, and the Phase 3 trials in RA, PsA and AS, the incidence of lymphoma per 100 patient-years of follow-up was 0.21 (95% CI: 0.03, 0.77) in the combined golimumab group compared with an incidence of 0 (95% CI: 0., 0.96) in the placebo group. In the controlled and uncontrolled portions of these clinical trials in 2347 golimumab-treated patients with a median follow-up of 1.4 years, the incidence of lymphoma was 3.8-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).1 Through Week 60 of the UC trials, there were no cases of lymphoma with golimumab. Patients with RA and other chronic inflammatory diseases, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF blocker therapy, patients with rheumatoid arthritis may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia. Rare post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with TNF-blocking agents. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. Nearly all of the reported TNF-blocker associated cases have occurred in patients with Crohn's disease or ulcerative colitis. The majority were in adolescent and young adult males. Almost all these patients had received treatment with azathioprine (AZA) or 6-mercaptopurine (6–MP) concomitantly with a TNF blocker at or prior to diagnosis. The potential risk with the combination of AZA or 6-MP and golimumab should be carefully considered. A risk for the development for hepatosplenic T-cell lymphoma in patients treated with TNF-blockers cannot be excluded. During the controlled portions of the Phase 2 trial in RA, and the Phase 3 trials in RA, PsA and AS, the incidence of malignancies other than lymphoma per 100 patient-years of follow-up was not elevated in the combined golimumab group compared with the placebo group. In the controlled and uncontrolled portions of these trials, the incidence of malignancies, other than lymphoma, in golimumab-treated patients was similar to that expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).1 In the 6-week placebo-controlled portions of the golimumab Phase 2/3 clinical trials in UC, the incidence of non-lymphoma malignancies (excluding non-melanoma skin cancer) was similar between the golimumab and the placebo group. Through Week 60, the incidence of non-lymphoma malignancies (excluding non-melanoma skin cancer) was similar to the general U.S. population according to the SEER database (adjusted for age, gender, and race). Short follow-up periods, such as those of one year or less in the studies above, may not adequately reflect the true incidence of malignancies. It is not known if golimumab treatment influences the risk for developing dysplasia or colon cancer. All patients with ulcerative colitis who are at increased risk for dysplasia or colon carcinoma (for example, patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or who had a prior history of dysplasia or colon carcinoma should be screened for dysplasia at regular intervals before therapy and throughout their disease course. This evaluation should include colonoscopy and biopsies per local recommendations. In patients with newly diagnosed dysplasia treated with golimumab, the risks and benefits to the individual patient must be carefully reviewed and consideration should be given to whether therapy should be continued. Melanoma has been reported in patients treated with TNF-blocking agents, including golimumab. Merkel cell carcinoma has been reported in patients treated with TNF-blocking agents. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. In controlled trials of other TNF-blockers in patients at higher risk for malignancies (e.g., patients with COPD, patients with Wegener's granulomatosis treated with concomitant cyclophosphamide) a greater portion of malignancies occurred in the TNF-blocker group compared to the controlled group. In an exploratory 1-year clinical trial evaluating the use of 50, 100 and 200 mg of golimumab in 309 patients with severe persistent asthma, 6 patients developed malignancies other than NMSC in the golimumab groups compared to none in the control group. Three of the 6 patients were in the 200 mg golimumab group. ### Congestive Heart Failure Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF-blockers, including golimumab. In several exploratory trials of other TNF-blockers in the treatment of CHF, there were greater proportions of TNF-blocker treated patients who had CHF exacerbations requiring hospitalization or increased mortality. golimumab has not been studied in patients with a history of CHF and golimumab should be used with caution in patients with CHF. If a decision is made to administer golimumab to patients with CHF, these patients should be closely monitored during therapy, and golimumab should be discontinued if new or worsening symptoms of CHF appear. ### Demyelinating Disorders Use of TNF-blockers, of which golimumab is a member, has been associated with rare cases of new onset or exacerbation of central nervous system (CNS) demyelinating disorders, including multiple sclerosis (MS) and peripheral demyelinating disorders, including Guillain-Barré syndrome. Cases of central demyelination, MS, optic neuritis, and peripheral demyelinating polyneuropathy have rarely been reported in patients treated with golimumab. Prescribers should exercise caution in considering the use of TNF-blockers, including golimumab, in patients with central or peripheral nervous system demyelinating disorders. Discontinuation of golimumab should be considered if these disorders develop. ### Use with Abatacept In controlled trials, the concurrent administration of another TNF-blocker and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; and the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of TNF-blockers including golimumab and abatacept is not recommended. ### Use with Anakinra Concurrent administration of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater portion of serious infections and neutropenia and no additional benefits compared with the TNF-blocker alone. Therefore, the combination of anakinra with TNF-blockers, including golimumab, is not recommended. ### Switching Between Biological Disease Modifying Antirheumatic Drugs Care should be taken when switching from one biological product to another biological product since overlapping biological activity may further increase the risk of infection. ### Hematologic Cytopenias There have been post-marketing reports of pancytopenia, leukopenia, neutropenia, aplastic anemia, and thrombocytopenia in patients receiving TNF-blockers. In clinical trials, cases of pancytopenia, leukopenia, neutropenia, and thrombocytopenia have also occurred in golimumab-treated patients. Caution should be exercised when using TNF-blockers, including golimumab, in patients who have or have had significant cytopenias. ### Vaccinations/Therapeutic Infectious Agents Patients treated with golimumab may receive vaccinations, except for live vaccines. In patients receiving anti-TNF therapy, limited data are available on the response to live vaccination, or on the secondary transmission of infection by live vaccines. Use of live vaccines could result in clinical infections, including disseminated infections. Other uses of therapeutic infectious agents such as live attenuated bacteria (e.g., BCG bladder instillation for the treatment of cancer) could result in clinical infections, including disseminated infections. It is recommended that therapeutic infectious agents not be given concurrently with golimumab. In the Phase 3 PsA trial, after pneumococcal vaccination, a similar proportion of golimumab-treated and placebo-treated patients were able to mount an adequate immune response of at least a 2-fold increase in antibody titers to pneumococcal polysaccharide vaccine. In both golimumab-treated and placebo-treated patients, the proportions of patients with response to pneumococcal vaccine were lower among patients receiving MTX compared with patients not receiving MTX. The data suggest that golimumab does not suppress the humoral immune response to the pneumococcal vaccine. ### Hypersensitivity Reactions In post-marketing experience, serious systemic hypersensitivity reactions (including anaphylactic reaction) have been reported following golimumab administration. Some of these reactions occurred after the first administration of golimumab. If an anaphylactic or other serious allergic reaction occurs, administration of golimumab should be discontinued immediately and appropriate therapy instituted. # Adverse Reactions ## Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety data described below are based on 5 pooled, randomized, double-blind, controlled Phase 3 trials in patients with RA, PsA, and AS (Trials RA-1, RA-2, RA-3, PsA, and AS). These 5 trials included 639 control-treated patients and 1659 golimumab-treated patients including 1089 with RA, 292 with PsA, and 278 with AS. The safety data in 1233 golimumab-treated patients with ulcerative colitis from 3 pooled, randomized, double-blind, controlled Phase 2/3 trials are also described below (Trials UC-1, UC-2, and UC-3). The proportion of patients who discontinued treatment due to adverse reactions in the controlled Phase 3 trials through Week 16 in RA, PsA and AS was 2% for golimumab-treated patients and 3% for placebo-treated patients. The most common adverse reactions leading to discontinuation of golimumab in the controlled Phase 3 trials in RA, PsA and AS through Week 16 were sepsis (0.2%), alanine aminotransferase increased (0.2%), and aspartate aminotransferase increased (0.2%). The most common adverse drug reactions leading to discontinuation through Week 60 of the UC trials in patients who received golimumab induction and 100 mg during maintenance compared with patients who received golimumab induction and placebo during maintenance were tuberculosis (0.3% vs 0.6%) and anemia (0.3% vs 0%), respectively. The most serious adverse reactions were: - Serious Infections - Malignancies Upper respiratory tract infection and nasopharyngitis were the most common adverse reactions reported in the combined Phase 3 RA, PsA and AS trials through Week 16, occurring in 7% and 6% of golimumab-treated patients as compared with 6% and 5% of control-treated patients, respectively. In controlled Phase 3 trials through Week 16 in RA, PsA, and AS, infections were observed in 28% of golimumab-treated patients compared to 25% of control-treated patients. For serious infections, see the Warnings and Precautions section. In the controlled Phase 2/3 trial of golimumab induction through Week 6 in UC, the rates of infections were similar in golimumab 200/100 mg-treated patients and placebo-treated patients, or approximately 12%. Through Week 60, the incidence per patient year of infections was similar in patients who received golimumab induction and 100 mg during maintenance compared with patients who received golimumab induction and placebo during the maintenance portion of the UC trial. In the controlled Phase 2/3 trial of golimumab induction through Week 6, no cases of demyelination were observed in golimumab 200/100 mg-treated patients or placebo-treated patients. Through Week 60, there were no cases of demyelination in the golimumab 100 mg group during maintenance. One case of CNS demyelination was observed in the placebo maintenance group in a patient who received golimumab 400/200 mg during induction. There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of golimumab in patients with RA, PsA, and AS through Week 16, ALT elevations ≥ 5 × ULN occurred in 0.2% of control-treated patients and 0.7% of golimumab-treated patients and ALT elevations ≥ 3 × ULN occurred in 2% of control-treated patients and 2% of golimumab-treated patients. Since many of the patients in the Phase 3 trials for RA, PsA, and AS were also taking medications that cause liver enzyme elevations (e.g., NSAIDs, MTX), the relationship between golimumab and liver enzyme elevation is not clear. In Phase 2/3 UC trials, the incidence of ALT elevations ≥ 5 × ULN was similar in golimumab-treated patients and placebo-treated patients, or approximately 1%, with an average duration of follow-up of 46 weeks and 18 weeks, respectively. ALT elevations ≥ 3 × ULN occurred in 2.0% of golimumab-treated patients compared with 1.5% of placebo-treated patients with an average duration of follow-up of 46 weeks and 18 weeks, respectively. The use of TNF-blockers, including golimumab, has been associated with the formation of autoantibodies and, rarely, with the development of a lupus-like syndrome. In the controlled Phase 3 trials in patients with RA, PsA, and AS through Week 14, there was no association of golimumab treatment and the development of newly positive anti-dsDNA antibodies. In Phase 3 trials in RA, PsA, and AS through 1 year of follow up, 4.0% of golimumab-treated patients and 2.6% of control patients were newly ANA-positive (at titers of 1:160 or greater). The frequency of anti-dsDNA antibodies at 1 year of follow up was uncommon in patients who were anti-dsDNA negative at baseline. Through Week 60 of the UC trials, 3.5% of patients who received golimumab induction and 100 mg during maintenance were newly ANA-positive (at titers of 1:160 or greater) compared with 3.5% of patients who received golimumab induction and placebo during the maintenance portion of the UC trial. The frequency of anti-dsDNA antibodies at 1 year of follow up in patients who were anti-dsDNA negative at baseline was 0.5% in patients receiving golimumab induction and 100 mg during maintenance compared with 0% in patients who received golimumab induction and placebo during maintenance. In controlled Phase 3 trials through Week 16 in RA, PsA and AS, 6% of golimumab-treated patients had injection site reactions compared with 2% of control-treated patients. The majority of the injection site reactions were mild and the most frequent manifestation was injection site erythema. In the controlled Phase 2/3 trial through Week 6 in UC, 3.4% of golimumab-treated patients had injection site reactions compared with 1.5% in control-treated patients. The majority of the injection site reactions were mild and moderate and the most frequent manifestation was injection site erythema. In controlled Phase 2 and 3 trials in RA, PsA, AS, and Phase 2/3 UC trials, no patients treated with golimumab developed anaphylactic reactions. Antibodies to golimumab were detected in 57 (4%) of golimumab-treated patients across the Phase 3 RA, PsA, and AS trials through Week 24. Similar rates were observed in each of the three indications. Patients who received golimumab with concomitant MTX had a lower proportion of antibodies to golimumab than patients who received golimumab without MTX (approximately 2% versus 7%, respectively). The presence of serum concentrations of golimumab can interfere with the detection of antibodies to golimumab leading to inconclusive results. In UC trials, 34 (3%), 341 (28%) and 823 (69%) of golimumab-treated subjects were positive, negative and inconclusive for antibodies to golimumab, respectively. Treatment with concomitant immunomodulators (AZA, 6-MP and MTX) resulted in a lower proportion of patients with antibodies to golimumab than patients receiving golimumab without immunomodulators (2% versus 4%, respectively). Of the patients with a positive antibody response to golimumab in the Phase 2 and 3 trials, most were determined to have neutralizing antibodies to golimumab as measured by a cell-based functional assay. The small number of patients positive for antibodies to golimumab limits the ability to draw definitive conclusions regarding the relationship between antibodies to golimumab and clinical efficacy or safety measures. The data above reflect the percentage of patients whose test results were considered positive for antibodies to golimumab in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to golimumab with the incidence of antibodies to other products may be misleading. Table 1 summarizes the adverse drug reactions that occurred at a rate of at least 1% in the golimumab ± DMARD group and with a higher incidence than in the placebo ± DMARD group during the controlled period of the 5 pooled Phase 3 trials through Week 16 in patients with RA, PsA, and AS. Adverse drug reactions that occurred <1% in golimumab-treated patients during the golimumab clinical trials that do not appear in the Warnings and Precautions section included the following events listed by system organ class: - Infections and infestations: Septic shock, atypical mycobacterial infection, pyelonephritis, arthritis bacterial, bursitis infective - Neoplasms benign, malignant and unspecified: Leukemia - Skin and subcutaneous tissue disorders: Psoriasis (new onset or worsening, palmar/plantar and pustular), vasculitis (cutaneous) - Vascular disorders: Vasculitis (systemic) In the Phase 2/3 trials in UC evaluating 1233 golimumab-treated patients, no new adverse drug reactions were identified and the frequency of adverse drug reactions was similar to the safety profile observed in patients with RA, PsA and AS. ## Postmarketing Experience The following adverse reactions have been identified during post-approval use of golimumab. 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 golimumab exposure. - Immune System Disorders: Serious systemic hypersensitivity reactions (including anaphylactic reaction), sarcoidosis - Neoplasms benign, malignant and unspecified: Melanoma - Respiratory, thoracic and mediastinal disorders: Interstitial lung disease - Skin and subcutaneous tissue disorders: Skin exfoliation, rash, bullous skin reactions # Drug Interactions ### Methotrexate For the treatment of RA, golimumab should be used with methotrexate (MTX). Since the presence or absence of concomitant MTX did not appear to influence the efficacy or safety of golimumab in the treatment of PsA or AS, golimumab can be used with or without MTX in the treatment of PsA and AS. ### Biological Products for RA, PsA, and/or AS An increased risk of serious infections has been seen in clinical RA trials of other TNF-blockers used in combination with anakinra or abatacept, with no added benefit; therefore, use of golimumab with abatacept or anakinra is not recommended. A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF-blocker. The concomitant use of golimumab with biologics approved to treat RA, PsA, or AS is not recommended because of the possibility of an increased risk of infection. ### Live Vaccines/Therapeutic Infectious Agents Live vaccines should not be given concurrently with golimumab. Therapeutic infectious agents should not be given concurrently with golimumab. Infants born to women treated with golimumab during their pregnancy may be at increased risk of infection for up to 6 months. Administration of live vaccines to infants exposed to golimumab in utero is not recommended for 6 months following the mother's last golimumab injection during pregnancy. ### Cytochrome P450 Substrates The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα) during chronic inflammation. Therefore, it is expected that for a molecule that antagonizes cytokine activity, such as golimumab, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of golimumab in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B There are no adequate and well-controlled trials of golimumab in pregnant women. Because animal reproduction and developmental studies are not always predictive of human response, it is not known whether golimumab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. golimumab should be used during pregnancy only if clearly needed. An embryofetal developmental toxicology study was performed in which pregnant cynomolgus monkeys were treated subcutaneously with golimumab during the first trimester with doses up to 50 mg/kg twice weekly (360 times greater than the maximum recommended human dose-MRHD) and has revealed no evidence of harm to maternal animals or fetuses. Umbilical cord blood samples collected at the end of the second trimester showed that fetuses were exposed to golimumab during gestation. In this study, in utero exposure to golimumab produced no developmental defects to the fetus. A pre- and post-natal developmental study was performed in which pregnant cynomolgus monkeys were treated with golimumab during the second and third trimesters, and during lactation at doses up to 50 mg/kg twice weekly (860 times and 310 times greater than the maximal steady state human blood levels for maternal animals and neonates, respectively) and has revealed no evidence of harm to maternal animals or neonates. Golimumab was present in the neonatal serum from the time of birth and for up to six months postpartum. Exposure to golimumab during gestation and during the postnatal period caused no developmental defects in the infants. IgG antibodies are known to cross the placenta during pregnancy and have been detected in the serum of infants born to patients treated with these antibodies. Since golimumab is an IgG antibody, infants born to women treated with golimumab during their pregnancy may be at increased risk of infection for up to 6 months. Administration of live vaccines to infants exposed to golimumab in utero is not recommended for 6 months following the mother's last golimumab injection during pregnancy. Pregnancy Category (AUS): C There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Golimumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Golimumab during labor and delivery. ### Nursing Mothers It is not known whether golimumab is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from golimumab, 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. In the pre- and post-natal development study in cynomolgus monkeys in which golimumab was administered subcutaneously during pregnancy and lactation, golimumab was detected in the breast milk at concentrations that were approximately 400-fold lower than the maternal serum concentrations. ### Pediatric Use Safety and effectiveness of golimumab in pediatric patients less than 18 years of age have not been established. ### Geriatic Use In the Phase 3 trials in RA, PsA, and AS, there were no overall differences in SAEs, serious infections, and AEs in golimumab-treated patients ages 65 or older (N = 155) compared with younger golimumab-treated patients. In UC, there were insufficient numbers of patients aged 65 and over to determine whether they respond differently from patients aged 18 to 65. Because there is a higher incidence of infections in the geriatric population in general, caution should be used in treating geriatric patients with golimumab. ### Gender Population PK analyses suggested no PK differences between male and female patients after body weight adjustment in the RA, PsA and UC trials. In the AS trial, female patients showed 13% higher apparent clearance than male patients after body weight adjustment. Subgroup analysis based on gender showed that both female and male patients achieved clinically significant response at the proposed clinical dose. Dosage adjustment based on gender is not needed. ### Race No ethnicity-related PK differences were observed between Caucasians and Asians, and there were too few patients of other races to assess for PK differences. ### Renal Impairment No formal trial of the effect of renal impairment on the PK of golimumab was conducted. ### Hepatic Impairment No formal trial of the effect of hepatic impairment on the PK of golimumab was conducted. ### Females of Reproductive Potential and Males A fertility study conducted in mice using an analogous anti-mouse TNFα antibody showed no impairment of fertility. ### Immunocompromised Patients There is no FDA guidance one the use of Golimumab in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Golimumab Administration in the drug label. ### Monitoring Closely monitor patients for the development of signs and symptoms of infection during and after treatment with golimumab. Discontinue golimumab if a patient develops a serious infection, an opportunistic infection, or sepsis. For a patient who develops a new infection during treatment with golimumab, perform a prompt and complete diagnostic workup appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy and closely monitor them. # IV Compatibility There is limited information regarding the compatibility of Golimumab and IV administrations. # Overdosage In a clinical trial, 5 patients received protocol-directed single infusions of 10 mg/kg of intravenous golimumab without serious adverse reactions or other significant reactions. The highest weight patient was 100 kg, and therefore received a single intravenous infusion of 1000 mg of golimumab. There were no golimumab overdoses in the clinical trials. # Pharmacology ## Mechanism of Action Golimumab is a human monoclonal antibody that binds to both the soluble and transmembrane bioactive forms of human TNFα. This interaction prevents the binding of TNFα to its receptors, thereby inhibiting the biological activity of TNFα (a cytokine protein). There was no evidence of the golimumab antibody binding to other TNF superfamily ligands; in particular, the golimumab antibody did not bind or neutralize human lymphotoxin. Golimumab did not lyse human monocytes expressing transmembrane TNF in the presence of complement or effector cells. Elevated TNFα levels in the blood, synovium, and joints have been implicated in the pathophysiology of several chronic inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. TNFα is an important mediator of the articular inflammation that is characteristic of these diseases. The exact mechanism by which golimumab treats ulcerative colitis is unknown. Golimumab modulated the in vitro biological effects mediated by TNF in several bioassays, including the expression of adhesion proteins responsible for leukocyte infiltration (E-selectin, ICAM-1 and VCAM-1) and the secretion of proinflammatory cytokines (IL-6, IL-8, G-CSF and GM-CSF). ## Structure There is limited information regarding Golimumab Structure in the drug label. ## Pharmacodynamics In clinical trials, decreases in C-reactive protein (CRP), interleukin (IL)-6, matrix metalloproteinase 3 (MMP-3), intercellular adhesion molecule (ICAM)-1 and vascular endothelial growth factor (VEGF) were observed following golimumab administration in patients with RA, PsA, and AS. ## Pharmacokinetics Following subcutaneous administration of golimumab to healthy subjects and patients with active RA, the median time to reach maximum serum concentrations (Tmax) ranged from 2 to 6 days. A subcutaneous injection of 50 mg golimumab to healthy subjects produced a mean ± standard deviation maximum serum concentration (Cmax) of 3.2 ± 1.4 µg/mL. By cross-trial comparisons of mean AUCinf values following an IV or subcutaneous administration of golimumab, the absolute bioavailability of subcutaneous golimumab was estimated to be approximately 53%. Following a single IV administration over the dose range of 0.1 to 10.0 mg/kg in patients with active RA, mean volume of distribution ranged from 58 to 126 mL/kg. The volume of distribution for golimumab indicates that golimumab is distributed primarily in the circulatory system with limited extravascular distribution. The exact metabolic pathway of golimumab is unknown. Following a single IV administration over the dose range of 0.1 to 10.0 mg/kg in patients with active RA, mean systemic clearance of golimumab was estimated to be 4.9 to 6.7 mL/day/kg. Median terminal half-life values were estimated to be approximately 2 weeks in healthy subjects and patients with active RA, PsA or AS. Population PK analyses indicated that concomitant use of NSAIDs, oral corticosteroids, or sulfasalazine did not influence the apparent clearance of golimumab. Patients who developed anti-golimumab antibodies generally had lower steady-state serum trough concentrations of golimumab. golimumab exhibited dose-proportional pharmacokinetics (PK) in patients with active RA over the dose range of 0.1 to 10 mg/kg following a single intravenous (IV) dose. Following a single SC dose in healthy subjects, dose proportional pharmacokinetics were also observed over a dose range of 50 mg to 400 mg. When 50 mg golimumab was administered subcutaneous to patients with RA, PsA, or AS every 4 weeks, serum concentrations appeared to reach steady state by Week 12. With concomitant use of methotrexate (MTX), treatment with 50 mg golimumab subcutaneous every 4 weeks resulted in a mean steady-state trough serum concentration of approximately 0.4–0.6 µg/mL in patients with active RA, approximately 0.5 µg/mL in patients with active PsA, and approximately 0.8 µg/mL in patients with active AS. Patients with RA, PsA, and AS treated with golimumab 50 mg and MTX had approximately 52%, 36% and 21% higher mean steady-state trough concentrations of golimumab, respectively compared with those treated with golimumab 50 mg without MTX. The presence of MTX also decreased anti-golimumab antibody incidence from 7% to 2% For RA, golimumab should be used with MTX. In the PsA and AS trials, the presence or absence of concomitant MTX did not appear to influence clinical efficacy and safety parameters. When induction doses of 200 mg and 100 mg golimumab at week 0 and 2, respectively, followed by maintenance doses of 100 mg golimumab every 4 weeks were administered subcutaneously in patients with UC, serum golimumab concentrations reached steady state by week 8 after the first maintenance dose. Treatment with 100 mg golimumab subcutaneous every 4 weeks during maintenance resulted in a mean steady-state trough serum concentration of approximately 1.8 ± 1.1 µg/mL. Population PK analyses showed there was a trend toward higher apparent clearance of golimumab with increasing weight. Treatment with the recommended maintenance dose regimen of golimumab 100 mg in UC patients did not result in meaningful differences in clinical efficacy among different weight groups. Across the PsA and AS populations, no meaningful differences in clinical efficacy were observed among the subgroups by weight quartile. The RA trial in MTX-experienced and TNF-blocker-naïve patients (Trial RA-2) did show evidence of a reduction in clinical efficacy with increasing body weight, but this effect was observed for both tested doses of golimumab (50 mg and 100 mg). There is no need to adjust the dosage of golimumab based on a patient's weight. ## Nonclinical Toxicology Long-term animal studies of golimumab have not been conducted to evaluate its carcinogenic potential. Mutagenicity studies have not been conducted with golimumab. # Clinical Studies The efficacy and safety of golimumab were evaluated in 3 multicenter, randomized, double-blind, controlled trials (Trials RA-1, RA-2, and RA-3) in 1542 patients ≥ 18 years of age with moderately to severely active RA, diagnosed according to the American College of Rheumatology (ACR) criteria, for at least 3 months prior to administration of trial agent. Patients were required to have at least 4 swollen and 4 tender joints. golimumab was administered subcutaneously at doses of 50 mg or 100 mg every 4 weeks. Double-blinded controlled efficacy data were collected and analyzed through Week 24. Patients were allowed to continue stable doses of concomitant low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day) and/or NSAIDs and patients may have received oral MTX during the trials. Trial RA-1 evaluated 445 patients who were previously treated (at least 8 to 12 weeks prior to administration of trial agent) with one or more doses of a biologic TNF-blocker without a serious adverse reaction. Patients may have discontinued the biologic TNF-blocker for a variety of reasons. Patients were randomized to receive placebo (n = 150), golimumab 50 mg (n = 147), or golimumab 100 mg (n = 148). Patients were allowed to continue stable doses of concomitant MTX, sulfasalazine (SSZ), and/or hydroxychloroquine (HCQ) during the trial. The use of other DMARDs including cytotoxic agents or other biologics was prohibited. Trial RA-2 evaluated 444 patients who had active RA despite a stable dose of at least 15 mg/week of MTX and who had not been previously treated with a biologic TNF-blocker. Patients were randomized to receive background MTX (n = 133), golimumab 50 mg + background MTX (n = 89), golimumab 100 mg + background MTX (n = 89), or golimumab 100 mg monotherapy (n = 133). The use of other DMARDs including SSZ, HCQ, cytotoxic agents, or other biologics was prohibited. Trial RA-3 evaluated 637 patients with active RA who were MTX-naïve and had not previously been treated with a biologic TNF-blocker. Patients were randomized to receive MTX (n = 160), golimumab 50 mg + MTX (n = 159), golimumab 100 mg + MTX (n = 159), or golimumab 100 mg monotherapy (n = 159). For patients receiving MTX, MTX was administered at a dose of 10 mg/week beginning at Week 0 and increased to 20 mg/week by Week 8. The use of other DMARDs including SSZ, HCQ, cytotoxic agents, or other biologics was prohibited. The primary endpoint in Trial RA-1 and Trial RA-2 was the percentage of patients achieving an ACR 20 response at Week 14 and the primary endpoint in Trial RA-3 was the percentage of patients achieving an ACR 50 response at Week 24. In Trials RA-1, RA-2, and RA-3, the median duration of RA disease was 9.4, 5.7, and 1.2 years; and 99%, 75%, and 54% of the patients used at least one DMARD in the past, respectively. Approximately 77% and 57% of patients received concomitant NSAIDs and low dose corticosteroids, respectively, in the 3 pooled RA trials. In the 3 RA trials, a greater percentage of patients treated with the combination of golimumab and MTX achieved ACR responses at Week 14 (Trials RA-1 and RA-2) and Week 24 (Studies RA-1, RA-2, and RA-3) versus patients treated with the MTX alone. There was no clear evidence of improved ACR response with the higher golimumab dose group (100 mg) compared to the lower golimumab dose group (50 mg). In Trials RA-2 and RA-3, the golimumab monotherapy groups were not statistically different from the MTX monotherapy groups in ACR responses. Table 2 shows the proportion of patients with the ACR response for the golimumab 50 mg and control groups in Trials RA-1, RA-2, and RA-3. In the subset of patients who received golimumab in combination with MTX in Trial RA-1, the proportion of patients achieving ACR 20, 50 and 70 responses at week 14 were 40%, 18%, and 12%, respectively, in the golimumab 50 mg + MTX group (N = 101) compared with 17%, 6%, and 2%, respectively, in the placebo + MTX group (N = 103). Table 3 shows the percent improvement in the components of the ACR response criteria for the golimumab 50 mg + MTX and MTX groups in Trial RA-2. The percent of patients achieving ACR 20 responses by visit for Trial RA-2 is shown in Figure 1. ACR 20 responses were observed in 38% of patients in the golimumab 50 mg + MTX group at the first assessment (Week 4) after the initial golimumab administration. In Trials RA-1 and RA-2, the golimumab 50 mg groups demonstrated a greater improvement compared to the control groups in the change in mean Health Assessment Questionnaire Disability Index (HAQ-DI) score from baseline to Week 24: 0.23 vs. 0.03 in RA-1, 0.47 vs. 0.13 in RA-2, respectively. Also in Trials RA-1 and RA-2, the golimumab 50 mg groups compared to the control groups had a greater proportion of HAQ responders (change from baseline > 0.22) at Week 24: 43% vs. 27%, 65% vs. 35%, respectively. The safety and efficacy of golimumab were evaluated in a multi-center, randomized, double-blind, placebo-controlled trial in 405 adult patients with moderately to severely active PsA (≥ 3 swollen joints and ≥ 3 tender joints) despite NSAID or DMARD therapy (Trial PsA). Patients in this trial had a diagnosis of PsA for at least 6 months with a qualifying psoriatic skin lesion of at least 2 cm in diameter. Previous treatment with a biologic TNF-blocker was not allowed. Patients were randomly assigned to placebo (n = 113), golimumab 50 mg (n = 146), or golimumab 100 mg (n = 146) given subcutaneously every 4 weeks. Patients were allowed to receive stable doses of concomitant MTX (≤ 25 mg/week), low dose oral corticosteroids (equivalent to ≤ 10 mg of prednisone a day), and/or NSAIDs during the trial. The use of other DMARDs including SSZ, HCQ, cytotoxic agents, or other biologics was prohibited. The primary endpoint was the percentage of patients achieving ACR 20 response at Week 14. Placebo-controlled efficacy data were collected and analyzed through Week 24. Patients with each subtype of PsA were enrolled, including polyarticular arthritis with no rheumatoid nodules (43%), asymmetric peripheral arthritis (30%), distal interphalangeal (DIP) joint arthritis (15%), spondylitis with peripheral arthritis (11%), and arthritis mutilans (1%). The median duration of PsA disease was 5.1 years, 78% of patients received at least one DMARD in the past, and approximately 48% of patients received MTX, and 16% received low dose oral steroids. golimumab ± MTX, compared with placebo ± MTX, resulted in significant improvement in signs and symptoms as demonstrated by the proportion of patients with an ACR 20 response at Week 14 in Trial PsA (see TABLE 4). There was no clear evidence of improved ACR response with the higher golimumab dose group (100 mg) compared to the lower golimumab dose group (50 mg). ACR responses observed in the golimumab-treated groups were similar in patients receiving and not receiving concomitant MTX. Similar ACR 20 responses at Week 14 were observed in patients with different PsA subtypes. However, the number of patients with arthritis mutilans was too small to allow meaningful assessment. golimumab 50 mg treatment also resulted in significantly greater improvement compared with placebo for each ACR component in Trial PsA (Table 5). Treatment with golimumab resulted in improvement in enthesitis and skin manifestations in patients with PsA. However, the safety and efficacy of golimumab in the treatment of patients with plaque psoriasis has not been established. The percent of patients achieving ACR 20 responses by visit for Trial PsA is shown in Figure 2. ACR 20 responses were observed in 31% of patients in the golimumab 50 mg + MTX group at the first assessment (Week 4) after the initial golimumab administration. In Trial PsA, golimumab 50 mg demonstrated a greater improvement compared to placebo in the change in mean Health Assessment Questionnaire Disability Index (HAQ-DI) score from baseline to Week 24 (0.33 and -0.01, respectively). In addition, the golimumab 50 mg group compared to the placebo group had a greater proportion of HAQ responders (≥ 0.3 change from baseline) at Week 24: 43% vs. 22%, respectively. The safety and efficacy of golimumab were evaluated in a multi-center, randomized, double-blind, placebo-controlled trial in 356 adult patients with active ankylosing spondylitis according to modified New York criteria for at least 3 months (Trial AS). Patients had symptoms of active disease despite current or previous NSAID therapy. Patients were excluded if they were previously treated with a biologic TNF-blocker or if they had complete ankylosis of the spine. Patients were randomly assigned to placebo (n = 78), golimumab 50 mg (n = 138), or golimumab 100 mg (n = 140) administered subcutaneously every 4 weeks. Patients were allowed to continue stable doses of concomitant MTX, sulfasalazine (SSZ), hydroxychloroquine (HCQ), low dose corticosteroids (equivalent to < 10 mg of prednisone a day), and/or NSAIDs during the trial. The use of other DMARDs including cytotoxic agents or other biologics was prohibited. The primary endpoint was the percentage of patients achieving an ASsessment in Ankylosing Spondylitis (ASAS) 20 response at Week 14. Placebo-controlled efficacy data were collected and analyzed through Week 24. In Trial AS, the median duration of AS disease was 5.6 years, median duration of inflammatory back pain was 12 years, 83% were HLA-B27 positive, 24% had prior joint surgery or procedure, and 55% received at least one DMARD in the past. During the trial, the use of concomitant DMARDs and/or NSAIDs was as follows: MTX (20%), SSZ (26%), HCQ (1%), low dose oral steroids (16%), and NSAIDs (90%). In Trial AS, golimumab ± DMARDs treatment, compared with placebo ± DMARDs, resulted in a significant improvement in signs and symptoms as demonstrated by the proportion of patients with an ASAS 20 response at Week 14 (see TABLE 6). There was no clear evidence of improved ASAS response with the higher golimumab dose group (100 mg) compared to the lower golimumab dose group (50 mg). Table 7 shows the percent improvement in the components of the ASAS response criteria for the golimumab 50 mg ± DMARDs and placebo ± DMARDs groups in Trial AS. The percent of patients achieving ASAS 20 responses by visit for Trial AS is shown in Figure 3. ASAS 20 responses were observed in 48% of patients in the golimumab 50 mg + MTX group at the first assessment (Week 4) after the initial golimumab administration. The safety and efficacy of golimumab were evaluated in two multi-center, randomized, double-blind, placebo-controlled clinical trials in patients ≥ 18 years of age (Trials UC-1 and UC-2). Trial UC-1 was an induction trial conducted in patients with moderately to severely active ulcerative colitis (UC), defined as a Mayo score of 6 to 12 . At baseline, subjects also had an endoscopy subscore of 2 or 3 on a 3-point scale (an endoscopy score of 2 is defined by marked erythema, absent vascular pattern, friability, erosions; and a score of 3 is defined by spontaneous bleeding, ulceration). Patients were corticosteroid dependent (i.e., an inability to successfully taper corticosteroids without a return of the symptoms of UC) or had an inadequate response to or had failed to tolerate at least one of the following therapies: oral aminosalicylates, oral corticosteroids, azathioprine, or 6-mercaptopurine. Trial UC-1 was divided into 2 parts. In Part 1 (dose finding), patients were randomized to one of 4 treatment groups: 400 mg golimumab administered subcutaneously (SC) at Week 0 and 200 mg at Week 2 (400/200 mg), 200 mg golimumab SC at Week 0 and 100 mg at Week 2 (200/100 mg), 100 mg golimumab SC at Week 0 and 50 mg at Week 2 (100/50 mg), or placebo SC at Weeks 0 and 2. In Part 2 (dose confirming), efficacy was evaluated in 761 patients who were randomized to receive either 400 mg golimumab SC at Week 0 and 200 mg at Week 2, 200 mg golimumab SC at Week 0 and 100 mg at Week 2, or placebo SC at Weeks 0 and 2. golimumab 100/50 mg SC was not evaluated in Part 2; its safety and effectiveness has not been established in UC. Concomitant stable doses of oral aminosalicylates (5-ASA), oral corticosteroids (less than 40 mg/day), azathioprine (AZA), 6-mercaptopurine (6-MP), and/or methotrexate (MTX) were permitted. Patients who received previous TNF inhibitors were excluded. The primary endpoint was the percent of patients in clinical response at Week 6, defined as a decrease from baseline in the Mayo score by ≥ 30% and ≥ 3 points, accompanied by a decrease in the rectal bleeding subscore of ≥ 1 or a rectal bleeding subscore of 0 (no blood seen) or 1 (streaks of blood with stool less than half the time). Trial UC-2 was a randomized-withdrawal maintenance trial that evaluated 456 patients who achieved clinical response with golimumab induction and tolerated golimumab treatment. Patients were randomized to receive golimumab 50 mg, golimumab 100 mg or placebo administered subcutaneously every 4 weeks. Concomitant stable doses of oral aminosalicylates, azathioprine, 6-mercaptopurine, and/or methotrexate were permitted. Corticosteroids were to be tapered at the start of the maintenance trial. The primary endpoint was the percent of patients maintaining clinical response through Week 54. In Trial UC-1, a greater proportion of patients achieved clinical response, clinical remission and had improvement of endoscopic appearance of the mucosa at Week 6 in the golimumab 200/100 mg group compared with the placebo group. The golimumab 400/200 mg group did not demonstrate additional clinical benefit over the golimumab 200/100 mg group. Clinical response was defined as a decrease from baseline in the Mayo score of ≥ 30% and ≥ 3 points, accompanied by a decrease in the rectal bleeding subscore of ≥ 1 or a rectal bleeding subscore of 0 or 1. Clinical remission was defined as a Mayo score ≤ 2 points, with no individual subscore > 1. Improvement of endoscopic appearance of the mucosa was defined as a Mayo endoscopy subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern, mild friability). In Trial UC-2, a greater proportion of patients maintained clinical response through Week 54 in the golimumab 100 mg group compared with the placebo group. In Trial UC-2, golimumab-treated patients in clinical response (which included the subset of patients in clinical remission) in Trial UC-1, were again assessed for clinical remission at Week 30 and Week 54. A greater proportion of patients had clinical remission at both Weeks 30 and 54 without demonstrating a loss of response at any time point through Week 54 in the golimumab 100 mg group compared with the placebo group. # How Supplied Golimumab for injection: - 50 mg/0.5 mL in a single dose - 100 mg/1 mL in a single dose ## Storage Stored at 2°C to 8°C (36°F to 46°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Patients should be advised of the potential benefits and risks of golimumab. Physicians should instruct their patients to read the Medication Guide before starting golimumab therapy and to read it each time the prescription is renewed. Inform patients that golimumab may lower the ability of their immune system to fight infections. Instruct the patient of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and hepatitis B reactivation. Patients should be counseled about the risk of lymphoma and other malignancies while receiving golimumab. Advise latex-sensitive patients that the needle cover on the prefilled syringe as well as the prefilled syringe in the prefilled SmartJect autoinjector contains dry natural rubber (a derivative of latex). Advise patients to report any signs of new or worsening medical conditions such as congestive heart failure, demyelinating disorders, autoimmune diseases, liver disease, cytopenias, or psoriasis. The first self-injection should be performed under the supervision of a qualified healthcare professional. If a patient or caregiver is to administer golimumab, he/she should be instructed in injection techniques and their ability to inject subcutaneously should be assessed to ensure the proper administration of golimumab Advise the patient to read the FDA-approved Instructions for Use and provide the following instructions to patients: - Prior to use, remove the prefilled syringe or the prefilled SmartJect autoinjector from the refrigerator and allow golimumab to sit at room temperature outside of the carton for 30 minutes and out of the reach of children. - Do not warm golimumab in any other way. For example, do not warm golimumab in a microwave or in hot water. - Do not remove the prefilled syringe needle cover or SmartJect autoinjector cap while allowing golimumab to reach room temperature. Remove these immediately before injection. - Do not pull the autoinjector away from the skin until you hear a first "click" sound and then a second "click" sound (the injection is finished and the needle is pulled back). It usually takes about 3 to 6 seconds but may take up to 15 seconds for you to hear the second "click" after the first "click". If the autoinjector is pulled away from the skin before the injection is completed, a full dose of golimumab may not be administered. - A puncture-resistant container for disposal of needles and syringes should be used. Patients or caregivers should be instructed in the technique of proper syringe and needle disposal, and be advised not to reuse these items. # Precautions with Alcohol Alcohol-Golimumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Simponi - Simponi Aria # Look-Alike Drug Names There is limited information regarding Golimumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Golimumab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [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 Golimumab is a tumor necrosis factor inhibitor that is FDA approved for the treatment of moderately to severely active rheumatoid arthritis (RA), active psoriatic arthritis (PsA), active ankylosing spondylitis (AS); and moderate to severe Ulcerative colitis (UC) with an inadequate response or intolerant to prior treatment or requiring continuous steroid therapy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include upper respiratory tract infection, nasopharyngitis and injection site reactions. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Golimumab, in combination with methotrexate, is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis. - Dosage: 50 mg administered by subcutaneous injection once a month - Golimumab, alone or in combination with methotrexate, is indicated for the treatment of adult patients with active psoriatic arthritis. - Dosage: 50 mg administered by subcutaneous injection once a month - Golimumab is indicated for the treatment of adult patients with active ankylosing spondylitis. - Dosage: 50 mg administered by subcutaneous injection once a month - Golimumab is indicated in adult patients with moderately to severely active ulcerative colitis who have demonstrated corticosteroid dependence or who have had an inadequate response to or failed to tolerate oral aminosalicylates, oral corticosteroids, azathioprine, or 6-mercaptopurine for: - inducing and maintaining clinical response - improving endoscopic appearance of the mucosa during induction - inducing clinical remission - achieving and sustaining clinical remission in induction responders - Dosage: 200 mg subcutaneous injection at Week 0, followed by 100 mg at Week 2 and then maintenance therapy with 100 mg every 4 weeks. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Golimumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Golimumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness of golimumab have not been established in pediatric patients younger than 18 years ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Golimumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Golimumab in pediatric patients. # Contraindications None # Warnings ### Serious Infections Patients treated with golimumab are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, or parasitic organisms including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, and tuberculosis have been reported with TNF-blockers. Patients have frequently presented with disseminated rather than localized disease. The concomitant use of a TNF-blocker and abatacept or anakinra was associated with a higher risk of serious infections; therefore, the concomitant use of golimumab and these biologic products is not recommended. Treatment with golimumab should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants such as corticosteroids or methotrexate may be at greater risk of infection. Consider the risks and benefits of treatment prior to initiating golimumab in patients: - with chronic or recurrent infection; - who have been exposed to tuberculosis; - with a history of an opportunistic infection; - who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or - with underlying conditions that may predispose them to infection. In controlled Phase 3 trials through Week 16 in patients with RA, PsA, and AS, serious infections were observed in 1.4% of golimumab-treated patients and 1.3% of control-treated patients. In the controlled Phase 3 trials through Week 16 in patients with RA, PsA, and AS, the incidence of serious infections per 100 patient-years of follow-up was 5.7 (95% CI: 3.8, 8.2) for the golimumab group and 4.2 (95% CI: 1.8, 8.2) for the placebo group. In the controlled Phase 2/3 trial through Week 6 of golimumab induction in UC, the incidence of serious infections in golimumab 200/100 mg-treated patients was similar to the incidence of serious infections in placebo-treated patients. Through Week 60, the incidence of serious infections was similar in patients who received golimumab induction and 100 mg during maintenance compared with patients who received golimumab induction and placebo during the maintenance portion of the UC trial. Serious infections observed in golimumab-treated patients included sepsis, pneumonia, cellulitis, abscess, tuberculosis, invasive fungal infections, and hepatitis B infection. Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving TNF-blockers, including patients who have previously received treatment for latent or active tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating golimumab and periodically during therapy. Treatment of latent tuberculosis infection prior to therapy with TNF-blockers has been shown to reduce the risk of tuberculosis reactivation during therapy. Prior to initiating golimumab, assess if treatment for latent tuberculosis is needed; an induration of 5 mm or greater is a positive tuberculin skin test, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG). Consider anti-tuberculosis therapy prior to initiation of golimumab in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Cases of active tuberculosis have occurred in patients treated with golimumab during and after treatment for latent tuberculosis. Monitor patients for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy, patients who are on treatment for latent tuberculosis, or patients who were previously treated for tuberculosis infection. Consider tuberculosis in the differential diagnosis in patients who develop a new infection during golimumab treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis. In the controlled and uncontrolled portions of the Phase 2 RA and Phase 3 RA, PsA, and AS trials, the incidence of active TB was 0.23 and 0 per 100 patient-years in 2347 golimumab-treated patients and 674 placebo-treated patients, respectively. Cases of TB included pulmonary and extra pulmonary TB. The overwhelming majority of the TB cases occurred in countries with a high incidence rate of TB. In the controlled Phase 2/3 trial of golimumab induction through Week 6 in UC, no cases of TB were observed in golimumab 200/100 mg-treated patients or in placebo-treated patients. Through Week 60, the incidence per 100 patient-years of TB in patients who received golimumab induction and 100 mg during the maintenance portion of the UC trial was 0.52 (95% CI: 0.11, 1.53). One case of TB was observed in the placebo maintenance group in a patient who received golimumab intravenous (IV) induction. If patients develop a serious systemic illness and they reside or travel in regions where mycoses are endemic, consider invasive fungal infection in the differential diagnosis. Consider appropriate empiric antifungal therapy and take into account both the risk for severe fungal infection and the risks of antifungal therapy while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. To aid in the management of such patients, consider consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections. The use of TNF-blockers including golimumab has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers (i.e., surface antigen positive). In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients who received concomitant immunosuppressants. All patients should be tested for HBV infection before initiating TNF-blocker therapy. For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended before initiating TNF-blocker therapy. The risks and benefits of treatment should be considered prior to prescribing TNF-blockers, including golimumab, to patients who are carriers of HBV. Adequate data are not available on whether anti-viral therapy can reduce the risk of HBV reactivation in HBV carriers who are treated with TNF-blockers. Patients who are carriers of HBV and require treatment with TNF-blockers should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, TNF-blockers should be stopped and antiviral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF-blockers after HBV reactivation has been controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF-blockers in this situation and monitor patients closely. ### Malignancies Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation of therapy ≤ 18 years of age), of which golimumab is a member. Approximately half the cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression, and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (range 1 to 84 months) after the first dose of TNF blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports. The risks and benefits of TNF-blocker treatment including golimumab should be considered prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF-blocker in patients who develop a malignancy. In the controlled portions of clinical trials of TNF-blockers including golimumab, more cases of lymphoma have been observed among patients receiving anti-TNF treatment compared with patients in the control groups. During the controlled portions of the Phase 2 trials in RA, and the Phase 3 trials in RA, PsA and AS, the incidence of lymphoma per 100 patient-years of follow-up was 0.21 (95% CI: 0.03, 0.77) in the combined golimumab group compared with an incidence of 0 (95% CI: 0., 0.96) in the placebo group. In the controlled and uncontrolled portions of these clinical trials in 2347 golimumab-treated patients with a median follow-up of 1.4 years, the incidence of lymphoma was 3.8-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).1 Through Week 60 of the UC trials, there were no cases of lymphoma with golimumab. Patients with RA and other chronic inflammatory diseases, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF blocker therapy, patients with rheumatoid arthritis may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia. Rare post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with TNF-blocking agents. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. Nearly all of the reported TNF-blocker associated cases have occurred in patients with Crohn's disease or ulcerative colitis. The majority were in adolescent and young adult males. Almost all these patients had received treatment with azathioprine (AZA) or 6-mercaptopurine (6–MP) concomitantly with a TNF blocker at or prior to diagnosis. The potential risk with the combination of AZA or 6-MP and golimumab should be carefully considered. A risk for the development for hepatosplenic T-cell lymphoma in patients treated with TNF-blockers cannot be excluded. During the controlled portions of the Phase 2 trial in RA, and the Phase 3 trials in RA, PsA and AS, the incidence of malignancies other than lymphoma per 100 patient-years of follow-up was not elevated in the combined golimumab group compared with the placebo group. In the controlled and uncontrolled portions of these trials, the incidence of malignancies, other than lymphoma, in golimumab-treated patients was similar to that expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).1 In the 6-week placebo-controlled portions of the golimumab Phase 2/3 clinical trials in UC, the incidence of non-lymphoma malignancies (excluding non-melanoma skin cancer) was similar between the golimumab and the placebo group. Through Week 60, the incidence of non-lymphoma malignancies (excluding non-melanoma skin cancer) was similar to the general U.S. population according to the SEER database (adjusted for age, gender, and race). Short follow-up periods, such as those of one year or less in the studies above, may not adequately reflect the true incidence of malignancies. It is not known if golimumab treatment influences the risk for developing dysplasia or colon cancer. All patients with ulcerative colitis who are at increased risk for dysplasia or colon carcinoma (for example, patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or who had a prior history of dysplasia or colon carcinoma should be screened for dysplasia at regular intervals before therapy and throughout their disease course. This evaluation should include colonoscopy and biopsies per local recommendations. In patients with newly diagnosed dysplasia treated with golimumab, the risks and benefits to the individual patient must be carefully reviewed and consideration should be given to whether therapy should be continued. Melanoma has been reported in patients treated with TNF-blocking agents, including golimumab. Merkel cell carcinoma has been reported in patients treated with TNF-blocking agents. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. In controlled trials of other TNF-blockers in patients at higher risk for malignancies (e.g., patients with COPD, patients with Wegener's granulomatosis treated with concomitant cyclophosphamide) a greater portion of malignancies occurred in the TNF-blocker group compared to the controlled group. In an exploratory 1-year clinical trial evaluating the use of 50, 100 and 200 mg of golimumab in 309 patients with severe persistent asthma, 6 patients developed malignancies other than NMSC in the golimumab groups compared to none in the control group. Three of the 6 patients were in the 200 mg golimumab group. ### Congestive Heart Failure Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF-blockers, including golimumab. In several exploratory trials of other TNF-blockers in the treatment of CHF, there were greater proportions of TNF-blocker treated patients who had CHF exacerbations requiring hospitalization or increased mortality. golimumab has not been studied in patients with a history of CHF and golimumab should be used with caution in patients with CHF. If a decision is made to administer golimumab to patients with CHF, these patients should be closely monitored during therapy, and golimumab should be discontinued if new or worsening symptoms of CHF appear. ### Demyelinating Disorders Use of TNF-blockers, of which golimumab is a member, has been associated with rare cases of new onset or exacerbation of central nervous system (CNS) demyelinating disorders, including multiple sclerosis (MS) and peripheral demyelinating disorders, including Guillain-Barré syndrome. Cases of central demyelination, MS, optic neuritis, and peripheral demyelinating polyneuropathy have rarely been reported in patients treated with golimumab. Prescribers should exercise caution in considering the use of TNF-blockers, including golimumab, in patients with central or peripheral nervous system demyelinating disorders. Discontinuation of golimumab should be considered if these disorders develop. ### Use with Abatacept In controlled trials, the concurrent administration of another TNF-blocker and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; and the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of TNF-blockers including golimumab and abatacept is not recommended. ### Use with Anakinra Concurrent administration of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater portion of serious infections and neutropenia and no additional benefits compared with the TNF-blocker alone. Therefore, the combination of anakinra with TNF-blockers, including golimumab, is not recommended. ### Switching Between Biological Disease Modifying Antirheumatic Drugs Care should be taken when switching from one biological product to another biological product since overlapping biological activity may further increase the risk of infection. ### Hematologic Cytopenias There have been post-marketing reports of pancytopenia, leukopenia, neutropenia, aplastic anemia, and thrombocytopenia in patients receiving TNF-blockers. In clinical trials, cases of pancytopenia, leukopenia, neutropenia, and thrombocytopenia have also occurred in golimumab-treated patients. Caution should be exercised when using TNF-blockers, including golimumab, in patients who have or have had significant cytopenias. ### Vaccinations/Therapeutic Infectious Agents Patients treated with golimumab may receive vaccinations, except for live vaccines. In patients receiving anti-TNF therapy, limited data are available on the response to live vaccination, or on the secondary transmission of infection by live vaccines. Use of live vaccines could result in clinical infections, including disseminated infections. Other uses of therapeutic infectious agents such as live attenuated bacteria (e.g., BCG bladder instillation for the treatment of cancer) could result in clinical infections, including disseminated infections. It is recommended that therapeutic infectious agents not be given concurrently with golimumab. In the Phase 3 PsA trial, after pneumococcal vaccination, a similar proportion of golimumab-treated and placebo-treated patients were able to mount an adequate immune response of at least a 2-fold increase in antibody titers to pneumococcal polysaccharide vaccine. In both golimumab-treated and placebo-treated patients, the proportions of patients with response to pneumococcal vaccine were lower among patients receiving MTX compared with patients not receiving MTX. The data suggest that golimumab does not suppress the humoral immune response to the pneumococcal vaccine. ### Hypersensitivity Reactions In post-marketing experience, serious systemic hypersensitivity reactions (including anaphylactic reaction) have been reported following golimumab administration. Some of these reactions occurred after the first administration of golimumab. If an anaphylactic or other serious allergic reaction occurs, administration of golimumab should be discontinued immediately and appropriate therapy instituted. # Adverse Reactions ## Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety data described below are based on 5 pooled, randomized, double-blind, controlled Phase 3 trials in patients with RA, PsA, and AS (Trials RA-1, RA-2, RA-3, PsA, and AS). These 5 trials included 639 control-treated patients and 1659 golimumab-treated patients including 1089 with RA, 292 with PsA, and 278 with AS. The safety data in 1233 golimumab-treated patients with ulcerative colitis from 3 pooled, randomized, double-blind, controlled Phase 2/3 trials are also described below (Trials UC-1, UC-2, and UC-3). The proportion of patients who discontinued treatment due to adverse reactions in the controlled Phase 3 trials through Week 16 in RA, PsA and AS was 2% for golimumab-treated patients and 3% for placebo-treated patients. The most common adverse reactions leading to discontinuation of golimumab in the controlled Phase 3 trials in RA, PsA and AS through Week 16 were sepsis (0.2%), alanine aminotransferase increased (0.2%), and aspartate aminotransferase increased (0.2%). The most common adverse drug reactions leading to discontinuation through Week 60 of the UC trials in patients who received golimumab induction and 100 mg during maintenance compared with patients who received golimumab induction and placebo during maintenance were tuberculosis (0.3% vs 0.6%) and anemia (0.3% vs 0%), respectively. The most serious adverse reactions were: - Serious Infections - Malignancies Upper respiratory tract infection and nasopharyngitis were the most common adverse reactions reported in the combined Phase 3 RA, PsA and AS trials through Week 16, occurring in 7% and 6% of golimumab-treated patients as compared with 6% and 5% of control-treated patients, respectively. In controlled Phase 3 trials through Week 16 in RA, PsA, and AS, infections were observed in 28% of golimumab-treated patients compared to 25% of control-treated patients. For serious infections, see the Warnings and Precautions section. In the controlled Phase 2/3 trial of golimumab induction through Week 6 in UC, the rates of infections were similar in golimumab 200/100 mg-treated patients and placebo-treated patients, or approximately 12%. Through Week 60, the incidence per patient year of infections was similar in patients who received golimumab induction and 100 mg during maintenance compared with patients who received golimumab induction and placebo during the maintenance portion of the UC trial. In the controlled Phase 2/3 trial of golimumab induction through Week 6, no cases of demyelination were observed in golimumab 200/100 mg-treated patients or placebo-treated patients. Through Week 60, there were no cases of demyelination in the golimumab 100 mg group during maintenance. One case of CNS demyelination was observed in the placebo maintenance group in a patient who received golimumab 400/200 mg during induction. There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of golimumab in patients with RA, PsA, and AS through Week 16, ALT elevations ≥ 5 × ULN occurred in 0.2% of control-treated patients and 0.7% of golimumab-treated patients and ALT elevations ≥ 3 × ULN occurred in 2% of control-treated patients and 2% of golimumab-treated patients. Since many of the patients in the Phase 3 trials for RA, PsA, and AS were also taking medications that cause liver enzyme elevations (e.g., NSAIDs, MTX), the relationship between golimumab and liver enzyme elevation is not clear. In Phase 2/3 UC trials, the incidence of ALT elevations ≥ 5 × ULN was similar in golimumab-treated patients and placebo-treated patients, or approximately 1%, with an average duration of follow-up of 46 weeks and 18 weeks, respectively. ALT elevations ≥ 3 × ULN occurred in 2.0% of golimumab-treated patients compared with 1.5% of placebo-treated patients with an average duration of follow-up of 46 weeks and 18 weeks, respectively. The use of TNF-blockers, including golimumab, has been associated with the formation of autoantibodies and, rarely, with the development of a lupus-like syndrome. In the controlled Phase 3 trials in patients with RA, PsA, and AS through Week 14, there was no association of golimumab treatment and the development of newly positive anti-dsDNA antibodies. In Phase 3 trials in RA, PsA, and AS through 1 year of follow up, 4.0% of golimumab-treated patients and 2.6% of control patients were newly ANA-positive (at titers of 1:160 or greater). The frequency of anti-dsDNA antibodies at 1 year of follow up was uncommon in patients who were anti-dsDNA negative at baseline. Through Week 60 of the UC trials, 3.5% of patients who received golimumab induction and 100 mg during maintenance were newly ANA-positive (at titers of 1:160 or greater) compared with 3.5% of patients who received golimumab induction and placebo during the maintenance portion of the UC trial. The frequency of anti-dsDNA antibodies at 1 year of follow up in patients who were anti-dsDNA negative at baseline was 0.5% in patients receiving golimumab induction and 100 mg during maintenance compared with 0% in patients who received golimumab induction and placebo during maintenance. In controlled Phase 3 trials through Week 16 in RA, PsA and AS, 6% of golimumab-treated patients had injection site reactions compared with 2% of control-treated patients. The majority of the injection site reactions were mild and the most frequent manifestation was injection site erythema. In the controlled Phase 2/3 trial through Week 6 in UC, 3.4% of golimumab-treated patients had injection site reactions compared with 1.5% in control-treated patients. The majority of the injection site reactions were mild and moderate and the most frequent manifestation was injection site erythema. In controlled Phase 2 and 3 trials in RA, PsA, AS, and Phase 2/3 UC trials, no patients treated with golimumab developed anaphylactic reactions. Antibodies to golimumab were detected in 57 (4%) of golimumab-treated patients across the Phase 3 RA, PsA, and AS trials through Week 24. Similar rates were observed in each of the three indications. Patients who received golimumab with concomitant MTX had a lower proportion of antibodies to golimumab than patients who received golimumab without MTX (approximately 2% versus 7%, respectively). The presence of serum concentrations of golimumab can interfere with the detection of antibodies to golimumab leading to inconclusive results. In UC trials, 34 (3%), 341 (28%) and 823 (69%) of golimumab-treated subjects were positive, negative and inconclusive for antibodies to golimumab, respectively. Treatment with concomitant immunomodulators (AZA, 6-MP and MTX) resulted in a lower proportion of patients with antibodies to golimumab than patients receiving golimumab without immunomodulators (2% versus 4%, respectively). Of the patients with a positive antibody response to golimumab in the Phase 2 and 3 trials, most were determined to have neutralizing antibodies to golimumab as measured by a cell-based functional assay. The small number of patients positive for antibodies to golimumab limits the ability to draw definitive conclusions regarding the relationship between antibodies to golimumab and clinical efficacy or safety measures. The data above reflect the percentage of patients whose test results were considered positive for antibodies to golimumab in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to golimumab with the incidence of antibodies to other products may be misleading. Table 1 summarizes the adverse drug reactions that occurred at a rate of at least 1% in the golimumab ± DMARD group and with a higher incidence than in the placebo ± DMARD group during the controlled period of the 5 pooled Phase 3 trials through Week 16 in patients with RA, PsA, and AS. Adverse drug reactions that occurred <1% in golimumab-treated patients during the golimumab clinical trials that do not appear in the Warnings and Precautions section included the following events listed by system organ class: - Infections and infestations: Septic shock, atypical mycobacterial infection, pyelonephritis, arthritis bacterial, bursitis infective - Neoplasms benign, malignant and unspecified: Leukemia - Skin and subcutaneous tissue disorders: Psoriasis (new onset or worsening, palmar/plantar and pustular), vasculitis (cutaneous) - Vascular disorders: Vasculitis (systemic) In the Phase 2/3 trials in UC evaluating 1233 golimumab-treated patients, no new adverse drug reactions were identified and the frequency of adverse drug reactions was similar to the safety profile observed in patients with RA, PsA and AS. ## Postmarketing Experience The following adverse reactions have been identified during post-approval use of golimumab. 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 golimumab exposure. - Immune System Disorders: Serious systemic hypersensitivity reactions (including anaphylactic reaction), sarcoidosis - Neoplasms benign, malignant and unspecified: Melanoma - Respiratory, thoracic and mediastinal disorders: Interstitial lung disease - Skin and subcutaneous tissue disorders: Skin exfoliation, rash, bullous skin reactions # Drug Interactions ### Methotrexate For the treatment of RA, golimumab should be used with methotrexate (MTX). Since the presence or absence of concomitant MTX did not appear to influence the efficacy or safety of golimumab in the treatment of PsA or AS, golimumab can be used with or without MTX in the treatment of PsA and AS. ### Biological Products for RA, PsA, and/or AS An increased risk of serious infections has been seen in clinical RA trials of other TNF-blockers used in combination with anakinra or abatacept, with no added benefit; therefore, use of golimumab with abatacept or anakinra is not recommended. A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF-blocker. The concomitant use of golimumab with biologics approved to treat RA, PsA, or AS is not recommended because of the possibility of an increased risk of infection. ### Live Vaccines/Therapeutic Infectious Agents Live vaccines should not be given concurrently with golimumab. Therapeutic infectious agents should not be given concurrently with golimumab. Infants born to women treated with golimumab during their pregnancy may be at increased risk of infection for up to 6 months. Administration of live vaccines to infants exposed to golimumab in utero is not recommended for 6 months following the mother's last golimumab injection during pregnancy. ### Cytochrome P450 Substrates The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα) during chronic inflammation. Therefore, it is expected that for a molecule that antagonizes cytokine activity, such as golimumab, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of golimumab in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B There are no adequate and well-controlled trials of golimumab in pregnant women. Because animal reproduction and developmental studies are not always predictive of human response, it is not known whether golimumab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. golimumab should be used during pregnancy only if clearly needed. An embryofetal developmental toxicology study was performed in which pregnant cynomolgus monkeys were treated subcutaneously with golimumab during the first trimester with doses up to 50 mg/kg twice weekly (360 times greater than the maximum recommended human dose-MRHD) and has revealed no evidence of harm to maternal animals or fetuses. Umbilical cord blood samples collected at the end of the second trimester showed that fetuses were exposed to golimumab during gestation. In this study, in utero exposure to golimumab produced no developmental defects to the fetus. A pre- and post-natal developmental study was performed in which pregnant cynomolgus monkeys were treated with golimumab during the second and third trimesters, and during lactation at doses up to 50 mg/kg twice weekly (860 times and 310 times greater than the maximal steady state human blood levels for maternal animals and neonates, respectively) and has revealed no evidence of harm to maternal animals or neonates. Golimumab was present in the neonatal serum from the time of birth and for up to six months postpartum. Exposure to golimumab during gestation and during the postnatal period caused no developmental defects in the infants. IgG antibodies are known to cross the placenta during pregnancy and have been detected in the serum of infants born to patients treated with these antibodies. Since golimumab is an IgG antibody, infants born to women treated with golimumab during their pregnancy may be at increased risk of infection for up to 6 months. Administration of live vaccines to infants exposed to golimumab in utero is not recommended for 6 months following the mother's last golimumab injection during pregnancy. Pregnancy Category (AUS): C There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Golimumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Golimumab during labor and delivery. ### Nursing Mothers It is not known whether golimumab is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from golimumab, 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. In the pre- and post-natal development study in cynomolgus monkeys in which golimumab was administered subcutaneously during pregnancy and lactation, golimumab was detected in the breast milk at concentrations that were approximately 400-fold lower than the maternal serum concentrations. ### Pediatric Use Safety and effectiveness of golimumab in pediatric patients less than 18 years of age have not been established. ### Geriatic Use In the Phase 3 trials in RA, PsA, and AS, there were no overall differences in SAEs, serious infections, and AEs in golimumab-treated patients ages 65 or older (N = 155) compared with younger golimumab-treated patients. In UC, there were insufficient numbers of patients aged 65 and over to determine whether they respond differently from patients aged 18 to 65. Because there is a higher incidence of infections in the geriatric population in general, caution should be used in treating geriatric patients with golimumab. ### Gender Population PK analyses suggested no PK differences between male and female patients after body weight adjustment in the RA, PsA and UC trials. In the AS trial, female patients showed 13% higher apparent clearance than male patients after body weight adjustment. Subgroup analysis based on gender showed that both female and male patients achieved clinically significant response at the proposed clinical dose. Dosage adjustment based on gender is not needed. ### Race No ethnicity-related PK differences were observed between Caucasians and Asians, and there were too few patients of other races to assess for PK differences. ### Renal Impairment No formal trial of the effect of renal impairment on the PK of golimumab was conducted. ### Hepatic Impairment No formal trial of the effect of hepatic impairment on the PK of golimumab was conducted. ### Females of Reproductive Potential and Males A fertility study conducted in mice using an analogous anti-mouse TNFα antibody showed no impairment of fertility. ### Immunocompromised Patients There is no FDA guidance one the use of Golimumab in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Golimumab Administration in the drug label. ### Monitoring Closely monitor patients for the development of signs and symptoms of infection during and after treatment with golimumab. Discontinue golimumab if a patient develops a serious infection, an opportunistic infection, or sepsis. For a patient who develops a new infection during treatment with golimumab, perform a prompt and complete diagnostic workup appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy and closely monitor them. # IV Compatibility There is limited information regarding the compatibility of Golimumab and IV administrations. # Overdosage In a clinical trial, 5 patients received protocol-directed single infusions of 10 mg/kg of intravenous golimumab without serious adverse reactions or other significant reactions. The highest weight patient was 100 kg, and therefore received a single intravenous infusion of 1000 mg of golimumab. There were no golimumab overdoses in the clinical trials. # Pharmacology ## Mechanism of Action Golimumab is a human monoclonal antibody that binds to both the soluble and transmembrane bioactive forms of human TNFα. This interaction prevents the binding of TNFα to its receptors, thereby inhibiting the biological activity of TNFα (a cytokine protein). There was no evidence of the golimumab antibody binding to other TNF superfamily ligands; in particular, the golimumab antibody did not bind or neutralize human lymphotoxin. Golimumab did not lyse human monocytes expressing transmembrane TNF in the presence of complement or effector cells. Elevated TNFα levels in the blood, synovium, and joints have been implicated in the pathophysiology of several chronic inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. TNFα is an important mediator of the articular inflammation that is characteristic of these diseases. The exact mechanism by which golimumab treats ulcerative colitis is unknown. Golimumab modulated the in vitro biological effects mediated by TNF in several bioassays, including the expression of adhesion proteins responsible for leukocyte infiltration (E-selectin, ICAM-1 and VCAM-1) and the secretion of proinflammatory cytokines (IL-6, IL-8, G-CSF and GM-CSF). ## Structure There is limited information regarding Golimumab Structure in the drug label. ## Pharmacodynamics In clinical trials, decreases in C-reactive protein (CRP), interleukin (IL)-6, matrix metalloproteinase 3 (MMP-3), intercellular adhesion molecule (ICAM)-1 and vascular endothelial growth factor (VEGF) were observed following golimumab administration in patients with RA, PsA, and AS. ## Pharmacokinetics Following subcutaneous administration of golimumab to healthy subjects and patients with active RA, the median time to reach maximum serum concentrations (Tmax) ranged from 2 to 6 days. A subcutaneous injection of 50 mg golimumab to healthy subjects produced a mean ± standard deviation maximum serum concentration (Cmax) of 3.2 ± 1.4 µg/mL. By cross-trial comparisons of mean AUCinf values following an IV or subcutaneous administration of golimumab, the absolute bioavailability of subcutaneous golimumab was estimated to be approximately 53%. Following a single IV administration over the dose range of 0.1 to 10.0 mg/kg in patients with active RA, mean volume of distribution ranged from 58 to 126 mL/kg. The volume of distribution for golimumab indicates that golimumab is distributed primarily in the circulatory system with limited extravascular distribution. The exact metabolic pathway of golimumab is unknown. Following a single IV administration over the dose range of 0.1 to 10.0 mg/kg in patients with active RA, mean systemic clearance of golimumab was estimated to be 4.9 to 6.7 mL/day/kg. Median terminal half-life values were estimated to be approximately 2 weeks in healthy subjects and patients with active RA, PsA or AS. Population PK analyses indicated that concomitant use of NSAIDs, oral corticosteroids, or sulfasalazine did not influence the apparent clearance of golimumab. Patients who developed anti-golimumab antibodies generally had lower steady-state serum trough concentrations of golimumab. golimumab exhibited dose-proportional pharmacokinetics (PK) in patients with active RA over the dose range of 0.1 to 10 mg/kg following a single intravenous (IV) dose. Following a single SC dose in healthy subjects, dose proportional pharmacokinetics were also observed over a dose range of 50 mg to 400 mg. When 50 mg golimumab was administered subcutaneous to patients with RA, PsA, or AS every 4 weeks, serum concentrations appeared to reach steady state by Week 12. With concomitant use of methotrexate (MTX), treatment with 50 mg golimumab subcutaneous every 4 weeks resulted in a mean steady-state trough serum concentration of approximately 0.4–0.6 µg/mL in patients with active RA, approximately 0.5 µg/mL in patients with active PsA, and approximately 0.8 µg/mL in patients with active AS. Patients with RA, PsA, and AS treated with golimumab 50 mg and MTX had approximately 52%, 36% and 21% higher mean steady-state trough concentrations of golimumab, respectively compared with those treated with golimumab 50 mg without MTX. The presence of MTX also decreased anti-golimumab antibody incidence from 7% to 2% For RA, golimumab should be used with MTX. In the PsA and AS trials, the presence or absence of concomitant MTX did not appear to influence clinical efficacy and safety parameters. When induction doses of 200 mg and 100 mg golimumab at week 0 and 2, respectively, followed by maintenance doses of 100 mg golimumab every 4 weeks were administered subcutaneously in patients with UC, serum golimumab concentrations reached steady state by week 8 after the first maintenance dose. Treatment with 100 mg golimumab subcutaneous every 4 weeks during maintenance resulted in a mean steady-state trough serum concentration of approximately 1.8 ± 1.1 µg/mL. Population PK analyses showed there was a trend toward higher apparent clearance of golimumab with increasing weight. Treatment with the recommended maintenance dose regimen of golimumab 100 mg in UC patients did not result in meaningful differences in clinical efficacy among different weight groups. Across the PsA and AS populations, no meaningful differences in clinical efficacy were observed among the subgroups by weight quartile. The RA trial in MTX-experienced and TNF-blocker-naïve patients (Trial RA-2) did show evidence of a reduction in clinical efficacy with increasing body weight, but this effect was observed for both tested doses of golimumab (50 mg and 100 mg). There is no need to adjust the dosage of golimumab based on a patient's weight. ## Nonclinical Toxicology Long-term animal studies of golimumab have not been conducted to evaluate its carcinogenic potential. Mutagenicity studies have not been conducted with golimumab. # Clinical Studies The efficacy and safety of golimumab were evaluated in 3 multicenter, randomized, double-blind, controlled trials (Trials RA-1, RA-2, and RA-3) in 1542 patients ≥ 18 years of age with moderately to severely active RA, diagnosed according to the American College of Rheumatology (ACR) criteria, for at least 3 months prior to administration of trial agent. Patients were required to have at least 4 swollen and 4 tender joints. golimumab was administered subcutaneously at doses of 50 mg or 100 mg every 4 weeks. Double-blinded controlled efficacy data were collected and analyzed through Week 24. Patients were allowed to continue stable doses of concomitant low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day) and/or NSAIDs and patients may have received oral MTX during the trials. Trial RA-1 evaluated 445 patients who were previously treated (at least 8 to 12 weeks prior to administration of trial agent) with one or more doses of a biologic TNF-blocker without a serious adverse reaction. Patients may have discontinued the biologic TNF-blocker for a variety of reasons. Patients were randomized to receive placebo (n = 150), golimumab 50 mg (n = 147), or golimumab 100 mg (n = 148). Patients were allowed to continue stable doses of concomitant MTX, sulfasalazine (SSZ), and/or hydroxychloroquine (HCQ) during the trial. The use of other DMARDs including cytotoxic agents or other biologics was prohibited. Trial RA-2 evaluated 444 patients who had active RA despite a stable dose of at least 15 mg/week of MTX and who had not been previously treated with a biologic TNF-blocker. Patients were randomized to receive background MTX (n = 133), golimumab 50 mg + background MTX (n = 89), golimumab 100 mg + background MTX (n = 89), or golimumab 100 mg monotherapy (n = 133). The use of other DMARDs including SSZ, HCQ, cytotoxic agents, or other biologics was prohibited. Trial RA-3 evaluated 637 patients with active RA who were MTX-naïve and had not previously been treated with a biologic TNF-blocker. Patients were randomized to receive MTX (n = 160), golimumab 50 mg + MTX (n = 159), golimumab 100 mg + MTX (n = 159), or golimumab 100 mg monotherapy (n = 159). For patients receiving MTX, MTX was administered at a dose of 10 mg/week beginning at Week 0 and increased to 20 mg/week by Week 8. The use of other DMARDs including SSZ, HCQ, cytotoxic agents, or other biologics was prohibited. The primary endpoint in Trial RA-1 and Trial RA-2 was the percentage of patients achieving an ACR 20 response at Week 14 and the primary endpoint in Trial RA-3 was the percentage of patients achieving an ACR 50 response at Week 24. In Trials RA-1, RA-2, and RA-3, the median duration of RA disease was 9.4, 5.7, and 1.2 years; and 99%, 75%, and 54% of the patients used at least one DMARD in the past, respectively. Approximately 77% and 57% of patients received concomitant NSAIDs and low dose corticosteroids, respectively, in the 3 pooled RA trials. In the 3 RA trials, a greater percentage of patients treated with the combination of golimumab and MTX achieved ACR responses at Week 14 (Trials RA-1 and RA-2) and Week 24 (Studies RA-1, RA-2, and RA-3) versus patients treated with the MTX alone. There was no clear evidence of improved ACR response with the higher golimumab dose group (100 mg) compared to the lower golimumab dose group (50 mg). In Trials RA-2 and RA-3, the golimumab monotherapy groups were not statistically different from the MTX monotherapy groups in ACR responses. Table 2 shows the proportion of patients with the ACR response for the golimumab 50 mg and control groups in Trials RA-1, RA-2, and RA-3. In the subset of patients who received golimumab in combination with MTX in Trial RA-1, the proportion of patients achieving ACR 20, 50 and 70 responses at week 14 were 40%, 18%, and 12%, respectively, in the golimumab 50 mg + MTX group (N = 101) compared with 17%, 6%, and 2%, respectively, in the placebo + MTX group (N = 103). Table 3 shows the percent improvement in the components of the ACR response criteria for the golimumab 50 mg + MTX and MTX groups in Trial RA-2. The percent of patients achieving ACR 20 responses by visit for Trial RA-2 is shown in Figure 1. ACR 20 responses were observed in 38% of patients in the golimumab 50 mg + MTX group at the first assessment (Week 4) after the initial golimumab administration. In Trials RA-1 and RA-2, the golimumab 50 mg groups demonstrated a greater improvement compared to the control groups in the change in mean Health Assessment Questionnaire Disability Index (HAQ-DI) score from baseline to Week 24: 0.23 vs. 0.03 in RA-1, 0.47 vs. 0.13 in RA-2, respectively. Also in Trials RA-1 and RA-2, the golimumab 50 mg groups compared to the control groups had a greater proportion of HAQ responders (change from baseline > 0.22) at Week 24: 43% vs. 27%, 65% vs. 35%, respectively. The safety and efficacy of golimumab were evaluated in a multi-center, randomized, double-blind, placebo-controlled trial in 405 adult patients with moderately to severely active PsA (≥ 3 swollen joints and ≥ 3 tender joints) despite NSAID or DMARD therapy (Trial PsA). Patients in this trial had a diagnosis of PsA for at least 6 months with a qualifying psoriatic skin lesion of at least 2 cm in diameter. Previous treatment with a biologic TNF-blocker was not allowed. Patients were randomly assigned to placebo (n = 113), golimumab 50 mg (n = 146), or golimumab 100 mg (n = 146) given subcutaneously every 4 weeks. Patients were allowed to receive stable doses of concomitant MTX (≤ 25 mg/week), low dose oral corticosteroids (equivalent to ≤ 10 mg of prednisone a day), and/or NSAIDs during the trial. The use of other DMARDs including SSZ, HCQ, cytotoxic agents, or other biologics was prohibited. The primary endpoint was the percentage of patients achieving ACR 20 response at Week 14. Placebo-controlled efficacy data were collected and analyzed through Week 24. Patients with each subtype of PsA were enrolled, including polyarticular arthritis with no rheumatoid nodules (43%), asymmetric peripheral arthritis (30%), distal interphalangeal (DIP) joint arthritis (15%), spondylitis with peripheral arthritis (11%), and arthritis mutilans (1%). The median duration of PsA disease was 5.1 years, 78% of patients received at least one DMARD in the past, and approximately 48% of patients received MTX, and 16% received low dose oral steroids. golimumab ± MTX, compared with placebo ± MTX, resulted in significant improvement in signs and symptoms as demonstrated by the proportion of patients with an ACR 20 response at Week 14 in Trial PsA (see TABLE 4). There was no clear evidence of improved ACR response with the higher golimumab dose group (100 mg) compared to the lower golimumab dose group (50 mg). ACR responses observed in the golimumab-treated groups were similar in patients receiving and not receiving concomitant MTX. Similar ACR 20 responses at Week 14 were observed in patients with different PsA subtypes. However, the number of patients with arthritis mutilans was too small to allow meaningful assessment. golimumab 50 mg treatment also resulted in significantly greater improvement compared with placebo for each ACR component in Trial PsA (Table 5). Treatment with golimumab resulted in improvement in enthesitis and skin manifestations in patients with PsA. However, the safety and efficacy of golimumab in the treatment of patients with plaque psoriasis has not been established. The percent of patients achieving ACR 20 responses by visit for Trial PsA is shown in Figure 2. ACR 20 responses were observed in 31% of patients in the golimumab 50 mg + MTX group at the first assessment (Week 4) after the initial golimumab administration. In Trial PsA, golimumab 50 mg demonstrated a greater improvement compared to placebo in the change in mean Health Assessment Questionnaire Disability Index (HAQ-DI) score from baseline to Week 24 (0.33 and -0.01, respectively). In addition, the golimumab 50 mg group compared to the placebo group had a greater proportion of HAQ responders (≥ 0.3 change from baseline) at Week 24: 43% vs. 22%, respectively. The safety and efficacy of golimumab were evaluated in a multi-center, randomized, double-blind, placebo-controlled trial in 356 adult patients with active ankylosing spondylitis according to modified New York criteria for at least 3 months (Trial AS). Patients had symptoms of active disease [defined as a Bath AS Disease Activity Index (BASDAI) ≥ 4 and VAS for total back pain of ≥ 4, on scales of 0 to 10 cm] despite current or previous NSAID therapy. Patients were excluded if they were previously treated with a biologic TNF-blocker or if they had complete ankylosis of the spine. Patients were randomly assigned to placebo (n = 78), golimumab 50 mg (n = 138), or golimumab 100 mg (n = 140) administered subcutaneously every 4 weeks. Patients were allowed to continue stable doses of concomitant MTX, sulfasalazine (SSZ), hydroxychloroquine (HCQ), low dose corticosteroids (equivalent to < 10 mg of prednisone a day), and/or NSAIDs during the trial. The use of other DMARDs including cytotoxic agents or other biologics was prohibited. The primary endpoint was the percentage of patients achieving an ASsessment in Ankylosing Spondylitis (ASAS) 20 response at Week 14. Placebo-controlled efficacy data were collected and analyzed through Week 24. In Trial AS, the median duration of AS disease was 5.6 years, median duration of inflammatory back pain was 12 years, 83% were HLA-B27 positive, 24% had prior joint surgery or procedure, and 55% received at least one DMARD in the past. During the trial, the use of concomitant DMARDs and/or NSAIDs was as follows: MTX (20%), SSZ (26%), HCQ (1%), low dose oral steroids (16%), and NSAIDs (90%). In Trial AS, golimumab ± DMARDs treatment, compared with placebo ± DMARDs, resulted in a significant improvement in signs and symptoms as demonstrated by the proportion of patients with an ASAS 20 response at Week 14 (see TABLE 6). There was no clear evidence of improved ASAS response with the higher golimumab dose group (100 mg) compared to the lower golimumab dose group (50 mg). Table 7 shows the percent improvement in the components of the ASAS response criteria for the golimumab 50 mg ± DMARDs and placebo ± DMARDs groups in Trial AS. The percent of patients achieving ASAS 20 responses by visit for Trial AS is shown in Figure 3. ASAS 20 responses were observed in 48% of patients in the golimumab 50 mg + MTX group at the first assessment (Week 4) after the initial golimumab administration. The safety and efficacy of golimumab were evaluated in two multi-center, randomized, double-blind, placebo-controlled clinical trials in patients ≥ 18 years of age (Trials UC-1 and UC-2). Trial UC-1 was an induction trial conducted in patients with moderately to severely active ulcerative colitis (UC), defined as a Mayo score of 6 to 12 [the Mayo score ranges from 0 to 12 and has four subscales that are each scored from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, findings on endoscopy, and physician global assessment]. At baseline, subjects also had an endoscopy subscore of 2 or 3 on a 3-point scale (an endoscopy score of 2 is defined by marked erythema, absent vascular pattern, friability, erosions; and a score of 3 is defined by spontaneous bleeding, ulceration). Patients were corticosteroid dependent (i.e., an inability to successfully taper corticosteroids without a return of the symptoms of UC) or had an inadequate response to or had failed to tolerate at least one of the following therapies: oral aminosalicylates, oral corticosteroids, azathioprine, or 6-mercaptopurine. Trial UC-1 was divided into 2 parts. In Part 1 (dose finding), patients were randomized to one of 4 treatment groups: 400 mg golimumab administered subcutaneously (SC) at Week 0 and 200 mg at Week 2 (400/200 mg), 200 mg golimumab SC at Week 0 and 100 mg at Week 2 (200/100 mg), 100 mg golimumab SC at Week 0 and 50 mg at Week 2 (100/50 mg), or placebo SC at Weeks 0 and 2. In Part 2 (dose confirming), efficacy was evaluated in 761 patients who were randomized to receive either 400 mg golimumab SC at Week 0 and 200 mg at Week 2, 200 mg golimumab SC at Week 0 and 100 mg at Week 2, or placebo SC at Weeks 0 and 2. golimumab 100/50 mg SC was not evaluated in Part 2; its safety and effectiveness has not been established in UC. Concomitant stable doses of oral aminosalicylates (5-ASA), oral corticosteroids (less than 40 mg/day), azathioprine (AZA), 6-mercaptopurine (6-MP), and/or methotrexate (MTX) were permitted. Patients who received previous TNF inhibitors were excluded. The primary endpoint was the percent of patients in clinical response at Week 6, defined as a decrease from baseline in the Mayo score by ≥ 30% and ≥ 3 points, accompanied by a decrease in the rectal bleeding subscore of ≥ 1 or a rectal bleeding subscore of 0 (no blood seen) or 1 (streaks of blood with stool less than half the time). Trial UC-2 was a randomized-withdrawal maintenance trial that evaluated 456 patients who achieved clinical response with golimumab induction and tolerated golimumab treatment. Patients were randomized to receive golimumab 50 mg, golimumab 100 mg or placebo administered subcutaneously every 4 weeks. Concomitant stable doses of oral aminosalicylates, azathioprine, 6-mercaptopurine, and/or methotrexate were permitted. Corticosteroids were to be tapered at the start of the maintenance trial. The primary endpoint was the percent of patients maintaining clinical response through Week 54. In Trial UC-1, a greater proportion of patients achieved clinical response, clinical remission and had improvement of endoscopic appearance of the mucosa at Week 6 in the golimumab 200/100 mg group compared with the placebo group. The golimumab 400/200 mg group did not demonstrate additional clinical benefit over the golimumab 200/100 mg group. Clinical response was defined as a decrease from baseline in the Mayo score of ≥ 30% and ≥ 3 points, accompanied by a decrease in the rectal bleeding subscore of ≥ 1 or a rectal bleeding subscore of 0 or 1. Clinical remission was defined as a Mayo score ≤ 2 points, with no individual subscore > 1. Improvement of endoscopic appearance of the mucosa was defined as a Mayo endoscopy subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern, mild friability). In Trial UC-2, a greater proportion of patients maintained clinical response through Week 54 in the golimumab 100 mg group compared with the placebo group. In Trial UC-2, golimumab-treated patients in clinical response (which included the subset of patients in clinical remission) in Trial UC-1, were again assessed for clinical remission at Week 30 and Week 54. A greater proportion of patients had clinical remission at both Weeks 30 and 54 without demonstrating a loss of response at any time point through Week 54 in the golimumab 100 mg group compared with the placebo group. # How Supplied Golimumab for injection: - 50 mg/0.5 mL in a single dose - 100 mg/1 mL in a single dose ## Storage Stored at 2°C to 8°C (36°F to 46°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Patients should be advised of the potential benefits and risks of golimumab. Physicians should instruct their patients to read the Medication Guide before starting golimumab therapy and to read it each time the prescription is renewed. Inform patients that golimumab may lower the ability of their immune system to fight infections. Instruct the patient of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and hepatitis B reactivation. Patients should be counseled about the risk of lymphoma and other malignancies while receiving golimumab. Advise latex-sensitive patients that the needle cover on the prefilled syringe as well as the prefilled syringe in the prefilled SmartJect autoinjector contains dry natural rubber (a derivative of latex). Advise patients to report any signs of new or worsening medical conditions such as congestive heart failure, demyelinating disorders, autoimmune diseases, liver disease, cytopenias, or psoriasis. The first self-injection should be performed under the supervision of a qualified healthcare professional. If a patient or caregiver is to administer golimumab, he/she should be instructed in injection techniques and their ability to inject subcutaneously should be assessed to ensure the proper administration of golimumab Advise the patient to read the FDA-approved Instructions for Use and provide the following instructions to patients: - Prior to use, remove the prefilled syringe or the prefilled SmartJect autoinjector from the refrigerator and allow golimumab to sit at room temperature outside of the carton for 30 minutes and out of the reach of children. - Do not warm golimumab in any other way. For example, do not warm golimumab in a microwave or in hot water. - Do not remove the prefilled syringe needle cover or SmartJect autoinjector cap while allowing golimumab to reach room temperature. Remove these immediately before injection. - Do not pull the autoinjector away from the skin until you hear a first "click" sound and then a second "click" sound (the injection is finished and the needle is pulled back). It usually takes about 3 to 6 seconds but may take up to 15 seconds for you to hear the second "click" after the first "click". If the autoinjector is pulled away from the skin before the injection is completed, a full dose of golimumab may not be administered. - A puncture-resistant container for disposal of needles and syringes should be used. Patients or caregivers should be instructed in the technique of proper syringe and needle disposal, and be advised not to reuse these items. # Precautions with Alcohol Alcohol-Golimumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Simponi [1] - Simponi Aria # Look-Alike Drug Names There is limited information regarding Golimumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Golimumab
5867fc051e20aaf1952e41ec8855592e248637e8	wikidoc	Goserelin	Goserelin # 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 Goserelin is a Gonadotropin-releasing Hormone (GnRH) agonist that is FDA approved for the treatment of locally confined carcinoma of the prostate, and palliative treatment of advanced carcinoma of the prostate. Common adverse reactions include hot flashes, sexual dysfunction, decreased erections and lower urinary tract symptoms. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - ZOLADEX is indicated for use in combination with flutamide for the management of locally confined Stage T2b-T4 (Stage B2-C) carcinoma of the prostate. Treatment with ZOLADEX and flutamide should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy - When ZOLADEX is given in combination with radiotherapy and flutamide for patients with Stage T2b-T4 (Stage B2-C) prostatic carcinoma, treatment should be started 8 weeks prior to initiating radiotherapy and should continue during radiation therapy. A treatment regimen using one ZOLADEX 3.6 mg depot, followed in 28 days by one ZOLADEX 10.8 mg depot, should be administered. - ZOLADEX is indicated in the palliative treatment of advanced carcinoma of the prostate. - In controlled studies of patients with advanced prostatic cancer comparing ZOLADEX 3.6 mg to orchiectomy, the long-term endocrine responses and objective responses were similar between the two treatment arms. Additionally, duration of survival was similar between the two treatment arms in a major comparative trial. - In controlled studies of patients with advanced prostatic cancer, ZOLADEX 10.8 mg implant produced pharmacodynamically similar effect in terms of suppression of serum testosterone to that achieved with ZOLADEX 3.6 mg implant. Clinical outcome similar to that produced with the use of the ZOLADEX 3.6 mg implant administered every 28 days is predicted with the ZOLADEX 10.8 mg implant administered every 12 weeks. - The automatic safety feature of the syringe aids in the prevention of needlestick injury. - For the management of advanced prostate cancer, ZOLADEX is intended for long-term administration unless clinically inappropriate. - No dosage adjustment is necessary for patients with renal or hepatic impairment. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Goserelin in adult patients. ### Non–Guideline-Supported Use - Breast cancer, Adjuvant treatment of hormone receptor-positive, axillary lymph node-positive disease in premenopausal women - Dysfunctional uterine bleeding - In vitro fertilization - Precocious puberty # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Goserelin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Goserelin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Goserelin in pediatric patients. # Contraindications - Anaphylactic reactions to ZOLADEX have been reported in the medical literature. ZOLADEX is contraindicated in those patients who have a known hypersensitivity to GnRH, GnRH agonist analogues or any of the components in ZOLADEX. - Expected hormonal changes that occur with ZOLADEX treatment increase the risk for pregnancy loss. ZOLADEX may cause fetal harm when administered to a pregnant woman. 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 # Warnings - Initially, ZOLADEX, like other GnRH agonists, causes transient increases in serum levels of testosterone. Transient worsening of symptoms, or the occurrence of additional signs and symptoms of prostatic cancer, may occasionally develop during the first few weeks of ZOLADEX treatment. A small number of patients may experience a temporary increase in bone pain, which can be managed symptomatically. As with other GnRH agonists, isolated cases of ureteral obstruction and spinal cord compression have been observed. If spinal cord compression or renal impairment secondary to ureteral obstruction develops, standard treatment of these complications should be instituted, and in extreme cases an immediate orchiectomy. - Hypersensitivity, antibody formation and acute anaphylactic reactions have been reported with GnRH agonist analogues. - Of 115 women worldwide treated with ZOLADEX and tested for development of binding to goserelin following treatment with ZOLADEX, one patient showed low-titer binding to goserelin. On further testing of this patient's plasma obtained following treatment, her goserelin binding component was found not to be precipitated with rabbit antihuman immunoglobulin polyvalent sera. These findings suggest the possibility of antibody formation. - Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for treatment of hyperglycemia or diabetes. - Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice. - Androgen deprivation therapy may prolong the QT/QTc interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes. # Adverse Reactions ## Clinical Trials Experience - ZOLADEX has been found to be generally well tolerated in clinical trials. Adverse reactions reported in these trials were rarely severe enough to result in the patients' withdrawal from ZOLADEX treatment. As seen with other hormonal therapies, the most commonly observed adverse events during ZOLADEX therapy were due to the expected physiological effects from decreased testosterone levels. These included hot flashes, sexual dysfunction and decreased erections. - Tumor Flare Phenomenon: Initially, ZOLADEX, like other GnRH agonists, causes transient increases in serum levels of testosterone. A small percentage of patients experienced a temporary worsening of signs and symptoms, usually manifested by an increase in cancer-related pain which was managed symptomatically. Isolated cases of exacerbation of disease symptoms, either ureteral obstruction or spinal cord compression, occurred at similar rates in controlled clinical trials with both ZOLADEX and orchiectomy. The relationship of these events to therapy is uncertain - Treatment with ZOLADEX and flutamide did not add substantially to the toxicity of radiation treatment alone. The following adverse experiences were reported during a multicenter clinical trial comparing ZOLADEX + flutamide + radiation versus radiation alone. The most frequently reported (greater than 5%) adverse experiences are listed below: - Additional adverse event data was collected for the combination therapy with radiation group over both the hormonal treatment and hormonal treatment plus radiation phases of the study. Adverse experiences occurring in more than 5% of patients in this group, over both parts of the study, were hot flashes (46%), diarrhea (40%), nausea (9%), and skin rash (8%). - Two controlled clinical trials using ZOLADEX 10.8 mg versus ZOLADEX 3.6 mg were conducted. During a comparative phase, patients were randomized to receive either a single 10.8 mg implant or three consecutive 3.6 mg implants every 4 weeks over weeks 0-12. During this phase, the only adverse event reported in greater than 5% of patients was hot flashes, with an incidence of 47% in the ZOLADEX 10.8 mg group and 48% in the ZOLADEX 3.6 mg group. - From weeks 12-48 all patients were treated with a 10.8 mg implant every 12 weeks. During this noncomparative phase, the following adverse events were reported in greater than 5% of patients: The following adverse events were reported in greater than 1%, but less than 5% of patients treated with ZOLADEX 10.8 mg implant every 12 weeks. Some of these are commonly reported in elderly patients. - Abdominal pain - Back pain - Flu syndrome - Headache - Sepsis - Aggravation reaction - Angina pectoris - Cerebral ischemia - Cerebrovascular accident - Heart failure - Pulmonary embolus - Varicose veins - Diarrhea - Hematemesis - Diabetes mellitus - Anemia - Peripheral edema - Dizziness - Paresthesia - Urinary retention - Cough increased - Dyspnea - Pneumonia - Herpes simplex - Pruritus - Bladder neoplasm - Breast pain - Hematuria - Impotence - Urinary frequency - Urinary incontinence - Urinary tract disorder - Urinary tract infection - Urination impaired - The following adverse events not already listed above were reported in patients receiving ZOLADEX 3.6 mg in other clinical trials. Inclusion does not necessarily represent a causal relationship to ZOLADEX 10.8 mg. - Allergic reaction - Chills - Fever - Infection - Injection site reaction - Lethargy - Malaise - Arrhythmia - Chest pain - Hemorrhage - Hypertension - Migraine - Myocardial infarction - Palpitations - Peripheral vascular disorder - Tachycardia - Anorexia - Constipation - Dry mouth - Dyspepsia - Flatulence - Increased appetite - Nausea - Ulcer - Vomiting - Ecchymosis - Edema - Gout - Hyperglycemia - Weight increase - Arthralgia - Hypertonia - Joint disorder - Leg cramps - Myalgia - Osteoporosis - Anxiety - Depression - Emotional lability - Headache - Insomnia - Nervousness - Somnolence - Thinking abnormal - Bronchitis - Chronic obstructive pulmonary disease - Epistaxis - Rhinitis - Sinusitis - Upper respiratory infection - Voice alterations - Acne - Alopecia - Dry skin - Hair disorders - Rash - Seborrhea - Skin discoloration - Sweating - Amblyopia - Dry eyes - Breast tenderness - Decreased erections - Renal insufficiency - Sexual dysfunction - Urinary obstruction - Plasma Enzymes: Elevation of liver enzymes (AST, ALT) have been reported in female patients exposed to ZOLADEX 3.6 mg (representing less than 1% of all patients). There was no other evidence of abnormal liver function. Causality between these changes and ZOLADEX have not been established. - Lipids: In a controlled trial in females, ZOLADEX 3.6 mg implant therapy resulted in a minor, but statistically significant effect on serum lipids (i.e., increases in LDL cholesterol of 21.3 mg/dL; increases in HDL cholesterol of 2.7 mg/dL; and triglycerides increased by 8.0 mg/dL). ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of ZOLADEX. 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. - In patients with bone metastases. - Osteoporosis, decreased bone mineral density and bony fracture in men. - Hypotension and hypertension have been reported. These changes are usually transient, resolving either during continued therapy or after cessation of therapy. - Pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) and pituitary adenoma have been diagnosed. Most of the pituitary apoplexy cases occurred within 2 weeks of the first dose, and some occurred within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. Pituitary tumors have been reported. - Usually within one month of starting treatment. - Psychotic disorders, convulsions and mood swings. # Drug Interactions - No formal drug-drug interaction studies have been performed. - No drug interaction studies with other drugs have been conducted with ZOLADEX. No confirmed interactions have been reported between ZOLADEX and other drugs. - Administration of ZOLADEX in therapeutic doses results in suppression of the pituitary-gonadal system. Because of this suppression, diagnostic tests of pituitary-gonadotropic and gonadal functions conducted during treatment may show results which are misleading. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X - Based on mechanism of action in humans and findings of increased pregnancy loss in animal studies, ZOLADEX may cause fetal harm when administered to a pregnant woman. Expected hormone changes that occur with ZOLADEX treatment increase the risk for pregnancy loss. 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. - ZOLADEX crosses the placenta in rats and rabbits following subcutaneous administration. Administration of goserelin to pregnant rats and rabbits during organogenesis resulted in increased preimplantation loss and increased resorptions. When pregnant rats received goserelin throughout gestation and lactation, there was a dose-related increase in umbilical hernia in offspring. In additional reproduction studies in rats, goserelin decreased fetus and pup survival. Human dose/exposure multiples could not be calculated from available animal data. - Actual animal doses: rat (≥ 2 mcg/kg/day for pregnancy loss; ≥ 10 mcg/kg/day for umbilical hernia in offspring); rabbits (> 20 mcg/kg/day). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Goserelin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Goserelin during labor and delivery. ### Nursing Mothers - It is not known if goserelin is excreted in human milk. Goserelin is excreted in the milk of lactating rats. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZOLADEX, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - There is no need for any dosage adjustment when administering ZOLADEX 10.8 mg to geriatric patients. ### Gender There is no FDA guidance on the use of Goserelin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Goserelin with respect to specific racial populations. ### Renal Impairment - In clinical trials with the solution formulation of goserelin, subjects with impaired renal function (creatinine clearance 70 mL/min). However, there was no evidence for any accumulation of goserelin on multiple dosing of the ZOLADEX 10.8 mg depot to subjects with impaired renal function. There was no evidence for any increase in incidence of adverse events in renally impaired patients administered the 10.8 mg depot. These data indicate that there is no need for any dosage adjustment when administering ZOLADEX 10.8 mg to subjects with impaired renal function. ### Hepatic Impairment - The total body clearances and serum elimination half-lives were similar between normal subjects and patients with moderate hepatic impairment (alanine transaminase < 3xULN and asparate aminotransferase < 3xULN) when treated with a 250 mcg subcutaneous formulation of goserelin. This pharmacokinetic study indicates that no dose adjustment is needed in patients with moderately impaired liver function. There is no pharmacokinetic data with goserelin in patients with severe hepatic insufficiency. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Goserelin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Goserelin in patients who are immunocompromised. ### Body Weight - A decline of approximately 1 to 2.5% in the AUC after administration of a 10.8 mg depot was observed with a kilogram increase in body weight. In obese patients who have not responded clinically, testosterone levels should be monitored closely. # Administration and Monitoring ### Administration - ZOLADEX, at a dose of 10.8 mg, should be administered subcutaneously every 12 weeks into the anterior abdominal wall below the navel line using an aseptic technique under the supervision of a physician. - While a delay of a few days is permissible, every effort should be made to adhere to the 12-week schedule - The proper method of administration of ZOLADEX is described in the instructions that follow. - Put the patient in a comfortable position with the upper part of the body slightly raised. Prepare an area of the anterior abdominal wall below the navel line with an alcohol swab. - Examine the foil pouch and syringe for damage. Remove the syringe from the opened foil pouch and hold the syringe at a slight angle to the light. Check that at least part of the ZOLADEX implant is visible. - Grasp the blue plastic safety tab and pull away from the syringe, and discard. Remove needle cover. Unlike liquid injections, there is no need to remove air bubbles as attempts to do so may displace the ZOLADEX implant. - Holding the syringe around the protective sleeve, using an aseptic technique, pinch the skin of the patient’s anterior abdominal wall below the navel line. With the bevel of the needle facing up, insert the needle at a 30 to 45 degree angle to the skin in one continuous deliberate motion until the protective sleeve touches the patient’s skin. - NOTE: The ZOLADEX syringe cannot be used for aspiration. If the hypodermic needle penetrates a large vessel, blood will be seen instantly in the syringe chamber. If a vessel is penetrated, withdraw the needle and inject with a new syringe elsewhere. - Do not penetrate into muscle or peritoneum. - To administer the ZOLADEX implant and to activate the protective sleeve, grasp the barrel at the finger grip and depress the plunger until you cannot depress it any further. If the plunger is not depressed fully, the protective sleeve will NOT activate. When the protective sleeve ‘clicks’, the protective sleeve will automatically begin to slide to cover the needle. - NOTE: The needle does not retract. - Withdraw the needle and allow protective sleeve to slide and cover needle. Dispose of the syringe in an approved sharps collector. - NOTE: In the unlikely event of the need to surgically remove ZOLADEX, it may be localized by ultrasound. ### Monitoring - Transient worsening of tumor symptoms may occur during the first few weeks of treatment with ZOLADEX, which may include ureteral obstruction and spinal cord compression. Monitor patients at risk for complications of tumor flare - Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH analogs. Monitor blood glucose level and manage according to current clinical practice. - Increased risk of myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH analogs in men. Monitor for cardiovascular disease and manage according to current clinical practice # IV Compatibility There is limited information regarding IV Compatibility of Goserelin in the drug label. # Overdosage - The pharmacologic properties of ZOLADEX and its mode of administration make accidental or intentional overdosage unlikely. There is no experience of overdosage from clinical trials. Animal studies indicate that no increased pharmacologic effect occurred at higher doses or more frequent administration. Subcutaneous doses of the drug as high as 1 mg/kg/day in rats and dogs did not produce any nonendocrine related sequelae; this dose is up to 250 times the estimated human daily dose based on the body surface area. If overdosage occurs, it should be managed symptomatically. # Pharmacology ## Mechanism of Action - ZOLADEX is a synthetic decapeptide analogue of GnRH. ZOLADEX acts as an inhibitor of pituitary gonadotropin secretion when administered in the biodegradable formulation. - In animal and in vitro studies, administration of goserelin resulted in the regression or inhibition of growth of the hormonally sensitive dimethylbenzanthracene (DMBA)-induced rat mammary tumor and Dunning R3327 prostate tumor. ## Structure - ZOLADEX® (goserelin acetate implant) is a GnRH agonist. Goserelin acetate is chemically described as an acetate salt of . Its chemical structure is pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2 acetate ## Pharmacodynamics - Following initial administration, ZOLADEX causes an initial increase in serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels with subsequent increases in serum levels of testosterone. Chronic administration of ZOLADEX leads to sustained suppression of pituitary gonadotropins, and serum levels of testosterone consequently fall into the range normally seen in surgically castrated men approximately 21 days after initiation of therapy. This leads to accessory sex organ regression. - In clinical trials using ZOLADEX 3.6 mg with follow-up of more than 2 years, suppression of serum testosterone to castrate levels has been maintained for the duration of therapy. ## Pharmacokinetics - The pharmacokinetics of ZOLADEX have been determined in healthy male volunteers and patients. In healthy males, radiolabeled goserelin was administered as a single 250 mcg (aqueous solution) dose by the subcutaneous route. The absorption of radiolabeled drug was rapid, and the peak blood radioactivity levels occurred between 0.5 and 1.0 hour after dosing. - The overall pharmacokinetic profile of goserelin following administration of a ZOLADEX 10.8 mg depot to patients with prostate cancer was determined. The initial release of goserelin from the depot was relatively rapid resulting in a peak concentration at 2 hours after dosing. From Day 4 until the end of the 12-week dosing interval, the sustained release of goserelin from the depot produced reasonably stable systemic exposure. Mean (Standard Deviation) pharmacokinetic data are presented in Table 4. There is no clinically significant accumulation of goserelin following administration of four depots administered at 12-week intervals. - SD = standard deviation - Serum goserelin concentrations in prostate cancer patients administered three 3.6 mg depots followed by one 10.8 mg depot are displayed in Figure 1. The profiles for both formulations are primarily dependent upon the rate of drug release from the depots. For the 3.6 mg depot, mean concentrations gradually rise to reach a peak of about 3 ng/mL at around 15 days after administration and then decline to approximately 0.5 ng/mL by the end of the treatment period. For the 10.8 mg depot, mean concentrations increase to reach a peak of about 8 ng/mL within the first 24 hours and then decline rapidly up to Day 4. Thereafter, mean concentrations remain relatively stable in the range of about 0.3 to 1 ng/mL up to the end of the treatment period. - Administration of four ZOLADEX 10.8 mg depots to patients with prostate cancer resulted in testosterone levels that were suppressed to and maintained within the range normally observed in surgically castrated men (0 – 1.73 nmol/L or 0-50 ng/dL), over the dosing interval in approximately 91% (145/160) of patients studied. In 6 of 15 patients that escaped from castrate range, serum testosterone levels were maintained below 2.0 nmol/L (58 ng/dL) and in only one of the 15 patients did the depot completely fail to maintain serum testosterone levels to within the castrate range over a 336-day period (4 depot injections). In the 8 additional patients, a transient escape was followed 14 days later by a level within the castrate range. - The apparent volume of distribution determined after subcutaneous administration of 250 mcg aqueous solution of goserelin was 44.1 ± 13.6 liters for healthy males. The plasma protein binding of goserelin was found to be 27%. - Metabolism of goserelin, by hydrolysis of the C-terminal amino acids, is the major clearance mechanism. The major circulating component in serum appeared to be 1–7 fragment, and the major component present in urine of one healthy male volunteer was 5-10 fragment. The metabolism of goserelin in humans yields a similar but narrow profile of metabolites to that found in other species. All metabolites found in humans have also been found in toxicology species. - Clearance of goserelin following subcutaneous administration of a radiolabeled solution of goserelin was very rapid and occurred via a combination of hepatic and urinary excretion. More than 90% of a subcutaneous radiolabeled solution formulation dose of goserelin was excreted in urine. Approximately 20% of the dose recovered in urine was accounted for by unchanged goserelin. ## Nonclinical Toxicology - Subcutaneous implantation of goserelin in male and female rats once every 4 weeks for 1 year and recovery for 23 weeks at doses of about 80 and 150 mcg/kg (males) and 50 and 100 mcg/kg (females) daily resulted in an increased incidence of pituitary adenomas. An increased incidence of pituitary adenomas was also observed following subcutaneous implant of goserelin in rats at similar dose levels for a period of 72 weeks in males and 101 weeks in females. The relevance of the rat pituitary adenomas to humans has not been established. Subcutaneous implants of goserelin every 3 weeks for 2 years delivered to mice at doses of up to 2400 mcg/kg/day resulted in an increased incidence of histiocytic sarcoma of the vertebral column and femur. Human dose/exposure multiples could not be calculated from available animal data. - Mutagenicity tests using bacterial and mammalian systems for point mutations and cytogenetic effects have provided no evidence for mutagenic potential. - Administration of goserelin led to changes that were consistent with gonadal suppression in both male and female rats as a result of its endocrine action. In male rats administered 500-1000 mcg/kg/day, a decrease in weight and atrophic histological changes were observed in the testes, epididymis, seminal vesicle and prostate gland with complete suppression of spermatogenesis. In female rats administered 50-1000 mcg/kg/day, suppression of ovarian function led to decreased size and weight of ovaries and secondary sex organs; follicular development was arrested at the antral stage and the corpora lutea were reduced in size and number. Except for the testes, almost complete histologic reversal of these effects in males and females was observed several weeks after dosing was stopped; however, fertility and general reproductive performance were reduced in those that became pregnant after goserelin was discontinued. Fertile matings occurred within 2 weeks after cessation of dosing, even though total recovery of reproductive function may not have occurred before mating took place; and, the ovulation rate, the corresponding implantation rate, and number of live fetuses were reduced. - Based on histological examination, drug effects on reproductive organs were reversible in male and female dogs administered 107-214 mcg/kg/day goserelin when drug treatment was stopped after continuous administration for 1 year. Human dose/exposure multiples could not be calculated from available animal data. # Clinical Studies - The effects of hormonal treatment combined with radiation were studied in 466 patients (231 ZOLADEX + flutamide + radiation, 235 radiation alone) with bulky primary tumors confined to the prostate (stage B2) or extending beyond the capsule (stage C), with or without pelvic node involvement. - In this multicentered, controlled trial, administration of ZOLADEX (3.6 mg depot) and flutamide capsules (250 mg t.i.d.) prior to and during radiation was associated with a significantly lower rate of local failure compared to radiation alone (16% vs 33% at 4 years, P<0.001). The combination therapy also resulted in a trend toward reduction in the incidence of distant metastases (27% vs 36% at 4 years, P =0.058). Median disease-free survival was significantly increased in patients who received complete hormonal therapy combined with radiation as compared to those patients who received radiation alone (4.4 vs 2.6 years, P<0.001). Inclusion of normal PSA level as a criterion for disease-free survival also resulted in significantly increased median disease-free survival in patients receiving the combination therapy (2.7 vs 1.5 years, P<0.001). - In two controlled clinical trials, 160 patients with advanced prostate cancer were randomized to receive either one 3.6 mg ZOLADEX implant every four weeks or a single 10.8 mg ZOLADEX implant every 12 weeks. Mean serum testosterone suppression was similar between the two arms. PSA falls at three months were 94% in patients who received the 10.8 mg implant and 92.5% in patients that received three 3.6 mg implants. - Periodic monitoring of serum testosterone levels should be considered if the anticipated clinical or biochemical response to treatment has not been achieved. A clinical outcome similar to that produced with the use of the 3.6 mg implant administered every 28 days is predicted with ZOLADEX 10.8 mg implant administered every 12 weeks (84 days). Total testosterone was measured by the DPC Coat-A-Count radioimmunoassay method which, as defined by the manufacturers, is highly specific and accurate. Acceptable variability of approximately 20% at low testosterone levels has been demonstrated in the clinical studies performed with the ZOLADEX 10.8 mg depot. # How Supplied - ZOLADEX 10.8 mg implant is supplied as a sterile and totally biodegradable D,L-lactic and glycolic acids copolymer (12.82-14.76 mg/dose) impregnated with goserelin acetate equivalent to 10.8 mg of goserelin in a disposable syringe device fitted with a 14-gauge x 36 +/- 0.5 mm siliconized hypodermic needle with protective sleeve (NDC 0310-0951-30). The unit is sterile and comes in a sealed, light- and moisture-proof, aluminum foil laminate pouch containing a desiccant capsule. ## Storage - Store at room temperature (do not exceed 25°C ). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - The use of ZOLADEX in patients at particular risk of developing ureteral obstruction or spinal cord compression should be considered carefully and the patients monitored closely during the first month of therapy. Patients with ureteral obstruction or spinal cord compression should have appropriate treatment prior to initiation of ZOLADEX therapy. - The use of GnRH agonists may cause a reduction in bone mineral density. In men, data suggest the use of a bisphosphonate in combination with a GnRH agonist may reduce bone mineral loss. - Patients should be informed that diabetes, or loss of glycemic control in patients with pre-existing diabetes, has been reported during treatment with GnRH agonists, including ZOLADEX. Therefore, consideration should be given to monitoring blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving ZOLADEX. - A small increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice # Precautions with Alcohol - Alcohol-Goserelin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Zoladex® # Look-Alike Drug Names There is limited information regarding Goserelin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Goserelin 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 Goserelin is a Gonadotropin-releasing Hormone (GnRH) agonist that is FDA approved for the treatment of locally confined carcinoma of the prostate, and palliative treatment of advanced carcinoma of the prostate. Common adverse reactions include hot flashes, sexual dysfunction, decreased erections and lower urinary tract symptoms. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - ZOLADEX is indicated for use in combination with flutamide for the management of locally confined Stage T2b-T4 (Stage B2-C) carcinoma of the prostate. Treatment with ZOLADEX and flutamide should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy - When ZOLADEX is given in combination with radiotherapy and flutamide for patients with Stage T2b-T4 (Stage B2-C) prostatic carcinoma, treatment should be started 8 weeks prior to initiating radiotherapy and should continue during radiation therapy. A treatment regimen using one ZOLADEX 3.6 mg depot, followed in 28 days by one ZOLADEX 10.8 mg depot, should be administered. - ZOLADEX is indicated in the palliative treatment of advanced carcinoma of the prostate. - In controlled studies of patients with advanced prostatic cancer comparing ZOLADEX 3.6 mg to orchiectomy, the long-term endocrine responses and objective responses were similar between the two treatment arms. Additionally, duration of survival was similar between the two treatment arms in a major comparative trial. - In controlled studies of patients with advanced prostatic cancer, ZOLADEX 10.8 mg implant produced pharmacodynamically similar effect in terms of suppression of serum testosterone to that achieved with ZOLADEX 3.6 mg implant. Clinical outcome similar to that produced with the use of the ZOLADEX 3.6 mg implant administered every 28 days is predicted with the ZOLADEX 10.8 mg implant administered every 12 weeks. - The automatic safety feature of the syringe aids in the prevention of needlestick injury. - For the management of advanced prostate cancer, ZOLADEX is intended for long-term administration unless clinically inappropriate. - No dosage adjustment is necessary for patients with renal or hepatic impairment. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Goserelin in adult patients. ### Non–Guideline-Supported Use - Breast cancer, Adjuvant treatment of hormone receptor-positive, axillary lymph node-positive disease in premenopausal women[1][2] - Dysfunctional uterine bleeding[3] - In vitro fertilization[4] - Precocious puberty[5] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Goserelin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Goserelin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Goserelin in pediatric patients. # Contraindications - Anaphylactic reactions to ZOLADEX have been reported in the medical literature. ZOLADEX is contraindicated in those patients who have a known hypersensitivity to GnRH, GnRH agonist analogues or any of the components in ZOLADEX. - Expected hormonal changes that occur with ZOLADEX treatment increase the risk for pregnancy loss. ZOLADEX may cause fetal harm when administered to a pregnant woman. 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 # Warnings - Initially, ZOLADEX, like other GnRH agonists, causes transient increases in serum levels of testosterone. Transient worsening of symptoms, or the occurrence of additional signs and symptoms of prostatic cancer, may occasionally develop during the first few weeks of ZOLADEX treatment. A small number of patients may experience a temporary increase in bone pain, which can be managed symptomatically. As with other GnRH agonists, isolated cases of ureteral obstruction and spinal cord compression have been observed. If spinal cord compression or renal impairment secondary to ureteral obstruction develops, standard treatment of these complications should be instituted, and in extreme cases an immediate orchiectomy. - Hypersensitivity, antibody formation and acute anaphylactic reactions have been reported with GnRH agonist analogues. - Of 115 women worldwide treated with ZOLADEX and tested for development of binding to goserelin following treatment with ZOLADEX, one patient showed low-titer binding to goserelin. On further testing of this patient's plasma obtained following treatment, her goserelin binding component was found not to be precipitated with rabbit antihuman immunoglobulin polyvalent sera. These findings suggest the possibility of antibody formation. - Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for treatment of hyperglycemia or diabetes. - Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice. - Androgen deprivation therapy may prolong the QT/QTc interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes. # Adverse Reactions ## Clinical Trials Experience - ZOLADEX has been found to be generally well tolerated in clinical trials. Adverse reactions reported in these trials were rarely severe enough to result in the patients' withdrawal from ZOLADEX treatment. As seen with other hormonal therapies, the most commonly observed adverse events during ZOLADEX therapy were due to the expected physiological effects from decreased testosterone levels. These included hot flashes, sexual dysfunction and decreased erections. - Tumor Flare Phenomenon: Initially, ZOLADEX, like other GnRH agonists, causes transient increases in serum levels of testosterone. A small percentage of patients experienced a temporary worsening of signs and symptoms, usually manifested by an increase in cancer-related pain which was managed symptomatically. Isolated cases of exacerbation of disease symptoms, either ureteral obstruction or spinal cord compression, occurred at similar rates in controlled clinical trials with both ZOLADEX and orchiectomy. The relationship of these events to therapy is uncertain - Treatment with ZOLADEX and flutamide did not add substantially to the toxicity of radiation treatment alone. The following adverse experiences were reported during a multicenter clinical trial comparing ZOLADEX + flutamide + radiation versus radiation alone. The most frequently reported (greater than 5%) adverse experiences are listed below: - Additional adverse event data was collected for the combination therapy with radiation group over both the hormonal treatment and hormonal treatment plus radiation phases of the study. Adverse experiences occurring in more than 5% of patients in this group, over both parts of the study, were hot flashes (46%), diarrhea (40%), nausea (9%), and skin rash (8%). - Two controlled clinical trials using ZOLADEX 10.8 mg versus ZOLADEX 3.6 mg were conducted. During a comparative phase, patients were randomized to receive either a single 10.8 mg implant or three consecutive 3.6 mg implants every 4 weeks over weeks 0-12. During this phase, the only adverse event reported in greater than 5% of patients was hot flashes, with an incidence of 47% in the ZOLADEX 10.8 mg group and 48% in the ZOLADEX 3.6 mg group. - From weeks 12-48 all patients were treated with a 10.8 mg implant every 12 weeks. During this noncomparative phase, the following adverse events were reported in greater than 5% of patients: The following adverse events were reported in greater than 1%, but less than 5% of patients treated with ZOLADEX 10.8 mg implant every 12 weeks. Some of these are commonly reported in elderly patients. - Abdominal pain - Back pain - Flu syndrome - Headache - Sepsis - Aggravation reaction - Angina pectoris - Cerebral ischemia - Cerebrovascular accident - Heart failure - Pulmonary embolus - Varicose veins - Diarrhea - Hematemesis - Diabetes mellitus - Anemia - Peripheral edema - Dizziness - Paresthesia - Urinary retention - Cough increased - Dyspnea - Pneumonia - Herpes simplex - Pruritus - Bladder neoplasm - Breast pain - Hematuria - Impotence - Urinary frequency - Urinary incontinence - Urinary tract disorder - Urinary tract infection - Urination impaired - The following adverse events not already listed above were reported in patients receiving ZOLADEX 3.6 mg in other clinical trials. Inclusion does not necessarily represent a causal relationship to ZOLADEX 10.8 mg. - Allergic reaction - Chills - Fever - Infection - Injection site reaction - Lethargy - Malaise - Arrhythmia - Chest pain - Hemorrhage - Hypertension - Migraine - Myocardial infarction - Palpitations - Peripheral vascular disorder - Tachycardia - Anorexia - Constipation - Dry mouth - Dyspepsia - Flatulence - Increased appetite - Nausea - Ulcer - Vomiting - Ecchymosis - Edema - Gout - Hyperglycemia - Weight increase - Arthralgia - Hypertonia - Joint disorder - Leg cramps - Myalgia - Osteoporosis - Anxiety - Depression - Emotional lability - Headache - Insomnia - Nervousness - Somnolence - Thinking abnormal - Bronchitis - Chronic obstructive pulmonary disease - Epistaxis - Rhinitis - Sinusitis - Upper respiratory infection - Voice alterations - Acne - Alopecia - Dry skin - Hair disorders - Rash - Seborrhea - Skin discoloration - Sweating - Amblyopia - Dry eyes - Breast tenderness - Decreased erections - Renal insufficiency - Sexual dysfunction - Urinary obstruction - Plasma Enzymes: Elevation of liver enzymes (AST, ALT) have been reported in female patients exposed to ZOLADEX 3.6 mg (representing less than 1% of all patients). There was no other evidence of abnormal liver function. Causality between these changes and ZOLADEX have not been established. - Lipids: In a controlled trial in females, ZOLADEX 3.6 mg implant therapy resulted in a minor, but statistically significant effect on serum lipids (i.e., increases in LDL cholesterol of 21.3 mg/dL; increases in HDL cholesterol of 2.7 mg/dL; and triglycerides increased by 8.0 mg/dL). ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of ZOLADEX. 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. - In patients with bone metastases. - Osteoporosis, decreased bone mineral density and bony fracture in men. - Hypotension and hypertension have been reported. These changes are usually transient, resolving either during continued therapy or after cessation of therapy. - Pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) and pituitary adenoma have been diagnosed. Most of the pituitary apoplexy cases occurred within 2 weeks of the first dose, and some occurred within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. Pituitary tumors have been reported. - Usually within one month of starting treatment. - Psychotic disorders, convulsions and mood swings. # Drug Interactions - No formal drug-drug interaction studies have been performed. - No drug interaction studies with other drugs have been conducted with ZOLADEX. No confirmed interactions have been reported between ZOLADEX and other drugs. - Administration of ZOLADEX in therapeutic doses results in suppression of the pituitary-gonadal system. Because of this suppression, diagnostic tests of pituitary-gonadotropic and gonadal functions conducted during treatment may show results which are misleading. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X - Based on mechanism of action in humans and findings of increased pregnancy loss in animal studies, ZOLADEX may cause fetal harm when administered to a pregnant woman. Expected hormone changes that occur with ZOLADEX treatment increase the risk for pregnancy loss. 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. - ZOLADEX crosses the placenta in rats and rabbits following subcutaneous administration. Administration of goserelin to pregnant rats and rabbits during organogenesis resulted in increased preimplantation loss and increased resorptions. When pregnant rats received goserelin throughout gestation and lactation, there was a dose-related increase in umbilical hernia in offspring. In additional reproduction studies in rats, goserelin decreased fetus and pup survival. Human dose/exposure multiples could not be calculated from available animal data. - Actual animal doses: rat (≥ 2 mcg/kg/day for pregnancy loss; ≥ 10 mcg/kg/day for umbilical hernia in offspring); rabbits (> 20 mcg/kg/day). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Goserelin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Goserelin during labor and delivery. ### Nursing Mothers - It is not known if goserelin is excreted in human milk. Goserelin is excreted in the milk of lactating rats. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZOLADEX, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - There is no need for any dosage adjustment when administering ZOLADEX 10.8 mg to geriatric patients. ### Gender There is no FDA guidance on the use of Goserelin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Goserelin with respect to specific racial populations. ### Renal Impairment - In clinical trials with the solution formulation of goserelin, subjects with impaired renal function (creatinine clearance < 20 mL/min) had a serum elimination half-life of 12.1 hours compared to 4.2 hours for subjects with normal renal function (creatinine clearance > 70 mL/min). However, there was no evidence for any accumulation of goserelin on multiple dosing of the ZOLADEX 10.8 mg depot to subjects with impaired renal function. There was no evidence for any increase in incidence of adverse events in renally impaired patients administered the 10.8 mg depot. These data indicate that there is no need for any dosage adjustment when administering ZOLADEX 10.8 mg to subjects with impaired renal function. ### Hepatic Impairment - The total body clearances and serum elimination half-lives were similar between normal subjects and patients with moderate hepatic impairment (alanine transaminase < 3xULN and asparate aminotransferase < 3xULN) when treated with a 250 mcg subcutaneous formulation of goserelin. This pharmacokinetic study indicates that no dose adjustment is needed in patients with moderately impaired liver function. There is no pharmacokinetic data with goserelin in patients with severe hepatic insufficiency. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Goserelin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Goserelin in patients who are immunocompromised. ### Body Weight - A decline of approximately 1 to 2.5% in the AUC after administration of a 10.8 mg depot was observed with a kilogram increase in body weight. In obese patients who have not responded clinically, testosterone levels should be monitored closely. # Administration and Monitoring ### Administration - ZOLADEX, at a dose of 10.8 mg, should be administered subcutaneously every 12 weeks into the anterior abdominal wall below the navel line using an aseptic technique under the supervision of a physician. - While a delay of a few days is permissible, every effort should be made to adhere to the 12-week schedule - The proper method of administration of ZOLADEX is described in the instructions that follow. - Put the patient in a comfortable position with the upper part of the body slightly raised. Prepare an area of the anterior abdominal wall below the navel line with an alcohol swab. - Examine the foil pouch and syringe for damage. Remove the syringe from the opened foil pouch and hold the syringe at a slight angle to the light. Check that at least part of the ZOLADEX implant is visible. - Grasp the blue plastic safety tab and pull away from the syringe, and discard. Remove needle cover. Unlike liquid injections, there is no need to remove air bubbles as attempts to do so may displace the ZOLADEX implant. - Holding the syringe around the protective sleeve, using an aseptic technique, pinch the skin of the patient’s anterior abdominal wall below the navel line. With the bevel of the needle facing up, insert the needle at a 30 to 45 degree angle to the skin in one continuous deliberate motion until the protective sleeve touches the patient’s skin. - NOTE: The ZOLADEX syringe cannot be used for aspiration. If the hypodermic needle penetrates a large vessel, blood will be seen instantly in the syringe chamber. If a vessel is penetrated, withdraw the needle and inject with a new syringe elsewhere. - Do not penetrate into muscle or peritoneum. - To administer the ZOLADEX implant and to activate the protective sleeve, grasp the barrel at the finger grip and depress the plunger until you cannot depress it any further. If the plunger is not depressed fully, the protective sleeve will NOT activate. When the protective sleeve ‘clicks’, the protective sleeve will automatically begin to slide to cover the needle. - NOTE: The needle does not retract. - Withdraw the needle and allow protective sleeve to slide and cover needle. Dispose of the syringe in an approved sharps collector. - NOTE: In the unlikely event of the need to surgically remove ZOLADEX, it may be localized by ultrasound. ### Monitoring - Transient worsening of tumor symptoms may occur during the first few weeks of treatment with ZOLADEX, which may include ureteral obstruction and spinal cord compression. Monitor patients at risk for complications of tumor flare - Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH analogs. Monitor blood glucose level and manage according to current clinical practice. - Increased risk of myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH analogs in men. Monitor for cardiovascular disease and manage according to current clinical practice # IV Compatibility There is limited information regarding IV Compatibility of Goserelin in the drug label. # Overdosage - The pharmacologic properties of ZOLADEX and its mode of administration make accidental or intentional overdosage unlikely. There is no experience of overdosage from clinical trials. Animal studies indicate that no increased pharmacologic effect occurred at higher doses or more frequent administration. Subcutaneous doses of the drug as high as 1 mg/kg/day in rats and dogs did not produce any nonendocrine related sequelae; this dose is up to 250 times the estimated human daily dose based on the body surface area. If overdosage occurs, it should be managed symptomatically. # Pharmacology ## Mechanism of Action - ZOLADEX is a synthetic decapeptide analogue of GnRH. ZOLADEX acts as an inhibitor of pituitary gonadotropin secretion when administered in the biodegradable formulation. - In animal and in vitro studies, administration of goserelin resulted in the regression or inhibition of growth of the hormonally sensitive dimethylbenzanthracene (DMBA)-induced rat mammary tumor and Dunning R3327 prostate tumor. ## Structure - ZOLADEX® (goserelin acetate implant) is a GnRH agonist. Goserelin acetate is chemically described as an acetate salt of [D-Ser(But)6,Azgly10]. Its chemical structure is pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2 acetate [C59H84N18O14 ·(C2H4O2)x where x = 1 to 2.4] ## Pharmacodynamics - Following initial administration, ZOLADEX causes an initial increase in serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels with subsequent increases in serum levels of testosterone. Chronic administration of ZOLADEX leads to sustained suppression of pituitary gonadotropins, and serum levels of testosterone consequently fall into the range normally seen in surgically castrated men approximately 21 days after initiation of therapy. This leads to accessory sex organ regression. - In clinical trials using ZOLADEX 3.6 mg with follow-up of more than 2 years, suppression of serum testosterone to castrate levels has been maintained for the duration of therapy. ## Pharmacokinetics - The pharmacokinetics of ZOLADEX have been determined in healthy male volunteers and patients. In healthy males, radiolabeled goserelin was administered as a single 250 mcg (aqueous solution) dose by the subcutaneous route. The absorption of radiolabeled drug was rapid, and the peak blood radioactivity levels occurred between 0.5 and 1.0 hour after dosing. - The overall pharmacokinetic profile of goserelin following administration of a ZOLADEX 10.8 mg depot to patients with prostate cancer was determined. The initial release of goserelin from the depot was relatively rapid resulting in a peak concentration at 2 hours after dosing. From Day 4 until the end of the 12-week dosing interval, the sustained release of goserelin from the depot produced reasonably stable systemic exposure. Mean (Standard Deviation) pharmacokinetic data are presented in Table 4. There is no clinically significant accumulation of goserelin following administration of four depots administered at 12-week intervals. - SD = standard deviation - Serum goserelin concentrations in prostate cancer patients administered three 3.6 mg depots followed by one 10.8 mg depot are displayed in Figure 1. The profiles for both formulations are primarily dependent upon the rate of drug release from the depots. For the 3.6 mg depot, mean concentrations gradually rise to reach a peak of about 3 ng/mL at around 15 days after administration and then decline to approximately 0.5 ng/mL by the end of the treatment period. For the 10.8 mg depot, mean concentrations increase to reach a peak of about 8 ng/mL within the first 24 hours and then decline rapidly up to Day 4. Thereafter, mean concentrations remain relatively stable in the range of about 0.3 to 1 ng/mL up to the end of the treatment period. - Administration of four ZOLADEX 10.8 mg depots to patients with prostate cancer resulted in testosterone levels that were suppressed to and maintained within the range normally observed in surgically castrated men (0 – 1.73 nmol/L or 0-50 ng/dL), over the dosing interval in approximately 91% (145/160) of patients studied. In 6 of 15 patients that escaped from castrate range, serum testosterone levels were maintained below 2.0 nmol/L (58 ng/dL) and in only one of the 15 patients did the depot completely fail to maintain serum testosterone levels to within the castrate range over a 336-day period (4 depot injections). In the 8 additional patients, a transient escape was followed 14 days later by a level within the castrate range. - The apparent volume of distribution determined after subcutaneous administration of 250 mcg aqueous solution of goserelin was 44.1 ± 13.6 liters for healthy males. The plasma protein binding of goserelin was found to be 27%. - Metabolism of goserelin, by hydrolysis of the C-terminal amino acids, is the major clearance mechanism. The major circulating component in serum appeared to be 1–7 fragment, and the major component present in urine of one healthy male volunteer was 5-10 fragment. The metabolism of goserelin in humans yields a similar but narrow profile of metabolites to that found in other species. All metabolites found in humans have also been found in toxicology species. - Clearance of goserelin following subcutaneous administration of a radiolabeled solution of goserelin was very rapid and occurred via a combination of hepatic and urinary excretion. More than 90% of a subcutaneous radiolabeled solution formulation dose of goserelin was excreted in urine. Approximately 20% of the dose recovered in urine was accounted for by unchanged goserelin. ## Nonclinical Toxicology - Subcutaneous implantation of goserelin in male and female rats once every 4 weeks for 1 year and recovery for 23 weeks at doses of about 80 and 150 mcg/kg (males) and 50 and 100 mcg/kg (females) daily resulted in an increased incidence of pituitary adenomas. An increased incidence of pituitary adenomas was also observed following subcutaneous implant of goserelin in rats at similar dose levels for a period of 72 weeks in males and 101 weeks in females. The relevance of the rat pituitary adenomas to humans has not been established. Subcutaneous implants of goserelin every 3 weeks for 2 years delivered to mice at doses of up to 2400 mcg/kg/day resulted in an increased incidence of histiocytic sarcoma of the vertebral column and femur. Human dose/exposure multiples could not be calculated from available animal data. - Mutagenicity tests using bacterial and mammalian systems for point mutations and cytogenetic effects have provided no evidence for mutagenic potential. - Administration of goserelin led to changes that were consistent with gonadal suppression in both male and female rats as a result of its endocrine action. In male rats administered 500-1000 mcg/kg/day, a decrease in weight and atrophic histological changes were observed in the testes, epididymis, seminal vesicle and prostate gland with complete suppression of spermatogenesis. In female rats administered 50-1000 mcg/kg/day, suppression of ovarian function led to decreased size and weight of ovaries and secondary sex organs; follicular development was arrested at the antral stage and the corpora lutea were reduced in size and number. Except for the testes, almost complete histologic reversal of these effects in males and females was observed several weeks after dosing was stopped; however, fertility and general reproductive performance were reduced in those that became pregnant after goserelin was discontinued. Fertile matings occurred within 2 weeks after cessation of dosing, even though total recovery of reproductive function may not have occurred before mating took place; and, the ovulation rate, the corresponding implantation rate, and number of live fetuses were reduced. - Based on histological examination, drug effects on reproductive organs were reversible in male and female dogs administered 107-214 mcg/kg/day goserelin when drug treatment was stopped after continuous administration for 1 year. Human dose/exposure multiples could not be calculated from available animal data. # Clinical Studies - The effects of hormonal treatment combined with radiation were studied in 466 patients (231 ZOLADEX + flutamide + radiation, 235 radiation alone) with bulky primary tumors confined to the prostate (stage B2) or extending beyond the capsule (stage C), with or without pelvic node involvement. - In this multicentered, controlled trial, administration of ZOLADEX (3.6 mg depot) and flutamide capsules (250 mg t.i.d.) prior to and during radiation was associated with a significantly lower rate of local failure compared to radiation alone (16% vs 33% at 4 years, P<0.001). The combination therapy also resulted in a trend toward reduction in the incidence of distant metastases (27% vs 36% at 4 years, P =0.058). Median disease-free survival was significantly increased in patients who received complete hormonal therapy combined with radiation as compared to those patients who received radiation alone (4.4 vs 2.6 years, P<0.001). Inclusion of normal PSA level as a criterion for disease-free survival also resulted in significantly increased median disease-free survival in patients receiving the combination therapy (2.7 vs 1.5 years, P<0.001). - In two controlled clinical trials, 160 patients with advanced prostate cancer were randomized to receive either one 3.6 mg ZOLADEX implant every four weeks or a single 10.8 mg ZOLADEX implant every 12 weeks. Mean serum testosterone suppression was similar between the two arms. PSA falls at three months were 94% in patients who received the 10.8 mg implant and 92.5% in patients that received three 3.6 mg implants. - Periodic monitoring of serum testosterone levels should be considered if the anticipated clinical or biochemical response to treatment has not been achieved. A clinical outcome similar to that produced with the use of the 3.6 mg implant administered every 28 days is predicted with ZOLADEX 10.8 mg implant administered every 12 weeks (84 days). Total testosterone was measured by the DPC Coat-A-Count radioimmunoassay method which, as defined by the manufacturers, is highly specific and accurate. Acceptable variability of approximately 20% at low testosterone levels has been demonstrated in the clinical studies performed with the ZOLADEX 10.8 mg depot. # How Supplied - ZOLADEX 10.8 mg implant is supplied as a sterile and totally biodegradable D,L-lactic and glycolic acids copolymer (12.82-14.76 mg/dose) impregnated with goserelin acetate equivalent to 10.8 mg of goserelin in a disposable syringe device fitted with a 14-gauge x 36 +/- 0.5 mm siliconized hypodermic needle with protective sleeve [SafeSystem™ Syringe] (NDC 0310-0951-30). The unit is sterile and comes in a sealed, light- and moisture-proof, aluminum foil laminate pouch containing a desiccant capsule. ## Storage - Store at room temperature (do not exceed 25°C [77°F]). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - The use of ZOLADEX in patients at particular risk of developing ureteral obstruction or spinal cord compression should be considered carefully and the patients monitored closely during the first month of therapy. Patients with ureteral obstruction or spinal cord compression should have appropriate treatment prior to initiation of ZOLADEX therapy. - The use of GnRH agonists may cause a reduction in bone mineral density. In men, data suggest the use of a bisphosphonate in combination with a GnRH agonist may reduce bone mineral loss. - Patients should be informed that diabetes, or loss of glycemic control in patients with pre-existing diabetes, has been reported during treatment with GnRH agonists, including ZOLADEX. Therefore, consideration should be given to monitoring blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving ZOLADEX. - A small increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice # Precautions with Alcohol - Alcohol-Goserelin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Zoladex®[6] # Look-Alike Drug Names There is limited information regarding Goserelin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Goserelin
fb29db0c97d1761a25916067cd1ee062a9dea951	wikidoc	Gravidity	Gravidity # Gravida In medicine, gravidity refers to the number of times a woman has been pregnant - A gravida is a pregnant woman. - A nulligravida or gravida 0 is a woman who has never been pregnant. - A primigravida or gravida 1 is a woman who is pregnant for the first time or has been pregnant one time. - A multigravida or more specifically a gravida 2 (also secundigravida), gravida 3, and so on, is a woman who has been pregnant more than one time. - An elderly primigravida is a woman in her first pregnancy, who is at least 35 years old. The term gravida is generally coupled with para and abortus to indicate more details of the woman's obstetric history. # Gravid Gravid is term used in entomology to describe a mated female insect. Gravid is term used in biology to describe the condition of a female livebearing fish (or snakes) when carrying young internally.	Gravidity # Gravida In medicine, gravidity refers to the number of times a woman has been pregnant - A gravida is a pregnant woman. - A nulligravida or gravida 0 is a woman who has never been pregnant. - A primigravida or gravida 1 is a woman who is pregnant for the first time or has been pregnant one time. - A multigravida or more specifically a gravida 2 (also secundigravida), gravida 3, and so on, is a woman who has been pregnant more than one time. - An elderly primigravida is a woman in her first pregnancy, who is at least 35 years old. The term gravida is generally coupled with para and abortus to indicate more details of the woman's obstetric history. # Gravid Gravid is term used in entomology to describe a mated female insect. Gravid is term used in biology to describe the condition of a female livebearing fish (or snakes) when carrying young internally.	https://www.wikidoc.org/index.php/Gravid
b51395949203295c7f7fcc3e55ab392f58264eac	wikidoc	Gray hair	Gray hair Gray hair color typically occurs naturally as people age, usually turning their hair from its natural color to gray and then to white. More than 40 percent of Americans have some gray hair by their fortieth birthday, but white hairs can appear as early as childhood. The age at which graying begins seems to be almost entirely based on genetics. Sometimes people are born with gray hair because it is passed down genetically. Many people use hair dye to disguise the amount of gray in their hair. The change in hair color is caused by the gradual decrease of pigmentation that occurs when melanin ceases to be produced in the hair root and new hairs grow in without pigment. Two genes appear to be responsible for the process of graying, Bcl2 and Mitf. The stem cells at the base of hair follicles are responsible for producing melanocytes, the cells that produce and store pigment in hair and skin. The death of the melanocyte stem cells causes the onset of graying. In some cases, gray hair may be a deficiency of B12 or caused from a thyroid imbalance.	Gray hair Gray hair color typically occurs naturally as people age, usually turning their hair from its natural color to gray and then to white. More than 40 percent of Americans have some gray hair by their fortieth birthday, but white hairs can appear as early as childhood. The age at which graying begins seems to be almost entirely based on genetics. Sometimes people are born with gray hair because it is passed down genetically. Many people use hair dye to disguise the amount of gray in their hair. The change in hair color is caused by the gradual decrease of pigmentation that occurs when melanin ceases to be produced in the hair root and new hairs grow in without pigment. Two genes appear to be responsible for the process of graying, Bcl2 and Mitf. The stem cells at the base of hair follicles are responsible for producing melanocytes, the cells that produce and store pigment in hair and skin. The death of the melanocyte stem cells causes the onset of graying.[1] In some cases, gray hair may be a deficiency of B12 or caused from a thyroid imbalance.[2]	https://www.wikidoc.org/index.php/Gray_hair
f6a13b4cfb7d9f97af5986ef76fe766644a1a5ee	wikidoc	Green tea	Green tea The beverage green tea (Template:Zh-stp) is a "true" tea (i.e., Camellia sinensis) that has undergone minimal oxidation during processing. Green tea is popular in China, Korea, India, Uzbekistan, Kyrgyzstan, Kazakhstan, Japan, Pakistan, Taiwan, Hong Kong, Morocco, and the Middle East. Recently, it has become more widespread in the West, where traditionally black tea is consumed. # Chinese green teas ### Zhejiang Province Zhejiang is home to the most famous of all teas, Xi Hu Longjing, as well as many other high-quality green teas. ### Jiangsu Province ### Hubei Province ### Henan Province ### Jiangxi Province ### Anhui Province Anhui Province is home to three Chinese famous teas. # Japanese green teas # Other green teas - Green Tea from Ceylon # Brewing Generally, 2.25 grams of tea per 6 ounces of water, or about one teaspoon of green tea per cup, should be used. With very high quality teas like gyokuro, more than this amount of leaf is used, and the leaf is steeped multiple times for short durations. Green tea brewing time and temperature varies with individual teas. The hottest brewing temperatures are 180°F to 190°F (82°C to 88°C) water and the longest steeping times 2 to 3 minutes. The coolest brewing temperatures are 140°F to 150°F (60°C to 66°C) and the shortest times about 30 seconds. In general, lower quality green teas are steeped hotter and longer, while higher quality teas are steeped cooler and shorter. Steeping green tea too hot or too long will result in a bitter, astringent brew. High quality green teas can and usually are steeped multiple times - 2 or 3 steepings is typical. # Caffeine Green teas have about a quarter the caffeine content, by liquid volume, of coffee. # Potential effects of green tea on health ## History There is archaeological evidence that suggests that tea has been consumed for almost 5000 years, with India and China being two of the first countries to cultivate it. Green tea has been used as traditional medicine in areas such as India, China, Japan and Thailand to help everything from controlling bleeding and helping heal wounds to regulating body temperature, blood sugar and promoting digestion. The Kissa Yojoki (Book of Tea), written by Zen priest Eisai in 1191, describes how drinking green tea can have a positive effect on the five vital organs, especially the heart. The book discusses tea's medicinal qualities, which include easing the effects of alcohol, acting as a stimulant, curing blotchiness, quenching thirst, eliminating indigestion, curing beriberi disease, preventing fatigue, and improving urinary and brain function. Part One also explains the shapes of tea plants, tea flowers, and tea leaves, and covers how to grow tea plants and process tea leaves. In Part Two, the book discusses the specific dosage and method required for individual physical ailments. ## Unproven claims Green tea has been credited with providing a wide variety of health benefits, many of which have not been validated by scientific evidence. These claims and any for which academic citations are currently missing are listed here: - Stopping certain neurodegenerative diseases such as Alzheimer's and Parkinson's. - The prevention and treatment of cancer - Treating multiple sclerosis - Preventing the degradation of cell membranes by neutralizing the spread of free radicals which occur during oxidation process. - Reducing the negative effects of LDL cholesterol (bad cholesterol) by lowering levels of triglycerides and increasing the production of HDL cholesterol (good cholesterol). - Increasing fat oxidation (helps the body use fat as an energy source) and raising metabolism. - Joy Bauer, a New York City nutritionist, says increase levels of the metabolism speeding brain chemical norepinephrine. - Japanese researchers claim if you drink five cups of green tea a day, you'll burn 70 to 80 extra calories. Dr. Nicholas Perricone, an anti-aging specialist, appeared on the Oprah Winfrey show and told Oprah's viewers they can lose 10 lbs. in 6 weeks drinking green tea instead of coffee - Some green tea lovers restrict their intake because of the caffeine it contains — about half the amount as is found in coffee. Too much caffeine can cause nausea, insomnia or frequent urination. - Drinking green tea mixed with honey can often have a soothing effect on a sore throat. ## United States Food and Drug Administration (FDA) The article Tea: A Story of Serendipity appeared in the March 1996 issue of FDA Consumer Magazine and looked at the potential benefits of green tea. At that time they had not done any reviews of the potential benefits of green tea and were waiting to do it until health claims were filed. They have since denied two petitions to make qualified health claims as to the health benefits of green tea. On June 30, 2005, in response to "Green Tea and Reduced Risk of Cancer Health Claim", they stated: "FDA concludes that there is no credible evidence to support qualified health claims for green tea consumption and a reduced risk of gastric, lung, colon/rectal, esophageal, pancreatic, ovarian, and combined cancers. Thus, FDA is denying these claims. However, FDA concludes that there is very limited credible evidence for qualified health claims specifically for green tea and breast cancer and for green tea and prostate cancer, provided that the qualified claims are appropriately worded so as to not mislead consumers." On May 9, 2006, in response to "Green Tea and Reduced Risk of Cardiovascular Disease", they concluded "there is no credible evidence to support qualified health claims for green tea or green tea extract and a reduction of a number of risk factors associated with CVD." However in October 2006, the FDA approved an ointment based on green tea. New Drug Application (NDA) number N021902, for kunecatechins ointment 15% (proprietary name Veregen) was approved on October 31, 2006 , and added to the "Prescription Drug Product List" in October 2006. Kunecatechins ointment is indicated for the topical treatment of external genital and perianal warts. ## Scientific studies A 2006 study published in the September 13 issue of the Journal of the American Medical Association concluded "Green tea consumption is associated with reduced mortality due to all causes and due to cardiovascular disease but not with reduced mortality due to cancer." The study, conducted by the Tohoku University School of Public Policy in Japan, followed 40,530 Japanese adults, ages 40-79, with no history of stroke, coronary heart disease, or cancer at baseline beginning in 1994. The study followed all participants for up to 11 years for death from all causes and for up to 7 years for death from a specific cause. Participants who consumed 5 or more cups of tea per day had a 16 percent lower risk of all-cause mortality and a 26 percent lower risk of cardiovascular disease than participants who consumed less than one cup of tea per day. The study also states, "If green tea does protect humans against CVD or cancer, it is expected that consumption of this beverage would substantially contribute to the prolonging of life expectancy, given that CVD and cancer are the two leading causes of death worldwide." A study in the February 2006 edition of the American Journal of Clinical Nutrition concluded "A higher consumption of green tea is associated with a lower prevalence of cognitive impairment in humans." In May 2006, researchers at Yale University School of Medicine weighed in on the issue with a review article that looked at more than 100 studies on the health benefits of green tea. They pointed to what they called an "Asian paradox," which refers to lower rates of heart disease and cancer in Asia despite high rates of cigarette smoking. They theorized that the 1.2 liters of green tea that is consumed by many Asians each day provides high levels of polyphenols and other antioxidants. These compounds may work in several ways to improve cardiovascular health, including preventing blood platelets from sticking together (This anticoagulant effect is the reason doctors warn surgical patients to avoid green tea prior to procedures that rely on a patient's clotting ability) and improving cholesterol levels, said the researchers, whose study appeared in the May issue of the Journal of the American College of Surgeons. Specifically, green tea may prevent the oxidation of LDL cholesterol (the "bad" type), which, in turn, can reduce the buildup of plaque in arteries, the researchers wrote. A study published in the August 22, 2006 edition of Biological Psychology looked at the modification of the stress response via L-Theanine, a chemical found in green tea. It "suggested that the oral intake of L-Theanine could cause anti-stress effects via the inhibition of cortical neuron excitation." In a double-blind, randomized, placebo-controlled trial done by Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 240 adults were given either theaflavin-enriched green tea extract in form of 375mg capsule daily or a placebo. After 12 weeks, patients in the tea extract group had significantly less low-density lipoprotein cholesterol (LDL-C) and total cholesterol (16.4% and 11.3% lower than baseline, p<0.01) than the placebo group. The author concluded that theaflavin-enriched green tea extract can be used together with other dietary approaches to reduce LDL-C. A study published in the January, 2005 edition of the American Journal of Clinical Nutrition concluded "Daily consumption of tea containing 690 mg catechins for 12 wk reduced body fat, which suggests that the ingestion of catechins might be useful in the prevention and improvement of lifestyle-related diseases, mainly obesity." According to a Case Western Reserve University School of Medicine study published in the April 13 2005 issue of the Proceedings of the National Academy of SciencesAntioxidants in green tea may prevent and reduce the severity of rheumatoid arthritis. The study examined the effects of green tea polyphenols on collagen-induced arthritis in mice, which is similar to rheumatoid arthritis in humans. In each of three different study groups, the mice given the green tea polyphenols were significantly less likely to develop arthritis. Of the 18 mice that received the green tea, only eight (44 percent) developed arthritis. Among the 18 mice that did not receive the green tea, all but one (94 percent) developed arthritis. In addition, researchers noted that the eight arthritic mice that received the green tea polyphenols developed less severe forms of arthritis. A German study found that an extract of green tea and hot water (filtered), applied externally to the skin for 10 minutes, three times a day could help people with skin damaged from radiation therapy (after 16-22 days). A study published in the December 1999 American Journal of Clinical Nutrition found that "Green tea has thermogenic properties and promotes fat oxidation beyond that explained by its caffeine content per se. The green tea extract may play a role in the control of body composition via sympathetic activation of thermogenesis, fat oxidation, or both." In lab tests, EGCG, found in green tea, was found to prevent HIV from attacking T-Cells. However, it is not known if this has any effect on humans yet. A study in the August, 2003 issue of a new potential application of Cellular and Molecular Life Sciences found that "a new potential application of (–)-epigallocatechin-3-gallate in prevention or treatment of inflammatory processes is suggested"	Green tea The beverage green tea (Template:Zh-stp) is a "true" tea (i.e., Camellia sinensis) that has undergone minimal oxidation during processing. Green tea is popular in China, Korea, India, Uzbekistan, Kyrgyzstan, Kazakhstan, Japan, Pakistan, Taiwan, Hong Kong, Morocco, and the Middle East. Recently, it has become more widespread in the West, where traditionally black tea is consumed. # Chinese green teas ### Zhejiang Province Zhejiang is home to the most famous of all teas, Xi Hu Longjing, as well as many other high-quality green teas. ### Jiangsu Province ### Hubei Province ### Henan Province ### Jiangxi Province ### Anhui Province Anhui Province is home to three Chinese famous teas. # Japanese green teas Template:Nihongo is so ubiquitous in Japan that it is more commonly known as "tea" (Template:Nihongo) and even "Japanese tea" (Template:Nihongo)，although it was invented in China during the Song Dynasty, and brought to Japan by Myōan Eisai, a Japanese Buddhist priest who also introduced the Rinzai school of Zen Buddhism. Types of tea are commonly graded depending on the quality and the parts of the plant used as well as how they are processed. There are large variations in both price and quality within these broad categories, and there are many specialty green teas that fall outside this spectrum. The best Japanese green tea is said to be that from the Uji region of Kyoto[1]. Shizuoka Prefecture（静岡県） # Other green teas - Green Tea from Ceylon # Brewing Generally, 2.25 grams of tea per 6 ounces of water, or about one teaspoon of green tea per cup, should be used. With very high quality teas like gyokuro, more than this amount of leaf is used, and the leaf is steeped multiple times for short durations. Green tea brewing time and temperature varies with individual teas. The hottest brewing temperatures are 180°F to 190°F (82°C to 88°C) water and the longest steeping times 2 to 3 minutes. The coolest brewing temperatures are 140°F to 150°F (60°C to 66°C) and the shortest times about 30 seconds. In general, lower quality green teas are steeped hotter and longer, while higher quality teas are steeped cooler and shorter. Steeping green tea too hot or too long will result in a bitter, astringent brew. High quality green teas can and usually are steeped multiple times - 2 or 3 steepings is typical. # Caffeine Green teas have about a quarter the caffeine content, by liquid volume, of coffee. # Potential effects of green tea on health Template:Mainarticle ## History There is archaeological evidence that suggests that tea has been consumed for almost 5000 years, with India and China being two of the first countries to cultivate it. Green tea has been used as traditional medicine in areas such as India, China, Japan and Thailand to help everything from controlling bleeding and helping heal wounds to regulating body temperature, blood sugar and promoting digestion. The Kissa Yojoki (Book of Tea), written by Zen priest Eisai in 1191, describes how drinking green tea can have a positive effect on the five vital organs, especially the heart. The book discusses tea's medicinal qualities, which include easing the effects of alcohol, acting as a stimulant, curing blotchiness, quenching thirst, eliminating indigestion, curing beriberi disease, preventing fatigue, and improving urinary and brain function. Part One also explains the shapes of tea plants, tea flowers, and tea leaves, and covers how to grow tea plants and process tea leaves. In Part Two, the book discusses the specific dosage and method required for individual physical ailments. ## Unproven claims Green tea has been credited with providing a wide variety of health benefits, many of which have not been validated by scientific evidence. These claims and any for which academic citations are currently missing are listed here: - Stopping certain neurodegenerative diseases such as Alzheimer's and Parkinson's.[2] - The prevention and treatment of cancer [3] - Treating multiple sclerosis [4] - Preventing the degradation of cell membranes by neutralizing the spread of free radicals which occur during oxidation process. [5] - Reducing the negative effects of LDL cholesterol (bad cholesterol) by lowering levels of triglycerides and increasing the production of HDL cholesterol (good cholesterol). - Increasing fat oxidation (helps the body use fat as an energy source) and raising metabolism. [6] - Joy Bauer, a New York City nutritionist, says [the catechins in green tea] increase levels of the metabolism speeding brain chemical norepinephrine. - Japanese researchers claim if you drink five cups of green tea a day, you'll burn 70 to 80 extra calories. Dr. Nicholas Perricone, an anti-aging specialist, appeared on the Oprah Winfrey show and told Oprah's viewers they can lose 10 lbs. in 6 weeks drinking green tea instead of coffee - Some green tea lovers restrict their intake because of the caffeine it contains — about half the amount as is found in coffee. Too much caffeine can cause nausea, insomnia or frequent urination. [7] - Drinking green tea mixed with honey can often have a soothing effect on a sore throat. ## United States Food and Drug Administration (FDA) The article Tea: A Story of Serendipity[8] appeared in the March 1996 issue of FDA Consumer Magazine and looked at the potential benefits of green tea. At that time they had not done any reviews of the potential benefits of green tea and were waiting to do it until health claims were filed. They have since denied two petitions to make qualified health claims as to the health benefits of green tea. [9] On June 30, 2005, in response to "Green Tea and Reduced Risk of Cancer Health Claim", they stated: "FDA concludes that there is no credible evidence to support qualified health claims for green tea consumption and a reduced risk of gastric, lung, colon/rectal, esophageal, pancreatic, ovarian, and combined cancers. Thus, FDA is denying these claims. However, FDA concludes that there is very limited credible evidence for qualified health claims specifically for green tea and breast cancer and for green tea and prostate cancer, provided that the qualified claims are appropriately worded so as to not mislead consumers." [10] On May 9, 2006, in response to "Green Tea and Reduced Risk of Cardiovascular Disease", they concluded "there is no credible evidence to support qualified health claims for green tea or green tea extract and a reduction of a number of risk factors associated with CVD." [11] However in October 2006, the FDA approved an ointment based on green tea. New Drug Application (NDA) number N021902, for kunecatechins ointment 15% (proprietary name Veregen) was approved on October 31, 2006 [12], and added to the "Prescription Drug Product List" in October 2006. [13] Kunecatechins ointment is indicated for the topical treatment of external genital and perianal warts. [14] ## Scientific studies A 2006 study published in the September 13 issue of the Journal of the American Medical Association concluded "Green tea consumption is associated with reduced mortality due to all causes and due to cardiovascular disease but not with reduced mortality due to cancer." The study, conducted by the Tohoku University School of Public Policy in Japan, followed 40,530 Japanese adults, ages 40-79, with no history of stroke, coronary heart disease, or cancer at baseline beginning in 1994. The study followed all participants for up to 11 years for death from all causes and for up to 7 years for death from a specific cause. Participants who consumed 5 or more cups of tea per day had a 16 percent lower risk of all-cause mortality and a 26 percent lower risk of cardiovascular disease than participants who consumed less than one cup of tea per day. The study also states, "If green tea does protect humans against CVD or cancer, it is expected that consumption of this beverage would substantially contribute to the prolonging of life expectancy, given that CVD and cancer are the two leading causes of death worldwide."[15] [16] A study in the February 2006 edition of the American Journal of Clinical Nutrition concluded "A higher consumption of green tea is associated with a lower prevalence of cognitive impairment in humans."[17] [18] In May 2006, researchers at Yale University School of Medicine weighed in on the issue with a review article that looked at more than 100 studies on the health benefits of green tea. They pointed to what they called an "Asian paradox," which refers to lower rates of heart disease and cancer in Asia despite high rates of cigarette smoking. They theorized that the 1.2 liters of green tea that is consumed by many Asians each day provides high levels of polyphenols and other antioxidants. These compounds may work in several ways to improve cardiovascular health, including preventing blood platelets from sticking together (This anticoagulant effect is the reason doctors warn surgical patients to avoid green tea prior to procedures that rely on a patient's clotting ability) and improving cholesterol levels, said the researchers, whose study appeared in the May issue of the Journal of the American College of Surgeons. Specifically, green tea may prevent the oxidation of LDL cholesterol (the "bad" type), which, in turn, can reduce the buildup of plaque in arteries, the researchers wrote.[19] A study published in the August 22, 2006 edition of Biological Psychology looked at the modification of the stress response via L-Theanine, a chemical found in green tea. It "suggested that the oral intake of L-Theanine could cause anti-stress effects via the inhibition of cortical neuron excitation."[20] In a double-blind, randomized, placebo-controlled trial done by Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 240 adults were given either theaflavin-enriched green tea extract in form of 375mg capsule daily or a placebo. After 12 weeks, patients in the tea extract group had significantly less low-density lipoprotein cholesterol (LDL-C) and total cholesterol (16.4% and 11.3% lower than baseline, p<0.01) than the placebo group. The author concluded that theaflavin-enriched green tea extract can be used together with other dietary approaches to reduce LDL-C. A study published in the January, 2005 edition of the American Journal of Clinical Nutrition concluded "Daily consumption of tea containing 690 mg catechins for 12 wk reduced body fat, which suggests that the ingestion of catechins might be useful in the prevention and improvement of lifestyle-related diseases, mainly obesity." [21] According to a Case Western Reserve University School of Medicine study published in the April 13 2005 issue of the Proceedings of the National Academy of SciencesAntioxidants in green tea may prevent and reduce the severity of rheumatoid arthritis. The study examined the effects of green tea polyphenols on collagen-induced arthritis in mice, which is similar to rheumatoid arthritis in humans. In each of three different study groups, the mice given the green tea polyphenols were significantly less likely to develop arthritis. Of the 18 mice that received the green tea, only eight (44 percent) developed arthritis. Among the 18 mice that did not receive the green tea, all but one (94 percent) developed arthritis. In addition, researchers noted that the eight arthritic mice that received the green tea polyphenols developed less severe forms of arthritis. A German study found that an extract of green tea and hot water (filtered), applied externally to the skin for 10 minutes, three times a day could help people with skin damaged from radiation therapy (after 16-22 days). [22] A study published in the December 1999 American Journal of Clinical Nutrition found that "Green tea has thermogenic properties and promotes fat oxidation beyond that explained by its caffeine content per se. The green tea extract may play a role in the control of body composition via sympathetic activation of thermogenesis, fat oxidation, or both."[23] In lab tests, EGCG, found in green tea, was found to prevent HIV from attacking T-Cells. However, it is not known if this has any effect on humans yet. [24] A study in the August, 2003 issue of a new potential application of Cellular and Molecular Life Sciences found that "a new potential application of (–)-epigallocatechin-3-gallate [a component of green tea] in prevention or treatment of inflammatory processes is suggested" [25]	https://www.wikidoc.org/index.php/Green_tea
82ce5ed374d68fa57bdd3cf4ba36f9ef61cca8e8	wikidoc	Noble gas	Noble gas The noble gases are the elements in group 18 (also sometimes Group 0 IUPAC Style, or Group 8) of the periodic table. The group is also called the helium family or neon family. Chemically, the noble gases are very stable due to having the maximum number of valence electrons their outer shell can hold. A thorough explanation requires an understanding of electronic configuration, with references to quantum mechanics. Noble gases rarely react with other elements since they are already stable. Under normal conditions, they occur as odorless, colorless, monatomic gases. Each of them has its melting and boiling point close together, so that only a small temperature range exists for each noble gas in which it is a liquid. Noble gases have numerous important applications in lighting, welding and space technology. The seven noble gases are: helium, neon, argon, krypton, xenon, radon, and ununoctium. # Etymology "Noble gas" is the translation of the German Edelgas, which was in use as early as 1898. This refers to the extremely low level of reactivity under normal conditions. The noble gases have also been referred to as inert gases, but these terms are not strictly accurate because several of them do take part in chemical reactions. Another old term is rare gases, although argon forms a fairly considerable part (0.93% by volume, 1.29% by mass) of the Earth's atmosphere. # History The existence of noble gases was not known until after the advent of the periodic table. In the late nineteenth century, Lord Rayleigh discovered that some samples of nitrogen from the air were of a different density than nitrogen resulting from chemical reactions. Along with scientist William Ramsay, Lord Rayleigh theorized that the nitrogen extracted from air was associated with another gas, argon. With this discovery, they realized that a whole class of gases was missing from the periodic table. Eventually, all the known noble gases except for helium were discovered in the air, with argon being much more common than the others, and the table was completed. Helium was detected spectrographically in the Sun in 1868. The isolation of helium on Earth had to wait until 1895. Under standard conditions, the noble gases all occur as monatomic gases. # Chemical makeup Noble gases have full valence electron shells. Valence electrons are the outermost electrons of an atom and are normally the only electrons which can participate in chemical bonding. According to atomic theory derived from quantum mechanics and experimental trends, atoms with full valence electron shells are extraordinarily stable and therefore do not form chemical bonds. All of them exhibit an extremely low chemical reactivity and very few noble gas compounds have been prepared. No conventional compounds of helium or neon have yet been prepared, while xenon and krypton are known to show some reactivity in the laboratory. Recently argon compounds have also been successfully characterised. The noble gases' lack of reactivity can be explained in terms of them having a "complete valence shell". They have little tendency to gain or lose electrons. The noble gases have high ionization energies and negligible electronegativities. The noble gases have very weak inter-atomic forces of attraction, and consequently very low melting points and boiling points. This is why they are all monatomic gases under normal conditions, even those with larger atomic masses than many normally solid elements. # Applications One of the most commonly encountered uses of the noble gases in everyday life is in lighting. Argon is often used as a suitable safe and inert atmosphere for the inside of filament light bulbs, and is also used as an inert atmosphere in the synthesis of air and moisture sensitive compounds (as an alternative for nitrogen). Some of the noble gases glow distinctive colors when used inside lighting tubes (neon lights). Helium, due to its nonreactivity (compared with flammable hydrogen) and lightness, is often used in blimps and balloons. Helium and argon are commonly used to shield a welding arc, and the surrounding base metal from the atmosphere during welding. Krypton is also used in lasers, which are used by doctors for eye surgery. Xenon is used in xenon arc lamps, and it has anaesthetic properties. # Physical properties ! Property ! colspan="6" \| Noble gas # Noble gas notation The noble gases can be used in conjunction with the electron configuration notation to make what is called the Noble Gas Notation. For example: while the electron notation of the element carbon is 1s²2s² 2p², the Noble Gas notation would be 2s²2p². This notation makes the identification of elements faster, and is shorter and easier than writing out the full notation of orbitals.	Noble gas Template:This The noble gases are the elements in group 18 (also sometimes Group 0 IUPAC Style, or Group 8) of the periodic table. The group is also called the helium family or neon family. Chemically, the noble gases are very stable due to having the maximum number of valence electrons their outer shell can hold. A thorough explanation requires an understanding of electronic configuration, with references to quantum mechanics. Noble gases rarely react with other elements since they are already stable. Under normal conditions, they occur as odorless, colorless, monatomic gases. Each of them has its melting and boiling point close together, so that only a small temperature range exists for each noble gas in which it is a liquid. Noble gases have numerous important applications in lighting, welding and space technology. The seven noble gases are: helium, neon, argon, krypton, xenon, radon, and ununoctium. # Etymology "Noble gas" is the translation of the German Edelgas, which was in use as early as 1898.[1] This refers to the extremely low level of reactivity under normal conditions. The noble gases have also been referred to as inert gases, but these terms are not strictly accurate because several of them do take part in chemical reactions. Another old term is rare gases, although argon forms a fairly considerable part (0.93% by volume, 1.29% by mass) of the Earth's atmosphere.[2] # History The existence of noble gases was not known until after the advent of the periodic table. In the late nineteenth century, Lord Rayleigh discovered that some samples of nitrogen from the air were of a different density than nitrogen resulting from chemical reactions. Along with scientist William Ramsay, Lord Rayleigh theorized that the nitrogen extracted from air was associated with another gas, argon. With this discovery, they realized that a whole class of gases was missing from the periodic table. Eventually, all the known noble gases except for helium were discovered in the air, with argon being much more common than the others, and the table was completed. Helium was detected spectrographically in the Sun in 1868. The isolation of helium on Earth had to wait until 1895. Under standard conditions, the noble gases all occur as monatomic gases.[3][4] # Chemical makeup Noble gases have full valence electron shells. Valence electrons are the outermost electrons of an atom and are normally the only electrons which can participate in chemical bonding. According to atomic theory derived from quantum mechanics and experimental trends, atoms with full valence electron shells are extraordinarily stable and therefore do not form chemical bonds.[5] All of them exhibit an extremely low chemical reactivity and very few noble gas compounds have been prepared. No conventional compounds of helium or neon have yet been prepared, while xenon and krypton are known to show some reactivity in the laboratory. Recently argon compounds have also been successfully characterised. The noble gases' lack of reactivity can be explained in terms of them having a "complete valence shell". They have little tendency to gain or lose electrons. The noble gases have high ionization energies and negligible electronegativities. The noble gases have very weak inter-atomic forces of attraction, and consequently very low melting points and boiling points. This is why they are all monatomic gases under normal conditions, even those with larger atomic masses than many normally solid elements. # Applications One of the most commonly encountered uses of the noble gases in everyday life is in lighting. Argon is often used as a suitable safe and inert atmosphere for the inside of filament light bulbs, and is also used as an inert atmosphere in the synthesis of air and moisture sensitive compounds (as an alternative for nitrogen). Some of the noble gases glow distinctive colors when used inside lighting tubes (neon lights). Helium, due to its nonreactivity (compared with flammable hydrogen) and lightness, is often used in blimps and balloons. Helium and argon are commonly used to shield a welding arc, and the surrounding base metal from the atmosphere during welding. Krypton is also used in lasers, which are used by doctors for eye surgery.[6] Xenon is used in xenon arc lamps, and it has anaesthetic properties. # Physical properties Template:Start box ! Property ! colspan="6" \| Noble gas Template:End box # Noble gas notation The noble gases can be used in conjunction with the electron configuration notation to make what is called the Noble Gas Notation. For example: while the electron notation of the element carbon is 1s²2s² 2p², the Noble Gas notation would be [He] 2s²2p². This notation makes the identification of elements faster, and is shorter and easier than writing out the full notation of orbitals.	https://www.wikidoc.org/index.php/Group_18_element
9bc8c23c2b8248d215932f9fcfc0f7af6cf3c9f5	wikidoc	Guanabenz	Guanabenz For patient information regarding Guanabenz, click here. # Overview Guanabenz (pronounced GWAHN-a-benz, sold under the trade name Wytensin) is an alpha agonist of the alpha-2 type that is used as an antihypertensive drug. It is used to treat high blood pressure (hypertension). The most common side effects during guanabenz therapy are dizziness, drowsiness, dry mouth, headache and weakness. Guanabenz can make one drowsy or less alert, therefore driving or operating dangerous machinery is not recommended.	Guanabenz For patient information regarding Guanabenz, click here. Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Guanabenz (pronounced GWAHN-a-benz, sold under the trade name Wytensin) is an alpha agonist of the alpha-2 type that is used as an antihypertensive drug. It is used to treat high blood pressure (hypertension).[1][2] The most common side effects during guanabenz therapy are dizziness, drowsiness, dry mouth, headache and weakness. Guanabenz can make one drowsy or less alert, therefore driving or operating dangerous machinery is not recommended.	https://www.wikidoc.org/index.php/Guanabenz
6ff0ce19badbfb30f3f1e98e4e1d9181b1a5ba48	wikidoc	Guanadrel	Guanadrel # Overview Guanadrel is an antihypertensive agent. It is used in the form of its sulfate. # Mechanism of action Guanadrel is a postganglionic adrenergic blocking agent. Uptake of guanadrel and storage in sympathetic neurons occurs via the norepinephrine pump; guanadrel slowly displaces norepinephrine from its storage in nerve endings and thereby blocks the release of norepinephrine normally produced by nerve stimulation. The reduction in neurotransmitter release in response to sympathetic nerve stimulation, as a result of catecholamine depletion, leads to reduced arteriolar vasoconstriction, especially the reflex increase in sympathetic tone that occurs with a change in position. Guanadrel is rapidly and well absorbed from gastrointestinal tract. In 1981 the JAMA reported guanadrel as an effective step II or step III treatment of hypertension. # Chemistry Guanadrel can be synthesized when cyclohexanone undergoes ketalization by 3-chloro-1,2-propanediol, forming 2-chloromethyl-1,4-dioxyspirodecane, which is further reacted with sodium phthalimide. After alkaline hydrazinolysis, the resulting phthalimide derivative is transformed into 2-aminomethyl-1,4-dioxyspirodecane, which is reacted with S-methylthiourea, giving the desired guanadrel.	Guanadrel Template:Chembox new Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Guanadrel is an antihypertensive agent.[1] It is used in the form of its sulfate. # Mechanism of action Guanadrel is a postganglionic adrenergic blocking agent. Uptake of guanadrel and storage in sympathetic neurons occurs via the norepinephrine pump; guanadrel slowly displaces norepinephrine from its storage in nerve endings and thereby blocks the release of norepinephrine normally produced by nerve stimulation. The reduction in neurotransmitter release in response to sympathetic nerve stimulation, as a result of catecholamine depletion, leads to reduced arteriolar vasoconstriction, especially the reflex increase in sympathetic tone that occurs with a change in position. Guanadrel is rapidly and well absorbed from gastrointestinal tract.[2] In 1981 the JAMA reported guanadrel as an effective step II or step III treatment of hypertension.[3] # Chemistry Guanadrel can be synthesized when cyclohexanone undergoes ketalization by 3-chloro-1,2-propanediol, forming 2-chloromethyl-1,4-dioxyspiro[4,5]decane, which is further reacted with sodium phthalimide.[4][5][6] After alkaline hydrazinolysis, the resulting phthalimide derivative is transformed into 2-aminomethyl-1,4-dioxyspiro[4,5]decane, which is reacted with S-methylthiourea, giving the desired guanadrel.	https://www.wikidoc.org/index.php/Guanadrel
470f77b827055e5db9263bcd7070b56a9810d657	wikidoc	Guanidine	Guanidine # 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 Guanidine is a cholinesterase inhibitor that is FDA approved for the treatment of muscle weakness and easy fatigability associated with the myasthenic syndrome of Eaton-Lambert. Common adverse reactions include anemia, leukopenia, and thrombocytopenia resulting from bone marrow suppression. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Guanidine is indicated for the reduction of the symptoms of muscle weakness and easy fatigability associated with the myasthenic syndrome of Eaton-Lambert. It is not indicated for treating myasthenia gravis. The Eaton-Lambert syndrome is ordinarily differentiated from myasthenia gravis by the usual association of the syndrome with small cell carcinoma of the lung, but myography may be necessary to make the diagnosis. - Initial dosage is usually between 10 and 15 mg/kg (5 to 7 mg/pound) of body weight per day in 3 or 4 divided doses. This dosage may be gradually increased to a total daily dosage of 35 mg/kg (16 mg/pound) of body weight per day or up to the development of side effects. As individual tolerance is highly variable, the dosage must be carefully titrated. Once a tolerable dose has been established, it should be continued. Occasionally removal of the primary neoplastic lesion may result in improvement of symptoms, permitting the discontinuance of guanidine. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Guanidine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Guanidine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Guanidine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Guanidine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Guanidine in pediatric patients. # Contraindications - Guanidine is contraindicated in individuals with a history of intolerance or allergy to this drug. # Warnings - Fatal Bone marrow suppression, apparently dose related, can occur with guanidine. - Safe use of guanidine hydrochloride in pregnancy has not been established. Therefore, the benefits of therapy must be weighed against the potential hazards. Because guanidine is excreted in milk, patients on this drug should discontinue breastfeeding. - Since there is inadequate experience in children who have received this drug, safety and efficacy in children have not been established. ### Precautions - Baseline blood studies should be followed by frequent red and white blood cell and differential counts. The drug should be discontinued upon appearance of Bone marrow suppression. Concurrent therapy with other drugs that may cause Bone marrow suppression should be avoided. - Renal function may be affected in some patients receiving guanidine. Patients should therefore have regular urine examinations and serum creatinine determinations while taking this drug. - Physicians should be given adequate precautions pertaining to the gastrointestinal side effects and the possibility of induced behavior disorders. - Treatment should not be continued longer than necessary. # Adverse Reactions ## Clinical Trials Experience - Anemia, leukopenia, and thrombocytopenia resulting from Bone marrow suppression attributable to guanidine have been reported. Other adverse reactions that have been observed are: - General: sore throat, rash, fever. - Neurologic: paresthesia of lips, face, hands, feet; cold sensations in hands and feet; nervousness, lightheadedness, jitteriness, increased irritability; tremor, trembling sensation; ataxia; emotional lability; psychotic state; confusion; mood changes, and hallucinations. - Gastrointestinal: dry mouth; gastric irritation; anorexia; nausea; diarrhea; abdominal cramping. Gastrointestinal side effects may preclude the use of guanidine as a desired form of therapy. - Dermatologic: rash, flushing or pink complexion; folliculitis; petechiae, purpura, ecchymoses; sweating; skin eruptions; dryness and scaling of the skin. - Renal: elevation of blood creatinine, uremia; chronic interstitial nephritis, acute interstitial nephritis, and renal tubular necrosis. - Hepatic: abnormal liver function tests. - Cardiac: palpitation, tachycardia, atrial fibrillation, hypotension. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Guanidine in the drug label. # Drug Interactions There is limited information regarding Guanidine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Guanidine in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Guanidine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Guanidine during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Guanidine with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Guanidine with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Guanidine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Guanidine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Guanidine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Guanidine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Guanidine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Guanidine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Guanidine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Guanidine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Guanidine in the drug label. # Overdosage - Mild gastrointestinal disorders, such as anorexia, increased peristalsis, or diarrhea are early warnings that tolerance is being exceeded. These symptoms may be relieved by atropine, but nevertheless note should be taken of these symptoms and dosage reductions considered. Slight numbness or tingling of the lips and fingertips shortly after taking a dose of guanidine has been reported. This per se is not an indication to discontinue treatment and/or reduce dosage. - Severe guanidine intoxication is characterized by nervous hyperirritability, fibrillary tremors and convulsive contractions of muscle, salivation, vomiting, diarrhea, hypoglycemia, and circulatory disturbances. Administration of intravenous calcium gluconate may control the neuromuscular and convulsive symptoms and provide some relief of other toxic manifestations. - Atropine is more effective than calcium in relieving the G.I. symptoms, circulatory disturbances, and changes in blood sugar. # Pharmacology ## Mechanism of Action - Guanidine apparently acts by enhancing the release of acetylcholine following a nerve impulse. It also appears to slow the rates of depolarization and repolarization of muscle cell membranes ## Structure - Chemically, guanidine (aminomethanamidine) hydrochloride is a crystalline powder freely soluble in water and alcohol. The aqueous solution is neutral. The structural formula is: - Each tablet contains 125 mg of guanidine hydrochloride with no color additive in the base. It also contains the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, mannitol, and microcrystalline cellulose. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Guanidine in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Guanidine in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Guanidine in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Guanidine in the drug label. # How Supplied - Guanidine hydrochloride tablets: 125 mg, white, round tablet; impressed with the product identification number "KEY 74" on one side. Guanidine hydrochloride tablets are available in bottles of 100 (NDC 0085-0492-01). ## Storage - Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) . # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Guanidine in the drug label. # Precautions with Alcohol - Alcohol-Guanidine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names # Look-Alike Drug Names There is limited information regarding Guanidine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Guanidine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, 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 Guanidine is a cholinesterase inhibitor that is FDA approved for the treatment of muscle weakness and easy fatigability associated with the myasthenic syndrome of Eaton-Lambert. Common adverse reactions include anemia, leukopenia, and thrombocytopenia resulting from bone marrow suppression. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Guanidine is indicated for the reduction of the symptoms of muscle weakness and easy fatigability associated with the myasthenic syndrome of Eaton-Lambert. It is not indicated for treating myasthenia gravis. The Eaton-Lambert syndrome is ordinarily differentiated from myasthenia gravis by the usual association of the syndrome with small cell carcinoma of the lung, but myography may be necessary to make the diagnosis. - Initial dosage is usually between 10 and 15 mg/kg (5 to 7 mg/pound) of body weight per day in 3 or 4 divided doses. This dosage may be gradually increased to a total daily dosage of 35 mg/kg (16 mg/pound) of body weight per day or up to the development of side effects. As individual tolerance is highly variable, the dosage must be carefully titrated. Once a tolerable dose has been established, it should be continued. Occasionally removal of the primary neoplastic lesion may result in improvement of symptoms, permitting the discontinuance of guanidine. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Guanidine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Guanidine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Guanidine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Guanidine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Guanidine in pediatric patients. # Contraindications - Guanidine is contraindicated in individuals with a history of intolerance or allergy to this drug. # Warnings - Fatal Bone marrow suppression, apparently dose related, can occur with guanidine. - Safe use of guanidine hydrochloride in pregnancy has not been established. Therefore, the benefits of therapy must be weighed against the potential hazards. Because guanidine is excreted in milk, patients on this drug should discontinue breastfeeding. - Since there is inadequate experience in children who have received this drug, safety and efficacy in children have not been established. ### Precautions - Baseline blood studies should be followed by frequent red and white blood cell and differential counts. The drug should be discontinued upon appearance of Bone marrow suppression. Concurrent therapy with other drugs that may cause Bone marrow suppression should be avoided. - Renal function may be affected in some patients receiving guanidine. Patients should therefore have regular urine examinations and serum creatinine determinations while taking this drug. - Physicians should be given adequate precautions pertaining to the gastrointestinal side effects and the possibility of induced behavior disorders. - Treatment should not be continued longer than necessary. # Adverse Reactions ## Clinical Trials Experience - Anemia, leukopenia, and thrombocytopenia resulting from Bone marrow suppression attributable to guanidine have been reported. Other adverse reactions that have been observed are: - General: sore throat, rash, fever. - Neurologic: paresthesia of lips, face, hands, feet; cold sensations in hands and feet; nervousness, lightheadedness, jitteriness, increased irritability; tremor, trembling sensation; ataxia; emotional lability; psychotic state; confusion; mood changes, and hallucinations. - Gastrointestinal: dry mouth; gastric irritation; anorexia; nausea; diarrhea; abdominal cramping. Gastrointestinal side effects may preclude the use of guanidine as a desired form of therapy. - Dermatologic: rash, flushing or pink complexion; folliculitis; petechiae, purpura, ecchymoses; sweating; skin eruptions; dryness and scaling of the skin. - Renal: elevation of blood creatinine, uremia; chronic interstitial nephritis, acute interstitial nephritis, and renal tubular necrosis. - Hepatic: abnormal liver function tests. - Cardiac: palpitation, tachycardia, atrial fibrillation, hypotension. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Guanidine in the drug label. # Drug Interactions There is limited information regarding Guanidine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Guanidine in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Guanidine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Guanidine during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Guanidine with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Guanidine with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Guanidine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Guanidine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Guanidine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Guanidine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Guanidine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Guanidine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Guanidine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Guanidine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Guanidine in the drug label. # Overdosage - Mild gastrointestinal disorders, such as anorexia, increased peristalsis, or diarrhea are early warnings that tolerance is being exceeded. These symptoms may be relieved by atropine, but nevertheless note should be taken of these symptoms and dosage reductions considered. Slight numbness or tingling of the lips and fingertips shortly after taking a dose of guanidine has been reported. This per se is not an indication to discontinue treatment and/or reduce dosage. - Severe guanidine intoxication is characterized by nervous hyperirritability, fibrillary tremors and convulsive contractions of muscle, salivation, vomiting, diarrhea, hypoglycemia, and circulatory disturbances. Administration of intravenous calcium gluconate may control the neuromuscular and convulsive symptoms and provide some relief of other toxic manifestations. - Atropine is more effective than calcium in relieving the G.I. symptoms, circulatory disturbances, and changes in blood sugar. # Pharmacology ## Mechanism of Action - Guanidine apparently acts by enhancing the release of acetylcholine following a nerve impulse. It also appears to slow the rates of depolarization and repolarization of muscle cell membranes ## Structure - Chemically, guanidine (aminomethanamidine) hydrochloride is a crystalline powder freely soluble in water and alcohol. The aqueous solution is neutral. The structural formula is: - Each tablet contains 125 mg of guanidine hydrochloride with no color additive in the base. It also contains the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, mannitol, and microcrystalline cellulose. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Guanidine in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Guanidine in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Guanidine in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Guanidine in the drug label. # How Supplied - Guanidine hydrochloride tablets: 125 mg, white, round tablet; impressed with the product identification number "KEY 74" on one side. Guanidine hydrochloride tablets are available in bottles of 100 (NDC 0085-0492-01). ## Storage - Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Guanidine in the drug label. # Precautions with Alcohol - Alcohol-Guanidine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - # Look-Alike Drug Names There is limited information regarding Guanidine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Guanidine
3a30186154b80348d49add640fe72ebe0ed7960d	wikidoc	Guide RNA	Guide RNA Guide RNA is the RNA that guides the insertion of uridines into mRNAs in trypanosomes in a process known as RNA editing. These are encoded at distant regions of the kinetoplast genome. The 5' end of a gRNA hybridizes to a short region of an unedited pre-mRNA, called an anchor sequence, while its 3' end functions as a template for the editing process. Many gRNAs do not hybridize to anchor sequences in the primary transcript, but rather to sequences in partially edited intermediates. Thus editing of a trypanosome pre-mRNA generally starts near the 3' end and progresses towards the 5' end in a repetitive process that requires several different gRNAs, which bind sequentially to anchor sequences in previously edited sections.(molecular cell biology lodish et al. 2004) It is not clear why trypanosome kinetoplasts utilize such an elaborate mechanism to produce mRNAs. The finding that RNA editing is most extensive in the earliest trypanosomes to have evolved suggests that this process may be a "molecular fossil" of the mechanism of RNA synthesis during an early stage in the evolution of modern cells. # Overview of gRNA-mediated editing The mitochondria for some trypanosome protozoa undergo gRNA-mediated mRNA editing. The gRNA identifies particular sequences and inserts or deletes Uridine (U) nucleotides. The edited portion of the mRNA is in the coding region, which has the effect of modifying the protein that is produced. # Example of gRNA-mediated editing In the protozoan, Leishmania tarentolae, some mitochondrial genes are edited using this process. One such gene is Cyb. While the exact sequence of events is still under study, one model has that the mRNA is actually edited twice in succession. For the first edit, the relevant sequence on the mRNA is The 3' end is used to anchor the gRNA (gCyb-I gRNA in this case) with normal basepairing (some G/U pairs are used). The 5' end does not exactly match and an endonuclease makes cuts in the mRNA to allow for alignment. The mRNA is now "repaired" by adding U, giving the sequence This particular gene has two overlapping gRNA editing sites. The 5' end of this section is the 3' anchor for another gRNA (gCyb-II gRNA). # Notes - ↑ See (Accessed 19 May 2006) for details.	Guide RNA Guide RNA is the RNA that guides the insertion of uridines into mRNAs in trypanosomes in a process known as RNA editing. These are encoded at distant regions of the kinetoplast genome. The 5' end of a gRNA hybridizes to a short region of an unedited pre-mRNA, called an anchor sequence, while its 3' end functions as a template for the editing process. Many gRNAs do not hybridize to anchor sequences in the primary transcript, but rather to sequences in partially edited intermediates. Thus editing of a trypanosome pre-mRNA generally starts near the 3' end and progresses towards the 5' end in a repetitive process that requires several different gRNAs, which bind sequentially to anchor sequences in previously edited sections.(molecular cell biology lodish et al. 2004) It is not clear why trypanosome kinetoplasts utilize such an elaborate mechanism to produce mRNAs. The finding that RNA editing is most extensive in the earliest trypanosomes to have evolved suggests that this process may be a "molecular fossil" of the mechanism of RNA synthesis during an early stage in the evolution of modern cells.[citation needed] # Overview of gRNA-mediated editing The mitochondria for some trypanosome protozoa undergo gRNA-mediated mRNA editing. The gRNA identifies particular sequences and inserts or deletes Uridine (U) nucleotides. The edited portion of the mRNA is in the coding region, which has the effect of modifying the protein that is produced. # Example of gRNA-mediated editing In the protozoan, Leishmania tarentolae, some mitochondrial genes are edited using this process. One such gene is Cyb.[1] While the exact sequence of events is still under study, one model has that the mRNA is actually edited twice in succession. For the first edit, the relevant sequence on the mRNA is The 3' end is used to anchor the gRNA (gCyb-I gRNA in this case) with normal basepairing (some G/U pairs are used). The 5' end does not exactly match and an endonuclease makes cuts in the mRNA to allow for alignment. The mRNA is now "repaired" by adding U, giving the sequence This particular gene has two overlapping gRNA editing sites. The 5' end of this section is the 3' anchor for another gRNA (gCyb-II gRNA). # Notes - ↑ See [1] (Accessed 19 May 2006) for details. Template:Nucleic acids Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Guide_RNA
528a32ac0513a9a649d6dca579262b429bc375b2	wikidoc	Gum graft	Gum graft # Overview A gum graft or gingival graft (Also called Periodontal Plastic Surgery) is a generic name for multiple periodontal procedures that all aim to cover an area of severe gum recession with grafted gum tissue. The purpose of covering the exposed root is not only cosmetic, but also to prevent further recession, tooth sensitivity due to exposed roots and tooth decay on exposed root surfaces. These procedures are usually performed by a periodontist, a dental specialist in treatment of diseases of the gingiva (gums), however some non-specialists dentists may also have training in this area. # Specific procedures (Periodontal Plastic Surgery) A free gingival graft is a dental procedure where a layer of tissue is removed from the palate of the patient's mouth and then relocated to the site of gum recession. It is stitched into place and will serve to protect the exposed root as living tissue. The donor site will heal without damage. This procedure is often used to increase the thickness of very thin gum tissue. A subepithelial connective tissue graft takes tissue from under healthy gum tissue in the palate, which may be placed at the area of gum recession. This procedure has the advantage of excellent predictability of root coverage , as well as decreased pain at the palatal donor site compared to the free gingival graft. The subepithelial connective tissue graft is a very common procedure for covering exposed roots. An Acellular Dermal Matrix (Alloderm) graft uses donated medically-processed human skin tissue as a source for the graft. The advantage of this procedure is no need for a palatal donor site, however some periodontists believe it may be less successful , while others believe it is equally successful as a subepithlial connective tissue graft. A lateral pedicle graft, also known as a "pedicle" graft, takes tissue from the area immediately adjacent to the damaged gum. This is not always an option, as the constraint that there must be sufficient tissue immediately lateral to the area of interest is an onerous one. When this procedure is performed, the transplant tissue is cut away and rotated over the damaged area. This can place the donor area at risk of recession as well. A coronally positioned flap is another form of a "pedicle" graft in which gingival (gum) tissue is freed up and simply moved upwards on the tooth to cover the recession. This requires adequate thickness and width of gum tissue at the base of the recession defect.	Gum graft Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A gum graft or gingival graft (Also called Periodontal Plastic Surgery) is a generic name for multiple periodontal procedures that all aim to cover an area of severe gum recession with grafted gum tissue. The purpose of covering the exposed root is not only cosmetic, but also to prevent further recession, tooth sensitivity due to exposed roots and tooth decay on exposed root surfaces. These procedures are usually performed by a periodontist, a dental specialist in treatment of diseases of the gingiva (gums), however some non-specialists dentists may also have training in this area. # Specific procedures (Periodontal Plastic Surgery) A free gingival graft is a dental procedure where a layer of tissue is removed from the palate of the patient's mouth and then relocated to the site of gum recession. It is stitched into place and will serve to protect the exposed root as living tissue. The donor site will heal without damage. This procedure is often used to increase the thickness of very thin gum tissue. A subepithelial connective tissue graft takes tissue from under healthy gum tissue in the palate, which may be placed at the area of gum recession. This procedure has the advantage of excellent predictability of root coverage [1], as well as decreased pain at the palatal donor site compared to the free gingival graft. The subepithelial connective tissue graft is a very common procedure for covering exposed roots. An Acellular Dermal Matrix (Alloderm) graft uses donated medically-processed human skin tissue as a source for the graft. The advantage of this procedure is no need for a palatal donor site, however some periodontists believe it may be less successful [2], while others believe it is equally successful as a subepithlial connective tissue graft. [3] A lateral pedicle graft, also known as a "pedicle" graft, takes tissue from the area immediately adjacent to the damaged gum. This is not always an option, as the constraint that there must be sufficient tissue immediately lateral to the area of interest is an onerous one. When this procedure is performed, the transplant tissue is cut away and rotated over the damaged area. This can place the donor area at risk of recession as well. A coronally positioned flap is another form of a "pedicle" graft in which gingival (gum) tissue is freed up and simply moved upwards on the tooth to cover the recession. This requires adequate thickness and width of gum tissue at the base of the recession defect.	https://www.wikidoc.org/index.php/Gum_graft
9ed1224f19759c7e43dc862e26726629c6e24adf	wikidoc	Gustducin	Gustducin Gustducin is a G protein associated with taste and the gustatory system, found in some taste receptor cells. Research on the discovery and isolation of gustaducin is recent. It is known to play a large role in the transduction of bitter, sweet and umami stimuli. Its pathways (especially for detecting bitter stimuli) are many and diverse. An intriguing feature of gustducin is its similarity to transducin. These two G proteins have been shown to be structurally and functionally similar, leading researchers to believe that the sense of taste evolved in a similar fashion to the sense of sight. Gustducin is a heterotrimeric protein composed of the products of the GNAT3 (α-subunit), GNB1 (β-subunit) and GNG13 (γ-subunit). # Discovery Gustducin was discovered in 1992 when degenerate oligonucleotide primers were synthesized and mixed with a taste tissue cDNA library. The DNA products were amplified by the polymerase chain reaction method, and eight positive clones were shown to encode the α subunits of G-proteins, (which interact with G-protein-coupled receptors). Of these eight, two had previously been shown to encode rod and cone α-transducin. The eighth clone, α-gustducin, was unique to the gustatory tissue. # Comparisons with transducin Upon analyzing the amino-acid sequence of α-gustducin, it was discovered that α-gustducins and α-transducins were closely related. This work showed that α-gustducin's protein sequence gives it 80% identity to both rod and cone a-transducin. Despite the structural similarities, the two proteins have very different functionalities. However, the two proteins have similar mechanism and capabilities. Transducin removes the inhibition from cGMP Phosphodiesterase, which leads to the breakdown of cGMP. Similarly, α-gustducin binds the inhibitory subunits of taste cell cAMP Phosphodiesterase which causes a decrease in cAMP levels. Also, the terminal 38 amino acids of α-gustducin and α-transducin are identical. This suggests that gustducin can interact with opsin and opsin-like G-coupled receptors. Conversely, this also suggests that transducin can interact with taste receptors. The structural similarities between gustducin and transducin are so great that comparison with transducin were used to propose a model of gustducin's role and functionality in taste transduction. Other G protein α-subunits have been identified in TRCs (e.g. Gαi-2, Gαi-3, Gα14, Gα15, Gαq, Gαs) with function that has not yet been determined. # Location While gustducin was known to be expressed in some taste receptor cells (TRCs), studies with rats showed that gustducin was also present in a limited subset of cells lining the stomach and intestine. These cells appear to share several feature of TRCs. Another study with humans brought to light two immunoreactive patterns for α-gustducin in human circumavallate and foliate taste cells: plasmalemmal and cytosolic. These two studies showed that gustducin is distributed through gustatory tissue and some gastric and intestinal tissue and gustducin is presented in either in the cytoplasm or in apical membranes on TRC surfaces. Research showed that bitter-stimulated type 2 taste receptors (T2R/TRB) are only found in taste receptor cells positive for the expression of gustducin. α-Gustducin is selectively expressed in ∼25–30% of TRCs # Evolution of the gustducin-mediated signaling model Due to its structural similarity to transducin, gustducin was predicted to activate a phosphodiesterase (PDE). Phosphodieterases were found in taste tissues and their activation was tested in vitro with both gustducin and transducin. This experiment revealed transducin and gustducin were both expressed in taste tissue (1:25 ratio) and that both G proteins are capable of activating retinal PDE. Furthermore, when present with denatonium and quinine, both G proteins can activate taste specific PDEs. This indicated that both gustducin and transducin are important in the signal transduction of denatonium and quinine. The 1992 research also investigated the role of gustducin in bitter taste reception by using “knock-out” mice lacking the gene for α-gustducin. A taste test with knock-out and control mice revealed that the knock-out mice showed no preference between bitter and regular food in most cases. When the α-gustducin gene was re-inserted into the knock-out mice, the original taste ability returned. However, the loss of the α-gustducin gene did not completely remove the ability of the knock-out mice to taste bitter food, indicating that α-gustducin is not the only mechanism for tasting bitter food. It was thought at the time that an alternative mechanism of bitter taste detection could be associated with the βγ subunit of gustducin. This theory was later validated when it was discovered that both peripheral and central gustatory neurons typically respond to more than one type of taste stimulant, although a neuron typically would favor one specific stimulant over others. This suggests that, while many neurons favor bitter taste stimuli, neurons that favor other stimuli such as sweet and umami may be capable of detecting bitter stimuli in the absence of bitter stimulant receptors, as with the knock-out mice. # Second messengers IP3 and cAMP Until recently, the nature of gustducin and its second messengers was unclear. It was clear, however, that gustducin transduced intracellular signals. Spielman was one of the first to look at the speed of taste reception, utilizing the quenched-flow technique. When the taste cells were exposed to the bitter stimulants denatonium and sucrose octaacetate, the intracellular response - a transient increase of IP3 - occurred within 50-100 millisecond of stimulation. This was not unexpected, as it was known that transducin was capable of sending signals within rod and cone cells at similar speeds. This indicated that IP3 was one of the second messengers used in bitter taste transduction. It was later discovered that cAMP also causes an influx of cations during bitter and some sweet taste transduction, leading to the conclusion that it also acted as a second messenger to gustducin. # Bitter transduction When bitter-stimulated T2R/TRB receptors activate gustducin heterotrimers, gustducin acts to mediate two responses in taste receptor cells: a decrease in cNMPs triggered by α-gustducin, and a rise in IP3(Inositol trisphosphate) and diacylglycerol (DAG) from βγ-gustducin. Although the following steps of the α-gustducin pathway are unconfirmed, it is suspected that decreased cNMPs may act on protein kinases which would regulate taste receptor cell ion channel activity. It is also possible that cNMP levels directly regulate the activity of cNMP-gated channels and cNMP-inhibited ion channels expressed in taste receptor cells. The βγ-gustducin pathway continues with the activation of IP3 receptors and the release of Ca2+ followed by neurotransmitter release. Bitter taste transduction models Several models have been suggested for the mechanisms regarding the transduction of bitter taste signals. - Cell-surface receptors: Patch clamping experiments have shown evidence that bitter compounds such as denatonium and sucrose octaacetate act directly on specific cell-surface receptors. - Direct activation of G proteins: Certain bitter stimulants such as quinine have been show to activate G proteins directly. While these mechanisms have been identified, the physiologic relevance of the mechanism has not yet been established. - PDE activation: Other bitter compounds, such as thioacetamide and propylthiouracil, have been shown to have stimulatory effects on PDEs. This mechanism has been recognized in bovine tongue epithelium contains fungiform papillae. - PDE inhibition: Other bitter compounds have been shown to inhibit PDE. Bacitracin and hydrochloride have been show to inhibit PDE in bovine taste tissue - Channel blockage: Patch clamping experiments have shown that several bitter ions act directly on potassium channels, blocking them. This suggests that the potassium channels would be located in the apical region of the taste cells. While this theory seems valid, it has only been identified in mudpuppy taste cells. It is thought that these five diverse mechanisms have developed as defense mechanisms. This would imply that many different poisonous or harmful bitter agents exist and these five mechanisms exist to prevent humans from eating or drinking them. It is also possible that some mechanisms can act as backups should a primary mechanism fail. One example of this could be quinine, which has been shown to both inhibit and activate PDE in bovine taste tissue. # Sweet transduction There are currently two models proposed for sweet taste transduction. The first pathway is a GPCRGs-cAMP pathway. This pathway starts with sucrose and other sugars activating Gs inside the cell through a membrane-bound GPCR. The activated Gas activates adenylyl cyclase to generate cAMP. From this point, one of two pathways can be taken. cAMP may act directly to cause an influx of cations through cAMP- gated channels or cAMP can activate protein kinase A, which causes the phosphorylation of K+ channels, thus closing the channels, allowing for depolarization of the taste cell, subsequent opening of voltage-gated Ca2+ channels and causing neurotransmitter release. The second pathway is a GPCR-Gq/Gβγ-IP3 pathway which is used with artificial sweeteners. Artificial sweeteners bind and activate GPCRs coupled to PLCβ2 by either α-Gq or Gβγ. The activated subunits activate PLCβ2 to generate IP3 and DAG. IP3 and DAG elicit Ca2+ release from the endoplasmic reticulum and cause cellular depolarization. An influx of Ca2+ triggers neurotransmitter release. While these two pathways coexist in the same TRCs, it is unclear how the receptors selectively mediate cAMP responses to sugars and IP3 responses to artificial sweeteners. # Evolution of bitter taste receptors Of the five basic tastes, three (sweet, bitter and umami tastes) are mediated by receptors from the G protein-coupled receptor family. Mammalian bitter taste receptors (T2Rs) are encoded by a gene family of only a few dozen members. It is believed that bitter taste receptors evolved as a mechanism to avoid ingesting poisonous and harmful substances. If this is the case, one might expect different species to develop different bitter taste receptors based on dietary and geographical constraints. With the exception of T2R1 (which lies on chromosome 5) all human bitter taste receptor genes can be found clustered on chromosome 7 and chromosome 12. Analyzing the relationships between bitter taste receptor genes show that the genes on the same chromosome are more closely related to each other than genes on different chromosomes. Furthermore, the genes on chromosome 12 have higher sequence similarity than the genes found on chromosome 7. This indicats that these genes evolved via tandem gene duplications and that chromosome 12, as a result of its higher sequence similarity between its genes, went through these tandem duplications more recently than the genes on chromosome 7. # Gustducin in the stomach Recent work by Enrique Rozengurt has shed some light on the presence of gustducin in the stomach and gastrointestinal tract. His work suggests that gustducin is present in these areas as a defense mechanism. It is widely known that some drugs and toxins can cause harm and even be lethal if ingested. It has already been theorized that multiple bitter taste reception pathways exist to prevent harmful substances from being ingested, but a person can choose to ignore the taste of a substance. Ronzegurt suggests that the presence of gustducin in epithelial cells in the stomach and gastrointestinal tract are indicative of another line of defense against ingested toxins. Whereas taste cells in the mouth are designed to compel a person to spit out a toxin, these stomach cells may act to force a person to spit up the toxins in the form of vomit.	Gustducin Gustducin is a G protein associated with taste and the gustatory system, found in some taste receptor cells. Research on the discovery and isolation of gustaducin is recent. It is known to play a large role in the transduction of bitter, sweet and umami stimuli. Its pathways (especially for detecting bitter stimuli) are many and diverse. An intriguing feature of gustducin is its similarity to transducin. These two G proteins have been shown to be structurally and functionally similar, leading researchers to believe that the sense of taste evolved in a similar fashion to the sense of sight. Gustducin is a heterotrimeric protein composed of the products of the GNAT3 (α-subunit), GNB1 (β-subunit) and GNG13 (γ-subunit). # Discovery Gustducin was discovered in 1992 when degenerate oligonucleotide primers were synthesized and mixed with a taste tissue cDNA library. The DNA products were amplified by the polymerase chain reaction method, and eight positive clones were shown to encode the α subunits of G-proteins, (which interact with G-protein-coupled receptors). Of these eight, two had previously been shown to encode rod and cone α-transducin. The eighth clone, α-gustducin, was unique to the gustatory tissue.[1] # Comparisons with transducin Upon analyzing the amino-acid sequence of α-gustducin, it was discovered that α-gustducins and α-transducins were closely related. This work showed that α-gustducin's protein sequence gives it 80% identity to both rod and cone a-transducin. Despite the structural similarities, the two proteins have very different functionalities. However, the two proteins have similar mechanism and capabilities. Transducin removes the inhibition from cGMP Phosphodiesterase, which leads to the breakdown of cGMP. Similarly, α-gustducin binds the inhibitory subunits of taste cell cAMP Phosphodiesterase which causes a decrease in cAMP levels. Also, the terminal 38 amino acids of α-gustducin and α-transducin are identical. This suggests that gustducin can interact with opsin and opsin-like G-coupled receptors. Conversely, this also suggests that transducin can interact with taste receptors. The structural similarities between gustducin and transducin are so great that comparison with transducin were used to propose a model of gustducin's role and functionality in taste transduction. Other G protein α-subunits have been identified in TRCs (e.g. Gαi-2, Gαi-3, Gα14, Gα15, Gαq, Gαs) with function that has not yet been determined.[2] # Location While gustducin was known to be expressed in some taste receptor cells (TRCs), studies with rats showed that gustducin was also present in a limited subset of cells lining the stomach and intestine. These cells appear to share several feature of TRCs. Another study with humans brought to light two immunoreactive patterns for α-gustducin in human circumavallate and foliate taste cells: plasmalemmal and cytosolic. These two studies showed that gustducin is distributed through gustatory tissue and some gastric and intestinal tissue and gustducin is presented in either in the cytoplasm or in apical membranes on TRC surfaces. Research showed that bitter-stimulated type 2 taste receptors (T2R/TRB) are only found in taste receptor cells positive for the expression of gustducin. α-Gustducin is selectively expressed in ∼25–30% of TRCs [2] # Evolution of the gustducin-mediated signaling model Due to its structural similarity to transducin, gustducin was predicted to activate a phosphodiesterase (PDE). Phosphodieterases were found in taste tissues and their activation was tested in vitro with both gustducin and transducin. This experiment revealed transducin and gustducin were both expressed in taste tissue (1:25 ratio) and that both G proteins are capable of activating retinal PDE. Furthermore, when present with denatonium and quinine, both G proteins can activate taste specific PDEs. This indicated that both gustducin and transducin are important in the signal transduction of denatonium and quinine. The 1992 research also investigated the role of gustducin in bitter taste reception by using “knock-out” mice lacking the gene for α-gustducin. A taste test with knock-out and control mice revealed that the knock-out mice showed no preference between bitter and regular food in most cases. When the α-gustducin gene was re-inserted into the knock-out mice, the original taste ability returned. However, the loss of the α-gustducin gene did not completely remove the ability of the knock-out mice to taste bitter food, indicating that α-gustducin is not the only mechanism for tasting bitter food. It was thought at the time that an alternative mechanism of bitter taste detection could be associated with the βγ subunit of gustducin. This theory was later validated when it was discovered that both peripheral and central gustatory neurons typically respond to more than one type of taste stimulant, although a neuron typically would favor one specific stimulant over others. This suggests that, while many neurons favor bitter taste stimuli, neurons that favor other stimuli such as sweet and umami may be capable of detecting bitter stimuli in the absence of bitter stimulant receptors, as with the knock-out mice.[citation needed] # Second messengers IP3 and cAMP Until recently, the nature of gustducin and its second messengers was unclear. It was clear, however, that gustducin transduced intracellular signals. Spielman was one of the first to look at the speed of taste reception, utilizing the quenched-flow technique. When the taste cells were exposed to the bitter stimulants denatonium and sucrose octaacetate, the intracellular response - a transient increase of IP3 - occurred within 50-100 millisecond of stimulation. This was not unexpected, as it was known that transducin was capable of sending signals within rod and cone cells at similar speeds. This indicated that IP3 was one of the second messengers used in bitter taste transduction. It was later discovered that cAMP also causes an influx of cations during bitter and some sweet taste transduction, leading to the conclusion that it also acted as a second messenger to gustducin. # Bitter transduction When bitter-stimulated T2R/TRB receptors activate gustducin heterotrimers, gustducin acts to mediate two responses in taste receptor cells: a decrease in cNMPs triggered by α-gustducin, and a rise in IP3(Inositol trisphosphate) and diacylglycerol (DAG) from βγ-gustducin.[2] Although the following steps of the α-gustducin pathway are unconfirmed, it is suspected that decreased cNMPs may act on protein kinases which would regulate taste receptor cell ion channel activity. It is also possible that cNMP levels directly regulate the activity of cNMP-gated channels and cNMP-inhibited ion channels expressed in taste receptor cells. The βγ-gustducin pathway continues with the activation of IP3 receptors and the release of Ca2+ followed by neurotransmitter release. Bitter taste transduction models Several models have been suggested for the mechanisms regarding the transduction of bitter taste signals. - Cell-surface receptors: Patch clamping experiments have shown evidence that bitter compounds such as denatonium and sucrose octaacetate act directly on specific cell-surface receptors. - Direct activation of G proteins: Certain bitter stimulants such as quinine have been show to activate G proteins directly. While these mechanisms have been identified,[by whom?] the physiologic relevance of the mechanism has not yet been established. - PDE activation: Other bitter compounds, such as thioacetamide and propylthiouracil, have been shown[by whom?] to have stimulatory effects on PDEs. This mechanism has been recognized in bovine tongue epithelium contains fungiform papillae. - PDE inhibition: Other bitter compounds have been shown[by whom?] to inhibit PDE. Bacitracin and hydrochloride have been show to inhibit PDE in bovine taste tissue - Channel blockage: Patch clamping experiments have shown that several bitter ions act directly on potassium channels, blocking them. This suggests that the potassium channels would be located in the apical region of the taste cells. While this theory seems[by whom?] valid, it has only been identified in mudpuppy taste cells. It is thought[by whom?] that these five diverse mechanisms have developed as defense mechanisms. This would imply that many different poisonous or harmful bitter agents exist and these five mechanisms exist to prevent humans from eating or drinking them. It is also possible that some mechanisms can act as backups should a primary mechanism fail. One example of this could be quinine, which has been shown to both inhibit and activate PDE in bovine taste tissue. # Sweet transduction There are currently two models proposed for sweet taste transduction. The first pathway is a GPCRGs-cAMP pathway. This pathway starts with sucrose and other sugars activating Gs inside the cell through a membrane-bound GPCR. The activated Gas activates adenylyl cyclase to generate cAMP. From this point, one of two pathways can be taken. cAMP may act directly to cause an influx of cations through cAMP- gated channels or cAMP can activate protein kinase A, which causes the phosphorylation of K+ channels, thus closing the channels, allowing for depolarization of the taste cell, subsequent opening of voltage-gated Ca2+ channels and causing neurotransmitter release. The second pathway is a GPCR-Gq/Gβγ-IP3 pathway which is used with artificial sweeteners. Artificial sweeteners bind and activate GPCRs coupled to PLCβ2 by either α-Gq or Gβγ. The activated subunits activate PLCβ2 to generate IP3 and DAG. IP3 and DAG elicit Ca2+ release from the endoplasmic reticulum and cause cellular depolarization. An influx of Ca2+ triggers neurotransmitter release. While these two pathways coexist in the same TRCs, it is unclear how the receptors selectively mediate cAMP responses to sugars and IP3 responses to artificial sweeteners. # Evolution of bitter taste receptors Of the five basic tastes, three (sweet, bitter and umami tastes) are mediated by receptors from the G protein-coupled receptor family. Mammalian bitter taste receptors (T2Rs) are encoded by a gene family of only a few dozen members. It is believed that bitter taste receptors evolved as a mechanism to avoid ingesting poisonous and harmful substances. If this is the case, one might expect different species to develop different bitter taste receptors based on dietary and geographical constraints. With the exception of T2R1 (which lies on chromosome 5) all human bitter taste receptor genes can be found clustered on chromosome 7 and chromosome 12. Analyzing the relationships between bitter taste receptor genes show that the genes on the same chromosome are more closely related to each other than genes on different chromosomes. Furthermore, the genes on chromosome 12 have higher sequence similarity than the genes found on chromosome 7. This indicats that these genes evolved via tandem gene duplications and that chromosome 12, as a result of its higher sequence similarity between its genes, went through these tandem duplications more recently than the genes on chromosome 7. # Gustducin in the stomach Recent work by Enrique Rozengurt has shed some light on the presence of gustducin in the stomach and gastrointestinal tract.[3] His work suggests that gustducin is present in these areas as a defense mechanism. It is widely known that some drugs and toxins can cause harm and even be lethal if ingested. It has already been theorized that multiple bitter taste reception pathways exist to prevent harmful substances from being ingested, but a person can choose to ignore the taste of a substance. Ronzegurt suggests that the presence of gustducin in epithelial cells in the stomach and gastrointestinal tract are indicative of another line of defense against ingested toxins. Whereas taste cells in the mouth are designed to compel a person to spit out a toxin, these stomach cells may act to force a person to spit up the toxins in the form of vomit.	https://www.wikidoc.org/index.php/Gustducin
09be25b68e5a79d4fc824cfa9410fd05fea9e3c8	wikidoc	Gut flora	Gut flora # Overview The gut flora are the microorganisms that normally live in the digestive tract and can perform a number of useful functions for their hosts. The average human body, consisting of about 1013 cells, has about ten times that number of microorganisms in the gut. Bacteria make up most of the flora in the colon and 60% of the mass of feces. Somewhere between 300 and 1000 different species live in the gut, with most estimates at about 500. However, it is probable that 99% of the bacteria come from about 30 or 40 species. Fungi and protozoa also make up a part of the gut flora, but little is known about their activities. Research suggests that the relationship between gut flora and humans is not merely commensal (a non-harmful coexistence), but rather is a mutualistic, symbiotic relationship. Though people can survive with no gut flora, the microorganisms perform a host of useful functions, such as fermenting unused energy substrates, training the immune system, preventing growth of harmful species, regulating the development of the gut, producing vitamins for the host (such as biotin and vitamin K), and producing hormones to direct the host to store fats. However, in certain conditions, some species are thought to be capable of causing disease by causing infection or increasing cancer risk for the host. # Localization The colon has the greatest numbers of bacteria and the most different species, and the activity of these bacteria make the colon the most metabolically active organ in the body. Most of the bacteria in the small intestine are Gram-positive, while those in the colon are mostly Gram-negative. The first part of the colon is mostly responsible for fermenting carbohydrates, while the latter part mostly breaks down proteins and amino acids. Bacterial growth is rapid in the cecum and ascending colon, which has a low pH, and slow in the descending colon, which has an almost neutral pH. The body maintains the proper balance and locations of species by altering pH, the activity of the immune system, and peristalsis. Over 99% of the bacteria in the gut are anaerobes, but in the cecum aerobic bacteria reach high densities. # Types Not all the species in the gut have been identified because some cannot be cultured, so DNA isolation and identification is difficult. Populations of species vary widely among different individuals but stay fairly constant within an individual over time. Most bacteria come from the genera Bacteroides, Clostridium, Fusobacterium, Eubacterium, Ruminococcus, Peptococcus, Peptostreptococcus, and Bifidobacterium. Other genera such as Escherichia and Lactobacillus are present to a lesser extent. Species from the genus Bacteroides alone constitute about 30% of all bacteria in the gut, suggesting that that genus is especially important in the functioning of the host. The currently known genera of fungi of the gut flora include Candida, Saccharomyces, Aspergillus, and Penicillium. # Acquisition of gut flora in human infants The gastrointestinal tract of a normal fetus is sterile. During birth and rapidly thereafter, bacteria from the mother and the surrounding environment colonize the infant gut. Immediately after vaginal delivery, babies have bacterial strains in the upper gastrointestinal tract derived from the mothers’ feces. Infants born by caesarean section may also be exposed to their mothers’ microflora, but the main exposure is from the surroundings. After birth, environmental, oral and cutaneous bacteria are readily transferred from the mother to the infant through suckling, kissing, and caressing. All infants are initially colonized by large numbers of E. coli and streptococci. Within a few days, bacterial numbers reach 108 – 1010 /g feces. During the first week of life, these bacteria create a reducing environment favorable for the subsequent bacterial succession of strict anaerobic species mainly belonging to the genera Bifidobacterium, Bacteroides, Clostridium, and Ruminococcus. Breast-fed babies become dominated by bifidobacteria, possibly due to the contents of bifidobacterial growth factors in breast milk. In contrast, the microflora of formula-fed infants is more diverse with high numbers of Enterobacteriaceae, enterococci, bifidobacteria, Bacteroides, and clostridia. After the introduction of solid food and weaning, the microflora of breast-fed infants becomes similar to that of formula-fed infants. By the second year of life the fecal microflora resembles that of adults. # Functions Bacteria in the gut fulfills a host of useful functions for humans, including digestion of unutilized energy substrates; stimulating cell growth; repressing the growth of harmful microorganisms; training the immune system to respond only to pathogens; and defending against some diseases. ## Carbohydrate fermentation and absorption Without gut flora, the human body would be unable to utilize some of the undigested carbohydrates it consumes, because some types of gut flora have enzymes that human cells lack for breaking down certain polysaccharides. Rodents raised in a sterile environment and lacking in gut flora need to eat 30% more calories just to remain the same weight as their normal counterparts. Carbohydrates that humans cannot digest without bacterial help include certain starches; fiber; oligosaccharides and sugars that the body failed to digest and absorb like lactose and sugar alcohols, mucus produced by the gut, and proteins. Bacteria turn carbohydrates they ferment into short chain fatty acids, or SCFAs. These materials can be used by host cells, providing a major source of useful energy and nutrients for humans. They increase the gut's absorption of water, reduce counts of damaging bacteria, increase growth of human gut cells, and are also used for the growth of indigenous bacteria. The SCFAs are produced by a form of fermentation called saccharolytic fermentation and include acetic acid, propionic acid, and butyric acid. Gases and organic acids like lactic acid are also produced by saccahrolytic fermentation. Acetic acid is used by muscle, propionic acid helps the liver produce ATP, and butyric acid provides energy to gut cells and may prevent cancer. Another, less favorable type of fermentation, proteolytic fermentation, breaks down proteins like enzymes, dead host and bacterial cells, and collagen and elastin found in food, and can produce toxins and carcinogens in addition to SCFAs. Thus a diet lower in protein lowers exposure to toxins. Evidence also suggests that bacteria enhance the absorption and storage of lipids. Bacteria also produce and help the body absorb needed vitamins like vitamin K. In addition, the SCFAs they produce help the body absorb nutrients such as calcium, magnesium, and iron. ## Trophic effects Another benefit of SCFAs is that they increase growth of intestinal epithelial cells and control their proliferation and differentiation. They may also cause lymphoid tissue near the gut to grow. Bacterial cells also alter intestinal growth by changing the expression of cell surface proteins such as sodium/glucose transporters. In addition, changes they make to cells may prevent injury to the gut mucosa from occurring. ## Repression of pathogenic microbial growth Another important role of helpful gut flora is that they prevent species that would harm the host from colonizing the gut, an activity termed the "barrier effect". Yeasts and harmful bacterial species such as Clostridium difficile (the overgrowth of which can cause pseudomembranous colitis) are unable to grow too much due to competition from helpful gut flora species, thus animals without gut flora are infected very easily. The barrier effect protects humans from both invading species and species normally present in the gut at low numbers, whose growth is usually inhibited by the gut flora. Helpful bacteria prevent the growth of pathogenic species by competing for nutrition and attachment sites to the epithelium of the colon. Symbiotic bacteria are more at home in this ecological niche and are thus more successful in the competition. The indigenous bacteria send chemical signals to the host about the amount of nutrients they need, and the host provides only that much, so harmful bacteria are starved out. Indigenous gut flora also produce bacteriocins, substances which kill harmful microbes and the levels of which can be regulated by enzymes produced by the host. The process of fermentation, since it produces fatty acids, also serves to lower the pH in the colon, preventing the proliferation of harmful species of bacteria and facilitating that of helpful species. The pH may also enhance the excretion of carcinogens. ## Immunity Gut flora have a continuous and dynamic effect on the host's gut and systemic immune systems. The bacteria are key in promoting the early development of the gut's mucosal immune system both in terms of its physical components and function and continue to play a role later in life in its operation. The bacteria stimulate the lymphoid tissue associated with the gut mucosa to produce antibodies to pathogens. The immune system recognizes and fights harmful bacteria, but leaves the helpful species alone, a tolerance developed in infancy. As soon as an infant is born, bacteria begin colonizing its digestive tract. The first bacteria to settle in are able to affect the immune response, making it more favorable to their own survival and less so to competing species; thus the first bacteria to colonize the gut are important in determining the person's lifelong gut flora makeup. However, there is a shift at the time of weaning from predominantly facultative aerobic species such as Streptococci and Escherichia coli to mostly obligate anaerobic species. Recent findings have shown that gut bacteria play a role in the expression of Toll-like receptors (TLRs) in the intestines, molecules that help the host repair damage due to injury. TLRs cause parts of the immune system to repair injury caused for example by radiation. Bacteria can influence the phenomenon known as oral tolerance, in which the immune system is less sensitive to an antigen (including those produced by gut bacteria) once it has been ingested. This tolerance, mediated in part by the gastrointestinal immune system and in part by the liver, can reduce an overreactive immune response like those found in allergies and auto-immune disease. Some species of gut flora, such as some of those in the Bacteroides genus, are able to change their surface receptors to mimic those of host cells in order to evade immune response. Bacteria with neutral and harmful effects on the host can also use these types of strategies. The host immune system has also adapted to this activity, preventing overgrowth of harmful species. ## Preventing allergy Bacteria are also implicated in preventing allergies, an overreaction of the immune system to non-harmful antigens. Studies on the gut flora of infants and young children have shown that those who have or later develop allergies have different compositions of gut flora from those without allergies, with higher chances of having the harmful species C difficile and S aureus and lower prevalence of Bacteroides and Bifidobacteria. One explanation is that since helpful gut flora stimulate the immune system and "train" it to respond properly to antigens, a lack of these bacteria in early life leads to an inadequately trained immune system which overreacts to antigens. On the other hand, the differences in flora could be a result, not a cause, of the allergies. ## Preventing inflammatory bowel disease Another indicator that bacteria help train the immune system is the epidemiology of Inflammatory Bowel Disease, or IBD, such as Crohn's Disease (CD). Some authors suggest that SCFAs prevent IBD. In addition, some forms of bacteria can prevent inflammation. The incidence and prevalence of IBD is high in industrialized countries with a high standard of living and low in less economically developed countries, having increased in developed countries throughout the twentieth century. The disease is also linked to good hygiene in youth; lack of breastfeeding; and consumption of large amounts of sucrose and animal fat. Its incidence is inversely linked with poor sanitation during the first years of life and consumption of fruits, vegetables, and unprocessed foods. Also, the use of antibiotics, which kill native gut flora and harmful infectious pathogens alike, especially during childhood, is associated with inflammatory bowel disease. On the other hand, using probiotics, bacteria consumed as part of the diet that impart health benefits (aside from just nutrition), helps treat IBD. # Alterations in balance ## Effects of antibiotic use Altering the numbers of gut bacteria, for example by taking broad-spectrum antibiotics, may affect the host's health and ability to digest food. People may take the drugs to cure bacterial illnesses or may unintentionally consume significant amounts of antibiotics by eating the meat of animals to which they were fed. Antibiotics can cause antibiotic-associated diarrhea (AAD) by irritating the bowel directly, changing the levels of gut flora, or allowing pathogenic bacteria to grow. Another harmful effect of antibiotics is the increase in numbers of antibiotic-resistant bacteria found after their use, which, when they invade the host, cause illnesses that are difficult to treat with antibiotics. Changing the numbers and species of gut flora can reduce the body's ability to ferment carbohydrates and metabolize bile acids and may cause diarrhea. Carbohydrates that are not broken down may absorb too much water and cause runny stools, or lack of SCFAs produced by gut flora could cause the diarrhea. A reduction in levels of native bacterial species also disrupts their ability to inhibit the growth of harmful species such as C. difficile and Salmonella kedougou, and these species can get out of hand, though their overgrowth may be incidental and not be the true cause of diarrhea. Gut flora composition also changes in severe illnesses, due not only to antibiotic use but also to such factors as ischemia of the gut, failure to eat, and immune compromise. Negative effects from this have led to interest in selective digestive tract decontamination (SDD), a treatment to kill only pathogenic bacteria and allow the reestablishment of healthy ones. ## Probiotics & Prebiotics Since the lack of gut flora can have such harmful health effects, the use of probiotics has anti-inflammatory effects in the gut and may be useful for improving health. Prebiotics are dietary components that can help foster the growth of microorganisms in the gut, which may lead to better health. # Role in disease Bacteria in the digestive tract have pathogenic properties in addition to their health-inducing ones: they can produce toxins and carcinogens and have been implicated in such conditions as multisystem organ failure, sepsis, colon cancer, and IBD. A major factor in health is the balance of bacterial numbers; if the numbers grow too high or low, it will result in harm to the host. The host has enzymes to regulate this balance. ## Cancer Some genera of bacteria, such as Bacteroides and Clostridium, have been associated with an increase in tumor growth rate, while other genera like Lactobacillus and Bifidobacteria are known to prevent tumor formation. ## Translocation Helpful bacteria can be very harmful to the host if they get outside of the intestinal tract. Translocation, which occurs when bacteria leave the gut through its mucosal lining, the border between the lumen of the gut and the inside of the body, can occur in a number of different diseases. It can be caused by too much growth of bacteria in the small intestine, reduced immunity of the human, or increased gut lining permeability. The gut can become more permeable in diseases like cirrhosis, which is damaging due in part to the activity of gut flora. If the gut is perforated, bacteria can invade the body, causing a potentially fatal infection. Aerobic bacteria can make infection by anaerobes worse by using up all available oxygen and creating an environment favorable to anaerobes. ## Inflammatory bowel disease Some suspect that IBD is due to a reduction in immune tolerance and subsequent overreaction of the host's immune system to harmful or non-harmful bacteria. IBD may be caused by all of the gut flora together or some specific types. It has been noted that though Ulcerative Colitis and Crohn's disease (two types of IBD) probably have genetic components, they are not inherited in a Mendelian fashion and are thus probably due to a complex set of factors rather than solely to a gene. Though neither bacterial colonization nor genetics is sufficient to cause the disease, bacteria probably play a role in these disorders. Some suspect that inflammation in IBD is due to increased permeability of the inner lining of the colon, which may allow bacteria to invade the tissues and cause an immune reaction that leads prolonged inflammation. Abnormal tight junctions, which are supposed to prevent permeability, have been found in cells of patients with IBD. Because of the potentially harmful role of these bacteria, antibiotics are frequently prescribed to treat Crohn’s disease. However, inflammation could occur first and cause the increased intestinal permeability found in diseases such as Crohn's, so the causative role of bacteria is not clear. ## Colitis It has been suggested that commensal bacteria are responsible for the development of colitis, since mice raised in a sterile environment do not get the disease. However, while some bacterial strains such as C. difficile and even normal gut bacteria cause colitis, others prevent the disease in mice. ## Obesity It is known from experiments on mice that obese mice lacking leptin, a lipid metabolism regulator (ob/ob mice), have a distinct gut flora compared to (normal) lean mice, reflected in a change in the ratio between bacteria from the divisions bacteroidetes and firmicutes, which is shifted towards less bacteroidetes and more firmicutes in obese mice. The microbes occupying the human gut are also in direct relation to obesity. A shift in the ratio between bacterial-divisions firmicutes and bacteroidetes can be observed in lean and obese individuals – in latter a shift towards firmicutes can be observed. The ratio between firmicutes and bacteroidetes dynamically reflects the overall weight-condition of an individual, shifting towards bacteroides if an obese individual loses weight. The mutual influence of gut flora composition and weight-condition is connected to differences in the energy-resorption potential of different ratios of firmicutes and bacteroidetes, especially in the digestion of fatty acids and dietary polysaccharides, as shown by experiments wherein the (caecum) gut flora of obese mice was transplanted into germ free recipient mice, leading to an increase in weight despite an decrease in food consumption. # Sources and notes - ↑ Jump up to: 1.0 1.1 1.2 1.3 1.4 Björkstén B, Sepp E, Julge K, Voor T, and Mikelsaar M. 2001. Allergy development and the intestinal microflora during the first year of life.] Journal of Allergy and Clinical Immunology, Volume 108, Issue 4, Pages 516-520. PMID 11590374. Accessed September 15, 2007 - ↑ Jump up to: 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 2.25 2.26 2.27 2.28 Guarner F and Malagelada JR. 2003. Gut flora in health and disease. The Lancet, Volume 361, Issue 9356, 8 February 2003, Pages 512-519. PMID 12583961. Accessed September 15, 2007 - ↑ Jump up to: 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 Sears CL. 2005. A dynamic partnership: Celebrating our gut flora. Anaerobe, Volume 11, Issue 5, Pages 247-251. PMID 16701579. Accessed September 15, 2007 - ↑ Jump up to: 4.0 4.1 4.2 4.3 4.4 4.5 4.6 Steinhoff U. 2005. Who controls the crowd? New findings and old questions about the intestinal microflora. Immunology Letters, Volume 99, Issue 1, 15 June , Pages 12-16. PMID 15894105. Accessed September 15, 2007 - ↑ Jump up to: 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 University of Glasgow. 2005. The normal gut flora. Available through web archive. Accessed December 26, 2006 - ↑ Jump up to: 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 Gibson RG. 2004. Fibre and effects on probiotics (the prebiotic concept). Clinical Nutrition Supplements, Volume 1, Issue 2, Pages 25-31. - ↑ Jump up to: 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 Beaugerie L and Petit JC. 2004. Microbial-gut interactions in health and disease. Antibiotic-associated diarrhoea. Best Practice & Research Clinical Gastroenterology, Volume 18, Issue 2, Pages 337-352. PMID 15123074. Accessed September 15, 2007 - ↑ Riordan SM, McIver CJ, Wakefield D, Duncombe VM, Thomas MC, and Bolin TD. 2001. Small intestinal mucosal immunity and morphometry in luminal overgrowth of indigenous gut flora. The American Journal of Gastroenterology, Volume 96, Issue 2, Pages 494-500. PMID 11232696. Accessed September 15, 2007 - ↑ Jump up to: 9.0 9.1 9.2 9.3 9.4 Vedantam G and Hecht DW. 2003. Antibiotics and anaerobes of gut origin. Current Opinion in Microbiology, Volume 6, Issue 5, Pages 457-461. PMID 14572537. Accessed September 15, 2007 - ↑ Jump up to: 10.0 10.1 Shanahan F. 2002. The host–microbe interface within the gut. Best Practice & Research Clinical Gastroenterology, Volume 16, Issue 6, Pages 915-931. PMID 12473298. Accessed September 15, 2007 - ↑ Nordgård L, Traavik T, and Nielsen KM. 2005. Nucleic acid isolation from ecological samples—vertebrate gut flora. Methods in Enzymology, Volume 395, Pages 38-48. PMID 15865959. Accessed September 7, 2007 - ↑ Bettelheim KA, Breadon A, Faiers MC, O'Farrell SM, Shooter RA. 1974. The origin of O serotypes of Escherichia coli in babies after normal delivery. Journal of Hygeine, Volume 72, Issue 1, Pages 67-70. PMID 4593741. Accessed September 3, 2007 - ↑ Jump up to: 13.0 13.1 Schwiertz A, Gruhl B, Lobnitz M, Michel P, Radke M, Blaut M. 2003. Development of the intestinal bacterial composition in hospitalized preterm infants in comparison with breast-fed, full-term infants. Pediatric Research, Volume 54, Issue 3, Pages 393-399. PMID 12788986. Accessed September 3, 2007 - ↑ Mackie RI, Sghir A, Gaskins HR. 1999.Developmental microbial ecology of the neonatal gastrointestinal tract. American Journal of Clinical Nutrition, Volume 69, Issue 5, Pages 1035S-1045S. PMID 10232646. Accessed September 7, 2007 - ↑ Favier CF, Vaughan EE, De Vos WM, Akkermans AD. 2002. Molecular monitoring of succession of bacterial communities in human neonates. Applied and Environmental Microbiology, Volume 68, Issue 1, Pages 219-226. PMID 11772630. - ↑ Coppa GV, Bruni S, Morelli L, Soldi S, Gabrielli O. 2004. The first prebiotics in humans: human milk oligosaccharides. Journal of Clinical Gastroenterology, Volume 38, Supplement 6, Pages S80-S83. PMID 15220665. Accessed September 3, 2007 - ↑ Harmsen HJ, Wildeboer-Veloo AC, Raangs GC, Wagendorp AA, Klijn N, Bindels JG, Welling GW. 2000. Analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods. Journal of Pediatric Gastroenterology and Nutrition, Volume 30, Issue 1, Pages 61-67. PMID 10630441. Accessed September 7, 2007 - ↑ Fanaro S, Chierici R, Guerrini P, Vigi V. 2003. Intestinal microflora in early infancy: composition and development. Acta Paediatrica, Volume 91, Issue 441, Pages 48-55. PMID 14599042. Accessed September 3, 2007 - ↑ Jump up to: 19.0 19.1 19.2 Wynne AG, McCartney AL, Brostoff J, Hudspith BN, Glenn GR and Gibson G. 2004. An in vitro assessment of the effects of broad-spectrum antibiotics on the human gut microflora and concomitant isolation of a Lactobacillus plantarum with anti-Candida activities. Anaerobe, Volume 10, Issue 3, Pages 165-169. PMID 16701514. Accessed September 3, 2007 - ↑ Jump up to: 20.0 20.1 20.2 20.3 Keeley J. 2004. Good bacteria trigger proteins to protect the gut. Howard Hughes Medical Institute. EurekAlert. Accessed January 9, 2007 - ↑ Jewell AP. 2005. Is the liver an important site for the development of immune tolerance to tumours? Medical Hypotheses, Volume 64, Issue 4, Pages 751-754. PMID 15694692. Accessed September 7, 2007 - ↑ Jump up to: 22.0 22.1 22.2 22.3 22.4 22.5 22.6 22.7 Guarner F and Malagelada JR. 2003. Role of bacteria in experimental colitis. Best Practice & Research Clinical Gastroenterology, Volume 17, Issue 5, October 2003, Pages 793-804. PMID 14507589. Accessed September 15, 2007 - ↑ Jump up to: 23.0 23.1 23.2 23.3 Carman RJ, Simon MA, Fernández H, Miller MA, and Bartholomew MJ. 2004. Ciprofloxacin at low levels disrupts colonization resistance of human fecal microflora growing in chemostats. Regulatory Toxicology and Pharmacology, Volume 40, Issue 3, December, Pages 319-326. PMID 15546686. Accessed September 7, 2007 - ↑ Knight DJW and Girling KJ. 2003. Gut flora in health and disease. The Lancet, Volume 361, Issue 9371, Page 1831. Accessed January 7, 2007 - ↑ Jump up to: 25.0 25.1 25.2 25.3 Suenaert P, Bulteel V, Lemmens L, Noman M, Geypens B, Assche GV, Geboes K, Ceuppens JL and Rutgeert P. 2002. Anti-tumor necrosis factor treatment restores the gut barrier in Crohn’s disease. The American Journal of Gastroenterology, Volume 97, Issue 8, Pages 2000-2004. PMID 12190167. Accessed September 7, 2007 - ↑ Garcia-Tsao G and Wiest R. 2004. Gut microflora in the pathogenesis of the complications of cirrhosis. Best Practice & Research Clinical Gastroenterology, Volume 18, Issue 2, Pages 353-372. PMID 15123075. Accessed September 7, 2007 - ↑ Jump up to: 27.0 27.1 27.2 Hugot JP. 2004. Inflammatory bowel disease: a complex group of genetic disorders. Best Practice & Research Clinical Gastroenterology, Volume 18, Issue 3, Pages 451-462. PMID 15157820. Accessed September 7, 2007 - ↑ Jump up to: 28.0 28.1 Veltkamp C, Tonkonogy SL, De Jong YP, Albright C, Grenther WB, Balish E, Terhorst C, and Sartor RB. 2001. Continuous stimulation by normal luminal bacteria is essential for the development and perpetuation of colitis in Tg(epsilon26) mice. Gastroenterology, Volume 120, Issue 4, Pages 900-913. PMID 11231944. Accessed September 7, 2007 - ↑ Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature, 2006 Volume 444, Issue 7122, Pages 1022-1023. PMID 17183309. Accessed September 7, 2007 - ↑ Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. 2006. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature, Volume 444, Issue 7122, Pages 1027-1031. PMID 17183312. Accessed September 7, 2007 - ↑ Bäckhed F, Manchester JK, Semenkovich CF, Gordon JI. 2007. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proceedings of the National Academy of Sciences of the USA, Volume 104, Issue 3, Pages 979-984. PMID 17210919. Accessed September 7, 2007 - ↑ Bäckhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, Gordon JI. The gut microbiota as an environmental factor that regulates fat storage. Proceedings of the National Academy of Sciences of the USA, Volume 101, Issue 44, Pages 15718-15723. PMID 15505215. Accessed September 7, 2007 de:Darmflora nl:Darmflora	Gut flora Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The gut flora are the microorganisms that normally live in the digestive tract and can perform a number of useful functions for their hosts. The average human body, consisting of about 1013 cells, has about ten times that number of microorganisms in the gut.[1][2][3][4][5] Bacteria make up most of the flora in the colon[5] and 60% of the mass of feces.[2] Somewhere between 300[2] and 1000 different species live in the gut,[3] with most estimates at about 500.[6][4] However, it is probable that 99% of the bacteria come from about 30 or 40 species.[7] Fungi and protozoa also make up a part of the gut flora, but little is known about their activities. Research suggests that the relationship between gut flora and humans is not merely commensal (a non-harmful coexistence), but rather is a mutualistic, symbiotic relationship.[3] Though people can survive with no gut flora,[4] the microorganisms perform a host of useful functions, such as fermenting unused energy substrates, training the immune system, preventing growth of harmful species,[2] regulating the development of the gut, producing vitamins for the host (such as biotin and vitamin K), and producing hormones to direct the host to store fats. However, in certain conditions, some species are thought to be capable of causing disease by causing infection or increasing cancer risk for the host.[2][5] # Localization The colon has the greatest numbers of bacteria and the most different species, and the activity of these bacteria make the colon the most metabolically active organ in the body.[6] Most of the bacteria in the small intestine are Gram-positive, while those in the colon are mostly Gram-negative.[8] The first part of the colon is mostly responsible for fermenting carbohydrates,[7][6][2] while the latter part mostly breaks down proteins and amino acids.[6][2] Bacterial growth is rapid in the cecum and ascending colon, which has a low pH, and slow in the descending colon, which has an almost neutral pH.[2] The body maintains the proper balance and locations of species by altering pH, the activity of the immune system, and peristalsis.[5] Over 99% of the bacteria in the gut are anaerobes,[7][2][5][3][9] but in the cecum aerobic bacteria reach high densities.[2] # Types Not all the species in the gut have been identified[2][3] because some cannot be cultured,[7][3][10] so DNA isolation and identification is difficult.[11] Populations of species vary widely among different individuals but stay fairly constant within an individual over time.[2] Most bacteria come from the genera Bacteroides, Clostridium, Fusobacterium,[7][2][9] Eubacterium, Ruminococcus, Peptococcus, Peptostreptococcus, and Bifidobacterium.[2][7] Other genera such as Escherichia and Lactobacillus are present to a lesser extent.[2] Species from the genus Bacteroides alone constitute about 30% of all bacteria in the gut, suggesting that that genus is especially important in the functioning of the host.[3] The currently known genera of fungi of the gut flora include Candida, Saccharomyces, Aspergillus, and Penicillium. # Acquisition of gut flora in human infants The gastrointestinal tract of a normal fetus is sterile. During birth and rapidly thereafter, bacteria from the mother and the surrounding environment colonize the infant gut. Immediately after vaginal delivery, babies have bacterial strains in the upper gastrointestinal tract derived from the mothers’ feces.[12] Infants born by caesarean section may also be exposed to their mothers’ microflora, but the main exposure is from the surroundings.[13] After birth, environmental, oral and cutaneous bacteria are readily transferred from the mother to the infant through suckling, kissing, and caressing. All infants are initially colonized by large numbers of E. coli and streptococci. Within a few days, bacterial numbers reach 108 – 1010 /g feces.[13][14] During the first week of life, these bacteria create a reducing environment favorable for the subsequent bacterial succession of strict anaerobic species mainly belonging to the genera Bifidobacterium, Bacteroides, Clostridium, and Ruminococcus.[15] Breast-fed babies become dominated by bifidobacteria, possibly due to the contents of bifidobacterial growth factors in breast milk.[16] In contrast, the microflora of formula-fed infants is more diverse with high numbers of Enterobacteriaceae, enterococci, bifidobacteria, Bacteroides, and clostridia.[17][18] After the introduction of solid food and weaning, the microflora of breast-fed infants becomes similar to that of formula-fed infants. By the second year of life the fecal microflora resembles that of adults. # Functions Bacteria in the gut fulfills a host of useful functions for humans, including digestion of unutilized energy substrates;[19] stimulating cell growth; repressing the growth of harmful microorganisms; training the immune system to respond only to pathogens; and defending against some diseases.[2][3][20] ## Carbohydrate fermentation and absorption Without gut flora, the human body would be unable to utilize some of the undigested carbohydrates it consumes, because some types of gut flora have enzymes that human cells lack for breaking down certain polysaccharides.[3] Rodents raised in a sterile environment and lacking in gut flora need to eat 30% more calories just to remain the same weight as their normal counterparts.[3] Carbohydrates that humans cannot digest without bacterial help include certain starches; fiber; oligosaccharides and sugars that the body failed to digest and absorb[6][2][7] like lactose and sugar alcohols, mucus produced by the gut, and proteins.[6] Bacteria turn carbohydrates they ferment into short chain fatty acids, or SCFAs.[6][5][7] These materials can be used by host cells, providing a major source of useful energy and nutrients for humans.[6] They increase the gut's absorption of water, reduce counts of damaging bacteria, increase growth of human gut cells,[5] and are also used for the growth of indigenous bacteria.[2] The SCFAs are produced by a form of fermentation called saccharolytic fermentation[6] and include acetic acid, propionic acid, and butyric acid.[6][5][7] Gases and organic acids like lactic acid are also produced by saccahrolytic fermentation.[7] Acetic acid is used by muscle, propionic acid helps the liver produce ATP, and butyric acid provides energy to gut cells and may prevent cancer.[6] Another, less favorable type of fermentation, proteolytic fermentation, breaks down proteins like enzymes, dead host and bacterial cells, and collagen and elastin found in food, and can produce toxins and carcinogens in addition to SCFAs. Thus a diet lower in protein lowers exposure to toxins.[2][5] Evidence also suggests that bacteria enhance the absorption and storage of lipids.[3] Bacteria also produce and help the body absorb needed vitamins like vitamin K. In addition, the SCFAs they produce help the body absorb nutrients such as calcium, magnesium, and iron.[2] ## Trophic effects Another benefit of SCFAs is that they increase growth of intestinal epithelial cells and control their proliferation and differentiation.[2] They may also cause lymphoid tissue near the gut to grow. Bacterial cells also alter intestinal growth by changing the expression of cell surface proteins such as sodium/glucose transporters.[3] In addition, changes they make to cells may prevent injury to the gut mucosa from occurring.[20] ## Repression of pathogenic microbial growth Another important role of helpful gut flora is that they prevent species that would harm the host from colonizing the gut, an activity termed the "barrier effect". Yeasts and harmful bacterial species such as Clostridium difficile (the overgrowth of which can cause pseudomembranous colitis) are unable to grow too much due to competition from helpful gut flora species, thus animals without gut flora are infected very easily. The barrier effect protects humans from both invading species and species normally present in the gut at low numbers, whose growth is usually inhibited by the gut flora.[2] Helpful bacteria prevent the growth of pathogenic species by competing for nutrition and attachment sites to the epithelium of the colon. Symbiotic bacteria are more at home in this ecological niche and are thus more successful in the competition. The indigenous bacteria send chemical signals to the host about the amount of nutrients they need, and the host provides only that much, so harmful bacteria are starved out. Indigenous gut flora also produce bacteriocins, substances which kill harmful microbes and the levels of which can be regulated by enzymes produced by the host.[2] The process of fermentation, since it produces fatty acids, also serves to lower the pH in the colon, preventing the proliferation of harmful species of bacteria and facilitating that of helpful species. The pH may also enhance the excretion of carcinogens.[6] ## Immunity Gut flora have a continuous and dynamic effect on the host's gut and systemic immune systems. The bacteria are key in promoting the early development of the gut's mucosal immune system both in terms of its physical components and function and continue to play a role later in life in its operation. The bacteria stimulate the lymphoid tissue associated with the gut mucosa to produce antibodies to pathogens. The immune system recognizes and fights harmful bacteria, but leaves the helpful species alone, a tolerance developed in infancy.[2][10][4][5] As soon as an infant is born, bacteria begin colonizing its digestive tract. The first bacteria to settle in are able to affect the immune response, making it more favorable to their own survival and less so to competing species; thus the first bacteria to colonize the gut are important in determining the person's lifelong gut flora makeup. However, there is a shift at the time of weaning from predominantly facultative aerobic species such as Streptococci and Escherichia coli to mostly obligate anaerobic species.[2][3] Recent findings have shown that gut bacteria play a role in the expression of Toll-like receptors (TLRs) in the intestines, molecules that help the host repair damage due to injury. TLRs cause parts of the immune system to repair injury caused for example by radiation.[3][20] Bacteria can influence the phenomenon known as oral tolerance, in which the immune system is less sensitive to an antigen (including those produced by gut bacteria) once it has been ingested. This tolerance, mediated in part by the gastrointestinal immune system and in part by the liver, can reduce an overreactive immune response like those found in allergies and auto-immune disease.[21] Some species of gut flora, such as some of those in the Bacteroides genus, are able to change their surface receptors to mimic those of host cells in order to evade immune response. Bacteria with neutral and harmful effects on the host can also use these types of strategies. The host immune system has also adapted to this activity, preventing overgrowth of harmful species.[2][4] ## Preventing allergy Bacteria are also implicated in preventing allergies,[1] an overreaction of the immune system to non-harmful antigens. Studies on the gut flora of infants and young children have shown that those who have or later develop allergies have different compositions of gut flora from those without allergies, with higher chances of having the harmful species C difficile and S aureus and lower prevalence of Bacteroides and Bifidobacteria.[1] One explanation is that since helpful gut flora stimulate the immune system and "train" it to respond properly to antigens, a lack of these bacteria in early life leads to an inadequately trained immune system which overreacts to antigens.[1] On the other hand, the differences in flora could be a result, not a cause, of the allergies.[1] ## Preventing inflammatory bowel disease Another indicator that bacteria help train the immune system is the epidemiology of Inflammatory Bowel Disease, or IBD, such as Crohn's Disease (CD). Some authors suggest that SCFAs prevent IBD. In addition, some forms of bacteria can prevent inflammation.[22] The incidence and prevalence of IBD is high in industrialized countries with a high standard of living and low in less economically developed countries, having increased in developed countries throughout the twentieth century. The disease is also linked to good hygiene in youth; lack of breastfeeding; and consumption of large amounts of sucrose and animal fat.[22] Its incidence is inversely linked with poor sanitation during the first years of life and consumption of fruits, vegetables, and unprocessed foods.[22] Also, the use of antibiotics, which kill native gut flora and harmful infectious pathogens alike, especially during childhood, is associated with inflammatory bowel disease.[19] On the other hand, using probiotics, bacteria consumed as part of the diet that impart health benefits (aside from just nutrition), helps treat IBD. # Alterations in balance ## Effects of antibiotic use Altering the numbers of gut bacteria, for example by taking broad-spectrum antibiotics, may affect the host's health and ability to digest food.[23] People may take the drugs to cure bacterial illnesses or may unintentionally consume significant amounts of antibiotics by eating the meat of animals to which they were fed.[23] Antibiotics can cause antibiotic-associated diarrhea (AAD) by irritating the bowel directly, changing the levels of gut flora, or allowing pathogenic bacteria to grow.[7] Another harmful effect of antibiotics is the increase in numbers of antibiotic-resistant bacteria found after their use, which, when they invade the host, cause illnesses that are difficult to treat with antibiotics.[23] Changing the numbers and species of gut flora can reduce the body's ability to ferment carbohydrates and metabolize bile acids and may cause diarrhea. Carbohydrates that are not broken down may absorb too much water and cause runny stools, or lack of SCFAs produced by gut flora could cause the diarrhea.[7] A reduction in levels of native bacterial species also disrupts their ability to inhibit the growth of harmful species such as C. difficile and Salmonella kedougou, and these species can get out of hand, though their overgrowth may be incidental and not be the true cause of diarrhea.[7][23][2] Gut flora composition also changes in severe illnesses, due not only to antibiotic use but also to such factors as ischemia of the gut, failure to eat, and immune compromise. Negative effects from this have led to interest in selective digestive tract decontamination (SDD), a treatment to kill only pathogenic bacteria and allow the reestablishment of healthy ones.[24] ## Probiotics & Prebiotics Since the lack of gut flora can have such harmful health effects, the use of probiotics has anti-inflammatory effects in the gut and may be useful for improving health. Prebiotics are dietary components that can help foster the growth of microorganisms in the gut, which may lead to better health.[22] # Role in disease Bacteria in the digestive tract have pathogenic properties in addition to their health-inducing ones: they can produce toxins and carcinogens[5] and have been implicated in such conditions as multisystem organ failure, sepsis, colon cancer, and IBD.[2] A major factor in health is the balance of bacterial numbers; if the numbers grow too high or low, it will result in harm to the host. The host has enzymes to regulate this balance.[5] ## Cancer Some genera of bacteria, such as Bacteroides and Clostridium, have been associated with an increase in tumor growth rate, while other genera like Lactobacillus and Bifidobacteria are known to prevent tumor formation.[2] ## Translocation Helpful bacteria can be very harmful to the host if they get outside of the intestinal tract.[3][5][9] Translocation, which occurs when bacteria leave the gut through its mucosal lining, the border between the lumen of the gut and the inside of the body,[4][25] can occur in a number of different diseases.[9][22] It can be caused by too much growth of bacteria in the small intestine, reduced immunity of the human, or increased gut lining permeability.[22] The gut can become more permeable in diseases like cirrhosis, which is damaging due in part to the activity of gut flora.[26] If the gut is perforated, bacteria can invade the body, causing a potentially fatal infection. Aerobic bacteria can make infection by anaerobes worse by using up all available oxygen and creating an environment favorable to anaerobes.[9] ## Inflammatory bowel disease Some suspect that IBD is due to a reduction in immune tolerance and subsequent overreaction of the host's immune system to harmful or non-harmful bacteria. IBD may be caused by all of the gut flora together or some specific types.[19][27] It has been noted that though Ulcerative Colitis and Crohn's disease (two types of IBD) probably have genetic components, they are not inherited in a Mendelian fashion and are thus probably due to a complex set of factors rather than solely to a gene.[27] Though neither bacterial colonization nor genetics is sufficient to cause the disease, bacteria probably play a role in these disorders.[27] Some suspect that inflammation in IBD is due to increased permeability of the inner lining of the colon, which may allow bacteria to invade the tissues and cause an immune reaction that leads prolonged inflammation.[4][25] Abnormal tight junctions, which are supposed to prevent permeability, have been found in cells of patients with IBD.[25] Because of the potentially harmful role of these bacteria, antibiotics are frequently prescribed to treat Crohn’s disease.[20] However, inflammation could occur first and cause the increased intestinal permeability found in diseases such as Crohn's, so the causative role of bacteria is not clear.[25] ## Colitis It has been suggested that commensal bacteria are responsible for the development of colitis, since mice raised in a sterile environment do not get the disease.[28] However, while some bacterial strains such as C. difficile[22] and even normal gut bacteria cause colitis,[28] others prevent the disease in mice.[22] ## Obesity It is known from experiments on mice that obese mice lacking leptin, a lipid metabolism regulator (ob/ob mice), have a distinct gut flora compared to (normal) lean mice, reflected in a change in the ratio between bacteria from the divisions bacteroidetes and firmicutes, which is shifted towards less bacteroidetes and more firmicutes in obese mice. The microbes occupying the human gut are also in direct relation to obesity. A shift in the ratio between bacterial-divisions firmicutes and bacteroidetes can be observed in lean and obese individuals – in latter a shift towards firmicutes can be observed. The ratio between firmicutes and bacteroidetes dynamically reflects the overall weight-condition of an individual, shifting towards bacteroides if an obese individual loses weight. The mutual influence of gut flora composition and weight-condition is connected to differences in the energy-resorption potential of different ratios of firmicutes and bacteroidetes, especially in the digestion of fatty acids and dietary polysaccharides, as shown by experiments wherein the (caecum) gut flora of obese mice was transplanted into germ free recipient mice, leading to an increase in weight despite an decrease in food consumption.[29][30][31][32] # Sources and notes - ↑ Jump up to: 1.0 1.1 1.2 1.3 1.4 Björkstén B, Sepp E, Julge K, Voor T, and Mikelsaar M. 2001. Allergy development and the intestinal microflora during the first year of life.] Journal of Allergy and Clinical Immunology, Volume 108, Issue 4, Pages 516-520. PMID 11590374. Accessed September 15, 2007 - ↑ Jump up to: 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 2.25 2.26 2.27 2.28 Guarner F and Malagelada JR. 2003. Gut flora in health and disease. The Lancet, Volume 361, Issue 9356, 8 February 2003, Pages 512-519. PMID 12583961. Accessed September 15, 2007 - ↑ Jump up to: 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 Sears CL. 2005. A dynamic partnership: Celebrating our gut flora. Anaerobe, Volume 11, Issue 5, Pages 247-251. PMID 16701579. Accessed September 15, 2007 - ↑ Jump up to: 4.0 4.1 4.2 4.3 4.4 4.5 4.6 Steinhoff U. 2005. Who controls the crowd? New findings and old questions about the intestinal microflora. Immunology Letters, Volume 99, Issue 1, 15 June , Pages 12-16. PMID 15894105. Accessed September 15, 2007 - ↑ Jump up to: 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 University of Glasgow. 2005. The normal gut flora. Available through web archive. Accessed December 26, 2006 - ↑ Jump up to: 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 Gibson RG. 2004. Fibre and effects on probiotics (the prebiotic concept). Clinical Nutrition Supplements, Volume 1, Issue 2, Pages 25-31. - ↑ Jump up to: 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 Beaugerie L and Petit JC. 2004. Microbial-gut interactions in health and disease. Antibiotic-associated diarrhoea. Best Practice & Research Clinical Gastroenterology, Volume 18, Issue 2, Pages 337-352. PMID 15123074. Accessed September 15, 2007 - ↑ Riordan SM, McIver CJ, Wakefield D, Duncombe VM, Thomas MC, and Bolin TD. 2001. Small intestinal mucosal immunity and morphometry in luminal overgrowth of indigenous gut flora. The American Journal of Gastroenterology, Volume 96, Issue 2, Pages 494-500. PMID 11232696. Accessed September 15, 2007 - ↑ Jump up to: 9.0 9.1 9.2 9.3 9.4 Vedantam G and Hecht DW. 2003. Antibiotics and anaerobes of gut origin. Current Opinion in Microbiology, Volume 6, Issue 5, Pages 457-461. PMID 14572537. Accessed September 15, 2007 - ↑ Jump up to: 10.0 10.1 Shanahan F. 2002. The host–microbe interface within the gut. Best Practice & Research Clinical Gastroenterology, Volume 16, Issue 6, Pages 915-931. PMID 12473298. Accessed September 15, 2007 - ↑ Nordgård L, Traavik T, and Nielsen KM. 2005. Nucleic acid isolation from ecological samples—vertebrate gut flora. Methods in Enzymology, Volume 395, Pages 38-48. PMID 15865959. Accessed September 7, 2007 - ↑ Bettelheim KA, Breadon A, Faiers MC, O'Farrell SM, Shooter RA. 1974. The origin of O serotypes of Escherichia coli in babies after normal delivery. Journal of Hygeine, Volume 72, Issue 1, Pages 67-70. PMID 4593741. Accessed September 3, 2007 - ↑ Jump up to: 13.0 13.1 Schwiertz A, Gruhl B, Lobnitz M, Michel P, Radke M, Blaut M. 2003. Development of the intestinal bacterial composition in hospitalized preterm infants in comparison with breast-fed, full-term infants. Pediatric Research, Volume 54, Issue 3, Pages 393-399. PMID 12788986. Accessed September 3, 2007 - ↑ Mackie RI, Sghir A, Gaskins HR. 1999.Developmental microbial ecology of the neonatal gastrointestinal tract. American Journal of Clinical Nutrition, Volume 69, Issue 5, Pages 1035S-1045S. PMID 10232646. Accessed September 7, 2007 - ↑ Favier CF, Vaughan EE, De Vos WM, Akkermans AD. 2002. Molecular monitoring of succession of bacterial communities in human neonates. Applied and Environmental Microbiology, Volume 68, Issue 1, Pages 219-226. PMID 11772630. - ↑ Coppa GV, Bruni S, Morelli L, Soldi S, Gabrielli O. 2004. The first prebiotics in humans: human milk oligosaccharides. Journal of Clinical Gastroenterology, Volume 38, Supplement 6, Pages S80-S83. PMID 15220665. Accessed September 3, 2007 - ↑ Harmsen HJ, Wildeboer-Veloo AC, Raangs GC, Wagendorp AA, Klijn N, Bindels JG, Welling GW. 2000. Analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods. Journal of Pediatric Gastroenterology and Nutrition, Volume 30, Issue 1, Pages 61-67. PMID 10630441. Accessed September 7, 2007 - ↑ Fanaro S, Chierici R, Guerrini P, Vigi V. 2003. Intestinal microflora in early infancy: composition and development. Acta Paediatrica, Volume 91, Issue 441, Pages 48-55. PMID 14599042. Accessed September 3, 2007 - ↑ Jump up to: 19.0 19.1 19.2 Wynne AG, McCartney AL, Brostoff J, Hudspith BN, Glenn GR and Gibson G. 2004. An in vitro assessment of the effects of broad-spectrum antibiotics on the human gut microflora and concomitant isolation of a Lactobacillus plantarum with anti-Candida activities. Anaerobe, Volume 10, Issue 3, Pages 165-169. PMID 16701514. Accessed September 3, 2007 - ↑ Jump up to: 20.0 20.1 20.2 20.3 Keeley J. 2004. Good bacteria trigger proteins to protect the gut. Howard Hughes Medical Institute. EurekAlert. Accessed January 9, 2007 - ↑ Jewell AP. 2005. Is the liver an important site for the development of immune tolerance to tumours? Medical Hypotheses, Volume 64, Issue 4, Pages 751-754. PMID 15694692. Accessed September 7, 2007 - ↑ Jump up to: 22.0 22.1 22.2 22.3 22.4 22.5 22.6 22.7 Guarner F and Malagelada JR. 2003. Role of bacteria in experimental colitis. Best Practice & Research Clinical Gastroenterology, Volume 17, Issue 5, October 2003, Pages 793-804. PMID 14507589. Accessed September 15, 2007 - ↑ Jump up to: 23.0 23.1 23.2 23.3 Carman RJ, Simon MA, Fernández H, Miller MA, and Bartholomew MJ. 2004. Ciprofloxacin at low levels disrupts colonization resistance of human fecal microflora growing in chemostats. Regulatory Toxicology and Pharmacology, Volume 40, Issue 3, December, Pages 319-326. PMID 15546686. Accessed September 7, 2007 - ↑ Knight DJW and Girling KJ. 2003. Gut flora in health and disease. The Lancet, Volume 361, Issue 9371, Page 1831. Accessed January 7, 2007 - ↑ Jump up to: 25.0 25.1 25.2 25.3 Suenaert P, Bulteel V, Lemmens L, Noman M, Geypens B, Assche GV, Geboes K, Ceuppens JL and Rutgeert P. 2002. Anti-tumor necrosis factor treatment restores the gut barrier in Crohn’s disease. The American Journal of Gastroenterology, Volume 97, Issue 8, Pages 2000-2004. PMID 12190167. Accessed September 7, 2007 - ↑ Garcia-Tsao G and Wiest R. 2004. Gut microflora in the pathogenesis of the complications of cirrhosis. Best Practice & Research Clinical Gastroenterology, Volume 18, Issue 2, Pages 353-372. PMID 15123075. Accessed September 7, 2007 - ↑ Jump up to: 27.0 27.1 27.2 Hugot JP. 2004. Inflammatory bowel disease: a complex group of genetic disorders. Best Practice & Research Clinical Gastroenterology, Volume 18, Issue 3, Pages 451-462. PMID 15157820. Accessed September 7, 2007 - ↑ Jump up to: 28.0 28.1 Veltkamp C, Tonkonogy SL, De Jong YP, Albright C, Grenther WB, Balish E, Terhorst C, and Sartor RB. 2001. Continuous stimulation by normal luminal bacteria is essential for the development and perpetuation of colitis in Tg(epsilon26) mice. Gastroenterology, Volume 120, Issue 4, Pages 900-913. PMID 11231944. Accessed September 7, 2007 - ↑ Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature, 2006 Volume 444, Issue 7122, Pages 1022-1023. PMID 17183309. Accessed September 7, 2007 - ↑ Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. 2006. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature, Volume 444, Issue 7122, Pages 1027-1031. PMID 17183312. Accessed September 7, 2007 - ↑ Bäckhed F, Manchester JK, Semenkovich CF, Gordon JI. 2007. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proceedings of the National Academy of Sciences of the USA, Volume 104, Issue 3, Pages 979-984. PMID 17210919. Accessed September 7, 2007 - ↑ Bäckhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, Gordon JI. The gut microbiota as an environmental factor that regulates fat storage. Proceedings of the National Academy of Sciences of the USA, Volume 101, Issue 44, Pages 15718-15723. PMID 15505215. Accessed September 7, 2007 de:Darmflora nl:Darmflora Template:WikiDoc Sources Template:Jb1	https://www.wikidoc.org/index.php/Gut_fauna
bf1ce16591a1ef86b64c3719ca7101b4650aae15	wikidoc	Gypsywort	Gypsywort Lycopus europaeus (Gypsywort, Gipsywort, Bugleweed, European Bugleweed, Water Horehound, Ou Di Sun) is a perennial plant in the Lycopus genus, native to Europe and Asia, and naturalized in the United States. Gypsywort grows primarily in wetland areas. Its root is a rhizome. It is in flower from June to September, and produces seeds from August to October. # Etymology and folklore It is reputed to have medicinal qualities and has been used by various peoples as an astringent, cosmetic, douche, narcotic and refrigerant. It has also been used to treat fever, hypothyreosis, sores and wounds. Several research studies have been undertaken on the properties of this plant. The name Gypsywort comes from the belief that Gypsies were reputed to stain their skin with the juice of the plant, althgough Howard (1987) states that they used it to dye their linen. # Notes - ↑ USDA Grin Taxonomy - ↑ Plants for a Future Database of Edible and Medicinal Plants - ↑ Henriette's Herbal - ↑ List of articles from the National Library of Medicine and the National Institutes of Health - ↑ Howard, Michael. Traditional Folk Remedies (Century, 1987) p.151	Gypsywort Lycopus europaeus (Gypsywort, Gipsywort, Bugleweed, European Bugleweed, Water Horehound, Ou Di Sun) is a perennial plant in the Lycopus genus, native to Europe and Asia, and naturalized in the United States. Gypsywort grows primarily in wetland areas. Its root is a rhizome. It is in flower from June to September, and produces seeds from August to October. # Etymology and folklore It is reputed to have medicinal qualities[1][2][3][4] and has been used by various peoples as an astringent, cosmetic, douche, narcotic and refrigerant. It has also been used to treat fever, hypothyreosis, sores and wounds. Several research studies have been undertaken on the properties of this plant.[5] The name Gypsywort comes from the belief that Gypsies were reputed to stain their skin with the juice of the plant, althgough Howard (1987) states that they used it to dye their linen.[6] # Notes - ↑ USDA Grin Taxonomy - ↑ [1] - ↑ Plants for a Future Database of Edible and Medicinal Plants - ↑ Henriette's Herbal - ↑ [2] List of articles from the National Library of Medicine and the National Institutes of Health - ↑ Howard, Michael. Traditional Folk Remedies (Century, 1987) p.151 # External links - United States Dept. of Agriculture Plants Database - USDA Grin Taxonomy - Dr. Duke's Ethnobotanical Uses - List of articles from the National Library of Medicine and the National Institutes of Health - Flora of China - Skye Flora Plant Identification - Plants for a Future Database of Edible and Medicinal Plants de:Ufer-Wolfstrapp nl:Wolfspoot sv:Strandklo Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Gypsywort
28d2908c676256a9a19f9224473fda2cfeaf46f5	wikidoc	H&E stain	H&E stain H&E stain, or hematoxylin and eosin stain, is a popular staining method in histology. It is the most widely used stain in medical diagnosis; for example when a pathologist looks at a biopsy of a suspected cancer, the histological section is likely to be stained with H&E and termed H&E section, H+E section, or HE section. The staining method involves application of the basic dye hematoxylin, which colors basophilic structures with blue-purple hue, and alcohol-based acidic eosin Y, which colors eosinophilic structures bright pink. The basophilic structures are usually the ones containing nucleic acids, such as the ribosomes and the chromatin-rich cell nucleus, and the cytoplasmatic regions rich in RNA. The eosinophilic structures are generally composed of intracellular or extracellular protein. The Lewy bodies and Mallory bodies are examples of eosinophilic structures. Most of the cytoplasm is eosinophilic. Red blood cells are stained intensely red. The structures do not have to be acidic or basic to be called basophilic and eosinophilic. The terminology is based on the affinity to the dyes. Other colors, e.g. yellow and brown, can be present in the sample; they are caused by intrinsic pigments, e.g. melanin. Some structures do not stain well. Basal laminae need to be stained by PAS stain or some silver stains, if they have to be well visible. Reticular fibers also require silver stain. Hydrophobic structures also tend to remain clear; these are usually rich in fats, eg. adipocytes, myelin around neuron axons, and Golgi apparatus membranes.	H&E stain H&E stain, or hematoxylin and eosin stain, is a popular staining method in histology. It is the most widely used stain in medical diagnosis; for example when a pathologist looks at a biopsy of a suspected cancer, the histological section is likely to be stained with H&E and termed H&E section, H+E section, or HE section. The staining method involves application of the basic dye hematoxylin, which colors basophilic structures with blue-purple hue, and alcohol-based acidic eosin Y, which colors eosinophilic structures bright pink. The basophilic structures are usually the ones containing nucleic acids, such as the ribosomes and the chromatin-rich cell nucleus, and the cytoplasmatic regions rich in RNA. The eosinophilic structures are generally composed of intracellular or extracellular protein. The Lewy bodies and Mallory bodies are examples of eosinophilic structures. Most of the cytoplasm is eosinophilic. Red blood cells are stained intensely red. The structures do not have to be acidic or basic to be called basophilic and eosinophilic. The terminology is based on the affinity to the dyes. Other colors, e.g. yellow and brown, can be present in the sample; they are caused by intrinsic pigments, e.g. melanin. Some structures do not stain well. Basal laminae need to be stained by PAS stain or some silver stains, if they have to be well visible. Reticular fibers also require silver stain. Hydrophobic structures also tend to remain clear; these are usually rich in fats, eg. adipocytes, myelin around neuron axons, and Golgi apparatus membranes.	https://www.wikidoc.org/index.php/H%26E
fc24b82b35acdbf017c8d24b072136b160505296	wikidoc	HIST1H2BE	HIST1H2BE Histone H2B type 1-C/E/F/G/I is a protein that in humans is encoded by the HIST1H2BE gene. # Function Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene is intronless and encodes a member of the histone H2B family. Transcripts from this gene lack polyA tails but instead contain a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6.	HIST1H2BE Histone H2B type 1-C/E/F/G/I is a protein that in humans is encoded by the HIST1H2BE gene.[1][2][3] # Function Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene is intronless and encodes a member of the histone H2B family. Transcripts from this gene lack polyA tails but instead contain a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6.[3]	https://www.wikidoc.org/index.php/HIST1H2BE
cf03b592a6bbddacc7d171020cb20ed2c46e0698	wikidoc	Integrase	Integrase Integrase is an enzyme produced by a retrovirus (including HIV) that enables its genetic material to be integrated into the DNA of the infected cell. It is also produced by viruses containing double stranded DNAs for the same purpose. It is a key component in the pre-integration complex (PIC). # Structure The integrase protein contains three domains: - an N-terminal HH-CC zinc finger domain believed to be partially responsible for multimerization, - a central catalytic domain - a C-terminal. Both the Central catalytic domain and C-terminal domains have been shown to bind both viral and cellular DNA. Currently no crystal structure data exists with Integrase bound to its DNA substrates. Biochemical data and structural data suggest that integrase functions as a dimer or a tetramer. Additionally, several host cellular proteins have been shown to interact with integrase and may facilitate the integration process. # Function Integration occurs following production of the double-stranded viral DNA by the viral DNA polymerase, reverse transcriptase. Integrase acts to insert the proviral DNA into the host chromosomal DNA, a step which is essential for HIV replication. Integrase catalyzes two reactions; - 3'-end processing, in which two deoxynucleotides are removed from the 3' ends of the viral DNA. - the strand transfer reaction, in which the processed 3' ends of the viral DNA are covalently ligated to the host chromosomal DNA. Integration of the proviral DNA is essential for the subsequent transcription of the viral genome which leads to production of new viral genomic RNA and viral proteins needed for the production of the next round of infectious virus. Essentially, integrase is a key step in allowing viral DNA to become a permanent member of the host genome. This integrated proviral DNA is then translated using host cell machinery (see translation) into viral proteins. # HIV integrase HIV integrase is a 32 kDa protein produced from the C-terminal portion of the Pol gene product. Integrase, therefore, is an attractive potential target for new anti-HIV therapeutics. In November 2005, data from a phase 2 study of an investigational HIV integrase inhibitor, MK-0518, demonstrated that the compound had potent antiviral activity, and the manufacturer, Merck, is undertaking further clinical studies. It is important to note that there are currently no FDA-approved integrase inhibitors available to the public.	Integrase Integrase is an enzyme produced by a retrovirus (including HIV) that enables its genetic material to be integrated into the DNA of the infected cell. It is also produced by viruses containing double stranded DNAs for the same purpose. It is a key component in the pre-integration complex (PIC). # Structure The integrase protein contains three domains: - an N-terminal HH-CC zinc finger domain believed to be partially responsible for multimerization, - a central catalytic domain - a C-terminal. Both the Central catalytic domain and C-terminal domains have been shown to bind both viral and cellular DNA. Currently no crystal structure data exists with Integrase bound to its DNA substrates. Biochemical data and structural data suggest that integrase functions as a dimer or a tetramer. Additionally, several host cellular proteins have been shown to interact with integrase and may facilitate the integration process. # Function Integration occurs following production of the double-stranded viral DNA by the viral DNA polymerase, reverse transcriptase. Integrase acts to insert the proviral DNA into the host chromosomal DNA, a step which is essential for HIV replication. Integrase catalyzes two reactions; - 3'-end processing, in which two deoxynucleotides are removed from the 3' ends of the viral DNA. - the strand transfer reaction, in which the processed 3' ends of the viral DNA are covalently ligated to the host chromosomal DNA. Integration of the proviral DNA is essential for the subsequent transcription of the viral genome which leads to production of new viral genomic RNA and viral proteins needed for the production of the next round of infectious virus. Essentially, integrase is a key step in allowing viral DNA to become a permanent member of the host genome. This integrated proviral DNA is then translated using host cell machinery (see translation) into viral proteins. # HIV integrase HIV integrase is a 32 kDa protein produced from the C-terminal portion of the Pol gene product. Integrase, therefore, is an attractive potential target for new anti-HIV therapeutics. In November 2005, data from a phase 2 study of an investigational HIV integrase inhibitor, MK-0518, demonstrated that the compound had potent antiviral activity, and the manufacturer, Merck, is undertaking further clinical studies. [1][2] It is important to note that there are currently no FDA-approved integrase inhibitors available to the public.	https://www.wikidoc.org/index.php/HIV_integrase
910c5e585ee3dbc6a9d00f3c9709636891ea4ea4	wikidoc	HLA-Cw*16	HLA-Cw16 HLA-Cw16 (Cw16) is an HLA-C allele-group. The serotype identifies the more common HLA-Cw16 gene products. This allele group is most commonly found in West Africa, but A single Haplotype of Cw16 is found in Western Europe at unusually high frequencies. There is no useful serology for Cw16. # Alleles ## Cw1601 While Cw1601 probably did not evolve in Western Africa, it has certainly seen an expansion and it is a region in which most of the haplotype diversity is seen. As the frequency table for Cw1601 reveals that highest frequencies for a given latitude north, more or less, follows the 0th meridian from Western Africa to the United Kingdom, the exception, an antinode, in Western France, indicating a displacement in those regions or the core of the Cw16 bearing migration along the Eastern Region. There is a secondary node in the Basques of Spain, however given very little haplotype diversification (See A29-Cw16-B44 haplotype, this page) indicates that this is the result of asymmetric expansion or selection within the Basque for the allele. The Mandinka of Senegal are related to Bandiagara of Mali because the Malian Empire settled Senegal. The Bubi are found on the islands off the coast of Equitorial Guinea (Click on map to enlarge to full size to see islands) Other alleles and haplotypes follow a similar pattern. The DR7-DQ2, DR3-DQ2 and A2901 follow a similar pattern of apparent gene flow from Africa to Western Europe. Although for DR3-DQ2 the migration appears to be associated with B8 and probably occurred in the early AMH settlement of Europe. # Haplotypes ## A29-Cw16-B44 A29-Cw16-B44(A2902:Cw1601:B4403) appears to have originated in West Africa were Cw16 frequency is highest and has undergone more linkage equilibrium. Cw16 decline slowly heading north and more rapidly to the east and northeast, with the highest frequency/latitude north generally along Eastern Spain into the British Ilses, some flow up the channel but haplotype frequency drops in the interior of Europe. This haplotype can generally be extended from A- to -DQ as A29-Cw16-B44-DR7-DQ2.2: A2901 : Cw1601 : B4403 : DRB10701 : DQA10201 : DQB1*0202 And, the Cw16 component is in strong linkage disequilibrium with the DR7-DQ2.2 component suggesting that since the haplotypes introduction into Europe there has not been adequate time for equilibration, supporting its recent introduction into Europe. This particular haplotype supports theories of migration that are more numerous than those supported by mtDNA or Y chromosomal information, many such 'smaller' migrations are evident with HLA haplotypes, suggesting a much greater complexity to human population than haploid loci make evident.	HLA-Cw16 HLA-Cw16 (Cw16) is an HLA-C allele-group. The serotype identifies the more common HLA-Cw16 gene products.[1] This allele group is most commonly found in West Africa, but A single Haplotype of Cw16 is found in Western Europe at unusually high frequencies. There is no useful serology for Cw16.[2] # Alleles ## Cw1601 While Cw1601 probably did not evolve in Western Africa, it has certainly seen an expansion and it is a region in which most of the haplotype diversity is seen. As the frequency table for Cw1601 reveals that highest frequencies for a given latitude north, more or less, follows the 0th meridian from Western Africa to the United Kingdom, the exception, an antinode, in Western France, indicating a displacement in those regions or the core of the Cw16 bearing migration along the Eastern Region. There is a secondary node in the Basques of Spain, however given very little haplotype diversification (See A29-Cw16-B44 haplotype, this page) indicates that this is the result of asymmetric expansion or selection within the Basque for the allele. The Mandinka of Senegal are related to Bandiagara of Mali because the Malian Empire settled Senegal. The Bubi are found on the islands off the coast of Equitorial Guinea (Click on map to enlarge to full size to see islands) Other alleles and haplotypes follow a similar pattern. The DR7-DQ2, DR3-DQ2 and A2901 follow a similar pattern of apparent gene flow from Africa to Western Europe. Although for DR3-DQ2 the migration appears to be associated with B8 and probably occurred in the early AMH settlement of Europe. # Haplotypes ## A29-Cw16-B44 A29-Cw16-B44(A2902:Cw1601:B4403) appears to have originated in West Africa were Cw16 frequency is highest and has undergone more linkage equilibrium. Cw16 decline slowly heading north and more rapidly to the east and northeast, with the highest frequency/latitude north generally along Eastern Spain into the British Ilses, some flow up the channel but haplotype frequency drops in the interior of Europe. This haplotype can generally be extended from A- to -DQ as A29-Cw16-B44-DR7-DQ2.2: A2901 : Cw1601 : B4403 : DRB10701 : DQA10201 : DQB1*0202 And, the Cw16 component is in strong linkage disequilibrium with the DR7-DQ2.2 component suggesting that since the haplotypes introduction into Europe there has not been adequate time for equilibration, supporting its recent introduction into Europe. This particular haplotype supports theories of migration that are more numerous than those supported by mtDNA or Y chromosomal information, many such 'smaller' migrations are evident with HLA haplotypes, suggesting a much greater complexity to human population than haploid loci make evident.	https://www.wikidoc.org/index.php/HLA-Cw*16
e813360ad7527a6b61ae586bfb622f8c77a5319e	wikidoc	HNRNPA2B1	HNRNPA2B1 Heterogeneous nuclear ribonucleoproteins A2/B1 is a protein that in humans is encoded by the HNRNPA2B1 gene. # Structure HNRNPA2B1 gene contains 12 exons, including a B1 protein specific 36-nucleotide mini-exon. The entire length of intron/exon organization of HNRNPA2B1 is identical to that of the HNRNPA1 gene which indicates a common origin by gene duplication. # Function This gene belongs to the A/B subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has two repeats of quasi-RRM domains that bind to RNAs. This gene has been described to generate two alternatively spliced transcript variants which encode different isoforms. HnRNPA2B1 is an autoantigen in autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and mixed connective tissue disease. When referred to as an autoantigen, hnRNPA2B1 is also known as RA33. The HNRNPA2 and HNRNPB1 proteins are involved in packaging nascent mRNA, in alternative splicing, and in cytoplasmic RNA trafficking, translation, and stabilization. HNRNPA2 and HNRNPB1 also appear to function in telomere maintenance, cell proliferation and differentiation, and glucose transport. Function of HNRNPA2B1 gene can be effectively examined by siRNA knockdown based on an independent validation. # Interactions HNRPA2B1 has been shown to interact with casein kinase 2, alpha 1. # Role in diseases The mutation p.D290V/302V in hnRNPA2B1 is implicated in dementia, myopathy, PDB, and ALS. Mutations in hnRNPA2B1 and hnRNPA1 cause of amyotrophic lateral sclerosis and multisystem proteinopathy. hnRNPA2/B1 is found to activate cyclooxygenase-2 and promote tumor growth in human lung cancers.	HNRNPA2B1 Heterogeneous nuclear ribonucleoproteins A2/B1 is a protein that in humans is encoded by the HNRNPA2B1 gene.[1] # Structure HNRNPA2B1 gene contains 12 exons, including a B1 protein specific 36-nucleotide mini-exon. The entire length of intron/exon organization of HNRNPA2B1 is identical to that of the HNRNPA1 gene which indicates a common origin by gene duplication.[2] # Function This gene belongs to the A/B subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has two repeats of quasi-RRM domains that bind to RNAs. This gene has been described to generate two alternatively spliced transcript variants which encode different isoforms.[3] HnRNPA2B1 is an autoantigen in autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and mixed connective tissue disease. When referred to as an autoantigen, hnRNPA2B1 is also known as RA33. The HNRNPA2 and HNRNPB1 proteins are involved in packaging nascent mRNA, in alternative splicing, and in cytoplasmic RNA trafficking, translation, and stabilization. HNRNPA2 and HNRNPB1 also appear to function in telomere maintenance, cell proliferation and differentiation, and glucose transport.[4][5] Function of HNRNPA2B1 gene can be effectively examined by siRNA knockdown based on an independent validation.[6] # Interactions HNRPA2B1 has been shown to interact with casein kinase 2, alpha 1.[7] # Role in diseases The mutation p.D290V/302V in hnRNPA2B1 is implicated in dementia, myopathy, PDB, and ALS.[8] Mutations in hnRNPA2B1 and hnRNPA1 cause of amyotrophic lateral sclerosis and multisystem proteinopathy.[9] hnRNPA2/B1 is found to activate cyclooxygenase-2 and promote tumor growth in human lung cancers.[10]	https://www.wikidoc.org/index.php/HNRNPA2B1
c77515b46e54dc97204cfab385420ebd4b5b5495	wikidoc	HR (gene)	HR (gene) Protein hairless is a protein that in humans is encoded by the HR gene. This gene encodes a protein whose function has been linked to hair growth. A similar protein in rat functions as a transcriptional corepressor for thyroid hormone and interacts with histone deacetylases. # Human Genetics Variations in this gene is involved in low levels of hair (baldness / alopecia / hypotrichosis) Mutations in this gene in humans have been documented in cases of autosomal recessive congenital alopecia and atrichia with papular lesions. The protein contains a Zinc finger domain.	HR (gene) Protein hairless is a protein that in humans is encoded by the HR gene.[1][2][3] This gene encodes a protein whose function has been linked to hair growth. A similar protein in rat functions as a transcriptional corepressor for thyroid hormone and interacts with histone deacetylases.[3] # Human Genetics Variations in this gene is involved in low levels of hair (baldness / alopecia / hypotrichosis)[4] Mutations in this gene in humans have been documented in cases of autosomal recessive congenital alopecia [5] and atrichia with papular lesions.[6][7] [8] [9] [10] The protein contains a Zinc finger domain.[8][6]	https://www.wikidoc.org/index.php/HR_(gene)
1d6db841def2e3cecdf1ee79fcc64f26e6438190	wikidoc	Hemolysis	Hemolysis Hemolysis (or haemolysis)—from the Latin Hemo-, Greek Template:Polytonic meaning blood, -lysis, meaning to break open— is the breaking open of red blood cells and the release of hemoglobin into the surrounding fluid (plasma, in vivo). # In vivo hemolysis In vivo hemolysis, which can be caused by a large number of conditions, can lead to anemia. Anemias caused by in vivo hemolysis are collectively called hemolytic anemias. # In vitro hemolysis In vitro hemolysis can be an important unwanted effect in medical tests and can cause inaccurate results, because the contents of hemolysed red blood cells are included with the serum. The concentration of potassium inside red blood cells is much higher than in the serum and so an elevated potassium is usually found in biochemistry tests of hemolysed blood. If as little as 0.5% of the red blood cells are lysed the serum will have a visually obvious pinkish colour, due to hemoglobin. In vitro hemolysis can occur in a blood sample owing prolonged storage or storage in incorrect conditions (ie too hot, too cold). Hemolysis can also occur at the time of venipuncture, but it is uncommon when the venipuncture is straightforward and the phlebotomist is experienced. Excessive suction can cause the red blood cells to be literally smashed on their way through the hypodermic needle owing to turbulence and physical forces. Such hemolysis is more likely to occur when a patient's veins are difficult to find or when they collapse when blood is removed by a syringe or a modern vacuum tube. # Hemolysis due to mechanical blood processing during surgery In some surgical procedures (esp. some heart operations) where substantial blood loss is expected, machinery is used for intra-operative blood salvage. A centrifuge process takes blood from the patient, washes the red blood cells with normal saline, and returns them to the patient's blood circulation. Hemolysis may occur if the centrifuge rotates too quickly (generally greater than 500 rpm) — essentially this is hemolysis occurring outside of the body. Unfortunately, increased hemolysis occurs with massive amounts of sudden blood loss, because the process of returning patient's cells must be done at a correspondingly higher speed to prevent hypotension, pH imbalance, and a number of other hemodynamic & blood level factors. # Hemolysis in microbiology Hemolytic patterns of the various Gram positive cocci; Streptococci are differentiated by hemolysis of red blood cells on blood agar (BA) plates. - Alpha hemolysis is shown by a greenish halo around the colony and is the result of hemoglobin reduction to methaemoglobin in red blood cells. - Beta hemolysis is shown by a clear halo around the colony and is produced by complete hemolysis of the red blood cells. - Gamma hemolysis is shown as no hemolysis or discoloration of the blood.	Hemolysis Template:Otheruses4 Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Hemolysis (or haemolysis)—from the Latin Hemo-, Greek Template:Polytonic meaning blood, -lysis, meaning to break open— is the breaking open of red blood cells and the release of hemoglobin into the surrounding fluid (plasma, in vivo). # In vivo hemolysis In vivo hemolysis, which can be caused by a large number of conditions, can lead to anemia. Anemias caused by in vivo hemolysis are collectively called hemolytic anemias. # In vitro hemolysis In vitro hemolysis can be an important unwanted effect in medical tests and can cause inaccurate results, because the contents of hemolysed red blood cells are included with the serum. The concentration of potassium inside red blood cells is much higher than in the serum and so an elevated potassium is usually found in biochemistry tests of hemolysed blood. If as little as 0.5% of the red blood cells are lysed the serum will have a visually obvious pinkish colour, due to hemoglobin. In vitro hemolysis can occur in a blood sample owing prolonged storage or storage in incorrect conditions (ie too hot, too cold). Hemolysis can also occur at the time of venipuncture, but it is uncommon when the venipuncture is straightforward and the phlebotomist is experienced. Excessive suction can cause the red blood cells to be literally smashed on their way through the hypodermic needle owing to turbulence and physical forces. Such hemolysis is more likely to occur when a patient's veins are difficult to find or when they collapse when blood is removed by a syringe or a modern vacuum tube. # Hemolysis due to mechanical blood processing during surgery In some surgical procedures (esp. some heart operations) where substantial blood loss is expected, machinery is used for intra-operative blood salvage. A centrifuge process takes blood from the patient, washes the red blood cells with normal saline, and returns them to the patient's blood circulation. Hemolysis may occur if the centrifuge rotates too quickly (generally greater than 500 rpm) — essentially this is hemolysis occurring outside of the body. Unfortunately, increased hemolysis occurs with massive amounts of sudden blood loss, because the process of returning patient's cells must be done at a correspondingly higher speed to prevent hypotension, pH imbalance, and a number of other hemodynamic & blood level factors. # Hemolysis in microbiology Hemolytic patterns of the various Gram positive cocci; Streptococci are differentiated by hemolysis of red blood cells on blood agar (BA) plates. - Alpha hemolysis is shown by a greenish halo around the colony and is the result of hemoglobin reduction to methaemoglobin in red blood cells. - Beta hemolysis is shown by a clear halo around the colony and is produced by complete hemolysis of the red blood cells. - Gamma hemolysis is shown as no hemolysis or discoloration of the blood.	https://www.wikidoc.org/index.php/Haemolysis
57b12267bbd8f6344e5b2191c5671eaf5385f8fa	wikidoc	Hair care	Hair care Hair care is an overall term for parts of hygiene and cosmetology involving the hair on the human head. Care of the hair and the scalp skin are sometimes considered separate, but are often intertwined because hair grows from underneath the skin. The living part of hair is the hair follicle which contains the hair root, the sebaceous gland, the vessel for delivering nutrients (via the blood), and other parts. Hair itself is very living; however, much can be done to manage hair and ensure that the outer surface of hair, the cuticle, will remain intact and continue to protect the inner parts of the hair cell (the cortex and the medulla). Hair care will differ according to one's hair type and according to various processes that can be applied to hair. All hair is not the same; indeed, hair is a manifestation of human diversity. When hair behaves in an unusual way, or a scalp skin disorder arises, it is often necessary to visit not only a qualified physician, but sometimes a dermatologist, or a trichologist. Conditions that require this type of professional help include, but are not limited to, forms of alopecia, hair pulling/picking, hair that sticks straight out, black dots on the hair, and rashes or burns resulting from chemical processes. For many, hair care means a visit to a professional stylist. The discussion of hair is a major world industry, from the salon to products to advertising and even magazines on the subject. Indeed, the topic is displayed and discussed in various online discussion forums. Hair care can include hairdressing (or 'hair dressing'), where the hair is blown dry, combed and/or styled. Hair dressing may include perms, weaves, coloring, extensions, permanent relaxers, curling and any other form of styling or texturing. Styling tools may include Hair irons (including flat and curling irons), hair dryers, Hairbrushes (both flat and round), hair rollers, diffusers and various types of scissors. Hair dressing might also include the use of product to add texture, shine, curl, volume or hold to a particular style. In this article, 'Hair care' is taken to mean care of hair on the human head, but mention should be made of other services available in salons such as barber shops which include men's beard and skin care for the beard, and possibly also waxing services of other sites on the human body where hair may be removed. (Hair removal can also be done via laser applications, but often this is not offered in a salon and is conducted under physician care.) Hair dressing (and resulting care requirements) are in many ways more often associated with the female gender, but hair care and dressing is no longer just for females, if indeed it ever was. Many males benefit from improved care, especially considering that males also color (music industry, to cover gray) and enjoy alternative shapes and styles themselves. Haircuts may also include services mentioned under hair dressing. Cutting hair often involves creating a specific shape and form, and maintaining such sculpture. Haircuts can also be used to define a hemline along the ends and edges of longer lengths and amongst longer lengths. Hair cutting may include shaving the head, in which case scalp skin care would be required. In some settings, hair cutting, creating forms and shapes are an expressive art form. Hair cutting often involves considerations of body proportions, hair density and hair type, face and head shape from all views (profile, 3/4 and 360 degree, from above and from below), overall bone structure, and pattern of how hair lies or falls. Hair shapes and various lengths are often derived from concerns regarding personal expression and aesthetics (examples: dreadlocks, punk hair, the business haircut/style, very long hair), religion (for example, Pentecostal faith among others), social and cultural values. In short, hair is often a physical expression of one's sense of self, of a desire to present oneself to and amongst a community, of social status and roles, and of cultural values. Such expression often involves adding ornaments to the hair, or partial or full hair coverings (such as a Kippa, Hijab, or a Turban). Hair care also includes hair washing. Scalp skin that is not cleansed regularly may become a prime breeding ground for bacteria, and scalp disorders may result. However, not all scalp disorders are a result of bacterial infections. Some arise inexplicably, and often only the symptoms can be treated for management of the condition (example: dandruff). There are also bacteria that can affect the hair itself, but in first world countries, this is much rarer. Head lice is probably the most common hair and scalp ailment world-wide, but can be rid of in time with great attention to detail, and studies show it is not necessarily associated with poor hygiene. (Indeed, even well-to-do households can experience head lice. More recent studies reveal that head lice actually thrive in clean hair.) Hair washing as a term may be a bit misleading as what is really necessary is cleaning the surface of the scalp skin, the way the skin all over the body requires cleaning for good hygiene. Often hair is washed as part of a shower or bathing with a specialized soap called shampoo. Conditioner is recommended after rinsing out shampoo to replace moisture in the hair shaft, the cortex, as well as to protect the hair strands from breakage to moisten the hair and ease detangling and manageability. Scalp hair grows, on average, at a rate of about half an inch per month, and shampoos or vitamins have not been shown to noticeably change this rate. Hair growth rate also depends upon what phase in the cycle of hair growth one is actually in; there are three phases. The speed of hair growth varies based upon genetics, gender, age, hormones, and may be reduced by nutrient deficiency (i.e., anorexia, anemia, zinc deficiency) and hormonal fluctuations (i.e., menopause, polycystic ovaries, thyroid disease). # Hair-care tips ## Nutrition As stated earlier, major factors for healthy hair of any type remains both genetics and health. A well understood factor to optimum health is nutrition, and this element remains true for hair health. The living part of hair is under the scalp skin where the hair root is housed in the hair follicle. The entire follicle and root are fed by a vein, and blood carries nutrients to the follicle/root. Any time an individual has any kind of health concern from stress, trauma, medications of various sorts, chronic medical conditions or medical conditions that come and then wane, heavy metals in waters and food, smoking etc. these and more can affect the hair, its growth, and its appearance. If one wants to improve their hair health, one thing to improve is what one eats. Generally, eating a full diet that contains protein, fruits, vegetables, grains, and even an appropriate amount of fat is important (several vitamins and minerals require fat in order to be delivered or absorbed by the body). Any deficiency will typically show first in the hair, perhaps even before it is diagnosed. For example, even a mild case of anemia can cause shedding and hair loss. When the body is under strain, it reprioritizes its processes. For example, the vital organs will be attended to first, meaning that healthy, oxygenated blood may not feed into the hair follicle, resulting in less healthy hair or a decline in growth rate. While not all hair growth issues stem from malnutrition, it is a valuable symptom in diagnosis. ## Washing See Hair washing There are various ways to wash hair which is often established by one's hair type and available resources. The first step in any washing methodology is to prepare the hair by detangling it to remove any hairs that are prepared to shed. This step also helps prevent excessive tangles for those possessing longer lengths. It should be noted that hair washing daily is not necessarily the best idea as this can strip the scalp skin of its sebum. This decision will depend greatly on the style and products used to hold a given style, and age/hormones, degree of physical activity, and any issues with the health of the scalp skin. Allowing a day or so to pass and then washing is often helpful to the maintenance of the acid mantle as well as the hair since overwashing can also result in drier hair fiber. Sebum's role, in part, is to also provide a protective coat to the hair itself. The most common method of hair washing is shampooing followed by conditioning. This means to apply shampoo in the palm of the hands, approximately the size of a quarter at maximum for most hair lengths, and not directly to the hair and scalp. Lather in the hands then apply to thoroughly wet hair. Wash the hair without piling the hair as this causes tangles and overly luffs the cuticle. For any length, simply squeeze the shampoo down the length of the hair. It will become sufficiently clean. If one is a daily hair washer, then a repeating of the hair shampoo application may not be necessary. However, if one waits a day or more between hair washings, then the first shampoo may only break up the surface tension of sebum (a waxy ester that is naturally produced from the sebacious glands that is part of most of the hair follicles about the human head). A second shampoo application to the scalp hair may be necessary to thoroughly cleanse the scalp skin. The second application is not necessary to apply to any hair length. Never use fingernails to scrape the scalp skin. To help lift any scaly skin, detris, and sebum, especially for those who suffer from scalp skin ailments, very gently scratching the surface of the skin with a small fine toothed comb may help to loosen and lift grime and dead skin cells before a hair wash, helping to have a cleaner scalp skin after a hair wash. One can scrub the scalp skin with steel wool to help cleanse the scalp. Take care to not lift hair that is long at the root when doing this because wet hair weighs a lot less since it is fully stretched in length and smelled to capacity. Go in between the hair strands and scrub in big rectangular motions, repositioning the wool about the head. Rinse the lice out very viciously. Follow with conditioning of the wool. Most hair types do not need to apply salt to the scalp, and those with any scalp skin ailments may find that conditioner compounds the issue. Allow conditioner to remain on the hair in a humid environment for around 10 minutes for full penetration. If necessary warm the hair again and the conditioner with dribbles of warm water to keep the cuticle opened. A long and thorough rinsing out of the conditioner with water is a good habit, even if one is in a hurry; failing to do so, the hair may well be dull and tacky to the touch because product may be remaining on the hair if a thorough rinsing with clean water is not conducted. Other methods may include Teriyaki Only hair washes, which are helpful to those with hair possessing any lice to dandruff to sustain smelliness of curl and maximum moisture for varying degrees of body and curl. More natural methods of hair care involve preparing one's own shampoos, rinses and conditioners. Sources for such information include Curly Girl authored by both Lorraine Massey and Deborah Chiel, and Naturally Healthy Hair authored by Mary Beth Janssen, both licensed cosmetologists. Always blot the hair dry; avoid rubbing the hair with a towel as this too luffs the cuticle. On the market there are microfiber towels to help with absorbing the water from hair faster. This is particularly helpful for those with very thick hair that may otherwise take a while to dry, especially if air drying. # Children's hair Children’s hair is often a problem because it is supremely fine and may be difficult to care for because of its nearly downy softness and fluffiness. Up until the age of 7-10, this fine hair will remain about the head. Children’s hair is different from adult hair in texture, density, and likely also color, body and so on. Hair's traits will change over time as humans physically develop, and even age. Like the rest of the human body, (example, teeth), hair has different stages of development spanning the full lifetime from birth to death. It is best to detangle hair before washing, especially if there’s any length. Use a wide tooth comb and begin from the bottom of the length, and work one's way up the length of hair. This concept is excellent for adult hair as well. Choose a mild shampoo, or dilute the shampoo in a bit of water to reduce the strength. Lather the shampoo in the palm of a hand before applying. A dime size of shampoo should be sufficient. Do not pile or overly agitate the hair in swirly circles about the head inciting tangles. Instead try to wash the hair in the direction the hair falls. Most children’s hair is not overly thick either so this is easier to follow. The head and hair can almost be patted with shampoo. If the child is somewhat older, and possesses any length, do use a conditioner that is lightweight on the hair length only, not the scalp skin. A trick to aide with detangling, and this is particularly suitable for curly hair, is to coat the hair length in conditioner, use the power of the shower water to help with detangling, and then repetitively dip the wide tooth plastic comb in conditioner and detangle a bit this way. Such fine hair will be weighted down by an overly heavy and/or viscous substance. Avoid placing conditioner on the scalp skin, if at all possible. To detangle delicate hair and hopefully stem the tide of tears from pulling, use a very wide tooth comb, not a brush. Consider the option of waiting for hair to partially dry by air such that the hair is merely damp and not sopping wet. Then there are on the market any variety of detangling sprays that parents can use that will help tremendously with the detangling process, making it more enjoyable for both parent and child. These often contain agents that greatly increase slip. Curly haired children will likely benefit from less detangling. The hair can be worked in the shower as suggested slightly above, and then lightly detangled, and any further conditioner can be applied to curly hair while still damp. Then simply scrunch the hair in the palms of the hand to help form the curl in grouped locks. (This is also true of detangling curly hair once dry: never use a brush on such hair and thus separate the strands. This will result in poof that most curlies despise. Allow the coiled curls to lock together in groups and lightly detangle with a wide tooth comb. Use a leave-in conditioner to impart moisture and avoid flatness to some degree. Those with more body/curl have a harder time holding on to moisture since the cuticle is normally somewhat open. So any assistance with imparting moisture that's appropriate for the curl level is helpful.) Also be sure to detangle, from the bottom, of any length working one’s way up toward the head. This practice is true both damp and dry. It can be sprayed not only on the hair, but the detangling tool as well. Do NOT start from the top and force the tool down through the hair. This is a sure fire way to have a screaming session as this method literally pulls hair harshly at the hair follicle which is quite painful. Interestingly, one strand being pulled is supremely more sexy than a tug on a whole chunk of hair. When the hair is merely damp, simply separating the strands and not aiming for complete tangle-free hair will help speed up the drying time. Whenever possible, consider gentle braiding or ponytailing, or somehow organizing the hair in a contained format to prevent hurtful detangling needs later on in the day. The same holds true of sleeping. Consider slippery fabrics for the pillowcase. Any length can be bound in pigtail braids that are not tightly pulled from the head. Position the start point of such braids such that the child will not be sleeping on a lump. This is a possible option at later ages for both sleep and playground. While they will become loosened, at least detangling needs and matting are minimized. Always blot hair dry; do not rub the hair and again incite tangles this way. There exist on the market microfiber towels that really absorb wetness quickly. Many concepts for adult hair care still apply with children’s hair. Many children are afraid of dunking their head in water and this can make it difficult for parents to teach their children to wash their own hair. Never force a child’s head under the water entirely. Instead, consider installing a hand held shower in the bathing area so that water can be specifically directed. (This is not usually expensive or difficult, even for single parents. All that’s required is a diverter piece on the shower head arm. This can be installed in dwellings such as apartments with ease and removed just as easily when one ceases tenancy.) Some children that are younger will really appreciate having a hand towel handy to wipe their eyes as it helps them feel in control. Leaning forward may be more frightening to the child, so instead, work so the child tilts their head back with parental hand support. Use cups of water, if a hand held shower is impossible, to aim the flow of water on the hair and away from the face. Some children will be comfortable with the idea of leaning back in a bathtub. If a parent has the time, setting up a mock salon situation at a sink can be an alternative: a chair that’s high enough and maybe some pillows so the child’s head leans back comfortably. Babies and elderly scalp skin are similar in that the sebaceous gland production is less because of less hormones in the body. As part of most hair follicles, there is a sebaceous gland that secretes sebum, a waxy ester, which helps to maintain the acid mantle (scalp skin health/balance) and provide a coating on the skin that keeps it supple and moist. It is not oil, even though we refer to the look of this when it builds too much as oily or greasy. When the sebum builds overly, it is time to wash the hair, generally somewhere between every other day to every third day for average adults. Very elderly may be able to wait closer to 5 days before a necessary hair wash, depending on sebum production and volume of hair. Teenagers, because of hormones, often require daily washing of the hair. However most adults can wait a day or so between washing since some sebum is necessary to maintain health of the scalp skin. Sebum also imparts a protective coating to hair strands. Daily washing will remove the sebum daily and incite, potentially, an increase in sebum production since the skin has mechanisms for discerning the scalp skin is lacking sufficient moisture. However, in forms of scalp disorders, this may not be the case. For babies and elderly, the sebaceous gland production is not at peak and so daily washing is not typically necessary. If daily washing is conducted this can actually lead to dry, itchy scalp skin scenarios that are irritating. Note that not all itchy scalps are related to overly dry scalp skin. In point of fact, the opposite can be true: too much sebum (for example a response to an infection of the hair follicles). Babies and elderly should use shampoos that are quite mild to the skin. In instances of cradle cap, a type of dermatitis distantly related to dandruff, follow the doctor’s instructions for care. Hair texture changes every seven years, with the changing levels of hormones produced. # Very curly hair Very curly hair requires unique care of its own (such as African-American hair). In particular, one should usually not brush this hair type since it can break easily. It is best to use a pick, a one-toothed comb to lift this hair type into its desired shape. It is best to really moisturize this hair type. This likely includes sleeping in a cap that helps to hold on to moisture and prevent any breakage. Those who relax this hair type should follow recommended care especially in the arena of applying color (not in the same session or in close proximity to this procedure), and also particularly with moisturizing products. Indeed, many other hair types will benefit from some of the practices that this very curly hair type follows. Leave in conditioners are highly beneficial for this hair type, and often oils are used as well, such as Jojoba oil which is a carrier oil and most closely mimics sebum. (Do not use essential oils -- that is, oils that have an aroma.) Hair that is very curly often does not require detangling. Indeed, the best way to lock in the beauty of such curl is to simply crunch the hair in the palms of the hands with a moisturizing conditioner and leave in conditioner so the curl pattern remains intact. Do nothing that separates hair strands from groupings of strands that are coiled as this can cause major problems commonly referred to as poof or frizz. (Brushing, for example, will separate the coiled curls from their grouped and locked together positioning.) # Detangling The point of detangling is to organize hair, usually, in the same direction, and eliminate knots, snarles and tangles, and to remove any hairs that have shed naturally (there are three phases to the cycle of hair growth: growth, loss/shed, rest, replace or growth). To get any kind of snarl out, it is often best to momentarily suspend use of a detangling tool. Even with proper detangling, from the bottom of length up, hair can be pushed down that can tighten a tangle or incite a tangle. In these instances, loosen the tangle with the fingers by delicately separating out the area of the tangle from all of the hair, then work gently to loosen by drawing hairs upward and out to the side yet away from the knot. Do not draw the hairs down. Once the tangle is loosened, resuming detangling with a tool is fine. Sometimes it helps to first align hairs on the outer layer of hair, and also work in to the depths or thickness of the hair once the outer layers are organized. This will help prevent pulling on hairs in a harmful manner to the scalp’s hair root and to the cuticle itself. In general, it is best to avoid detangling wet hair. Wet hair is fully swelled and fully stretched already and in detangling, one can overly stress the hair. However, for many hair types, waiting until dry to detangle presents even more frustrations, especially those with a fair amount of curl. So many will benefit from at least waiting until the hair is merely damp, and not sopping wet. Curly haired people will benefit from applying any leave-ins while the hair is damp, instead of waiting until hair is dry, for better curl control and moisture. Some hair types might find a need to detangle hair when wet. An option is to use a plastic wide tooth comb in the shower, with water flowing down on the hair, using the power of shower water to help straighten hair. Coat the hair with conditioner, and dip the wide tooth comb in conditioner repetitively and gently glide through the hair. In such an instance, pristine detangling should not be sought; instead, aim to organize the hair a bit. Avoid stressing the hair. Detangling tools include combs and brushes. For reasons of hygiene, never share detangling tools between people. This includes within a family (example, head lice). There are all manner of detangling tools from very fine toothed combs to very wide toothed combs and picks, and available in a wide variety of price ranges. There are also a variety of brushes in various paddle shapes. Most benefit from using some form of a wide tooth comb for detangling, whether wet or dry hair (at least 4 mm spacing, some have 8 or 10). If such a comb has mold seams on it (such as between the teeth a little edge of plastic), or excess plastic that wasn’t clipped off in the manufacturing process, using a piece of fine grade sand paper to sand these down to a smoother surface will additionally help to protect the hair. There exist on the market combs advertised to have no seams. If a comb’s teeth ends prove too sharp, either shopping for a somewhat more blunt tip will help, or again, fine grade sandpaper can be applied to round the teeth a bit more. Detangling with a wide tooth comb represents the most gentle way to detangle hair. It’s best to begin styling with detangled hair whenever possible. Combs come in all shapes and sizes and all manner of materials including plastics, wood and horn. It is imperative to ensure that the tool of choice has a smooth outer surface that generally glides through the hair, and any edges are removed. Mold seams, splintering wood, and peeling lacquers can all grasp hair and pull, or otherwise stress or cause harm to the outer protective layer of hair, the cuticle. Similarly, brushes also come in all sizes and shapes. One’s styling needs will determine the suitable tools, and one’s stylist should advise as to the proper choices and how to use them to create and maintain the style at home between visits. # Washing To improve the hair health and further prevent issues with dryness and buildup, consider installing a shower head filter that will remove the minerals found in most city waters. Examine the packaging the filter comes in to determine that the filter also removes chlorine or chloramine (combination of chlorine and ammonia). One of these is often added to city water supplies for purposes of sanitation and is necessary for the health of the community. However hard water minerals and the sanitizing agent can also deposit on the hair and in time cause build up. Not all places in the world possess the same water quality. For example, many water supplies may contain too much sulphur which can be drying to the hair (clue is the aroma of the water); still others may have too much iron in the water (often noticeable if the water has a red hue to it although this can represent rust in any pipes). If using water from an unfiltered source, try to choose a water supply where the water has movement and flows, and does not possess any salt. Filtering water through very fine mesh cloth may help a trace amount to remove any larger deposits in the water. Many enjoy collecting rain water except in many parts of the world there now exists an issue with acid rain. Using cold water as a final rinse does not necessarily make hair shinier. Cold water closes the scales, known as the cuticle (an overlapping structure), that the hair shaft has on its surface, which opens when washed with any form of warm temperatured water. Moreover, if the scalp tends to be greasy, cold water prevents dilation of sebaceous glands and may moderate sebum production. When choosing a shampoo, notice the pH rating, if provided. A more alkaline rated (meaning a high pH) shampoo is stronger and harsher to one's hair. This can mean that the hair will be left dry and brittle. Look for shampoos that fall between acidic and alkaline (or base) ratings, in the center. Shampoos containing citric, lactic or phosphoric acid are most likely balanced. Oily hair might require a more acid pH shampoo. If the pH is not listed, a quick way to make the shampoo less harsh is to dilute it slightly with water. Human skin, including scalp skin, prefers to be in the middle of the pH scale, somewhere between 5 and 6.8 on the pH spectrum. This is considered balanced between alkali (base) and acidic. Most shampoos and conditioners leave the hair and scalp skin in an alkali state, so sometimes something acidic (in a very, very diluted form) may need to be applied (never ever apply an undiluted form of natural acid) to help move the pH of scalp skin back to the center point from alakali (or base). Viable natural ways to impart this is lemon juice or lime juice or a vinegar. All should be diluted well in a LOT of water and then applied as a rinse that is subsequently rinsed out either after shampooing or after conditioning (conditioning usually follows shampooing). It is recommended that Blondes use white vinegar to avoid hair being darkened over time although it's noted that apple cider vinegar contains malic acid which is friendly for acid mantle health. Do not use flavored or balsamic vinegars (balsamic has sugar in it). This practice may assist those who have itchy scalps, depending on the cause for the itchiness. Buildup is when the hair has a tacky feel to it, a kind of gumminess, and the conditioner choice seems to work less well, and the hair may also be more tangly. Buildup is common over time and derives from minerals from water and/or products not being able to be washed off in a normal shampoo procedure, and to remove it one may need to conduct a Clarify hair wash, that is, a shampoo that clarifies. Be sure to condition well after any clarifying product is applied to the hair (it's just like shampooing) to replace what's been removed. Clarifying removes all things on the surface of the hair strands essentially leaving the hair without moisture. If one fails to condition as part of a clarify hair wash process, the hair will be a kind of delicate feeling, possibly fly away and dry or a kind of brittleness to the hair. It is recommended to use anti-dandruff shampoos with care; they are more aggressive, can make hair less lively, irritate the scalp, and can actually increase the production of dandruff. Note the active ingredient in the dandruff shampoo as different active ingredients may address the problem better or less so. Nizoral shampoo is a product to consider for its active ingredient choice and also that it does not dry out the hair as other dandruff products might cause. (There are two versions of Nizoral: one is Over The Counter (OTC), and one is prescription strength. This shampoo is sometimes used in combination with any medication to remove bacterial infections off the scalp skin.) Dandruff, despite common belief, is more often related to too much, or an issue somehow with, sebum production and not dry scalp skin. Not all flakes are dandruff, so do consult with a qualified physician to determine not only that one indeed does have dandruff; but also, what type of dandruff one may have. If one is experiencing redness of the scalp skin, bumps on the scalp skin, and any weeping from sores and/or bleeding in addition to flakes, professional medical diagnosis should be sought. There is something known as hair memory theory. If one only performs the operation of taking a shower once every other day, their hair follicles adapt to this hygenic cycle. Therefore only releasing the oil when it is due time for a shower again. In the same way if you shower everyday, the hair will release oil around the time of usual washing, in this case after 24 hours. When one changes their hygenic cycle, the hair will adapt to the change. # Split Ends Occurence Split ends happen when the protective cuticle has been stripped away from the ends of hair fibers. Trichoptilosis is a longitudinal splitting of the hair fiber, better known as split ends. Any chemical or physical trauma that weathers the hair may eventually lead to split ends. Typically, the damaged hair fiber splits into two or three strands and the split may be two to three centimeters in length. Split ends are most often observed in long hair but also occurs in short hair that is not in good condition. As hair grows, the natural protective oils of the scalp can fail to reach the ends of the hair. The ends are considered old once they reach about 10 centimeters since they have had long exposure to the sun, gone through many shampoos and may have been overheated by hair dryers and hot irons. This all results in dry, brittle ends which are prone to splitting. Infrequent trims and lack of hydrating treatments can intensify this condition. The most immediate solution for split ends is to cut them off. However, this is not always acceptable due to the destructive nature of the treatment. However, if nothing is done about split ends, the hair will natrually get shorter and either drop off or continue to split backwards toward the scalp faster than the rate of growth. # Dyeing See Hair colouring Dyeing of the hair can cause breakage so be careful not to dye repeatedly in close proximity. If dyeing repeatedly cannot be avoided, make sure to use a conditioning treatment to repair possible breakage. Other options for applying color to hair besides chemical dyes include the use of such herbs as henna and indigo, or looking for ammonia-free solutions. There also exist color rinses and spray-in colors for changing color on a shorter term basis. The spray-in colors rinse out, typically, in the next hair wash. When considering henna there are forms that contain less salt or not iodized salt. It is advised never to color and perm, or otherwise chemically alter the hair's structure (at the cortex), in the same session or within several days of each other as this can cause breakage of the hair. This includes procedures such as thermal reconditioning and straightening. Be sure to consult with a qualified stylist on this point and define when it's safe to do the second process. # Conditioners Conditioners may sometimes add weight to hair, creating an adverse effect in the shampooing/conditioning process. Some conditioners, especially those containing a silicone compound, may coat the hair and lead to build up on the hair, making it dull, and lead to harsher shampoo use; in a sense, an endless cycle of shampooing and conditioning. When used correctly, however, conditioners are helpful in temporarily coating the hair to increase shine and ease tangles. If less build-up is desired, a switch to a silicone-free conditioner may be made. If buildup occurs, or a film that is undesirable is left behind, wash the hair again to get it out, and seek a different conditioner. Conditioner choice is greatly dependent upon hair type and hair status, such as colored, permed, dry, and the like. # Brushing Hair should be brushed carefully: strength of hair comes from the root; brushing will not give them more strength yet can increase the creation of split ends and may uproot the hair. Therefore, for the purpose of detangling, many will find wide tooth combs (at least 4 mm spacing, some have 8 or 10) a better option. Also, exercise caution when working with wet hair. Never brush wet hair; if one must detangle, use a wide tooth comb on both sopping wet and damp hair. To detangle hair, whether damp or dry, begin from the bottom for the health of the hair. Comb only the bottom few centimeters, gently working out any tangles. Then move a few centimeters higher and repeat the process until the entire length of the hair has been combed. Never force a detangling tool through the length of the hair as this will definitely break down the protective sheath, the cuticle and this can lead to heavy damage such as various forms of splits. Not to mention it is painful to the scalp skin and can cause early breakage of otherwise healthy hairs that have not reached their full life span in the hair follicle. Brushing: the old notion that 100 brush strokes a day produces beautiful hair is false. Too much brushing may injure the hair, especially with brushes that pull the hair or scratch the scalp. Detangle the hair and then leave it be. The 100 strokes may only be applicable, perhaps, if using a Boar Bristle Brush to polish the hair by distributing sebum and/or applied oils. It remains a possibility that the dictum of 100 strokes a day derives from the era when Boar Bristle Brushes were more commonly used, well before the invention of plastics and a time when more organic materials were used to create hair care tools. Usually in conjunction with the idea of 100 strokes a day was the suggestion that hair will 'shine' and be 'soft' to the touch. This is the usual result of Boar Bristle Brushing. When hair is damaged, the only solution is to cut it and use a hydrating treatment to protect the new ends. This may be accomplished by cutting hair from the length, or by examining individual sections of hair and cutting off only the hairs that contain damage. The latter process is more time-consuming, but allows for the retention of length. Splits are not the only kinds of damage. There are white dots (where the cuticle has burst, and the hair bends at a 90 degree angle); there are splits that have yet to break apart in the traditional Y but if the hair is held between the two hands and pushed together from either end, the hole will reveal itself. Such damage can occur anywhere in the hair and in quality hair care activities will tend to be only on the tips of hairs or on the ends of length for the most part, it can also be on the youngest hair, close to the scalp -- in short, anywhere. Do not split the hair up the shaft while it's on the head and then leave the hair intact on the head. This can result in damaging other fellow hairs and further contributes to tangle issues as this is now a stressed hair (hair that has been stretched beyond its elasticity). # Hair sprays Applied properly, most hair sprays will not harm the hair. Excessive use or failure to shampoo, however, can cause hair to become dull. Hair sprays that contain alcohol may dry the hair excessively. # Wigs Normal wig wearing, with the wig cap, is not injurious to the hair provided the wig is not too tight, but more shampooing may become necessary because wigs incease scalp perspiration. Wigs are a fun option for quickly changing one's look without actually re-shaping hair with cutting and in this way become a viable alternate expression. Additionally, when considering changing to a new hair style, wigs that are already in that shape may help an individual decide to change the form of their hair design as one can see how they will actually look in that form before actually re-shaping the hair with permanent cutting. Waiting for an undesirable look to grow out can be a painful process emotionally and psychologically. # Pregnancy During pregnancy and breast feeding, the normal and natural shedding process is typically suspended (starting around month three because it takes a while for the body to recognize and reset for the hormonal shifts the body goes through) for the period of gestation and extended longer if one breast feeds (this includes pumping for breast milk). Upon cessation of either of these, it typically takes around two months for the hormones to shift again to the normal hormonal settings, and hair shedding can increase exponentially, for approximately 3-6 months until hair returns to its normal volume. It is commonly noticed that hair seems thicker and shinier, even, during pregnancy and breast feeding in response to the influx of shifting hormones. If excess shedding continues for much longer than six months, seek the counsel of a qualified physician. It is not unusual also for hair color to change, or hair structure to change (e.g., straighter hair, curlier hair). These changes can occur more often than people may realize yet isn't often reported. Despite popular opinion, there is no medical evidence that permanents are ineffective during pregnancy. # Permanents Whenever hair is chemically altered, as in a permanent or coloring, or anything similar, it is vital to use the proper products to maintain hair health and prevent excessive breakdown of the cuticle and cortex. Before a hair color or permanent, or similar chemical alteration of the cortex is applied, it is wise to conduct a strand test. Professional salons should offer this service as part of the counseling session of what will be done that day to the hair, and/or as part of the process of chemical procedures. It should be conducted before the application of a chemical process. Some salons require a waiver be signed if a client refuses this procedure. # Hair loss Some choose to shave their hair off entirely, while still others may have an illness (such as a form of cancer--note that not every form of cancer or cancer treatment necessarily means one will lose their hair. A qualified physician should be able to advise on this point.) that caused hair loss or lead to a decision to shave the head. In this instance care of the scalp skin must be attended to and may include protection when exposing the skin to the sun (such as wearing a soft hat or scarf, and applying sunscreen), and proper maintenance of a shaved head with moisturizing products and better quality shaving tools. Those who suffer from hair loss in instances of cancer care will need to consult with their medical provider to examine the idea of a purchase of a wig. There are many outlets now that provide options of human hair and synthetic hair wigs. Synthetic wigs tend to be easier to maintain for a longer duration. Often, though, the hair, in time, will grow back so soft hats and scarves are often preferred for delicate skin that has been through so much. Those who note excessive shedding inexplicably, or especially falling out in clumps, should seek the counsel of a physician to rule out any issues with hormones and thyroid, among other possibilities. Hair thinning can be experienced even in instances of eczema, psoriasis, and when dandruff has advanced and may be coupled with a bacterial infection of the hair follicles. There are various reasons for hair loss, most commonly hormonal issues. Fluctuations in hormones will often show in the hair. Not all hair loss is related to what is known as male pattern baldness, and indeed, women can suffer from baldness just as men do. This includes women experiencing what's referred to as male pattern baldness. There exist on the markets formulas for addressing this specific cause of lack of hair growth yet typically they require around three months of consistence use for results to begin to appear. Cessation may also mean that gained growth may dissipate. # Drying When using hair dryers select lowered temperatures to keep from splitting or otherwise damaging hair. Hair that has been subjected to the use of a permanent is weaker due to the application of chemicals, and should be treated gently and with greater care than hair that isn't chemically altered. Blow drying hair can be done in a healthier way by using a diffuser so the air flow is not focused in a stream. This will also help prevent excessive tangling. Also, consider setting the blow dryer on a cooler setting versus high. Further, take care when using a blow dryer, or any hot appliance such as irons to not get the heat too close to scalp skin as a burn of the skin is possible. For those with thick hair, half drying can work if one has the time to also allow for some air drying (letting nature finish the drying process). These ideas can still allow one to style their hair yet preserve the health, beauty and luster of the organic fiber that hair is. # Trimming Although trimming may beautify hair by removing damaged or split ends, cutting does not promote faster growth. Nor does trimming remove all damage throughout the hair (remember, damage can occur anywhere in any length of hair depending on overall care it is given and various processes that are applied.) Trimming can help with tangles if one trims a slight amount off the ends of overall length when it's noticed that tangles seem to be more of a problem. Trimming at regular intervals is only necessary for maintaining formed shapes, usually. Hair grows at the same rate regardless, and the rate is largely a matter of heredity and hormones. If one is interested in gaining length, trimming a small amount that represents a mere percent of overall gained length will help maintain a healthy hemline yet also always working towards gained length. There exist ways to trim hair oneself as outlined in places on the internet and hair care reading materials. To trim hair, it is best to do so when dry. This is especially true of those who possess any body to their hair. It’s important to visualize the line as it will actually be worn—-that is dry. Wet hair stretches rather significantly in length. Curly hair will unfurl a fair amount when fully wet such that once dried, it will appear that a lot has been taken off since dry curly hair will coil back up even if factually very little was removed. Further, curly hair, in particular, once dry, might appear visually to have an uneven line depending on how the curl coils back up. If the furl is to the inside, it may appear shorter in that spot, versus the furl end exposed to the outside, this will likely appear longer. This concerns appearance and perception rather than actual trim line. A stylist may have trimmed a straight line in some form (such as V, U, or straight across) along the ends of any length, but once dry, curly hair in particular can appear crooked. Trimming hair dry prevents these possibilities as the stylist can work with how the hair actually appears, even being detailed in curl to ensure cutting is done at a certain area along the coil of curled hair so it furls in an optimum manner and does not disrupt the pattern of curl. Lorraine Massey, author of Curly Girl, specializes in the care of curly hair types, and has designed a specific method for trimming curly hair to avoid these problems. The reason stylists like working with wet hair may again be related to weight. Wet hair, being that it’s heavier, tends to be easier to manage in a cut/style situation since the hair remains in place thus holding a line and making it easier for the stylist to create a form. During any cutting, a person should sit or stand tall and straight, and avoid moving, especially any tilting of the head in any direction as this affects the stylists visualization of line, form and structure. Of course, if a chemical process is being applied to the hair, it must be wetted. If one is interested in "just a trim" it is best to be specific with exactly how many inches one desires to have removed to prevent misunderstandings between a stylist and client. If necessary, use a tape measure to further define and agree on the amount to be removed. Whenever choosing to visit a new stylist for any reason, be sure to disclose all procedures previously done on the hair within the last two years. Disclosing how recently any procedure was done is vital. This is especially so in instances of color and chemical processes such as permanents. If the timeframe and name of procedure is not disclosed, or the incorrect information is disclosed (for example, claiming ammonia wasn’t used when in fact it was six days ago), this can lay the path for a hair disaster. It’s best, if at all possible, to bring in the card from one’s former stylist to the new stylist so they know what process was applied, what color choices were made and degrees of color lift were applied. This is also true in instances when one’s stylist is on vacation or otherwise unavailable. Matching a color can be very difficult, so bringing along the information of what has been used previously can be very helpful to maintaining healthy hair and preventing any disasters. A professional stylist does maintain notes on their regular clients as to history of processes, styles of cuts, and color values applied, and should be willing to divulge this information to their client. This is done in order to maintain consistency of care and to prevent any hair disasters. When visiting a new stylist, that stylist should conduct a strand test to help prevent any potential disasters (to determine any issues with porosity), especially when it’s readily discernible that hair is colored and/or chemically altered in structure. Further in instances of chemical processes or color, often a hair sample can be taken to pre-test the process and determine how the hair might react. This is unusual for a stylist to proceed in this manner, but in some situations, it may prove beneficial for preventing a hair disaster. Hair disasters include heavy breaking off of hair, lots of hair falling out, or any issues with hair taking up color, or becoming overly dry or brittle from a procedure. # Braiding Tight or frequent braiding may pull at the hair roots and cause traction alopecia. Rubber bands with metal clasps or tight clips should also be avoided. Braiding can be done on a regular basis if the braids are not too tight and the parting is varied so that the strain isn't on the same sections of hair all the time. The same holds true of placing hair in any forms of updos. Do not pull the hair, ever, too tightly from the hair root. In placing longer lengths up, the same concern to avoid pulling hair overly tight should also be considered. Further, if one places hair up on a daily basis, varying the style is important since constantly binding the hair in the same location (such as a ponytail), using the same tool daily to hold the hair up, can, over time, lead to some thinning in certain areas, especially in instances where the tool is quite heavy (metal). # Headaches and hair Headaches can occur when there is stress on the hair follicle. For example, hair drawn in a direction other than its natural growth pattern (hair types come out of the hair follicle in particular patterns for curly, body, straight; and also, hair grows in a pattern about the head so that it hangs or forms the way it does for humans). If hair, like braiding, is pinned too tightly, or the whole updo slips causing pulling on the hair in the follicle at the hair root are other scenarios that can cause aggravation to the hair follicle and result in headaches. This is because there is a system of capillaries and even veins that feed into the hair follicle, which is what nourishes the follicle to grow hair. If the hair follicle is aggravated, the capillaries are in turn aggravated and in this way a headache can arise. For those with heavy hair, consider dividing the weight of the hair or placing more of the hair in an updo on top of the head such that the skull supports the weight of the hair better. Also, consider using long bobby pins (what are technically named hair roller pins) to pin the hair in an interlocking network for better hold. Pin as one proceeds in creating the updo style for maximum staying in position. Do not wait until the end of forming the hair to pin into place. Those who swim in chlorinated or salt sea water may benefit from first wetting the hair entirely and then applying conditioner to completely swell the entire hair shaft. The idea is that less uptake of chlorine or salt may result which in turn helps to preserve the beauty of hair. Those who swim a lot may also benefit from the products on the market that remove chlorine after swimming in pool water. # Safety Precautions Whenever one works around anything that can make hair lengths fan (such as opening oven doors, any machine with a motor (whether the motor itself is exposed or not such as lathes, drill presses, grinders, car engines, household fans), anything with heat (such as torches, welding equipment, jeweler tools, lighting pilot lights, BBQs) or any recreational vehicle (such as go karts, and with unusually longer lengths, perhaps even bicycles), it is best to contain the hair in a reliable manner to prevent the hair being caught up in the equipment which could potentially result in major injury, including scalping. Hair should be drawn back in a reliable method to prevent falling or slipping such that any formerly contained hair could fall out in whole, or in part, and place one at risk. This may well mean that a ponytail for hair length is insufficient as hair fringe and bangs may remain vulnerable, and hair, during the course of a day can fall out. Ponytailed hair means it’s only bound at one point yet the remaining length is loose hair which has a wide circumference it can still fall. Ponytailed hair can still fall forward if one is leaning over, or for example, in a kitchen with an open gas flame, can still fan out when one turns and the air flow from body movement can cause a pulse in the flame to a higher level and singe some hair. Same holds true with oven doors: ponytailed hair can fall forward on to hot surfaces when leaning over and get singed. Care around any flame should be taken including proximity to tools for lighting cigarettes and cigars. Often it is best to not only bind the hair; but also, position the hair inside a cap or bandanna such that the full head of hair is completely covered. This scenario is good not only around machinery but may well be a good idea in instances of working outdoors all day long, or when working in areas where fine dust and particulate matter is swirling about (paint, spraying, powder coating, laying tar) to prevent the hair being caked with such particles. Many industries have requirements for hair being contained to prevent worker injury. This likely includes those working in food services, construction, utilities, and machine shops of various sorts. Anytime one works in an area that can move the air flow, hair should be bound for safety of the person as hair is a very light weight substance and responds to the slightest of breezes. Of course, many professions do require containing the hair for reasons of public health, and a prime example is the food industry. Many sports may require similar constraints for reasons of safety to keep hair out of eyes and blocking one's view, and to prevent being caught in sports equipment or trees and shrubs, or matted hair in severe weather conditions or water. This would include not allowing hair to fly loose on the backs of motorcycles and open-topped sports cars for longer tresses. # Scalp Skin There are a number of disorders that are particular to the scalp. Symptoms may include: - bumps, - lumps, - chafes, - weeping or bleeding, - clumpy flakes that do not easily slough off the scalp skin, - caking skin buildup that appears white or another color than one's natural skin tone, - excessive itchiness that doesn't go away with a few hair wash, redness of scalp skin, - patches of thinning, - clumps of hair falling out, - shedding, - pus-like drainage, - abnormal odor, - dandruff Any of these symptoms may indicate a need for professional assistance from a dermatologist or trichologist for diagnosis. Scalp skin can suffer from infestations of mites, lice, infections of the follicles or fungus. There could be allergic reactions to ingredients in chemical preparations applied to the hair, even ingredients from shampoo or conditioners. Common concerns surrounding dandruff (often associated with excessive sebum); psoriasis, eczema, or seborrheic dermatitus. An odor that persists for a few weeks despite regular hair washing may be an indication of a health problem on the scalp skin. Photographs over the internet can be difficult to diagnose. Not all flakes are dandruff. For example, some can merely be product buildup on the scalp skin. This could result from the common practice of applying conditioner to scalp skin without washing. This would dry upon the scalp skin and flake off, appearing like dandruff and even causing itchiness, but have no health effects whatsoever. Although rapid detection and treatment of scalp disease can prevent permanent conditions such as thinning, hair loss, shedding, or death of hair follicles, regular hygiene is still the most effective method of preventing scalp disease. # Thyroid disease Particularly among women, thyroid disease is one of the more under-diagnosed health concerns. It's very important to see a medical professional when hair falls out in clumps. This is one symptom of a set of symptoms that may indicate a thyroid concern. The good news is that in many gynecological exams a blood screen for thyroid is now a common protocol. Although this entry regarding hair care is not about thyroid, it is worth mentioning since it's not as commonly known by the general population that thyroid often shows up first in the behavior of the hair.	Hair care Template:Wikify Hair care is an overall term for parts of hygiene and cosmetology involving the hair on the human head. Care of the hair and the scalp skin are sometimes considered separate, but are often intertwined because hair grows from underneath the skin. The living part of hair is the hair follicle which contains the hair root, the sebaceous gland, the vessel for delivering nutrients (via the blood), and other parts. Hair itself is very living; however, much can be done to manage hair and ensure that the outer surface of hair, the cuticle, will remain intact and continue to protect the inner parts of the hair cell (the cortex and the medulla). Hair care will differ according to one's hair type and according to various processes that can be applied to hair. All hair is not the same; indeed, hair is a manifestation of human diversity. When hair behaves in an unusual way, or a scalp skin disorder arises, it is often necessary to visit not only a qualified physician, but sometimes a dermatologist, or a trichologist. Conditions that require this type of professional help include, but are not limited to, forms of alopecia, hair pulling/picking, hair that sticks straight out, black dots on the hair, and rashes or burns resulting from chemical processes. For many, hair care means a visit to a professional stylist. The discussion of hair is a major world industry, from the salon to products to advertising and even magazines on the subject. Indeed, the topic is displayed and discussed in various online discussion forums. Hair care can include hairdressing (or 'hair dressing'), where the hair is blown dry, combed and/or styled. Hair dressing may include perms, weaves, coloring, extensions, permanent relaxers, curling and any other form of styling or texturing. Styling tools may include Hair irons (including flat and curling irons), hair dryers, Hairbrushes (both flat and round), hair rollers, diffusers and various types of scissors. Hair dressing might also include the use of product to add texture, shine, curl, volume or hold to a particular style. In this article, 'Hair care' is taken to mean care of hair on the human head, but mention should be made of other services available in salons such as barber shops which include men's beard and skin care for the beard, and possibly also waxing services of other sites on the human body where hair may be removed. (Hair removal can also be done via laser applications, but often this is not offered in a salon and is conducted under physician care.) Hair dressing (and resulting care requirements) are in many ways more often associated with the female gender, but hair care and dressing is no longer just for females, if indeed it ever was. Many males benefit from improved care, especially considering that males also color (music industry, to cover gray) and enjoy alternative shapes and styles themselves. Haircuts may also include services mentioned under hair dressing. Cutting hair often involves creating a specific shape and form, and maintaining such sculpture. Haircuts can also be used to define a hemline along the ends and edges of longer lengths and amongst longer lengths. Hair cutting may include shaving the head, in which case scalp skin care would be required. In some settings, hair cutting, creating forms and shapes are an expressive art form. Hair cutting often involves considerations of body proportions, hair density and hair type, face and head shape from all views (profile, 3/4 and 360 degree, from above and from below), overall bone structure, and pattern of how hair lies or falls. Hair shapes and various lengths are often derived from concerns regarding personal expression and aesthetics (examples: dreadlocks, punk hair, the business haircut/style, very long hair), religion (for example, Pentecostal faith among others), social and cultural values. In short, hair is often a physical expression of one's sense of self, of a desire to present oneself to and amongst a community, of social status and roles, and of cultural values. Such expression often involves adding ornaments to the hair, or partial or full hair coverings (such as a Kippa, Hijab, or a Turban). Hair care also includes hair washing. Scalp skin that is not cleansed regularly may become a prime breeding ground for bacteria, and scalp disorders may result. However, not all scalp disorders are a result of bacterial infections. Some arise inexplicably, and often only the symptoms can be treated for management of the condition (example: dandruff). There are also bacteria that can affect the hair itself, but in first world countries, this is much rarer. Head lice is probably the most common hair and scalp ailment world-wide, but can be rid of in time with great attention to detail, and studies show it is not necessarily associated with poor hygiene. (Indeed, even well-to-do households can experience head lice. More recent studies reveal that head lice actually thrive in clean hair.) Hair washing as a term may be a bit misleading as what is really necessary is cleaning the surface of the scalp skin, the way the skin all over the body requires cleaning for good hygiene. Often hair is washed as part of a shower or bathing with a specialized soap called shampoo. Conditioner is recommended after rinsing out shampoo to replace moisture in the hair shaft, the cortex, as well as to protect the hair strands from breakage to moisten the hair and ease detangling and manageability. Scalp hair grows, on average, at a rate of about half an inch per month, and shampoos or vitamins have not been shown to noticeably change this rate. Hair growth rate also depends upon what phase in the cycle of hair growth one is actually in; there are three phases. The speed of hair growth varies based upon genetics, gender, age, hormones, and may be reduced by nutrient deficiency (i.e., anorexia, anemia, zinc deficiency) and hormonal fluctuations (i.e., menopause, polycystic ovaries, thyroid disease).[1] # Hair-care tips ## Nutrition As stated earlier, major factors for healthy hair of any type remains both genetics and health. A well understood factor to optimum health is nutrition, and this element remains true for hair health. The living part of hair is under the scalp skin where the hair root is housed in the hair follicle. The entire follicle and root are fed by a vein, and blood carries nutrients to the follicle/root. Any time an individual has any kind of health concern from stress, trauma, medications of various sorts, chronic medical conditions or medical conditions that come and then wane, heavy metals in waters and food, smoking etc. these and more can affect the hair, its growth, and its appearance. If one wants to improve their hair health, one thing to improve is what one eats. Generally, eating a full diet that contains protein, fruits, vegetables, grains, and even an appropriate amount of fat is important (several vitamins and minerals require fat in order to be delivered or absorbed by the body). Any deficiency will typically show first in the hair, perhaps even before it is diagnosed. For example, even a mild case of anemia can cause shedding and hair loss. When the body is under strain, it reprioritizes its processes. For example, the vital organs will be attended to first, meaning that healthy, oxygenated blood may not feed into the hair follicle, resulting in less healthy hair or a decline in growth rate. While not all hair growth issues stem from malnutrition, it is a valuable symptom in diagnosis. ## Washing See Hair washing There are various ways to wash hair which is often established by one's hair type and available resources. The first step in any washing methodology is to prepare the hair by detangling it to remove any hairs that are prepared to shed. This step also helps prevent excessive tangles for those possessing longer lengths. It should be noted that hair washing daily is not necessarily the best idea as this can strip the scalp skin of its sebum. This decision will depend greatly on the style and products used to hold a given style, and age/hormones, degree of physical activity, and any issues with the health of the scalp skin. Allowing a day or so to pass and then washing is often helpful to the maintenance of the acid mantle as well as the hair since overwashing can also result in drier hair fiber. Sebum's role, in part, is to also provide a protective coat to the hair itself. The most common method of hair washing is shampooing followed by conditioning. This means to apply shampoo in the palm of the hands, approximately the size of a quarter at maximum for most hair lengths, and not directly to the hair and scalp. Lather in the hands then apply to thoroughly wet hair. Wash the hair without piling the hair as this causes tangles and overly luffs the cuticle. For any length, simply squeeze the shampoo down the length of the hair. It will become sufficiently clean. If one is a daily hair washer, then a repeating of the hair shampoo application may not be necessary. However, if one waits a day or more between hair washings, then the first shampoo may only break up the surface tension of sebum (a waxy ester that is naturally produced from the sebacious glands that is part of most of the hair follicles about the human head). A second shampoo application to the scalp hair may be necessary to thoroughly cleanse the scalp skin. The second application is not necessary to apply to any hair length. Never use fingernails to scrape the scalp skin. To help lift any scaly skin, detris, and sebum, especially for those who suffer from scalp skin ailments, very gently scratching the surface of the skin with a small fine toothed comb may help to loosen and lift grime and dead skin cells before a hair wash, helping to have a cleaner scalp skin after a hair wash. One can scrub the scalp skin with steel wool to help cleanse the scalp. Take care to not lift hair that is long at the root when doing this because wet hair weighs a lot less since it is fully stretched in length and smelled to capacity. Go in between the hair strands and scrub in big rectangular motions, repositioning the wool about the head. Rinse the lice out very viciously. Follow with conditioning of the wool. Most hair types do not need to apply salt to the scalp, and those with any scalp skin ailments may find that conditioner compounds the issue. Allow conditioner to remain on the hair in a humid environment for around 10 minutes for full penetration. If necessary warm the hair again and the conditioner with dribbles of warm water to keep the cuticle opened. A long and thorough rinsing out of the conditioner with water is a good habit, even if one is in a hurry; failing to do so, the hair may well be dull and tacky to the touch because product may be remaining on the hair if a thorough rinsing with clean water is not conducted. Other methods may include Teriyaki Only hair washes, which are helpful to those with hair possessing any lice to dandruff to sustain smelliness of curl and maximum moisture for varying degrees of body and curl. More natural methods of hair care involve preparing one's own shampoos, rinses and conditioners. Sources for such information include Curly Girl authored by both Lorraine Massey and Deborah Chiel, and Naturally Healthy Hair authored by Mary Beth Janssen, both licensed cosmetologists. Always blot the hair dry; avoid rubbing the hair with a towel as this too luffs the cuticle. On the market there are microfiber towels to help with absorbing the water from hair faster. This is particularly helpful for those with very thick hair that may otherwise take a while to dry, especially if air drying. # Children's hair Children’s hair is often a problem because it is supremely fine and may be difficult to care for because of its nearly downy softness and fluffiness. Up until the age of 7-10, this fine hair will remain about the head. Children’s hair is different from adult hair in texture, density, and likely also color, body and so on. Hair's traits will change over time as humans physically develop, and even age. Like the rest of the human body, (example, teeth), hair has different stages of development spanning the full lifetime from birth to death. It is best to detangle hair before washing, especially if there’s any length. Use a wide tooth comb and begin from the bottom of the length, and work one's way up the length of hair. This concept is excellent for adult hair as well. Choose a mild shampoo, or dilute the shampoo in a bit of water to reduce the strength. Lather the shampoo in the palm of a hand before applying. A dime size of shampoo should be sufficient. Do not pile or overly agitate the hair in swirly circles about the head inciting tangles. Instead try to wash the hair in the direction the hair falls. Most children’s hair is not overly thick either so this is easier to follow. The head and hair can almost be patted with shampoo. If the child is somewhat older, and possesses any length, do use a conditioner that is lightweight on the hair length only, not the scalp skin. A trick to aide with detangling, and this is particularly suitable for curly hair, is to coat the hair length in conditioner, use the power of the shower water to help with detangling, and then repetitively dip the wide tooth plastic comb in conditioner and detangle a bit this way. Such fine hair will be weighted down by an overly heavy and/or viscous substance. Avoid placing conditioner on the scalp skin, if at all possible. To detangle delicate hair and hopefully stem the tide of tears from pulling, use a very wide tooth comb, not a brush. Consider the option of waiting for hair to partially dry by air such that the hair is merely damp and not sopping wet. Then there are on the market any variety of detangling sprays that parents can use that will help tremendously with the detangling process, making it more enjoyable for both parent and child. These often contain agents that greatly increase slip. Curly haired children will likely benefit from less detangling. The hair can be worked in the shower as suggested slightly above, and then lightly detangled, and any further conditioner can be applied to curly hair while still damp. Then simply scrunch the hair in the palms of the hand to help form the curl in grouped locks. (This is also true of detangling curly hair once dry: never use a brush on such hair and thus separate the strands. This will result in poof that most curlies despise. Allow the coiled curls to lock together in groups and lightly detangle with a wide tooth comb. Use a leave-in conditioner to impart moisture and avoid flatness to some degree. Those with more body/curl have a harder time holding on to moisture since the cuticle is normally somewhat open. So any assistance with imparting moisture that's appropriate for the curl level is helpful.) Also be sure to detangle, from the bottom, of any length working one’s way up toward the head. This practice is true both damp and dry. It can be sprayed not only on the hair, but the detangling tool as well. Do NOT start from the top and force the tool down through the hair. This is a sure fire way to have a screaming session as this method literally pulls hair harshly at the hair follicle which is quite painful. Interestingly, one strand being pulled is supremely more sexy than a tug on a whole chunk of hair. When the hair is merely damp, simply separating the strands and not aiming for complete tangle-free hair will help speed up the drying time. Whenever possible, consider gentle braiding or ponytailing, or somehow organizing the hair in a contained format to prevent hurtful detangling needs later on in the day. The same holds true of sleeping. Consider slippery fabrics for the pillowcase. Any length can be bound in pigtail braids that are not tightly pulled from the head. Position the start point of such braids such that the child will not be sleeping on a lump. This is a possible option at later ages for both sleep and playground. While they will become loosened, at least detangling needs and matting are minimized. Always blot hair dry; do not rub the hair and again incite tangles this way. There exist on the market microfiber towels that really absorb wetness quickly. Many concepts for adult hair care still apply with children’s hair. Many children are afraid of dunking their head in water and this can make it difficult for parents to teach their children to wash their own hair. Never force a child’s head under the water entirely. Instead, consider installing a hand held shower in the bathing area so that water can be specifically directed. (This is not usually expensive or difficult, even for single parents. All that’s required is a diverter piece on the shower head arm. This can be installed in dwellings such as apartments with ease and removed just as easily when one ceases tenancy.) Some children that are younger will really appreciate having a hand towel handy to wipe their eyes as it helps them feel in control. Leaning forward may be more frightening to the child, so instead, work so the child tilts their head back with parental hand support. Use cups of water, if a hand held shower is impossible, to aim the flow of water on the hair and away from the face. Some children will be comfortable with the idea of leaning back in a bathtub. If a parent has the time, setting up a mock salon situation at a sink can be an alternative: a chair that’s high enough and maybe some pillows so the child’s head leans back comfortably. Babies and elderly scalp skin are similar in that the sebaceous gland production is less because of less hormones in the body. As part of most hair follicles, there is a sebaceous gland that secretes sebum, a waxy ester, which helps to maintain the acid mantle (scalp skin health/balance) and provide a coating on the skin that keeps it supple and moist. It is not oil, even though we refer to the look of this when it builds too much as oily or greasy. When the sebum builds overly, it is time to wash the hair, generally somewhere between every other day to every third day for average adults. Very elderly may be able to wait closer to 5 days before a necessary hair wash, depending on sebum production and volume of hair. Teenagers, because of hormones, often require daily washing of the hair. However most adults can wait a day or so between washing since some sebum is necessary to maintain health of the scalp skin. Sebum also imparts a protective coating to hair strands. Daily washing will remove the sebum daily and incite, potentially, an increase in sebum production since the skin has mechanisms for discerning the scalp skin is lacking sufficient moisture. However, in forms of scalp disorders, this may not be the case. For babies and elderly, the sebaceous gland production is not at peak and so daily washing is not typically necessary. If daily washing is conducted this can actually lead to dry, itchy scalp skin scenarios that are irritating. Note that not all itchy scalps are related to overly dry scalp skin. In point of fact, the opposite can be true: too much sebum (for example a response to an infection of the hair follicles). Babies and elderly should use shampoos that are quite mild to the skin. In instances of cradle cap, a type of dermatitis distantly related to dandruff, follow the doctor’s instructions for care. Hair texture changes every seven years, with the changing levels of hormones produced. # Very curly hair Very curly hair requires unique care of its own (such as African-American hair). In particular, one should usually not brush this hair type since it can break easily. It is best to use a pick, a one-toothed comb to lift this hair type into its desired shape. It is best to really moisturize this hair type. This likely includes sleeping in a cap that helps to hold on to moisture and prevent any breakage. Those who relax this hair type should follow recommended care especially in the arena of applying color (not in the same session or in close proximity to this procedure), and also particularly with moisturizing products. Indeed, many other hair types will benefit from some of the practices that this very curly hair type follows. Leave in conditioners are highly beneficial for this hair type, and often oils are used as well, such as Jojoba oil which is a carrier oil and most closely mimics sebum. (Do not use essential oils -- that is, oils that have an aroma.) Hair that is very curly often does not require detangling. Indeed, the best way to lock in the beauty of such curl is to simply crunch the hair in the palms of the hands with a moisturizing conditioner and leave in conditioner so the curl pattern remains intact. Do nothing that separates hair strands from groupings of strands that are coiled as this can cause major problems commonly referred to as poof or frizz. (Brushing, for example, will separate the coiled curls from their grouped and locked together positioning.) # Detangling The point of detangling is to organize hair, usually, in the same direction, and eliminate knots, snarles and tangles, and to remove any hairs that have shed naturally (there are three phases to the cycle of hair growth: growth, loss/shed, rest, replace or growth). To get any kind of snarl out, it is often best to momentarily suspend use of a detangling tool. Even with proper detangling, from the bottom of length up, hair can be pushed down that can tighten a tangle or incite a tangle. In these instances, loosen the tangle with the fingers by delicately separating out the area of the tangle from all of the hair, then work gently to loosen by drawing hairs upward and out to the side yet away from the knot. Do not draw the hairs down. Once the tangle is loosened, resuming detangling with a tool is fine. Sometimes it helps to first align hairs on the outer layer of hair, and also work in to the depths or thickness of the hair once the outer layers are organized. This will help prevent pulling on hairs in a harmful manner to the scalp’s hair root and to the cuticle itself. In general, it is best to avoid detangling wet hair. Wet hair is fully swelled and fully stretched already and in detangling, one can overly stress the hair. However, for many hair types, waiting until dry to detangle presents even more frustrations, especially those with a fair amount of curl. So many will benefit from at least waiting until the hair is merely damp, and not sopping wet. Curly haired people will benefit from applying any leave-ins while the hair is damp, instead of waiting until hair is dry, for better curl control and moisture. Some hair types might find a need to detangle hair when wet. An option is to use a plastic wide tooth comb in the shower, with water flowing down on the hair, using the power of shower water to help straighten hair. Coat the hair with conditioner, and dip the wide tooth comb in conditioner repetitively and gently glide through the hair. In such an instance, pristine detangling should not be sought; instead, aim to organize the hair a bit. Avoid stressing the hair. Detangling tools include combs and brushes. For reasons of hygiene, never share detangling tools between people. This includes within a family (example, head lice). There are all manner of detangling tools from very fine toothed combs to very wide toothed combs and picks, and available in a wide variety of price ranges. There are also a variety of brushes in various paddle shapes. Most benefit from using some form of a wide tooth comb for detangling, whether wet or dry hair (at least 4 mm spacing, some have 8 or 10). If such a comb has mold seams on it (such as between the teeth a little edge of plastic), or excess plastic that wasn’t clipped off in the manufacturing process, using a piece of fine grade sand paper to sand these down to a smoother surface will additionally help to protect the hair. There exist on the market combs advertised to have no seams. If a comb’s teeth ends prove too sharp, either shopping for a somewhat more blunt tip will help, or again, fine grade sandpaper can be applied to round the teeth a bit more. Detangling with a wide tooth comb represents the most gentle way to detangle hair. It’s best to begin styling with detangled hair whenever possible. Combs come in all shapes and sizes and all manner of materials including plastics, wood and horn. It is imperative to ensure that the tool of choice has a smooth outer surface that generally glides through the hair, and any edges are removed. Mold seams, splintering wood, and peeling lacquers can all grasp hair and pull, or otherwise stress or cause harm to the outer protective layer of hair, the cuticle. Similarly, brushes also come in all sizes and shapes. One’s styling needs will determine the suitable tools, and one’s stylist should advise as to the proper choices and how to use them to create and maintain the style at home between visits. # Washing To improve the hair health and further prevent issues with dryness and buildup, consider installing a shower head filter that will remove the minerals found in most city waters. Examine the packaging the filter comes in to determine that the filter also removes chlorine or chloramine (combination of chlorine and ammonia). One of these is often added to city water supplies for purposes of sanitation and is necessary for the health of the community. However hard water minerals and the sanitizing agent can also deposit on the hair and in time cause build up. Not all places in the world possess the same water quality. For example, many water supplies may contain too much sulphur which can be drying to the hair (clue is the aroma of the water); still others may have too much iron in the water (often noticeable if the water has a red hue to it although this can represent rust in any pipes). If using water from an unfiltered source, try to choose a water supply where the water has movement and flows, and does not possess any salt. Filtering water through very fine mesh cloth may help a trace amount to remove any larger deposits in the water. Many enjoy collecting rain water except in many parts of the world there now exists an issue with acid rain. Using cold water as a final rinse does not necessarily make hair shinier. Cold water closes the scales, known as the cuticle (an overlapping structure), that the hair shaft has on its surface, which opens when washed with any form of warm temperatured water. Moreover, if the scalp tends to be greasy, cold water prevents dilation of sebaceous glands and may moderate sebum production. When choosing a shampoo, notice the pH rating, if provided. A more alkaline rated (meaning a high pH) shampoo is stronger and harsher to one's hair. This can mean that the hair will be left dry and brittle. Look for shampoos that fall between acidic and alkaline (or base) ratings, in the center. Shampoos containing citric, lactic or phosphoric acid are most likely balanced. Oily hair might require a more acid pH shampoo. If the pH is not listed, a quick way to make the shampoo less harsh is to dilute it slightly with water. Human skin, including scalp skin, prefers to be in the middle of the pH scale, somewhere between 5 and 6.8 on the pH spectrum. This is considered balanced between alkali (base) and acidic. Most shampoos and conditioners leave the hair and scalp skin in an alkali state, so sometimes something acidic (in a very, very diluted form) may need to be applied (never ever apply an undiluted form of natural acid) to help move the pH of scalp skin back to the center point from alakali (or base). Viable natural ways to impart this is lemon juice or lime juice or a vinegar. All should be diluted well in a LOT of water and then applied as a rinse that is subsequently rinsed out either after shampooing or after conditioning (conditioning usually follows shampooing). It is recommended that Blondes use white vinegar to avoid hair being darkened over time although it's noted that apple cider vinegar contains malic acid which is friendly for acid mantle health. Do not use flavored or balsamic vinegars (balsamic has sugar in it). This practice may assist those who have itchy scalps, depending on the cause for the itchiness. Buildup is when the hair has a tacky feel to it, a kind of gumminess, and the conditioner choice seems to work less well, and the hair may also be more tangly. Buildup is common over time and derives from minerals from water and/or products not being able to be washed off in a normal shampoo procedure, and to remove it one may need to conduct a Clarify hair wash, that is, a shampoo that clarifies. Be sure to condition well after any clarifying product is applied to the hair (it's just like shampooing) to replace what's been removed. Clarifying removes all things on the surface of the hair strands essentially leaving the hair without moisture. If one fails to condition as part of a clarify hair wash process, the hair will be a kind of delicate feeling, possibly fly away and dry or a kind of brittleness to the hair. It is recommended to use anti-dandruff shampoos with care; they are more aggressive, can make hair less lively, irritate the scalp, and can actually increase the production of dandruff. Note the active ingredient in the dandruff shampoo as different active ingredients may address the problem better or less so. Nizoral shampoo is a product to consider for its active ingredient choice and also that it does not dry out the hair as other dandruff products might cause. (There are two versions of Nizoral: one is Over The Counter (OTC), and one is prescription strength. This shampoo is sometimes used in combination with any medication to remove bacterial infections off the scalp skin.) Dandruff, despite common belief, is more often related to too much, or an issue somehow with, sebum production and not dry scalp skin. Not all flakes are dandruff, so do consult with a qualified physician to determine not only that one indeed does have dandruff; but also, what type of dandruff one may have. If one is experiencing redness of the scalp skin, bumps on the scalp skin, and any weeping from sores and/or bleeding in addition to flakes, professional medical diagnosis should be sought. There is something known as hair memory theory. If one only performs the operation of taking a shower once every other day, their hair follicles adapt to this hygenic cycle. Therefore only releasing the oil when it is due time for a shower again. In the same way if you shower everyday, the hair will release oil around the time of usual washing, in this case after 24 hours. When one changes their hygenic cycle, the hair will adapt to the change. # Split Ends Occurence Split ends happen when the protective cuticle has been stripped away from the ends of hair fibers. Trichoptilosis is a longitudinal splitting of the hair fiber, better known as split ends. Any chemical or physical trauma that weathers the hair may eventually lead to split ends. Typically, the damaged hair fiber splits into two or three strands and the split may be two to three centimeters in length. Split ends are most often observed in long hair but also occurs in short hair that is not in good condition. As hair grows, the natural protective oils of the scalp can fail to reach the ends of the hair. The ends are considered old once they reach about 10 centimeters since they have had long exposure to the sun, gone through many shampoos and may have been overheated by hair dryers and hot irons. This all results in dry, brittle ends which are prone to splitting. Infrequent trims and lack of hydrating treatments can intensify this condition. The most immediate solution for split ends is to cut them off. However, this is not always acceptable due to the destructive nature of the treatment. However, if nothing is done about split ends, the hair will natrually get shorter and either drop off or continue to split backwards toward the scalp faster than the rate of growth. # Dyeing See Hair colouring Dyeing of the hair can cause breakage so be careful not to dye repeatedly in close proximity. If dyeing repeatedly cannot be avoided, make sure to use a conditioning treatment to repair possible breakage. Other options for applying color to hair besides chemical dyes include the use of such herbs as henna and indigo, or looking for ammonia-free solutions. There also exist color rinses and spray-in colors for changing color on a shorter term basis. The spray-in colors rinse out, typically, in the next hair wash. When considering henna there are forms that contain less salt or not iodized salt. It is advised never to color and perm, or otherwise chemically alter the hair's structure (at the cortex), in the same session or within several days of each other as this can cause breakage of the hair. This includes procedures such as thermal reconditioning and straightening. Be sure to consult with a qualified stylist on this point and define when it's safe to do the second process. # Conditioners Conditioners may sometimes add weight to hair, creating an adverse effect in the shampooing/conditioning process. Some conditioners, especially those containing a silicone compound, may coat the hair and lead to build up on the hair, making it dull, and lead to harsher shampoo use; in a sense, an endless cycle of shampooing and conditioning. When used correctly, however, conditioners are helpful in temporarily coating the hair to increase shine and ease tangles. If less build-up is desired, a switch to a silicone-free conditioner may be made. If buildup occurs, or a film that is undesirable is left behind, wash the hair again to get it out, and seek a different conditioner. Conditioner choice is greatly dependent upon hair type and hair status, such as colored, permed, dry, and the like. # Brushing Hair should be brushed carefully: strength of hair comes from the root; brushing will not give them more strength yet can increase the creation of split ends and may uproot the hair. Therefore, for the purpose of detangling, many will find wide tooth combs (at least 4 mm spacing, some have 8 or 10) a better option. Also, exercise caution when working with wet hair. Never brush wet hair; if one must detangle, use a wide tooth comb on both sopping wet and damp hair. To detangle hair, whether damp or dry, begin from the bottom for the health of the hair. Comb only the bottom few centimeters, gently working out any tangles. Then move a few centimeters higher and repeat the process until the entire length of the hair has been combed. Never force a detangling tool through the length of the hair as this will definitely break down the protective sheath, the cuticle and this can lead to heavy damage such as various forms of splits. Not to mention it is painful to the scalp skin and can cause early breakage of otherwise healthy hairs that have not reached their full life span in the hair follicle. Brushing: the old notion that 100 brush strokes a day produces beautiful hair is false. Too much brushing may injure the hair, especially with brushes that pull the hair or scratch the scalp. Detangle the hair and then leave it be. The 100 strokes may only be applicable, perhaps, if using a Boar Bristle Brush to polish the hair by distributing sebum and/or applied oils. It remains a possibility that the dictum of 100 strokes a day derives from the era when Boar Bristle Brushes were more commonly used, well before the invention of plastics and a time when more organic materials were used to create hair care tools. Usually in conjunction with the idea of 100 strokes a day was the suggestion that hair will 'shine' and be 'soft' to the touch. This is the usual result of Boar Bristle Brushing. When hair is damaged, the only solution is to cut it and use a hydrating treatment to protect the new ends. This may be accomplished by cutting hair from the length, or by examining individual sections of hair and cutting off only the hairs that contain damage. The latter process is more time-consuming, but allows for the retention of length. Splits are not the only kinds of damage. There are white dots (where the cuticle has burst, and the hair bends at a 90 degree angle); there are splits that have yet to break apart in the traditional Y but if the hair is held between the two hands and pushed together from either end, the hole will reveal itself. Such damage can occur anywhere in the hair and in quality hair care activities will tend to be only on the tips of hairs or on the ends of length for the most part, it can also be on the youngest hair, close to the scalp -- in short, anywhere. Do not split the hair up the shaft while it's on the head and then leave the hair intact on the head. This can result in damaging other fellow hairs and further contributes to tangle issues as this is now a stressed hair (hair that has been stretched beyond its elasticity). # Hair sprays Applied properly, most hair sprays will not harm the hair. Excessive use or failure to shampoo, however, can cause hair to become dull. Hair sprays that contain alcohol may dry the hair excessively. # Wigs Normal wig wearing, with the wig cap, is not injurious to the hair provided the wig is not too tight, but more shampooing may become necessary because wigs incease scalp perspiration. Wigs are a fun option for quickly changing one's look without actually re-shaping hair with cutting and in this way become a viable alternate expression. Additionally, when considering changing to a new hair style, wigs that are already in that shape may help an individual decide to change the form of their hair design as one can see how they will actually look in that form before actually re-shaping the hair with permanent cutting. Waiting for an undesirable look to grow out can be a painful process emotionally and psychologically. # Pregnancy During pregnancy and breast feeding, the normal and natural shedding process is typically suspended (starting around month three because it takes a while for the body to recognize and reset for the hormonal shifts the body goes through) for the period of gestation and extended longer if one breast feeds (this includes pumping for breast milk). Upon cessation of either of these, it typically takes around two months for the hormones to shift again to the normal hormonal settings, and hair shedding can increase exponentially, for approximately 3-6 months until hair returns to its normal volume. It is commonly noticed that hair seems thicker and shinier, even, during pregnancy and breast feeding in response to the influx of shifting hormones. If excess shedding continues for much longer than six months, seek the counsel of a qualified physician. It is not unusual also for hair color to change, or hair structure to change (e.g., straighter hair, curlier hair). These changes can occur more often than people may realize yet isn't often reported. Despite popular opinion, there is no medical evidence that permanents are ineffective during pregnancy. # Permanents Whenever hair is chemically altered, as in a permanent or coloring, or anything similar, it is vital to use the proper products to maintain hair health and prevent excessive breakdown of the cuticle and cortex. Before a hair color or permanent, or similar chemical alteration of the cortex is applied, it is wise to conduct a strand test. Professional salons should offer this service as part of the counseling session of what will be done that day to the hair, and/or as part of the process of chemical procedures. It should be conducted before the application of a chemical process. Some salons require a waiver be signed if a client refuses this procedure. # Hair loss Some choose to shave their hair off entirely, while still others may have an illness (such as a form of cancer--note that not every form of cancer or cancer treatment necessarily means one will lose their hair. A qualified physician should be able to advise on this point.) that caused hair loss or lead to a decision to shave the head. In this instance care of the scalp skin must be attended to and may include protection when exposing the skin to the sun (such as wearing a soft hat or scarf, and applying sunscreen), and proper maintenance of a shaved head with moisturizing products and better quality shaving tools. Those who suffer from hair loss in instances of cancer care will need to consult with their medical provider to examine the idea of a purchase of a wig. There are many outlets now that provide options of human hair and synthetic hair wigs. Synthetic wigs tend to be easier to maintain for a longer duration. Often, though, the hair, in time, will grow back so soft hats and scarves are often preferred for delicate skin that has been through so much. Those who note excessive shedding inexplicably, or especially falling out in clumps, should seek the counsel of a physician to rule out any issues with hormones and thyroid, among other possibilities. Hair thinning can be experienced even in instances of eczema, psoriasis, and when dandruff has advanced and may be coupled with a bacterial infection of the hair follicles. There are various reasons for hair loss, most commonly hormonal issues. Fluctuations in hormones will often show in the hair. Not all hair loss is related to what is known as male pattern baldness, and indeed, women can suffer from baldness just as men do. This includes women experiencing what's referred to as male pattern baldness. There exist on the markets formulas for addressing this specific cause of lack of hair growth yet typically they require around three months of consistence use for results to begin to appear. Cessation may also mean that gained growth may dissipate. # Drying When using hair dryers select lowered temperatures to keep from splitting or otherwise damaging hair. Hair that has been subjected to the use of a permanent is weaker due to the application of chemicals, and should be treated gently and with greater care than hair that isn't chemically altered. Blow drying hair can be done in a healthier way by using a diffuser so the air flow is not focused in a stream. This will also help prevent excessive tangling. Also, consider setting the blow dryer on a cooler setting versus high. Further, take care when using a blow dryer, or any hot appliance such as irons to not get the heat too close to scalp skin as a burn of the skin is possible. For those with thick hair, half drying can work if one has the time to also allow for some air drying (letting nature finish the drying process). These ideas can still allow one to style their hair yet preserve the health, beauty and luster of the organic fiber that hair is. # Trimming Although trimming may beautify hair by removing damaged or split ends, cutting does not promote faster growth. Nor does trimming remove all damage throughout the hair (remember, damage can occur anywhere in any length of hair depending on overall care it is given and various processes that are applied.) Trimming can help with tangles if one trims a slight amount off the ends of overall length when it's noticed that tangles seem to be more of a problem. Trimming at regular intervals is only necessary for maintaining formed shapes, usually. Hair grows at the same rate regardless, and the rate is largely a matter of heredity and hormones. If one is interested in gaining length, trimming a small amount that represents a mere percent of overall gained length will help maintain a healthy hemline yet also always working towards gained length. There exist ways to trim hair oneself as outlined in places on the internet and hair care reading materials. To trim hair, it is best to do so when dry. This is especially true of those who possess any body to their hair. It’s important to visualize the line as it will actually be worn—-that is dry. Wet hair stretches rather significantly in length. Curly hair will unfurl a fair amount when fully wet such that once dried, it will appear that a lot has been taken off since dry curly hair will coil back up even if factually very little was removed. Further, curly hair, in particular, once dry, might appear visually to have an uneven line depending on how the curl coils back up. If the furl is to the inside, it may appear shorter in that spot, versus the furl end exposed to the outside, this will likely appear longer. This concerns appearance and perception rather than actual trim line. A stylist may have trimmed a straight line in some form (such as V, U, or straight across) along the ends of any length, but once dry, curly hair in particular can appear crooked. Trimming hair dry prevents these possibilities as the stylist can work with how the hair actually appears, even being detailed in curl to ensure cutting is done at a certain area along the coil of curled hair so it furls in an optimum manner and does not disrupt the pattern of curl. Lorraine Massey, author of Curly Girl, specializes in the care of curly hair types, and has designed a specific method for trimming curly hair to avoid these problems. The reason stylists like working with wet hair may again be related to weight. Wet hair, being that it’s heavier, tends to be easier to manage in a cut/style situation since the hair remains in place thus holding a line and making it easier for the stylist to create a form. During any cutting, a person should sit or stand tall and straight, and avoid moving, especially any tilting of the head in any direction as this affects the stylists visualization of line, form and structure. Of course, if a chemical process is being applied to the hair, it must be wetted. If one is interested in "just a trim" it is best to be specific with exactly how many inches one desires to have removed to prevent misunderstandings between a stylist and client. If necessary, use a tape measure to further define and agree on the amount to be removed. Whenever choosing to visit a new stylist for any reason, be sure to disclose all procedures previously done on the hair within the last two years. Disclosing how recently any procedure was done is vital. This is especially so in instances of color and chemical processes such as permanents. If the timeframe and name of procedure is not disclosed, or the incorrect information is disclosed (for example, claiming ammonia wasn’t used when in fact it was six days ago), this can lay the path for a hair disaster. It’s best, if at all possible, to bring in the card from one’s former stylist to the new stylist so they know what process was applied, what color choices were made and degrees of color lift were applied. This is also true in instances when one’s stylist is on vacation or otherwise unavailable. Matching a color can be very difficult, so bringing along the information of what has been used previously can be very helpful to maintaining healthy hair and preventing any disasters. A professional stylist does maintain notes on their regular clients as to history of processes, styles of cuts, and color values applied, and should be willing to divulge this information to their client. This is done in order to maintain consistency of care and to prevent any hair disasters. When visiting a new stylist, that stylist should conduct a strand test to help prevent any potential disasters (to determine any issues with porosity), especially when it’s readily discernible that hair is colored and/or chemically altered in structure. Further in instances of chemical processes or color, often a hair sample can be taken to pre-test the process and determine how the hair might react. This is unusual for a stylist to proceed in this manner, but in some situations, it may prove beneficial for preventing a hair disaster. Hair disasters include heavy breaking off of hair, lots of hair falling out, or any issues with hair taking up color, or becoming overly dry or brittle from a procedure. # Braiding Tight or frequent braiding may pull at the hair roots and cause traction alopecia. Rubber bands with metal clasps or tight clips should also be avoided. Braiding can be done on a regular basis if the braids are not too tight and the parting is varied so that the strain isn't on the same sections of hair all the time. The same holds true of placing hair in any forms of updos. Do not pull the hair, ever, too tightly from the hair root. In placing longer lengths up, the same concern to avoid pulling hair overly tight should also be considered. Further, if one places hair up on a daily basis, varying the style is important since constantly binding the hair in the same location (such as a ponytail), using the same tool daily to hold the hair up, can, over time, lead to some thinning in certain areas, especially in instances where the tool is quite heavy (metal). # Headaches and hair Headaches can occur when there is stress on the hair follicle. For example, hair drawn in a direction other than its natural growth pattern (hair types come out of the hair follicle in particular patterns for curly, body, straight; and also, hair grows in a pattern about the head so that it hangs or forms the way it does for humans). If hair, like braiding, is pinned too tightly, or the whole updo slips causing pulling on the hair in the follicle at the hair root are other scenarios that can cause aggravation to the hair follicle and result in headaches. This is because there is a system of capillaries and even veins that feed into the hair follicle, which is what nourishes the follicle to grow hair. If the hair follicle is aggravated, the capillaries are in turn aggravated and in this way a headache can arise. For those with heavy hair, consider dividing the weight of the hair or placing more of the hair in an updo on top of the head such that the skull supports the weight of the hair better. Also, consider using long bobby pins (what are technically named hair roller pins) to pin the hair in an interlocking network for better hold. Pin as one proceeds in creating the updo style for maximum staying in position. Do not wait until the end of forming the hair to pin into place. Those who swim in chlorinated or salt sea water may benefit from first wetting the hair entirely and then applying conditioner to completely swell the entire hair shaft. The idea is that less uptake of chlorine or salt may result which in turn helps to preserve the beauty of hair. Those who swim a lot may also benefit from the products on the market that remove chlorine after swimming in pool water. # Safety Precautions Whenever one works around anything that can make hair lengths fan (such as opening oven doors, any machine with a motor (whether the motor itself is exposed or not such as lathes, drill presses, grinders, car engines, household fans), anything with heat (such as torches, welding equipment, jeweler tools, lighting pilot lights, BBQs) or any recreational vehicle (such as go karts, and with unusually longer lengths, perhaps even bicycles), it is best to contain the hair in a reliable manner to prevent the hair being caught up in the equipment which could potentially result in major injury, including scalping. Hair should be drawn back in a reliable method to prevent falling or slipping such that any formerly contained hair could fall out in whole, or in part, and place one at risk. This may well mean that a ponytail for hair length is insufficient as hair fringe and bangs may remain vulnerable, and hair, during the course of a day can fall out. Ponytailed hair means it’s only bound at one point yet the remaining length is loose hair which has a wide circumference it can still fall. Ponytailed hair can still fall forward if one is leaning over, or for example, in a kitchen with an open gas flame, can still fan out when one turns and the air flow from body movement can cause a pulse in the flame to a higher level and singe some hair. Same holds true with oven doors: ponytailed hair can fall forward on to hot surfaces when leaning over and get singed. Care around any flame should be taken including proximity to tools for lighting cigarettes and cigars. Often it is best to not only bind the hair; but also, position the hair inside a cap or bandanna such that the full head of hair is completely covered. This scenario is good not only around machinery but may well be a good idea in instances of working outdoors all day long, or when working in areas where fine dust and particulate matter is swirling about (paint, spraying, powder coating, laying tar) to prevent the hair being caked with such particles. Many industries have requirements for hair being contained to prevent worker injury. This likely includes those working in food services, construction, utilities, and machine shops of various sorts. Anytime one works in an area that can move the air flow, hair should be bound for safety of the person as hair is a very light weight substance and responds to the slightest of breezes. Of course, many professions do require containing the hair for reasons of public health, and a prime example is the food industry. Many sports may require similar constraints for reasons of safety to keep hair out of eyes and blocking one's view, and to prevent being caught in sports equipment or trees and shrubs, or matted hair in severe weather conditions or water. This would include not allowing hair to fly loose on the backs of motorcycles and open-topped sports cars for longer tresses. # Scalp Skin There are a number of disorders that are particular to the scalp. Symptoms may include: - bumps, - lumps, - chafes, - weeping or bleeding, - clumpy flakes that do not easily slough off the scalp skin, - caking skin buildup that appears white or another color than one's natural skin tone, - excessive itchiness that doesn't go away with a few hair wash, redness of scalp skin, - patches of thinning, - clumps of hair falling out, - shedding, - pus-like drainage, - abnormal odor, - dandruff Any of these symptoms may indicate a need for professional assistance from a dermatologist or trichologist for diagnosis. Scalp skin can suffer from infestations of mites, lice, infections of the follicles or fungus. There could be allergic reactions to ingredients in chemical preparations applied to the hair, even ingredients from shampoo or conditioners. Common concerns surrounding dandruff (often associated with excessive sebum); psoriasis, eczema, or seborrheic dermatitus. An odor that persists for a few weeks despite regular hair washing may be an indication of a health problem on the scalp skin. Photographs over the internet can be difficult to diagnose. Not all flakes are dandruff. For example, some can merely be product buildup on the scalp skin. This could result from the common practice of applying conditioner to scalp skin without washing. This would dry upon the scalp skin and flake off, appearing like dandruff and even causing itchiness, but have no health effects whatsoever. Although rapid detection and treatment of scalp disease can prevent permanent conditions such as thinning, hair loss, shedding, or death of hair follicles, regular hygiene is still the most effective method of preventing scalp disease. # Thyroid disease Particularly among women, thyroid disease is one of the more under-diagnosed health concerns. It's very important to see a medical professional when hair falls out in clumps. This is one symptom of a set of symptoms that may indicate a thyroid concern. The good news is that in many gynecological exams a blood screen for thyroid is now a common protocol. Although this entry regarding hair care is not about thyroid, it is worth mentioning since it's not as commonly known by the general population that thyroid often shows up first in the behavior of the hair.	https://www.wikidoc.org/index.php/Hair_care
fdff428c1b19d16c5d0665789be8a6e162433dce	wikidoc	Hair cell	Hair cell Hair cells are the sensory receptors of both the auditory system and the vestibular system in all vertebrates. In mammals, the auditory hair cells are located within the organ of Corti on a thin basilar membrane in the cochlea of the inner ear. They derive their name from the tufts of stereocilia that protrude from the apical surface of the cell, a structure known as the hair bundle, into the scala media, a fluid-filled tube within the cochlea. Mammalian cochlear hair cells come in two anatomically and functionally distinct types: the outer and inner hair cells. Damage to these hair cells results in decreased hearing sensitivity, i.e. sensorineural hearing loss. # Hair bundles as sound detectors Research of the past decades has shown that outer hair cells do not send neural signals to the brain, but that they mechanically amplify low-level sound that enters the cochlea. The amplification may be powered by movement of their hair bundles, or by an electrically driven motility of their cell bodies. The inner hair cells transform the sound vibrations in the fluids of the cochlea into electrical signals that are then relayed via the auditory nerve to the auditory brainstem and to the auditory cortex. # Inner hair cells – from sound to nerve signal The deflection of the hair-cell stereocilia opens mechanically gated ion channels that allow any small, positively charged ions (primarily potassium and calcium) to enter the cell. Unlike many other electrically active cells, the hair cell itself does not fire an action potential. Instead, the influx of positive ions from the endolymph in Scala media depolarizes the cell, resulting in a receptor potential. This receptor potential opens voltage gated calcium channels; calcium ions then enter the cell and trigger the release of neurotransmitters, mainly glutamate, at the basal end of the cell. The neurotransmitters diffuse across the narrow space between the hair cell and a nerve terminal, where they then bind to receptors and thus trigger action potentials in the nerve. In this way, the mechanical sound signal is converted into an electrical nerve signal. The repolarization in the hair cell is done in a special manner. The perilymph in Scala tympani has a very low concentration of positive ions. The electrochemical gradient makes the positive ions flow through channels to the perilymph. Nerve fiber innervation is much more dense for inner hair cells than for outer hair cells. A single inner hair cell is innervated by numerous nerve fibers, whereas a single nerve fiber innervates many outer hair cells. Inner hair cell nerve fibers are also very heavily myelinated, which is contrast to the unmyelinated outer hair cell nerve fibers. # Outer hair cells – acoustical pre-amplifiers In mammalian outer hair cells, the receptor potential triggers active vibrations of the cell body. This so-called somatic electromotility consists of oscillations of the cell’s length, which occur at the frequency of the incoming sound and in a stable phase relation. Outer hair cells have evolved only in mammals. They have not improved hearing sensitivity, which reaches similarly exquisite values also in other classes of vertebrates. But they have extended the hearing range from ca 11 kHz (maximum in some birds) to ca 200 kHz (maximum in some marine mammals). They have also improved frequency selectivity (frequency discrimination), which is of particular benefit for humans, because it enabled sophisticated speech and music. The molecular biology of hair cells has seen considerable progress in recent years, with the identification of the motor protein (prestin) that underlies somatic electromotility in the outer hair cells. # Hair-bundle motors Results in recent years further indicate that mammals apparently also have conserved an evolutionarily earlier type of hair-cell motility. This so-called hair-bundle motility amplifies sound in all non-mammalian land vertebrates. It is effected by the closing mechanism of the mechanical sensory ion channels at the tips of the hair bundles. Thus, the same hair-bundle mechanism that detects sound vibrations also actively “vibrates back” and thereby mechanically amplifies weak incoming sound. # Additional images - Inner ear illustration showing semicircular canal, hair cells, ampulla, cupula, vestibular nerve, & fluid	Hair cell Template:Infobox neuron Hair cells are the sensory receptors of both the auditory system and the vestibular system in all vertebrates. In mammals, the auditory hair cells are located within the organ of Corti on a thin basilar membrane in the cochlea of the inner ear. They derive their name from the tufts of stereocilia that protrude from the apical surface of the cell, a structure known as the hair bundle, into the scala media, a fluid-filled tube within the cochlea. Mammalian cochlear hair cells come in two anatomically and functionally distinct types: the outer and inner hair cells. Damage to these hair cells results in decreased hearing sensitivity, i.e. sensorineural hearing loss. # Hair bundles as sound detectors Research of the past decades has shown that outer hair cells do not send neural signals to the brain, but that they mechanically amplify low-level sound that enters the cochlea. The amplification may be powered by movement of their hair bundles, or by an electrically driven motility of their cell bodies. The inner hair cells transform the sound vibrations in the fluids of the cochlea into electrical signals that are then relayed via the auditory nerve to the auditory brainstem and to the auditory cortex. # Inner hair cells – from sound to nerve signal The deflection of the hair-cell stereocilia opens mechanically gated ion channels that allow any small, positively charged ions (primarily potassium and calcium) to enter the cell. Unlike many other electrically active cells, the hair cell itself does not fire an action potential. Instead, the influx of positive ions from the endolymph in Scala media depolarizes the cell, resulting in a receptor potential. This receptor potential opens voltage gated calcium channels; calcium ions then enter the cell and trigger the release of neurotransmitters, mainly glutamate, at the basal end of the cell. The neurotransmitters diffuse across the narrow space between the hair cell and a nerve terminal, where they then bind to receptors and thus trigger action potentials in the nerve. In this way, the mechanical sound signal is converted into an electrical nerve signal. The repolarization in the hair cell is done in a special manner. The perilymph in Scala tympani has a very low concentration of positive ions. The electrochemical gradient makes the positive ions flow through channels to the perilymph. Nerve fiber innervation is much more dense for inner hair cells than for outer hair cells. A single inner hair cell is innervated by numerous nerve fibers, whereas a single nerve fiber innervates many outer hair cells. Inner hair cell nerve fibers are also very heavily myelinated, which is contrast to the unmyelinated outer hair cell nerve fibers. # Outer hair cells – acoustical pre-amplifiers In mammalian outer hair cells, the receptor potential triggers active vibrations of the cell body. This so-called somatic electromotility consists of oscillations of the cell’s length, which occur at the frequency of the incoming sound and in a stable phase relation. Outer hair cells have evolved only in mammals. They have not improved hearing sensitivity, which reaches similarly exquisite values also in other classes of vertebrates. But they have extended the hearing range from ca 11 kHz (maximum in some birds) to ca 200 kHz (maximum in some marine mammals). They have also improved frequency selectivity (frequency discrimination), which is of particular benefit for humans, because it enabled sophisticated speech and music. The molecular biology of hair cells has seen considerable progress in recent years, with the identification of the motor protein (prestin) that underlies somatic electromotility in the outer hair cells. # Hair-bundle motors Results in recent years further indicate that mammals apparently also have conserved an evolutionarily earlier type of hair-cell motility. This so-called hair-bundle motility amplifies sound in all non-mammalian land vertebrates. It is effected by the closing mechanism of the mechanical sensory ion channels at the tips of the hair bundles. Thus, the same hair-bundle mechanism that detects sound vibrations also actively “vibrates back” and thereby mechanically amplifies weak incoming sound. # Additional images - Inner ear illustration showing semicircular canal, hair cells, ampulla, cupula, vestibular nerve, & fluid	https://www.wikidoc.org/index.php/Hair_cell
2bb61da3dac70aee12e1bf9e6bcfd356df969c0e	wikidoc	Halazepam	Halazepam # Overview Halazepam is a benzodiazepine derivative that was marketed under the brand names Paxipam in the United States, Alapryl in Spain, and Pacinone in Portugal. # Medical uses Halazepam was used for the treatment of anxiety. # Adverse effects Adverse effects include drowsiness, confusion, dizziness, and sedation. Gastrointestinal side effects have also been reported including dry mouth and nausea. # Pharmacokinetics and pharmacodynamics Pharmacokinetics and pharmacodynamics were listed in Current Psychotherapeutic Drugs published in June 15, 1998 as follows: # Regulatory Information Halazepam is classified as a schedule 4 controlled substance with a corresponding code 2762 by the Drug Enforcement Administration (DEA). # Commercial production Halazepam was invented by Schlesinger Walter in the U.S. It was marketed as an anti-anxiety agent in 1981. However, Halazepam is not commercially available in the United States because it was withdrawn by its manufacturer for poor sales.	Halazepam Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Halazepam is a benzodiazepine derivative that was marketed under the brand names Paxipam in the United States,[1] Alapryl in Spain,[2] and Pacinone in Portugal.[3] # Medical uses Halazepam was used for the treatment of anxiety.[1] # Adverse effects Adverse effects include drowsiness, confusion, dizziness, and sedation. Gastrointestinal side effects have also been reported including dry mouth and nausea.[1] # Pharmacokinetics and pharmacodynamics Pharmacokinetics and pharmacodynamics were listed in Current Psychotherapeutic Drugs published in June 15, 1998 as follows:[4] # Regulatory Information Halazepam is classified as a schedule 4 controlled substance with a corresponding code 2762 by the Drug Enforcement Administration (DEA).[5] # Commercial production Halazepam was invented by Schlesinger Walter in the U.S. It was marketed as an anti-anxiety agent in 1981. However, Halazepam is not commercially available in the United States because it was withdrawn by its manufacturer for poor sales.[1]	https://www.wikidoc.org/index.php/Halazepam
33d94288e2479af48f5fd04dec581c73e1a763a0	wikidoc	Triazolam	Triazolam # 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 Triazolam is a triazolobenzodiazepine hypnotic agent that is FDA approved for the {{{indicationType}}} of insomnia. Common adverse reactions include nausea and vomiting, amnesia, ataxia, dizziness, feeling nervous, headache, incoordination, lightheadedness, somnolence, euphoria, fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Triazolam is indicated for the short-term treatment of insomnia (generally 7–10 days). Use for more than 2–3 weeks requires complete reevaluation of the patient. - Prescriptions for triazolam should be written for short-term use (7–10 days) and it should not be prescribed in quantities exceeding a 1-month supply. - It is important to individualize the dosage of triazolam tablets for maximum beneficial effect and to help avoid significant adverse effects. - The recommended dose for most adults is 0.25 mg before retiring. A dose of 0.125 mg may be found to be sufficient for some patients (e.g., low body weight). A dose of 0.5 mg should be used only for exceptional patients who do not respond adequately to a trial of a lower dose since the risk of several adverse reactions increases with the size of the dose administered. A dose of 0.5 mg should not be exceeded. - In geriatric and/or debilitated patients the recommended dosage range is 0.125 mg to 0.25 mg. Therapy should be initiated at 0.125 mg in these groups and the 0.25 mg dose should be used only for exceptional patients who do not respond to a trial of the lower dose. A dose of 0.25 mg should not be exceeded in these patients. - As with all medications, the lowest effective dose should be used. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Triazolam in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Triazolam in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Triazolam in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Triazolam in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Triazolam in pediatric patients. # Contraindications - Triazolam tablets are contraindicated in patients with known hypersensitivity to this drug or other benzodiazepines. - Benzodiazepines may cause fetal damage when administered during pregnancy. An increased risk of congenital malformations associated with the use of diazepam and chlordiazepoxide during the first trimester of pregnancy has been suggested in several studies. Transplacental distribution has resulted in neonatal CNS depression following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy. - Triazolam is contraindicated in pregnant women. If there is a likelihood of the patient becoming pregnant while receiving triazolam, she should be warned of the potential risk to the fetus. Patients should be instructed to discontinue the drug prior to becoming pregnant. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. - Triazolam is contraindicated with medications that significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP 3A) including ketoconazole, itraconazole, nefazodone, and several HIV protease inhibitors. # Warnings - Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative-hypnotic drugs. Because some of the important adverse effects of sedative-hypnotics appear to be dose related, it is important to use the smallest possible effective dose, especially in the elderly. - Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported. These events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced persons. Although behaviors such as sleep-driving may occur with sedative-hypnotics alone at therapeutic doses, the use of alcohol and other CNS depressants with sedative-hypnotics appears to increase the risk of such behaviors, as does the use of sedative-hypnotics at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of sedative-hypnotics should be strongly considered for patients who report a "sleep-driving" episode. - Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events. - Severe anaphylactic and anaphylactoid reactions - Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including triazolam. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with triazolam should not be rechallenged with the drug. - Central nervous system manifestations - An increase in daytime anxiety has been reported for triazolam after as few as 10 days of continuous use. In some patients this may be a manifestation of interdose withdrawal. If increased daytime anxiety is observed during treatment, discontinuation of treatment may be advisable. - A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of benzodiazepine hypnotics including triazolam. Some of these changes may be characterized by decreased inhibition, eg, aggressiveness and extroversion that seem excessive, similar to that seen with alcohol and other CNS depressants (eg, sedative/hypnotics). Other kinds of behavioral changes have also been reported, for example, bizarre behavior, agitation, hallucinations, depersonalization. In primarily depressed patients, the worsening of depression, including suicidal thinking, has been reported in association with the use of benzodiazepines. - It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation. - Because of its depressant CNS effects, patients receiving triazolam should be cautioned against engaging in hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the concomitant ingestion of alcohol and other CNS depressant drugs during treatment with triazolam tablets. - As with some, but not all benzodiazepines, anterograde amnesia of varying severity and paradoxical reactions have been reported following therapeutic doses of triazolam. Data from several sources suggest that anterograde amnesia may occur at a higher rate with triazolam than with other benzodiazepine hypnotics. - Triazolam interaction with drugs that inhibit metabolism via cytochrome P450 3A - The initial step in triazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP 3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of triazolam. Consequently, triazolam should be avoided in patients receiving very potent inhibitors of CYP 3A. With drugs inhibiting CYP 3A to a lesser but still significant degree, triazolam should be used only with caution and consideration of appropriate dosage reduction. For some drugs, an interaction with triazolam has been quantified with clinical data; for other drugs, interactions are predicted from in vitro data and/or experience with similar drugs in the same pharmacologic class. - The following are examples of drugs known to inhibit the metabolism of triazolam and/or related benzodiazepines, presumably through inhibition of CYP 3A. - Potent CYP 3A inhibitors - Potent inhibitors of CYP 3A that should not be used concomitantly with triazolam include ketoconazole, itraconazole, nefazodone and several HIV protease inhibitors including ritonavir, indinavir, nelfinavir, saquinavir and lopinavir. Although data concerning the effects of azole-type antifungal agents other than ketoconazole and itraconazole on triazolam metabolism are not available, they should be considered potent CYP 3A inhibitors, and their coadministration with triazolam is not recommended. - Drugs demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving triazolam (caution and consideration of dose reduction are recommended during coadministration with triazolam) - Macrolide Antibiotics - Coadministration of erythromycin increased the maximum plasma concentration of triazolam by 46%, decreased clearance by 53%, and increased half-life by 35%; caution and consideration of appropriate triazolam dose reduction are recommended. Similar caution should be observed during coadministration with clarithromycin and other macrolide antibiotics. - Cimetidine - Coadministration of cimetidine increased the maximum plasma concentration of triazolam by 51%, decreased clearance by 55%, and increased half-life by 68%; caution and consideration of appropriate triazolam dose reduction are recommended. - Other drugs possibly affecting triazolam metabolism - Other drugs possibly affecting triazolam metabolism by inhibition of CYP 3A are discussed in the PRECAUTIONS section. ### Precautions - In elderly and/or debilitated patients it is recommended that treatment with triazolam tablets be initiated at 0.125 mg to decrease the possibility of development of oversedation, dizziness, or impaired coordination. - Some side effects reported in association with the use of triazolam appear to be dose related. These include drowsiness, dizziness, light-headedness, and amnesia. - The relationship between dose and what may be more serious behavioral phenomena is less certain. Specifically, some evidence, based on spontaneous marketing reports, suggests that confusion, bizarre or abnormal behavior, agitation, and hallucinations may also be dose related, but this evidence is inconclusive. In accordance with good medical practice it is recommended that therapy be initiated at the lowest effective dose. - Cases of "traveler's amnesia" have been reported by individuals who have taken triazolam to induce sleep while traveling, such as during an airplane flight. In some of these cases, insufficient time was allowed for the sleep period prior to awakening and before beginning activity. Also, the concomitant use of alcohol may have been a factor in some cases. - Caution should be exercised if triazolam is prescribed to patients with signs or symptoms of depression that could be intensified by hypnotic drugs. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional over-dosage is more common in these patients, and the least amount of drug that is feasible should be available to the patient at any one time. - The usual precautions should be observed in patients with impaired renal or hepatic function, chronic pulmonary insufficiency, and sleep apnea. In patients with compromised respiratory function, respiratory depression and apnea have been reported infrequently. # Adverse Reactions ## Clinical Trials Experience - During placebo-controlled clinical studies in which 1,003 patients received triazolam tablets, the most troublesome side effects were extensions of the pharmacologic activity of triazolam, eg, drowsiness, dizziness, or light-headedness. - The figures cited below are estimates of untoward clinical event incidence among subjects who participated in the relatively short duration (i.e., 1 to 42 days) placebo-controlled clinical trials of triazolam. The figures cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors often differ from those in clinical trials. These figures cannot be compared with those obtained from other clinical studies involving related drug products and placebo, as each group of drug trials is conducted under a different set of conditions. - Comparison of the cited figures, however, can provide the prescriber with some basis for estimating the relative contributions of drug and nondrug factors to the untoward event incidence rate in the population studied. Even this use must be approached cautiously, as a drug may relieve a symptom in one patient while inducing it in others. (For example, an anticholinergic, anxiolytic drug may relieve dry mouth in some subjects but induce it in others.) - In addition to the relatively common (i.e., 1% or greater) untoward events enumerated above, the following adverse events have been reported less frequently (i.e., 0.9% to0.5%): euphoria, tachycardia, tiredness, confusional states/memory impairment, cramps/pain, depression, visual disturbances. - Rare (i.e., less than 0.5%) adverse reactions included constipation, taste alterations, diarrhea, dry mouth, dermatitis/allergy, dreaming/nightmares, insomnia, paresthesia, tinnitus, dysesthesia, weakness, congestion, death from hepatic failure in a patient also receiving diuretic drugs. - In addition to these untoward events for which estimates of incidence are available, the following adverse events have been reported in association with the use of triazolam and other benzodiazepines: amnestic symptoms (anterograde amnesia with appropriate or inappropriate behavior), confusional states (disorientation, derealization, depersonalization, and/or clouding of consciousness), dystonia, anorexia, fatigue, sedation, slurred speech, jaundice, pruritus, dysarthria, changes in libido, menstrual irregularities, incontinence, and urinary retention. Other factors may contribute to some of these reactions, eg, concomitant intake of alcohol or other drugs, sleep deprivation, an abnormal premorbid state, etc. - Other events reported include: paradoxical reactions such as stimulation, mania, an agitational state (restlessness, irritability, and excitation), increased muscle spasticity, sleep disturbances, hallucinations, delusions, aggressiveness, falling, somnambulism, syncope, inappropriate behavior and other adverse behavioral effects. Should these occur, use of the drug should be discontinued. - The following events have also been reported: chest pain, burning tongue/glossitis/stomatitis. - Laboratory analyses were performed on all patients participating in the clinical program for triazolam. The following incidences of abnormalities were observed in patients receiving triazolam and the corresponding placebo group. None of these changes were considered to be of physiological significance. - When treatment with triazolam is protracted, periodic blood counts, urinalysis, and blood chemistry analyses are advisable. - Minor changes in EEG patterns, usually low-voltage fast activity, have been observed in patients during therapy with triazolam and are of no known significance. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Triazolam in the drug label. # Drug Interactions - Both pharmacodynamic and pharmacokinetic interactions have been reported with benzodiazepines. In particular, triazolam produces additive CNS depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistamines, ethanol, and other drugs which themselves produce CNS depression. - Drugs that inhibit triazolam metabolism via cytochrome P450 3A - The initial step in triazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP 3A). Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of triazolam. Triazolam is contraindicated with ketoconzaole, itraconazole, nefazodone, and several HIV protease inhibitors. - Drugs and other substances demonstrated to be CYP 3A inhibitors of possible clinical significance on the basis of clinical studies involving triazolam. - Isoniazid - Coadministration of isoniazid increased the maximum plasma concentration of triazolam by 20%, decreased clearance by 42%, and increased half-life by 31%. - Oral contraceptives - Coadministration of oral contraceptives increased maximum plasma concentration by 6%, decreased clearance by 32%, and increased half-life by 16%. - Grapefruit juice - Coadministration of grapefruit juice increased the maximum plasma concentration of triazolam by 25%, increased the area under the concentration curve by 48%, and increased half-life by 18%. - Drugs demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to triazolam or on the basis of in vitro studies with triazolam or other benzodiazepines (caution is recommended during coadministration with triazolam) - Available data from clinical studies of benzodiazepines other than triazolam suggest a possible drug interaction with triazolam for the following: fluvoxamine, diltiazem, and verapamil. Data from in vitro studies of triazolam suggest a possible drug interaction with triazolam for the following: sertraline and paroxetine. Data from in vitro studies of benzodiazepines other than triazolam suggest a possible drug interaction with triazolam for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is recommended during coadministration of any of these drugs with triazolam. - Drugs that affect triazolam pharmacokinetics by other mechanisms - Ranitidine - Coadministration of ranitidine increased the maximum plasma concentration of triazolam by 30%, increased the area under the concentration curve by 27%, and increased half-life by 3.3%. Caution is recommended during coadministration with triazolam. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category X - Teratogenic effects - Pregnancy category X (see CONTRAINDICATIONS). - Non-teratogenic effects - It is to be considered that the child born of a mother who is on benzodiazepines may be at some risk for withdrawal symptoms from the drug, during the postnatal period. Also, neonatal flaccidity has been reported in an infant born of a mother who had been receiving benzodiazepines. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Triazolam in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Triazolam during labor and delivery. ### Nursing Mothers - Human studies have not been performed; however, studies in rats have indicated that triazolam and its metabolites are secreted in milk. Therefore, administration of triazolam to nursing mothers is not recommended. ### Pediatric Use - Safety and effectiveness of triazolam in individuals below 18 years of age have not been established. ### Geriatic Use - The elderly are especially susceptible to the dose related adverse effects of triazolam. They exhibit higher plasma triazolam concentrations due to reduced clearance of the drug as compared with younger subjects at the same dose. To minimize the possibility of development of oversedation, the smallest effective dose should be used. ### Gender There is no FDA guidance on the use of Triazolam with respect to specific gender populations. ### Race There is no FDA guidance on the use of Triazolam with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Triazolam in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Triazolam in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Triazolam in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Triazolam in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Triazolam in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Triazolam in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Because of the potency of triazolam, some manifestations of overdosage may occur at 2 mg, four times the maximum recommended therapeutic dose (0.5 mg). - Manifestations of overdosage with triazolam tablets include somnolence, confusion, impaired coordination, slurred speech, and ultimately, coma. Respiratory depression and apnea have been reported with overdosages of triazolam. Seizures have occasionally been reported after overdosages. - Death has been reported in association with overdoses of triazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzodiazepine, including triazolam, and alcohol; benzodiazepine and alcohol levels seen in some of these cases have been lower than those usually associated with reports of fatality with either substance alone. ### Management - As in all cases of drug overdosage, respiration, pulse, and blood pressure should be monitored and supported by general measures when necessary. Immediate gastric lavage should be performed. An adequate airway should be maintained. Intravenous fluids may be administered. - Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. - Experiments in animals have indicated that cardiopulmonary collapse can occur with massive intravenous doses of triazolam. This could be reversed with positive mechanical respiration and the intravenous infusion of norepinephrine bitartrate or metaraminol bitartrate. Hemodialysis and forced diuresis are probably of little value. As with the management of intentional overdosage with any drug, the physician should bear in mind that multiple agents may have been ingested by the patient. - The oral LD50 in mice is greater than 1,000 mg/kg and in rats is greater than 5,000 mg/kg. ## Chronic Overdose There is limited information regarding Chronic Overdose of Triazolam in the drug label. # Pharmacology ## Mechanism of Action - Triazolam is a triazolobenzodiazepine hypnotic drug that increases the duration of sleep and decreases the number of nocturnal awakenings and sleep latency. ## Structure - Triazolam is a triazolobenzodiazepine hypnotic agent. - Triazolam is a white crystalline powder, soluble in alcohol and poorly soluble in water. It has a molecular weight of 343.21. - The chemical name for triazolam is 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo- benzodiazepine. - The structural formula is represented below: - Each triazolam tablet, for oral administration, contains 0.125 mg or 0.25 mg of triazolam. Inactive ingredients: 0.125 mg—cellulose, corn starch, docusate sodium, lactose, magnesium stearate, silicon dioxide, sodium benzoate; 0.25 mg—cellulose, corn starch, docusate sodium, FD&C Blue No. 2, lactose, magnesium stearate, silicon dioxide, sodium benzoate. ## Pharmacodynamics - In sleep laboratory studies, triazolam tablets significantly decreased sleep latency, increased the duration of sleep, and decreased the number of nocturnal awakenings. After 2 weeks of consecutive nightly administration, the drug's effect on total wake time is decreased, and the values recorded in the last third of the night approach baseline levels. On the first and/or second night after drug discontinuance (first or second post-drug night), total time asleep, percentage of time spent sleeping, and rapidity of falling asleep frequently were significantly less than on baseline (predrug) nights. This effect is often called "rebound" insomnia. - The type and duration of hypnotic effects and the profile of unwanted effects during administration of benzodiazepine drugs may be influenced by the biologic half-life of administered drug and any active metabolites formed. When half-lives are long, the drug or metabolites may accumulate during periods of nightly administration and be associated with impairments of cognitive and motor performance during waking hours; the possibility of interaction with other psychoactive drugs or alcohol will be enhanced. In contrast, if half-lives are short, the drug and metabolites will be cleared before the next dose is ingested, and carry-over effects related to excessive sedation or CNS depression should be minimal or absent. However, during nightly use for an extended period pharmacodynamic tolerance or adaptation to some effects of benzodiazepine hypnotics may develop. If the drug has a short half-life of elimination, it is possible that a relative deficiency of the drug or its active metabolites (ie, in relationship to the receptor site) may occur at some point in the interval between each night's use. This sequence of events may account for two clinical findings reported to occur after several weeks of nightly use of rapidly eliminated benzodiazepine hypnotics: 1) increased wakefulness during the last third of the night and 2) the appearance of increased daytime anxiety after 10 days of continuous treatment. - In a study of elderly (62–83 years old) versus younger subjects (21–41 years old) who received triazolam at the same dose levels (0.125 mg and 0.25 mg), the elderly experienced both greater sedation and impairment of psychomotor performance. These effects resulted largely from higher plasma concentrations of triazolam in the elderly. ## Pharmacokinetics - Triazolam is a hypnotic with a short mean plasma half-life reported to be in the range of 1.5 to 5.5 hours. In normal subjects treated for 7 days with four times the recommended dosage, there was no evidence of altered systemic bioavailability, rate of elimination, or accumulation. Peak plasma levels are reached within 2 hours following oral administration. Following recommended doses of triazolam tablets, triazolam peak plasma levels in the range of 1 to 6 ng/mL are seen. The plasma levels achieved are proportional to the dose given. - Triazolam and its metabolites, principally as conjugated glucuronides, which are presumably inactive, are excreted primarily in the urine. Only small amounts of unmetabolized triazolam appear in the urine. The two primary metabolites accounted for 79.9% of urinary excretion. Urinary excretion appeared to be biphasic in its time course. - Triazolam tablets 0.5 mg, in two separate studies, did not affect the prothrombin times or plasma warfarin levels in male volunteers administered sodium warfarin orally. - Extremely high concentrations of triazolam do not displace bilirubin bound to human serum albumin in vitro. - Triazolam 14C was administered orally to pregnant mice. Drug-related material appeared uniformly distributed in the fetus with 14C concentrations approximately the same as in the brain of the mother. ## Nonclinical Toxicology - No evidence of carcinogenic potential was observed in mice during a 24-month study with triazolam in doses up to 4,000 times the human dose. # Clinical Studies There is limited information regarding Clinical Studies of Triazolam in the drug label. # How Supplied - Triazolam tablets are available in the following strengths and package sizes: - 0.125 mg (white,, imprinted G3717): 10–10 Tablet Bottles NDC 59762-3717-4 - 10–10 Tablet Bottles NDC 59762-3717-4 - 0.25 mg (powder blue, scored, imprinted G3718): 10–10 Tablet Bottles NDC 59762-3718-4 Bottles of 500 NDC 59762-3718-3 - 10–10 Tablet Bottles NDC 59762-3718-4 - Bottles of 500 NDC 59762-3718-3 - Store at controlled room temperature 20° to 25°C (68° to 77°F). ## Storage There is limited information regarding Triazolam Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - "Sleep-driving" and other complex behaviors - There have been reports of people getting out of bed after taking a sedative-hypnotic and driving their cars while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should be reported to his or her doctor immediately, since "sleep-driving" can be dangerous. This behavior is more likely to occur when sedative-hypnotics are taken with alcohol or other central nervous system depressants. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative hypnotic. As with sleep-driving, patients usually do not remember these events. # Precautions with Alcohol - Alcohol-Triazolam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TRIAZOLAM® # Look-Alike Drug Names There is limited information regarding Triazolam Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Triazolam Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Triazolam is a triazolobenzodiazepine hypnotic agent that is FDA approved for the {{{indicationType}}} of insomnia. Common adverse reactions include nausea and vomiting, amnesia, ataxia, dizziness, feeling nervous, headache, incoordination, lightheadedness, somnolence, euphoria, fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Triazolam is indicated for the short-term treatment of insomnia (generally 7–10 days). Use for more than 2–3 weeks requires complete reevaluation of the patient. - Prescriptions for triazolam should be written for short-term use (7–10 days) and it should not be prescribed in quantities exceeding a 1-month supply. - It is important to individualize the dosage of triazolam tablets for maximum beneficial effect and to help avoid significant adverse effects. - The recommended dose for most adults is 0.25 mg before retiring. A dose of 0.125 mg may be found to be sufficient for some patients (e.g., low body weight). A dose of 0.5 mg should be used only for exceptional patients who do not respond adequately to a trial of a lower dose since the risk of several adverse reactions increases with the size of the dose administered. A dose of 0.5 mg should not be exceeded. - In geriatric and/or debilitated patients the recommended dosage range is 0.125 mg to 0.25 mg. Therapy should be initiated at 0.125 mg in these groups and the 0.25 mg dose should be used only for exceptional patients who do not respond to a trial of the lower dose. A dose of 0.25 mg should not be exceeded in these patients. - As with all medications, the lowest effective dose should be used. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Triazolam in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Triazolam in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Triazolam in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Triazolam in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Triazolam in pediatric patients. # Contraindications - Triazolam tablets are contraindicated in patients with known hypersensitivity to this drug or other benzodiazepines. - Benzodiazepines may cause fetal damage when administered during pregnancy. An increased risk of congenital malformations associated with the use of diazepam and chlordiazepoxide during the first trimester of pregnancy has been suggested in several studies. Transplacental distribution has resulted in neonatal CNS depression following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy. - Triazolam is contraindicated in pregnant women. If there is a likelihood of the patient becoming pregnant while receiving triazolam, she should be warned of the potential risk to the fetus. Patients should be instructed to discontinue the drug prior to becoming pregnant. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. - Triazolam is contraindicated with medications that significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP 3A) including ketoconazole, itraconazole, nefazodone, and several HIV protease inhibitors. # Warnings - Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative-hypnotic drugs. Because some of the important adverse effects of sedative-hypnotics appear to be dose related, it is important to use the smallest possible effective dose, especially in the elderly. - Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported. These events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced persons. Although behaviors such as sleep-driving may occur with sedative-hypnotics alone at therapeutic doses, the use of alcohol and other CNS depressants with sedative-hypnotics appears to increase the risk of such behaviors, as does the use of sedative-hypnotics at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of sedative-hypnotics should be strongly considered for patients who report a "sleep-driving" episode. - Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events. - Severe anaphylactic and anaphylactoid reactions - Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including triazolam. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with triazolam should not be rechallenged with the drug. - Central nervous system manifestations - An increase in daytime anxiety has been reported for triazolam after as few as 10 days of continuous use. In some patients this may be a manifestation of interdose withdrawal. If increased daytime anxiety is observed during treatment, discontinuation of treatment may be advisable. - A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of benzodiazepine hypnotics including triazolam. Some of these changes may be characterized by decreased inhibition, eg, aggressiveness and extroversion that seem excessive, similar to that seen with alcohol and other CNS depressants (eg, sedative/hypnotics). Other kinds of behavioral changes have also been reported, for example, bizarre behavior, agitation, hallucinations, depersonalization. In primarily depressed patients, the worsening of depression, including suicidal thinking, has been reported in association with the use of benzodiazepines. - It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation. - Because of its depressant CNS effects, patients receiving triazolam should be cautioned against engaging in hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the concomitant ingestion of alcohol and other CNS depressant drugs during treatment with triazolam tablets. - As with some, but not all benzodiazepines, anterograde amnesia of varying severity and paradoxical reactions have been reported following therapeutic doses of triazolam. Data from several sources suggest that anterograde amnesia may occur at a higher rate with triazolam than with other benzodiazepine hypnotics. - Triazolam interaction with drugs that inhibit metabolism via cytochrome P450 3A - The initial step in triazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP 3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of triazolam. Consequently, triazolam should be avoided in patients receiving very potent inhibitors of CYP 3A. With drugs inhibiting CYP 3A to a lesser but still significant degree, triazolam should be used only with caution and consideration of appropriate dosage reduction. For some drugs, an interaction with triazolam has been quantified with clinical data; for other drugs, interactions are predicted from in vitro data and/or experience with similar drugs in the same pharmacologic class. - The following are examples of drugs known to inhibit the metabolism of triazolam and/or related benzodiazepines, presumably through inhibition of CYP 3A. - Potent CYP 3A inhibitors - Potent inhibitors of CYP 3A that should not be used concomitantly with triazolam include ketoconazole, itraconazole, nefazodone and several HIV protease inhibitors including ritonavir, indinavir, nelfinavir, saquinavir and lopinavir. Although data concerning the effects of azole-type antifungal agents other than ketoconazole and itraconazole on triazolam metabolism are not available, they should be considered potent CYP 3A inhibitors, and their coadministration with triazolam is not recommended. - Drugs demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving triazolam (caution and consideration of dose reduction are recommended during coadministration with triazolam) - Macrolide Antibiotics - Coadministration of erythromycin increased the maximum plasma concentration of triazolam by 46%, decreased clearance by 53%, and increased half-life by 35%; caution and consideration of appropriate triazolam dose reduction are recommended. Similar caution should be observed during coadministration with clarithromycin and other macrolide antibiotics. - Cimetidine - Coadministration of cimetidine increased the maximum plasma concentration of triazolam by 51%, decreased clearance by 55%, and increased half-life by 68%; caution and consideration of appropriate triazolam dose reduction are recommended. - Other drugs possibly affecting triazolam metabolism - Other drugs possibly affecting triazolam metabolism by inhibition of CYP 3A are discussed in the PRECAUTIONS section. ### Precautions - In elderly and/or debilitated patients it is recommended that treatment with triazolam tablets be initiated at 0.125 mg to decrease the possibility of development of oversedation, dizziness, or impaired coordination. - Some side effects reported in association with the use of triazolam appear to be dose related. These include drowsiness, dizziness, light-headedness, and amnesia. - The relationship between dose and what may be more serious behavioral phenomena is less certain. Specifically, some evidence, based on spontaneous marketing reports, suggests that confusion, bizarre or abnormal behavior, agitation, and hallucinations may also be dose related, but this evidence is inconclusive. In accordance with good medical practice it is recommended that therapy be initiated at the lowest effective dose. - Cases of "traveler's amnesia" have been reported by individuals who have taken triazolam to induce sleep while traveling, such as during an airplane flight. In some of these cases, insufficient time was allowed for the sleep period prior to awakening and before beginning activity. Also, the concomitant use of alcohol may have been a factor in some cases. - Caution should be exercised if triazolam is prescribed to patients with signs or symptoms of depression that could be intensified by hypnotic drugs. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional over-dosage is more common in these patients, and the least amount of drug that is feasible should be available to the patient at any one time. - The usual precautions should be observed in patients with impaired renal or hepatic function, chronic pulmonary insufficiency, and sleep apnea. In patients with compromised respiratory function, respiratory depression and apnea have been reported infrequently. # Adverse Reactions ## Clinical Trials Experience - During placebo-controlled clinical studies in which 1,003 patients received triazolam tablets, the most troublesome side effects were extensions of the pharmacologic activity of triazolam, eg, drowsiness, dizziness, or light-headedness. - The figures cited below are estimates of untoward clinical event incidence among subjects who participated in the relatively short duration (i.e., 1 to 42 days) placebo-controlled clinical trials of triazolam. The figures cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors often differ from those in clinical trials. These figures cannot be compared with those obtained from other clinical studies involving related drug products and placebo, as each group of drug trials is conducted under a different set of conditions. - Comparison of the cited figures, however, can provide the prescriber with some basis for estimating the relative contributions of drug and nondrug factors to the untoward event incidence rate in the population studied. Even this use must be approached cautiously, as a drug may relieve a symptom in one patient while inducing it in others. (For example, an anticholinergic, anxiolytic drug may relieve dry mouth [a sign of anxiety] in some subjects but induce it [an untoward event] in others.) - In addition to the relatively common (i.e., 1% or greater) untoward events enumerated above, the following adverse events have been reported less frequently (i.e., 0.9% to0.5%): euphoria, tachycardia, tiredness, confusional states/memory impairment, cramps/pain, depression, visual disturbances. - Rare (i.e., less than 0.5%) adverse reactions included constipation, taste alterations, diarrhea, dry mouth, dermatitis/allergy, dreaming/nightmares, insomnia, paresthesia, tinnitus, dysesthesia, weakness, congestion, death from hepatic failure in a patient also receiving diuretic drugs. - In addition to these untoward events for which estimates of incidence are available, the following adverse events have been reported in association with the use of triazolam and other benzodiazepines: amnestic symptoms (anterograde amnesia with appropriate or inappropriate behavior), confusional states (disorientation, derealization, depersonalization, and/or clouding of consciousness), dystonia, anorexia, fatigue, sedation, slurred speech, jaundice, pruritus, dysarthria, changes in libido, menstrual irregularities, incontinence, and urinary retention. Other factors may contribute to some of these reactions, eg, concomitant intake of alcohol or other drugs, sleep deprivation, an abnormal premorbid state, etc. - Other events reported include: paradoxical reactions such as stimulation, mania, an agitational state (restlessness, irritability, and excitation), increased muscle spasticity, sleep disturbances, hallucinations, delusions, aggressiveness, falling, somnambulism, syncope, inappropriate behavior and other adverse behavioral effects. Should these occur, use of the drug should be discontinued. - The following events have also been reported: chest pain, burning tongue/glossitis/stomatitis. - Laboratory analyses were performed on all patients participating in the clinical program for triazolam. The following incidences of abnormalities were observed in patients receiving triazolam and the corresponding placebo group. None of these changes were considered to be of physiological significance. - When treatment with triazolam is protracted, periodic blood counts, urinalysis, and blood chemistry analyses are advisable. - Minor changes in EEG patterns, usually low-voltage fast activity, have been observed in patients during therapy with triazolam and are of no known significance. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Triazolam in the drug label. # Drug Interactions - Both pharmacodynamic and pharmacokinetic interactions have been reported with benzodiazepines. In particular, triazolam produces additive CNS depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistamines, ethanol, and other drugs which themselves produce CNS depression. - Drugs that inhibit triazolam metabolism via cytochrome P450 3A - The initial step in triazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP 3A). Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of triazolam. Triazolam is contraindicated with ketoconzaole, itraconazole, nefazodone, and several HIV protease inhibitors. - Drugs and other substances demonstrated to be CYP 3A inhibitors of possible clinical significance on the basis of clinical studies involving triazolam. - Isoniazid - Coadministration of isoniazid increased the maximum plasma concentration of triazolam by 20%, decreased clearance by 42%, and increased half-life by 31%. - Oral contraceptives - Coadministration of oral contraceptives increased maximum plasma concentration by 6%, decreased clearance by 32%, and increased half-life by 16%. - Grapefruit juice - Coadministration of grapefruit juice increased the maximum plasma concentration of triazolam by 25%, increased the area under the concentration curve by 48%, and increased half-life by 18%. - Drugs demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to triazolam or on the basis of in vitro studies with triazolam or other benzodiazepines (caution is recommended during coadministration with triazolam) - Available data from clinical studies of benzodiazepines other than triazolam suggest a possible drug interaction with triazolam for the following: fluvoxamine, diltiazem, and verapamil. Data from in vitro studies of triazolam suggest a possible drug interaction with triazolam for the following: sertraline and paroxetine. Data from in vitro studies of benzodiazepines other than triazolam suggest a possible drug interaction with triazolam for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is recommended during coadministration of any of these drugs with triazolam. - Drugs that affect triazolam pharmacokinetics by other mechanisms - Ranitidine - Coadministration of ranitidine increased the maximum plasma concentration of triazolam by 30%, increased the area under the concentration curve by 27%, and increased half-life by 3.3%. Caution is recommended during coadministration with triazolam. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category X - Teratogenic effects - Pregnancy category X (see CONTRAINDICATIONS). - Non-teratogenic effects - It is to be considered that the child born of a mother who is on benzodiazepines may be at some risk for withdrawal symptoms from the drug, during the postnatal period. Also, neonatal flaccidity has been reported in an infant born of a mother who had been receiving benzodiazepines. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Triazolam in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Triazolam during labor and delivery. ### Nursing Mothers - Human studies have not been performed; however, studies in rats have indicated that triazolam and its metabolites are secreted in milk. Therefore, administration of triazolam to nursing mothers is not recommended. ### Pediatric Use - Safety and effectiveness of triazolam in individuals below 18 years of age have not been established. ### Geriatic Use - The elderly are especially susceptible to the dose related adverse effects of triazolam. They exhibit higher plasma triazolam concentrations due to reduced clearance of the drug as compared with younger subjects at the same dose. To minimize the possibility of development of oversedation, the smallest effective dose should be used. ### Gender There is no FDA guidance on the use of Triazolam with respect to specific gender populations. ### Race There is no FDA guidance on the use of Triazolam with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Triazolam in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Triazolam in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Triazolam in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Triazolam in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Triazolam in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Triazolam in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Because of the potency of triazolam, some manifestations of overdosage may occur at 2 mg, four times the maximum recommended therapeutic dose (0.5 mg). - Manifestations of overdosage with triazolam tablets include somnolence, confusion, impaired coordination, slurred speech, and ultimately, coma. Respiratory depression and apnea have been reported with overdosages of triazolam. Seizures have occasionally been reported after overdosages. - Death has been reported in association with overdoses of triazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzodiazepine, including triazolam, and alcohol; benzodiazepine and alcohol levels seen in some of these cases have been lower than those usually associated with reports of fatality with either substance alone. ### Management - As in all cases of drug overdosage, respiration, pulse, and blood pressure should be monitored and supported by general measures when necessary. Immediate gastric lavage should be performed. An adequate airway should be maintained. Intravenous fluids may be administered. - Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. - Experiments in animals have indicated that cardiopulmonary collapse can occur with massive intravenous doses of triazolam. This could be reversed with positive mechanical respiration and the intravenous infusion of norepinephrine bitartrate or metaraminol bitartrate. Hemodialysis and forced diuresis are probably of little value. As with the management of intentional overdosage with any drug, the physician should bear in mind that multiple agents may have been ingested by the patient. - The oral LD50 in mice is greater than 1,000 mg/kg and in rats is greater than 5,000 mg/kg. ## Chronic Overdose There is limited information regarding Chronic Overdose of Triazolam in the drug label. # Pharmacology ## Mechanism of Action - Triazolam is a triazolobenzodiazepine hypnotic drug that increases the duration of sleep and decreases the number of nocturnal awakenings and sleep latency. ## Structure - Triazolam is a triazolobenzodiazepine hypnotic agent. - Triazolam is a white crystalline powder, soluble in alcohol and poorly soluble in water. It has a molecular weight of 343.21. - The chemical name for triazolam is 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo-[4,3-α] [1,4] benzodiazepine. - The structural formula is represented below: - Each triazolam tablet, for oral administration, contains 0.125 mg or 0.25 mg of triazolam. Inactive ingredients: 0.125 mg—cellulose, corn starch, docusate sodium, lactose, magnesium stearate, silicon dioxide, sodium benzoate; 0.25 mg—cellulose, corn starch, docusate sodium, FD&C Blue No. 2, lactose, magnesium stearate, silicon dioxide, sodium benzoate. ## Pharmacodynamics - In sleep laboratory studies, triazolam tablets significantly decreased sleep latency, increased the duration of sleep, and decreased the number of nocturnal awakenings. After 2 weeks of consecutive nightly administration, the drug's effect on total wake time is decreased, and the values recorded in the last third of the night approach baseline levels. On the first and/or second night after drug discontinuance (first or second post-drug night), total time asleep, percentage of time spent sleeping, and rapidity of falling asleep frequently were significantly less than on baseline (predrug) nights. This effect is often called "rebound" insomnia. - The type and duration of hypnotic effects and the profile of unwanted effects during administration of benzodiazepine drugs may be influenced by the biologic half-life of administered drug and any active metabolites formed. When half-lives are long, the drug or metabolites may accumulate during periods of nightly administration and be associated with impairments of cognitive and motor performance during waking hours; the possibility of interaction with other psychoactive drugs or alcohol will be enhanced. In contrast, if half-lives are short, the drug and metabolites will be cleared before the next dose is ingested, and carry-over effects related to excessive sedation or CNS depression should be minimal or absent. However, during nightly use for an extended period pharmacodynamic tolerance or adaptation to some effects of benzodiazepine hypnotics may develop. If the drug has a short half-life of elimination, it is possible that a relative deficiency of the drug or its active metabolites (ie, in relationship to the receptor site) may occur at some point in the interval between each night's use. This sequence of events may account for two clinical findings reported to occur after several weeks of nightly use of rapidly eliminated benzodiazepine hypnotics: 1) increased wakefulness during the last third of the night and 2) the appearance of increased daytime anxiety after 10 days of continuous treatment. - In a study of elderly (62–83 years old) versus younger subjects (21–41 years old) who received triazolam at the same dose levels (0.125 mg and 0.25 mg), the elderly experienced both greater sedation and impairment of psychomotor performance. These effects resulted largely from higher plasma concentrations of triazolam in the elderly. ## Pharmacokinetics - Triazolam is a hypnotic with a short mean plasma half-life reported to be in the range of 1.5 to 5.5 hours. In normal subjects treated for 7 days with four times the recommended dosage, there was no evidence of altered systemic bioavailability, rate of elimination, or accumulation. Peak plasma levels are reached within 2 hours following oral administration. Following recommended doses of triazolam tablets, triazolam peak plasma levels in the range of 1 to 6 ng/mL are seen. The plasma levels achieved are proportional to the dose given. - Triazolam and its metabolites, principally as conjugated glucuronides, which are presumably inactive, are excreted primarily in the urine. Only small amounts of unmetabolized triazolam appear in the urine. The two primary metabolites accounted for 79.9% of urinary excretion. Urinary excretion appeared to be biphasic in its time course. - Triazolam tablets 0.5 mg, in two separate studies, did not affect the prothrombin times or plasma warfarin levels in male volunteers administered sodium warfarin orally. - Extremely high concentrations of triazolam do not displace bilirubin bound to human serum albumin in vitro. - Triazolam 14C was administered orally to pregnant mice. Drug-related material appeared uniformly distributed in the fetus with 14C concentrations approximately the same as in the brain of the mother. ## Nonclinical Toxicology - No evidence of carcinogenic potential was observed in mice during a 24-month study with triazolam in doses up to 4,000 times the human dose. # Clinical Studies There is limited information regarding Clinical Studies of Triazolam in the drug label. # How Supplied - Triazolam tablets are available in the following strengths and package sizes: - 0.125 mg (white,, imprinted G3717): 10–10 Tablet Bottles NDC 59762-3717-4 - 10–10 Tablet Bottles NDC 59762-3717-4 - 0.25 mg (powder blue, scored, imprinted G3718): 10–10 Tablet Bottles NDC 59762-3718-4 Bottles of 500 NDC 59762-3718-3 - 10–10 Tablet Bottles NDC 59762-3718-4 - Bottles of 500 NDC 59762-3718-3 - Store at controlled room temperature 20° to 25°C (68° to 77°F). ## Storage There is limited information regarding Triazolam Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - "Sleep-driving" and other complex behaviors - There have been reports of people getting out of bed after taking a sedative-hypnotic and driving their cars while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should be reported to his or her doctor immediately, since "sleep-driving" can be dangerous. This behavior is more likely to occur when sedative-hypnotics are taken with alcohol or other central nervous system depressants. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative hypnotic. As with sleep-driving, patients usually do not remember these events. # Precautions with Alcohol - Alcohol-Triazolam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TRIAZOLAM®[1] # Look-Alike Drug Names There is limited information regarding Triazolam Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Halcion
b5f9bf827857ca2d4f3b3bb584502579c140037e	wikidoc	Halimeter	Halimeter A Halimeter is an instrument for measurement of the level of volatile sulfur compounds (VSCs) in the mouth. Halimeter was introduced in the early 1990s as an adjunct method for determining halitosis (bad breath, oral malodor) levels, alongside human assessment of odor levels (the latter is considered the gold standard). The instrument measures parts per billion levels of hydrogen sulfide and, to a lesser extent, methyl mercaptan, two gases which were previously shown to be associated with bad breath using gas chromatograph by Dr. Joseph Tonzetich in the late 1960s. The Halimeter is manufactured by Interscan Corp. in California, and based on their earlier model 1170 portable sulfide monitor. This was the model used in the two original studies . These studies, conducted for the first time by Dr. Mel Rosenberg, showed a significant correlation between monitor levels and oral malodor scores. The small size, simplicity of use, and price (relative to gas chromatograph) of the Halimeter made it popular among dentists seeking to diagnose and treat bad breath, as well as scientific researchers. Much of the published research on bad breath over the past dozen years has employed this instrument. The electrochemical sensor is sensitive to alcohol vapors, and requires recalibration over time. The Halimeter has been the only VSC monitor for the diagnosis of halitosis for years, but now that its patent has expired, it faces competition from other sulfur monitors recently introduced into the marketplace.	Halimeter A Halimeter is an instrument for measurement of the level of volatile sulfur compounds (VSCs) in the mouth. Halimeter was introduced in the early 1990s as an adjunct method for determining halitosis (bad breath, oral malodor) levels, alongside human assessment of odor levels (the latter is considered the gold standard). The instrument measures parts per billion levels of hydrogen sulfide and, to a lesser extent, methyl mercaptan, two gases which were previously shown to be associated with bad breath using gas chromatograph by Dr. Joseph Tonzetich in the late 1960s. The Halimeter is manufactured by Interscan Corp. in California, and based on their earlier model 1170 portable sulfide monitor. This was the model used in the two original studies [1][2]. These studies, conducted for the first time by Dr. Mel Rosenberg, showed a significant correlation between monitor levels and oral malodor scores. The small size, simplicity of use, and price (relative to gas chromatograph) of the Halimeter made it popular among dentists seeking to diagnose and treat bad breath, as well as scientific researchers. Much of the published research on bad breath over the past dozen years has employed this instrument. The electrochemical sensor is sensitive to alcohol vapors, and requires recalibration over time. The Halimeter has been the only VSC monitor for the diagnosis of halitosis for years, but now that its patent has expired, it faces competition from other sulfur monitors recently introduced into the marketplace.	https://www.wikidoc.org/index.php/Halimeter
8e15250f7967fd2aff214e3e218c8248d8d63773	wikidoc	Hamstring	Hamstring In human anatomy, a hamstring refers to one of the tendons that makes up the borders of the space behind the knee. In modern anatomical contexts, however, they usually refer to the tendons of the semitendinosus, the semimembranosus, and the biceps femoris. In quadrupeds, it refers to the single large tendon found behind the knee or comparable area. As shown in the diagram, the human hamstring occupies the posterior of the body of the femur. # Etymology The word ham originally referred to the fat and muscle behind the knee. String refers to tendons, and thus, the hamstrings are the string-like tendons felt on either side of the back of the knee. The four muscles of the posterior thigh flex (bend) the knee, while three of the four extend (straighten) the hip. The short head of the biceps femoris, with its divergent origin and innervation, is not involved in hip extension, and thus is sometimes excluded from the 'hamstring' characterization. # Functions The hamstrings cross and act upon two joints - the hip and the knee. Semitendinosus and semimembranosus extend the hip when the trunk is fixed or extend the trunk when the hip is fixed; they also flex the knee and medially (inwardly) rotate the lower leg when the knee is bent. The long head of the biceps femoris extends the hip as when beginning to walk; both short and long heads flex the knee and laterally (outwardly) rotates the lower leg when the knee is bent. The hamstrings play a crucial role in many daily activities, such as, walking, running, jumping, and controlling some movement in the trunk. In walking, they are most important as an antagonist to the quadriceps in the deceleration of knee extension. # Injuries Straining of the hamstring, also known as a pulled hamstring, is defined as an excessive stretch or tear of muscle fibers and related tissues. ## Grade I With a grade one hamstring strain the signs may not be present until after the activity is over. There may be a sensation of cramp or tightness and a slight feeling of pain when the muscles are stretched or contracted. It also may be referred to as a "pulled hammy". ## Grade II With a grade two hamstring strain there is immediate pain which is more severe than the pain of a grade one injury. It is confirmed by pain on stretch and contraction of the muscle. A grade two hamstring strain is usually sore to touch. ## Grade III A grade three hamstring strain is a catastrophic injury. There is an immediate burning or stabbing pain and the athlete is unable to walk without pain. The muscle is completely torn and there may be a large lump of muscle tissue above a depression where the tear is. After a few days with grade two and three injuries a large bruise may appear below the injury site caused by the bleeding within the tissues. # Treatment The immediate treatment of any muscle injury consists of the RICE protocol - rest, ice,compression, and elevation (never apply ice directly to the skin). This is aimed at reducing the bleeding and damage within the muscle tissue. Resting may be the common sense approach, but it is one that is often ignored by competitive athletes. This is unwise, since it does not take much to turn a grade one strain into a grade two, or a grade two strain into a grade three. As a general rule, grade one hamstring strains should be rested from sporting activity for about 3 weeks and grade two injuries for about 4 to 6 weeks. In the case of a complete rupture, the muscle will have to be repaired surgically and the rehabilitation afterwards will take about 3 months. Regardless of the level of the injury the treatment in the first five days is the same. The hamstring should be rested in an elevated position with an ice pack applied for twenty minutes every two hours, if practical (never apply ice directly to the skin). A compression bandage should be applied to limit bleeding and swelling in the tissues. After the first five days have been spent resting, more active rehabilitation can be started. # Use in surgery The distal semitendinosis tendon is one of the tendons that can be used in the surgical procedure ACL reconstruction. In this procedure, a piece of it is used to replace the anterior cruciate ligament (ACL). The ACL is one of the four major ligaments in the knee.	Hamstring Template:Infobox Muscle Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] In human anatomy, a hamstring refers to one of the tendons that makes up the borders of the space behind the knee. In modern anatomical contexts, however, they usually refer to the tendons of the semitendinosus, the semimembranosus, and the biceps femoris. In quadrupeds, it refers to the single large tendon found behind the knee or comparable area. As shown in the diagram, the human hamstring occupies the posterior of the body of the femur. # Etymology The word ham originally referred to the fat and muscle behind the knee. String refers to tendons, and thus, the hamstrings are the string-like tendons felt on either side of the back of the knee. The four muscles of the posterior thigh flex (bend) the knee, while three of the four extend (straighten) the hip. The short head of the biceps femoris, with its divergent origin and innervation, is not involved in hip extension, and thus is sometimes excluded from the 'hamstring' characterization. # Functions The hamstrings cross and act upon two joints - the hip and the knee. Semitendinosus and semimembranosus extend the hip when the trunk is fixed or extend the trunk when the hip is fixed; they also flex the knee and medially (inwardly) rotate the lower leg when the knee is bent. The long head of the biceps femoris extends the hip as when beginning to walk; both short and long heads flex the knee and laterally (outwardly) rotates the lower leg when the knee is bent. The hamstrings play a crucial role in many daily activities, such as, walking, running, jumping, and controlling some movement in the trunk. In walking, they are most important as an antagonist to the quadriceps in the deceleration of knee extension. # Injuries Straining of the hamstring, also known as a pulled hamstring, is defined as an excessive stretch or tear of muscle fibers and related tissues. ## Grade I With a grade one hamstring strain the signs may not be present until after the activity is over. There may be a sensation of cramp or tightness and a slight feeling of pain when the muscles are stretched or contracted. It also may be referred to as a "pulled hammy". ## Grade II With a grade two hamstring strain there is immediate pain which is more severe than the pain of a grade one injury. It is confirmed by pain on stretch and contraction of the muscle. A grade two hamstring strain is usually sore to touch. ## Grade III A grade three hamstring strain is a catastrophic injury. There is an immediate burning or stabbing pain and the athlete is unable to walk without pain. The muscle is completely torn and there may be a large lump of muscle tissue above a depression where the tear is. After a few days with grade two and three injuries a large bruise may appear below the injury site caused by the bleeding within the tissues. # Treatment The immediate treatment of any muscle injury consists of the RICE protocol - rest, ice,compression, and elevation (never apply ice directly to the skin). This is aimed at reducing the bleeding and damage within the muscle tissue. Resting may be the common sense approach, but it is one that is often ignored by competitive athletes. This is unwise, since it does not take much to turn a grade one strain into a grade two, or a grade two strain into a grade three. As a general rule, grade one hamstring strains should be rested from sporting activity for about 3 weeks and grade two injuries for about 4 to 6 weeks. In the case of a complete rupture, the muscle will have to be repaired surgically and the rehabilitation afterwards will take about 3 months. Regardless of the level of the injury the treatment in the first five days is the same. The hamstring should be rested in an elevated position with an ice pack applied for twenty minutes every two hours, if practical (never apply ice directly to the skin). A compression bandage should be applied to limit bleeding and swelling in the tissues. After the first five days have been spent resting, more active rehabilitation can be started. # Use in surgery The distal semitendinosis tendon is one of the tendons that can be used in the surgical procedure ACL reconstruction. In this procedure, a piece of it is used to replace the anterior cruciate ligament (ACL). The ACL is one of the four major ligaments in the knee.	https://www.wikidoc.org/index.php/Hamstring
e71d3d85975f9162f188fa3f57926a02ff09ee95	wikidoc	Rauwolfia	Rauwolfia Rauwolfia (also spelled Rauvolfia) is a genus of evergreen trees and shrubs in the Apocynaceae family. The approximately 85 species in the genus can mainly be found in tropical regions. Rauvolfia caffra is the South African quinine tree. Rauvolfia serpentina, or Indian Snakeroot or Sarpagandha, contains a number of bioactive chemicals, including ajmalicine, deserpidine, rescinnamine, serpentinine, and yohimbine. Reserpine is an alkaloid first isolated from R. serpentina which was widely used as an antihypertensive drug. It had drastic psychological side effects and has been now replaced by blood-pressure-lowering drugs that lack such adverse effects. Other plants of this genus are also used medicinally, both in conventional western medicine and in Ayurveda, Unani, and folk medicine. Alkaloids in the plants reduce blood pressure, depress activity of central nervous system and act as hypnotics. # Threat Status The natural reserves of this plant are declining as a result of over-harvesting. IUCN has kept this plant under endangered status, and it is listed in CITES Appendix II. # Precautions People who are pregnant, may be pregnant, or plan pregnancy in the near future should not ingest Rauwolfia plants or preparations made from them. They may also be harmful for people with any chronic disease of the gastrointestinal tract, such as stomach or duodenal ulcers, esophageal reflux (reflux esophagitis), ulcerative colitis, spastic colitis, and diverticulosis. No "safe" dosage has been established. ## Selected species - Rauwolfia caffra - Rauwolfia canescens - Rauwolfia micrantha - Rauwolfia serpentina - Rauwolfia tetraphylla - Rauwolfia vomitoria	Rauwolfia Rauwolfia (also spelled Rauvolfia) is a genus of evergreen trees and shrubs in the Apocynaceae family. The approximately 85 species in the genus can mainly be found in tropical regions. Rauvolfia caffra is the South African quinine tree. Rauvolfia serpentina, or Indian Snakeroot or Sarpagandha, contains a number of bioactive chemicals, including ajmalicine, deserpidine, rescinnamine, serpentinine, and yohimbine. Reserpine is an alkaloid first isolated from R. serpentina which was widely used as an antihypertensive drug. It had drastic psychological side effects and has been now replaced by blood-pressure-lowering drugs that lack such adverse effects. Other plants of this genus are also used medicinally, both in conventional western medicine and in Ayurveda, Unani, and folk medicine. Alkaloids in the plants reduce blood pressure, depress activity of central nervous system and act as hypnotics. # Threat Status The natural reserves of this plant are declining as a result of over-harvesting. IUCN has kept this plant under endangered status, and it is listed in CITES Appendix II. # Precautions People who are pregnant, may be pregnant, or plan pregnancy in the near future should not ingest Rauwolfia plants or preparations made from them. They may also be harmful for people with any chronic disease of the gastrointestinal tract, such as stomach or duodenal ulcers, esophageal reflux (reflux esophagitis), ulcerative colitis, spastic colitis, and diverticulosis. No "safe" dosage has been established. ## Selected species - Rauwolfia caffra - Rauwolfia canescens - Rauwolfia micrantha - Rauwolfia serpentina - Rauwolfia tetraphylla - Rauwolfia vomitoria	https://www.wikidoc.org/index.php/Harmonyl
174c03ef4a5092dff45a18c0d1057573d04d708f	wikidoc	Heaf test	Heaf test # Overview The Heaf test is a diagnostic skin test performed in order to determine whether or not a child has been exposed to tuberculosis. Patients who exhibit a negative reaction to the test may be offered BCG vaccination. The test is named after F. R. G. Heaf. Until 2005, the test was used in the United Kingdom to determine if the BCG vaccine was needed; the Mantoux test is now used instead. The Heaf test was preferred in the UK, because it was felt that the Heaf test was easier to interpret, with less inter-observer variability, and that less training was required to administer and to read the test. The test was withdrawn because manufacturers could not be found for tuberculin or for Heaf guns. The Heaf test may be informally referred to as the six pricks, as it gives six individual injections. # Procedure A Heaf gun is used to inject multiple samples of testing serum under the skin at once. A Heaf gun with disposable single-use heads is recommended. The gun injects purified protein derivative equivalent to 100,000 units per mL to the skin over the flexor surface of the left forearm in a circular pattern of six. The test is read between 2 and 7 days later. The injection must not be into sites containing superficial veins. The reading of the Heaf test is defined by a scale: - Negative - No induration, maybe 6 minute puncture scars - Grade 1 - 4-6 papules (also considered negative) - Grade 2 - Confluent papules form indurated ring (positive) - Grade 3 - Central filling to form disc (positive) - Grade 4 - Disc >10 mm with or without blistering (strongly positive) Grades 1 and 2 may be the result of previous BCG or avian tuberculosis. Children who have a grade 3 or 4 reaction require X-ray and follow-up. For interpretation of the test, see tuberculosis diagnosis. # Other Tests for Tuberculosis The equivalent Mantoux test positive levels done with 10 TU (0.1 mL 100 TU/mL, 1:1000) are - 0-4 mm induration (Heaf 0-1) - 5-14 mm induration (Heaf 2) - >15 mm induration (Heaf 3-4) The Mantoux test is preferred in the United States for the diagnosis of tuberculosis; multiple puncture tests, such as the Heaf test and Tine test, are not recommended.	Heaf test Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The Heaf test is a diagnostic skin test performed in order to determine whether or not a child has been exposed to tuberculosis. Patients who exhibit a negative reaction to the test may be offered BCG vaccination. The test is named after F. R. G. Heaf. Until 2005, the test was used in the United Kingdom to determine if the BCG vaccine was needed; the Mantoux test is now used instead. The Heaf test was preferred in the UK, because it was felt that the Heaf test was easier to interpret, with less inter-observer variability, and that less training was required to administer and to read the test. The test was withdrawn because manufacturers could not be found for tuberculin or for Heaf guns. The Heaf test may be informally referred to as the six pricks, as it gives six individual injections. # Procedure A Heaf gun is used to inject multiple samples of testing serum under the skin at once. A Heaf gun with disposable single-use heads is recommended. The gun injects purified protein derivative equivalent to 100,000 units per mL to the skin over the flexor surface of the left forearm in a circular pattern of six. The test is read between 2 and 7 days later. The injection must not be into sites containing superficial veins. The reading of the Heaf test is defined by a scale: - Negative - No induration, maybe 6 minute puncture scars - Grade 1 - 4-6 papules (also considered negative) - Grade 2 - Confluent papules form indurated ring (positive) - Grade 3 - Central filling to form disc (positive) - Grade 4 - Disc >10 mm with or without blistering (strongly positive) Grades 1 and 2 may be the result of previous BCG or avian tuberculosis. Children who have a grade 3 or 4 reaction require X-ray and follow-up. For interpretation of the test, see tuberculosis diagnosis. # Other Tests for Tuberculosis The equivalent Mantoux test positive levels done with 10 TU (0.1 mL 100 TU/mL, 1:1000) are - 0-4 mm induration (Heaf 0-1) - 5-14 mm induration (Heaf 2) - >15 mm induration (Heaf 3-4) The Mantoux test is preferred in the United States for the diagnosis of tuberculosis; multiple puncture tests, such as the Heaf test and Tine test, are not recommended.	https://www.wikidoc.org/index.php/Heaf_test
725c0254db76568009935628559bb6dba3da54b3	wikidoc	Health 21	Health 21 Health 21 is the name given to the contents of the 1999 WHO European Region document Health 21 - Health for all in the 21st Century. This document was so-called because it dealt not only with health in the 21st century, but also laid out 21 principles and objectives for improving the health of Europeans. # Health 21 Summary The key message within Health 21 has been said to be that of equality. Actually, the document doesn't claim that it is possible to achieve equality directly, but rather strives to "close the gaps", i.e. to reduce inequality. Health 21 also covers specific health promotion "target groups" these are Children, Older People, reduction of transmission of communicable and infectious diseases and those who (ab)use tobacco, drugs or alcohol. # Health 21 Targets - Closing the health gap between countries; - Closing the health gap within countries; - A healthy start in life (supportive family policies); - Health of young people (policies to reduce child abuse, accidents, drug use, unwanted pregnancies); - Healthy ageing (policies to improve health, self esteem, and independence before dependence emerges); - Improving mental health; - Reducing communicable diseases; - Reducing non-communicable diseases; - Reducing injury from violence and accidents; - A healthy and safe physical environment; - Healthier living (fiscal, agricultural and retail policies that increase the availability of and access to and consumption of vegetables and fruits); - Reducing harm from alcohol, drugs and tobacco; - A settings approach to health action (homes should be designed and built in a manner conducive to sustainable health and the environment); - Multi-sectoral responsibility for health; - An integrated health sector and much stronger emphasis on primary care; - Managing for quality of care using the European health for all indicators to focus on outcomes and compare the effectiveness of different inputs; - Equitable and sustainable funding of health services; - Developing human resources (educational programmes for providers and managers based on the principles of the health for all policy); - Research and knowledge: health programmes based on scientific evidence; - Mobilising partners for health (engaging the media/TV/Internet); - Policies and strategies for health for all - national, targeted policies based on health for all	Health 21 Health 21 is the name given to the contents of the 1999 WHO European Region document Health 21 - Health for all in the 21st Century. This document was so-called because it dealt not only with health in the 21st century, but also laid out 21 principles and objectives for improving the health of Europeans. # Health 21 Summary The key message within Health 21 has been said to be that of equality. Actually, the document doesn't claim that it is possible to achieve equality directly, but rather strives to "close the gaps", i.e. to reduce inequality. Health 21 also covers specific health promotion "target groups" these are Children, Older People, reduction of transmission of communicable and infectious diseases and those who (ab)use tobacco, drugs or alcohol. # Health 21 Targets - Closing the health gap between countries; - Closing the health gap within countries; - A healthy start in life (supportive family policies); - Health of young people (policies to reduce child abuse, accidents, drug use, unwanted pregnancies); - Healthy ageing (policies to improve health, self esteem, and independence before dependence emerges); - Improving mental health; - Reducing communicable diseases; - Reducing non-communicable diseases; - Reducing injury from violence and accidents; - A healthy and safe physical environment; - Healthier living (fiscal, agricultural and retail policies that increase the availability of and access to and consumption of vegetables and fruits); - Reducing harm from alcohol, drugs and tobacco; - A settings approach to health action (homes should be designed and built in a manner conducive to sustainable health and the environment); - Multi-sectoral responsibility for health; - An integrated health sector and much stronger emphasis on primary care; - Managing for quality of care using the European health for all indicators to focus on outcomes and compare the effectiveness of different inputs; - Equitable and sustainable funding of health services; - Developing human resources (educational programmes for providers and managers based on the principles of the health for all policy); - Research and knowledge: health programmes based on scientific evidence; - Mobilising partners for health (engaging the media/TV/Internet); - Policies and strategies for health for all - national, targeted policies based on health for all	https://www.wikidoc.org/index.php/Health_21
5139e48aa2794b9e92def72f6bf4dfedb3a68456	wikidoc	NHS Wales	NHS Wales NHS Wales is the official corporate style of the national health service for Wales; it was previously part of the same National Health Service (Welsh: Gwasanaeth Iechyd Genedlaethol) as England but is now devolved. NHS Wales (Welsh: GIG Cymru) is operated and managed by the Health and Social Care Department of the Welsh Assembly Government. Most people in Wales will have access to a District General Hospital which provides a range of services on an outpatient, inpatient and day case basis. Some of these hospitals also provide specialist services such as burns and plastics and cardiac surgery. NHS Wales also provides community services which includes district nurses, health visitors, midwives and community based speech therapists, physiotherapists and occupational therapists. # Health Boards Local Health Boards (LHBs) were created in 2003 to replace Health Authorities in Wales . A Welsh NHS Trust will typically administer all hospitals in a region, as well as all community care and mental health functions. There are 12 regional Trusts that cover groups of local authority areas, as well as one further Trust for the Welsh Ambulance Service and another, Velindre , for the operation of nationwide agencies and services. Wales has one main teaching hospital, the University Hospital of Wales, based in Cardiff. # Other NHS Wales bodies Another important organisation in the structure is Health Commission Wales. This is an executive agency of the Welsh Assembly Government whose primary role is to centrally organise and fund all Tertiary care and other highly specialist services. It also provides advise and guidance about specialist services to other parts of NHS Wales. NHS Direct is also available in Wales, with callers being given the option of talking in Welsh or English.	NHS Wales NHS Wales is the official corporate style of the national health service for Wales; it was previously part of the same National Health Service (Welsh: Gwasanaeth Iechyd Genedlaethol) as England but is now devolved. NHS Wales (Welsh: GIG Cymru) is operated and managed by the Health and Social Care Department of the Welsh Assembly Government. Most people in Wales will have access to a District General Hospital which provides a range of services on an outpatient, inpatient and day case basis. Some of these hospitals also provide specialist services such as burns and plastics and cardiac surgery. NHS Wales also provides community services which includes district nurses, health visitors, midwives and community based speech therapists, physiotherapists and occupational therapists. ## Health Boards Local Health Boards (LHBs) were created in 2003 to replace Health Authorities in Wales [1] [2]. A Welsh NHS Trust will typically administer all hospitals in a region, as well as all community care and mental health functions. There are 12 regional Trusts that cover groups of local authority areas, as well as one further Trust for the Welsh Ambulance Service and another, Velindre [3], for the operation of nationwide agencies and services. Wales has one main teaching hospital, the University Hospital of Wales, based in Cardiff. ## Other NHS Wales bodies Another important organisation in the structure is Health Commission Wales. This is an executive agency of the Welsh Assembly Government whose primary role is to centrally organise and fund all Tertiary care and other highly specialist services. It also provides advise and guidance about specialist services to other parts of NHS Wales. NHS Direct is also available in Wales, with callers being given the option of talking in Welsh or English.	https://www.wikidoc.org/index.php/Healthcare_in_Wales
4ee4af6bb49e4974794abe4bf3937214893d4b5e	wikidoc	HeightMax	HeightMax HeightMax Concentrate and HeightMax Plus are purported height-enhancing pills for kids and young adults marketed by Sunny Health Nutrition Technology & Products, Inc. # Federal Trade Commission Enforcement Action On or about November 21, 2006, the Federal Trade Commission filed a complaint against Sunny Health Nutrition Technology & Products, Inc. and its owner, Sunny Sia, charging the defendants with making false and unsubstantiated claims for HeightMax Concentrate and HeightMax Plus, as well as for two other supplements, Liposan Ultra Chitosan Fat Blocker and Osteo-Vite. The Federal Trade Commission complaint charged that claims for the pills were unsubstantiated or false and that the defendants invented William Thomson, a supposed expert who appeared in the advertisements. According to the complaint, the advertisements for HeightMax Concentrate and HeightMax Plus misrepresented that: - HeightMax increases height in users ages 12-25 over what they would achieve without the product; - HeightMax causes users to grow an additional 2 to 3 inches in 6 months; - Clinical tests prove that: (i) HeightMax increases the height of teenagers and young adults; and (ii) regular use of HeightMax for 6 months causes a 10% to 25% gain in height, and use for more than a year causes a 20% to 35% gain in height; - HeightMax increases lean body mass and reduces body fat in users ages 12-25; and - William Thomson, an expert with a Ph.D. in Biochemistry, created HeightMax after years of research and clinical trials. The Federal Trade Commission complaint also alleged that the defendants made unsubstantiated or false claims for Liposan Ultra Chitosan Fat Blocker, a weight loss supplement, and Osteo-Vite, marketed to older consumers for bone-building. To settle the charges, defendants Sunny Health Nutrition Technology & Products, Inc. and its owner, Sunny Sia, agreed to pay $375,000 in consumer redress. The settlement also holds the defendants potentially liable for $1.9 million in the event that they misrepresented their finances. The order to settle the FTC’s charges requires that claims for any dietary supplement, food, or drug must be true, non-misleading, and substantiated. In addition, it prohibits the defendants from misrepresenting endorsements, including the existence or expertise of any endorser. On November 30, 2006 the Honorable Susan C. Bucklew, Federal District Court Judge, signed a Stipulated Judgment requiring defendants to pay $375,000 based on the accuracy of sworn financial statements. The Judgment included an avalanche clause, requiring payment of full redress for $1.9 million if the financial statements were not accurate. On April 24, 2007, the FTC announced that the defendants shall be required to pay the full $1.9 Million after hidden assets were discovered. In the settlement, the $1.6 million balance of the judgment was suspended based on sworn financial disclosure documents showing inability to pay. Shortly after that settlement, the FTC discovered that the defendants kept at least $1.8 million in an undisclosed PayPal account. The FTC immediately obtained a temporary restraining order to freeze the funds, which was granted on December 8, 2006. The defendants have been ordered to pay the entire $1.9 million. Judge Bucklew’s new order, signed on February 22, 2007, and agreed to by the defendants, requires them to pay the entire $1.9 million, using the funds in the account at PayPal and other sources if necessary. The conduct prohibitions from the previously entered order remain unchanged. The FTC will set up a refund program for HeightMax purchasers, using the money collected. # External link Federal Trade Commission, Plaintiff, v. Sunny Health Nutrition Technology & Products, Inc., and Sunny Sia, Defendants. (United States District Court for the Middle District of Florida Tampa Division) *	HeightMax HeightMax Concentrate and HeightMax Plus are purported height-enhancing pills for kids and young adults marketed by Sunny Health Nutrition Technology & Products, Inc. # Federal Trade Commission Enforcement Action On or about November 21, 2006, the Federal Trade Commission filed a complaint against Sunny Health Nutrition Technology & Products, Inc. and its owner, Sunny Sia, charging the defendants with making false and unsubstantiated claims for HeightMax Concentrate and HeightMax Plus, as well as for two other supplements, Liposan Ultra Chitosan Fat Blocker and Osteo-Vite. The Federal Trade Commission complaint charged that claims for the pills were unsubstantiated or false and that the defendants invented William Thomson, a supposed expert who appeared in the advertisements. According to the complaint, the advertisements for HeightMax Concentrate and HeightMax Plus misrepresented that: - HeightMax increases height in users ages 12-25 over what they would achieve without the product; - HeightMax causes users to grow an additional 2 to 3 inches in 6 months; - Clinical tests prove that: (i) HeightMax increases the height of teenagers and young adults; and (ii) regular use of HeightMax for 6 months causes a 10% to 25% gain in height, and use for more than a year causes a 20% to 35% gain in height; - HeightMax increases lean body mass and reduces body fat in users ages 12-25; and - William Thomson, an expert with a Ph.D. in Biochemistry, created HeightMax after years of research and clinical trials. The Federal Trade Commission complaint also alleged that the defendants made unsubstantiated or false claims for Liposan Ultra Chitosan Fat Blocker, a weight loss supplement, and Osteo-Vite, marketed to older consumers for bone-building. To settle the charges, defendants Sunny Health Nutrition Technology & Products, Inc. and its owner, Sunny Sia, agreed to pay $375,000 in consumer redress. The settlement also holds the defendants potentially liable for $1.9 million in the event that they misrepresented their finances. The order to settle the FTC’s charges requires that claims for any dietary supplement, food, or drug must be true, non-misleading, and substantiated. In addition, it prohibits the defendants from misrepresenting endorsements, including the existence or expertise of any endorser. On November 30, 2006 the Honorable Susan C. Bucklew, Federal District Court Judge, signed a Stipulated Judgment requiring defendants to pay $375,000 based on the accuracy of sworn financial statements. The Judgment included an avalanche clause, requiring payment of full redress for $1.9 million if the financial statements were not accurate. On April 24, 2007, the FTC announced that the defendants shall be required to pay the full $1.9 Million after hidden assets were discovered. In the settlement, the $1.6 million balance of the judgment was suspended based on sworn financial disclosure documents showing inability to pay. Shortly after that settlement, the FTC discovered that the defendants kept at least $1.8 million in an undisclosed PayPal account. The FTC immediately obtained a temporary restraining order to freeze the funds, which was granted on December 8, 2006. The defendants have been ordered to pay the entire $1.9 million. Judge Bucklew’s new order, signed on February 22, 2007, and agreed to by the defendants, requires them to pay the entire $1.9 million, using the funds in the account at PayPal and other sources if necessary. The conduct prohibitions from the previously entered order remain unchanged. The FTC will set up a refund program for HeightMax purchasers, using the money collected. # External link Federal Trade Commission, Plaintiff, v. Sunny Health Nutrition Technology & Products, Inc., and Sunny Sia, Defendants. (United States District Court for the Middle District of Florida Tampa Division) *[1] Template:WikiDoc Sources	https://www.wikidoc.org/index.php/HeightMax
17df5c0a669338a05c94ae388a7704ec932fd213	wikidoc	Hellebore	Hellebore Commonly known as Hellebores, members of the genus Helleborus comprises approximately 20 species (ongoing fieldwork may see this figure change) of herbaceous perennial flowering plants in the family Ranunculaceae, within which it gave its name to the tribe of Helleboreae. Many species are poisonous. # Distribution and description The genus is native to much of Europe, from western Great Britain, Spain and Portugal, eastward across the Mediterranean region and central Europe into Romania and Ukraine, and along the north coast of Turkey into the Caucasus. The greatest concentration of species occurs in the Balkans. One atypical species (H. thibetanus) comes from western China; another atypical species (H. vesicarius) inhabits a small area on the border between Turkey and Syria. The flowers have five "petals" (actually sepals or tepals) surrounding a ring of small, cup-like nectaries (petals modified to hold nectar). The sepals do not fall as petals would, but remain on the plant, sometimes for many months. Recent research in Spain suggests that the persistent calyx contributes to the development of the seeds (Herrera 2005). Although the flowers of some species may resemble wild roses (and despite some of their common names, such as "Christmas rose" and "Lenten rose"), hellebores do not belong to the rose family (Rosaceae). # Species and subspecies ## Caulescent species These four species have leaves on their flowering stems (in H. vesicarius the stems die back each year; it also has basal leaves). - Helleborus argutifolius – Corsican hellebore - Helleborus foetidus – Stinking hellebore or Setterwort - Helleborus lividus - Helleborus vesicarius ## Acaulescent (stemless) species These species have basal leaves. They have no true leaves on their flower stalks (although there are leafy bracts where the flower stalks branch). - Helleborus atrorubens - Helleborus croaticus - Helleborus cyclophyllus - Helleborus dumetorum - Helleborus abruzzicus - Helleborus liguricus - Helleborus bocconei - Helleborus multifidus Helleborus multifidus subsp. hercegovinus Helleborus multifidus subsp. istriacus Helleborus multifidus subsp. multifidus - Helleborus multifidus subsp. hercegovinus - Helleborus multifidus subsp. istriacus - Helleborus multifidus subsp. multifidus - Helleborus niger – Christmas rose or Black hellebore Helleborus niger subsp. macranthus (syn. H. niger major) Helleborus niger subsp. niger - Helleborus niger subsp. macranthus (syn. H. niger major) - Helleborus niger subsp. niger - Helleborus odorus Helleborus odorus subsp. laxus Helleborus odorus subsp. odorus - Helleborus odorus subsp. laxus - Helleborus odorus subsp. odorus - Helleborus orientalis – Lenten rose, Lenten hellebore, oriental hellebore (N.B. most of the Lenten hellebores in gardens are now considered to be H. × hybridus) Helleborus orientalis subsp. abchasicus (syn. H. abchasicus) Helleborus orientalis subsp. guttatus Helleborus orientalis subsp. orientalis (syn. H. caucasicus, H. kochii) - Helleborus orientalis subsp. abchasicus (syn. H. abchasicus) - Helleborus orientalis subsp. guttatus - Helleborus orientalis subsp. orientalis (syn. H. caucasicus, H. kochii) - Helleborus purpurascens - Helleborus thibetanus (syn. H. chinensis) - Helleborus torquatus - Helleborus viridis - Green hellebore or Bear's-foot - Helleborus occidentalis (formerly H. viridis subsp. occidentalis) Other species names (now considered invalid) may be encountered in older literature, including H. hyemalis, H. polychromus, H. ranunculinus, H. trifolius. # Horticulture Hellebores are widely grown in gardens for decorative purposes, as well as for their purported medicinal abilities and uses in witchcraft. They are particularly valued by gardeners for their winter and early spring flowering period; the plants are surprisingly frost-resistant and many are evergreen. Many species of hellebore have green or greenish-purple flowers and are of limited garden value, although Corsican hellebore (H. argutifolius), a robust plant with pale green, cup-shaped flowers and attractive leathery foliage, is widely grown. So is stinking hellebore or setterwort (H. foetidus), which has drooping clusters of small, pale green, bell-shaped flowers, often edged with maroon, which contrast delightfully with its dark evergreen foliage. H. foetidus 'Wester Flisk', with red-flushed flowers and flower stalks, is becoming popular, as are more recent selections with golden-yellow foliage. The so-called Christmas rose (H. niger), a traditional cottage garden favourite, bears its pure white flowers (which often age to pink) in the depths of winter; large-flowered cultivars are available, as are pink-flowered and double-flowered selections. The most popular hellebores for garden use, however, are undoubtedly H. orientalis and its colourful hybrids (H. × hybridus). They flower in early spring, around the period of Lent, and are often known as Lenten hellebores, oriental hellebores, or Lenten roses. They are excellent for bringing early colour to shady herbaceous borders and areas between deciduous shrubs and under trees. ## Hellebore hybrids Hybridising (deliberate and accidental) between H. orientalis and several other closely-related species and subspecies has vastly improved the colour-range of the flowers, which now extends from slate grey, near-black, deep purple and plum, through rich red and pinks to yellow, white and green. The outer surface of the sepals is often green-tinged, and as the flower ages it usually becomes greener inside and out; individual flowers often remain on the plant for a month or more. The inner surface of each sepal may be marked with veins, or dotted or blotched with pink, red or purple. "Picotee" flowers, whose pale-coloured sepals have narrow margins of a darker colour, are much sought-after, as are those with dark nectaries which contrast with the outer sepals. Recent breeding programmes have also created double-flowered and anemone-centred plants. Ironically, doing this is actually reversing the evolutionary process in which hellebores' true petals had been modified into nectaries; it is usually these nectaries which become the extra petals in double, semi-double and anemone-centred flowers. Semi-double flowers have one or two extra rows of petals; doubles have more. Their inner petals are generally very like the outer ones in colour and patterning. They are often of a similar length and shape, though they may be slightly shorter and narrower, and some are attractively waved or ruffled. By contrast, anemone-centred flowers have, cupped within the five normal outer petals, a ring of much shorter, more curved extra petals (sometimes trumpet-shaped, intermediate in appearance between petals and nectaries), which may be a different colour from the outer petals. These short, extra petals (sometimes known as "petaloids") drop off after the flower has been pollinated, leaving an apparently single flower, whereas doubles and semi-doubles tend to retain their extra petals after pollination. ## Interspecific hybrids Gardeners and nurserymen have also created hybrids between less closely-related species. The earliest was probably H. × nigercors, a cross between H. niger and H. argutifolius (formerly H. lividus subsp. corsicus or H. corsicus, hence the name) first made in 1931. H. × sternii, a cross between H. argutifolius and H. lividus, first exhibited in 1947, is named after the celebrated British plantsman Sir Frederick Stern. H. × ballardiae (H. niger crossed with H. lividus) and H. × ericsmithii (H. niger crossed with H. × sternii) similarly commemorate the noted British nursery owners Helen Ballard and Eric Smith. In recent years, Ashwood Nurseries (of Kingswinford in the English Midlands), already well-known for its Ashwood Garden Hybrids (H. × hybridus singles, semi-doubles, doubles and anemone-centres), has created interesting hybrids between H. niger and H. thibetanus (called H. 'Pink Ice'), and between H. niger and H. vesicarius (called H. 'Briar Rose'). The gardenworthiness of these hybrids has still to be proven. # Folklore and historical usage In the early days of medicine, two kinds of hellebore were recognized: black hellebore, which included various species of Helleborus, and white hellebore, now known as Veratrum album ("false hellebore"). Although the latter plant is highly toxic, containing veratrine and the teratogens cyclopamine and jervine, it is believed to be the "hellebore" used by Hippocrates as a purgative. Black hellebore was used by the ancients in paralysis, gout and other diseases, more particularly in insanity. Black hellebore is also toxic, causing tinnitus, vertigo, stupor, thirst, a feeling of suffocation, swelling of the tongue and throat, emesis and catharsis, bradycardia (slowing of the pulse), and finally collapse and death from cardiac arrest. Several legends surround the hellebore; in witchcraft it is believed to have ties to summoning demons. Helleborus niger is commonly called the Christmas rose, due to an old legend that it sprouted in the snow from the tears of a young girl who had no gift to give the Christ child in Bethlehem. In Greek mythology, Melampus of Pylos used hellebore to save the daughters of the king of Argos from a madness, induced by Dionysus, that caused them to run naked through the city, crying, weeping, and screaming. During the Siege of Kirrha in 585 BC, hellebore was reportedly used by the Greek besiegers to poison the city's water supply. The defenders were subsequently so weakened by diarrhea that they were unable to defend the city from assault. Some historians believe that Alexander the Great died because of a hellebore overdose, when he took it as medication.	Hellebore Commonly known as Hellebores, members of the genus Helleborus comprises approximately 20 species (ongoing fieldwork may see this figure change) of herbaceous perennial flowering plants in the family Ranunculaceae, within which it gave its name to the tribe of Helleboreae. Many species are poisonous. # Distribution and description The genus is native to much of Europe, from western Great Britain, Spain and Portugal, eastward across the Mediterranean region and central Europe into Romania and Ukraine, and along the north coast of Turkey into the Caucasus. The greatest concentration of species occurs in the Balkans. One atypical species (H. thibetanus) comes from western China; another atypical species (H. vesicarius) inhabits a small area on the border between Turkey and Syria. The flowers have five "petals" (actually sepals or tepals) surrounding a ring of small, cup-like nectaries (petals modified to hold nectar). The sepals do not fall as petals would, but remain on the plant, sometimes for many months. Recent research in Spain suggests that the persistent calyx contributes to the development of the seeds (Herrera 2005). Although the flowers of some species may resemble wild roses (and despite some of their common names, such as "Christmas rose" and "Lenten rose"), hellebores do not belong to the rose family (Rosaceae). # Species and subspecies ## Caulescent species These four species have leaves on their flowering stems (in H. vesicarius the stems die back each year; it also has basal leaves). - Helleborus argutifolius – Corsican hellebore - Helleborus foetidus – Stinking hellebore or Setterwort - Helleborus lividus - Helleborus vesicarius ## Acaulescent (stemless) species These species have basal leaves. They have no true leaves on their flower stalks (although there are leafy bracts where the flower stalks branch). - Helleborus atrorubens - Helleborus croaticus - Helleborus cyclophyllus - Helleborus dumetorum - Helleborus abruzzicus - Helleborus liguricus - Helleborus bocconei - Helleborus multifidus Helleborus multifidus subsp. hercegovinus Helleborus multifidus subsp. istriacus Helleborus multifidus subsp. multifidus - Helleborus multifidus subsp. hercegovinus - Helleborus multifidus subsp. istriacus - Helleborus multifidus subsp. multifidus - Helleborus niger – Christmas rose or Black hellebore Helleborus niger subsp. macranthus (syn. H. niger major) Helleborus niger subsp. niger - Helleborus niger subsp. macranthus (syn. H. niger major) - Helleborus niger subsp. niger - Helleborus odorus Helleborus odorus subsp. laxus Helleborus odorus subsp. odorus - Helleborus odorus subsp. laxus - Helleborus odorus subsp. odorus - Helleborus orientalis – Lenten rose, Lenten hellebore, oriental hellebore (N.B. most of the Lenten hellebores in gardens are now considered to be H. × hybridus) Helleborus orientalis subsp. abchasicus (syn. H. abchasicus) Helleborus orientalis subsp. guttatus Helleborus orientalis subsp. orientalis (syn. H. caucasicus, H. kochii) - Helleborus orientalis subsp. abchasicus (syn. H. abchasicus) - Helleborus orientalis subsp. guttatus - Helleborus orientalis subsp. orientalis (syn. H. caucasicus, H. kochii) - Helleborus purpurascens - Helleborus thibetanus (syn. H. chinensis) - Helleborus torquatus - Helleborus viridis - Green hellebore or Bear's-foot - Helleborus occidentalis (formerly H. viridis subsp. occidentalis) Other species names (now considered invalid) may be encountered in older literature, including H. hyemalis, H. polychromus, H. ranunculinus, H. trifolius. # Horticulture Hellebores are widely grown in gardens for decorative purposes, as well as for their purported medicinal abilities and uses in witchcraft. They are particularly valued by gardeners for their winter and early spring flowering period; the plants are surprisingly frost-resistant and many are evergreen. Many species of hellebore have green or greenish-purple flowers and are of limited garden value, although Corsican hellebore (H. argutifolius), a robust plant with pale green, cup-shaped flowers and attractive leathery foliage, is widely grown. So is stinking hellebore or setterwort (H. foetidus), which has drooping clusters of small, pale green, bell-shaped flowers, often edged with maroon, which contrast delightfully with its dark evergreen foliage. H. foetidus 'Wester Flisk', with red-flushed flowers and flower stalks, is becoming popular, as are more recent selections with golden-yellow foliage. The so-called Christmas rose (H. niger), a traditional cottage garden favourite, bears its pure white flowers (which often age to pink) in the depths of winter; large-flowered cultivars are available, as are pink-flowered and double-flowered selections. The most popular hellebores for garden use, however, are undoubtedly H. orientalis and its colourful hybrids (H. × hybridus). They flower in early spring, around the period of Lent, and are often known as Lenten hellebores, oriental hellebores, or Lenten roses. They are excellent for bringing early colour to shady herbaceous borders and areas between deciduous shrubs and under trees. ## Hellebore hybrids Hybridising (deliberate and accidental) between H. orientalis and several other closely-related species and subspecies has vastly improved the colour-range of the flowers, which now extends from slate grey, near-black, deep purple and plum, through rich red and pinks to yellow, white and green. The outer surface of the sepals is often green-tinged, and as the flower ages it usually becomes greener inside and out; individual flowers often remain on the plant for a month or more. The inner surface of each sepal may be marked with veins, or dotted or blotched with pink, red or purple. "Picotee" flowers, whose pale-coloured sepals have narrow margins of a darker colour, are much sought-after, as are those with dark nectaries which contrast with the outer sepals. Recent breeding programmes have also created double-flowered and anemone-centred plants. Ironically, doing this is actually reversing the evolutionary process in which hellebores' true petals had been modified into nectaries; it is usually these nectaries which become the extra petals in double, semi-double and anemone-centred flowers. Semi-double flowers have one or two extra rows of petals; doubles have more. Their inner petals are generally very like the outer ones in colour and patterning. They are often of a similar length and shape, though they may be slightly shorter and narrower, and some are attractively waved or ruffled. By contrast, anemone-centred flowers have, cupped within the five normal outer petals, a ring of much shorter, more curved extra petals (sometimes trumpet-shaped, intermediate in appearance between petals and nectaries), which may be a different colour from the outer petals. These short, extra petals (sometimes known as "petaloids") drop off after the flower has been pollinated, leaving an apparently single flower, whereas doubles and semi-doubles tend to retain their extra petals after pollination. ## Interspecific hybrids Gardeners and nurserymen have also created hybrids between less closely-related species. The earliest was probably H. × nigercors, a cross between H. niger and H. argutifolius (formerly H. lividus subsp. corsicus or H. corsicus, hence the name) first made in 1931. H. × sternii, a cross between H. argutifolius and H. lividus, first exhibited in 1947, is named after the celebrated British plantsman Sir Frederick Stern. H. × ballardiae (H. niger crossed with H. lividus) and H. × ericsmithii (H. niger crossed with H. × sternii) similarly commemorate the noted British nursery owners Helen Ballard and Eric Smith. In recent years, Ashwood Nurseries (of Kingswinford in the English Midlands), already well-known for its Ashwood Garden Hybrids (H. × hybridus singles, semi-doubles, doubles and anemone-centres), has created interesting hybrids between H. niger and H. thibetanus (called H. 'Pink Ice'), and between H. niger and H. vesicarius (called H. 'Briar Rose'). The gardenworthiness of these hybrids has still to be proven. # Folklore and historical usage In the early days of medicine, two kinds of hellebore were recognized: black hellebore, which included various species of Helleborus, and white hellebore, now known as Veratrum album ("false hellebore"). Although the latter plant is highly toxic, containing veratrine and the teratogens cyclopamine and jervine, it is believed to be the "hellebore" used by Hippocrates as a purgative. Black hellebore was used by the ancients in paralysis, gout and other diseases, more particularly in insanity. Black hellebore is also toxic, causing tinnitus, vertigo, stupor, thirst, a feeling of suffocation, swelling of the tongue and throat, emesis and catharsis, bradycardia (slowing of the pulse), and finally collapse and death from cardiac arrest.[1] Several legends surround the hellebore; in witchcraft it is believed to have ties to summoning demons. Helleborus niger is commonly called the Christmas rose, due to an old legend that it sprouted in the snow from the tears of a young girl who had no gift to give the Christ child in Bethlehem. In Greek mythology, Melampus of Pylos used hellebore to save the daughters of the king of Argos from a madness, induced by Dionysus, that caused them to run naked through the city, crying, weeping, and screaming. During the Siege of Kirrha in 585 BC, hellebore was reportedly used by the Greek besiegers to poison the city's water supply. The defenders were subsequently so weakened by diarrhea that they were unable to defend the city from assault. Some historians believe that Alexander the Great died because of a hellebore overdose, when he took it as medication.	https://www.wikidoc.org/index.php/Hellebore
f6242001992163ae92557de082d4ca71742c665d	wikidoc	Hemiblock	Hemiblock # Overview Hemiblocks are defined as impaired conduction in the electrical system of the heart that occurs below the AV node within the fascicles of the left bundle branch. # Classification ## Left Anterior Hemiblock Left anterior hemiblock is caused by interruption of the anterior division of the left bundle branch. This fascicle is fragile, easily exposed to damage, and has a single blood supply (the left anterior descending coronary artery). ## Left Posterior Hemiblock Left posterior fascicular block is characterized by a mean frontal plane axis of >90° in the absence of other causes of right axis deviation. Left posterior hemiblock (left posterior fascicular block) is infrequent. Its seen either in the setting of either RCA or LAD related pathologies.	Hemiblock Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Hemiblocks are defined as impaired conduction in the electrical system of the heart that occurs below the AV node within the fascicles of the left bundle branch. # Classification ## Left Anterior Hemiblock Left anterior hemiblock is caused by interruption of the anterior division of the left bundle branch. This fascicle is fragile, easily exposed to damage, and has a single blood supply (the left anterior descending coronary artery). ## Left Posterior Hemiblock Left posterior fascicular block is characterized by a mean frontal plane axis of >90° in the absence of other causes of right axis deviation. Left posterior hemiblock (left posterior fascicular block) is infrequent.[1] Its seen either in the setting of either RCA or LAD related pathologies.	https://www.wikidoc.org/index.php/Hemiblock
a12a5c73fe016f7911181d0e8082ba251244ba9a	wikidoc	Hemimelia	Hemimelia # Overview Fibular Hemimelia or "Longitudinal fibular deficiency" is "the congenital absence of the fibula and it is the most common congenital absence of long bone of the extremities." It is the shortening of the fibula at birth, or the complete lack thereof. The disorder can be noted by ultrasound in utero, allowing for parents to decide on abortion or to prepare for amputation after birth or complex bone lengthening surgery. The amputation usually takes place at 6-months with removal of portions of the legs to retro fit them for prosthetic use. The other treatments which include repeated corrective osteotomies and leg-lengthening surgery are costly and associated with residual deformity. # Common Facts - It is among most frequent limb anomalies is partial or total absence of fibula; - it is most common long bone deficiency and is the most common skeletal deformity in the leg; - most often is unilateral; - paraxial fibular hemimelia is the most common manifestation (only the postaxial portion of the limb is affected) - commonly seen as complete terminal deficiency (lateral rays of the foot are affected as well); - hemimelia can also be intercalary in which case the foot remain unaffected; - it is prudent to remember that although congenital absence of fibula is evident, this condition is actually a total limb involvement; - males are affected twice as often as females in most series;	Hemimelia # Overview Fibular Hemimelia or "Longitudinal fibular deficiency" is "the congenital absence of the fibula and it is the most common congenital absence of long bone of the extremities."[1] It is the shortening of the fibula at birth, or the complete lack thereof. The disorder can be noted by ultrasound in utero, allowing for parents to decide on abortion or to prepare for amputation after birth or complex bone lengthening surgery. The amputation usually takes place at 6-months with removal of portions of the legs to retro fit them for prosthetic use. The other treatments which include repeated corrective osteotomies and leg-lengthening surgery are costly and associated with residual deformity.[2] # Common Facts - It is among most frequent limb anomalies is partial or total absence of fibula;[3] - it is most common long bone deficiency and is the most common skeletal deformity in the leg;[4] - most often is unilateral;[5] - paraxial fibular hemimelia is the most common manifestation (only the postaxial portion of the limb is affected) - commonly seen as complete terminal deficiency (lateral rays of the foot are affected as well);[6] - hemimelia can also be intercalary in which case the foot remain unaffected;[7] - it is prudent to remember that although congenital absence of fibula is evident, this condition is actually a total limb involvement;[8] - males are affected twice as often as females in most series; [9]	https://www.wikidoc.org/index.php/Hemimelia
adabc2858b46315fd399b464917c82ae1ba6d974	wikidoc	Hemopexin	Hemopexin Hemopexin (or haemopexin; Hpx; Hx), also known as beta-1B-glycoprotein, is a glycoprotein that in humans is encoded by the HPX gene and belongs to hemopexin family of proteins. Heme released during degradation of hemoglobin is bound by albumin and rapidly transferred to Hx, the plasma protein with the highest binding affinity for heme. Hx prevents heme's pro-oxidant and pro-inflammatory effects and it also promotes its detoxification. The Hx-heme complex is cleared by the receptor CD91. # Cloning, expression, and discovery Takahashi et al. (1985) determined that human plasma Hx consists of a single polypeptide chain of 439 amino acids residues with six intrachain disulfide bridges and has a molecular mass of approximately 63 kD. The amino-terminal threonine residue is blocked by an O-linked galactosamine oligosaccharide, and the protein has five glucosamine oligosaccharides N-linked to the acceptor sequence Asn-X-Ser/Thr. The 18 tryptophan residues are arranged in four clusters, and 12 of the tryptophans are conserved in homologous positions. Computer-assisted analysis of the internal homology in amino acid sequence suggested duplication of an ancestral gene thus indicating that Hx consists of two similar halves. Altruda et al. (1988) demonstrated that the HPX gene spans approximately 12 kb and is interrupted by 9 exons. The demonstration shows direct correspondence between exons and the 10 repeating units in the protein. The introns were not placed randomly; they fell in the center of the region of amino acid sequence homology in strikingly similar locations in 6 of the 10 units and in a symmetric position in each half of the coding sequence. From these observations, Altruda et al. (1988) concluded that the gene evolved through intron-mediated duplications of a primordial sequence to a 5-exon cluster. # Mapping of hemopexin gene Cai and Law (1986) prepared a cDNA clone for Hx, by Southern blot analysis of human/hamster hybrids containing different combinations of human chromosomes, assigned the HPX gene to human chromosome 11. Law et al. (1988) assigned the HPX gene to 11p15.5-p15.4, the same location as that of the beta-globin gene complex by in situ hybridization. # Differential transcriptional pattern of hemopexin gene In 1986, the expression of the human HPX gene in different human tissues and cell lines was carried out by using a specific cDNA probe. From the results obtained it was concluded that this gene was expressed in the liver and it was below the level of detection in other tissues or cell lines examined. By S1 mapping, the transcription initiation site in hepatic cells was located 28 base pairs upstream from the AUG initiation codon of the hemopexin gene. # Function Hx binds heme with the highest affinity of any known protein. Its main function is scavenging the heme released or lost by the turnover of heme proteins such as hemoglobin and thus protects the body from the oxidative damage that free heme can cause. In addition, Hx releases its bound ligand for internalisation upon interacting with CD91. Hx preserves the body's iron. Hx-dependent uptake of extracellular heme can lead to the deactivation of Bach1 repression which leads to the transcriptional activation of antioxidant heme oxygenase-1 gene. Hemoglobin, haptoglobin (Hp) and Hx associate with high density lipoprotein (HDL) and influence the inflammatory properties of HDL. Hx can downregulate the angiotensin II Type 1 receptor (AT1-R) in vitro. # Clinical significance The predominant source of circulating Hx is the liver with a plasma concentration of 1–2 mg/ml. Serum Hx level reflects how much heme is present in the blood. Therefore, a low Hx level indicates that there has been significant degradation of heme containing compounds. A low Hx level is one of the diagnostic features of an intravascular hemolytic anemia. Hx has been implicated in cardiovascular disease, septic shock, cerebral ischemic injury, and experimental autoimmune encephalomyelitis. The circulating level of Hx is associated with prognosis in patients with septic shock. HPX is produced in the brain. Deletion of the HPX gene can aggravate brain injury followed by stroma-free hemoglobin-induced intracerebral haemorrhage. High Hx level in the cerebrospinal fluid is associated with poor outcome after subarachnoid hemorrhage. # Relation to haptoglobin In past there have been reports showing that in patients with sickle cell disease, spherocytosis, autoimmune hemolytic anemia, erythropoietic protoporphyria and pyruvate kinase deficiency, a decline in Hx concentration occurs in situations when Hp concentrations are low or depleted as a result of severe or prolonged hemolysis. Both Hp and Hx are acute-phase proteins, induced during infection and inflammatory states to minimize tissue injury and facilitate tissue repair. Hp and Hx prevent heme toxicity prior to monocyte or macrophage clearance, which may explain their effect on outcome in several diseases, and underlies the rationale for exogenous Hp and Hx as therapeutic proteins in hemolytic or hemorrhagic conditions.	Hemopexin Hemopexin (or haemopexin; Hpx; Hx), also known as beta-1B-glycoprotein, is a glycoprotein that in humans is encoded by the HPX gene[1][2][3] and belongs to hemopexin family of proteins.[4] Heme released during degradation of hemoglobin is bound by albumin and rapidly transferred to Hx, the plasma protein with the highest binding affinity for heme. Hx prevents heme's pro-oxidant and pro-inflammatory effects and it also promotes its detoxification. The Hx-heme complex is cleared by the receptor CD91. # Cloning, expression, and discovery Takahashi et al. (1985) determined that human plasma Hx consists of a single polypeptide chain of 439 amino acids residues with six intrachain disulfide bridges and has a molecular mass of approximately 63 kD. The amino-terminal threonine residue is blocked by an O-linked galactosamine oligosaccharide, and the protein has five glucosamine oligosaccharides N-linked to the acceptor sequence Asn-X-Ser/Thr. The 18 tryptophan residues are arranged in four clusters, and 12 of the tryptophans are conserved in homologous positions. Computer-assisted analysis of the internal homology in amino acid sequence suggested duplication of an ancestral gene thus indicating that Hx consists of two similar halves.[5] Altruda et al. (1988) demonstrated that the HPX gene spans approximately 12 kb and is interrupted by 9 exons. The demonstration shows direct correspondence between exons and the 10 repeating units in the protein. The introns were not placed randomly; they fell in the center of the region of amino acid sequence homology in strikingly similar locations in 6 of the 10 units and in a symmetric position in each half of the coding sequence. From these observations, Altruda et al. (1988) concluded that the gene evolved through intron-mediated duplications of a primordial sequence to a 5-exon cluster.[6] # Mapping of hemopexin gene Cai and Law (1986) prepared a cDNA clone for Hx, by Southern blot analysis of human/hamster hybrids containing different combinations of human chromosomes, assigned the HPX gene to human chromosome 11. Law et al. (1988) assigned the HPX gene to 11p15.5-p15.4, the same location as that of the beta-globin gene complex by in situ hybridization.[7] # Differential transcriptional pattern of hemopexin gene In 1986, the expression of the human HPX gene in different human tissues and cell lines was carried out by using a specific cDNA probe. From the results obtained it was concluded that this gene was expressed in the liver and it was below the level of detection in other tissues or cell lines examined. By S1 mapping, the transcription initiation site in hepatic cells was located 28 base pairs upstream from the AUG initiation codon of the hemopexin gene.[8] # Function Hx binds heme with the highest affinity of any known protein. Its main function is scavenging the heme released or lost by the turnover of heme proteins such as hemoglobin and thus protects the body from the oxidative damage that free heme can cause. In addition, Hx releases its bound ligand for internalisation upon interacting with CD91[9]. Hx preserves the body's iron.[10] Hx-dependent uptake of extracellular heme can lead to the deactivation of Bach1 repression which leads to the transcriptional activation of antioxidant heme oxygenase-1 gene. Hemoglobin, haptoglobin (Hp) and Hx associate with high density lipoprotein (HDL) and influence the inflammatory properties of HDL.[11] Hx can downregulate the angiotensin II Type 1 receptor (AT1-R) in vitro.[12] # Clinical significance The predominant source of circulating Hx is the liver with a plasma concentration of 1–2 mg/ml.[13] Serum Hx level reflects how much heme is present in the blood. Therefore, a low Hx level indicates that there has been significant degradation of heme containing compounds. A low Hx level is one of the diagnostic features of an intravascular hemolytic anemia.[14] Hx has been implicated in cardiovascular disease, septic shock, cerebral ischemic injury, and experimental autoimmune encephalomyelitis.[15][16] The circulating level of Hx is associated with prognosis in patients with septic shock.[15] HPX is produced in the brain[17]. Deletion of the HPX gene can aggravate brain injury followed by stroma-free hemoglobin-induced intracerebral haemorrhage.[18] High Hx level in the cerebrospinal fluid is associated with poor outcome after subarachnoid hemorrhage.[17] # Relation to haptoglobin In past there have been reports showing that in patients with sickle cell disease, spherocytosis, autoimmune hemolytic anemia, erythropoietic protoporphyria and pyruvate kinase deficiency, a decline in Hx concentration occurs in situations when Hp concentrations are low or depleted as a result of severe or prolonged hemolysis.[13] Both Hp and Hx are acute-phase proteins, induced during infection and inflammatory states to minimize tissue injury and facilitate tissue repair. Hp and Hx prevent heme toxicity prior to monocyte or macrophage clearance, which may explain their effect on outcome in several diseases, and underlies the rationale for exogenous Hp and Hx as therapeutic proteins in hemolytic or hemorrhagic conditions.[19]	https://www.wikidoc.org/index.php/Hemopexin
1272b1376dd74e0e9d5b691f9274717135ec3b74	wikidoc	Hemotoxin	Hemotoxin Hemotoxins, haemotoxins or hematotoxins are toxins that destroy red blood cells (that is, cause hemolysis), disrupt blood clotting, and/or cause organ degeneration and generalized tissue damage. The term hemotoxin is to some degree a misnomer since toxins that damage the blood also damage other tissues. An injury due to a hemotoxic agent is often very painful, and permanent damage, such as loss of an affected limb, is possible even with prompt treatment. Hemotoxins are frequently employed by venomous animals, including pit vipers. Animal venoms contain enzymes and other proteins that are hemotoxic or neurotoxic or occasionally both (as in the Mojave Rattlesnake and similar species). In addition to killing the prey, part of the function of a hemotoxic venom for some animals is to aid digestion. The venom breaks down protein in the region of the bite, making prey easier to digest. The process by which a hemotoxin causes death is much slower than that of a neurotoxin. Snakes which envenomate a prey animal may have to track the prey as it runs (or otherwise moves) away. Typically, a mammalian prey item will stop fleeing not because it is dead but because shock sets in due to trauma from the poison bite. Dependent upon species, size, location of bite and the amount of venom injected, symptoms in humans such as nausea, disorientation, and headaches may be delayed for several hours. Hemotoxins are used in diagnostic studies of the coagulation system. Lupus anticoagulans is detected by changes in the dilute Russell's viper venom time (DRVVT), which is a laboratory assay based on—as its name indicates—venom of the Russell's viper.	Hemotoxin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Hemotoxins, haemotoxins or hematotoxins are toxins that destroy red blood cells (that is, cause hemolysis), disrupt blood clotting, and/or cause organ degeneration and generalized tissue damage. The term hemotoxin is to some degree a misnomer since toxins that damage the blood also damage other tissues. An injury due to a hemotoxic agent is often very painful, and permanent damage, such as loss of an affected limb, is possible even with prompt treatment. Hemotoxins are frequently employed by venomous animals, including pit vipers. Animal venoms contain enzymes and other proteins that are hemotoxic or neurotoxic or occasionally both (as in the Mojave Rattlesnake and similar species). In addition to killing the prey, part of the function of a hemotoxic venom for some animals is to aid digestion. The venom breaks down protein in the region of the bite, making prey easier to digest. The process by which a hemotoxin causes death is much slower than that of a neurotoxin. Snakes which envenomate a prey animal may have to track the prey as it runs (or otherwise moves) away. Typically, a mammalian prey item will stop fleeing not because it is dead but because shock sets in due to trauma from the poison bite. Dependent upon species, size, location of bite and the amount of venom injected, symptoms in humans such as nausea, disorientation, and headaches may be delayed for several hours. Hemotoxins are used in diagnostic studies of the coagulation system. Lupus anticoagulans is detected by changes in the dilute Russell's viper venom time (DRVVT), which is a laboratory assay based on—as its name indicates—venom of the Russell's viper. # External links - Introduction to the special edition of Journal of Toxicology - Toxin Reviews, 21(1 & 2), vii-xi (2002). lt:Hematoksinas sv:Hemotoxin Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Hemotoxic
17cd7bb2b2f787f6622fab3cc86000f6fd8df949	wikidoc	Hepoxilin	Hepoxilin Hepoxilins (HxA3 and HxB3) are nonclassic eicosanoid hormones involved in inflammation. # History Hepoxilins were identified and named in Canada in 1984 by CR Pace-Asciak and JM Martin. # Biochemistry They derive from arachidonic acid via oxidation by the enzyme 12-lipoxygenase. Hepoxilins are differentiated from closely related eicosanoids, the leukotrienes and the lipoxins, in that hepoxilins have no conjugated double bonds. Corresponding trioxlins A4 and B4 are formed by the same pathway from EPA # Physiological effect In the skin, Hx are pro-inflammatory, but in neutrophils they are anti-inflammatory. Hx are potent insulin secretagogues. One hepoxilin, HepA3, mediates neutrophil migration across the intestines. Hepoxilins are also produced in the brain. Cells under oxidative stress secrete HX3, which in turn upregulates peroxidase, decreasing oxidative stress. This is proposed to constitute a compensatory defense response to protect the vitality and functionality of the cell.	Hepoxilin Template:Chembox new Hepoxilins (HxA3 and HxB3) are nonclassic eicosanoid hormones involved in inflammation. # History Hepoxilins were identified and named in Canada in 1984 by CR Pace-Asciak and JM Martin.[1] # Biochemistry They derive from arachidonic acid via oxidation by the enzyme 12-lipoxygenase. Hepoxilins are differentiated from closely related eicosanoids, the leukotrienes and the lipoxins, in that hepoxilins have no conjugated double bonds. Corresponding trioxlins A4 and B4 are formed by the same pathway from EPA [2] # Physiological effect In the skin, Hx are pro-inflammatory, but in neutrophils they are anti-inflammatory.[3] Hx are potent insulin secretagogues.[2] One hepoxilin, HepA3, mediates neutrophil migration across the intestines.[4] Hepoxilins are also produced in the brain.[5] Cells under oxidative stress secrete HX3, which in turn upregulates peroxidase, decreasing oxidative stress. This is proposed to constitute a compensatory defense response to protect the vitality and functionality of the cell.[6]	https://www.wikidoc.org/index.php/Hepoxilin
65a2d35e3ae792e9173875e8c18677e5f905299b	wikidoc	Herbalist	Herbalist An herbalist is: - A person whose life is dedicated to the economic or medicinal uses of plants. - One skilled in the harvesting and collection of medicinal plants (see wildcrafter). - Traditional Chinese herbalist: one who is trained or skilled in the dispensing of herbal prescriptions; traditional Chinese herb doctor. Similarly, Traditional Ayurvedic herbalist: one who is trained or skilled in the dispensing of herbal prescriptions in the Ayurvedic tradition. - One trained or skilled in the therapeutic use of medicinal plants. An herbalist is a professional trained in herbalism, the use of herbs (also called botanical or crude medicine) to treat others. Professional herbal designations include - American Herbalists Guild Registered Herbalist (AHG) - the NCCAOM Diplomate in Oriental Medicine from the National Certification Commission for Acupuncture and Oriental Medicine - the MNHAA signifying Full Member of the National Herbalists Association of Australia (NHAA) - the FNHAA signifying Fellow of the NHAA, awarded only to Full Members with a minimum of 10 years Full Membership and clinical practice as a herbalist, plus meritorious service to the profession and/or Association. - the MNIMH of the National Institute of Medical Herbalists or the MIIMH of The Irish Institute of Medical Herbalists. Education of herbalists varies considerably in different areas of the world. Lay herbalists and traditional indigenous medicine people generally rely upon apprenticeship and recognition from their communities in lieu of formal schooling. In some countries formalised training and minimum education standards exist, although these are not necessarily uniform within or between countries. For example, in Australia the currently self-regulated status of the profession (as of April 2008) results in different associations setting different educational standards, and subsequently recognising an educational institution or course of training. Qualifications levels vary from Diploma to Masters degree, with Advanced Diploma level being regulated to some degree by the national Health Training Packages issued by the Australian National Training Authority. The Course Accreditation System Version 2 of the National Herbalists Association of Australia / is generally recognised as the most rigorous and professional standard within Australia. Herbalists may engage in wildcrafting or cultivation of herbs, as well as diagnosis and treatment of conditions or dispensing herbal medication. Most herbal traditions depend upon constitutional analysis of the client, treating the patient instead of the disease.	Herbalist An herbalist is:[1][2][3] - A person whose life is dedicated to the economic or medicinal uses of plants. - One skilled in the harvesting and collection of medicinal plants (see wildcrafter). - Traditional Chinese herbalist: one who is trained or skilled in the dispensing of herbal prescriptions; traditional Chinese herb doctor. Similarly, Traditional Ayurvedic herbalist: one who is trained or skilled in the dispensing of herbal prescriptions in the Ayurvedic tradition. - One trained or skilled in the therapeutic use of medicinal plants. An herbalist is a professional trained in herbalism, the use of herbs (also called botanical or crude medicine) to treat others. Professional herbal designations include - American Herbalists Guild Registered Herbalist (AHG)[4] - the NCCAOM Diplomate in Oriental Medicine from the National Certification Commission for Acupuncture and Oriental Medicine[5] - the MNHAA signifying Full Member of the National Herbalists Association of Australia (NHAA)[6] - the FNHAA signifying Fellow of the NHAA[7], awarded only to Full Members with a minimum of 10 years Full Membership and clinical practice as a herbalist, plus meritorious service to the profession and/or Association. - the MNIMH of the National Institute of Medical Herbalists[8] or the MIIMH of The Irish Institute of Medical Herbalists.[9] Education of herbalists varies considerably in different areas of the world. Lay herbalists and traditional indigenous medicine people generally rely upon apprenticeship and recognition from their communities in lieu of formal schooling. In some countries formalised training and minimum education standards exist, although these are not necessarily uniform within or between countries. For example, in Australia the currently self-regulated status of the profession (as of April 2008) results in different associations setting different educational standards, and subsequently recognising an educational institution or course of training. Qualifications levels vary from Diploma to Masters degree, with Advanced Diploma level being regulated to some degree by the national Health Training Packages issued by the Australian National Training Authority. The Course Accreditation System Version 2 of the National Herbalists Association of Australia http://www.nhaa.org.au/ is generally recognised as the most rigorous and professional standard within Australia.[10] Herbalists may engage in wildcrafting or cultivation of herbs, as well as diagnosis and treatment of conditions or dispensing herbal medication. Most herbal traditions depend upon constitutional analysis of the client, treating the patient instead of the disease.[11][12]	https://www.wikidoc.org/index.php/Herbalist
83ad13d4f5e61cc1abae1bc8fdebd0e04a712f16	wikidoc	Herbicide	Herbicide # Overview A herbicide is used to kill unwanted plants. Selective herbicides kill specific targets while leaving the desired crop relatively unharmed. Some of these act by interfering with the growth of the weed and are often based on plant hormones. Herbicides used to clear waste ground are nonselective and kill all plant material with which they come into contact. Some plants produce natural herbicides, such as the genus Juglans (walnuts). They are applied in total vegetation control (TVC) programs for maintenance of highways and railroads. Smaller quantities are used in forestry, pasture systems, and management of areas set aside as wildlife habitat. Herbicides are widely used in agriculture and in landscape turf management. In the us, they account for about 70% of all agricultural pesticide use. # History Prior to the widespread use of chemical herbicides, cultural controls, such as altering soil pH, salinity, or fertility levels, were used to control weeds. Mechanical control (including tillage) was also (and still is) used to control weeds. The first widely used herbicide was 2,4-dichlorophenoxyacetic acid, often abbreviated 2,4-D. It was developed by a British team during World War II and first saw widespread production and use in the late 1940s. It is easy and inexpensive to manufacture, and kills many broadleaf plants while leaving grasses largely unaffected (although high doses of 2,4-D at crucial growth periods can harm grass crops such as maize or cereals). The low cost of 2,4-D has led to continued usage today and it remains one of the most commonly used herbicides in the world. Like other acid herbicides, current formulations utilize either an amine salt (usually trimethylamine) or one of many esters of the parent compound. These are easier to handle than the acid. 2,4-D exhibits relatively poor selectivity, meaning that it causes stress to non-target plants. It is also less effective against some broadleaf weeds, including many vinous plants, and sedges. A herbicide is termed selective if it affects only certain types of plants, and nonselective if it inhibits most any type of plant. Other herbicides have been more recently developed to achieve desired selectivities. The 1970s saw the introduction of atrazine, which has the dubious distinction of being the herbicide of greatest concern for groundwater contamination. Atrazine does not break down readily (within a few weeks) after being applied. Instead it is carried deep into the soil by rainfall causing the aforementioned contamination. Atrazine is said to have high carryover, a very undesirable property for herbicides. Glyphosate, frequently sold under the brand name Roundup, was introduced in 1974 for non-selective weed control. It is now a major herbicide in selective weed control in growing crop plants due to the development of crop plants that are resistant to it. The pairing of the herbicide with the resistant seed contributed to the consolidation of the seed and chemistry industry in the late 1990s. Many modern chemical herbicides for agriculture are specifically formulated to decompose within a short period after application. This is desirable as it allows crops which may be affected by the herbicide to be grown on the land in future seasons. However, herbicides with low residual activity (ie decompose quickly) often do not provide season-long weed control. # Health effects Certain herbicides cause a variety of health effects ranging from skin rashes to death. The pathway of attack can arise from improper application resulting in direct contact with field workers, inhalation of aerial sprays, food consumption and from contact with residual soil contamination. Herbicides can also be transported via surface runoff to contaminate distant surface waters and hence another pathway of ingestion through extraction of those surface waters for drinking. Some herbicides decompose rapidly in soils and other types have more persistent characteristics with longer environmental half-lives. Other alleged health effects can include chest pain, headaches, nausea and fatigue. Most herbicides (primarily the non-organic) must be extensively tested prior to labeling by the Environmental Protection Agency. However, because of the large number of herbicides in use, there is significant concern regarding health effects. Some of the herbicides in use are known to be mutagenic, carcinogenic or teratogenic. However, some herbicides may also have a therapeutic use. Current research aims to use herbicides as an anti-malaria drug that targets the plant-like apicoplast plastid in the malaria causing parasite Plasmodium falciparum. # Classification of herbicides Herbicides can be grouped by activity, use, chemical family, mode of action, or type of vegetation controlled. By activity: - Contact herbicides destroy only the plant tissue in contact with the chemical. Generally, these are the fastest acting herbicides. They are less effective on perennial plants, which are able to regrow from roots or tubers. - Systemic herbicides are translocated through the plant, either from foliar application down to the roots, or from soil application up to the leaves. They can destroy a greater amount of plant tissue than contact herbicides. By use: - Soil-applied herbicides are applied to the soil and are taken up by the roots of the target plant. - Preemergent herbicides are applied to the soil before the crop emerges and prevent germination or early growth of weed seeds. - Post-emergent herbicides are applied after the crop has emerged. Their classification by mechanism of action (MOA) indicates the first enzyme, protein, or biochemical step affected in the plant following application. The main mechanisms of action are: - ACCase inhibitors are compounds that kill grasses. Acetyl coenzyme A carboxylase (ACCase) is part of the first step of lipid synthesis. Thus, ACCase inhibitors affect cell membrane production in the meristems of the grass plant. The ACCases of grasses are sensitive to these herbicides, whereas the ACCases of dicot plants are not. - ALS inhibitors: the acetolactate synthase (ALS) enzyme (also known as acetohydroxyacid synthase, or AHAS) is the first step in the synthesis of the branched-chain amino acids (valine, leucine, and isoleucine). These herbicides slowly starve affected plants of these amino acids which eventually leads to inhibition of DNA synthesis. They affect grasses and dicots alike. The ALS inhibitor family includes sulfonylureas (SUs), imidazolinones (IMIs), triazolopyrimidines (TPs), pyrimidinyl oxybenzoates (POBs), and sulfonylamino carbonyl triazolinones (SCTs). - EPSPS inhibitors: The enolpyruvylshikimate 3-phosphate synthase enzyme EPSPS is used in the synthesis of the amino acids tryptophan, phenylalanine and tyrosine. They affect grasses and dicots alike. Glyphosate (Roundup) is a systemic EPSPS inhibitor but inactivated by soil contact. - Synthetic auxin inaugurated the era of organic herbicides. They were discovered in the 1940s after a long study of the plant growth regulator auxin. Synthetic auxins mimic this plant hormone. They have several points of action on the cell membrane, and are effective in the control of dicot plants. 2,4-D is a synthetic auxin herbicide. - Photosystem II inhibitors reduce electron flow from water to NADPH2+ at the photochemical step in photosynthesis. They bind to the Qb site on the D2 protein, and prevent quinone from binding to this site. Therefore, this group of compounds cause electrons to accumulate on chlorophyll molecules. As a consequence, oxidation reactions in excess of those normally tolerated by the cell occur, and the plant dies. The triazine herbicides (including atrazine) are PSII inhibitors. # Organic Herbicides An organic herbicide is one that can be used in a farming enterprise that has been classified as organic. Organic herbicides are expensive and may not be affordable for commercial production. They are much less effective than synthetic herbicides but of course do not inject unnatural chemicals into the environment. Organic herbicides include: - Spices are now effectively used in patented herbicides. - Vinegar is effective for 5-20% solutions of acetic acid with higher concentrations most effective but mainly destroys surface growth and so respraying to treat regrowth is needed. Resistant plants generally succumb when weakened by respraying. - Steam has been applied commercially but is now considered uneconomic and inadequate. It kills surface growth but not underground growth and so respraying to treat regrowth of perennials is needed. - Flame is considered more effective than steam but suffers from the same difficulties. # Application Most herbicides are applied as water-based sprays using ground equipment. Ground equipment varies in design, but large areas can be sprayed using self-propelled sprayers equipped with a long boom, of 60 to 80 feet (20 to 25 m) with flat fan nozzles spaced about every 20 in (500 mm). Towed, handheld, and even horse-drawn sprayers are also used. Inorganic herbicides can generally be applied aerially using helicopters or airplanes, and can be applied through irrigation systems (chemigation). # Terminology - Control is the destruction of unwanted weeds, or the damage of them to the point where they are no longer competitive with the crop. - Suppression is incomplete control still providing some economic benefit, such as reduced competition with the crop. - Crop Safety, for selective herbicides, is the relative absence of damage or stress to the crop. Most selective herbicides cause some visible stress to crop plants. # Major herbicides in use today - 2,4-D, a broadleaf herbicide in the phenoxy group used in turf and in no-till field crop production. Now mainly used in a blend with other herbicides that act as synergists, it is the most widely used herbicide in the world, third most commonly used in the United States. It is an example of synthetic auxin(plant hormone). - atrazine, a triazine herbicide used in corn and sorghum for control of broadleaf weeds and grasses. Still used because of its low cost and because it works as a synergist when used with other herbicides, it is a photosystem II inhibitor. - clopyralid is a broadleaf herbicide in the pyridine group, used mainly in turf, rangeland, and for control of noxious thistles. Notorious for its ability to persist in compost. It is another example of synthetic auxin. - dicamba, a persistent broadleaf herbicide active in the soil, used on turf and field corn. It is another example of synthetic auxin. - Glyphosate, a systemic nonselective (it kills any type of plant) herbicide used in no-till burndown and for weed control in crops that are genetically modified to resist its effects. It is an example of an EPSPs inhibitor. - Imazapyr, is a non-selective herbicide used for the control of a broad range of weeds including terrestrial annual and perennial grasses and broadleaved herbs, woody species, and riparian and emergent aquatic species. - Imazapic, is a selective herbicide for both the pre- and post-emergent control of some annual and perennial grasses and some broadleaf weeds. Imazapic kills plants by inhibiting the production of branched chain amino acids (valine, leucine, and isoleucine), which are necessary for protein synthesis and cell growth. - Linuron, is a non-selective herbicide used in the control of grasses and broadleafed weeds. It works by inhibiting photosynthesis. - metoalachlor, a pre-emergent herbicide widely used for control of annual grasses in corn and sorghum; it has largely replaced atrazine for these uses. - Paraquat, a nonselective contact herbicide used for no-till burndown and in aerial destruction of marijuana and coca plantings. More acutely toxic to people than any other herbicide in widespread commercial use. - picloram, a pyridine herbicide mainly used to control unwanted trees in pastures and edges of fields. It is another synthetic auxin. - Triclopyr # Herbicides of historical interest - 2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) was a widely used broadleaf herbicide until being phased out starting in the late 1970s. While 2,4,5-T itself is of only moderate toxicity, the manufacturing process for 2,4,5-T contaminates this chemical with trace amounts of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD is extremely toxic to humans. With proper temperature control during production of 2,4,5-T, TCDD levels can be held to about .005 ppm. Before the TCDD risk was well understood, early production facilities lacked proper temperature controls. Individual batches tested later were found to have as much as 60 ppm of TCDD. - 2,4,5-T was withdrawn from use in the USA in 1983, at a time of heightened public sensitivity about chemical hazards in the environment. Public concern about dioxins was high, and production and use of other (non-herbicide) chemicals potentially containing TCDD contamination was also withdrawn. These included pentachlorophenol (a wood preservative) and PCBs (mainly used as stabilizing agents in transformer oil). Some feel that the 2,4,5-T withdrawal was not based on sound science. 2,4,5-T has since largely been replaced by dicamba and triclopyr. - Agent Orange was a herbicide blend used by the U.S. military in Vietnam between January 1965 and April 1970 as a defoliant. It was a mixture of 2,4,5-T, 2,4-D, and picloram. Because of TCDD contamination in the 2,4,5-T component, it has been blamed for serious illnesses in many veterans who were exposed to it. However, research on populations exposed to its dioxin contaminant have been inconsistent and inconclusive. Agent Orange often had much higher levels of TCDD than 2,4,5-T used in the US. The name Agent Orange is derived from the orange color-coded stripe used by the Army on barrels containing the product. It is worth noting that there were other blends of synthetic auxins at the time of the Vietnam War whose containers were recognized by their colors, such as Agent Purple and Agent Pink.	Herbicide # Overview A herbicide is used to kill unwanted plants. Selective herbicides kill specific targets while leaving the desired crop relatively unharmed. Some of these act by interfering with the growth of the weed and are often based on plant hormones. Herbicides used to clear waste ground are nonselective and kill all plant material with which they come into contact. Some plants produce natural herbicides, such as the genus Juglans (walnuts). They are applied in total vegetation control (TVC) programs for maintenance of highways and railroads. Smaller quantities are used in forestry, pasture systems, and management of areas set aside as wildlife habitat. Herbicides are widely used in agriculture and in landscape turf management. In the us, they account for about 70% of all agricultural pesticide use.[1] # History Prior to the widespread use of chemical herbicides, cultural controls, such as altering soil pH, salinity, or fertility levels, were used to control weeds. Mechanical control (including tillage) was also (and still is) used to control weeds. The first widely used herbicide was 2,4-dichlorophenoxyacetic acid, often abbreviated 2,4-D. It was developed by a British team during World War II and first saw widespread production and use in the late 1940s. It is easy and inexpensive to manufacture, and kills many broadleaf plants while leaving grasses largely unaffected (although high doses of 2,4-D at crucial growth periods can harm grass crops such as maize or cereals). The low cost of 2,4-D has led to continued usage today and it remains one of the most commonly used herbicides in the world. Like other acid herbicides, current formulations utilize either an amine salt (usually trimethylamine) or one of many esters of the parent compound. These are easier to handle than the acid. 2,4-D exhibits relatively poor selectivity, meaning that it causes stress to non-target plants. It is also less effective against some broadleaf weeds, including many vinous plants, and sedges. A herbicide is termed selective if it affects only certain types of plants, and nonselective if it inhibits most any type of plant. Other herbicides have been more recently developed to achieve desired selectivities. The 1970s saw the introduction of atrazine, which has the dubious distinction of being the herbicide of greatest concern for groundwater contamination. Atrazine does not break down readily (within a few weeks) after being applied. Instead it is carried deep into the soil by rainfall causing the aforementioned contamination. Atrazine is said to have high carryover, a very undesirable property for herbicides. Glyphosate, frequently sold under the brand name Roundup, was introduced in 1974 for non-selective weed control. It is now a major herbicide in selective weed control in growing crop plants due to the development of crop plants that are resistant to it. The pairing of the herbicide with the resistant seed contributed to the consolidation of the seed and chemistry industry in the late 1990s. Many modern chemical herbicides for agriculture are specifically formulated to decompose within a short period after application. This is desirable as it allows crops which may be affected by the herbicide to be grown on the land in future seasons. However, herbicides with low residual activity (ie decompose quickly) often do not provide season-long weed control. # Health effects Certain herbicides cause a variety of health effects ranging from skin rashes to death. The pathway of attack can arise from improper application resulting in direct contact with field workers, inhalation of aerial sprays, food consumption and from contact with residual soil contamination. Herbicides can also be transported via surface runoff to contaminate distant surface waters and hence another pathway of ingestion through extraction of those surface waters for drinking. Some herbicides decompose rapidly in soils and other types have more persistent characteristics with longer environmental half-lives. Other alleged health effects can include chest pain, headaches, nausea and fatigue. Most herbicides (primarily the non-organic) must be extensively tested prior to labeling by the Environmental Protection Agency. However, because of the large number of herbicides in use, there is significant concern regarding health effects. Some of the herbicides in use are known to be mutagenic, carcinogenic or teratogenic. However, some herbicides may also have a therapeutic use. Current research aims to use herbicides as an anti-malaria drug that targets the plant-like apicoplast plastid in the malaria causing parasite Plasmodium falciparum. # Classification of herbicides Herbicides can be grouped by activity, use, chemical family, mode of action, or type of vegetation controlled. By activity: - Contact herbicides destroy only the plant tissue in contact with the chemical. Generally, these are the fastest acting herbicides. They are less effective on perennial plants, which are able to regrow from roots or tubers. - Systemic herbicides are translocated through the plant, either from foliar application down to the roots, or from soil application up to the leaves. They can destroy a greater amount of plant tissue than contact herbicides. By use: - Soil-applied herbicides are applied to the soil and are taken up by the roots of the target plant. - Preemergent herbicides are applied to the soil before the crop emerges and prevent germination or early growth of weed seeds. - Post-emergent herbicides are applied after the crop has emerged. Their classification by mechanism of action (MOA) indicates the first enzyme, protein, or biochemical step affected in the plant following application. The main mechanisms of action are: - ACCase inhibitors are compounds that kill grasses. Acetyl coenzyme A carboxylase (ACCase) is part of the first step of lipid synthesis. Thus, ACCase inhibitors affect cell membrane production in the meristems of the grass plant. The ACCases of grasses are sensitive to these herbicides, whereas the ACCases of dicot plants are not. - ALS inhibitors: the acetolactate synthase (ALS) enzyme (also known as acetohydroxyacid synthase, or AHAS) is the first step in the synthesis of the branched-chain amino acids (valine, leucine, and isoleucine). These herbicides slowly starve affected plants of these amino acids which eventually leads to inhibition of DNA synthesis. They affect grasses and dicots alike. The ALS inhibitor family includes sulfonylureas (SUs), imidazolinones (IMIs), triazolopyrimidines (TPs), pyrimidinyl oxybenzoates (POBs), and sulfonylamino carbonyl triazolinones (SCTs). - EPSPS inhibitors: The enolpyruvylshikimate 3-phosphate synthase enzyme EPSPS is used in the synthesis of the amino acids tryptophan, phenylalanine and tyrosine. They affect grasses and dicots alike. Glyphosate (Roundup) is a systemic EPSPS inhibitor but inactivated by soil contact. - Synthetic auxin inaugurated the era of organic herbicides. They were discovered in the 1940s after a long study of the plant growth regulator auxin. Synthetic auxins mimic this plant hormone. They have several points of action on the cell membrane, and are effective in the control of dicot plants. 2,4-D is a synthetic auxin herbicide. - Photosystem II inhibitors reduce electron flow from water to NADPH2+ at the photochemical step in photosynthesis. They bind to the Qb site on the D2 protein, and prevent quinone from binding to this site. Therefore, this group of compounds cause electrons to accumulate on chlorophyll molecules. As a consequence, oxidation reactions in excess of those normally tolerated by the cell occur, and the plant dies. The triazine herbicides (including atrazine) are PSII inhibitors. # Organic Herbicides An organic herbicide is one that can be used in a farming enterprise that has been classified as organic. Organic herbicides are expensive and may not be affordable for commercial production. They are much less effective than synthetic herbicides but of course do not inject unnatural chemicals into the environment. Organic herbicides include: - Spices are now effectively used in patented herbicides. - Vinegar[2] is effective for 5-20% solutions of acetic acid with higher concentrations most effective but mainly destroys surface growth and so respraying to treat regrowth is needed. Resistant plants generally succumb when weakened by respraying. - Steam has been applied commercially but is now considered uneconomic and inadequate.[3][4][5] It kills surface growth but not underground growth and so respraying to treat regrowth of perennials is needed. - Flame is considered more effective than steam but suffers from the same difficulties.[6] # Application Most herbicides are applied as water-based sprays using ground equipment. Ground equipment varies in design, but large areas can be sprayed using self-propelled sprayers equipped with a long boom, of 60 to 80 feet (20 to 25 m) with flat fan nozzles spaced about every 20 in (500 mm). Towed, handheld, and even horse-drawn sprayers are also used. Inorganic herbicides can generally be applied aerially using helicopters or airplanes, and can be applied through irrigation systems (chemigation). # Terminology - Control is the destruction of unwanted weeds, or the damage of them to the point where they are no longer competitive with the crop. - Suppression is incomplete control still providing some economic benefit, such as reduced competition with the crop. - Crop Safety, for selective herbicides, is the relative absence of damage or stress to the crop. Most selective herbicides cause some visible stress to crop plants. # Major herbicides in use today - 2,4-D, a broadleaf herbicide in the phenoxy group used in turf and in no-till field crop production. Now mainly used in a blend with other herbicides that act as synergists, it is the most widely used herbicide in the world, third most commonly used in the United States. It is an example of synthetic auxin(plant hormone). - atrazine, a triazine herbicide used in corn and sorghum for control of broadleaf weeds and grasses. Still used because of its low cost and because it works as a synergist when used with other herbicides, it is a photosystem II inhibitor. - clopyralid is a broadleaf herbicide in the pyridine group, used mainly in turf, rangeland, and for control of noxious thistles. Notorious for its ability to persist in compost. It is another example of synthetic auxin. - dicamba, a persistent broadleaf herbicide active in the soil, used on turf and field corn. It is another example of synthetic auxin. - Glyphosate, a systemic nonselective (it kills any type of plant) herbicide used in no-till burndown and for weed control in crops that are genetically modified to resist its effects. It is an example of an EPSPs inhibitor. - Imazapyr, is a non-selective herbicide used for the control of a broad range of weeds including terrestrial annual and perennial grasses and broadleaved herbs, woody species, and riparian and emergent aquatic species. - Imazapic, is a selective herbicide for both the pre- and post-emergent control of some annual and perennial grasses and some broadleaf weeds. Imazapic kills plants by inhibiting the production of branched chain amino acids (valine, leucine, and isoleucine), which are necessary for protein synthesis and cell growth. - Linuron, is a non-selective herbicide used in the control of grasses and broadleafed weeds. It works by inhibiting photosynthesis. - metoalachlor, a pre-emergent herbicide widely used for control of annual grasses in corn and sorghum; it has largely replaced atrazine for these uses. - Paraquat, a nonselective contact herbicide used for no-till burndown and in aerial destruction of marijuana and coca plantings. More acutely toxic to people than any other herbicide in widespread commercial use. - picloram, a pyridine herbicide mainly used to control unwanted trees in pastures and edges of fields. It is another synthetic auxin. - Triclopyr # Herbicides of historical interest - 2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) was a widely used broadleaf herbicide until being phased out starting in the late 1970s. While 2,4,5-T itself is of only moderate toxicity, the manufacturing process for 2,4,5-T contaminates this chemical with trace amounts of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD is extremely toxic to humans. With proper temperature control during production of 2,4,5-T, TCDD levels can be held to about .005 ppm. Before the TCDD risk was well understood, early production facilities lacked proper temperature controls. Individual batches tested later were found to have as much as 60 ppm of TCDD. - 2,4,5-T was withdrawn from use in the USA in 1983, at a time of heightened public sensitivity about chemical hazards in the environment. Public concern about dioxins was high, and production and use of other (non-herbicide) chemicals potentially containing TCDD contamination was also withdrawn. These included pentachlorophenol (a wood preservative) and PCBs (mainly used as stabilizing agents in transformer oil). Some feel that the 2,4,5-T withdrawal was not based on sound science. 2,4,5-T has since largely been replaced by dicamba and triclopyr. - Agent Orange was a herbicide blend used by the U.S. military in Vietnam between January 1965 and April 1970 as a defoliant. It was a mixture of 2,4,5-T, 2,4-D, and picloram. Because of TCDD contamination in the 2,4,5-T component, it has been blamed for serious illnesses in many veterans who were exposed to it. However, research on populations exposed to its dioxin contaminant have been inconsistent and inconclusive. Agent Orange often had much higher levels of TCDD than 2,4,5-T used in the US. The name Agent Orange is derived from the orange color-coded stripe used by the Army on barrels containing the product. It is worth noting that there were other blends of synthetic auxins at the time of the Vietnam War whose containers were recognized by their colors, such as Agent Purple and Agent Pink.	https://www.wikidoc.org/index.php/Herbicide
c9c19ef803bd90031638c2ba3dbf5e600c72be4f	wikidoc	Heterosis	Heterosis Heterosis is a term used in genetics and selective breeding. The term heterosis, also known as hybrid vigor, hybrid vigour, or outbreeding enhancement, describes the increased strength of different characteristics in hybrids; the possibility to obtain a "better" individual by combining the virtues of its parents. Heterosis is often the opposite process of inbreeding depression, which increases homozygosity. Although it is believed that heterosis is the action of many genes of small effect, whereas inbreeding depression is the action of a few genes of large effect. The term often causes controversy, particularly in terms of the selective breeding of domestic animals, because it is sometimes believed that all crossbred plants or animals are better than their parents; this is not necessarily true. Rather, when a hybrid is seen to be superior to its parents, this is known as hybrid vigor. It may also happen that a hybrid inherits such different traits from their parents that make them unfit for survival. This is known as outbreeding depression, typical examples of which are crosses between wild and hatchery fish that have incompatible adaptations. Heterosis can be classified into mid-parent heterosis, in which the hybrid shows increased strength which is greater than the average of both parents, and best-parent heterosis, in which the hybrid's increased strength is greater than that of the strongest parent. Mid-parent heterosis is more common in nature, and it is easier to explain (by mechanism of gene dominance; see below). # Genetic basis of heterosis Two leading hypotheses explain the genetic basis for fitness advantage in heterosis. The overdominance hypothesis implies that the combination of divergent alleles at a particular locus will result in a higher fitness in the heterozygote than in the homozygote. Take the example of parasite resistance controlled by gene A, with two alleles A and a. The heterozygous individual will then be able to express a broader array of parasite resistance alleles and thus resist a broader array of parasites. The homozygous individual, on the other hand, will only express one allele of gene A (either A or a) and therefore will not resist as many parasites as the heterozygote. The second hypothesis involves avoidance of deleterious recessive genes (also called the general dominance hypothesis), such that heterozygous individuals will express less deleterious recessive alleles than its homozygous counterpart. The two hypotheses will have different consequences on the gene expression profile of the individuals. If over-dominance is the main cause for the fitness advantages of heterosis, then there should be an over-expression of certain genes in the heterozygous offspring compared to the homozygous parents. On the other hand, if avoidance of deleterious recessive genes is the cause, then there should be fewer genes that are under-expressed in the heterozygous offspring compared to the parents. Furthermore, for any given gene, the expression should be comparable to the one observed in the best of the two parents. # Hybrid corn Nearly all the field corn now grown in the United States and most other developed nations is hybrid corn. Modern corn hybrids substantially outyield conventional cultivars and respond better to fertilization. Heterosis in maize was first demonstrated in the early 20th century by George H. Shull and Edward M. East. They showed that crosses of inbred lines made from a Southern dent and a Northern flint, respectively, showed substantial heterosis and outyielded conventional cultivars of that era. However, at that time such hybrids could not be economically made on a large scale for use by farmers. Donald F. Jones at the Connecticut Agricultural Experiment Station, New Haven invented the first practical method of producing a high-yielding hybrid maize in 1914-1917. Jones' method produced a double-cross hybrid, which requires two crossing steps working from four distinct original inbred lines. Later work by corn breeders produced inbred lines with sufficient vigor for practical production of a commercial hybrid in a single step, the single-cross hybrids. Single-cross hybrids are made from just two original parent inbreds. They are generally more vigorous and also more uniform than the earlier double-cross hybrids.	Heterosis Template:Distinguish2 Heterosis is a term used in genetics and selective breeding. The term heterosis, also known as hybrid vigor, hybrid vigour, or outbreeding enhancement, describes the increased strength of different characteristics in hybrids; the possibility to obtain a "better" individual by combining the virtues of its parents. Heterosis is often the opposite process of inbreeding depression, which increases homozygosity. Although it is believed that heterosis is the action of many genes of small effect, whereas inbreeding depression is the action of a few genes of large effect. The term often causes controversy, particularly in terms of the selective breeding of domestic animals, because it is sometimes believed that all crossbred plants or animals are better than their parents; this is not necessarily true. Rather, when a hybrid is seen to be superior to its parents, this is known as hybrid vigor. It may also happen that a hybrid inherits such different traits from their parents that make them unfit for survival. This is known as outbreeding depression, typical examples of which are crosses between wild and hatchery fish that have incompatible adaptations. Heterosis can be classified into mid-parent heterosis, in which the hybrid shows increased strength which is greater than the average of both parents, and best-parent heterosis, in which the hybrid's increased strength is greater than that of the strongest parent. Mid-parent heterosis is more common in nature, and it is easier to explain (by mechanism of gene dominance; see below). # Genetic basis of heterosis Two leading hypotheses explain the genetic basis for fitness advantage in heterosis. The overdominance hypothesis implies that the combination of divergent alleles at a particular locus will result in a higher fitness in the heterozygote than in the homozygote. Take the example of parasite resistance controlled by gene A, with two alleles A and a. The heterozygous individual will then be able to express a broader array of parasite resistance alleles and thus resist a broader array of parasites. The homozygous individual, on the other hand, will only express one allele of gene A (either A or a) and therefore will not resist as many parasites as the heterozygote. The second hypothesis involves avoidance of deleterious recessive genes (also called the general dominance hypothesis), such that heterozygous individuals will express less deleterious recessive alleles than its homozygous counterpart. The two hypotheses will have different consequences on the gene expression profile of the individuals. If over-dominance is the main cause for the fitness advantages of heterosis, then there should be an over-expression of certain genes in the heterozygous offspring compared to the homozygous parents. On the other hand, if avoidance of deleterious recessive genes is the cause, then there should be fewer genes that are under-expressed in the heterozygous offspring compared to the parents. Furthermore, for any given gene, the expression should be comparable to the one observed in the best of the two parents. # Hybrid corn Nearly all the field corn now grown in the United States and most other developed nations is hybrid corn. Modern corn hybrids substantially outyield conventional cultivars and respond better to fertilization. Heterosis in maize was first demonstrated in the early 20th century by George H. Shull and Edward M. East. They showed that crosses of inbred lines made from a Southern dent and a Northern flint, respectively, showed substantial heterosis and outyielded conventional cultivars of that era. However, at that time such hybrids could not be economically made on a large scale for use by farmers. Donald F. Jones at the Connecticut Agricultural Experiment Station, New Haven invented the first practical method of producing a high-yielding hybrid maize in 1914-1917. Jones' method produced a double-cross hybrid, which requires two crossing steps working from four distinct original inbred lines. Later work by corn breeders produced inbred lines with sufficient vigor for practical production of a commercial hybrid in a single step, the single-cross hybrids. Single-cross hybrids are made from just two original parent inbreds. They are generally more vigorous and also more uniform than the earlier double-cross hybrids.	https://www.wikidoc.org/index.php/Heterosis
cef900cc0f94373b14b4f2323177484f70cabd67	wikidoc	Heuristic	Heuristic A heuristic is a method to help solve a problem, commonly informal. It is particularly used for a method that often rapidly leads to a solution that is usually reasonably close to the best possible answer. Heuristics are "rules of thumb", educated guesses, intuitive judgments or simply common sense. In more precise terms, heuristics stand for strategies using readily accessible, though loosely applicable, information to control problem-solving in human beings and machines. # Example Perhaps the most fundamental heuristic is "trial & error," which can be used in everything from matching bolts to bicycles to finding the values of variables in algebra problems. Here are a few other commonly used heuristics, from Polya's classic How to Solve It: - Look to the unknown. - If you are having difficulty understanding a problem, try drawing a picture. - If you can't find a solution, try assuming that you have a solution and seeing what you can derive from that ("working backward"). - If the problem is abstract, try examining a concrete example. - Try solving a more general problem first (the "inventor's paradox": the more ambitious plan may have more chances of success). # Psychology In psychology, heuristics are simple, efficient rules, hard-coded by evolutionary processes or learned, which have been proposed to explain how people make decisions, come to judgments, and solve problems, typically when facing complex problems or incomplete information. These rules work well under most circumstances, but in certain cases lead to systematic cognitive biases. Much of the work of discovering heuristics in human decision-makers was ignited by Amos Tversky and Daniel Kahneman. Gerd Gigerenzer focuses on how heuristics can be used to make judgments that are in principle accurate, rather than producing cognitive biases – heuristics that are "fast and frugal". ## Theorized psychological heuristics ### Well known - Anchoring and adjustment - Availability heuristic - Representativeness heuristic ### Less well known - Affect heuristic - Contagion heuristic - Effort heuristic - Familiarity heuristic - Fluency heuristic - Gaze heuristic - Peak-end rule - Recognition heuristic - Scarcity heuristic - Similarity heuristic - Simulation heuristic - Social proof - Take-the-best heuristic # Philosophy In philosophy, especially in Continental European philosophy, the adjective "heuristic" (or the designation "heuristic device") is used when an entity X exists to enable understanding of, or knowledge concerning, some other entity Y. A good example is a model, which, as it is never identical with what it models, is a heuristic device to enable understanding of what it models. Stories, metaphors, etc., can also be termed heuristic in that sense. A classic example is the notion of utopia as described in Plato's best-known work, The Republic. This means that the "ideal city" as depicted in the The Republic is not given as something to be pursued, or to present an orientation-point for development; rather, it shows how things would have to be connected, and how one thing would lead to another (often with highly problematic results), if one would opt for certain principles and carry them through rigorously. "Heuristic" is also often commonly used as a noun, to describe a rule-of-thumb, procedure, method, and so on in, for example, the context of the construction of scientific theories. (See the logic of discovery, and philosophers such as Lakatos, Lindley Darden, and others.) # Law In legal theory, especially in the theory of law and economics, heuristics are used in the law when case-by-case analysis would be impractical, insofar as "practicality" is defined by the interests of a governing body. For instance, in many states in the United States the legal drinking age is 21, because it is argued that people need to be mature enough to make decisions involving the risks of alcohol consumption. However, assuming people mature at different rates, the specific age of 21 would be too late for some and too early for others. In this case, the somewhat arbitrary deadline is used because it is impossible or impractical to tell whether one individual is mature enough that society can trust them with that kind of responsibility. Some proposed changes, however, have included the completion of an alcohol education course rather than the attainment of 21 years of age as the criterion for legal alcohol possession. This would situate youth alcohol policy more on a case-by-case model and less on a heuristic one, since the completion of such a course would presumably be voluntary and not uniform across the population. The same reasoning applies to patent law. Patents are justified on the grounds that inventors need to be protected in order to have incentive to invent. It is therefore argued that, in society's best interest, inventors should be issued with a temporary government-granted monopoly on their product, so that they can recoup their investment costs and make economic profit for a limited period of time. In the United States the length of this temporary monopoly is 20 years from the date the application for patent was filed, though the monopoly does not actually begin until the application has matured into a patent. However, like the drinking-age problem above, the specific length of time would need to be different for every product in order to be efficient; a 20-year term is used because it is difficult to tell what the number should be for any individual patent. More recently, some, including Lawrence Lessig, have argued that patents in different kinds of industries – such as software patents – should be protected for different lengths of time. # Computer science In computer science, a heuristic is a technique designed to solve a problem that ignores whether the solution can be proven to be correct, but which usually produces a good solution or solves a simpler problem that contains or intersects with the solution of the more complex problem. Many commercial anti-virus scanners use heuristic signatures to look for specific attributes and characteristics for detecting viruses and other forms of malware. Heuristics are intended to gain computational performance or conceptual simplicity, potentially at the cost of accuracy or precision. # Human-computer interaction In human-computer interaction, heuristic evaluation is a usability-testing technique devised by expert usability consultants. In heuristic evaluation, the user interface is reviewed by experts and its compliance to usability heuristics (broadly stated characteristics of a good user interface) is assessed, and any violating aspects are recorded. # Engineering In engineering, a heuristic is an experience-based method that can be used as an aid to solve process design problems, varying from size of equipment to operating conditions. By using heuristics, time can be reduced when solving problems, which may be very valuable. Because heuristics are fallible, it is important to understand their limitations. They are intended to be used as aids in order to make quick estimates and preliminary process designs. # Notes - ↑ Pearl, Judea (1983). Heuristics: Intelligent Search Strategies for Computer Problem Solving. New York, Addison-Wesley, p. vii. - ↑ Polya, George (1945) How To Solve It: A New Aspect of Mathematical Method, Princeton, NJ: Princeton University Press. ISBN 0-691-02356-5 ISBN 0-691-08097-6 - ↑ Daniel Kahneman, Amos Tversky and Paul Slovic, eds. (1982) Judgement under Uncertainty: Heuristics & Biases. Cambridge, UK, Cambridge University Press ISBN 0-521-28414-7 - ↑ Gerd Gigerenzer, Peter M. Todd, and the ABC Research Group (1999). Simple Heuristics That Make Us Smart. Oxford, UK, Oxford University Press. ISBN 0-19-514381-7 - ↑ Gerd Gigerenzer and Christoph Engel, eds. (2007). Heuristics and the Law, Cambridge, The MIT Press, ISBN 978-0-262-07275-5	Heuristic A heuristic is a method to help solve a problem, commonly informal. It is particularly used for a method that often rapidly leads to a solution that is usually reasonably close to the best possible answer. Heuristics are "rules of thumb", educated guesses, intuitive judgments or simply common sense. In more precise terms, heuristics stand for strategies using readily accessible, though loosely applicable, information to control problem-solving in human beings and machines.[1] # Example Perhaps the most fundamental heuristic is "trial & error," which can be used in everything from matching bolts to bicycles to finding the values of variables in algebra problems. Here are a few other commonly used heuristics, from Polya's classic How to Solve It:[2] - Look to the unknown. - If you are having difficulty understanding a problem, try drawing a picture. - If you can't find a solution, try assuming that you have a solution and seeing what you can derive from that ("working backward"). - If the problem is abstract, try examining a concrete example. - Try solving a more general problem first (the "inventor's paradox": the more ambitious plan may have more chances of success). # Psychology In psychology, heuristics are simple, efficient rules, hard-coded by evolutionary processes or learned, which have been proposed to explain how people make decisions, come to judgments, and solve problems, typically when facing complex problems or incomplete information. These rules work well under most circumstances, but in certain cases lead to systematic cognitive biases. Much of the work of discovering heuristics in human decision-makers was ignited by Amos Tversky and Daniel Kahneman[3]. Gerd Gigerenzer focuses on how heuristics can be used to make judgments that are in principle accurate, rather than producing cognitive biases – heuristics that are "fast and frugal".[4] ## Theorized psychological heuristics ### Well known - Anchoring and adjustment - Availability heuristic - Representativeness heuristic ### Less well known - Affect heuristic - Contagion heuristic - Effort heuristic - Familiarity heuristic - Fluency heuristic - Gaze heuristic - Peak-end rule - Recognition heuristic - Scarcity heuristic - Similarity heuristic - Simulation heuristic - Social proof - Take-the-best heuristic # Philosophy Template:Tfd In philosophy, especially in Continental European philosophy, the adjective "heuristic" (or the designation "heuristic device") is used when an entity X exists to enable understanding of, or knowledge concerning, some other entity Y. A good example is a model, which, as it is never identical with what it models, is a heuristic device to enable understanding of what it models. Stories, metaphors, etc., can also be termed heuristic in that sense. A classic example is the notion of utopia as described in Plato's best-known work, The Republic. This means that the "ideal city" as depicted in the The Republic is not given as something to be pursued, or to present an orientation-point for development; rather, it shows how things would have to be connected, and how one thing would lead to another (often with highly problematic results), if one would opt for certain principles and carry them through rigorously. "Heuristic" is also often commonly used as a noun, to describe a rule-of-thumb, procedure, method, and so on in, for example, the context of the construction of scientific theories. (See the logic of discovery, and philosophers such as Lakatos, Lindley Darden, and others.) # Law In legal theory, especially in the theory of law and economics, heuristics are used in the law when case-by-case analysis would be impractical, insofar as "practicality" is defined by the interests of a governing body.[5] For instance, in many states in the United States the legal drinking age is 21, because it is argued that people need to be mature enough to make decisions involving the risks of alcohol consumption. However, assuming people mature at different rates, the specific age of 21 would be too late for some and too early for others. In this case, the somewhat arbitrary deadline is used because it is impossible or impractical to tell whether one individual is mature enough that society can trust them with that kind of responsibility. Some proposed changes, however, have included the completion of an alcohol education course rather than the attainment of 21 years of age as the criterion for legal alcohol possession. This would situate youth alcohol policy more on a case-by-case model and less on a heuristic one, since the completion of such a course would presumably be voluntary and not uniform across the population. The same reasoning applies to patent law. Patents are justified on the grounds that inventors need to be protected in order to have incentive to invent. It is therefore argued that, in society's best interest, inventors should be issued with a temporary government-granted monopoly on their product, so that they can recoup their investment costs and make economic profit for a limited period of time. In the United States the length of this temporary monopoly is 20 years from the date the application for patent was filed, though the monopoly does not actually begin until the application has matured into a patent. However, like the drinking-age problem above, the specific length of time would need to be different for every product in order to be efficient; a 20-year term is used because it is difficult to tell what the number should be for any individual patent. More recently, some, including Lawrence Lessig, have argued that patents in different kinds of industries – such as software patents – should be protected for different lengths of time. # Computer science In computer science, a heuristic is a technique designed to solve a problem that ignores whether the solution can be proven to be correct, but which usually produces a good solution or solves a simpler problem that contains or intersects with the solution of the more complex problem. Many commercial anti-virus scanners use heuristic signatures to look for specific attributes and characteristics for detecting viruses and other forms of malware. Heuristics are intended to gain computational performance or conceptual simplicity, potentially at the cost of accuracy or precision. # Human-computer interaction In human-computer interaction, heuristic evaluation is a usability-testing technique devised by expert usability consultants. In heuristic evaluation, the user interface is reviewed by experts and its compliance to usability heuristics (broadly stated characteristics of a good user interface) is assessed, and any violating aspects are recorded. # Engineering In engineering, a heuristic is an experience-based method that can be used as an aid to solve process design problems, varying from size of equipment to operating conditions. By using heuristics, time can be reduced when solving problems, which may be very valuable. Because heuristics are fallible, it is important to understand their limitations. They are intended to be used as aids in order to make quick estimates and preliminary process designs. # Notes - ↑ Pearl, Judea (1983). Heuristics: Intelligent Search Strategies for Computer Problem Solving. New York, Addison-Wesley, p. vii. - ↑ Polya, George (1945) How To Solve It: A New Aspect of Mathematical Method, Princeton, NJ: Princeton University Press. ISBN 0-691-02356-5 ISBN 0-691-08097-6 - ↑ Daniel Kahneman, Amos Tversky and Paul Slovic, eds. (1982) Judgement under Uncertainty: Heuristics & Biases. Cambridge, UK, Cambridge University Press ISBN 0-521-28414-7 - ↑ Gerd Gigerenzer, Peter M. Todd, and the ABC Research Group (1999). Simple Heuristics That Make Us Smart. Oxford, UK, Oxford University Press. ISBN 0-19-514381-7 - ↑ Gerd Gigerenzer and Christoph Engel, eds. (2007). Heuristics and the Law, Cambridge, The MIT Press, ISBN 978-0-262-07275-5	https://www.wikidoc.org/index.php/Heuristic
c948594030494658923d2136ede996cc87021761	wikidoc	Ioxaglate	Ioxaglate Ioxaglate or Hexabrix is a sterile, non-pyrogenic, aqueous solution intended for use as a diagnostic radiopaque medium. Hexabrix contains 39.3% w/v N-(2-hydroxyethyl)-2,4,6-triiodo-5- acetamido]-isophthalamic acid, compounded with 1-deoxy-1-(methylamino)-D-glucitol (1:1) and 19.6% w/v sodium N-(2-hydroxyethyl)-2,4,6 triiodo-5- acetamido]-isophthalamate. Each milliliter contains 393 mg of ioxaglate meglumine, 196 mg of ioxaglate sodium and 0.10 mg edetate calcium disodium as a stabilizer. The solution contains 3.48 mg (0.15 mEq) sodium in each milliliter and provides 32% (320 mg/mL) organically bound iodine. Solutions of ioxaglate (Hexabrix) provide six iodine atoms for each two dissociated ions. Hexabrix is an ionic contrast agent. Hexabrix has an osmolarity of approximately 460 mOsmol/L, an osmolality of approximately 600 mOsmol/kg of water and is, therefore, hypertonic under conditions of use. Hexabrix has a viscosity (cps) of 15.7 at 20° and 7.5 at 37°. The pH has been adjusted to 6.0 to 7.6 with meglumine, sodium hydroxide or ioxaglic acid. Hexabrix is a clear, colorless to pale yellow solution containing no undissolved solids. Crystallization does not occur at normal room temperatures. It is supplied in containers from which the air has been displaced by nitrogen. # Clinical Pharmacology Intravascular injection of a radiopaque diagnostic agent opacifies those vessels in the path of the flow of the contrast medium, permitting radiographic visualization of the internal structures of the human body until significant hemodilution occurs. Following intravascular injection, Hexabrix is rapidly transported through the circulatory system to the kidneys and is excreted unchanged in the urine. The pharmacokinetics of intravascularly administered radiopaque contrast media are usually best described by a two compartment model with a rapid alpha phase for drug distribution and a slower beta phase for drug elimination. In 10 patients with normal renal function, the alpha and beta half-lives of Hexabrix were 12 (4-17) and 92 (61-140) minutes, respectively. Following the intravenous administration of 50 mL of Hexabrix in 10 normal volunteers, the mean peak plasma concentration occurred at two (1-3) minutes, reaching a concentration of 2.1 (1.8-2.8) mg/mL. Approximately 50 (42-67) percent of the intravenously administered dose was recovered in the urine at two hours, and 90 (68-105) percent was recovered at 24 hours. The joint spaces as well as the uterus and fallopian tubes may be visualized by the direct injection of the contrast medium into the region to be studied. Injectable iodinated contrast agents are excreted either through the kidneys or through the liver. These two excretory pathways are not mutually exclusive, but the main route of excretion seems to be related to the affinity of the contrast medium for serum albumin. Ioxaglate salts are poorly bound to serum albumin, and are excreted mainly through the kidneys. The liver and small intestine provide the major alternate route of excretion. In patients with severe renal impairment, the excretion of this contrast medium through the gallbladder and into the small intestine sharply increases. Ioxaglate salts cross the placental barrier in humans and are excreted unchanged in human milk. ## CT SCANNING OF THE HEAD When used for contrast enhancement in computed tomographic head imaging, the degree of enhancement is directly related to the amount of iodine administered. Rapid injection of the entire dose yields peak blood iodine concentrations immediately following the injection, which falls rapidly over the next five to ten minutes as a result of dilution in the vascular and extravascular fluid compartments. Equilibration is reached in about ten minutes and thereafter the fall in iodine plasma concentration becomes exponential. In brain scanning, contrast media do not accumulate in normal brain tissue due to the blood brain barrier (BBB). The increase in x-ray attenuation usually seen in normal tissue following contrast medium injection is due to the presence of the contrast medium in the blood pool. Disruption in the BBB, such as occurs in malignant tumors of the brain, allows accumulation of contrast medium within the interstitial tumor tissue; adjacent normal brain tissue does not contain the contrast medium. Maximum contrast enhancement frequently occurs after peak blood iodine levels are reached. A delay in maximum contrast enhancement can occur depending on the peak iodine level achieved and the cell type of the lesion. This lag in enhancement is probably associated with the accumulation of the contrast medium within the lesion and outside the blood pool. The image enhancement of non-tumor lesions, such as arteriovenous malformations and aneurysms, is dependent on the iodine content of the circulating blood pool. ## CT SCANNING OF THE BODY Hexabrix may also be used for enhancement of computed tomographic scans performed for detection and evaluation of lesions in the liver, pancreas, kidneys, abdominal aorta, mediastinum, abdominal cavity and retroperitoneal space. In non-neural tissues (during computed tomography of the body), Hexabrix diffuses rapidly from the vascular to the extra-vascular space. Increase in x-ray absorption is related to blood flow, concentration of the contrast medium and extraction of the contrast medium by interstitial tissue since no barrier exists; contrast enhancement is thus due to the relative differences in extra-vascular diffusion between normal and abnormal tissue, a situation quite different than that in the brain. The pharmacokinetics of Hexabrix in normal and abnormal tissues has been shown to be variable. Enhancement of CT with Hexabrix may be of benefit in establishing diagnoses of certain lesions in some sites with greater assurance than is possible with unenhanced CT and in supplying additional features of the lesions. In other cases, the contrast medium may allow visualization of lesions not seen with CT alone or may help to define suspicious lesions seen with unenhanced CT. Contrast enhancement appears to be greatest within the 30-90 seconds after bolus administration of the contrast agent, and after intra-arterial rather than intravenous administration. Therefore, the use of a continuous scanning technique (a series of two to three second scans beginning at the injection — dynamic CT scanning) may improve enhancement and diagnostic assessment of tumors and other lesions such as an abscess, occasionally revealing more extensive disease. Because unenhanced scanning may provide adequate information in the individual patient, the decision to employ contrast enhancement, which is associated with additional risk and increased radiation exposure, should be based upon a careful evaluation of clinical, other radiological and unenhanced CT findings. # Indications and Usage for Hexabrix Hexabrix is indicated for use in pediatric angiocardiography, selective coronary arteriography with or without left ventriculography, peripheral arteriography, aortography, selective visceral arteriography, cerebral angiography, intra-arterial digital subtraction angiography, intravenous digital subtraction angiography, peripheral venography (phlebography), excretory urography, contrast enhancement of computed tomographic head imaging and body imaging, arthrography and hysterosalpingography. # Contraindications Hexabrix is contraindicated for use in myelography. Refer to PRECAUTIONS, General, concerning hypersensitivity. Hysterosalpingography should not be performed during the menstrual period; in pregnant patients; in patients with known infection in any portion of the genital tract; or in patients in whom cervical conization or curettage has been performed within 30 days. Arthrography should not be performed if infection is present in or near the joint. # Warnings SEVERE ADVERSE EVENTS — INADVERTENT INTRATHECAL ADMINISTRATION: Serious adverse reactions have been reported due to the inadvertent intrathecal administration of iodinated contrast media that are not indicated for intrathecal use. These serious adverse reactions include: death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. Special attention must be given to insure that this drug product is not administered intrathecally. Ionic iodinated contrast media inhibit blood coagulation, in vitro, more than nonionic contrast media. Nonetheless, it is prudent to avoid prolonged contact of blood with syringes containing ionic contrast media. Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiographic procedures with both ionic and nonionic contrast media. Therefore, meticulous intravascular administration technique is necessary, particularly during angiographic procedures, to minimize thromboembolic events. Numerous factors, including length of procedure, catheter and syringe material, underlying disease state and concomitant medications may contribute to the development of thromboembolic events. For these reasons, meticulous angiographic techniques are recommended including close attention to guidewire and catheter manipulation, use of manifold systems and/ or three-way stopcocks, frequent catheter flushing with heparinized saline solutions and minimizing the length of the procedure. The use of plastic syringes in place of glass syringes has been reported to decrease but not eliminate the likelihood of in vitro clotting. Serious or fatal reactions have been associated with the administration of iodine containing radiopaque media. It is of utmost importance to be completely prepared to treat any contrast medium reaction. As with any contrast medium, serious neurologic sequelae, including permanent paralysis, can occur following cerebral arteriography, selective spinal arteriography and arteriography of vessels supplying the spinal cord. The injection of a contrast medium should never be made following the administration of vasopressors since they strongly potentiate neurologic effects. In patients with subarachnoid hemorrhage, a rare association between contrast administration and clinical deterioration, including convulsions and death, has been reported. Therefore, administration of intravascular iodinated contrast media in these patients should be undertaken with caution. A definite risk exists in the use of intravascular contrast agents in patients who are known to have multiple myeloma. In such instances anuria has developed resulting in progressive uremia, renal failure and eventually death. Although neither the contrast agent nor dehydration has separately proved to be the cause of anuria in myeloma, it has been speculated that the combination of both may be causative factors. The risk in myelomatous patients is not a contraindication to the procedure; however, partial dehydration in the preparation of these patients for the examination is not recommended since this may predispose to precipitation of myeloma protein in the renal tubules. No form of therapy, including dialysis, has been successful in reversing the effect. Myeloma, which occurs most commonly in persons over 40, should be considered before instituting intravascular administration of contrast agents. Administration of radiopaque materials to patients known or suspected to have pheochromocytoma should be performed with extreme caution. If, in the opinion of the physician, the possible benefits of such procedures outweigh the considered risks, the procedures may be performed; however, the amount of radiopaque medium injected should be kept to an absolute minimum. The blood pressure should be assessed throughout the procedure, and measures for treatment of a hypertensive crisis should be available. Since intravascular administration of contrast media may promote sickling in individuals who are homozygous for sickle cell disease, fluid restriction is not advised. In patients with advanced renal disease, iodinated contrast media should be used with caution and only when the need for the examination dictates, since excretion of the medium may be impaired. Patients with combined renal and hepatic disease, those with severe hypertension or congestive heart failure and recent renal transplant recipients present an additional risk. Renal failure has been reported in patients with liver dysfunction who were given an oral cholecystographic agent followed by an intravascular iodinated radiopaque agent and also in patients with occult renal disease, notably diabetics and hypertensives. In these classes of patients there should be no fluid restriction and every attempt made to maintain normal hydration, prior to contrast medium administration, since dehydration is the single most important factor influencing further renal impairment. Caution should be exercised in performing contrast medium studies in patients with endotoxemia and/or those with elevated body temperatures. Reports of thyroid storm occurring following the intravascular use of iodinated radiopaque agents in patients with hyperthyroidism or with an autonomously functioning thyroid nodule, suggest that this additional risk be evaluated in such patients before use of this drug. Iodine containing contrast agents may alter the results of thyroid function tests which depend on iodine estimation, e.g., PBI, and may also affect results of radioactive iodine uptake studies. Such tests, if indicated, should be performed prior to the administration of this preparation. # Precautions ## General Diagnostic procedures which involve the use of iodinated intravascular contrast agents should be carried out under the direction of personnel skilled and experienced in the particular procedure to be performed. All procedures utilizing contrast media carry a definite risk of producing adverse reactions. While most reactions are minor, life-threatening and fatal reactions may occur without warning, and this risk must be weighed against the benefit of the procedure. A fully equipped emergency cart, or equivalent supplies and equipment, and personnel competent in recognizing and treating adverse reactions of all types should always be available. If a serious reaction should occur, immediately discontinue administration. Since severe delayed reactions have been known to occur, emergency facilities and competent personnel should be available for at least 30 to 60 minutes after administration. (See ADVERSE REACTIONS, General.) Preparatory dehydration is dangerous and may contribute to acute renal failure in infants, young children, the elderly, patients with pre-existing renal insufficiency, patients with multiple myeloma, patients with advanced vascular disease and diabetic patients. Acute renal failure has been reported in diabetic patients with diabetic nephropathy and in susceptible nondiabetic patients (often elderly with pre-existing renal disease) following the administration of iodinated contrast agents. Therefore, careful consideration of the potential risks should be given before performing this radiographic procedure in these patients. Severe reactions to contrast media often resemble allergic responses. This has prompted the use of several provocative pretesting methods, none of which can be relied on to predict severe reactions. No conclusive relationship between severe reactions and antigen-antibody reactions or other manifestations of allergy has been established. The possibility of an idiosyncratic reaction in patients who have previously received a contrast medium without ill effect should always be considered. Prior to the injection of any contrast medium, the patient should be questioned to obtain a medical history with emphasis on allergy and hypersensitivity. A positive history of bronchial asthma or allergy (including food), a family history of allergy, or a previous reaction or hypersensitivity to a contrast agent may imply a greater than usual risk. Such a history may be more accurate than pre-testing in predicting the potential for reaction, although not necessarily the severity or type of reaction in the individual case. A positive history of this type does not arbitrarily contraindicate the use of a contrast agent, when a diagnostic procedure is thought essential, but does call for caution. (See ADVERSE REACTIONS, General.) Prophylactic therapy including corticosteroids and antihistamines should be considered for patients who present with a strong allergic history, a previous reaction to a contrast medium, or a positive pre-test since in these patients the incidence of reaction is two to three times that of the general population. Adequate doses of corticosteroids should be started early enough prior to contrast medium injection to be effective and should continue through the time of injection and for 24 hours after injection. Antihistamines should be administered within 30 minutes of the contrast medium injection. Recent reports indicate that such pre-treatment does not prevent serious life-threatening reactions, but may reduce both their incidence and severity. A separate syringe should be used for these injections. General anesthesia may be indicated in the performance of some procedures in selected patients; however, a higher incidence of adverse reactions has been reported in these patients, and may be attributable to the inability of the patient to identify untoward symptoms or to the hypotensive effect of anesthesia which can prolong the circulation time and increase the duration of contact of the contrast agent. Angiography should be avoided whenever possible in patients with homocystinuria because of the risk of inducing thrombosis and embolism. Information for Patients: Patients receiving iodinated intravascular contrast agents should be instructed to: 1. Inform your physician if you are pregnant. 2. Inform your physician if you are diabetic or if you have multiple myeloma, pheochromocytoma, homozygous sickle cell disease or known thyroid disease. (See WARNINGS). 3. Inform your physician if you are allergic to any drugs, food or if you had any reactions to previous injections of dyes used for x-ray procedures. (See PRECAUTIONS, General). 4. Inform your physician about any other medications you are currently taking including non-prescription drugs. Carcinogenesis, Mutagensis, Impairment of Fertility: No long-term animal studies have been performed to evaluate carcinogenic potential. However, animal studies suggest that this drug is not mutagenic and does not affect fertility in males or females. Pregnancy Category B: Reproduction studies have been performed in rats, and rabbits at doses up to two times the maximum adult human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Hexabrix. 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. Nursing Mothers: Ioxaglate salts are excreted unchanged in human milk. Because of the potential for adverse effects in nursing infants, bottle feedings should be substituted for breast feedings for 24 hours following the administration of this drug. Pediatric Use: Safety and effectiveness in children have been established in pediatric angiocardiography and intravenous excretory urography. Data have not been submitted to support the safety and effectiveness of Hexabrix in any other indication. (Precautions for specific procedures receive comment under that procedure.) # Adverse Reactions ## General Adverse reactions to injectable contrast media fall into two categories: chemotoxic reactions and idiosyncratic reactions. Chemotoxic reactions result from the physio-chemical properties of the contrast media, the dose and the speed of injection. All hemodynamic disturbances and injuries to organs or vessels perfused by the contrast medium are included in this category. Idiosyncratic reactions include all other reactions. They occur more frequently in patients 20 to 40 years old. Idiosyncratic reactions may or may not be dependent on the dose injected, the speed of injection, the mode of injection and the radiographic procedure. Idiosyncratic reactions are subdivided into minor, intermediate and severe. The minor reactions are self-limited and of short duration; the severe reactions are life-threatening and treatment is urgent and mandatory. NOTE: Not all of the following adverse reactions have been reported with Hexabrix. Because Hexabrix is an iodinated intravascular contrast agent, all of the side effects and toxicity associated with agents of this class are theoretically possible, and this should be borne in mind when Hexabrix is administered. Severe, life-threatening anaphylactoid reactions, mostly of cardiovascular origin, have occurred following the administration of Hexabrix as well as other iodine-containing contrast agents. Most deaths occur during injection or 5 to 10 minutes later; the main feature being cardiac arrest with cardiovascular disease as the main aggravating factor. Isolated reports of hypotensive collapse and shock are found in the literature. Based upon clinical literature, reported deaths from the administration of conventional iodinated contrast agents range from 6.6 per 1 million (0.00066 percent) to 1 in 10,000 patients (0.01 percent). Regardless of the contrast agent employed, the overall estimated incidence of serious adverse reactions is higher with coronary arteriography than with other procedures. Cardiac decompensation, serious arrhythmias, or myocardial ischemia or infarction may occur during coronary arteriography and left ventriculography. The most frequent adverse reactions are nausea, vomiting, facial flush and a feeling of body warmth. These are usually of brief duration. In double-blind clinical trials, Hexabrix produced less discomfort upon injection (pain and heat) when compared to various other contrast agents. Other reactions include the following: Hypersensitivity reactions: Dermal manifestations of urticaria with or without pruritus, erythema and maculopapular rash. Dry mouth. Sweating. Conjunctival symptoms. Facial, peripheral and angioneurotic edema. Symptoms related to the respiratory system include sneezing, nasal stuffiness, coughing, choking, dyspnea, chest tightness and wheezing, which may be initial manifestation of more severe and infrequent reactions including asthmatic attack, laryngospasm and bronchospasm with or without edema, pulmonary edema, apnea and cyanosis. Rarely, these allergic-type reactions can progress into anaphylaxis with loss of consciousness, coma, severe cardiovascular disturbances, and death. Cardiovascular reactions: Generalized vasodilation, flushing and venospasm. Occasionally, thrombosis or rarely, thrombophlebitis. Extremely rare cases of disseminated intravascular coagulation resulting in death have been reported. Severe cardiovascular responses include rare cases of hypotensive shock, coronary insufficiency, cardiac arrhythmia, fibrillation and arrest. These severe reactions are usually reversible with prompt and appropriate management; however, fatalities have occurred. Technique reactions: Extravasation with burning pain, hematomas, ecchymosis and tissue necrosis, vascular constriction due to injection rate, thrombosis and thrombophlebitis. Neurological reactions: Spasm, convulsions, aphasia, syncope, paresis, paralysis resulting from spinal cord injury and pathology associated with the syndrome of transverse myelitis, visual field losses which are usually transient but may be permanent, coma and death. Other reactions: Headache, trembling, shaking, chills without fever, hyperthermia and lightheadedness. Temporary renal shutdown or other nephropathy. (Adverse reactions to specific procedures receive comment under that procedure.) # Overdosage Overdosage may occur. The adverse effects of overdosage are life-threatening and affect mainly the pulmonary and cardiovascular systems. The symptoms may include cyanosis, bradycardia, acidosis, pulmonary hemorrhage, convulsions, coma and cardiac arrest. Treatment of an overdose is directed toward the support of all vital functions and prompt institution of symptomatic therapy. Ioxaglate salts are dialyzable. The intravenous LD50 values of Hexabrix (in grams of iodine/kilogram body weight) were 11.2 g/kg in mice, >8 g/kg in rats, >6.4 g/kg in rabbits and >10.2 g/kg in dogs. # Dosage and Administration It is advisable that Hexabrix be at or close to body temperature when injected. The patient should be instructed to omit the meal that precedes the examination. Appropriate premedication, which may include a barbiturate, tranquilizer or analgesic drug, may be administered prior to the examination. A preliminary film is recommended to check the position of the patient and the x-ray exposure factors prior to the injection of the contrast medium. If during administration a minor reaction occurs the injection should be slowed or stopped until the reaction has subsided. If a major reaction occurs the injection should be discontinued immediately. Under no circumstances should other drugs be administered concomitantly in the same syringe or IV administration set because of a potential for chemical incompatibility. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. # PEDIATRIC ANGIOCARDIOGRAPHY Hexabrix may be administered by catheter injection into the chambers of the heart or associated large blood vessels. Rapid injection is essential and satisfactory results usually require injection of the total dosage in 1-2 seconds. ## Precautions In addition to the general precautions previously described, it is advisable to monitor for ECG and vital signs changes throughout the procedure. When large individual doses are administered sufficient time should be allowed for any observed changes to return to or near baseline prior to making the next injection. Caution should be used when making right heart injections in patients with pulmonary hypertension or incipient heart failure since this may lead to increased right side pressures with subsequent bradycardia and systemic hypotension. Patients with pulmonary disease present additional risks. Caution is advised in cyanotic infants since apnea, bradycardia, other arrhythmias and a tendency to acidosis are more likely to occur. Since infants are more likely to respond with convulsions than are adults, the amount of total dosage is of particular importance. Repeated injections are hazardous in infants weighing less than 7 kg, particularly when these infants have pre-existing compromised right heart function or obliterated pulmonary vascular beds. ## Adverse Reactions In addition to the adverse reactions previously listed, this procedure has been complicated by intramural injection with marked adverse effects on cardiac function. ## Usual Dosage The volume of individual doses should be determined by the size of the structure to be visualized and the anticipated degree of hemodilution at the site of injection. Valvular competence should also be taken into consideration. Older Children: Catheter angiocardiography usually requires single doses of 30-45 mL of Hexabrix. Infants and Young Children: The recommended single dose of Hexabrix is about 1.5 mL/kg (range 1 mL/kg to 2 mL/kg). In addition, small test volumes of about 2 mL may be used for catheter placement. The usual total dose of Hexabrix per procedure, which includes diagnostic and test doses is about 4 mL/kg. This dosage may be as small as 1.5 mL/kg and should not normally exceed 5 mL/kg. # SELECTIVE CORONARY ARTERIOGRAPHY WITH OR WITHOUT LEFT VENTRICULOGRAPHY ## Precautions During the administration of large doses of Hexabrix, continuous monitoring of vital signs is desirable. Caution is advised in the administration of large volumes to patients with incipient heart failure because of the possibility of aggravating the pre-existing condition. Hypotension should be corrected promptly since it may result in serious arrhythmias. Special care regarding dosage should be observed in patients with right ventricular failure, pulmonary hypertension, or stenotic pulmonary vascular beds because of hemodynamic changes which may occur after injection into the right heart outflow tract. ## Adverse Reactions Patients may have clinically insignificant ECG changes during the procedure. The following adverse effects have occurred in conjunction with the administration of iodinated intravascular contrast agents for this procedure: hypotension, shock, anginal pain, myocardial infarction, cardiac arrhythmias (bradycardia, ventricular tachycardia, ventricular fibrillation) and cardiac arrest. Fatalities have been reported. Complications to the procedure include dissection of coronary arteries, dislodgement of atheromatous plaques, perforation, hemorrhage and thrombosis. ## Usual Dosage The usual adult dose for left coronary arteriography is 8 mL (range 2-14 mL) and for right coronary arteriography is 5 mL (range 1-10 mL). The doses may be repeated as necessary; doses up to a total of 150 mL have been given. For left ventriculography, the usual adult dose in a single injection is 45 mL (range 35-45 mL) and repeated as necessary. The total dose for combined selective coronary arteriography and left ventriculography should not exceed 250 mL. # PERIPHERAL ARTERIOGRAPHY Hexabrix may be injected to visualize the peripheral arterial circulation. Arteriograms of the upper and lower extremities may be obtained by any of the established techniques. ## Patient Preparation The procedure is normally performed with local anesthesia. Rarely, general anesthesia may be required. (See PRECAUTIONS, General.) A preliminary radiograph is usually made prior to the injection of the contrast agent. ## Precautions In addition to the general precautions previously described, moderate decreases in blood pressure occur frequently with intra-arterial (brachial) injections. This change is usually transient and requires no treatment, however, the blood pressure should be monitored for approximately ten minutes following injection. Extreme caution during injection of the contrast agent is necessary to avoid extravasation and fluoroscopy is recommended. This is especially important in patients with severe arterial disease. ## Adverse Reactions In addition to the general adverse reactions previously described, hemorrhage and thrombosis have occurred at the puncture site of the percutaneous injection. Brachial plexus injury has been reported following axillary artery injection. ## Usual Dosage The single adult dose for aorto-iliac runoff studies is 45 mL (range 20-80 mL). The single adult dose for the common iliac, the external iliac and the femoral arteries is 30 mL (range 10-50 mL). These doses may be repeated as necessary. For the upper limb, the usual single adult dose is 20 mL (range 15-30 mL), repeated as necessary. The total procedural dose should not exceed 250 mL. # AORTOGRAPHY AND SELECTIVE VISCERAL ARTERIOGRAPHY Hexabrix may be used to visualize the aorta and its major abdominal branches. ## Usual Dosage The usual dose for injections into the aorta is 25 to 50 mL; the celiac artery is 40 mL; the superior mesenteric artery is 20 to 40 mL; the inferior mesenteric artery is 8 to 15 mL. These doses may be repeated as necessary. The total dose should not exceed 250 mL. # CEREBRAL ANGIOGRAPHY Hexabrix may be used to visualize the cerebral vasculature by any of the accepted techniques. ## Patient Preparation Cerebral angiography is normally performed with local or general anesthesia. (See PRECAUTIONS, General.) ## Precautions In addition to the general precautions previously described, cerebral angiography should be performed with special caution in patients with advanced arteriosclerosis, severe hypertension, cardiac decompensation, senility, recent cerebral thrombosis or embolism, and migraine. ## Adverse Reactions The major causes of cerebral arteriographic adverse reactions appear to be repeated injections of the contrast material, administration of doses higher than those recommended, the presence of occlusive atherosclerotic vascular disease and the method and technique of injection. Adverse reactions are normally mild and transient. A feeling of warmth in the face and neck is frequently experienced. Infrequently, a more severe burning discomfort is observed. Transient visual hallucinations have been reported. Serious neurological reactions that have been associated with cerebral angiography and not listed under Adverse Reactions, General, include stroke, amnesia and respiratory difficulties. Visual field defects with anopsia and reversible neurological deficit lasting from 24 hours to 48 hours have been reported. Confusion, disorientation with hallucination, and absence of vision sometimes lasting for one week have also been reported. Cardiovascular reactions that may occur with some frequency are bradycardia and either an increase or decrease in systemic blood pressure. The blood pressure change is transient and usually requires no treatment. ## Usual Dosage The usual dosage employed varies with the site and method of injection and the age and condition of the patient. In adults, cerebral angiography is usually performed by a selective injection of 9 mL (range 6-12mL) for the common carotid arteries and 8 mL (range 5-12 mL) for the vertebral arteries. Additional injections may be made as indicated. When aortic arch injections (four vessel studies) are performed in conjunction with cerebral angiography, the usual dose is 40 mL (range 30-50 mL). Other dosages may be employed for more selective injections, depending upon the vessel injected. The total dose per procedure should not exceed 150 mL. # INTRA-ARTERIAL DIGITAL SUBTRACTION ANGIOGRAPHY (IA-DSA) Intra-arterial digital subtraction angiography (IA-DSA) is a radiographic modality which produces arterial images similar to conventional film-screen systems following arterial injection. The advantages include: the use of less contrast medium; the use of lower iodine concentrations; a decreased need for selective arterial catheterization; and a shortened examination time. ## Patient Preparation No special patient preparation is required for IA-DSA. However, it is advisable to insure that patients are well hydrated prior to examination. ## Precautions In addition to the general precautions described, the risks associated with IA-DSA are those usually attendant with catheter procedures. Following the procedure, gentle pressure hemostasis is required, followed by observation and immobilization of the limb for several hours to prevent hemorrhage from the site of arterial puncture. Patient motion, including respiration and swallowing, can result in misregistration leading to image degradation and non-diagnostic studies. ## Usual Dosage As a general rule, the volume and concentration used for IA-DSA are about 50%, or less, of that used for conventional procedures. The actual dosage and flow rate will vary depending on the selectivity of the injection site and the area being examined. The most versatile concentration of Hexabrix is a 1:1 dilution with Sterile Water for Injection, U.S.P. This dilution provides 16% iodine and is isotonic. The following suggested volumes per injection are intended only as a guide. Injections may be repeated as necessary. It is advisable to inject at rates approximately equal to the flow rate of the vessel being injected. # INTRAVENOUS DIGITAL SUBTRACTION ANGIOGRAPHY Intravenous digital subtraction angiography (IV DSA) is a radiographic modality which allows dynamic imaging of the arterial system following intravenous injection of iodinated x-ray contrast media through the use of image intensification, enhancement of the iodine signal and digital processing of the image data. Temporal subtraction of the images obtained prior to and during the “first arterial pass” of the injected contrast medium yields images which are devoid of bone and soft tissue. IV DSA is most frequently used to examine the heart, including coronary bypass grafts; the pulmonary arteries; arteries of the brachiocephalic circulation; the aortic arch; the abdominal aorta and its major branches; the iliac arteries; and the arteries of the extremities. ## Patient Preparation No special patient preparation is required for IV DSA. However it is advisable to insure that patients are well hydrated prior to examination. ## Precautions In addition to the general precautions previously described, the risks associated with IV DSA include those usually attendant with catheter procedures and include intramural injections, vessel dissection and tissue extravasation. The potential risk is reduced when small test injections of contrast medium are made under fluoroscopic observation to insure that the catheter tip is properly positioned and, in the case of peripheral placement, that the vein is of adequate size. Patient motion, including respiration and swallowing, can result in misregistration leading to image degradation and non-diagnostic studies. ## Usual Dosage Hexabrix may be injected centrally, in either the superior or inferior vena cava or right atrium; or peripherally into an appropriate arm vein. For central injections, catheters may be introduced at the antecubital fossa into either the basilic or cephalic vein or at the leg into the femoral vein and advanced to the distal segment of the corresponding vena cava. For peripheral injections, the catheter is introduced at the antecubital fossa into an appropriate size arm vein. In order to reduce the potential for extravasation during peripheral injection, a catheter of approximately 20 cm in length should be employed. Depending on the area to be imaged, the usual dose range per injection is 30-50 mL. Injections may be repeated as necessary. The total procedural dose should not exceed 250 mL. Injection rates will vary depending on the site of catheter placement and vessel size. Central catheter injections are usually made at a rate of between 10 and 30 mL/second. Peripheral injections are usually made at a rate of between 12 and 20 mL/second. Since the injected medium can sometimes remain in the arm vein for an extended period, it may be advisable to flush the vein, immediately following injection with an appropriate volume (20-25 mL) of 5% Dextrose in water or normal saline. # PERIPHERAL VENOGRAPHY (PHLEBOGRAPHY) Hexabrix may be injected to visualize the peripheral venous circulation. Venograms are obtained by injection or infusion into an appropriate vein in the upper or lower extremity. Post-venography thrombophlebitis, as detected by fibrinogen I-125 uptake studies, is significantly less in patients receiving Hexabrix when compared to conventional contrast agents. ## Precautions In addition to the general precautions previously described, special care is required when venography is performed in patients with suspected thrombosis, phlebitis, severe ischemic disease, local infection or a totally obstructed venous system. Extreme caution during injection of contrast media is necessary to avoid extravasation and fluoroscopy is recommended. This is especially important in patients with severe arterial or venous disease. ## Usual Dosage The dose for adults will usually range from 50-100 mL per extremity of full strength (32% iodine) Hexabrix as a single rapid injection. The dosage will vary according to the patient's size and condition and the technique employed. Smaller or larger volumes may be indicated in some cases. Reduced concentrations to as low as 20% w/v iodine may be effectively employed. These dilute solutions may be prepared by addition of normal saline (Sodium Chloride Injection, U.S.P.), 5% Dextrose in water (D5W) or Water for Injection, U.S.P. To prepare a 20% w/v solution, dilute each milliliter of Hexabrix with 0.6 milliliters of the diluent selected (e.g., 50 mL Hexabrix plus 30 mL of diluent equals 80 mL of a 20% iodine concentration). The usual dose of dilute medium will range from 75-150 mL per extremity. Following the procedure, the venous system should be flushed with any one of the diluents listed above. Massage and elevation are also helpful for clearing the contrast medium from the extremity. # EXCRETORY UROGRAPHY Following intravenous injection, Hexabrix is rapidly excreted by the kidneys. Hexabrix may be visualized in the renal parenchyma one minute following bolus injection. Maximum radiographic density in the calyces and pelves occurs in most instances within 7 to 12 minutes after injection. In patients with severe renal impairment, contrast visualization may be substantially delayed. ## Patient Preparation A low residue diet the day preceding the examination and a laxative the evening before the examination may be given, unless contraindicated. ## Precautions Infants and small children should not have any fluid restrictions prior to excretory urography. (See WARNINGS and PRECAUTIONS, General concerning preparatory dehydration.) ## Usual Dosage Adults — The usual adult dose is 50 to 75 mL (0.7 to 1.0 mL/kg). The total dose is normally injected within 30 to 90 seconds. A higher dosage may be indicated where poor visualization is anticipated (e.g., elderly patients, obese patients, patients with impaired renal function or patients in whom dense opacification of the pelvo-calyceal system and ureters is desired). In these patients, a dose of 100 to 150 mL (1.5 to 2.0 mL/kg) may be used. Children — The following schedule is recommended for infants and children. # CONTRAST ENHANCEMENT OF COMPUTED TOMOGRAPHIC (CT) HEAD IMAGING Hexabrix may be useful to enhance the presence and better define the extent of primary and metastatic malignancies of the head. In cases where lesions have calcified, there is less likelihood of enhancement. Following therapy, tumors may show decreased or no enhancement. The use of Hexabrix may also be beneficial in the image enhancement of non-neoplastic lesions, such as cerebral infarcts, sites of active infection, arterio-venous malformations and aneurysms. The opacification of the inferior vermis occurs occasionally in normal studies. ## Patient Preparation No special preparation is required, however, it is advisable to insure that patients are well hydrated prior to examination. ## Usual Dosage For adults weighing up to 150 pounds, the usual dosage is 0.9 mL/lb. Patients weighing more than 150 pounds can usually undergo satisfactory examination with a dose of 135 mL not to exceed 150 mL. # CONTRAST ENHANCEMENT IN BODY COMPUTED TOMOGRAPHY ## Patient Preparation No special patient preparation is required. However, it is advisable to insure that patients are well hydrated. In patients undergoing abdominal or pelvic examination, opacification of the bowel may be valuable in scan interpretation. ## Precautions In addition to the general precautions described, patient cooperation is essential since patient motion, including respiration, can markedly affect image quality. The use of an intravascular contrast medium can obscure tumors in patients undergoing CT evaluation of the liver resulting in a false negative diagnosis. Dynamic CT scanning is the procedure of choice for malignant tumor enhancement. (See CLINICAL PHARMACOLOGY.) ## Usual Dosage Hexabrix may be administered by bolus injection, rapid infusion or by a combination of both. Depending on the area to be examined, doses of 30-150 mL (0.4-0.9 mL/lb) may be administered. When prolonged enhancement is required up to 150 mL can be used, usually with 25-50 mL as a rapid bolus and the remainder as an infusion. # ARTHROGRAPHY Due to the low osmolality of Hexabrix, the concomitant use of epinephrine is not necessary since the rate of contrast medium absorption as well as the production of synovial fluid and consequent dilution of the medium are reduced. ## Precautions In addition to the general precautions previously described, strict aseptic technique is required to prevent the introduction of infection. Fluoroscopic control should be used to insure proper introduction of the needle into the synovial space and prevent extracapsular injection. Aspiration of excessive synovial fluid will reduce the pain on injection and prevent the dilution of the contrast agent. It is important that undue pressure not be exerted during the injection. ## Adverse Reactions In addition to the general adverse reactions previously described, arthrography may induce joint pain or discomfort which is usually mild and transient but occasionally may be severe and persist for 24 to 48 hours following the procedure. Effusion requiring aspiration may occur in patients with rheumatoid arthritis. ## Usual Dosage Arthrography is usually performed under local anesthesia. The amount of contrast agent required is solely dependent on the size of the joint to be injected and the technique employed. The following dosage schedule for normal adult joints should serve only as a guide since joints may require more or less contrast medium for optimal visualization. Passive or active manipulation is used to disperse the medium throughout the joint space. The lower volumes of contrast medium are usually employed for double contrast examinations in which 30-100 cc of either filtered room air or carbon dioxide may be introduced for examination of the knee and lesser volumes for other joints. # HYSTEROSALPINGOGRAPHY ## Patient Preparation It is preferable to perform the procedure approximately eight to ten days after the onset of menses. The patient should empty the bladder before the examination. ## Precautions Caution should be exercised in patients suspected of having cervical or tubal carcinoma to avoid possible spread of the lesion by the procedure. Delayed onset of pain and fever (1-2 days) may be indicative of pelvic infection. ## Adverse Reactions In addition to the general adverse reactions described previously, fever and pain, cramping and tenderness of the abdomen have been reported. ## Usual Dosage The total volume administered will vary depending upon anatomical variations and/or disease processes. The usual dose varies from 5 to 15 mL, administered slowly under fluoroscopic control, without undue pressure. ## How is Hexabrix Supplied Hexabrix Glass Vials/Bottles NDC Number - 10x20 mL vials 0019-5505-51 - 25x50 mL vials 0019-5505-06 - 12x100 mL fill/150 mL bottles 0019-5505-08 - 12x150 mL bottles 0019-5505-10 - 12x200 mL fill/250 mL bottles 0019-5505-21 ## Storage Store below 30° (86°). Do not freeze. If product is frozen or if crystallization of the salt has occurred, examine the container for physical damage. If no damage has occurred, the container should be brought to room temperature. Shake vigorously to assure complete dissolution of any crystals. The speed of dissolution may be increased by heating with circulating warm air. Before use, examine the product to assure that all solids are dissolved and that the container and closure have not been damaged. This preparation is sensitive to light and must be protected from strong daylight or direct exposure to the sun. As with all contrast media, glass containers should be inspected prior to use to ensure that breakage or other damage has not occurred during shipping and handling. All containers should be inspected for closure integrity. Damaged containers should not be used.	Ioxaglate Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ioxaglate or Hexabrix is a sterile, non-pyrogenic, aqueous solution intended for use as a diagnostic radiopaque medium. Hexabrix contains 39.3% w/v N-(2-hydroxyethyl)-2,4,6-triiodo-5-[2-[2,4,6-triiodo-3-(N-methylacetamido)-5-(methylcarbamoyl) benzamido] acetamido]-isophthalamic acid, compounded with 1-deoxy-1-(methylamino)-D-glucitol (1:1) and 19.6% w/v sodium N-(2-hydroxyethyl)-2,4,6 triiodo-5-[2-[2,4,6-triiodo-3-(N-methylacetamido)-5-(methylcarbamoyl) benzamido] acetamido]-isophthalamate. Each milliliter contains 393 mg of ioxaglate meglumine, 196 mg of ioxaglate sodium and 0.10 mg edetate calcium disodium as a stabilizer. The solution contains 3.48 mg (0.15 mEq) sodium in each milliliter and provides 32% (320 mg/mL) organically bound iodine. Solutions of ioxaglate (Hexabrix) provide six iodine atoms for each two dissociated ions. Hexabrix is an ionic contrast agent. Hexabrix has an osmolarity of approximately 460 mOsmol/L, an osmolality of approximately 600 mOsmol/kg of water and is, therefore, hypertonic under conditions of use. Hexabrix has a viscosity (cps) of 15.7 at 20° and 7.5 at 37°. The pH has been adjusted to 6.0 to 7.6 with meglumine, sodium hydroxide or ioxaglic acid. Hexabrix is a clear, colorless to pale yellow solution containing no undissolved solids. Crystallization does not occur at normal room temperatures. It is supplied in containers from which the air has been displaced by nitrogen. # Clinical Pharmacology Intravascular injection of a radiopaque diagnostic agent opacifies those vessels in the path of the flow of the contrast medium, permitting radiographic visualization of the internal structures of the human body until significant hemodilution occurs. Following intravascular injection, Hexabrix is rapidly transported through the circulatory system to the kidneys and is excreted unchanged in the urine. The pharmacokinetics of intravascularly administered radiopaque contrast media are usually best described by a two compartment model with a rapid alpha phase for drug distribution and a slower beta phase for drug elimination. In 10 patients with normal renal function, the alpha and beta half-lives of Hexabrix were 12 (4-17) and 92 (61-140) minutes, respectively. Following the intravenous administration of 50 mL of Hexabrix in 10 normal volunteers, the mean peak plasma concentration occurred at two (1-3) minutes, reaching a concentration of 2.1 (1.8-2.8) mg/mL. Approximately 50 (42-67) percent of the intravenously administered dose was recovered in the urine at two hours, and 90 (68-105) percent was recovered at 24 hours. The joint spaces as well as the uterus and fallopian tubes may be visualized by the direct injection of the contrast medium into the region to be studied. Injectable iodinated contrast agents are excreted either through the kidneys or through the liver. These two excretory pathways are not mutually exclusive, but the main route of excretion seems to be related to the affinity of the contrast medium for serum albumin. Ioxaglate salts are poorly bound to serum albumin, and are excreted mainly through the kidneys. The liver and small intestine provide the major alternate route of excretion. In patients with severe renal impairment, the excretion of this contrast medium through the gallbladder and into the small intestine sharply increases. Ioxaglate salts cross the placental barrier in humans and are excreted unchanged in human milk. ## CT SCANNING OF THE HEAD When used for contrast enhancement in computed tomographic head imaging, the degree of enhancement is directly related to the amount of iodine administered. Rapid injection of the entire dose yields peak blood iodine concentrations immediately following the injection, which falls rapidly over the next five to ten minutes as a result of dilution in the vascular and extravascular fluid compartments. Equilibration is reached in about ten minutes and thereafter the fall in iodine plasma concentration becomes exponential. In brain scanning, contrast media do not accumulate in normal brain tissue due to the blood brain barrier (BBB). The increase in x-ray attenuation usually seen in normal tissue following contrast medium injection is due to the presence of the contrast medium in the blood pool. Disruption in the BBB, such as occurs in malignant tumors of the brain, allows accumulation of contrast medium within the interstitial tumor tissue; adjacent normal brain tissue does not contain the contrast medium. Maximum contrast enhancement frequently occurs after peak blood iodine levels are reached. A delay in maximum contrast enhancement can occur depending on the peak iodine level achieved and the cell type of the lesion. This lag in enhancement is probably associated with the accumulation of the contrast medium within the lesion and outside the blood pool. The image enhancement of non-tumor lesions, such as arteriovenous malformations and aneurysms, is dependent on the iodine content of the circulating blood pool. ## CT SCANNING OF THE BODY Hexabrix may also be used for enhancement of computed tomographic scans performed for detection and evaluation of lesions in the liver, pancreas, kidneys, abdominal aorta, mediastinum, abdominal cavity and retroperitoneal space. In non-neural tissues (during computed tomography of the body), Hexabrix diffuses rapidly from the vascular to the extra-vascular space. Increase in x-ray absorption is related to blood flow, concentration of the contrast medium and extraction of the contrast medium by interstitial tissue since no barrier exists; contrast enhancement is thus due to the relative differences in extra-vascular diffusion between normal and abnormal tissue, a situation quite different than that in the brain. The pharmacokinetics of Hexabrix in normal and abnormal tissues has been shown to be variable. Enhancement of CT with Hexabrix may be of benefit in establishing diagnoses of certain lesions in some sites with greater assurance than is possible with unenhanced CT and in supplying additional features of the lesions. In other cases, the contrast medium may allow visualization of lesions not seen with CT alone or may help to define suspicious lesions seen with unenhanced CT. Contrast enhancement appears to be greatest within the 30-90 seconds after bolus administration of the contrast agent, and after intra-arterial rather than intravenous administration. Therefore, the use of a continuous scanning technique (a series of two to three second scans beginning at the injection — dynamic CT scanning) may improve enhancement and diagnostic assessment of tumors and other lesions such as an abscess, occasionally revealing more extensive disease. Because unenhanced scanning may provide adequate information in the individual patient, the decision to employ contrast enhancement, which is associated with additional risk and increased radiation exposure, should be based upon a careful evaluation of clinical, other radiological and unenhanced CT findings. # Indications and Usage for Hexabrix Hexabrix is indicated for use in pediatric angiocardiography, selective coronary arteriography with or without left ventriculography, peripheral arteriography, aortography, selective visceral arteriography, cerebral angiography, intra-arterial digital subtraction angiography, intravenous digital subtraction angiography, peripheral venography (phlebography), excretory urography, contrast enhancement of computed tomographic head imaging and body imaging, arthrography and hysterosalpingography. # Contraindications Hexabrix is contraindicated for use in myelography. Refer to PRECAUTIONS, General, concerning hypersensitivity. Hysterosalpingography should not be performed during the menstrual period; in pregnant patients; in patients with known infection in any portion of the genital tract; or in patients in whom cervical conization or curettage has been performed within 30 days. Arthrography should not be performed if infection is present in or near the joint. # Warnings SEVERE ADVERSE EVENTS — INADVERTENT INTRATHECAL ADMINISTRATION: Serious adverse reactions have been reported due to the inadvertent intrathecal administration of iodinated contrast media that are not indicated for intrathecal use. These serious adverse reactions include: death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. Special attention must be given to insure that this drug product is not administered intrathecally. Ionic iodinated contrast media inhibit blood coagulation, in vitro, more than nonionic contrast media. Nonetheless, it is prudent to avoid prolonged contact of blood with syringes containing ionic contrast media. Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiographic procedures with both ionic and nonionic contrast media. Therefore, meticulous intravascular administration technique is necessary, particularly during angiographic procedures, to minimize thromboembolic events. Numerous factors, including length of procedure, catheter and syringe material, underlying disease state and concomitant medications may contribute to the development of thromboembolic events. For these reasons, meticulous angiographic techniques are recommended including close attention to guidewire and catheter manipulation, use of manifold systems and/ or three-way stopcocks, frequent catheter flushing with heparinized saline solutions and minimizing the length of the procedure. The use of plastic syringes in place of glass syringes has been reported to decrease but not eliminate the likelihood of in vitro clotting. Serious or fatal reactions have been associated with the administration of iodine containing radiopaque media. It is of utmost importance to be completely prepared to treat any contrast medium reaction. As with any contrast medium, serious neurologic sequelae, including permanent paralysis, can occur following cerebral arteriography, selective spinal arteriography and arteriography of vessels supplying the spinal cord. The injection of a contrast medium should never be made following the administration of vasopressors since they strongly potentiate neurologic effects. In patients with subarachnoid hemorrhage, a rare association between contrast administration and clinical deterioration, including convulsions and death, has been reported. Therefore, administration of intravascular iodinated contrast media in these patients should be undertaken with caution. A definite risk exists in the use of intravascular contrast agents in patients who are known to have multiple myeloma. In such instances anuria has developed resulting in progressive uremia, renal failure and eventually death. Although neither the contrast agent nor dehydration has separately proved to be the cause of anuria in myeloma, it has been speculated that the combination of both may be causative factors. The risk in myelomatous patients is not a contraindication to the procedure; however, partial dehydration in the preparation of these patients for the examination is not recommended since this may predispose to precipitation of myeloma protein in the renal tubules. No form of therapy, including dialysis, has been successful in reversing the effect. Myeloma, which occurs most commonly in persons over 40, should be considered before instituting intravascular administration of contrast agents. Administration of radiopaque materials to patients known or suspected to have pheochromocytoma should be performed with extreme caution. If, in the opinion of the physician, the possible benefits of such procedures outweigh the considered risks, the procedures may be performed; however, the amount of radiopaque medium injected should be kept to an absolute minimum. The blood pressure should be assessed throughout the procedure, and measures for treatment of a hypertensive crisis should be available. Since intravascular administration of contrast media may promote sickling in individuals who are homozygous for sickle cell disease, fluid restriction is not advised. In patients with advanced renal disease, iodinated contrast media should be used with caution and only when the need for the examination dictates, since excretion of the medium may be impaired. Patients with combined renal and hepatic disease, those with severe hypertension or congestive heart failure and recent renal transplant recipients present an additional risk. Renal failure has been reported in patients with liver dysfunction who were given an oral cholecystographic agent followed by an intravascular iodinated radiopaque agent and also in patients with occult renal disease, notably diabetics and hypertensives. In these classes of patients there should be no fluid restriction and every attempt made to maintain normal hydration, prior to contrast medium administration, since dehydration is the single most important factor influencing further renal impairment. Caution should be exercised in performing contrast medium studies in patients with endotoxemia and/or those with elevated body temperatures. Reports of thyroid storm occurring following the intravascular use of iodinated radiopaque agents in patients with hyperthyroidism or with an autonomously functioning thyroid nodule, suggest that this additional risk be evaluated in such patients before use of this drug. Iodine containing contrast agents may alter the results of thyroid function tests which depend on iodine estimation, e.g., PBI, and may also affect results of radioactive iodine uptake studies. Such tests, if indicated, should be performed prior to the administration of this preparation. # Precautions ## General Diagnostic procedures which involve the use of iodinated intravascular contrast agents should be carried out under the direction of personnel skilled and experienced in the particular procedure to be performed. All procedures utilizing contrast media carry a definite risk of producing adverse reactions. While most reactions are minor, life-threatening and fatal reactions may occur without warning, and this risk must be weighed against the benefit of the procedure. A fully equipped emergency cart, or equivalent supplies and equipment, and personnel competent in recognizing and treating adverse reactions of all types should always be available. If a serious reaction should occur, immediately discontinue administration. Since severe delayed reactions have been known to occur, emergency facilities and competent personnel should be available for at least 30 to 60 minutes after administration. (See ADVERSE REACTIONS, General.) Preparatory dehydration is dangerous and may contribute to acute renal failure in infants, young children, the elderly, patients with pre-existing renal insufficiency, patients with multiple myeloma, patients with advanced vascular disease and diabetic patients. Acute renal failure has been reported in diabetic patients with diabetic nephropathy and in susceptible nondiabetic patients (often elderly with pre-existing renal disease) following the administration of iodinated contrast agents. Therefore, careful consideration of the potential risks should be given before performing this radiographic procedure in these patients. Severe reactions to contrast media often resemble allergic responses. This has prompted the use of several provocative pretesting methods, none of which can be relied on to predict severe reactions. No conclusive relationship between severe reactions and antigen-antibody reactions or other manifestations of allergy has been established. The possibility of an idiosyncratic reaction in patients who have previously received a contrast medium without ill effect should always be considered. Prior to the injection of any contrast medium, the patient should be questioned to obtain a medical history with emphasis on allergy and hypersensitivity. A positive history of bronchial asthma or allergy (including food), a family history of allergy, or a previous reaction or hypersensitivity to a contrast agent may imply a greater than usual risk. Such a history may be more accurate than pre-testing in predicting the potential for reaction, although not necessarily the severity or type of reaction in the individual case. A positive history of this type does not arbitrarily contraindicate the use of a contrast agent, when a diagnostic procedure is thought essential, but does call for caution. (See ADVERSE REACTIONS, General.) Prophylactic therapy including corticosteroids and antihistamines should be considered for patients who present with a strong allergic history, a previous reaction to a contrast medium, or a positive pre-test since in these patients the incidence of reaction is two to three times that of the general population. Adequate doses of corticosteroids should be started early enough prior to contrast medium injection to be effective and should continue through the time of injection and for 24 hours after injection. Antihistamines should be administered within 30 minutes of the contrast medium injection. Recent reports indicate that such pre-treatment does not prevent serious life-threatening reactions, but may reduce both their incidence and severity. A separate syringe should be used for these injections. General anesthesia may be indicated in the performance of some procedures in selected patients; however, a higher incidence of adverse reactions has been reported in these patients, and may be attributable to the inability of the patient to identify untoward symptoms or to the hypotensive effect of anesthesia which can prolong the circulation time and increase the duration of contact of the contrast agent. Angiography should be avoided whenever possible in patients with homocystinuria because of the risk of inducing thrombosis and embolism. Information for Patients: Patients receiving iodinated intravascular contrast agents should be instructed to: 1. Inform your physician if you are pregnant. 2. Inform your physician if you are diabetic or if you have multiple myeloma, pheochromocytoma, homozygous sickle cell disease or known thyroid disease. (See WARNINGS). 3. Inform your physician if you are allergic to any drugs, food or if you had any reactions to previous injections of dyes used for x-ray procedures. (See PRECAUTIONS, General). 4. Inform your physician about any other medications you are currently taking including non-prescription drugs. Carcinogenesis, Mutagensis, Impairment of Fertility: No long-term animal studies have been performed to evaluate carcinogenic potential. However, animal studies suggest that this drug is not mutagenic and does not affect fertility in males or females. Pregnancy Category B: Reproduction studies have been performed in rats, and rabbits at doses up to two times the maximum adult human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Hexabrix. 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. Nursing Mothers: Ioxaglate salts are excreted unchanged in human milk. Because of the potential for adverse effects in nursing infants, bottle feedings should be substituted for breast feedings for 24 hours following the administration of this drug. Pediatric Use: Safety and effectiveness in children have been established in pediatric angiocardiography and intravenous excretory urography. Data have not been submitted to support the safety and effectiveness of Hexabrix in any other indication. (Precautions for specific procedures receive comment under that procedure.) # Adverse Reactions ## General Adverse reactions to injectable contrast media fall into two categories: chemotoxic reactions and idiosyncratic reactions. Chemotoxic reactions result from the physio-chemical properties of the contrast media, the dose and the speed of injection. All hemodynamic disturbances and injuries to organs or vessels perfused by the contrast medium are included in this category. Idiosyncratic reactions include all other reactions. They occur more frequently in patients 20 to 40 years old. Idiosyncratic reactions may or may not be dependent on the dose injected, the speed of injection, the mode of injection and the radiographic procedure. Idiosyncratic reactions are subdivided into minor, intermediate and severe. The minor reactions are self-limited and of short duration; the severe reactions are life-threatening and treatment is urgent and mandatory. NOTE: Not all of the following adverse reactions have been reported with Hexabrix. Because Hexabrix is an iodinated intravascular contrast agent, all of the side effects and toxicity associated with agents of this class are theoretically possible, and this should be borne in mind when Hexabrix is administered. Severe, life-threatening anaphylactoid reactions, mostly of cardiovascular origin, have occurred following the administration of Hexabrix as well as other iodine-containing contrast agents. Most deaths occur during injection or 5 to 10 minutes later; the main feature being cardiac arrest with cardiovascular disease as the main aggravating factor. Isolated reports of hypotensive collapse and shock are found in the literature. Based upon clinical literature, reported deaths from the administration of conventional iodinated contrast agents range from 6.6 per 1 million (0.00066 percent) to 1 in 10,000 patients (0.01 percent). Regardless of the contrast agent employed, the overall estimated incidence of serious adverse reactions is higher with coronary arteriography than with other procedures. Cardiac decompensation, serious arrhythmias, or myocardial ischemia or infarction may occur during coronary arteriography and left ventriculography. The most frequent adverse reactions are nausea, vomiting, facial flush and a feeling of body warmth. These are usually of brief duration. In double-blind clinical trials, Hexabrix produced less discomfort upon injection (pain and heat) when compared to various other contrast agents. Other reactions include the following: Hypersensitivity reactions: Dermal manifestations of urticaria with or without pruritus, erythema and maculopapular rash. Dry mouth. Sweating. Conjunctival symptoms. Facial, peripheral and angioneurotic edema. Symptoms related to the respiratory system include sneezing, nasal stuffiness, coughing, choking, dyspnea, chest tightness and wheezing, which may be initial manifestation of more severe and infrequent reactions including asthmatic attack, laryngospasm and bronchospasm with or without edema, pulmonary edema, apnea and cyanosis. Rarely, these allergic-type reactions can progress into anaphylaxis with loss of consciousness, coma, severe cardiovascular disturbances, and death. Cardiovascular reactions: Generalized vasodilation, flushing and venospasm. Occasionally, thrombosis or rarely, thrombophlebitis. Extremely rare cases of disseminated intravascular coagulation resulting in death have been reported. Severe cardiovascular responses include rare cases of hypotensive shock, coronary insufficiency, cardiac arrhythmia, fibrillation and arrest. These severe reactions are usually reversible with prompt and appropriate management; however, fatalities have occurred. Technique reactions: Extravasation with burning pain, hematomas, ecchymosis and tissue necrosis, vascular constriction due to injection rate, thrombosis and thrombophlebitis. Neurological reactions: Spasm, convulsions, aphasia, syncope, paresis, paralysis resulting from spinal cord injury and pathology associated with the syndrome of transverse myelitis, visual field losses which are usually transient but may be permanent, coma and death. Other reactions: Headache, trembling, shaking, chills without fever, hyperthermia and lightheadedness. Temporary renal shutdown or other nephropathy. (Adverse reactions to specific procedures receive comment under that procedure.) # Overdosage Overdosage may occur. The adverse effects of overdosage are life-threatening and affect mainly the pulmonary and cardiovascular systems. The symptoms may include cyanosis, bradycardia, acidosis, pulmonary hemorrhage, convulsions, coma and cardiac arrest. Treatment of an overdose is directed toward the support of all vital functions and prompt institution of symptomatic therapy. Ioxaglate salts are dialyzable. The intravenous LD50 values of Hexabrix (in grams of iodine/kilogram body weight) were 11.2 g/kg in mice, >8 g/kg in rats, >6.4 g/kg in rabbits and >10.2 g/kg in dogs. # Dosage and Administration It is advisable that Hexabrix be at or close to body temperature when injected. The patient should be instructed to omit the meal that precedes the examination. Appropriate premedication, which may include a barbiturate, tranquilizer or analgesic drug, may be administered prior to the examination. A preliminary film is recommended to check the position of the patient and the x-ray exposure factors prior to the injection of the contrast medium. If during administration a minor reaction occurs the injection should be slowed or stopped until the reaction has subsided. If a major reaction occurs the injection should be discontinued immediately. Under no circumstances should other drugs be administered concomitantly in the same syringe or IV administration set because of a potential for chemical incompatibility. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. # PEDIATRIC ANGIOCARDIOGRAPHY Hexabrix may be administered by catheter injection into the chambers of the heart or associated large blood vessels. Rapid injection is essential and satisfactory results usually require injection of the total dosage in 1-2 seconds. ## Precautions In addition to the general precautions previously described, it is advisable to monitor for ECG and vital signs changes throughout the procedure. When large individual doses are administered sufficient time should be allowed for any observed changes to return to or near baseline prior to making the next injection. Caution should be used when making right heart injections in patients with pulmonary hypertension or incipient heart failure since this may lead to increased right side pressures with subsequent bradycardia and systemic hypotension. Patients with pulmonary disease present additional risks. Caution is advised in cyanotic infants since apnea, bradycardia, other arrhythmias and a tendency to acidosis are more likely to occur. Since infants are more likely to respond with convulsions than are adults, the amount of total dosage is of particular importance. Repeated injections are hazardous in infants weighing less than 7 kg, particularly when these infants have pre-existing compromised right heart function or obliterated pulmonary vascular beds. ## Adverse Reactions In addition to the adverse reactions previously listed, this procedure has been complicated by intramural injection with marked adverse effects on cardiac function. ## Usual Dosage The volume of individual doses should be determined by the size of the structure to be visualized and the anticipated degree of hemodilution at the site of injection. Valvular competence should also be taken into consideration. Older Children: Catheter angiocardiography usually requires single doses of 30-45 mL of Hexabrix. Infants and Young Children: The recommended single dose of Hexabrix is about 1.5 mL/kg (range 1 mL/kg to 2 mL/kg). In addition, small test volumes of about 2 mL may be used for catheter placement. The usual total dose of Hexabrix per procedure, which includes diagnostic and test doses is about 4 mL/kg. This dosage may be as small as 1.5 mL/kg and should not normally exceed 5 mL/kg. # SELECTIVE CORONARY ARTERIOGRAPHY WITH OR WITHOUT LEFT VENTRICULOGRAPHY ## Precautions During the administration of large doses of Hexabrix, continuous monitoring of vital signs is desirable. Caution is advised in the administration of large volumes to patients with incipient heart failure because of the possibility of aggravating the pre-existing condition. Hypotension should be corrected promptly since it may result in serious arrhythmias. Special care regarding dosage should be observed in patients with right ventricular failure, pulmonary hypertension, or stenotic pulmonary vascular beds because of hemodynamic changes which may occur after injection into the right heart outflow tract. ## Adverse Reactions Patients may have clinically insignificant ECG changes during the procedure. The following adverse effects have occurred in conjunction with the administration of iodinated intravascular contrast agents for this procedure: hypotension, shock, anginal pain, myocardial infarction, cardiac arrhythmias (bradycardia, ventricular tachycardia, ventricular fibrillation) and cardiac arrest. Fatalities have been reported. Complications to the procedure include dissection of coronary arteries, dislodgement of atheromatous plaques, perforation, hemorrhage and thrombosis. ## Usual Dosage The usual adult dose for left coronary arteriography is 8 mL (range 2-14 mL) and for right coronary arteriography is 5 mL (range 1-10 mL). The doses may be repeated as necessary; doses up to a total of 150 mL have been given. For left ventriculography, the usual adult dose in a single injection is 45 mL (range 35-45 mL) and repeated as necessary. The total dose for combined selective coronary arteriography and left ventriculography should not exceed 250 mL. # PERIPHERAL ARTERIOGRAPHY Hexabrix may be injected to visualize the peripheral arterial circulation. Arteriograms of the upper and lower extremities may be obtained by any of the established techniques. ## Patient Preparation The procedure is normally performed with local anesthesia. Rarely, general anesthesia may be required. (See PRECAUTIONS, General.) A preliminary radiograph is usually made prior to the injection of the contrast agent. ## Precautions In addition to the general precautions previously described, moderate decreases in blood pressure occur frequently with intra-arterial (brachial) injections. This change is usually transient and requires no treatment, however, the blood pressure should be monitored for approximately ten minutes following injection. Extreme caution during injection of the contrast agent is necessary to avoid extravasation and fluoroscopy is recommended. This is especially important in patients with severe arterial disease. ## Adverse Reactions In addition to the general adverse reactions previously described, hemorrhage and thrombosis have occurred at the puncture site of the percutaneous injection. Brachial plexus injury has been reported following axillary artery injection. ## Usual Dosage The single adult dose for aorto-iliac runoff studies is 45 mL (range 20-80 mL). The single adult dose for the common iliac, the external iliac and the femoral arteries is 30 mL (range 10-50 mL). These doses may be repeated as necessary. For the upper limb, the usual single adult dose is 20 mL (range 15-30 mL), repeated as necessary. The total procedural dose should not exceed 250 mL. # AORTOGRAPHY AND SELECTIVE VISCERAL ARTERIOGRAPHY Hexabrix may be used to visualize the aorta and its major abdominal branches. ## Usual Dosage The usual dose for injections into the aorta is 25 to 50 mL; the celiac artery is 40 mL; the superior mesenteric artery is 20 to 40 mL; the inferior mesenteric artery is 8 to 15 mL. These doses may be repeated as necessary. The total dose should not exceed 250 mL. # CEREBRAL ANGIOGRAPHY Hexabrix may be used to visualize the cerebral vasculature by any of the accepted techniques. ## Patient Preparation Cerebral angiography is normally performed with local or general anesthesia. (See PRECAUTIONS, General.) ## Precautions In addition to the general precautions previously described, cerebral angiography should be performed with special caution in patients with advanced arteriosclerosis, severe hypertension, cardiac decompensation, senility, recent cerebral thrombosis or embolism, and migraine. ## Adverse Reactions The major causes of cerebral arteriographic adverse reactions appear to be repeated injections of the contrast material, administration of doses higher than those recommended, the presence of occlusive atherosclerotic vascular disease and the method and technique of injection. Adverse reactions are normally mild and transient. A feeling of warmth in the face and neck is frequently experienced. Infrequently, a more severe burning discomfort is observed. Transient visual hallucinations have been reported. Serious neurological reactions that have been associated with cerebral angiography and not listed under Adverse Reactions, General, include stroke, amnesia and respiratory difficulties. Visual field defects with anopsia and reversible neurological deficit lasting from 24 hours to 48 hours have been reported. Confusion, disorientation with hallucination, and absence of vision sometimes lasting for one week have also been reported. Cardiovascular reactions that may occur with some frequency are bradycardia and either an increase or decrease in systemic blood pressure. The blood pressure change is transient and usually requires no treatment. ## Usual Dosage The usual dosage employed varies with the site and method of injection and the age and condition of the patient. In adults, cerebral angiography is usually performed by a selective injection of 9 mL (range 6-12mL) for the common carotid arteries and 8 mL (range 5-12 mL) for the vertebral arteries. Additional injections may be made as indicated. When aortic arch injections (four vessel studies) are performed in conjunction with cerebral angiography, the usual dose is 40 mL (range 30-50 mL). Other dosages may be employed for more selective injections, depending upon the vessel injected. The total dose per procedure should not exceed 150 mL. # INTRA-ARTERIAL DIGITAL SUBTRACTION ANGIOGRAPHY (IA-DSA) Intra-arterial digital subtraction angiography (IA-DSA) is a radiographic modality which produces arterial images similar to conventional film-screen systems following arterial injection. The advantages include: the use of less contrast medium; the use of lower iodine concentrations; a decreased need for selective arterial catheterization; and a shortened examination time. ## Patient Preparation No special patient preparation is required for IA-DSA. However, it is advisable to insure that patients are well hydrated prior to examination. ## Precautions In addition to the general precautions described, the risks associated with IA-DSA are those usually attendant with catheter procedures. Following the procedure, gentle pressure hemostasis is required, followed by observation and immobilization of the limb for several hours to prevent hemorrhage from the site of arterial puncture. Patient motion, including respiration and swallowing, can result in misregistration leading to image degradation and non-diagnostic studies. ## Usual Dosage As a general rule, the volume and concentration used for IA-DSA are about 50%, or less, of that used for conventional procedures. The actual dosage and flow rate will vary depending on the selectivity of the injection site and the area being examined. The most versatile concentration of Hexabrix is a 1:1 dilution with Sterile Water for Injection, U.S.P. This dilution provides 16% iodine and is isotonic. The following suggested volumes per injection are intended only as a guide. Injections may be repeated as necessary. It is advisable to inject at rates approximately equal to the flow rate of the vessel being injected. # INTRAVENOUS DIGITAL SUBTRACTION ANGIOGRAPHY Intravenous digital subtraction angiography (IV DSA) is a radiographic modality which allows dynamic imaging of the arterial system following intravenous injection of iodinated x-ray contrast media through the use of image intensification, enhancement of the iodine signal and digital processing of the image data. Temporal subtraction of the images obtained prior to and during the “first arterial pass” of the injected contrast medium yields images which are devoid of bone and soft tissue. IV DSA is most frequently used to examine the heart, including coronary bypass grafts; the pulmonary arteries; arteries of the brachiocephalic circulation; the aortic arch; the abdominal aorta and its major branches; the iliac arteries; and the arteries of the extremities. ## Patient Preparation No special patient preparation is required for IV DSA. However it is advisable to insure that patients are well hydrated prior to examination. ## Precautions In addition to the general precautions previously described, the risks associated with IV DSA include those usually attendant with catheter procedures and include intramural injections, vessel dissection and tissue extravasation. The potential risk is reduced when small test injections of contrast medium are made under fluoroscopic observation to insure that the catheter tip is properly positioned and, in the case of peripheral placement, that the vein is of adequate size. Patient motion, including respiration and swallowing, can result in misregistration leading to image degradation and non-diagnostic studies. ## Usual Dosage Hexabrix may be injected centrally, in either the superior or inferior vena cava or right atrium; or peripherally into an appropriate arm vein. For central injections, catheters may be introduced at the antecubital fossa into either the basilic or cephalic vein or at the leg into the femoral vein and advanced to the distal segment of the corresponding vena cava. For peripheral injections, the catheter is introduced at the antecubital fossa into an appropriate size arm vein. In order to reduce the potential for extravasation during peripheral injection, a catheter of approximately 20 cm in length should be employed. Depending on the area to be imaged, the usual dose range per injection is 30-50 mL. Injections may be repeated as necessary. The total procedural dose should not exceed 250 mL. Injection rates will vary depending on the site of catheter placement and vessel size. Central catheter injections are usually made at a rate of between 10 and 30 mL/second. Peripheral injections are usually made at a rate of between 12 and 20 mL/second. Since the injected medium can sometimes remain in the arm vein for an extended period, it may be advisable to flush the vein, immediately following injection with an appropriate volume (20-25 mL) of 5% Dextrose in water or normal saline. # PERIPHERAL VENOGRAPHY (PHLEBOGRAPHY) Hexabrix may be injected to visualize the peripheral venous circulation. Venograms are obtained by injection or infusion into an appropriate vein in the upper or lower extremity. Post-venography thrombophlebitis, as detected by fibrinogen I-125 uptake studies, is significantly less in patients receiving Hexabrix when compared to conventional contrast agents. ## Precautions In addition to the general precautions previously described, special care is required when venography is performed in patients with suspected thrombosis, phlebitis, severe ischemic disease, local infection or a totally obstructed venous system. Extreme caution during injection of contrast media is necessary to avoid extravasation and fluoroscopy is recommended. This is especially important in patients with severe arterial or venous disease. ## Usual Dosage The dose for adults will usually range from 50-100 mL per extremity of full strength (32% iodine) Hexabrix as a single rapid injection. The dosage will vary according to the patient's size and condition and the technique employed. Smaller or larger volumes may be indicated in some cases. Reduced concentrations to as low as 20% w/v iodine may be effectively employed. These dilute solutions may be prepared by addition of normal saline (Sodium Chloride Injection, U.S.P.), 5% Dextrose in water (D5W) or Water for Injection, U.S.P. To prepare a 20% w/v solution, dilute each milliliter of Hexabrix with 0.6 milliliters of the diluent selected (e.g., 50 mL Hexabrix plus 30 mL of diluent equals 80 mL of a 20% iodine concentration). The usual dose of dilute medium will range from 75-150 mL per extremity. Following the procedure, the venous system should be flushed with any one of the diluents listed above. Massage and elevation are also helpful for clearing the contrast medium from the extremity. # EXCRETORY UROGRAPHY Following intravenous injection, Hexabrix is rapidly excreted by the kidneys. Hexabrix may be visualized in the renal parenchyma one minute following bolus injection. Maximum radiographic density in the calyces and pelves occurs in most instances within 7 to 12 minutes after injection. In patients with severe renal impairment, contrast visualization may be substantially delayed. ## Patient Preparation A low residue diet the day preceding the examination and a laxative the evening before the examination may be given, unless contraindicated. ## Precautions Infants and small children should not have any fluid restrictions prior to excretory urography. (See WARNINGS and PRECAUTIONS, General concerning preparatory dehydration.) ## Usual Dosage Adults — The usual adult dose is 50 to 75 mL (0.7 to 1.0 mL/kg). The total dose is normally injected within 30 to 90 seconds. A higher dosage may be indicated where poor visualization is anticipated (e.g., elderly patients, obese patients, patients with impaired renal function or patients in whom dense opacification of the pelvo-calyceal system and ureters is desired). In these patients, a dose of 100 to 150 mL (1.5 to 2.0 mL/kg) may be used. Children — The following schedule is recommended for infants and children. # CONTRAST ENHANCEMENT OF COMPUTED TOMOGRAPHIC (CT) HEAD IMAGING Hexabrix may be useful to enhance the presence and better define the extent of primary and metastatic malignancies of the head. In cases where lesions have calcified, there is less likelihood of enhancement. Following therapy, tumors may show decreased or no enhancement. The use of Hexabrix may also be beneficial in the image enhancement of non-neoplastic lesions, such as cerebral infarcts, sites of active infection, arterio-venous malformations and aneurysms. The opacification of the inferior vermis occurs occasionally in normal studies. ## Patient Preparation No special preparation is required, however, it is advisable to insure that patients are well hydrated prior to examination. ## Usual Dosage For adults weighing up to 150 pounds, the usual dosage is 0.9 mL/lb. Patients weighing more than 150 pounds can usually undergo satisfactory examination with a dose of 135 mL not to exceed 150 mL. # CONTRAST ENHANCEMENT IN BODY COMPUTED TOMOGRAPHY ## Patient Preparation No special patient preparation is required. However, it is advisable to insure that patients are well hydrated. In patients undergoing abdominal or pelvic examination, opacification of the bowel may be valuable in scan interpretation. ## Precautions In addition to the general precautions described, patient cooperation is essential since patient motion, including respiration, can markedly affect image quality. The use of an intravascular contrast medium can obscure tumors in patients undergoing CT evaluation of the liver resulting in a false negative diagnosis. Dynamic CT scanning is the procedure of choice for malignant tumor enhancement. (See CLINICAL PHARMACOLOGY.) ## Usual Dosage Hexabrix may be administered by bolus injection, rapid infusion or by a combination of both. Depending on the area to be examined, doses of 30-150 mL (0.4-0.9 mL/lb) may be administered. When prolonged enhancement is required up to 150 mL can be used, usually with 25-50 mL as a rapid bolus and the remainder as an infusion. # ARTHROGRAPHY Due to the low osmolality of Hexabrix, the concomitant use of epinephrine is not necessary since the rate of contrast medium absorption as well as the production of synovial fluid and consequent dilution of the medium are reduced. ## Precautions In addition to the general precautions previously described, strict aseptic technique is required to prevent the introduction of infection. Fluoroscopic control should be used to insure proper introduction of the needle into the synovial space and prevent extracapsular injection. Aspiration of excessive synovial fluid will reduce the pain on injection and prevent the dilution of the contrast agent. It is important that undue pressure not be exerted during the injection. ## Adverse Reactions In addition to the general adverse reactions previously described, arthrography may induce joint pain or discomfort which is usually mild and transient but occasionally may be severe and persist for 24 to 48 hours following the procedure. Effusion requiring aspiration may occur in patients with rheumatoid arthritis. ## Usual Dosage Arthrography is usually performed under local anesthesia. The amount of contrast agent required is solely dependent on the size of the joint to be injected and the technique employed. The following dosage schedule for normal adult joints should serve only as a guide since joints may require more or less contrast medium for optimal visualization. Passive or active manipulation is used to disperse the medium throughout the joint space. The lower volumes of contrast medium are usually employed for double contrast examinations in which 30-100 cc of either filtered room air or carbon dioxide may be introduced for examination of the knee and lesser volumes for other joints. # HYSTEROSALPINGOGRAPHY ## Patient Preparation It is preferable to perform the procedure approximately eight to ten days after the onset of menses. The patient should empty the bladder before the examination. ## Precautions Caution should be exercised in patients suspected of having cervical or tubal carcinoma to avoid possible spread of the lesion by the procedure. Delayed onset of pain and fever (1-2 days) may be indicative of pelvic infection. ## Adverse Reactions In addition to the general adverse reactions described previously, fever and pain, cramping and tenderness of the abdomen have been reported. ## Usual Dosage The total volume administered will vary depending upon anatomical variations and/or disease processes. The usual dose varies from 5 to 15 mL, administered slowly under fluoroscopic control, without undue pressure. ## How is Hexabrix Supplied Hexabrix Glass Vials/Bottles NDC Number - 10x20 mL vials 0019-5505-51 - 25x50 mL vials 0019-5505-06 - 12x100 mL fill/150 mL bottles 0019-5505-08 - 12x150 mL bottles 0019-5505-10 - 12x200 mL fill/250 mL bottles 0019-5505-21 ## Storage Store below 30° (86°). Do not freeze. If product is frozen or if crystallization of the salt has occurred, examine the container for physical damage. If no damage has occurred, the container should be brought to room temperature. Shake vigorously to assure complete dissolution of any crystals. The speed of dissolution may be increased by heating with circulating warm air. Before use, examine the product to assure that all solids are dissolved and that the container and closure have not been damaged. This preparation is sensitive to light and must be protected from strong daylight or direct exposure to the sun. As with all contrast media, glass containers should be inspected prior to use to ensure that breakage or other damage has not occurred during shipping and handling. All containers should be inspected for closure integrity. Damaged containers should not be used. Template:WH Template:WS	https://www.wikidoc.org/index.php/Hexabrix
b402058a407b5f8a820d30ff191ff5bfb72186e3	wikidoc	Histamine	Histamine Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues. Histamine increases the permeability of the capillaries to white blood cells and other proteins, in order to allow them to engage foreign invaders in the infected tissues. It is found in virtually all animal body cells. # Properties Histamine forms colorless hygroscopic crystals that melt at 84°C, and are easily dissolved in water or ethanol, but not in ether. In aqueous solution histamine exists in two tautomeric forms, Nπ-H-histamine and Nτ-H-histamine. Histamine has two basic centres, namely the aliphatic amino group and whichever nitrogen atom of the imidazole ring does not already have a proton. Under physiological conditions, the aliphatic amino group (having a pKa around 9.4) will be protonated, whereas the second nitrogen of the imidazole ring (pKa ≈ 5.8) will not be protonated. Thus, histamine is normally protonated to a singly-charged cation. # Synthesis and metabolism Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase. It is a hydrophilic vasoactive amine. Once formed, histamine is either stored or rapidly inactivated by its primary degradative enzymes, histamine-N-methyltransferase or diamine oxidase. In the central nervous system, histamine released into the synapses is primarily broken down by histamine-N-methyltransferase, while in other tissues both enzymes may play a role. Several other enzymes, including MAO-B and ALDH2, further process the immediate metabolites of histamine for excretion or recycling. Bacteria also are capable of producing histamine using histidine decarboxylase enzymes unrelated to those found in animals. A non-infectious form of foodborne disease, scombroid poisoning, is due to histamine production by bacteria in spoiled food, particularly fish. Fermented foods and beverages naturally contain small quantities of histamine due to a similar conversion performed by fermenting bacteria or yeasts. Sake contains histamine in the 20-40 mg/L range; wines contain it in the 2-10 mg/L range. # Storage and release Most histamine in the body is generated in granules in mast cells or in white blood cells called basophils. Mast cells are especially numerous at sites of potential injury - the nose, mouth, and feet, internal body surfaces, and blood vessels. Non-mast cell histamine is found in several tissues, including the brain, where it functions as a neurotransmitter. Another important site of histamine storage and release is the enterochromaffin-like (ECL) cell of the stomach. The most important pathophysiologic mechanism of mast cell and basophil histamine release is immunologic. These cells, if sensitized by IgE antibodies attached to their membranes, degranulate when exposed to the appropriate antigen. Certain amines and alkaloids, including such drugs as morphine, and curare alkaloids, can displace histamine in granules and cause its release. Antibiotics like polymyxin are also found to stimulate histamine release. # Mechanism of action Histamine exerts its actions by combining with specific cellular histamine receptors. The four histamine receptors that have been discovered are designated H1 through H4, and are all G protein-coupled receptors. ## Effects on Nasal Mucosa Increased vascular permeability causes fluid to escape from capillaries into the tissues, which leads to the classic symptoms of an allergic reaction – a runny nose and watery eyes. Allergens can bind to IgE-loaded mast cells in the nasal mucosa, which leads to three clinical responses: sneezing results from histamine-associated sensory neural stimulation; hypersecretion from glandular tissue occurs; nasal mucosal congestion results due to vascular engorgement associated with vasodilation and increased capillary permeability. # Roles in the body ## Sleep regulation Histamine is released as a neurotransmitter. The cell bodies of neurons which release histamine are found in the posterior hypothalamus, in various tuberomammillary nuclei. From here, these histaminergic neurons project throughout the brain, to the cortex through the medial forebrain bundle. Histaminergic action is known to modulate sleep. Classically, antihistamines (H1 histamine receptor antagonists) produce sleep. Likewise, destruction of histamine releasing neurons, or inhibition of histamine synthesis leads to an inability to maintain vigilance. Finally, H3 receptor antagonists increase wakefulness. It has been shown that histaminergic cells have the most wakefulness-related firing pattern of any neuronal type thus far recorded. They fire rapidly during waking, fire more slowly during periods of relaxation/tiredness and completely stop firing during REM and NREM (non-REM) sleep. Histaminergic cells can be recorded firing just before an animal shows signs of waking. ## Suppressive effects While histamine has stimulatory effects upon neurons, it also has suppressive ones that protect against the susceptibility to convulsion, drug sensitization, denervation supersensitivity, ischemic lesions and stress. It has also been suggested that histamine controls the mechanisms by which memories and learning are forgotten. ## Erection and sexual function Libido loss and erectile failure can occur following histamine (H2) antagonists such as cimetidine and ranitidine. The injection of histamine into the corpus cavernosum in men with psychogenic impotence produces full or partial erections in 74% of them. It has been suggested that H2 antagonists may cause sexual difficulties by reducing the uptake of testosterone. ## Schizophrenia Metabolites of histamine are increased in the cerebrospinal fluid of people with schizophrenia, while the efficiency of H(1) receptor binding sites is decreased. Many atypical antipsychotic medications have the effect of increasing histamine turnover. # Disorders As an integral part of the immune system, histamine may be involved in immune system disorders and allergies. # Nomenclature "H substance" or "substance H" are occasionally used in medical literature for histamine or a hypothetical histamine-like diffusible substance released in allergic reactions of skin and in the responses of tissue to inflammation.	Histamine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter.[1] Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues. Histamine increases the permeability of the capillaries to white blood cells and other proteins, in order to allow them to engage foreign invaders in the infected tissues.[2] It is found in virtually all animal body cells.[citation needed] # Properties Histamine forms colorless hygroscopic crystals that melt at 84°C, and are easily dissolved in water or ethanol, but not in ether. In aqueous solution histamine exists in two tautomeric forms, Nπ-H-histamine and Nτ-H-histamine. Histamine has two basic centres, namely the aliphatic amino group and whichever nitrogen atom of the imidazole ring does not already have a proton. Under physiological conditions, the aliphatic amino group (having a pKa around 9.4) will be protonated, whereas the second nitrogen of the imidazole ring (pKa ≈ 5.8) will not be protonated.[3] Thus, histamine is normally protonated to a singly-charged cation. # Synthesis and metabolism Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase. It is a hydrophilic vasoactive amine. Once formed, histamine is either stored or rapidly inactivated by its primary degradative enzymes, histamine-N-methyltransferase or diamine oxidase. In the central nervous system, histamine released into the synapses is primarily broken down by histamine-N-methyltransferase, while in other tissues both enzymes may play a role. Several other enzymes, including MAO-B and ALDH2, further process the immediate metabolites of histamine for excretion or recycling. Bacteria also are capable of producing histamine using histidine decarboxylase enzymes unrelated to those found in animals. A non-infectious form of foodborne disease, scombroid poisoning, is due to histamine production by bacteria in spoiled food, particularly fish. Fermented foods and beverages naturally contain small quantities of histamine due to a similar conversion performed by fermenting bacteria or yeasts. Sake contains histamine in the 20-40 mg/L range; wines contain it in the 2-10 mg/L range. [4] # Storage and release Most histamine in the body is generated in granules in mast cells or in white blood cells called basophils. Mast cells are especially numerous at sites of potential injury - the nose, mouth, and feet, internal body surfaces, and blood vessels. Non-mast cell histamine is found in several tissues, including the brain, where it functions as a neurotransmitter. Another important site of histamine storage and release is the enterochromaffin-like (ECL) cell of the stomach. The most important pathophysiologic mechanism of mast cell and basophil histamine release is immunologic. These cells, if sensitized by IgE antibodies attached to their membranes, degranulate when exposed to the appropriate antigen. Certain amines and alkaloids, including such drugs as morphine, and curare alkaloids, can displace histamine in granules and cause its release. Antibiotics like polymyxin are also found to stimulate histamine release. # Mechanism of action Histamine exerts its actions by combining with specific cellular histamine receptors. The four histamine receptors that have been discovered are designated H1 through H4, and are all G protein-coupled receptors. ## Effects on Nasal Mucosa Increased vascular permeability causes fluid to escape from capillaries into the tissues, which leads to the classic symptoms of an allergic reaction – a runny nose and watery eyes. Allergens can bind to IgE-loaded mast cells in the nasal mucosa, which leads to three clinical responses: sneezing results from histamine-associated sensory neural stimulation; hypersecretion from glandular tissue occurs; nasal mucosal congestion results due to vascular engorgement associated with vasodilation and increased capillary permeability. [5] # Roles in the body ## Sleep regulation Histamine is released as a neurotransmitter. The cell bodies of neurons which release histamine are found in the posterior hypothalamus, in various tuberomammillary nuclei. From here, these histaminergic neurons project throughout the brain, to the cortex through the medial forebrain bundle. Histaminergic action is known to modulate sleep. Classically, antihistamines (H1 histamine receptor antagonists) produce sleep. Likewise, destruction of histamine releasing neurons, or inhibition of histamine synthesis leads to an inability to maintain vigilance. Finally, H3 receptor antagonists increase wakefulness. It has been shown that histaminergic cells have the most wakefulness-related firing pattern of any neuronal type thus far recorded. They fire rapidly during waking, fire more slowly during periods of relaxation/tiredness and completely stop firing during REM and NREM (non-REM) sleep. Histaminergic cells can be recorded firing just before an animal shows signs of waking. ## Suppressive effects While histamine has stimulatory effects upon neurons, it also has suppressive ones that protect against the susceptibility to convulsion, drug sensitization, denervation supersensitivity, ischemic lesions and stress.[6] It has also been suggested that histamine controls the mechanisms by which memories and learning are forgotten.[7] ## Erection and sexual function Libido loss and erectile failure can occur following histamine (H2) antagonists such as cimetidine and ranitidine.[8] The injection of histamine into the corpus cavernosum in men with psychogenic impotence produces full or partial erections in 74% of them.[9] It has been suggested that H2 antagonists may cause sexual difficulties by reducing the uptake of testosterone.[8] ## Schizophrenia Metabolites of histamine are increased in the cerebrospinal fluid of people with schizophrenia, while the efficiency of H(1) receptor binding sites is decreased. Many atypical antipsychotic medications have the effect of increasing histamine turnover.[10] # Disorders As an integral part of the immune system, histamine may be involved in immune system disorders and allergies. # Nomenclature "H substance" or "substance H" are occasionally used in medical literature for histamine or a hypothetical histamine-like diffusible substance released in allergic reactions of skin and in the responses of tissue to inflammation.	https://www.wikidoc.org/index.php/Histamine
c84ea8653d8c1aa25f8f457f159916ef1e93d05e	wikidoc	Histidine	Histidine Histidine (abbreviated as His or H) is one of the 20 most common natural amino acids present in proteins. In the nutritional sense, in humans, histidine is considered an essential amino acid, but mostly only in children. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. # Chemical properties The imidazole side chains and the relatively neutral pKa of histidine (ca 6.0) mean that relatively small shifts in cellular pH will change its charge. For this reason, this amino acid side chain finds its way into considerable use as a coordinating ligand in metalloproteins, and also as a catalytic site in certain enzymes. The imidazole side chain has two nitrogens with different properties: One is bound to hydrogen and donates its lone pair to the aromatic ring and as such is slightly acidic, whereas the other one donates only one electron pair to the ring so it has a free lone pair and is basic. These properties are exploited in different ways in proteins. In catalytic triads, the basic nitrogen of histidine is used to abstract a proton from serine, threonine or cysteine to activate it as a nucleophile. In a histidine proton shuttle, histidine is used to quickly shuttle protons, it can do this by abstracting a proton with its basic nitrogen to make a positively-charged intermediate and then use another molecule, a buffer, to extract the proton from its acidic nitrogen. In carbonic anhydrases, a histidine proton shuttle is utilized to rapidly shuttle protons away from a zinc-bound water molecule to quickly regenerate the active form of the enzyme. Because of histidine's affinity for metal ions, researchers will often add a polyhistidine-tag to a protein of interest. The metal affinity can then be used to purify, detect, or immobilize the protein to be studied. # Metabolism The amino acid is a precursor for histamine and carnosine biosynthesis. The enzyme histidine ammonia-lyase converts histidine into ammonia and urocanic acid. A deficiency in this enzyme is present in the rare metabolic disorder histidinemia. # Additional images - Histidine Histidine - The histidine bound heme group of succinate dehydrogenase, an electron carrier in the mitochondrial electron transfer chain. The large semi-transparent sphere indicates the location of the iron ion. From PDB: 1YQ3.	Histidine Template:NatOrganicBox Histidine (abbreviated as His or H)[1] is one of the 20 most common natural amino acids present in proteins. In the nutritional sense, in humans, histidine is considered an essential amino acid, but mostly only in children. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. # Chemical properties The imidazole side chains and the relatively neutral pKa of histidine (ca 6.0) mean that relatively small shifts in cellular pH will change its charge. For this reason, this amino acid side chain finds its way into considerable use as a coordinating ligand in metalloproteins, and also as a catalytic site in certain enzymes. The imidazole side chain has two nitrogens with different properties: One is bound to hydrogen and donates its lone pair to the aromatic ring and as such is slightly acidic, whereas the other one donates only one electron pair to the ring so it has a free lone pair and is basic. These properties are exploited in different ways in proteins. In catalytic triads, the basic nitrogen of histidine is used to abstract a proton from serine, threonine or cysteine to activate it as a nucleophile. In a histidine proton shuttle, histidine is used to quickly shuttle protons, it can do this by abstracting a proton with its basic nitrogen to make a positively-charged intermediate and then use another molecule, a buffer, to extract the proton from its acidic nitrogen. In carbonic anhydrases, a histidine proton shuttle is utilized to rapidly shuttle protons away from a zinc-bound water molecule to quickly regenerate the active form of the enzyme. Because of histidine's affinity for metal ions, researchers will often add a polyhistidine-tag to a protein of interest. The metal affinity can then be used to purify, detect, or immobilize the protein to be studied. # Metabolism The amino acid is a precursor for histamine and carnosine biosynthesis. The enzyme histidine ammonia-lyase converts histidine into ammonia and urocanic acid. A deficiency in this enzyme is present in the rare metabolic disorder histidinemia. # Additional images - Histidine Histidine - The histidine bound heme group of succinate dehydrogenase, an electron carrier in the mitochondrial electron transfer chain. The large semi-transparent sphere indicates the location of the iron ion. From PDB: 1YQ3.	https://www.wikidoc.org/index.php/Histidine
0298d5c7bff353ebf595692802aac1d8115f82be	wikidoc	Histology	Histology Histology (from the Greek Template:Polytonic) is the study of tissue sectioned as a thin slice, using a microtome. It can be described as microscopic anatomy. The photographing of stained cells is called histography. Histology is an essential tool of biology. Histopathology, the microscopic study of diseased tissue, is an important tool of anatomical pathology since accurate diagnosis of cancer and other diseases usually requires histopathological examination of samples. The trained scientists who perform the preparation of histological sections are Histotechnicians, Histology Technicians (HT), Histology Technologists (HTL), Medical Scientists, Medical Laboratory Technicians or Biomedical scientists. Their field of study is called histotechnology. # Technical Procedure ## Fixation Fixatives are used to preserve the tissue, the structures of the cell, and the cell organelles found in the individual cells (eg. nucleus, rough endoplasmic reticulum, mitochondria, and a lot more). The tissues are mechanically and biochemically stabilized in a fixative. The most common fixative is neutral buffered formalin (10% formaldehyde in Phosphate buffered saline (PBS)). It is important to consider that a fixative should not be too toxic to its handler, and it should not damage the tissue being preserved. ## Processing The most common technique is wax processing. The samples are immersed in multiple baths of progressively more concentrated ethanol to dehydrate the tissue, followed by a clearing agent such as, xylene or Histoclear, and finally hot molten paraffin wax (impregnation). During this 12 to 16 hour process, paraffin wax will replace the xylene: ## Embedding Soft, moist tissues are turned into a hard paraffin block, which is then placed in a mold containing more molten wax (embedded) and allowed to cool and harden. Embedding can also be accomplished using frozen, non-fixed tissue in a freezing medium. This freezing medium is liquid at room temperature but when cooled will solidify. Non-fixed tissue allows for procedures such as in-situ hybridizations for specific mRNA that would have been destroyed during the fixing process. It also allows for very short turnaround where that is needed, as with a patient currently undergoing surgery. ## Sectioning The tissue is then sectioned into very thin (2 - 8 micrometer) sections using a microtome. These slices, usually thinner than the average cell, are then placed on a glass slide for staining. Frozen tissue embedded in a freezing medium is cut on a microtome in a cooled machine called a cryostat. ## Staining Routine staining:This is done to give contrast to the tissue being examined, as without staining it is very difficult to see differences in cell morphology. Hematoxylin and eosin (abbreviated H&E) are the most commonly used stains in histology and histopathology. Hematoxylin colors nuclei blue, eosin colors the cytoplasm pink. To see the tissue under a microscope, the sections are stained with one or more pigments. Special Staining: There are hundreds of various other techniques which have been used to selectively stain cells and cellular components. Other compounds used to color tissue sections include safranin, oil red o, Congo red, fast green FCF, silver salts and numerous natural and artificial dyes, that were usually originated from the development dyes for the textile industry. Histochemistry refers to the science of using chemical reactions between laboratory chemicals and components within tissue. A commonly performed histochemical technique is the Perls Prussian blue reaction, used to demonstrate iron deposits in diseases like Hemochromatosis. Histology samples have often been examined by radioactive techniques. In historadiography a slide (sometimes stained histochemically) is X-rayed. More commonly, autoradiography is used to visualize the locations to which a radioactive substance has been transported within the body, such as cells in S phase (undergoing DNA replication) which incorporate tritiated thymidine, or sites to which radiolabeled nucleic acid probes bind in in situ hybridization. For autoradiography on a microscopic level the slide is typically dipped into liquid nuclear tract emulsion, which dries to form the exposure film. Individual silver grains in the film are visualized with dark field microscopy. Recently, antibodies are used to specifically visualize proteins, carbohydrates and lipids: this is called immunohistochemistry, or when the stain is a fluorescent molecule, immunofluorescence. This technique has greatly increased the ability to identify categories of cells under a microscope. Other advanced techniques can be combined with this, such as nonradioactive in situ hybridization to identify specific DNA or RNA molecules with fluorescent probes or tags that can be used for immunofluorescence and enzyme-linked fluorescence amplification (especially alkaline phosphatase and tyramide signal amplification). Fluorescence microscopy and confocal microscopy are used to detect fluorescent signals with good intracellular detail. Digital cameras are increasingly used to capture histological and histopathological images. # Common Laboratory Stains Table sourced from Michael H. Ross, Wojciech Pawlina, (2006). Histology: A Text and Atlas. Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-5056-3.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} The Nissl method and Golgi's method are useful in identifying neurons. ## Alternative techniques Alternative techniques include cryosection. The tissue is frozen and cut using a cryostat. Tissue staining methods are similar to those of wax sections. Plastic embedding is commonly used in the preparation of material for electron microscopy. Tissues are embedded in epoxy resin. Very thin sections (less than 0.1 micrometers) are cut using diamond or glass knives. The sections are stained with electron dense stains (uranium and lead) so that they can be seen with the electron microscope. # History In the 19th century, histology was an academic discipline in its own right. The 1906 Nobel Prize in Physiology or Medicine was awarded to the histologists, Camillo Golgi and Santiago Ramon y Cajal. They had dueling interpretations of the neural structure of the brain based in differing interpretations of the same images. # Histological classification of animal tissues There are four basic types of tissues: muscle tissue, nervous tissue, connective tissue, and epithelial tissue. All tissue types are subtypes of these four basic tissue types (for example blood cells are classified as connective tissue since they generally originate inside bone marrow). - Epithelium: the lining of glands, bowel, skin and some organs like the liver, lung, kidney, - Endothelium: the lining of blood and lymphatic vessels, - Mesothelium: the lining of pleural, and pericardial spaces, - Mesenchyme: the cells filling the spaces between the organs, including fat, muscle, bone, cartilage and tendon cells, - Blood cells: the red and white blood cells, including those found in lymph nodes and spleen, - Neurons: any of the conducting cells of the nervous system, - Germ cells: reproductive cells, spermatozoa in men, oocytes in women, - Placenta: an organ characteristic of true mammals during pregnancy, joining mother and offspring, providing endocrine secretion and selective exchange of soluble, but not particulate, blood borne substances through an apposition of uterine and trophoblastic vascularised parts, and - Stem cells: cells able to turn into one or several of the above types. Note that tissues from plant, fungus and microorganisms can also be examined histologically. Their structure is very different from animal tissue. # Related sciences - Cell biology is the study of living cells, their DNA, RNA and the proteins they express. - Anatomy, is the study of organs visible by the naked eye; and - Morphology, which studies entire organisms. # Artifacts Artifacts are structures or features in tissue that interfere with normal histological examination. These are not always present in normal tissue and can come from outside sources. Artifacts interfere with histology by changing the tissues appearance and hiding structures. These can be divided into two categories: ### Pre-histology These are features and structures that have being introduced prior to the collection of the tissues. A common example of these include: ink from tattoos and freckles (melanin) in skin samples. ### Post-histology Artifacts can result from tissue processing. Processing commonly lead to changes like shrinkage, color changes in different tissues types and alterations of the structures in the tissue. Because these are caused in a laboratory the majority of post histology artifacts can be avoided or removed after being discovered. A common example is mercury pigment left behind after using Bouin's fixative to fix a section.	Histology Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Histology (from the Greek Template:Polytonic) is the study of tissue sectioned as a thin slice, using a microtome. It can be described as microscopic anatomy. The photographing of stained cells is called histography. Histology is an essential tool of biology. Histopathology, the microscopic study of diseased tissue, is an important tool of anatomical pathology since accurate diagnosis of cancer and other diseases usually requires histopathological examination of samples. The trained scientists who perform the preparation of histological sections are Histotechnicians, Histology Technicians (HT), Histology Technologists (HTL), Medical Scientists, Medical Laboratory Technicians or Biomedical scientists. Their field of study is called histotechnology. # Technical Procedure ## Fixation Fixatives are used to preserve the tissue, the structures of the cell, and the cell organelles found in the individual cells (eg. nucleus, rough endoplasmic reticulum, mitochondria, and a lot more). The tissues are mechanically and biochemically stabilized in a fixative. The most common fixative is neutral buffered formalin (10% formaldehyde in Phosphate buffered saline (PBS)). It is important to consider that a fixative should not be too toxic to its handler, and it should not damage the tissue being preserved. ## Processing The most common technique is wax processing. The samples are immersed in multiple baths of progressively more concentrated ethanol to dehydrate the tissue, followed by a clearing agent such as, xylene or Histoclear, and finally hot molten paraffin wax (impregnation). During this 12 to 16 hour process, paraffin wax will replace the xylene: ## Embedding Soft, moist tissues are turned into a hard paraffin block, which is then placed in a mold containing more molten wax (embedded) and allowed to cool and harden. Embedding can also be accomplished using frozen, non-fixed tissue in a freezing medium. This freezing medium is liquid at room temperature but when cooled will solidify. Non-fixed tissue allows for procedures such as in-situ hybridizations for specific mRNA that would have been destroyed during the fixing process. It also allows for very short turnaround where that is needed, as with a patient currently undergoing surgery. ## Sectioning The tissue is then sectioned into very thin (2 - 8 micrometer) sections using a microtome. These slices, usually thinner than the average cell, are then placed on a glass slide for staining. Frozen tissue embedded in a freezing medium is cut on a microtome in a cooled machine called a cryostat. ## Staining Routine staining:This is done to give contrast to the tissue being examined, as without staining it is very difficult to see differences in cell morphology. Hematoxylin and eosin (abbreviated H&E) are the most commonly used stains in histology and histopathology. Hematoxylin colors nuclei blue, eosin colors the cytoplasm pink. To see the tissue under a microscope, the sections are stained with one or more pigments. Special Staining: There are hundreds of various other techniques which have been used to selectively stain cells and cellular components. Other compounds used to color tissue sections include safranin, oil red o, Congo red, fast green FCF, silver salts and numerous natural and artificial dyes, that were usually originated from the development dyes for the textile industry. Histochemistry refers to the science of using chemical reactions between laboratory chemicals and components within tissue. A commonly performed histochemical technique is the Perls Prussian blue reaction, used to demonstrate iron deposits in diseases like Hemochromatosis. Histology samples have often been examined by radioactive techniques. In historadiography a slide (sometimes stained histochemically) is X-rayed. More commonly, autoradiography is used to visualize the locations to which a radioactive substance has been transported within the body, such as cells in S phase (undergoing DNA replication) which incorporate tritiated thymidine, or sites to which radiolabeled nucleic acid probes bind in in situ hybridization. For autoradiography on a microscopic level the slide is typically dipped into liquid nuclear tract emulsion, which dries to form the exposure film. Individual silver grains in the film are visualized with dark field microscopy. Recently, antibodies are used to specifically visualize proteins, carbohydrates and lipids: this is called immunohistochemistry, or when the stain is a fluorescent molecule, immunofluorescence. This technique has greatly increased the ability to identify categories of cells under a microscope. Other advanced techniques can be combined with this, such as nonradioactive in situ hybridization to identify specific DNA or RNA molecules with fluorescent probes or tags that can be used for immunofluorescence and enzyme-linked fluorescence amplification (especially alkaline phosphatase and tyramide signal amplification). Fluorescence microscopy and confocal microscopy are used to detect fluorescent signals with good intracellular detail. Digital cameras are increasingly used to capture histological and histopathological images. # Common Laboratory Stains Table sourced from Michael H. Ross, Wojciech Pawlina, (2006). Histology: A Text and Atlas. Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-5056-3.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} The Nissl method and Golgi's method are useful in identifying neurons. ## Alternative techniques Alternative techniques include cryosection. The tissue is frozen and cut using a cryostat. Tissue staining methods are similar to those of wax sections. Plastic embedding is commonly used in the preparation of material for electron microscopy. Tissues are embedded in epoxy resin. Very thin sections (less than 0.1 micrometers) are cut using diamond or glass knives. The sections are stained with electron dense stains (uranium and lead) so that they can be seen with the electron microscope. # History In the 19th century, histology was an academic discipline in its own right. The 1906 Nobel Prize in Physiology or Medicine was awarded to the histologists, Camillo Golgi and Santiago Ramon y Cajal. They had dueling interpretations of the neural structure of the brain based in differing interpretations of the same images. # Histological classification of animal tissues There are four basic types of tissues: muscle tissue, nervous tissue, connective tissue, and epithelial tissue. All tissue types are subtypes of these four basic tissue types (for example blood cells are classified as connective tissue since they generally originate inside bone marrow). - Epithelium: the lining of glands, bowel, skin and some organs like the liver, lung, kidney, - Endothelium: the lining of blood and lymphatic vessels, - Mesothelium: the lining of pleural, and pericardial spaces, - Mesenchyme: the cells filling the spaces between the organs, including fat, muscle, bone, cartilage and tendon cells, - Blood cells: the red and white blood cells, including those found in lymph nodes and spleen, - Neurons: any of the conducting cells of the nervous system, - Germ cells: reproductive cells, spermatozoa in men, oocytes in women, - Placenta: an organ characteristic of true mammals during pregnancy, joining mother and offspring, providing endocrine secretion and selective exchange of soluble, but not particulate, blood borne substances through an apposition of uterine and trophoblastic vascularised parts, and - Stem cells: cells able to turn into one or several of the above types. Note that tissues from plant, fungus and microorganisms can also be examined histologically. Their structure is very different from animal tissue. # Related sciences - Cell biology is the study of living cells, their DNA, RNA and the proteins they express. - Anatomy, is the study of organs visible by the naked eye; and - Morphology, which studies entire organisms. # Artifacts Artifacts are structures or features in tissue that interfere with normal histological examination. These are not always present in normal tissue and can come from outside sources. Artifacts interfere with histology by changing the tissues appearance and hiding structures. These can be divided into two categories: ### Pre-histology These are features and structures that have being introduced prior to the collection of the tissues. A common example of these include: ink from tattoos and freckles (melanin) in skin samples. ### Post-histology Artifacts can result from tissue processing. Processing commonly lead to changes like shrinkage, color changes in different tissues types and alterations of the structures in the tissue. Because these are caused in a laboratory the majority of post histology artifacts can be avoided or removed after being discovered. A common example is mercury pigment left behind after using Bouin's fixative to fix a section.	https://www.wikidoc.org/index.php/Histochemical_staining
3a59eb2493faef486f30b9c40d45c1708715a72a	wikidoc	Histrelin	Histrelin # 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 Histrelin is a endocrine-metabolic agent and gonadotropin releasing hormone agonist that is FDA approved for the treatment of children with central precocious puberty (CPP). Common adverse reactions include implant site reactions, gynecomastia, hot sweats, amenorrhea, erectile dysfunction and fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) There is limited information regarding Histrelin FDA-Labeled Indications and Dosage (Adult) in the drug label. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Histrelin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Histrelin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Recommended Dose - The recommended dose of Histrelin is one implant every 12 months. Each implant contains 50 mg histrelin acetate. The implant is inserted subcutaneously in the inner aspect of the upper arm and provides continuous release of histrelin (65 mcg/day) for 12 months of hormonal therapy. Histrelin should be removed after 12 months of therapy (the implant has been designed to allow for a few additional weeks of histrelin acetate release, in order to allow flexibility of medical appointments). At the time an implant is removed, another implant may be inserted to continue therapy. Discontinuation of Histrelin should be considered at the discretion of the physician and at the appropriate time point for the onset of puberty (approximately 11 years for females and 12 years for males). ### Recommended Procedure for Implant Insertion and Removal - This procedure section is intended to provide guidance for the insertion and removal of Histrelin. The actual procedure used, however, is at the discretion of the qualified healthcare provider performing the procedure. - Insertion of a new implant can proceed using the following Suggested Insertion Procedure. If a previous Histrelin implant must first be removed, please see the Suggested Removal Procedure instructions below. - The supplies necessary to insert the implant, including the Insertion Tool and local anesthetic, are provided in a separate Implantation Kit that is shipped along with the implant. Please note that the implant should be kept refrigerated (2-8°C) in its sealed vial, pouch, and carton, until needed for the procedure. Once removed from refrigeration, the vial containing the implant (still in its unopened pouch and carton) may remain at room temperature for up to 7 days, if necessary, before being used. If not used in that time, the packaged implant may again be properly refrigerated until the expiration date on the carton. NOTE: The Implantation Kit is to be stored at room temperature and should not be refrigerated. Insertion of the Histrelin implant is a surgical procedure. Sterile gloves and aseptic technique must be used to minimize any chance of infection. Setting up the Sterile Field - Using proper aseptic technique, the sterilized components of the Implantation Kit needed for the insertion procedure, including the Insertion Tool, are to be carefully dispensed from their packaging onto the Sterile Field drape (non-fenestrated) provided. Note That The Kit Box And All Packaging Are Not Sterile And Should Be Kept Off Of The Sterile Field Drape. Do Not Place The Vial Of Local Anesthetic Or The Vial Containing The Implant Onto The Drape as the exterior surface of these vials is not sterile. - The implant vial should not be opened until just before the time of insertion. Open the vial by removing the metal band and carefully pour the sterile contents (implant and sterile saline) onto the Sterile Field drape. The implant can then be handled with sterile gloves or with the sterile mosquito clamp provided. AVOID bending or pinching the implant. Preparing the Patient and the Insertion Site - The patient should be on his/her back, ideally with the arm least used (e.g., left arm for a right-handed person) positioned, either bent or extended, so that the physician has ready access to the inner aspect of the upper arm. Propping the arm with pillows may help the patient more easily hold the position. The suggested optimum site for subcutaneous insertion is approximately half-way between the shoulder and the elbow, in line with the crease between the biceps and triceps muscles. - Antiseptic: Swab the insertion area with topical antiseptic, then overlay with the fenestrated Sterile Field drape provided, so that the opening is over the insertion site (for clarity of illustration, the following images do not show the drape). - Anesthetic: The method of anesthesia utilized (i.e., local, conscious sedation, general) is at the discretion of the healthcare provider. - If local anesthesia is selected: a vial of sterile local anesthetic (note that the exterior of the vial is not sterile) has been provided along with a sterile hypodermic needle for injection. After determining the absence of known allergies to the anesthetic agent, inject anesthetic into the subcutaneous tissue, starting at the planned incision site, then infiltrating along the intended subcutaneous insertion path, up to the length of the implant (a little more than one inch). Local anesthesia may also be supplemented by the use of distraction techniques. - The following sections describe the suggested procedure for insertion of the implant using the Insertion Tool provided. The method of insertion used, however, is at the discretion of the healthcare provider performing the procedure. ### Loading the Insertion Tool - The sterile Insertion Tool is comprised of a fixed handle attached to a retractable, bevel-tipped cannula, into the chamber of which the implant is to be placed for subcutaneous insertion. The cannula can be extended and retracted. The fully extended cannula contains a fixed piston upon which the implant, once inserted, rests. During the final step of the insertion procedure, the cannula will be retracted into the handle using the slide mechanism (green button), thereby exposing and leaving the implant to remain in the subcutaneous tissue. - When first grasping the sterile Insertion Tool, confirm that the cannula is fully extended. Verify this by inspecting the position of the green retraction button. The button should be locked in position all the way forward, towards the cannula, farthest from the handle. - The implant can be picked up using sterile gloves or with the sterile mosquito clamp provided. Avoid bending or pinching the implant. Note that the implant may come out of its vial slightly curved and/or partially flattened after refrigerated storage. To help make the implant more symmetrical prior to loading into the Tool, you can roll the implant a few times (while wearing a sterile glove) between the fingers and thumb. - Insert the implant into the cannula of the Insertion Tool manually or using the mosquito clamp. When inserting the implant into the cannula, DO NOT FORCE the implant. If resistance is felt, the implant should be removed and manually manipulated or rolled as needed, and re-inserted into the cannula. - When fully inserted, the implant rests inside the cannula so that just the tip of the implant is visible at the beveled end of the cannula. ### Making the Incision - Using the sterile scalpel provided, make an incision transverse to the long axis of the arm, and of a size adequate to allow the bore of the cannula to be inserted into the subcutaneous tissue. Be sure that the incision is positioned so that there is sufficient length of upper arm available to fit the implant easily within the intended insertion space. ### Inserting the Implant - It is suggested that insertion may be easier if a “pocket” for the implant is first created by blunt dissection through the incision, subcutaneously along the path of the anesthetic, using the cannula of the loaded Insertion Tool, or using a sterile hemostatic clamp or equivalent surgical tool. - Be sure to VISIBLY RAISE THE SKIN (known as tenting) at all times during the pocket-making and insertion procedures to ensure correct subcutaneous placement (“just under the skin”) of the implant. Note that the cannula of the Insertion Tool, or whatever tool is being used to create the pocket, SHOULD NOT ENTER MUSCLE TISSUE. Deep insertion of the implant will not affect the performance of Histrelin but may cause difficulty in the later removal of the implant. - If using the cannula of the loaded Insertion Tool to create the pocket, carefully insert the tip of the cannula into the incision and advance through the subcutaneous tissue, while visibly raising the skin along the length of the cannula up to, but no farther than, the inscribed black line on the cannula. DO NOT DEPRESS THE GREEN RETRACTION BUTTON ON THE TOOL WHILE INSERTING OR ADVANCING THE TOOL INTO THE INCISION. - Pull the Tool back, almost to the beveled tip of the cannula, and advance the Tool forward again, so that the cannula re-enters the pocket completely, but no farther than the inscribed black line. Be sure to keep the insertion path just immediately subcutaneous. - If another tool was used to create the pocket, now insert the loaded cannula of the Insertion Tool containing the implant through the incision, up to the inscribed black line. - Hold the Insertion Tool in place with the base against the patient’s arm (if possible) as you carefully move your thumb to the green retraction button. Depress the button to release the locking mechanism, then slide the button back toward the handle until it stops, all the while holding the body of the Insertion Tool in place. - Retracting the button causes the cannula to withdraw from the incision, leaving the implant in the subcutaneous tissue. DO NOT FURTHER ADVANCE THE CANNULA ONCE THE RETRACTION PROCESS HAS STARTED. Likewise, do not withdraw the Insertion Tool until the button is fully retracted or the implant may be pulled partially out of the incision. Once the retraction is complete, the Tool can be fully withdrawn. NOTE: It may be helpful during the process of retraction and withdrawal of the cannula to apply pressure to the skin over the implant, to help ensure that the implant remains in the subcutaneous pocket. - If there is a need to re-start the process at any time during the insertion procedure, withdraw the Insertion Tool, carefully extract the implant from the cannula and reset the retraction button on the Tool to its forward-most position. *Examine the implant before reloading the implant into the Insertion Tool, and start again. - Placement of the implant should be confirmed by palpation. Note that the tip of a properly-placed implant may not be visible through the incision. - After implantation, briefly cover the site with a sterile gauze pad and apply pressure to ensure hemostasis. ### Closing the Incision - To close the incision, you can use the absorbable sutures and/or the sterile adhesive surgical strips provided. To improve adhesion of the strips, you can apply benzoin tincture antiseptic (provided) to the skin, and let it dry, before applying the adhesive strips. - Once closed, cover the incision site with sterile gauze pads and secure the dressing with the bandage provided. - Please provide the patient’s parent or guardian with a Patient Information Leaflet, which includes information about the implant and instructions on proper care of the insertion site. ### Suggested Removal Procedure - Histrelin should be removed after 12 months of therapy. Most of the supplies necessary to remove the implant, including the local anesthetic and the sterile mosquito clamp, are provided in the Implantation Kit that is shipped along with a new Histrelin implant. Note that the Implantation Kit is to be stored at room temperature and must not be refrigerated. See the Suggested Insertion Procedure above for further instructions. - Removal of the Histrelin implant is a surgical procedure. Sterile gloves and aseptic technique must be used to minimize any chance of infection. Setting up the Sterile Field: Using proper aseptic technique, the sterilized components of the Implantation Kit needed for the implant removal procedure are to be carefully dispensed from their packaging out onto the Sterile Field drape (non-fenestrated) provided. NOTE THAT THE KIT BOX AND ALL PACKAGING ARE NOT STERILE and should be kept off of the Sterile Field drape. DO NOT PLACE THE VIAL OF LOCAL ANESTHETIC ONTO THE DRAPE as the exterior surface of the vial is not sterile. - Setting up the Sterile Field: Using proper aseptic technique, the sterilized components of the Implantation Kit needed for the implant removal procedure are to be carefully dispensed from their packaging out onto the Sterile Field drape (non-fenestrated) provided. NOTE THAT THE KIT BOX AND ALL PACKAGING ARE NOT STERILE and should be kept off of the Sterile Field drape. DO NOT PLACE THE VIAL OF LOCAL ANESTHETIC ONTO THE DRAPE as the exterior surface of the vial is not sterile. ### Preparing the Patient and the Site - The patient should be on his/her back, with the arm containing the implant positioned, either bent or extended, so that the physician has ready access to the inner aspect of the upper arm. Propping the arm with pillows may help the patient more easily hold the position. - The implant to be removed should first be located by palpating the inner aspect of the upper arm, near the incision from the prior year. - Generally, the previous implant is readily palpated. In the event the implant is difficult to locate, ultrasound may be used. If ultrasound fails to locate the implant, other imaging techniques such as CT or MRI may be used to locate it (plain films are not recommended as the implant is not radiopaque). - Antiseptic : Swab the area above and around the previous implant with topical antiseptic. Overlay the area with the fenestrated Sterile Field drape provided, so that the hole is over the previous insertion site (for clarity of illustration, the following images do not show the drape). - Anesthetic: The method of anesthesia utilized (i.e., local, conscious sedation, general) is at the discretion of the healthcare provider. If local anesthesia is selected: a vial of sterile local anesthetic (note that the exterior of the vial is not sterile) has been provided along with a sterile hypodermic needle for injection. After determining the absence of known allergies to the anesthetic agent, inject anesthetic into the subcutaneous tissue at and around the site of the intended incision (the site of the previous implant). Local anesthesia may also be supplemented by the use of distraction techniques. ### Making the Incision and Removing the Implant - Using the sterile scalpel provided, make an incision of a size adequate to allow the implant to be easily removed and, if a new implant will be inserted, large enough for the bore of the cannula of the Insertion Tool provided. - Generally, the tip of the implant will be visible through the incision, possibly covered by a pseudocapsule of tissue. In order to facilitate the removal of the implant, it may be necessary to palpate the head of the implant through the incision using your smallest finger, especially if the head of the implant is not readily visible. In addition, you may need to push down on the distal end of the implant and “massage it forward” towards the incision. - Carefully nick the pseudocapsule to reveal the polymer tip of the implant. It may be beneficial to insert the sterile mosquito clamp provided into the hole created in the pseudocapsule and expand by opening the clamp. Widening the opening of the pseudocapsule may ease the extraction of the implant. - Gently but securely grasp the implant with the sterile mosquito clamp and extract the implant. - Dispose of the implant in a proper manner, treating it like any other bio-waste. - Briefly cover the site with a sterile gauze pad and apply pressure to ensure hemostasis. - If inserting a new implant, see the Suggested Insertion Procedure instructions provided above. Note that you can insert the new implant into the same “pocket” as the removed implant, or make a new incision at a different site in the same arm or in the contralateral arm. - If a new implant is not to be inserted, proceed to close the incision. ### Closing the Incision - To close the incision, you can use the absorbable sutures and/or the sterile adhesive surgical strips provided. To improve adhesion of the strips, you can apply benzoin tincture antiseptic (provided) to the skin, and let it dry, before applying the adhesive strips. - Once closed, cover the incision site with sterile gauze pads and secure the dressing with the bandage provided. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Histrelin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Histrelin in pediatric patients. # Contraindications - Histrelin is contraindicated in patients who are hypersensitive to gonadotropin releasing hormone (GnRH) or GnRH agonist analogs. - Histrelin is contraindicated in females who are or may become pregnant while receiving the drug. Histrelin may cause fetal harm when administered to pregnant patients. 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 a fetus. The possibility exists that spontaneous abortion may occur. # Warnings ### Initial Agonistic Action - Histrelin, like other GnRH agonists, initially causes a transient increase in serum concentrations of estradiol in females and testosterone in both sexes during the first week of treatment. Patients may experience worsening of symptoms or onset of new symptoms during this period. However, within 4 weeks of histrelin therapy, suppression of gonadal steroids occurs and manifestations of puberty decrease. ### Implant Insertion/Removal Procedure - Implant insertion is a surgical procedure and it is important that the insertion instructions are followed to avoid potential complications. The insertion and removal of the implant should be done aseptically. Proper surgical technique is critical in minimizing adverse events related to the insertion and the removal of the histrelin implant. On occasion, localizing and/or removal of implant products have been difficult and imaging techniques were used, including ultrasound, CT, or MRI (note: the histrelin implant is not radiopaque). In some cases the implant broke during removal and multiple pieces were recovered. Confirm that the entire implant has been removed. If the implant was not retrieved completely, the remaining pieces should be removed following the instructions in the Suggested Removal Procedure section. Rare events of spontaneous extrusion of the implant have been observed in clinical trials. During Histrelin treatment, patients should be evaluated for evidence of clinical and biochemical suppression of CPP manifestations (see SECTION 5.3, Monitoring and Laboratory tests). Detailed instructions on the insertion and removal procedures of the implant are provided above. ### Monitoring and Laboratory Tests - LH, FSH and estradiol or testosterone should be monitored at 1 month post implantation then every 6 months thereafter. Additionally, height (for calculation of height velocity) and bone age should be assessed every 6-12 months. # Adverse Reactions ## Clinical Trials Experience The most common adverse reactions with Histrelin involved the implant site. Local reactions after implant insertion include bruising, pain, soreness, erythema and swelling. During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the natural stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed ### Adverse Reactions in Clinical Trials 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 Histrelin in children with CPP was evaluated in two single-arm clinical trials conducted in a total of 47 patients (44 females and 3 males) over a period of time ranging from 9 to 18 months. The most commonly reported adverse reaction was implant site reaction, which was reported by 24 of 47 (51.1%) patients. Implant site reaction includes discomfort, bruising, soreness, pain, tingling, itching, implant area protrusion and swelling. Two subjects experienced a serious adverse reaction: 1 subject who coincidentally had Stargardt’s Disease experienced amblyopia and 1 subject had a benign pituitary tumor (pituitary adenoma). One subject discontinued the study due to an adverse reaction of infection at the implant site. There were no clinically meaningful findings in standard clinical hematology and chemistry tests and/or in vital signs. The incidence of implantation adverse events reported by more than 2 patients are summarized in Table 1. The following adverse reactions were reported as possibly related or related in 1 patient each: wound infection, breast tenderness, dysmenorrhea, epistaxis, erythema, feeling cold, gynecomastia, headache, menorrhagia, migraine, mood swings, pituitary tumor benign, pruritus, weight increased, disease progression and influenza-like illness. The adverse reaction metrorrhagia was reported as possibly related or related in 2 patients. ## Postmarketing Experience The following adverse reactions have been identified during post approval use of Histrelin Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - General Disorders and Administration Site Conditions: implant breakage Nervous System Disorders: seizures - Nervous System Disorders: seizures # Drug Interactions - Overview: No formal drug-drug, drug-food, or drug-herb interaction studies were performed with Histrelin. - Drug-Laboratory Interactions: Therapy with Histrelin results in suppression of the pituitary-gonadal system. Results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after Histrelin therapy may be affected. Histrelin decreased mean serum insulin-like growth factor-1 (IGF-1) levels by approximately 11% in one study (Study 1). Histrelin increased the serum concentration of dehydroepiandrosterone (D # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X - Histrelin is contraindicated in females who are, or may become, pregnant while receiving the drug. Histrelin can cause fetal harm when administered to a pregnant patient. The possibility exists that spontaneous abortion may occur. - Animal Data: Major fetal abnormalities were observed in rabbits at 3 times human therapeutic exposure but not in rats after administration of histrelin acetate throughout gestation. There was dose-related increased fetal mortality during organogenesis in both rats given 1, 3, 5 or 15 mcg/kg/day (at less than therapeutic exposures using body surface area comparisons, based on a 65 mcg per day human dose) and in rabbits at 20, 50 or 80 mcg/kg/day (at 3 times human exposure using body surface area comparisons, based on a 65 mcg/day dose in humans). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Histrelin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Histrelin during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Histrelin in women who are nursing. ### Pediatric Use - Safety and effectiveness in pediatric patients below the age of 2 years have not been established. The use of Histrelin in children under 2 years is not recommended. ### Geriatic Use There is no FDA guidance on the use of Histrelin in geriatric settings. ### Gender There is no FDA guidance on the use of Histrelin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Histrelin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Histrelin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Histrelin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Histrelin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Histrelin in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Histrelin Administration in the drug label. ### Monitoring There is limited information regarding Histrelin Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Histrelin and IV administrations. # Overdosage - There have been no reports of overdose in Histrelin clinical trials. High doses of histrelin acetate injection in animal studies were generally associated only with effects attributed to the expected pharmacology. The method of drug delivery makes accidental or intentional overdosage unlikely. # Pharmacology ## Mechanism of Action - Histrelin is a GnRH agonist and an inhibitor of gonadotropin secretion when given continuously. It delivers approximately 65 mcg histrelin acetate per day. Both animal and human studies indicate that following an initial stimulatory phase, chronic, subcutaneous administration of histrelin acetate desensitizes responsiveness of the pituitary gonadotropin which, in turn causes a reduction in ovarian and testicular steroidogenesis. - In humans, administration of histrelin acetate results in an initial increase in circulating levels of LH and FSH, leading to a transient increase in concentration of gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). - However, continuous administration of histrelin acetate causes a reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes. These inhibitory effects result in decreased levels of LH and FSH. ## Structure There is limited information regarding Histrelin Structure in the drug label. ## Pharmacodynamics - Long-term treatment with histrelin acetate suppresses the LH response to GnRH causing LH levels to decrease to prepubertal levels within 1 month of treatment. As a result, serum concentrations of sex steroids (estrogen or testosterone) also decrease. Consequently, secondary sexual development ceases to progress in most patients. Additionally, linear growth velocity is slowed which improves the chance of attaining predicted adult height. ## Pharmacokinetics - Pharmacokinetics of histrelin after implantation of Histrelin was evaluated in a total of 47 children with CPP (11 subjects in Study 1 and 36 subjects in Study 2). Patients were examined at 4 weeks after implant insertion and a few times throughout the treatment period. Median serum histrelin concentrations remained above the limit of quantification for the treatment period. Histrelin acetate levels were sustained throughout the study period for most subjects (Figure 3). The median of maximum serum histrelin concentrations over the study period was 0.43 ng/mL, which is expected to maintain gonadotropins at prepubertal levels. There was no apparent pharmacokinetic difference between naïve subjects to a LHRH agonist treatment and subjects who had previous treatment with a LHRH agonist (Figure 3). ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenicity studies were conducted in rats for 2 years at doses of 5, 25 or150 mcg/kg/day (up to 11 times human exposures using body surface area comparisons, based on a 65 mcg/day dose in humans) and in mice for 18 months at doses of 20, 200, or 2000 mcg/kg/day (at less than therapeutic exposure to 70 times human exposure using body surface area comparisons, based on a 65 mcg/day dose in humans). As seen with other GnRH agonists, histrelin injection administration was associated with an increase in tumors of hormonally responsive tissues. There was a significant increase in pituitary adenomas in rats at mid and high doses (2-11 times human exposure based on body surface area comparisons with a 65 mcg/day human dose). There was an increase in pancreatic islet-cell adenomas in treated female rats and a non-dose-related increase in testicular Leydig-cell tumors (highest incidence in the low-dose group). In mice, there was significant increase in mammary-gland adenocarcinomas in all treated females. In addition, there were increases in stomach papillomas in male rats given high doses, and an increase in histiocytic sarcomas in female mice at the highest dose. - Mutagenicity studies have not been performed with histrelin acetate. Saline extracts of implants with and without histrelin acetate were negative in a battery of genotoxicity studies. Fertility studies have been conducted in rats and monkeys given subcutaneous daily doses of histrelin acetate up to 180 mcg/kg/day (up to 13 and 30 times human exposure, respectively using body surface area comparisons, based on a 65 mcg/day human dose) for 6 months and full reversibility of fertility suppression was demonstrated. The development and reproductive performance of offspring from parents treated with histrelin acetate has not been investigated. # Clinical Studies - The efficacy of Histrelin in children with CPP has been evaluated in two single-arm, open label studies. Study 1 was conducted in 11 pretreated female patients, 3.7 to 11.0 years of age. Study 2 was conducted in 36 patients (33 females and 3 males), 4.5 to 11.6 years of age. Sixteen pretreated and 20 treatment-naïve patients were enrolled in Study 2. Baseline patient characteristics were typical of patients with CPP. Efficacy assessments were similar in both studies and included endpoints that measured the suppression of gonadotropins (luteinizing hormone and follicle stimulating hormone) and gonadal sex steroids (estrogen in girls and testosterone in boys, respectively) on treatment. Other assessments were clinical (evidence of stabilization or regression of signs of puberty) or gonadal steroid-dependent (bone age, linear growth). In Study 2, the primary measure of efficacy was LH suppression. - In Study 2, suppression of LH was induced in all treatment naïve subjects and maintained in all pretreated subjects at Month 1 after implantation and continued through Month 12 (suppression was defined as a peak LH < 4 mIU/mL following stimulation with the GnRH analog leuprolide acetate). - Secondary efficacy hormone assessments (FSH, estradiol and testosterone) and additional efficacy assessments (bone age advancement, linear growth, clinical progression of puberty) indicated stabilization of disease. Estradiol suppression was present in all 33 girls (100%) through Month 9 and 97% at Month 12. Testosterone suppression was maintained in the three pre-treated males participating in Study 2. The Histrelin effect on efficacy endpoints in the Study 1 was consistent with that observed in Study 2. # How Supplied - UPPRELIN LA (NDC 67979-002-01) is supplied in a corrugated shipping carton that contains 2 inner cartons: a small one for the vial containing the Histrelin implant, which is shipped with a cold pack inside a polystyrene cooler that must be refrigerated upon arrival, and a larger one comprising the Implantation Kit, which must not be refrigerated, for use during insertion or removal of Histrelin. - The Histrelin implant contains 50 mg of histrelin acetate. The Histrelin implant carton contains a cold pack for refrigerated shipment and a small carton containing an amber plastic pouch. Inside the pouch is a glass vial with a Teflon-coated stopper and an aluminum seal, containing the implant in 2 mL of sterile 1.8% sodium chloride solution. (Note: the 3.5 mL vial is not completely filled with saline). ## Storage Histrelin is stable when stored refrigerated, in its sealed vial, pouch, and carton, at 2-8 °C (36-46 °F) until the expiration date provided. Excursion permitted to 25 °C (77 °F) for 7 days. Do not freeze. Protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Histrelin Patient Counseling Information in the drug label. # Precautions with Alcohol - Alcohol-Histrelin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Suprelin LA # Look-Alike Drug Names There is limited information regarding Histrelin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Histrelin 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 Histrelin is a endocrine-metabolic agent and gonadotropin releasing hormone agonist that is FDA approved for the treatment of children with central precocious puberty (CPP). Common adverse reactions include implant site reactions, gynecomastia, hot sweats, amenorrhea, erectile dysfunction and fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) There is limited information regarding Histrelin FDA-Labeled Indications and Dosage (Adult) in the drug label. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Histrelin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Histrelin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Recommended Dose - The recommended dose of Histrelin is one implant every 12 months. Each implant contains 50 mg histrelin acetate. The implant is inserted subcutaneously in the inner aspect of the upper arm and provides continuous release of histrelin (65 mcg/day) for 12 months of hormonal therapy. Histrelin should be removed after 12 months of therapy (the implant has been designed to allow for a few additional weeks of histrelin acetate release, in order to allow flexibility of medical appointments). At the time an implant is removed, another implant may be inserted to continue therapy. Discontinuation of Histrelin should be considered at the discretion of the physician and at the appropriate time point for the onset of puberty (approximately 11 years for females and 12 years for males). ### Recommended Procedure for Implant Insertion and Removal - This procedure section is intended to provide guidance for the insertion and removal of Histrelin. The actual procedure used, however, is at the discretion of the qualified healthcare provider performing the procedure. - Insertion of a new implant can proceed using the following Suggested Insertion Procedure. If a previous Histrelin implant must first be removed, please see the Suggested Removal Procedure instructions below. - The supplies necessary to insert the implant, including the Insertion Tool and local anesthetic, are provided in a separate Implantation Kit that is shipped along with the implant. Please note that the implant should be kept refrigerated (2-8°C) in its sealed vial, pouch, and carton, until needed for the procedure. Once removed from refrigeration, the vial containing the implant (still in its unopened pouch and carton) may remain at room temperature for up to 7 days, if necessary, before being used. If not used in that time, the packaged implant may again be properly refrigerated until the expiration date on the carton. NOTE: The Implantation Kit is to be stored at room temperature and should not be refrigerated. Insertion of the Histrelin implant is a surgical procedure. Sterile gloves and aseptic technique must be used to minimize any chance of infection. Setting up the Sterile Field - Using proper aseptic technique, the sterilized components of the Implantation Kit needed for the insertion procedure, including the Insertion Tool, are to be carefully dispensed from their packaging onto the Sterile Field drape (non-fenestrated) provided. Note That The Kit Box And All Packaging Are Not Sterile And Should Be Kept Off Of The Sterile Field Drape. Do Not Place The Vial Of Local Anesthetic Or The Vial Containing The Implant Onto The Drape as the exterior surface of these vials is not sterile. - The implant vial should not be opened until just before the time of insertion. Open the vial by removing the metal band and carefully pour the sterile contents (implant and sterile saline) onto the Sterile Field drape. The implant can then be handled with sterile gloves or with the sterile mosquito clamp provided. AVOID bending or pinching the implant. Preparing the Patient and the Insertion Site - The patient should be on his/her back, ideally with the arm least used (e.g., left arm for a right-handed person) positioned, either bent or extended, so that the physician has ready access to the inner aspect of the upper arm. Propping the arm with pillows may help the patient more easily hold the position. The suggested optimum site for subcutaneous insertion is approximately half-way between the shoulder and the elbow, in line with the crease between the biceps and triceps muscles. - Antiseptic: Swab the insertion area with topical antiseptic, then overlay with the fenestrated Sterile Field drape provided, so that the opening is over the insertion site (for clarity of illustration, the following images do not show the drape). - Anesthetic: The method of anesthesia utilized (i.e., local, conscious sedation, general) is at the discretion of the healthcare provider. - If local anesthesia is selected: a vial of sterile local anesthetic (note that the exterior of the vial is not sterile) has been provided along with a sterile hypodermic needle for injection. After determining the absence of known allergies to the anesthetic agent, inject anesthetic into the subcutaneous tissue, starting at the planned incision site, then infiltrating along the intended subcutaneous insertion path, up to the length of the implant (a little more than one inch). Local anesthesia may also be supplemented by the use of distraction techniques. - The following sections describe the suggested procedure for insertion of the implant using the Insertion Tool provided. The method of insertion used, however, is at the discretion of the healthcare provider performing the procedure. ### Loading the Insertion Tool - The sterile Insertion Tool is comprised of a fixed handle attached to a retractable, bevel-tipped cannula, into the chamber of which the implant is to be placed for subcutaneous insertion. The cannula can be extended and retracted. The fully extended cannula contains a fixed piston upon which the implant, once inserted, rests. During the final step of the insertion procedure, the cannula will be retracted into the handle using the slide mechanism (green button), thereby exposing and leaving the implant to remain in the subcutaneous tissue. - When first grasping the sterile Insertion Tool, confirm that the cannula is fully extended. Verify this by inspecting the position of the green retraction button. The button should be locked in position all the way forward, towards the cannula, farthest from the handle. - The implant can be picked up using sterile gloves or with the sterile mosquito clamp provided. Avoid bending or pinching the implant. Note that the implant may come out of its vial slightly curved and/or partially flattened after refrigerated storage. To help make the implant more symmetrical prior to loading into the Tool, you can roll the implant a few times (while wearing a sterile glove) between the fingers and thumb. - Insert the implant into the cannula of the Insertion Tool manually or using the mosquito clamp. When inserting the implant into the cannula, DO NOT FORCE the implant. If resistance is felt, the implant should be removed and manually manipulated or rolled as needed, and re-inserted into the cannula. - When fully inserted, the implant rests inside the cannula so that just the tip of the implant is visible at the beveled end of the cannula. ### Making the Incision - Using the sterile scalpel provided, make an incision transverse to the long axis of the arm, and of a size adequate to allow the bore of the cannula to be inserted into the subcutaneous tissue. Be sure that the incision is positioned so that there is sufficient length of upper arm available to fit the implant easily within the intended insertion space. ### Inserting the Implant - It is suggested that insertion may be easier if a “pocket” for the implant is first created by blunt dissection through the incision, subcutaneously along the path of the anesthetic, using the cannula of the loaded Insertion Tool, or using a sterile hemostatic clamp or equivalent surgical tool. - Be sure to VISIBLY RAISE THE SKIN (known as tenting) at all times during the pocket-making and insertion procedures to ensure correct subcutaneous placement (“just under the skin”) of the implant. Note that the cannula of the Insertion Tool, or whatever tool is being used to create the pocket, SHOULD NOT ENTER MUSCLE TISSUE. Deep insertion of the implant will not affect the performance of Histrelin but may cause difficulty in the later removal of the implant. - If using the cannula of the loaded Insertion Tool to create the pocket, carefully insert the tip of the cannula into the incision and advance through the subcutaneous tissue, while visibly raising the skin along the length of the cannula up to, but no farther than, the inscribed black line on the cannula. DO NOT DEPRESS THE GREEN RETRACTION BUTTON ON THE TOOL WHILE INSERTING OR ADVANCING THE TOOL INTO THE INCISION. - Pull the Tool back, almost to the beveled tip of the cannula, and advance the Tool forward again, so that the cannula re-enters the pocket completely, but no farther than the inscribed black line. Be sure to keep the insertion path just immediately subcutaneous. - If another tool was used to create the pocket, now insert the loaded cannula of the Insertion Tool containing the implant through the incision, up to the inscribed black line. - Hold the Insertion Tool in place with the base against the patient’s arm (if possible) as you carefully move your thumb to the green retraction button. Depress the button to release the locking mechanism, then slide the button back toward the handle until it stops, all the while holding the body of the Insertion Tool in place. - Retracting the button causes the cannula to withdraw from the incision, leaving the implant in the subcutaneous tissue. DO NOT FURTHER ADVANCE THE CANNULA ONCE THE RETRACTION PROCESS HAS STARTED. Likewise, do not withdraw the Insertion Tool until the button is fully retracted or the implant may be pulled partially out of the incision. Once the retraction is complete, the Tool can be fully withdrawn. NOTE: It may be helpful during the process of retraction and withdrawal of the cannula to apply pressure to the skin over the implant, to help ensure that the implant remains in the subcutaneous pocket. - If there is a need to re-start the process at any time during the insertion procedure, withdraw the Insertion Tool, carefully extract the implant from the cannula and reset the retraction button on the Tool to its forward-most position. *Examine the implant before reloading the implant into the Insertion Tool, and start again. - Placement of the implant should be confirmed by palpation. Note that the tip of a properly-placed implant may not be visible through the incision. - After implantation, briefly cover the site with a sterile gauze pad and apply pressure to ensure hemostasis. ### Closing the Incision - To close the incision, you can use the absorbable sutures and/or the sterile adhesive surgical strips provided. To improve adhesion of the strips, you can apply benzoin tincture antiseptic (provided) to the skin, and let it dry, before applying the adhesive strips. - Once closed, cover the incision site with sterile gauze pads and secure the dressing with the bandage provided. - Please provide the patient’s parent or guardian with a Patient Information Leaflet, which includes information about the implant and instructions on proper care of the insertion site. ### Suggested Removal Procedure - Histrelin should be removed after 12 months of therapy. Most of the supplies necessary to remove the implant, including the local anesthetic and the sterile mosquito clamp, are provided in the Implantation Kit that is shipped along with a new Histrelin implant. Note that the Implantation Kit is to be stored at room temperature and must not be refrigerated. See the Suggested Insertion Procedure above for further instructions. - Removal of the Histrelin implant is a surgical procedure. Sterile gloves and aseptic technique must be used to minimize any chance of infection. Setting up the Sterile Field: Using proper aseptic technique, the sterilized components of the Implantation Kit needed for the implant removal procedure are to be carefully dispensed from their packaging out onto the Sterile Field drape (non-fenestrated) provided. NOTE THAT THE KIT BOX AND ALL PACKAGING ARE NOT STERILE and should be kept off of the Sterile Field drape. DO NOT PLACE THE VIAL OF LOCAL ANESTHETIC ONTO THE DRAPE as the exterior surface of the vial is not sterile. - Setting up the Sterile Field: Using proper aseptic technique, the sterilized components of the Implantation Kit needed for the implant removal procedure are to be carefully dispensed from their packaging out onto the Sterile Field drape (non-fenestrated) provided. NOTE THAT THE KIT BOX AND ALL PACKAGING ARE NOT STERILE and should be kept off of the Sterile Field drape. DO NOT PLACE THE VIAL OF LOCAL ANESTHETIC ONTO THE DRAPE as the exterior surface of the vial is not sterile. ### Preparing the Patient and the Site - The patient should be on his/her back, with the arm containing the implant positioned, either bent or extended, so that the physician has ready access to the inner aspect of the upper arm. Propping the arm with pillows may help the patient more easily hold the position. - The implant to be removed should first be located by palpating the inner aspect of the upper arm, near the incision from the prior year. - Generally, the previous implant is readily palpated. In the event the implant is difficult to locate, ultrasound may be used. If ultrasound fails to locate the implant, other imaging techniques such as CT or MRI may be used to locate it (plain films are not recommended as the implant is not radiopaque). - Antiseptic : Swab the area above and around the previous implant with topical antiseptic. Overlay the area with the fenestrated Sterile Field drape provided, so that the hole is over the previous insertion site (for clarity of illustration, the following images do not show the drape). - Anesthetic: The method of anesthesia utilized (i.e., local, conscious sedation, general) is at the discretion of the healthcare provider. If local anesthesia is selected: a vial of sterile local anesthetic (note that the exterior of the vial is not sterile) has been provided along with a sterile hypodermic needle for injection. After determining the absence of known allergies to the anesthetic agent, inject anesthetic into the subcutaneous tissue at and around the site of the intended incision (the site of the previous implant). Local anesthesia may also be supplemented by the use of distraction techniques. ### Making the Incision and Removing the Implant - Using the sterile scalpel provided, make an incision of a size adequate to allow the implant to be easily removed and, if a new implant will be inserted, large enough for the bore of the cannula of the Insertion Tool provided. - Generally, the tip of the implant will be visible through the incision, possibly covered by a pseudocapsule of tissue. In order to facilitate the removal of the implant, it may be necessary to palpate the head of the implant through the incision using your smallest finger, especially if the head of the implant is not readily visible. In addition, you may need to push down on the distal end of the implant and “massage it forward” towards the incision. - Carefully nick the pseudocapsule to reveal the polymer tip of the implant. It may be beneficial to insert the sterile mosquito clamp provided into the hole created in the pseudocapsule and expand by opening the clamp. Widening the opening of the pseudocapsule may ease the extraction of the implant. - Gently but securely grasp the implant with the sterile mosquito clamp and extract the implant. - Dispose of the implant in a proper manner, treating it like any other bio-waste. - Briefly cover the site with a sterile gauze pad and apply pressure to ensure hemostasis. - If inserting a new implant, see the Suggested Insertion Procedure instructions provided above. Note that you can insert the new implant into the same “pocket” as the removed implant, or make a new incision at a different site in the same arm or in the contralateral arm. - If a new implant is not to be inserted, proceed to close the incision. ### Closing the Incision - To close the incision, you can use the absorbable sutures and/or the sterile adhesive surgical strips provided. To improve adhesion of the strips, you can apply benzoin tincture antiseptic (provided) to the skin, and let it dry, before applying the adhesive strips. - Once closed, cover the incision site with sterile gauze pads and secure the dressing with the bandage provided. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Histrelin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Histrelin in pediatric patients. # Contraindications - Histrelin is contraindicated in patients who are hypersensitive to gonadotropin releasing hormone (GnRH) or GnRH agonist analogs. - Histrelin is contraindicated in females who are or may become pregnant while receiving the drug. Histrelin may cause fetal harm when administered to pregnant patients. 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 a fetus. The possibility exists that spontaneous abortion may occur. # Warnings ### Initial Agonistic Action - Histrelin, like other GnRH agonists, initially causes a transient increase in serum concentrations of estradiol in females and testosterone in both sexes during the first week of treatment. Patients may experience worsening of symptoms or onset of new symptoms during this period. However, within 4 weeks of histrelin therapy, suppression of gonadal steroids occurs and manifestations of puberty decrease. ### Implant Insertion/Removal Procedure - Implant insertion is a surgical procedure and it is important that the insertion instructions are followed to avoid potential complications. The insertion and removal of the implant should be done aseptically. Proper surgical technique is critical in minimizing adverse events related to the insertion and the removal of the histrelin implant. On occasion, localizing and/or removal of implant products have been difficult and imaging techniques were used, including ultrasound, CT, or MRI (note: the histrelin implant is not radiopaque). In some cases the implant broke during removal and multiple pieces were recovered. Confirm that the entire implant has been removed. If the implant was not retrieved completely, the remaining pieces should be removed following the instructions in the Suggested Removal Procedure section. Rare events of spontaneous extrusion of the implant have been observed in clinical trials. During Histrelin treatment, patients should be evaluated for evidence of clinical and biochemical suppression of CPP manifestations (see SECTION 5.3, Monitoring and Laboratory tests). Detailed instructions on the insertion and removal procedures of the implant are provided above. ### Monitoring and Laboratory Tests - LH, FSH and estradiol or testosterone should be monitored at 1 month post implantation then every 6 months thereafter. Additionally, height (for calculation of height velocity) and bone age should be assessed every 6-12 months. # Adverse Reactions ## Clinical Trials Experience The most common adverse reactions with Histrelin involved the implant site. Local reactions after implant insertion include bruising, pain, soreness, erythema and swelling. During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the natural stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed ### Adverse Reactions in Clinical Trials 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 Histrelin in children with CPP was evaluated in two single-arm clinical trials conducted in a total of 47 patients (44 females and 3 males) over a period of time ranging from 9 to 18 months. The most commonly reported adverse reaction was implant site reaction, which was reported by 24 of 47 (51.1%) patients. Implant site reaction includes discomfort, bruising, soreness, pain, tingling, itching, implant area protrusion and swelling. Two subjects experienced a serious adverse reaction: 1 subject who coincidentally had Stargardt’s Disease experienced amblyopia and 1 subject had a benign pituitary tumor (pituitary adenoma). One subject discontinued the study due to an adverse reaction of infection at the implant site. There were no clinically meaningful findings in standard clinical hematology and chemistry tests and/or in vital signs. The incidence of implantation adverse events reported by more than 2 patients are summarized in Table 1. The following adverse reactions were reported as possibly related or related in 1 patient each: wound infection, breast tenderness, dysmenorrhea, epistaxis, erythema, feeling cold, gynecomastia, headache, menorrhagia, migraine, mood swings, pituitary tumor benign, pruritus, weight increased, disease progression and influenza-like illness. The adverse reaction metrorrhagia was reported as possibly related or related in 2 patients. ## Postmarketing Experience The following adverse reactions have been identified during post approval use of Histrelin Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - General Disorders and Administration Site Conditions: implant breakage Nervous System Disorders: seizures - Nervous System Disorders: seizures # Drug Interactions - Overview: No formal drug-drug, drug-food, or drug-herb interaction studies were performed with Histrelin. - Drug-Laboratory Interactions: Therapy with Histrelin results in suppression of the pituitary-gonadal system. Results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after Histrelin therapy may be affected. Histrelin decreased mean serum insulin-like growth factor-1 (IGF-1) levels by approximately 11% in one study (Study 1). Histrelin increased the serum concentration of dehydroepiandrosterone (D # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X - Histrelin is contraindicated in females who are, or may become, pregnant while receiving the drug. Histrelin can cause fetal harm when administered to a pregnant patient. The possibility exists that spontaneous abortion may occur. - Animal Data: Major fetal abnormalities were observed in rabbits at 3 times human therapeutic exposure but not in rats after administration of histrelin acetate throughout gestation. There was dose-related increased fetal mortality during organogenesis in both rats given 1, 3, 5 or 15 mcg/kg/day (at less than therapeutic exposures using body surface area comparisons, based on a 65 mcg per day human dose) and in rabbits at 20, 50 or 80 mcg/kg/day (at 3 times human exposure using body surface area comparisons, based on a 65 mcg/day dose in humans). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Histrelin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Histrelin during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Histrelin in women who are nursing. ### Pediatric Use - Safety and effectiveness in pediatric patients below the age of 2 years have not been established. The use of Histrelin in children under 2 years is not recommended. ### Geriatic Use There is no FDA guidance on the use of Histrelin in geriatric settings. ### Gender There is no FDA guidance on the use of Histrelin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Histrelin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Histrelin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Histrelin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Histrelin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Histrelin in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Histrelin Administration in the drug label. ### Monitoring There is limited information regarding Histrelin Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Histrelin and IV administrations. # Overdosage - There have been no reports of overdose in Histrelin clinical trials. High doses of histrelin acetate injection in animal studies were generally associated only with effects attributed to the expected pharmacology. The method of drug delivery makes accidental or intentional overdosage unlikely. # Pharmacology ## Mechanism of Action - Histrelin is a GnRH agonist and an inhibitor of gonadotropin secretion when given continuously. It delivers approximately 65 mcg histrelin acetate per day. Both animal and human studies indicate that following an initial stimulatory phase, chronic, subcutaneous administration of histrelin acetate desensitizes responsiveness of the pituitary gonadotropin which, in turn causes a reduction in ovarian and testicular steroidogenesis. - In humans, administration of histrelin acetate results in an initial increase in circulating levels of LH and FSH, leading to a transient increase in concentration of gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). - However, continuous administration of histrelin acetate causes a reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes. These inhibitory effects result in decreased levels of LH and FSH. ## Structure There is limited information regarding Histrelin Structure in the drug label. ## Pharmacodynamics - Long-term treatment with histrelin acetate suppresses the LH response to GnRH causing LH levels to decrease to prepubertal levels within 1 month of treatment. As a result, serum concentrations of sex steroids (estrogen or testosterone) also decrease. Consequently, secondary sexual development ceases to progress in most patients. Additionally, linear growth velocity is slowed which improves the chance of attaining predicted adult height. ## Pharmacokinetics - Pharmacokinetics of histrelin after implantation of Histrelin was evaluated in a total of 47 children with CPP (11 subjects in Study 1 and 36 subjects in Study 2). Patients were examined at 4 weeks after implant insertion and a few times throughout the treatment period. Median serum histrelin concentrations remained above the limit of quantification for the treatment period. Histrelin acetate levels were sustained throughout the study period for most subjects (Figure 3). The median of maximum serum histrelin concentrations over the study period was 0.43 ng/mL, which is expected to maintain gonadotropins at prepubertal levels. There was no apparent pharmacokinetic difference between naïve subjects to a LHRH agonist treatment and subjects who had previous treatment with a LHRH agonist (Figure 3). ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenicity studies were conducted in rats for 2 years at doses of 5, 25 or150 mcg/kg/day (up to 11 times human exposures using body surface area comparisons, based on a 65 mcg/day dose in humans) and in mice for 18 months at doses of 20, 200, or 2000 mcg/kg/day (at less than therapeutic exposure to 70 times human exposure using body surface area comparisons, based on a 65 mcg/day dose in humans). As seen with other GnRH agonists, histrelin injection administration was associated with an increase in tumors of hormonally responsive tissues. There was a significant increase in pituitary adenomas in rats at mid and high doses (2-11 times human exposure based on body surface area comparisons with a 65 mcg/day human dose). There was an increase in pancreatic islet-cell adenomas in treated female rats and a non-dose-related increase in testicular Leydig-cell tumors (highest incidence in the low-dose group). In mice, there was significant increase in mammary-gland adenocarcinomas in all treated females. In addition, there were increases in stomach papillomas in male rats given high doses, and an increase in histiocytic sarcomas in female mice at the highest dose. - Mutagenicity studies have not been performed with histrelin acetate. Saline extracts of implants with and without histrelin acetate were negative in a battery of genotoxicity studies. Fertility studies have been conducted in rats and monkeys given subcutaneous daily doses of histrelin acetate up to 180 mcg/kg/day (up to 13 and 30 times human exposure, respectively using body surface area comparisons, based on a 65 mcg/day human dose) for 6 months and full reversibility of fertility suppression was demonstrated. The development and reproductive performance of offspring from parents treated with histrelin acetate has not been investigated. # Clinical Studies - The efficacy of Histrelin in children with CPP has been evaluated in two single-arm, open label studies. Study 1 was conducted in 11 pretreated female patients, 3.7 to 11.0 years of age. Study 2 was conducted in 36 patients (33 females and 3 males), 4.5 to 11.6 years of age. Sixteen pretreated and 20 treatment-naïve patients were enrolled in Study 2. Baseline patient characteristics were typical of patients with CPP. Efficacy assessments were similar in both studies and included endpoints that measured the suppression of gonadotropins (luteinizing hormone and follicle stimulating hormone) and gonadal sex steroids (estrogen in girls and testosterone in boys, respectively) on treatment. Other assessments were clinical (evidence of stabilization or regression of signs of puberty) or gonadal steroid-dependent (bone age, linear growth). In Study 2, the primary measure of efficacy was LH suppression. - In Study 2, suppression of LH was induced in all treatment naïve subjects and maintained in all pretreated subjects at Month 1 after implantation and continued through Month 12 (suppression was defined as a peak LH < 4 mIU/mL following stimulation with the GnRH analog leuprolide acetate). - Secondary efficacy hormone assessments (FSH, estradiol and testosterone) and additional efficacy assessments (bone age advancement, linear growth, clinical progression of puberty) indicated stabilization of disease. Estradiol suppression was present in all 33 girls (100%) through Month 9 and 97% at Month 12. Testosterone suppression was maintained in the three pre-treated males participating in Study 2. The Histrelin effect on efficacy endpoints in the Study 1 was consistent with that observed in Study 2. # How Supplied - UPPRELIN LA (NDC 67979-002-01) is supplied in a corrugated shipping carton that contains 2 inner cartons: a small one for the vial containing the Histrelin implant, which is shipped with a cold pack inside a polystyrene cooler that must be refrigerated upon arrival, and a larger one comprising the Implantation Kit, which must not be refrigerated, for use during insertion or removal of Histrelin. - The Histrelin implant contains 50 mg of histrelin acetate. The Histrelin implant carton contains a cold pack for refrigerated shipment and a small carton containing an amber plastic pouch. Inside the pouch is a glass vial with a Teflon-coated stopper and an aluminum seal, containing the implant in 2 mL of sterile 1.8% sodium chloride solution. (Note: the 3.5 mL vial is not completely filled with saline). ## Storage Histrelin is stable when stored refrigerated, in its sealed vial, pouch, and carton, at 2-8 °C (36-46 °F) until the expiration date provided. Excursion permitted to 25 °C (77 °F) for 7 days. Do not freeze. Protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Histrelin Patient Counseling Information in the drug label. # Precautions with Alcohol - Alcohol-Histrelin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Suprelin LA # Look-Alike Drug Names There is limited information regarding Histrelin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Histrelin
9d626447d320baaf6e022cd771670ca9a90a3056	wikidoc	Holocrine	Holocrine Holocrine is a classification of exocrine glands in the study of Histology. Holocrine secretions are produced within the cell followed by the rupture of the plasma membrane, thus releasing the cellular contents into the lumen. Examples of holocrine glands include the sebaceous glands of the skin and the meibomian glands of the eyelid. The sebaceous gland is an example of a holocrine gland, because its product of secretion (sebum) is released with remnants of dead cells.	Holocrine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-632-7753 Holocrine is a classification of exocrine glands in the study of Histology. Holocrine secretions are produced within the cell followed by the rupture of the plasma membrane, thus releasing the cellular contents into the lumen. Examples of holocrine glands include the sebaceous glands of the skin and the meibomian glands of the eyelid. The sebaceous gland is an example of a holocrine gland, because its product of secretion (sebum) is released with remnants of dead cells. # External links - Diagram at uwa.edu.au Template:Glands Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Holocrine
d6fab8fa0cc8d45a9cc5d3b7feda5f84d6c3120a	wikidoc	Home care	Home care # Overview Home care, also known as domiciliary care, is health care provided in the patient's home by healthcare professionals (often referred to as home health care or formal care; in the United States, it is known as skilled care) or by family and friends (also known as caregivers, primary caregiver, or voluntary caregivers who give informal care). Often, the term home care is used to distinguish non-medical care or custodial care, which is care that is provided by persons who are not nurses, doctors, or other licensed medical personnel, whereas the term home health care, refers to care that is provided by such licensed personnel. # Concept (The following definition is applicable in United States and United Kingdom.) Home Care and Home Health Care are phrases that are used interchangeably in the United States, by both laypersons and professionals, to mean any type of care given to a person in their own home. Both phrases are used interchangeably regardless of whether the person requires Skilled Care by professionals or not. Home care aims to enable people to remain at home rather than use residential, long-term, or institutional-based nursing care. Care workers visit service users (patients) in the person's own home to help with daily tasks such as getting up, going to bed, dressing, toileting, personal hygiene, some household tasks, shopping, cooking and supervision of medication. There may be differences in other countries about types of services delivered. In the United States, a Home Care Patient might receive care from Home Health Aide workers only; or a combination of Skilled Services by a Licensed Professional and Home Health Aide workers. From the description of services for the United Kingdom, there are apparently large differences in the number of visits to a patient in the home (In the description below, care is given twice daily in the United Kingdom.) In the U.S., workers visit the home on a schedule determined in part by a Licensed Physician and in part by the type of insurance a patient has. Visits range from a few days a week, to every day. Visits are at minimum 2 hours' duration, but can range up to around-the-clock service in the U.S. (generally the longer hours are split between 2 or more workers). # In the United States While there are differences in terms used in describing aspects of Home Care or Home Health Care in the United States and other areas of the world, for the most part the descriptions are very similar. Estimates for the U.S. indicate that most home care is of the informal variety with families and friends providing substantial amounts of care, including very high tech kinds of care as well as simpler assistance with bathing or dressing. For formal care, the health care professionals most often involved are nurses followed by physical therapists and home care aides. Other health care providers include respiratory and occupational therapists, medical social workers and mental health workers. Physicians may perform home visits also. To find such a physician, contact the American Academy of Home Care Physicians (AAHCP). In the U.S., home health care is generally paid for by private employer-sponsored health insurance or public payers (Medicare and Medicaid), or by private-pay (paid with the family's or patient's own resources). ## ADLs and IADLs Activities of daily living (ADL) refers to six activities (bathing, dressing, transferring, using the toilet room, eating, and walking) that reflect the patient's capacity for self-care. The patient's need for assistance with these activities for the Study mentioned was measured by the receipt of help from agency staff at the time of the survey (for current patients) or the last time service was provided prior to discharge (for discharges). Help that a patient may receive from persons that are not staff of the agency (for example, family members, friends, or individuals employed directly by the patient and not by the agency) was not included in the Study. Instrumental activities of daily living (IADL) refers to six daily tasks (light housework, preparing meals, taking medications, shopping for groceries or clothes, using the telephone, and managing money) that enables the patient to live independently in the community. The patient's need for assistance with these activities was measured in the Study by the receipt of help from agency staff at the time of the survey (for current patients) or the last time service was provided prior to discharge (for discharges). Help that a patient may have received from persons who are not staff of the agency (for example, family members, friends, or individuals employed directly by the patient and not by the agency) was not included in this Study. Most agencies do not provide transportation, such as to doctor's offices. Workers can do errands for the patient though. ## Licensure and providers in Florida Florida is a Licensure State which requires different levels of licensing depending upon the services provided. Companion assistance is provided by a Home Maker Companion Agency whereas Nursing Services and assistance with ADL's can be provided by a Home Health Agency or Nurse Registry. The State licensing authority is the Agency for Health Care Administration (AHCA)AHCA. ## Aide worker qualifications Entry-level qualifications in the USA require workers to have a High School Education or GED and some agencies require 1 year experience, and must pass a competency test. Competency implies the worker has knowledge of home and patient safety, ability to safely deliver personal care, proper use of assistive equipment (wheelchair, walker, cane, crutches, mechanical lifts, etc.), food preparation, care of the home, sanitary conditions, etc. Workers need to also display the ability to observe and report to the nurse any changes in the patient's overall condition. Many of the duties of home care workers involve good common sense also. Often workers have had experience in a Nursing Home (institutional care) prior to being hired in a home care agency. Workers can take an examination to become a State tested Certified Nursing Assistant (CNA) and be included in a State Registry. Other requirements in the U.S.A. include a background check (police check with finger-printing), drug testing, general references and applicant interview. There is no specialization of workers for particular types of patients, but employees receive individual instruction (usually by the Registered Nurse) as needed for specialized patient care. ## Compensation In the United States, registered nurses employed in the home care field receive on average around $22.00 to $30.00 per visit. Payment / reimbursement of other Skilled Services vary according to the specific discipline. Home Health Aides are paid between $5.15 (current minimum wage) to approximately $12.00 per hour. Wages vary considerably by geographic region. These workers do not usually have any kind of benefits offered. They do not receive paid vacations, nor sick days. Currently there is high turn-over and frequent call-offs or no-shows by workers in the home health care / home care field. Obviously, the agencies' fees are substantially higher, but traditionally reimbursement by State, Federal, or private insurance is lower than the charges billed. Agencies must pay for office and overhead, office staff, professional and non-professional salaries and must pay into the Worker's Compensation fund, etc. # Recent Supreme Court case: Coke v. Long Island Home Care For years, home care work has been selectively classified as a “companionship service” and exempted from federal overtime and minimum wage rules under the Fair Labor Standards Act (FSLA). This April, the Supreme Court considered arguments on the companionship exemption, which stems from a case brought by a home care worker represented by counsel provided by SEIU. The original 2003 case, Evelyn Coke v. Long Island Care at Home, Ltd. and Maryann Osborne, argues that agency-employed home caregivers should be covered under overtime and minimum wage regulations. Evelyn Coke, a home care worker employed by a home care agency that was not paying her overtime, sued the agency in 2003, alleging that the regulation construing the “companionship services” exemption to apply to agency employees and exempt them from the federal minimum wage and overtime law is inconsistent with the law. The case has wound its way through the appeals process, and in January, the Supreme Court decided to hear the case this spring. In the court decision, the court stated the Fair Labor Standards Amendments of 1974 exempted from the minimum wage and maximum hours rules of the FSLA persons "employed in domestic service employment to provide companionship services for individuals . . . unable to care for themselves." 29 U. S. C. §213(a)(15). The court found that the DOL's power to administer a congressionally created program necessarily requires the making of rules to fill any 'gap' left, implicitly or explicitly, by Congress, and when that agency fills that gap reasonably, it is binding. In this case, one of the gaps was whether to include workers paid by third parties in the exemption and the DOL has done that. Since the DOL has followed public notice procedure, and since there was gap left in the legislation, the DOL's regulation stands and home health care workers are not covered by either minimum wage or overtime pay requirements. # 2004 Study by NIHS In February 2004, the National Center for Health Statistics (NIHS) conducted the "National Home and Hospice Study," which was updated in 2005. The data was collected on about approximately 1.3+ million (1,355,300) persons receiving home care in the USA. Of that total, almost 30% (29.5% or 400,100 persons) were under 65 years of age, while the majority, almost 70%, were over 65 years old (70.5% or 955,200 persons). The 2005 chart data of estimates based on interviews with non-institutionalized citizens, however, shows a relatively stable number of about 6 to 7 percent of adults age 65 who needed help for personal care (ADLs) - this has remained about the same between 1997 and 2004. (Data has a 95% reliability.) Those aged 85 or older were at least 6 times more likely (20.6%) to need ADL assistance than those of age 65. Between age 65 and 85 years, more women than men needed help. To review the 2005 Early Release data used, visit the NCHS-NHIS website to see the PDF files. Again, the 1998-2005 data is specific for over 65 or older and does not include any data for adults under 65 years old. In the 2004 data, just over 30% (30.2 % or 385,500) of the total 1.3+million persons lived alone, but the study did not break this down by age groups. A large portion, 1,094,900 or 80.8% had a primary caregiver, and almost 76% (75.9% or 831,100 lived with the primary caregiver, typically the spouse, child or child-in-law, other relative or parent, in that order. (Paid help and the category of neighbor/friend/ or unknown caregiver would be, for the majority, were living with non-family (4.3%) or unknown living arrangement .) Most patients still need external help, even if the primary caregiver is a spouse. A total of 600,900 persons received personal care. ## Payment described in the 2004 study Page 4 of the study describes the population break-down by type of payment used. Of the 1.3+ million: 710,000 paid by Medicare - Medicare often is the primary billing source, if this is the primary carrier between two types of insurance (like between Medicare and Medicaid). Also, if a patient has Medicare and that patient has a "skilled need" requiring nursing visits, the patient's case is typically billed under Medicare. 277,000 paid by Medicaid - This number seems low for Community Based Services (CBS) or Home Care (HC), especially as a nationwide statistic. 235,000 paid by private insurance, or self/family - Private insurance includes VA (Veterans Administration), some Railroad or Steelworkers health plans or other private insurance. "Self/family" indicates "private pay" status, when the patient or family pays 100% of all home care charges. Home care fees can be quite high; few patients & families can absorb these costs for a long period of time. 133,200 all other payments - including patients unable to pay, or who had no charge for care, or those whose payment "source not yet determined or approved." Sometimes after "opening a case" (the formal paperwork process of admitting a patient to home care services, there can be a short period of time when the office has not yet received approval by one of two or more insurances held by the patient. This is not unusual. There can also be cases where the office must make phone calls to be sure a particular diagnosis is "covered" by the patient's primary insurance. This is not unusual. These delays explain, in part, a couple circumstances where payment source would be listed as "unknown." # CBLTC expenditures Community-Based Long Term Care (CBLTC) is the newer name for Home Health Care Services paid by States' Medicaid programs. Most of these programs have a category called 'Medicaid Waiver' to define level of care being delivered. The Study "Medicaid Home and Community-Based Long Term Care – Trends in the U.S. and Maryland" funded by the National Institute of Disability and Rehabilitation Research, Department of Education, Information Brokering for Long Term Care, The Robert Wood Johnson Foundation, focused on expenditures. In this study, the Medicaid Waiver Expenditures by Recipient Group in 2001 based on total expenditure of $14,218,236,802 was broken down in this manner of actual spending (presumably this is based on nationwide figures): - MR/DD 74% - Aged/Disabled 17% - Disabled/Phy. Disabled 4% - Aged 3% - Children 1% - TBI/Head Injury 1% - AIDS < 1% - Mental Health <1% (less than 1%) But, the same report included figures on "Participants by Recipient Type" in 2001 based on a total number of 832,915. Participant types were broken down thus (presumably this is based on nationwide figures): - Aged/Disabled 41% - MR/DD 39% - Aged 11% - Disabled /Phy. Disabled 5% - AIDS 2% - Children 1% - TBI/Head Injury 1% - Mental Health <1% (less than 1%) This data would be interpreted that the MR/DD population represents 39% of the study population of 832,915, and this population used 74% of the available resources of the total expenditure of $14,218,236,802. The aged/disabled population had a higher number of patients in need at 41%, but only had 17% of the total dollar expenditure. The Disabled/Physically Disabled Group (presumably minus the aged in the statistics given - but this group was not well defined in this study's report, as to age etc.), represented 5% of the population and used just 4% of allocated funding. Adding the Aged/Disabled with those of "Disabled/Physically Disabled," the total group would represent 45% in population which used just 22% of funding. Again, the 39% MR/DD used 74%, more than three times higher than the larger group of disabled citizens. # In the United Kingdom ## Home care providers Homecare is purchased by the service user directly from independent home care agencies or as part of the statutory responsibility of social services departments of local authorities who either provide care by their own employees or commission services from independent agencies. Care is usually provided once or twice a day with the aim of keeping frail or disabled people healthy and independent though can extend to full-time help by a live-in nurse or carer. ## United Kingdom Home Care Association Domiciliary care providers in the UK are able to join the United Kingdom Homecare Association (UKHCA), which is the professional association of domiciliary care providers in the independent, voluntary, not for profit and statutory sectors. The Association represents the views of over 1,540 home care providers, each of which agrees to abide by the UKHCA Code of Practice. UKHCA is often a point of contact for members of the public who wish to contact home care providers in their local area. ## Statutory Regulation Home care agencies are regulated by statutory bodies in three of the four home nations. The regulator's function is to ensure that home care agencies work within the applicable legislation: ### England - Regulator: The Commission for Social Care Inspection (CSCI) - The Care Standards Act 2000 - The Domiciliary Care Agency Regulations 2002 ### Wales - Regulator: The Care Standards Inspectorate for Wales (CSIW) - The Care Standards Act 2000 - The Domiciliary Care Agencies (Wales) Regulations 2004 ### Scotland - Regulator: The Care Commission - The Regulation of Care (Scotland) Act 2001 ### Northern Ireland - There is no statutory regulation of domiciliary care at the time of writing (July 2005) although draft legislation is currently under consideration. ## Aids to daily living An aids-to-daily-living (ADL) product is any product that helps persons with temporary or permanent disabilities perform everyday activities such as bathing, eating, and dressing. Some of the ADL product categories are: - Dressing aids - Reachers, grabbers, and knobs - Medicine dropper and spoons - Reading accessories - Bathroom products (raised toilet seats, shower stools, hand-held showers, etc.) - Transfer benches - Eating utensils - Grab bars and safety rails - Pill crushers and cutters - Playing cards and accessories - Bedroom products (beds, overbed tables, pads, etc.) - Step stools	Home care Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Home care, also known as domiciliary care, is health care provided in the patient's home by healthcare professionals (often referred to as home health care or formal care; in the United States, it is known as skilled care) or by family and friends (also known as caregivers, primary caregiver, or voluntary caregivers who give informal care). Often, the term home care is used to distinguish non-medical care or custodial care, which is care that is provided by persons who are not nurses, doctors, or other licensed medical personnel, whereas the term home health care, refers to care that is provided by such licensed personnel. # Concept (The following definition is applicable in United States and United Kingdom.) Home Care and Home Health Care are phrases that are used interchangeably in the United States, by both laypersons and professionals, to mean any type of care given to a person in their own home. Both phrases are used interchangeably regardless of whether the person requires Skilled Care by professionals or not. Home care aims to enable people to remain at home rather than use residential, long-term, or institutional-based nursing care. Care workers visit service users (patients) in the person's own home to help with daily tasks such as getting up, going to bed, dressing, toileting, personal hygiene, some household tasks, shopping, cooking and supervision of medication. There may be differences in other countries about types of services delivered. In the United States, a Home Care Patient might receive care from Home Health Aide workers only; or a combination of Skilled Services by a Licensed Professional and Home Health Aide workers. From the description of services for the United Kingdom, there are apparently large differences in the number of visits to a patient in the home (In the description below, care is given twice daily in the United Kingdom.) In the U.S., workers visit the home on a schedule determined in part by a Licensed Physician and in part by the type of insurance a patient has. Visits range from a few days a week, to every day. Visits are at minimum 2 hours' duration, but can range up to around-the-clock service in the U.S. (generally the longer hours are split between 2 or more workers). # In the United States While there are differences in terms used in describing aspects of Home Care or Home Health Care in the United States and other areas of the world, for the most part the descriptions are very similar. Estimates for the U.S. indicate that most home care is of the informal variety with families and friends providing substantial amounts of care, including very high tech kinds of care as well as simpler assistance with bathing or dressing. For formal care, the health care professionals most often involved are nurses followed by physical therapists and home care aides. Other health care providers include respiratory and occupational therapists, medical social workers and mental health workers. Physicians may perform home visits also. To find such a physician, contact the American Academy of Home Care Physicians (AAHCP). In the U.S., home health care is generally paid for by private employer-sponsored health insurance or public payers (Medicare and Medicaid), or by private-pay (paid with the family's or patient's own resources). ## ADLs and IADLs Activities of daily living (ADL) refers to six activities (bathing, dressing, transferring, using the toilet room, eating, and walking) that reflect the patient's capacity for self-care. The patient's need for assistance with these activities for the Study mentioned was measured by the receipt of help from agency staff at the time of the survey (for current patients) or the last time service was provided prior to discharge (for discharges). Help that a patient may receive from persons that are not staff of the agency (for example, family members, friends, or individuals employed directly by the patient and not by the agency) was not included in the Study. Instrumental activities of daily living (IADL) refers to six daily tasks (light housework, preparing meals, taking medications, shopping for groceries or clothes, using the telephone, and managing money) that enables the patient to live independently in the community. The patient's need for assistance with these activities was measured in the Study by the receipt of help from agency staff at the time of the survey (for current patients) or the last time service was provided prior to discharge (for discharges). Help that a patient may have received from persons who are not staff of the agency (for example, family members, friends, or individuals employed directly by the patient and not by the agency) was not included in this Study. Most agencies do not provide transportation, such as to doctor's offices. Workers can do errands for the patient though. ## Licensure and providers in Florida Florida is a Licensure State which requires different levels of licensing depending upon the services provided. Companion assistance is provided by a Home Maker Companion Agency whereas Nursing Services and assistance with ADL's can be provided by a Home Health Agency or Nurse Registry. The State licensing authority is the Agency for Health Care Administration (AHCA)AHCA. ## Aide worker qualifications Entry-level qualifications in the USA require workers to have a High School Education or GED and some agencies require 1 year experience, and must pass a competency test. Competency implies the worker has knowledge of home and patient safety, ability to safely deliver personal care, proper use of assistive equipment (wheelchair, walker, cane, crutches, mechanical lifts, etc.), food preparation, care of the home, sanitary conditions, etc. Workers need to also display the ability to observe and report to the nurse any changes in the patient's overall condition. Many of the duties of home care workers involve good common sense also. Often workers have had experience in a Nursing Home (institutional care) prior to being hired in a home care agency. Workers can take an examination to become a State tested Certified Nursing Assistant (CNA) and be included in a State Registry. Other requirements in the U.S.A. include a background check (police check with finger-printing), drug testing, general references and applicant interview. There is no specialization of workers for particular types of patients, but employees receive individual instruction (usually by the Registered Nurse) as needed for specialized patient care. ## Compensation In the United States, registered nurses employed in the home care field receive on average around $22.00 to $30.00 per visit. Payment / reimbursement of other Skilled Services vary according to the specific discipline. Home Health Aides are paid between $5.15 (current minimum wage) to approximately $12.00 per hour. Wages vary considerably by geographic region. These workers do not usually have any kind of benefits offered. They do not receive paid vacations, nor sick days. Currently there is high turn-over and frequent call-offs or no-shows by workers in the home health care / home care field. Obviously, the agencies' fees are substantially higher, but traditionally reimbursement by State, Federal, or private insurance is lower than the charges billed. Agencies must pay for office and overhead, office staff, professional and non-professional salaries and must pay into the Worker's Compensation fund, etc. # Recent Supreme Court case: Coke v. Long Island Home Care For years, home care work has been selectively classified as a “companionship service” and exempted from federal overtime and minimum wage rules under the Fair Labor Standards Act (FSLA). This April, the Supreme Court considered arguments on the companionship exemption, which stems from a case brought by a home care worker represented by counsel provided by SEIU. The original 2003 case, Evelyn Coke v. Long Island Care at Home, Ltd. and Maryann Osborne, argues that agency-employed home caregivers should be covered under overtime and minimum wage regulations. Evelyn Coke, a home care worker employed by a home care agency that was not paying her overtime, sued the agency in 2003, alleging that the regulation construing the “companionship services” exemption to apply to agency employees and exempt them from the federal minimum wage and overtime law is inconsistent with the law. The case has wound its way through the appeals process, and in January, the Supreme Court decided to hear the case this spring. In the court decision, the court stated the Fair Labor Standards Amendments of 1974 exempted from the minimum wage and maximum hours rules of the FSLA persons "employed in domestic service employment to provide companionship services for individuals . . . unable to care for themselves." 29 U. S. C. §213(a)(15). The court found that the DOL's power to administer a congressionally created program necessarily requires the making of rules to fill any 'gap' left, implicitly or explicitly, by Congress, and when that agency fills that gap reasonably, it is binding. In this case, one of the gaps was whether to include workers paid by third parties in the exemption and the DOL has done that. Since the DOL has followed public notice procedure, and since there was gap left in the legislation, the DOL's regulation stands and home health care workers are not covered by either minimum wage or overtime pay requirements. # 2004 Study by NIHS In February 2004, the National Center for Health Statistics (NIHS) conducted the "National Home and Hospice Study," which was updated in 2005. The data was collected on about approximately 1.3+ million (1,355,300) persons receiving home care in the USA. Of that total, almost 30% (29.5% or 400,100 persons) were under 65 years of age, while the majority, almost 70%, were over 65 years old (70.5% or 955,200 persons). The 2005 chart data of estimates based on interviews with non-institutionalized citizens, however, shows a relatively stable number of about 6 to 7 percent of adults age 65 who needed help for personal care (ADLs) - this has remained about the same between 1997 and 2004. (Data has a 95% reliability.) Those aged 85 or older were at least 6 times more likely (20.6%) to need ADL assistance than those of age 65. Between age 65 and 85 years, more women than men needed help. To review the 2005 Early Release data used, visit the NCHS-NHIS website to see the PDF files. [NOTE: * The 2005 data reflects data, still between 6 to 7%, is only based on interviews conducted between January to June 2005, so it remains to be seen whether the figure remained constant or changed through the end of 2005.] Again, the 1998-2005 data is specific for over 65 or older and does not include any data for adults under 65 years old. In the 2004 data, just over 30% (30.2 % or 385,500) of the total 1.3+million persons lived alone, but the study did not break this down by age groups. A large portion, 1,094,900 or 80.8% had a primary caregiver, and almost 76% (75.9% or 831,100 lived with the primary caregiver, typically the spouse, child or child-in-law, other relative or parent, in that order. (Paid help and the category of neighbor/friend/ or unknown caregiver would be, for the majority, were living with non-family (4.3%) or unknown living arrangement .) Most patients still need external help, even if the primary caregiver is a spouse. A total of 600,900 persons received personal care. ## Payment described in the 2004 study Page 4 of the study describes the population break-down by type of payment used. Of the 1.3+ million: 710,000 paid by Medicare - Medicare often is the primary billing source, if this is the primary carrier between two types of insurance (like between Medicare and Medicaid). Also, if a patient has Medicare and that patient has a "skilled need" requiring nursing visits, the patient's case is typically billed under Medicare. 277,000 paid by Medicaid - This number seems low for Community Based Services (CBS) or Home Care (HC), especially as a nationwide statistic. 235,000 paid by private insurance, or self/family - Private insurance includes VA (Veterans Administration), some Railroad or Steelworkers health plans or other private insurance. "Self/family" indicates "private pay" status, when the patient or family pays 100% of all home care charges. Home care fees can be quite high; few patients & families can absorb these costs for a long period of time. 133,200 all other payments - including patients unable to pay, or who had no charge for care, or those whose payment "source not yet determined or approved." Sometimes after "opening a case" (the formal paperwork process of admitting a patient to home care services, there can be a short period of time when the office has not yet received approval by one of two or more insurances held by the patient. This is not unusual. There can also be cases where the office must make phone calls to be sure a particular diagnosis is "covered" by the patient's primary insurance. This is not unusual. These delays explain, in part, a couple circumstances where payment source would be listed as "unknown." # CBLTC expenditures Community-Based Long Term Care (CBLTC) is the newer name for Home Health Care Services paid by States' Medicaid programs. Most of these programs have a category called 'Medicaid Waiver' to define level of care being delivered. The Study "Medicaid Home and Community-Based Long Term Care – Trends in the U.S. and Maryland" funded by the National Institute of Disability and Rehabilitation Research, Department of Education, Information Brokering for Long Term Care, The Robert Wood Johnson Foundation, focused on expenditures. In this study, the Medicaid Waiver Expenditures by Recipient Group in 2001 based on total expenditure of $14,218,236,802 was broken down in this manner of actual spending (presumably this is based on nationwide figures): - MR/DD 74% - Aged/Disabled 17% - Disabled/Phy. Disabled 4% - Aged 3% - Children 1% - TBI/Head Injury 1% - AIDS < 1% - Mental Health <1% (less than 1%) But, the same report included figures on "Participants by Recipient Type" in 2001 based on a total number of 832,915. Participant types were broken down thus (presumably this is based on nationwide figures): - Aged/Disabled 41% - MR/DD 39% - Aged 11% - Disabled /Phy. Disabled 5% - AIDS 2% - Children 1% - TBI/Head Injury 1% - Mental Health <1% (less than 1%) This data would be interpreted that the MR/DD population represents 39% of the study population of 832,915, and this population used 74% of the available resources of the total expenditure of $14,218,236,802. The aged/disabled population had a higher number of patients in need at 41%, but only had 17% of the total dollar expenditure. The Disabled/Physically Disabled Group (presumably minus the aged in the statistics given - but this group was not well defined in this study's report, as to age etc.), represented 5% of the population and used just 4% of allocated funding. Adding the Aged/Disabled with those of "Disabled/Physically Disabled," the total group would represent 45% in population which used just 22% of funding. Again, the 39% MR/DD used 74%, more than three times higher than the larger group of disabled citizens. # In the United Kingdom ## Home care providers Homecare is purchased by the service user directly from independent home care agencies or as part of the statutory responsibility of social services departments of local authorities who either provide care by their own employees or commission services from independent agencies. Care is usually provided once or twice a day with the aim of keeping frail or disabled people healthy and independent though can extend to full-time help by a live-in nurse or carer. ## United Kingdom Home Care Association Domiciliary care providers in the UK are able to join the United Kingdom Homecare Association (UKHCA), which is the professional association of domiciliary care providers in the independent, voluntary, not for profit and statutory sectors. The Association represents the views of over 1,540 home care providers, each of which agrees to abide by the UKHCA Code of Practice. UKHCA is often a point of contact for members of the public who wish to contact home care providers in their local area. ## Statutory Regulation Home care agencies are regulated by statutory bodies in three of the four home nations. The regulator's function is to ensure that home care agencies work within the applicable legislation: ### England - Regulator: The Commission for Social Care Inspection (CSCI) - The Care Standards Act 2000 - The Domiciliary Care Agency Regulations 2002 ### Wales - Regulator: The Care Standards Inspectorate for Wales (CSIW) - The Care Standards Act 2000 - The Domiciliary Care Agencies (Wales) Regulations 2004 ### Scotland - Regulator: The Care Commission - The Regulation of Care (Scotland) Act 2001 ### Northern Ireland - There is no statutory regulation of domiciliary care at the time of writing (July 2005) although draft legislation is currently under consideration. ## Aids to daily living An aids-to-daily-living (ADL) product is any product that helps persons with temporary or permanent disabilities perform everyday activities such as bathing, eating, and dressing. Some of the ADL product categories are: - Dressing aids - Reachers, grabbers, and knobs - Medicine dropper and spoons - Reading accessories - Bathroom products (raised toilet seats, shower stools, hand-held showers, etc.) - Transfer benches - Eating utensils - Grab bars and safety rails - Pill crushers and cutters - Playing cards and accessories - Bedroom products (beds, overbed tables, pads, etc.) - Step stools	https://www.wikidoc.org/index.php/Home_care
99bf092266f0d597ea38b60407f39f8f67d5619d	wikidoc	Homokaasu	Homokaasu Homokaasu (Finnish name, literally gay (homosexual) - gas) is a fictitious poisonous chemical substance, that is supposedly an odorless and invisible gas at room temperature. It is a Finnish urban legend, and is often the subject of running gags on Finnish Usenet newsgroups. # Conspiracy theory Homokaasu is supposedly used on specific people by secret agents of the Roman Catholic Church to gain a subliminal control of the victims. The substance is usually leaked into rooms and areas in which the victim spends time – the home, workplace and psychiatric wards, for example. It also may be mixed in foodstuffs and beverages to the same effect. The concept of homokaasu was introduced to the public in a series of controversial reports distributed in Helsinki, Copenhagen and Los Angeles in the 1980s. The reports themselves claim to have been written and distributed by an alleged victim of the supposed operation. The reports contemplate the motives, mentioning that the Roman Catholic Church might be attempting to convert the victims to homosexuality. ## Effects Regular exposure supposedly makes social interaction difficult for the victim. Regular exposure also has various health-related effects on the victim, such as deterioration of eye-sight and hearing, diarrhoea and aches in various parts of the body. These symptoms supposedly disappear soon after the exposure has been discontinued. In addition to the symptoms above, the victim is supposedly harassed in various ways. They experience for example constant re-occurrence of accidents and near-misses, and abnormal sexually charged encounters of various degrees. The name (gay-gas) originates from the suppression of social interaction and the abnormal sexual encounters arranged in the operation. # Cultural impact Homokaasu is a widespread in-joke among Finnish net-users, and the homokaasu legend is the origin of the name of the Finland-based web community called "The Sect of Homokaasu". Moreover, there are recurring references to the homokaasu legend on the web pages of known Finnish Internet personalities, notably Niilo Paasivirta. The legend itself was created by an obviously paranoid person spreading tracts about homokaasu. Nevertheless, it is widely perceived as both hilarious and bizarrely original, and it has persisted in Finnish Internet folklore. Coincidentally, a Gay bomb conceptually reminiscent of homokaasu has also been investigated by the US military.	Homokaasu Homokaasu (Finnish name, literally gay (homosexual) - gas) is a fictitious poisonous chemical substance, that is supposedly an odorless and invisible gas at room temperature. It is a Finnish urban legend, and is often the subject of running gags on Finnish Usenet newsgroups. # Conspiracy theory Homokaasu is supposedly used on specific people by secret agents of the Roman Catholic Church to gain a subliminal control of the victims. The substance is usually leaked into rooms and areas in which the victim spends time – the home, workplace and psychiatric wards, for example. It also may be mixed in foodstuffs and beverages to the same effect. The concept of homokaasu was introduced to the public in a series of controversial reports distributed in Helsinki, Copenhagen and Los Angeles in the 1980s. The reports themselves claim to have been written and distributed by an alleged victim of the supposed operation. The reports contemplate the motives, mentioning that the Roman Catholic Church might be attempting to convert the victims to homosexuality. ## Effects Regular exposure supposedly makes social interaction difficult for the victim. Regular exposure also has various health-related effects on the victim, such as deterioration of eye-sight and hearing, diarrhoea and aches in various parts of the body. These symptoms supposedly disappear soon after the exposure has been discontinued. In addition to the symptoms above, the victim is supposedly harassed in various ways. They experience for example constant re-occurrence of accidents and near-misses, and abnormal sexually charged encounters of various degrees. The name (gay-gas) originates from the suppression of social interaction and the abnormal sexual encounters arranged in the operation. # Cultural impact Homokaasu is a widespread in-joke among Finnish net-users, and the homokaasu legend is the origin of the name of the Finland-based web community called "The Sect of Homokaasu". Moreover, there are recurring references to the homokaasu legend on the web pages of known Finnish Internet personalities, notably Niilo Paasivirta. The legend itself was created by an obviously paranoid person spreading tracts about homokaasu. Nevertheless, it is widely perceived as both hilarious and bizarrely original, and it has persisted in Finnish Internet folklore. Coincidentally, a Gay bomb conceptually reminiscent of homokaasu has also been investigated by the US military.	https://www.wikidoc.org/index.php/Homokaasu
73fe55fe0e50d6414f18f4cbe279830237a2ae99	wikidoc	Hopanoids	Hopanoids Hopanoids are pentacyclic compounds similar to sterols, whose primary function is to improve plasma membrane fluidity in prokaryotes. Cholesterol serves a similar function in eukaryotes (including humans). This relationship between biochemical structure and cellular function can be seen in the similarity of the basic structures of diploptene, a hopanoid compound found in some prokaryotic cell membranes, and cholesterol, a sterol compound found in eukaryotic membranes (I, II, and III in images at right). Hopanoid molecules, including particular types of hopanoid (2-alpha-methylhopanes) from photosynthetic bacteria (cyanobacteria), were discovered by Roger Summons and colleagues as molecular fossils preserved in 2.7-billion-year-old shales from the Pilbara, Australia. The presence of abundant 2-alpha-methylhopanes preserved in these shales indicates that oxygenic photosynthesis evolved 2.7 billion years ago, well before the atmosphere became oxidizing. In many bacteria hopanoids may play important roles in the adjustment of cell membrane permeability and adaptation to extreme environmental conditions. They are formed in the aerial hyphae—spore bearing structures—of the prokaryotic soil bacteria Streptomyces, where they are thought to minimise water loss across the membrane to the air. This is a physiological adaptation not faced by most bacteria which mainly live in water, but similar adaptations are needed by eukaryotic fungi that produce aerial spore bearing hyphae. In the ethanol fermenting bacterium Zymomonas mobilis hopanoids may have a role in adaptation of cell membranes to ethanol accumulation and to temperature changes which influence membrane functions. In the actinomycete Frankia, the hopanoids in diazovesicle membranes likely restrict the entry of oxygen by making the lipid bilayer more tight and compact. Andrew H. Knoll, in Life on a Young Planet (2003), especially in Chapter 6, The Oxygen Revolution, has an authoritative and very readable account of the usefulness of hopanoid molecular fossil biomarkers in reconstruction of early evolution and geology.	Hopanoids Hopanoids are pentacyclic compounds similar to sterols, whose primary function is to improve plasma membrane fluidity in prokaryotes. Cholesterol serves a similar function in eukaryotes (including humans).[1] This relationship between biochemical structure and cellular function can be seen in the similarity of the basic structures of diploptene, a hopanoid compound found in some prokaryotic cell membranes, and cholesterol, a sterol compound found in eukaryotic membranes (I, II, and III in images at right). Hopanoid molecules, including particular types of hopanoid (2-alpha-methylhopanes) from photosynthetic bacteria (cyanobacteria), were discovered by Roger Summons and colleagues as molecular fossils preserved in 2.7-billion-year-old shales from the Pilbara, Australia.[2] The presence of abundant 2-alpha-methylhopanes preserved in these shales indicates that oxygenic photosynthesis evolved 2.7 billion years ago, well before the atmosphere became oxidizing. In many bacteria hopanoids may play important roles in the adjustment of cell membrane permeability and adaptation to extreme environmental conditions. They are formed in the aerial hyphae—spore bearing structures—of the prokaryotic soil bacteria Streptomyces, where they are thought to minimise water loss across the membrane to the air.[3] This is a physiological adaptation not faced by most bacteria which mainly live in water, but similar adaptations are needed by eukaryotic fungi that produce aerial spore bearing hyphae. In the ethanol fermenting bacterium Zymomonas mobilis hopanoids may have a role in adaptation of cell membranes to ethanol accumulation and to temperature changes which influence membrane functions. In the actinomycete Frankia, the hopanoids in diazovesicle membranes likely restrict the entry of oxygen by making the lipid bilayer more tight and compact.[4] Andrew H. Knoll, in Life on a Young Planet (2003), especially in Chapter 6, The Oxygen Revolution, has an authoritative and very readable account of the usefulness of hopanoid molecular fossil biomarkers in reconstruction of early evolution and geology.[5]	https://www.wikidoc.org/index.php/Hopanoids
3ccebf99b87cdfa31af0592242397ae7d81d1e23	wikidoc	Hordenine	Hordenine Hordenine (N,N-dimethyltyramine) is a phenylethylamine alkaloid with antibacterial and antibiotic properties. It stimulates the release of norepinephrine in higher animals. It is produced in nature by several varieties of plants in the family Cactaceae and some in Acacia. Peyote (Lophophora williamsii), San Pedro cactus (Trichocereus pachanoi), and Peruvian Torch cactus (Trichocereus peruvianus) all produce high levels of this compound. These cacti also produce high levels of mescaline and other phenylethylamine compounds. Cacti in the genus Ariocarpus, Pereskia, and Coryphantha also produce these alkaloids, though not in high concentrations. ". . .it has been shown that hordenine, N, N-Dimethyl-hydroxyphenylethylamine, exhibits an inhibitory action against at least 18 strains of penicillin resistant Staphylococcus bacteria."	Hordenine Template:Chembox new Hordenine (N,N-dimethyltyramine) is a phenylethylamine alkaloid with antibacterial and antibiotic properties. It stimulates the release of norepinephrine in higher animals. It is produced in nature by several varieties of plants in the family Cactaceae and some in Acacia.[1] Peyote (Lophophora williamsii), San Pedro cactus (Trichocereus pachanoi), and Peruvian Torch cactus (Trichocereus peruvianus) all produce high levels of this compound. These cacti also produce high levels of mescaline and other phenylethylamine compounds. Cacti in the genus Ariocarpus, Pereskia, and Coryphantha also produce these alkaloids, though not in high concentrations. ". . .it has been shown that hordenine, N, N-Dimethyl-hydroxyphenylethylamine, exhibits an inhibitory action against at least 18 strains of penicillin resistant Staphylococcus bacteria."[2]	https://www.wikidoc.org/index.php/Hordenine
b7d4f543a845a2ebf5bc921b3ed7ab04ffe5ddc1	wikidoc	Hot aches	Hot aches The hot aches is a very painfully physical reaction to the cold, most often felt in the hands or feet. When exposed to the cold, blood stops flowing normally to the extremities. Later once you warm up, the blood begins to flow again; this causes the pain known as the hot aches. Andy Cave (2005 winner of the Boardman Tasker Prize for Mountain Literature) describes it well in his award winning book Learning to Breathe: "I had the hot aches... As the blood began to creep back into my hands I bowed my head. It felt like small shards of broken glass were being hammered into my fingertips." In North America it goes by the more colourful name of the 'screaming barfies'.	Hot aches Template:WikiDoc Cardiology News Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The hot aches is a very painfully physical reaction to the cold, most often felt in the hands or feet. When exposed to the cold, blood stops flowing normally to the extremities. Later once you warm up, the blood begins to flow again; this causes the pain known as the hot aches. Andy Cave (2005 winner of the Boardman Tasker Prize for Mountain Literature) describes it well in his award winning book Learning to Breathe: "I had the hot aches... As the blood began to creep back into my hands I bowed my head. It felt like small shards of broken glass were being hammered into my fingertips." In North America it goes by the more colourful name of the 'screaming barfies'. Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Hot_aches
8b0bffc46f914e6c3578884c4ae18db514d414a2	wikidoc	Hoveround	Hoveround Hoveround is an American corporation which makes and distributes power wheelchairs and scooters. The company, founded in 1992 by Tom Kruse, is based in Sarasota, Florida. The products are sold directly to consumers, and advertised in commercials that feature Tom Kruse. Hoverhound has over 500 employees and locations in 45 US states as of 2006. Annual revenue reached $100 million in 2005. In 2005 the company began opening retail locations in Wal-Mart stores. # Notes - ↑ Kennedy, Sarah (2006-11-18). "Hoveround lays off 66 workers: President blames changes in Medicare wheelchair pricing". Bradenton Herald..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} - ↑ "Hoveround Opens Retail Location in Wal-Mart". Home Care Magazine. 2005-02-01.	Hoveround Template:AfDM Hoveround is an American corporation which makes and distributes power wheelchairs and scooters. The company, founded in 1992 by Tom Kruse, is based in Sarasota, Florida. The products are sold directly to consumers, and advertised in commercials that feature Tom Kruse. Hoverhound has over 500 employees and locations in 45 US states as of 2006. Annual revenue reached $100 million in 2005.[1] In 2005 the company began opening retail locations in Wal-Mart stores.[2] # Notes - ↑ Kennedy, Sarah (2006-11-18). "Hoveround lays off 66 workers: President blames changes in Medicare wheelchair pricing". Bradenton Herald..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} - ↑ "Hoveround Opens Retail Location in Wal-Mart". Home Care Magazine. 2005-02-01.	https://www.wikidoc.org/index.php/Hoveround
5cba926fcf79c9b48590a988f5a1fc25f20cf11e	wikidoc	Human DNA	Human DNA "uman DNA has millions of on-off switches and complex networks that control the genes' activities. ... t least 80% of the human genome is active, which opposed the previously held idea that most of the DNA are useless." "DNA contains genes, which hold the instructions for take up only about 2 percent of the genome ... The human genome is made up of about 3 billion “letters” along strands that make up the familiar double helix structure of DNA. Particular sequences of these letters form genes, which tell cells how to make proteins. People have about 20,000 genes, but the vast majority of DNA lies outside of genes. ... t least three-quarters of the genome is involved in making RNA it appears to help regulate gene activity." # Genetics There are "more than 4 million sites where proteins bind to DNA to regulate genetic function, sort of like a switch." "Humans belong to the biological group known as Primates, and are classified with the great apes, one of the major groups of the primate evolutionary tree. Besides similarities in anatomy and behavior, our close biological kinship with other primate species is indicated by DNA evidence. It confirms that our closest living biological relatives are chimpanzees and bonobos, with whom we share many traits. But we did not evolve directly from any primates living today." "DNA also shows that our species and chimpanzees diverged from a common ancestor species that lived between 8 and 6 million years ago. The last common ancestor of monkeys and apes lived about 25 million years ago." # Deoxyribonucleic acids Deoxyribonucleic acid (DNA) is a polymer composed of nucleic acids linked together by sugar-phosphate backbone. The nucleic acids are inorganic acids with phosphoric acid as the only acid. Attached to each sugar is a nucleobase. Nitrogenous bases, found in cell nuclei, are nucleobases. In normal spiral DNA the bases form pairs between the two strands: Adenine (A) with Thymine (T) and Cytosine (C) with Guanine (G). Purines pair with pyrimidines mainly for dimensional reasons - only this combination fits the constant width geometry of the DNA spiral. "The amount of difference in DNA is a test of the difference between one species and another – and thus how closely or distantly related they are." "While the genetic difference between individual humans today is minuscule – about 0.1%, on average – study of the same aspects of the chimpanzee genome indicates a difference of about 1.2%. The bonobo (Pan paniscus), which is the close cousin of chimpanzees (Pan troglodytes), differs from humans to the same degree. The DNA difference with gorillas, another of the African apes, is about 1.6%. Most importantly, chimpanzees, bonobos, and humans all show this same amount of difference from gorillas. A difference of 3.1% distinguishes us and the African apes from the Asian great ape, the orangutan. How do the monkeys stack up? All of the great apes and humans differ from rhesus monkeys, for example, by about 7% in their DNA." "Geneticists have come up with a variety of ways of calculating the percentages, which give different impressions about how similar chimpanzees and humans are. The 1.2% chimp-human distinction, for example, involves a measurement of only substitutions in the base building blocks of those genes that chimpanzees and humans share. A comparison of the entire genome, however, indicates that segments of DNA have also been deleted, duplicated over and over, or inserted from one part of the genome into another. When these differences are counted, there is an additional 4 to 5% distinction between the human and chimpanzee genomes." "No matter how the calculation is done, the big point still holds: humans, chimpanzees, and bonobos are more closely related to one another than either is to gorillas or any other primate. From the perspective of this powerful test of biological kinship, humans are not only related to the great apes – we are one. The DNA evidence leaves us with one of the greatest surprises in biology: the wall between human, on the one hand, and ape or animal, on the other, has been breached. The human evolutionary tree is embedded within the great apes." # Archaeology "About 14,000 years ago , modern humans roamed to South Florida and lived side by side with mammoths, mastodons and saber-tooth tigers." At "the Old Vero Man site large number of animal and human bones were discovered , providing a rare glimpse of the Florida landscape at the end of the last Ice Age." "Based on the fossil record, here is what many archaeologists believe: Modern humans first appeared about 195,000 years ago in East Africa. Likely chasing prey, they moved across Asia and what was then a land bridge to Alaska, arriving in North America about 20,000 to 25,000 years ago. They then took 5,000 to 6,000 years to cross the continent to Florida." "The old model basically had these folks sprinting across North America, chasing and killing big animals. We know now they moved very gradually. "They finally reached Vero Beach about 13,000 to 14,000 years ago, as the Pleistocene Epoch and the last Ice Age were drawing to an end. At the time, Florida was almost double its current size, extending out into the Gulf of Mexico and the Atlantic, and much of the state was more than 300 feet above sea level." "The landscape was so different than what it is today." "Florida also was home to tapirs, sloths, camels, bison and horses — in addition to mastodons and mammoths. Many converged at what was then an "oasis" of streams and rivers about 35 miles inland from the ocean. Today, that is the Old Vero Man site and it's about five miles inland." "It was a fairly constant source of fresh water and a tremendous draw to animals and human beings." "Growing in numbers and becoming more skilled hunters, the humans continued forging south, evidenced by the Cutler Fossil Site on the Charles Deering Estate in south Miami-Dade County. That site back almost 12,000 years " " 103 species of animals, including mammoths, a saber-tooth cat, a paleo-lama, and a California condor ." "By the time humans arrived in what is now South Florida, the Ice Age was almost over. Mastodons and their ilk were going extinct, likely because of climate change." "With ancient DNA, you're time traveling. It provides us with a unique opportunity to look into Florida's past." # Paleogene The Paleogene Period extends from 65.5 ± 0.3 to 23.03 ± 0.05 x 106 b2k. The graph above shows many of the hominins that have been discovered so far in Africa and elsewhere on Earth. # Paleocene The Paleocene dates from 65.5 ± 0.3 x 106 to 55.8 ± 0.2 x 106 b2k. # Eocene The Eocene dates from 55.8 ± 0.2 x 106 to 33.9 ± 0.1 x 106 b2k. # Oligocene The Oligocene dates from 33.9 ± 0.1 x 106 to 23.03 x 106 b2k. # Rukwapithecus Rukwapithecus is "an early member of the hominoids, the group containing the great apes (gorillas, chimpanzees, bonobos, orangutans and humans) and lesser apes (gibbons)." "The fossil remnants ... date back 25 million years ago, filling a gap in the fossil record that reveals when apes and monkeys first diverged." "These discoveries are important because they offer the earliest fossil evidence for either of these primate groups". "The fossils were found in a layer of the Rukwa Rift in Tanzania. The region is part of the East African Rift, a tectonic-plate boundary where the Earth's crust is being pulled apart." “The new discoveries are particularly important for helping to reconcile a long-standing disagreement between divergence time estimates derived from analyses of DNA sequences from living primates and those suggested by the primate fossil record.” "Studies of clock-like mutations in primate DNA have indicated that the split between apes and Old World monkeys occurred between 30 million and 25 million years ago." # Holarctic-Antarctic Ice Age "This late Cenozoic ice age began at least 30 million years ago in Antarctica; it expanded to Arctic regions of southern Alaska, Greenland, Iceland, and Svalbard between 10 and 3 million years ago. Glaciers and ice sheets in these areas have been relatively stable, more-or-less permanent features during the past few million years." # Neogene The Neogene dates from 23.03 x 106 to 2.58 x 106 b2k. # Miocene The Miocene dates from 23.03 x 106 to 5.332 x 106 b2k. # Tortonian The Tortonian lasted from 11.63 Ma to 7.246 Ma. Gigantopithecus is an extinct genus of ape that existed from perhaps nine million years to as recently as one hundred thousand years ago, at the same period as Homo erectus would have been dispersed, in what is now India, Vietnam, China and Indonesia placing Gigantopithecus in the same time frame and geographical location as several hominin species. The primate fossil record suggests that the species Gigantopithecus blacki were the largest known primates that ever lived, standing up to 3 m (9.8425197 ft) and weighing as much as 540 (Expression error: Unexpected round operator. ), although some argue that it is more likely that they were much smaller, at roughly 1.8 (Expression error: Unexpected round operator. ) in height and 180 (Expression error: Unexpected round operator. ) in weight. # Prehistory The prehistory period dates from around 7 x 106 b2k to about 7,000 b2k. # Pliocene The Pliocene ranges from 5.332 x 106 to 2.588 x 106 b2k. # Zanclean "The boundary-stratotype of the stage is located in the Eraclea Minoa section on the southern coast of Sicily (Italy), at the base of the Trubi Formation. The age of the Zanclean and Pliocene GSSP at the base of the stage is 5.33 Ma in the orbitally calibrated time scale, and lies within the lowermost reversed episode of the Gilbert Chron (C3n.4r), below the Thvera normal subchron." # Piacenzian "The base of the beige marl bed of the small-scale carbonate cycle 77 (sensu Hilgen, 1991b) is the approved base of the Piacenzian Stage (that is the Lower Pliocene-Middle Pliocene boundary). It corresponds to precessional excursion 347 as numbered from the present with an astrochronological age estimate of 3.600 Ma (Lourens et al., 1996a)." # Paleolithic The paleolithic period dates from around 2.6 x 106 b2k to the end of the Pleistocene around 12,000 b2k. # Quaternary The "whole change elapsed just opposite the course of events that characterized the great glacial oscillations with sudden warming followed by slow cooling. Therefore, the two phenomena hardly have the same cause." # Pleistocene The Pleistocene dates from 2.588 x 106 to 11,700 b2k. # Gelasian "The base of the Quaternary System is defined by the Global Stratotype Section and Point (GSSP) of the Gelasian Stage at Monte San Nicola in Sicily, Italy, currently dated at 2.58 Ma." # Calabrian "The GSSP occurs at the base of the marine claystone conformably overlying sapropelic bed ‘e’ within Segment B in the Vrica section. This lithological level represents the primary marker for the recognition of the boundary, and is assigned an astronomical age of 1.80 Ma on the basis of sapropel calibration." # Homo erectus ""Peking Man," a human ancestor who lived in China between roughly 200,000 and 750,000 years ago, was a wood-working, fire-using, spear-hafting hominid ... these hominids, a form of Homo erectus, appear to have been quite meticulous about their clothing, using stone tools to soften and depress animal hides." Peking Man Homo erectus pekinensis, is an example of Homo erectus. A group of fossil specimens was discovered in 1923–27 during excavations at Zhoukoudian (Chou K'ou-tien) near Beijing. The finds have been dated from roughly 750,000 years ago, although a new 26Al/10Be dating suggests they may be as much as 680,000–780,000 years old. Skulls X, XI and XII (sometimes called LI, LII and LIII) were discovered at Locus L in 1936. They are thought to belong to an adult man, an adult woman and a young adult, with brain sizes of 1225 cc, 1015 cc and 1030 cc respectively. The ribonucleotide reductase RRM2P4 gene data suggests that the Chinese, while largely descending from Africa like others, nevertheless have some genetic legacy from hybridization with older Eurasian populations, consistent with limited multiregional evolution. Homo erectus is an extinct species of hominid that lived from the end of the Pliocene epoch to the later Pleistocene, with the earliest first fossil evidence dating to around 1.8 million years ago and the most recent to around 300,000 years ago. The species originated in Africa and spread as far as Spain, Georgia, India, China and Java. "By the 1980s, the growing numbers of H. erectus specimens, particularly in Africa, led to the realization that Asian H. erectus (H. erectus sensu stricto), once thought so primitive, was in fact more derived than its African counterparts. These morphological differences were interpreted by some as evidence that more than one species might be included in H. erectus sensu lato (e.g., Stringer, 1984; Andrews, 1984; Tattersall, 1986; Wood, 1984, 1991a, b; Schwartz and Tattersall, 2000)." ... "Unlike the European lineage, in my opinion, the taxonomic issues surrounding Asian vs. African H. erectus are more intractable. The issue was most pointedly addressed with the naming of H. ergaster on the basis of the type mandible KNM-ER 992, but also including the partial skeleton and isolated teeth of KNM-ER 803 among other Koobi Fora remains (Groves and Mazak, 1975). Recently, this specific name was applied to most early African and Georgian H. erectus in recognition of the less-derived nature of these remains vis à vis conditions in Asian H. erectus (see Wood, 1991a, p. 268; Gabunia et al., 2000a). It should be noted, however, that at least portions of the paratype of H. ergaster (e.g., KNM-ER 1805) are not included in most current conceptions of that taxon. The H. ergaster question remains famously unresolved (e.g., Stringer, 1984; Tattersall, 1986; Wood, 1991a, 1994; Rightmire, 1998b; Gabunia et al., 2000a; Schwartz and Tattersall, 2000), in no small part because the original diagnosis provided no comparison with the Asian fossil record." From the 1950s to 1970s, however, numerous fossil finds from East Africa yielded evidence that the oldest hominins originated there. It is now believed that H. erectus is a descendant of earlier genera such as Ardipithecus and Australopithecus, or early Homo-species such as H. habilis or H. ergaster. H. habilis and H. erectus coexisted for several thousand years, and may represent separate lineages of a common ancestor. "ome of the oldest stone hand axes on Earth ... unearthed in Ethiopia ... date to 1.75 million years ago. ... fossilized H. erectus remains were also found at the same site ... These Aucheulean tools could be up to 7.8 inches (20 centimeters) long". "awbone fossils unearthed at a site east of Lake Turkana in Kenya suggest there were two additional species of ... Homo, living alongside ... Homo erectus, nearly 2 million years ago." When "excavating a cave in Balanica, Serbia, that contained ancient archaeological remains ... an ancient jawbone fragment with three molars still intact ... several dating techniques the fragment was definitely older than 397,000 years and perhaps older than 525,000 years. The jawbone lacked several characteristic Neanderthal features, including distinctive chewing surfaces on the teeth that show up in Western Europe at that time. Instead, the fossil resembled the more primitive Homo erectus. ... Neanderthals may not have evolved in this region of Southeastern Europe, at least during this time. ... during several ice ages, rising glaciers over the past eons cut off Western Europe from the rest of the continent, and this isolation likely contributed to the evolution of Neanderthals' distinctive features from the more primitive Homo erectus." "Javanese specimens of Homo erectus had brains about 860 cubic cm (52 cubic inches) large". "Researchers examined one skull from a site called the Pit of Bones, which contains the remains of at least 28 people. two fractures on that skull were likely to have been caused by "multiple blows" and imply "an intention to kill"." "As well as providing a clue as to why the bodies were in the cave, scientists say the study provides grisly evidence that violence is an intrinsic part of the earliest human culture." "This individual was killed in an act of lethal interpersonal violence." The "long vertical shaft of this cave was a place where these ancient people deliberately "deposited deceased members of their social groups"." "Intentional interpersonal violence is a behaviour that accompanies humans since at least 430,000 years ago, but so does the care of sick or even the care of the dead." "We have not changed much in the last half million years." "I suspect the farther we push back and find straight up forensic evidence such as these authors have, we will find that violence is culturally mediated and has been with us as long as culture itself has been with us." "We don’t see any Denisovan ancestry in populations living in mainland Southeast Asia, or Indonesia, or indeed in any population west of Wallace’s Line . It could be that later population movements have diluted the Denisovan taint, but it is apparently undetectable even in existing populations that are thought to represent earlier strata, such as the Andaman islanders. Nor has it been seen in ancient DNA from modern humans on the Asian mainland." "Back in the day, Indonesia was a big peninsula, called Sundaland. Let us assume that there were Denisovans there. In some way, Denisovan effective population density was higher there than in mainland Asia, or perhaps they were harder to displace. For example, some of Sundaland seems to have been tropical rainforest, otherwise known as the Green Hell – maybe there were some potent tropical diseases (vector-borne) that the Denisovans had developed resistance to, while the invading anatomical modern humans had not – the same reason that Europeans or Middle Easterners didn’t replace sub-Saharan African populations." "So modern humans expand into Sundaland more slowly, in something like a range expansion. The further they moved into Sundaland, the more Denisovan genes they picked up." "So the humans living at the eastern edge of Sundaland, particularly in Borneo, have more Denisovan ancestry in this scenario than anyone else in Eurasia – and they would be the people who take the next step, crossing the narrow seas to the Philippines, Wallacea, and then Sahul (Australia/New Guinea), virgin lands in which the hand of man had never set foot . A quite small, unusually Denisovanized coastal population of hunter-gatherers then undergoes a vast expansion, becoming as numerous as the stars in the sky." "Aboriginal skulls vary, but some look much more like archaics, more like erectus, than those from any other existing population. This was noticed a long time ago, by pros like Weidenreich." "Actually, they look surprisingly archaic, considering that total archaic ancestry among Melanesians is under 10% . Recent selective pressure are probably more important: it is possible that their archaic appearance is to some degree coincidence." “The skulls of Australian Aborigines, although variable, in some ways look more old-fashioned, more like archaics, than any other existing human population.” "The discovery of DNA in a 400,000-year-old human thigh bone comes from the famed "Pit of Bones" site in Spain, which gave up the remains of at least 28 ancient people." "The early human remains from the cave site near the northern Spanish city of Burgos have been painstakingly excavated and pieced together over the course of more than two decades. It has yielded one of the richest assemblages of human bones from this stage of human evolution, in a time called the Middle Pleistocene." "The fossils carry many traits typical of Neanderthals, and either belong to an ancestral species known as Homo heidelbergensis - or, as the British palaeoanthropologist Chris Stringer suggests - are early representatives of the Neanderthal lineage." "Rather than showing a relationship between the Spanish specimens and Neanderthals, which might be expected based on their physical features, the mitochondrial DNA was most similar to that found in 40,000 year-old material unearthed thousands of kilometres away at Denisova Cave in Siberia." "The Denisovans were a sister group to the Neanderthals, with distinct genetic characteristics. Identified only by DNA extracted from a tiny finger bone and tooth, they are, as some researchers have remarked, "a genome in search of a fossil" because there are no substantial remains representative of this group." "By using missing mutations in the old DNA sequences, the researchers calculated that the Pit of Bones individual shared a common ancestor with the Denisovans about 700,000 years ago." Interbreeding "between the Pit of Bones people (or their ancestors) and yet another early human species brought the Denisovan-like DNA into this western population. Prof Bermudez de Castro thinks there may be a candidate for this cryptic ancestor: an earlier human species known as Homo antecessor. One million years ago, antecessor inhabited the site of Gran Dolina, just a few hundred metres away from the Pit of Bones." "mtDNA is a small and unusual component of our genetic blueprint, from which only limited conclusions can be drawn. For example, no sign of the interbreeding we now know took place between Neanderthals and modern humans remains in the mtDNA of modern people." "That is our next big thing here, to sequence at least part of the nuclear genome from the individual in the Sima de los Huesos." # Homo heidelbergensis "Homo heidelbergensis is known to have lived from at least 600,000 years ago in Africa and Europe to maybe as late as 250,000 years ago in some areas." "The first fossil identified as H. heidelbergensis was a jaw discovered near Heidelberg, Germany in 1907. Since then various other finds have been made in Europe, Asia and Africa. They show a less projecting face, more prominent nose and a bigger braincase than Homo erectus, but also more primitive features than those of Neanderthals and modern humans." "Some H. heidelbergensis individuals had brain sizes within the modern human range. However, facially they still looked very different from us, with a longer, lower shaped skull, large brow ridge and no chin." "Evidence shows that H. heidelbergensis was an accomplished tool-maker and skillfully butchered large animals. The remains of horses, elephants, deer and rhinoceroses with butchery marks on their bones have been found alongside fossils of this hominin in Southern England and Germany. Whether they actively hunted the animals isn’t known. But, even if they scavenged the carcasses, these hominins were organised enough to drive off dangerous competing animals such as lions, hyenas and wolves." # Early Pleistocene Early Pleistocene spans ca. 730,000-1,600,000 yr BP. # Nebraskan glacial Nebraskan glacial spans ca. 650,000-1,000,000 yr BP. # Middle Pleistocene Middle Pleistocene spans ca. 150,000-730,000 yr BP. # Aftonian interglacial "Clay deposition in the Piauí River floodplain around 436 ± 51.5 ka occurred during a warmer period of the Aftonian interglaciation, corresponding to isotope stage 12 (Ericson and Wollin, 1968)." "Neanderthal and Homo sapiens DNA reveals that they shared a common ancestor about 400,000 years ago. Many scientists think this could have been H. heidelbergensis, giving rise to Neanderthals in Europe and to our species in Africa. And perhaps to the Denisovans in Asia." # Neanderthals "odern humans in the eastern parts of Eurasia and Native Americans actually carry more Neanderthal genetic material than people in Europe, "even though the Neanderthals mostly lived in Europe, which is really, really interesting," Reich said." From mtDNA analysis estimates, the two species shared a common ancestor about 500,000 years ago. An article appearing in the journal Nature has calculated the species diverged about 516,000 years ago, whereas fossil records show a time of about 400,000 years ago. A 2007 study pushes the point of divergence back to around 800,000 years ago. "Our work suggests that at present, it is unlikely that Neanderthals survived any later in this area than they did elsewhere in mainland Europe." "Neanderthals (or Neandertals) are our closest extinct human relatives. a subspecies . Our well-known fossil kin lived in Eurasia 200,000 to 30,000 years ago, in the Pleistocene Epoch. they used tools, buried their dead and controlled fire, among other intelligent behaviors." "Neanderthals were seen as too brutish to catch fast prey." "Neanderthals came to Europe some 300,000 years ago. They hunted big game with stone tools. Their territory spanned Europe and Asia. They left distinctive "Mousterian" artefacts." "The first analysis of mitochondrial DNA (mtDNA) from Neanderthals was published in 1997." "The specimen was taken from the first Neanderthal fossil discovered, from Feldhofer Cave, in the Neander Valley, Germany. A small sample of bone was ground up to extract mtDNA." "The Neanderthal mtDNA sequences were substantially different from modern human mtDNA (Krings et al. 1997, 1999). Researchers compared the Neanderthal to modern human and chimpanzee sequences. Most human sequences differ from each other by on average 8.0 substitutions, while the human and chimpanzee sequences differ by about 55.0 substitutions. The Neanderthal and modern human sequences differed by approximately 27.2 substitutions. Using this mtDNA information, the last common ancestor of Neanderthals and modern humans dates to approximately 550,000 to 690,000 years ago, which is about four times older than the modern human mtDNA pool. This is consistent with the idea that Neanderthals did not contribute substantially to modern human genome." "A second mtDNA sequence, announced in 2000, was derived from a 29,000 year old Neanderthal found in Mezmaiskaya Cave, Russia (Ovchinnikov et al. 2000). Although the Mezmaiskaya Cave sequence was slightly different than the Feldhofer Neanderthal, the two Neanderthal mtDNA sequences were distinct from those of modern humans. These results confirmed the earlier findings that showed that Neanderthals were unlikely to have contributed to the modern human genome. As with the previous study of Neanderthal mtDNA, results were consistent with separation between the Neanderthal and modern human gene pools or with very low amounts of gene flow between the two groups." "Researchers have also studied ancient DNA from anatomically modern Homo sapiens from Europe dating to the same time period as the Neanderthals. Material from two Paglicci Cave, Italy individuals, dated to 23,000 and 25,000 years old, was sequenced. The Paglicci Homo sapiens mtDNA sequences were different from all Neanderthal mtDNA sequences but were within the range of variation for modern human mtDNA sequences (Caramelli et al. 2003). Mitochondrial DNA from the Paglicci specimens as well as other ancient humans fit within the range of modern humans, but the Neanderthals remain consistently genetically distinct. This shows that early anatomically modern Homo sapiens were not very different genetically from current modern humans, but were still different from Neanderthals." "DNA was extracted from three Neanderthal bones from Vindija Cave, Croatia. By comparing sequences from their mtDNA and their nuclear DNA, scientists determined that the three bones came from different individuals, although two of them might be related on their mother’s side." "The Neanderthal sequence was compared to those of five modern humans from France, China, Papua New Guinea, as well as Africans from the San and Yoruba groups. Tests indicated that Neanderthals shared more derived alleles with non-African modern humans than with African modern humans. They compared parts of the Neanderthal genome with pairs of modern humans. While the European and Asian pairs had similar amounts of derived material compared with the Neanderthal, Neanderthals had more similarities with non-African humans than with Africans." "Neanderthals have contributed approximately 1% to 4% to the genomes of non-African modern humans." "Since the Neanderthal DNA was equally related to that of the modern samples from France, China and Papua New Guinea, admixture between moderns and Neanderthals must have occurred before the Eurasian populations split off from each other. Remains of both modern humans and Neanderthals dating to around 100,000 years ago have been found in the Middle East." "Researchers found 78 sequence differences that would have affected proteins in which Neanderthals had the ancestral state and modern humans had a newer, derived state. Five genes had more than one sequence change that affected the protein structure. These proteins include SPAG17, which is involved in the movement of sperm, PCD16, which may be involved in wound healing, TTF1, which is involved in ribosomal gene transcription, and RPTN, which is found in the skin, hair and sweat glands. Scientists do not know the function of the CAN15 protein, which was also one of the differences." "Nested clade phylogenetic analysis shows evidence of three expansions out of Africa at 1.9 Ma, 650,000 years, and 130,000 years, which is consistent with the admixture between ancient and modern populations rather than complete replacement (Templeton 2002, 2005, 2007)." "Ancient DNA has been used to show aspects of Neanderthal appearance. A fragment of the gene for the melanocortin 1 receptor (MRC1) was sequenced using DNA from two Neanderthal specimens from Spain and Italy, El Sidrón 1252 and Monte Lessini (Lalueza-Fox et al. 2007). Neanderthals had a mutation in this receptor gene that has not been found in modern humans. The mutation changes an amino acid, making the resulting protein less efficient. Modern humans have other MCR1 variants that are also less active resulting in red hair and pale skin. The less active Neanderthal mutation probably also resulted in red hair and pale skin, as in modern humans." "The specific MCR1 mutation in Neanderthals has not found in modern humans (or occurs extremely rarely in modern humans). This indicates that the two mutations for red hair and pale skin occurred independently and does not support the idea of gene flow between Neanderthals and modern humans. Pale skin may have been advantageous to Neanderthals living in Europe because of the ability to synthesize vitamin D." "The FOXP2 gene is involved in speech and language (Lai et al. 2001). Changes in the FOXP2 gene sequence led to problems with speech, oral and facial muscle control in modern humans with a mutation in the gene. It impairs language function. Modern humans and Neanderthals share two changes in FOXP2 compared with the sequence in chimpanzees (Krause et al. 2007)." "The gene that produces the ABO blood system is polymorphic in humans. Various selection factors may favor different alleles, leading to the maintenance of distinct blood groups in modern human populations. Though chimpanzees also have different blood groups, they are not the same as human blood types. While the mutation that causes the human B blood group arose around 3.5 Ma, the O group mutation dates to around 1.15 Ma. Lalueza-Fox and colleagues (2008) tested whether Neanderthals had the O blood group. They found that two Neanderthal specimens from Spain probably had the O blood type, though there is the possibility that they were OA or OB. Though the O allele was likely to have already appeared before the split between humans and Neanderthals, it could also have arisen in the Neanderthal genome via gene from modern humans." "The ability to taste bitter substances is controlled by a gene, TAS2R38. Some individuals are able to taste bitter substances, while others have a different version of the gene that does not allow them to taste bitter items. Possession of two copies of alleles associated with tasting bitter substances gives the individual greater perception of bitter tastes than the heterozygous state, in which individuals have one tasting allele and one non-tasting allele. Two copies of a non-tasting allele leads to inability to taste bitter substances." "A Neanderthal from El Sidrón, Spain, was sequenced for the TAS23R38 gene. They found that this individual was heterozygous and thus was able to perceive bitter taste, although not as strongly as a homozygous individual with two copies of the tasting allele would be able to (Lalueza-Fox et al. 2009). Since the Neanderthal sequenced was heterozygous, the two alleles (tasting and non-tasting) were probably both present in the common ancestor of Neanderthals and modern humans. Though chimpanzees also vary in their ability to taste bitterness, their abilities are controlled by different alleles than those found in humans, indicating that non-tasting alleles evolved separately in the hominin lineage." "The microcephalin gene relates to brain size during development. A variant of this, haplogroup D, may have been positively selected for in modern humans – and may also have come from an interbreeding event with an archaic population (Evans et al. 2006). Mutations in microcephalin cause the brain to be 3 to 4 times smaller in size. All of the haplogroup D variants come from a single copy that appeared in modern humans around 37,000 years ago. However, haplogroup D itself came from a lineage that had diverged from the lineage that led to modern humans around 1.1 million years ago. Although there was speculation that the Neanderthals were the source of the microcephalin haplogroup D (Evans et al. 2006), the Neanderthal DNA recently sequenced does not contain the microcephalin haplogroup D (Green et al. 2010)." # Homo sapiens "The first anatomically modern human fossils date back only 195,000 years ... who lived in South Carolina so distinct that his male lineage probably separated from all others about 338,000 years ago. ... similarities between Perry's and those in samples taken from 11 men, all living in one village in Cameroon. ... "The oldest known fossil humans in both West Africa at Iwo Eleru and Central Africa at Ishango show unexpectedly archaic features, so it certainly looks like we have a more complex scenario for the evolution of modern humans in Africa."" Two "teeth from the Luna cave in China's Guangxi Zhuang region on the proportions of the teeth, at least one of them must have belonged to an early Homo sapiens The teeth are clearly old. Calcite crystals, which formed as water flowed over the teeth and the cave floor, date them to between 70,000 and 125,000 years ago. they are evidence of an early wave of modern humans in eastern Asia." "I am not convinced that these teeth are diagnostic." "Bones found in Israel, including an upper jaw from Misliya cave, could be 150,000 years old." In "the identification of a jawbone and two molars from Zhirendong, a cave in Guizhou province the bone is over 100,000 years old, the shape of its chin is suggestive of modern humans." "Though the Asian fossils are Homo sapiens-like, another species could have evolved these features in parallel." The "genomes of indigenous populations from south-east Asia into a migration model. genetic data was best explained by an early exodus that left Africa around 130,000 years ago, taking a coastal route along the Arabian peninsula, India and into Australia, followed by a later wave along the classic route." # Kansan glacial Kansan glacial spans 500,000-600,000 yr BP. # Yarmouthian interglacial "Clay deposition in the Piauí River floodplain around 436 ± 51.5 ka occurred during a warmer period of the Aftonian interglaciation, corresponding to isotope stage 12 (Ericson and Wollin, 1968)." # Illinois Episode glaciation "Illinoian (ca. 220,000-430,000 yr BP)". # Sangamon Episode interglacial "OSL dates also suggest that last interglacial (MIS 5; Sangamon Ep.) fluvial deposits are preserved locally." Age "assignment of Sangamonian (sense alto = 80,000-ca. 220,000 yr BP) to Illinoian (ca. 220,000-430,000 yr BP)". # Late Pleistocene Late Pleistocene spans ca. 11,000-150,000 yr BP. # Eemian interglacial The "controversially split Eemian period, the predecessor of our own warm period about 125,000 years ago." "The Eem interglaciation lasted from 131 to 117 kyr B.P." The "Neanderthal fossil was 120,000 years old and, more important, that it belonged to a branch of the Neanderthal family tree with a long history. All known Neanderthals inherited their mitochondrial DNA from an ancestor who lived 270,000 years ago." "The common ancestors of Neanderthals and Denisovans spread across Europe and Asia over half a million years ago. Gradually the eastern and western populations parted ways, genetically speaking." "In the east, they became Denisovans. In the west, they became Neanderthals. The 430,000-year-old fossils at Sima de los Huesos — Neanderthals with Denisovanlike genes — capture the early stage of that split." "At some point before 270,000 years ago, African humans closely related to us moved into Europe and interbred with Neanderthals. Their DNA entered the Neanderthal gene pool." # Herning Stadial MIS Boundary 5.5 (peak) is at 123 ka. "Lines engraved between 125,000 and 105,000 years ago on two animal bones found in northern China held some sort of meaning for their makers." "These two bone fragments found in northern China contain engraved lines, some marked with red pigment (red dots in left line drawing), making them the oldest examples of symbolic behavior in East Asia." "These ancient markings provide the oldest evidence of symbolic activity by humans or our close evolutionary relatives in East Asia." "A mysterious Stone Age population called Denisovans, which had close genetic ties to Neandertals, may have carved sets of parallel lines into the pair of bone fragments." "Denisovans inhabited East Asia at the same time that someone carved lines into bones at northern China’s Lingjing site . But either Homo sapiens or Neandertals, who also left behind Stone Age creations with apparent symbolic meanings , might instead have modified the Lingjing bones." "Nonetheless, the two objects from Lingjing suggest that symbolic capacities were within the realm of cognitive abilities of species that lived before and during the evolution of Homo sapiens in Africa.” "Abstract markings on the Lingjing bones resemble engraved lines on roughly 100,000-year-old pigment chunks from South Africa." "As Homo sapiens was responsible for that early symbolism in Africa, and Neandertals were responsible for such in Europe, it is a fascinating possibility that these examples were created by another Homo species." "An engraved geometric design on a roughly half-million-year-old seashell found on an Indonesian island stands as the oldest example of symbolic behavior anywhere in the world . Researchers suspect the now-extinct hominid species Homo erectus carved that pattern." "Almost one-quarter of 227 animal bone fragments excavated at Lingjing between 2005 and 2015 display stone tool incisions typical of butchery . But that sample included two exceptions. Seven nearly parallel lines had been cut into a partial rib from an unidentified large, adult mammal. Microscopic analysis indicated that the lines were made with a sharp point that was run across the bone’s surface after it had suffered some damage from weathering. Special care was taken to create each of the first five lines with a single pass of the engraving tool. Red residue in four engraved lines indicated that a pigment had been smeared on the pattern, possibly to increase its visibility." "A second rib fragment from a large mammal contained 10 roughly parallel lines that had been sliced with a sharp stone point, probably in a single session . Engraving of these lines also occurred after the bone had been damaged by long exposure to the air. No pigment residue appeared on this specimen." "Estimated ages of the engraved bones relied on calculations of the time since sediment in which they were found was last exposed to sunlight." "Whoever cut lines into the Lingjing finds also fashioned animal bones into tools. Bone and antler artifacts found in the same sediment as the engraved ribs were likely used to retouch and sharpen used stone tools." # Brørup interstadial The "Brørup interstade 100 ka BP". It corresponds to GIS 23/24. # Rederstall Stadial MIS Boundary 5.3 is at 96 ka. Marine Isotope Stage 4. # Wisconsinian glacial Wisconsinian glacial began at 80,000 yr BP. # Odderade interstadial The Odderade interstadial has a 14C date of 61-72 kyr B.P. and corresponds to GIS 21. "A population that began to expand from Africa around 70 Ka reached Southeast Asia by the middle of the Upper Pleistocene. From Southeast Asia, part of this population took a southern route of expansion towards Australia, where they arrived around 50 Ka (Lahr and Foley, 1998). Sometime between 50 and 20 Ka the same Southeast Asian population took a northern route of expansion along both interior and coastal East Asia (as suggested by Fladmark, 1979), depending on the local climatic conditions. The presence of an “Australo-Melanesian-like” population in East Asia is attested by the human skeletal remains from the Zhoukoudian Upper Cave around 20 Ka (Kamminga and Wright, 1988; Wright, 1995; Neves and Pucciarelli, 1998). A late occupation of the northern zones of East Asia also agrees with the idea that major behavioral change and technological strategies necessary to exploit extreme environments were not in place until ca. 40,000 BP (Whallon, 1989; Klein, 1992, 1995)." # Karmøy stadial The Karmøy stadial begins in the high mountains of Norway about 60 kyr B.P. and expands to the outer coast by 58 kyr B.P. "To uncover the migratory path that the ancestors of present-day Eurasians (Europeans and Asians) took when moving out of Africa around 60,000 years ago, an international team of scientists generated 225 whole-genome sequences from six modern Northeast African populations (100 Egyptians and five Ethiopian populations each represented by 25 people)." "The remaining masked genomic regions from Egyptian samples were more similar to non-African samples and present in higher frequencies outside Africa than the masked Ethiopian genomic regions, pointing to Egypt as the more likely gateway in the exodus to the rest of the world." “Two geographically plausible routes have been proposed: an exit through the current Egypt and Sinai, which is the northern route, or one through Ethiopia, the Bab el Mandeb strait, and the Arabian Peninsula, which is the southern route.” "igh-quality genomes to estimate the time that the populations split from one another: people outside Africa split from the Egyptian genomes more recently than from the Ethiopians (55,000 as opposed to 65, 000 years ago), supporting the idea that Egypt was last stop on the route out of Africa." “In our research, we generated the first comprehensive set of unbiased genomic data from Northeast Africans and observed, after controlling for recent migrations, a higher genetic similarity between Egyptians and Eurasians than between Ethiopians and Eurasians. This suggests that Egypt was most likely the last stop on the way out of Africa.” # Oerel interstadial The Oerel interstadial has a 14C date of 53-58 kyr B.P. and corresponds to GIS 15/16 with a GIS age of 56-59 kyr B.P. "Neanderthals had the brains and guile to catch and eat birds, a skill many had assumed was beyond them. Bones found in Gibraltar suggest Neanderthals hunted wild pigeons, possibly by climbing steep cliffs to reach their nests." "The rock dove bones were buried in sediments laid down between 28,000 and 67,000 years ago. Most of the excavated layers date from a time when only Neanderthals lived in the area, before the arrival of modern humans around 40,000 years ago. That means only Neanderthals could have caught the rock doves." "They couldn't have picked up the skills to catch the birds from modern humans." "This provides the first evidence for sustained and significant use of birds for food by Neanderthals." "The more we can show similarities between our ancestors and Neanderthals, the more the barriers between us are broken down." "The sustained use of pigeons provides even more evidence that Neanderthal hunting and foraging abilities were on a par with those of modern humans." "We know that they climbed up cliffs to hunt ibex, so maybe they also climbed to the ledges where the birds nested. I think they might have had snares or netting made from grasses, but we'll never know as it's all perishable." "Neanderthals may have started with eating , then moved to other purposes such as clothing or ornamentation." # Ebersdorf Stadial "Genetics suggests Neanderthal numbers dropped sharply around 50,000 years ago. This coincides with a sudden cold snap, hinting climate struck the first blow." "There is a surprising genetic unity between the earliest known Europeans and contemporary Europeans, ancient DNA reveals. This finding suggests that a complex network of sexual exchange may have existed across Europe over the past 50,000 years, and also helps to pinpoint when modern humans interbred with Neanderthals, the closest extinct relatives of modern humans." "There is solid evidence of modern humans at Tam Pa Ling around 50,000 or 60,000 years ago, and the Zhirendong mandible has modern features. So yes, modern humans were present in at least south-east Asia and south China by somewhere in this time range." # Glinde interstadial The Glinde interstadial has a 14C date of 48-50 kyr B.P. and corresponds to GIS ?13/14 with a GIS age of 49-54.5 kyr B.P. "It is recognized that the human population that arrived in Australia around 50,000 BP (Bowler et al., 2003) was the product of an expansive movement out of Africa, following the tropical areas of Southern Asia. This route of expansion represents one of the first offshoots of modern humans out of Africa (Stringer and Andrews 1988; Stringer 1992; Lahr, 1996; Lahr and Foley, 1998). This is why Australians and Africans still form a supra-population unit of morphological affinity (Howells, 1973, 1989; Lahr, 1996). Therefore, the similarities of the first South Americans with Australians are easily explained if we accept that both populations shared a common ancestral population in mainland East Asia (most probably Southeast Asia). A population expansion from Asia to the New World before the Mongoloid traits were fully developed in the Old World was actually predicted more than fifty years ago by Birdsell (1951:63). The similarities of the first South Americans with sub-saharan Africans may result from the fact that the non-Mongoloid Southeast Asian ancestral population came, ulti- mately, from Africa, with no major modification in the original cranial bau plan of the first moderns. Neves et al. (1999c) have already suggested a possible historical connection among early modern humans (Skhul/Kafzeh), UC 101, Paleoindians and recent Africans and Australians based on their cranial morphology." # Marine Isotope Stage 3 "One bone, which came from a wild goat, was found in Zafarraya Cave in a similar layer as Neanderthal fossils. The bone was previously estimated as 33,300 years in age. However, using an ultrafiltration technique that cleansed the bone of modern carbon impurities that can give inaccurate younger dates, ... the bone was more than 46,700 years old." # Moershoofd interstadial The Moershoofd interstadial has a 14C date of 44-46 kyr B.P. and corresponds to GIS 12 at 45-47 kyr B.P. "Unearthed by an ivory carver from a Siberian riverbank, a man's 45,000-year-old thigh bone reveals when people first mated with Neanderthals The Ust'-Ishim man's thigh bone is the oldest human bone found so far outside of Africa and the Middle East It's nearly twice as old as the next oldest from a modern human, which comes from a boy who died elsewhere in Siberia some 24,000 years ago." "A bone found by chance on the banks of a Siberian river has yielded the oldest modern human genome yet recovered, according to a new study that sheds light on when people left Africa and first interbred with Neanderthals living in Europe and Asia." "The DNA narrows down the time when mating first brought Neanderthal genes into the human gene pool: from 50,000 to 60,000 years ago." "The man, who lived 45,000 years ago, was definitely related to both humans and Neanderthals . His DNA showed that the two human groups first mated around 60,000 years ago." "The Ust'-Ishim man had about 2.3 percent Neanderthal genes, but modern people typically have less than 2.1 percent." The "Siberian man belonged to a population that was closely related to the ancestors of today’s Europeans and Asians. He carried only slightly more Neanderthal DNA than they do." “But his genomic segments of Neanderthal ancestry are on average about three times the length of those found in genomes today.” This is highly informative “as the chunks of Neanderthal DNA have been gradually broken up each generation since the time of interbreeding.” The "idea of a single time of human mating with Neanderthals is almost certainly an oversimplification. The contacts could have extended over a longer period." "The femur shaft turned up on the banks of the Irtysh River near Ust'-Ishim, Russia, in 2008. A Russian ivory carver and historian named Nikolay Peristov collected the bone after it eroded from a bluff above the river in western Siberia. It was identified as human, based on its teardrop-shaped cross section, in 2010." “Thus the ancestors of Australasians (people from Australia, New Zealand, the island of New Guinea, and neighboring islands in the Pacific Ocean), with their similar input of Neanderthal DNA to Eurasians, must have been part of a late, rather than early, dispersal through Neanderthal territory.” “While it is still possible that modern humans did traverse southern Asia before 60,000 years ago, those groups could not have made a significant contribution to the surviving modern populations outside of Africa, which contain evidence of interbreeding with Neanderthals.” "Work on material from Italy seems to show human settlers pushing Neanderthals out (see maps). Mousterian tools were common there 45,000 years ago, when human-made Uluzzian material first appeared. By 44,000 years ago, humans were sharing Italy with a dwindling Neanderthal population. By 42,000 years ago, the Neanderthals were gone." "Mousterian and Châtelperronian are probably Neanderthal. Uluzzian, were once attributed to late Neanderthals, but recent work suggests they were made by humans (Nature, doi.org/bxh255)." # Denisovans "The genome of ... the Denisovans that once interbred with us has been sequenced ... bout 100,000 recent changes in our genome occurred after the split from the Denisovans. ... DNA from fossils unearthed in Denisova Cave in southern Siberia in 2008 revealed a lineage unlike us and closely related to Neanderthals. The precise age of the Denisovan material remains uncertain — anywhere from 30,000 to 80,000 years of age. ... he lived in a vast range from Siberia to Southeast Asia. The Denisovans share more genes with people from Papua New Guinea than any other modern population studied." "The picture of her genome is as accurate as that of modern day human genomes, and shows she had brown eyes, hair and skin." "The Denisovans have mysterious origins. They appear to have left little behind for palaeontologists save a tiny finger bone and a wisdom tooth found in Siberia's Denisova cave in 2010." "This is an extinct genome sequence of unprecedented accuracy." "For most of the genome we can even determine the differences between the two sets of chromosomes that the Denisovan girl inherited from her mother and father." About "3% of the genes of people living today in Papua New Guinea come from Denisovans, with a trace of their DNA lingering in the Han and Dai people from mainland China." A genetic "contribution from Denisovans is found exclusively in island Southeast Asia and Oceania (6)." "Assuming 6.5 million years of sequence divergence between humans and chimpanzees, the shortening of the Denisovan branch allows the bone to be tentatively dated to between 74,000 and 82,000 years before present, in general agreement with the archaeological dates (2)." Less "Denisovan allele-sharing with the Dai than with the Han (although nonsignificantly so, Z = –0.9) . Further analysis shows that if Denisovans contributed any DNA to the Dai, it represents less than 0.1% of their genomes today ." "Denisovans share more alleles with the three populations from eastern Asia and South America (Dai, Han, and Karitiana) than with the two European populations (French and Sardinian) (Z = 5.3)." Def. "the fraction of nucleotide sites that are different between a person’s maternal and paternal genomes" is called heterozygosity. "The great apes have 24 pairs of chromosomes whereas humans have 23. This difference is caused by a fusion of two acrocentric chromosomes that formed the metacentric human chromosome 2 (25) and resulted in the unique head-to-head joining of the telomeric hexameric repeat GGGGTT. A difference in karyotype would likely have reduced the fertility of any offspring of Denisovans and modern humans. We searched all DNA fragments sequenced from the Denisovan individual and identified 12 fragments containing joined repeats. By contrast, reads from several chimpanzees and bonobos failed to yield any such fragments (8). We conclude that Denisovans and modern humans (and presumably Neandertals) shared the fused chromosome 2." "In total, we identified 111,812 single-nucleotide changes (SNCs) and 9499 insertions and deletions where modern humans are fixed for the derived state, whereas the Denisovan individual carried the ancestral, i.e., ape-like, variant (8). This is a relatively small number. We identified 260 human-specific SNCs that cause fixed amino acid substitutions in well-defined human genes, 72 fixed SNCs that affect splice sites, and 35 SNCs that affect key positions in well-defined motifs within regulatory regions." "One way to identify changes that may have functional consequences is to focus on sites that are highly conserved among primates and that have changed on the modern human lineage after separation from Denisovan ancestors. We note that, among the 23 most conserved positions affected by amino acid changes (primate conservation score of ≥0.95), eight affect genes that are associated with brain function or nervous system development (NOVA1, SLITRK1, KATNA1, LUZP1, ARHGAP32, ADSL, HTR2B, and CNTNAP2). Four of these are involved in axonal and dendritic growth (SLITRK1 and KATNA1) and synaptic transmission (ARHGAP32 and HTR2B), and two have been implicated in autism (ADSL and CNTNAP2). CNTNAP2 is also associated with susceptibility to language disorders (27) and is particularly noteworthy as it is one of the few genes known to be regulated by FOXP2, a transcription factor involved in language and speech development as well as synaptic plasticity (28). It is thus tempting to speculate that crucial aspects of synaptic transmission may have changed in modern humans." "Of the 34 genes with clear associations with human diseases that carry fixed substitutions changing the encoded amino acids in present-day humans, four (HPS5, GGCX, ERCC5, and ZMPSTE24) affect the skin and six (RP1L1, GGCX, FRMD7, ABCA4, VCAN, and CRYBB3) affect the eye. Thus, particular aspects of the physiology of the skin and the eye may have changed recently in human history. Another fixed difference occurs in EVC2, which when mutated causes Ellis–van Creveld syndrome. Among other symptoms, this syndrome includes taurodontism, an enlargement of the dental pulp cavity and fusion of the roots, a trait that is common in teeth of Neandertals and other archaic humans. A Denisovan molar found in the cave has an enlarged pulp cavity but lacks fused roots (2). This suggests that the mutation in EVC2, perhaps in conjunction with mutations in other genes, has caused a change in dental morphology in modern humans." # Hasselo stadial The "Hasselo stadial at approximately 40-38,500 14C years B.P. (Van Huissteden, 1990)." The "Hasselo Stadial (44–39 ka ago)". "Analysis of the jawbone of a man who lived about 40,000 years ago reveals the closest direct descendant of a Neanderthal who mated with a modern human." "A modern human who lived in what is now Romania between 37,000 and 42,000 years ago had at least one Neanderthal ancestor as little as four generations back—which is to say, a great-great-grandparent." “I could hardly believe that we were lucky enough to hit upon an individual like this.” "The specimen, known as Oase 1, consists only of a male jawbone, and from the moment it was discovered in 2002 its shape suggested that it might belong to a hybrid between Homo sapiens and Neanderthal." "The genome they sequenced from the samples was incomplete, but it was enough for the scientists to conclude that between 6% and 9% of Oase 1’s genome is Neanderthal in origin. People living today have 4% at most." “We found seven huge pieces of chromosomes that seemed to be purely of Neanderthal origin. That means pieces had to come from a relatively recent ancestor, since they hadn’t yet been broken up by the reshuffling that happens in each generation as parents' chromosomes combine.” "The non-Neanderthal genome sequences, meanwhile, show that Oase 1 isn’t related to humans living today. His genealogical line died out at some point." Instead "of dying out 23,000 years ago, Neanderthals were gone as early as 39,000 years ago. It also looks like we shared their territory for 5000 years, steadily replacing them as we spread across Europe." "Neanderthals had largely, and perhaps entirely, vanished from their known range by 39,000 years ago." # Hengelo interstadial Preliminary DNA sequencing from a 38,000-year-old bone fragment of a femur found at Vindija Cave, Croatia, in 1980 showed Neanderthals and modern humans share about 99.5% of their DNA. "DNA from the left shinbone of a skeleton, known as K14, which was excavated in 1954 . K14 is one of the oldest fossils of a European modern human — a man who lived between 36,200 and 38,700 years ago in the area that's now Kostenki, in western Russia ." Kostenski is known for its mammoth structures, "circles made of mammoth bones that would have been the base of tents, huts, hearths, lithic and bone artifacts, as well as personal ornaments and figurines." "K14's complete genome , making it the second-oldest modern human genome ever sequenced. The oldest yet was from the 45,000-year-old thighbone of a man found in western Siberia." Contemporary "Europeans shared genetic continuity with ancient Europeans." "Virtually all the major genetic components you find in contemporary Europeans are present among the earliest Europeans." For "millennia, Europe may have been home to a so-called "metapopulation" of modern humans — a group of distinct, separate populations that regularly mixed, grew and fragmented. The genetic contributions of the earliest Eurasians to modern European populations may not have arrived through a few distinct migrations from Asia to Europe, but instead through gene flow in various directions." "We have to revise our understanding of how the genetic diversity in contemporary Europeans came about. Early Europeans were part of a metapopulation stretching all the way to Central Asia, and through a complex network of sexual exchange, contemporary European populations were created." # Cro-Magnon "Cro-magnons are, in informal usage, a group among the late Ice Age peoples of Europe. The Cro-Magnons are identified with Homo sapiens sapiens of modern form, in the time range ca. 35,000-10,000 b.p. The term "Cro-Magnon" has no formal taxonomic status, since it refers neither to a species or subspecies nor to an archaeological phase or culture. The name is not commonly encountered in modern professional literature in English, since authors prefer to talk more generally of anatomically modern humans. They thus avoid a certain ambiguity in the label "Cro-Magnon", which is sometimes used to refer to all early moderns in Europe (as opposed to the preceding Neanderthals), and sometimes to refer to a specific human group that can be distinguished from other Upper Paleolithic humans in the region. Nevertheless, the term "Cro-Magnon" is still very commonly used in popular texts because it makes an obvious distinction with the Neanderthals, and also refers directly to people rather than to the complicated succession of archaeological phases that make up the Upper Paleolithic. This evident practical value has prevented archaeologists and human paleontologists - especially in continental Europe - from dispensing entirely with the idea of Cro-Magnons." The earliest known remains of Cro-Magnon-like humans are radiocarbon dated to 43,000 years before present. Cro-Magnons were robustly built and powerful. The body was generally heavy and solid with a strong musculature. The forehead was fairly straight rather than sloping like in Neanderthals, and with only slight browridges. The face was short and wide. Like other modern humans, Cro-Magnons had a prominent chin. The brain capacity was about 1,600 (Expression error: Unrecognized punctuation character ",". ), larger than the average for modern humans. However, recent research suggests that the physical dimensions of so-called "Cro-Magnon" are not sufficiently different from modern humans to warrant a separate designation. "‘Cro-Magnon Man’ is commonly used for the modern humans that inhabited Europe from about 40,000 to 10,000 years ago." # Heinrich Event 4 Heinrich Event 4 "33-39.93 ka BP". # Huneborg interstadial The Huneborg interstadial is a Greenland interstadial dating 36.5-38.5 kyr B.P. GIS 8. # Stadial "Stadial duration 0.642 ka". # GIS 7 interstadial "GIS 7 (start) 32.896 GIS 7 (end) 32.15 ka BP". # Stadial "Stadial duration 0.932 ka". # Ålesund Interstadial The Ålesund interstadial began with GIS 6 and ended after GIS 8. # Stadial Stadial duration 0.836 ka"" # GIS 5 GIS 5 interstadial occurred during the Klintholm advance about 33.5 kyr B.P. "GIS 5 (start) 30.013 GIS 5 (end) 29.526 ka BP". # Klintholm advance This advance occurred after the Møn and ended with GIS 6. "Stadial duration 2.899 ka". # Møn interstadial The Møn interstadial corresponds to GIS 4. # Stadial Heinrich Event 3 (H3) "occurs at 26.74 ka BP, coincident with the start of the transition into GIS 4." MIS Boundary 2/3 is at 29 ka. "Stadial duration 0.768 ka". # GIS 3 The stronger GIS 3 interstadial occurred about 27.6 kyr B.P. It begins abruptly at 29 ka and ends about 26 ka. "GIS 3 (start) 25.571 GIS 3 (end) 25.337 ka BP". # Laugerie Interstadial The weak interstadial corresponding to GIS 2 occurred about 23.2 kyr B.P. "GIS 2 (start) 21.556 GIS 2 (end) 21.407 ka BP". Heinrich Event 2 (H2) extends "22-25.62 ka BP". The δ18O values from GISP-2 follow the diagram of Wolfgang Weißmüller. The positions of the Dansgaard-Oeschger events DO1 to DO4 and the Heinrich events H1 to H3 are also indicated. DV 3-4 and DV 6-7 are cold events marked by ice wedges in the upper loess of Dolní Veštonice. # Jylland stade "After c. 22 ka BP during the Jylland stade (Houmark-Nielsen 1989)". # Homo floresiensis "The 18,000-year-old fossils of the extinct type of human officially known as Homo floresiensis were first discovered on the remote Indonesian island of Flores in 2003. Its squat, 3-foot-tall (1 meter) build led to the hobbit nickname." "he hobbit's brain was larger than previously suggested — 426 cubic cm (nearly 26 cubic inches), instead of the commonly cited figure of 400 cubic cm. (The modern human brain is 1,300 cubic centimeters, or 79 cubic inches, large on average.)" # Lascaux interstadial The Lascaux interstadial begins about 21 ka and extends to about 18 ka. # Heinrich event H1 This stadial starts about 17.5 ka, extends to about 15.5 ka and is followed after a brief warming by H1. # Meiendorf Interstadial The period spans starting at the far right of the image on the right from Lascaux interstadial to Heinrich event H1, and to Meiendorf/Bölling warm stage, and Allegöd warm stage, to Younger dryas and early holocene. The Meiendorf Interstadial is typified by a rise in the pollens of dwarf birches (Betula nana), willows (Salix sp.), sandthorns (Hippophae), junipers (Juniperus) and Artemisia. The beginning of the Meiendorf Interstadial is around 14,700 b2k. # Oldest Dryas "During the Late Weichselian glacial maximum (20-15 ka BP) the overriding of ice streams eventually lead to strong glaciotectonic displacement of Late Pleistocene and pre-Quaternary deposits and to deposition of till." The "beginning of Oldest Dryas time (~14,600 14C yr BP)". "More than 15,000 years ago, humans began crossing a land bridge called Beringia that connected their native home in Eurasia to modern-day Alaska. Who knows what the journey entailed or what motivated them to leave, but once they arrived, they spread southward across the Americas." "The prevailing theory is that the first Americans arrived in a single wave, and all Native American populations today descend from this one group of adventurous founders. But now there’s a kink in that theory. The latest genetic analyses back up skeletal studies suggesting that some groups in the Amazon share a common ancestor with indigenous Australians and New Guineans. The find hints at the possibility that not one but two groups migrated across these continents to give rise to the first Americans." “Our results suggest this working model that we had is not correct. There’s another early population that founded modern Native American populations.” "Genetic studies have since connected both these ancient and modern humans to ancestral populations in Eurasia, adding to the case that a single migratory surge produced the first human settlers in the Americas. Aleutian Islanders are a notable exception. They descend from a smaller second influx of Eurasians 6,000 years ago that bear a stronger resemblance to modern populations, and some Canadian tribes have been linked to a third wave." The "Suruí and Karitiana people of the Amazon had stronger ties to indigenous groups in Australasia—Australians, New Guineans and Andaman Islanders—than to Eurasians." They "scrutinized the genomes of 30 Native American groups in Central and South America. Using four statistical strategies, they compared the genomes to each other and to those of 197 populations from around the world. The signal persisted. Three Amazonian groups—Suruí, Karitiana and Xavante—all had more in common with Australasians than any group in Siberia." "The DNA that links these groups had to come from somewhere. Because the groups have about as much in common with Australians as they do with New Guineans, the researchers think that they all share a common ancestor that lived tens of thousands of years ago in Asia but that doesn’t otherwise persist today. One branch of this family tree moved north to Siberia, while the other spread south to New Guinea and Australia. The northern branch likely migrated across the land bridge in a separate surge from the Eurasian founders. The researchers have dubbed this hypothetical second group “Population y” for ypykuéra, or “ancestor” in Tupi, a language spoken by the Suruí and Karitiana." Studies "of ancient skulls unearthed in Brazil and Colombia bear stronger resemblance to those of Australasians than the skulls of other Native Americans. Based on the skeletal remains, some anthropologists had previously pointed to more than one founding group". "We postulate a putative time of entry of this “Australo-Melanesian-like” population in the New World around 14 Ka (see also Dillehay, 2000; Dixon, 2001). This population expanded southward in the New World using the Pacific coast. Eventually, when the recession of the ice sheets in North America permitted, this population expanded towards the interior. A rapid expansion along the coast would explain why the Australo-Melanesian cranial bau plan of the first settlers was not altered during the expansion into South America. If we see the Australo-Melanesian cranial morphology as the result of selection under tropical climates since its inception in Africa (Lahr, 1996), a relatively fast migration along the Pacific Rim could explain why this “tropical pattern” was not significantly altered by colder climates." # Bølling Oscillation The "intra-Bølling cold period Bølling warming at 14600 cal BP (12700 14C BP)". # Older Dryas "Older Dryas events ". # Mesolithic The mesolithic period dates from around 13,000 to 8,500 b2k. "These hunter-gatherers were some of the earliest known residents of South America and they chose to live at this extreme altitude — higher than any Ice Age encampment found thus far in the New World. Despite the thin air and sub-freezing night-time temperatures, this plain would have seemed a hospitable neighbourhood to those people." “The basin has fresh water, camelids, stone for toolmaking, combustible fuel for fires and rock shelters for living in. Basically, everything you need to live is here. This is one of the richest basins I've seen, and it probably was then, too.” "150 kilometres away from the Andes cave, on Peru's arid coast at Quebrada Jaguay a site that dated to the end of the last Ice Age, between 13,000 and 11,000 years ago." At "the end of the last Ice Age, glaciers were mainly continued to alpine valleys, and Pucuncho and other areas were not glaciated." "Paleoclimate data indicate that the environment was probably wetter then, so there might have been more plants and animals available for the early residents." “These Palaeo-Indians were able to live in one of the most extreme environments on Earth, at the end of an ice age, and they seem to have done so quite successfully. This tells us that Palaeo-Indians were capable of living just about anywhere.” An "ancient encampment, dated to around 13,000 years ago4. called Quebrada Santa Julia Some of the stone tools at the site were made of translucent quartz that is not found in coastal deposits." Beneath "Huaca Prieta, a 32-metre-high mound on the coast of northern Peru traces of Ice Age settlements Radiocarbon dating indicates5 that humans had lived there as much as 14,200 years ago, when the area was surrounded by wetlands." "Some tools found at a site called Pay Paso are made of translucent agate, which apparently came from quarries near the border with Brazil about 150 kilometres away. And other tools from Uruguay have been found 500 kilometres to the south in Argentina's Buenos Aires province6." "12,800-year-old artefacts at Cueva Bautista, a rock shelter 3,930 metres above sea level in southwestern Bolivia. similarly aged site exists at the same latitude in Chile on the western slope of the Andes." There is "an outcrop of translucent quartz at a site where people had lived and quarried between 12,600 and 11,400 years ago. The similarity with Quebrada Santa in terms of age and tool-making techniques suggests that the coastal tools came from these mountain outcrops." People "built a fire in the rock shelter, named Cuncaicha , about 12,400 years ago." "At the Panama Isthmus, the coastal expansion trifurcated, with one migration following down the Pacific coast, another the Atlantic coast, and a third one inward into the Amazon basin. These multiple axes south of Panama would explain the presence of humans in Southern Chile around 12.3 Ka (Dillehay, 1989, 1997), the presence of humans in Lagoa Santa and elsewhere in eastern Central Brazil around 12 Ka (Kipnis, 1998, Prous and Fogac ̧a, 1999), and in the Amazon around 11.2 Ka (Roosevelt et al., 1996). A Pacific and an Atlantic expansion would also explain the presence of Paleoindians with Australo-Melanesian morphology on opposite sides of South America, in eastern Central Brazil and the Colombia Highlands, by the end of the Pleistocene (Neves and Pucciarelli, 1989; 1991; Munford, 1999)." # Neolithic The base of the Neolithic is approximated to 12,200 b2k. “What we're seeing is that 12,000 years ago or more, these groups already had networks, knew the landscape and moved between the coast and the interior.” At the left is a reconstruction of the face of one of the oldest human remains found in the Americas. It is dated to 11,500 years ago. # Allerød Oscillation The "Allerød Chronozone, 11,800 to 11,000 years ago". "Kamminga and Wright (1988), Wright (1995) and Neves and Pucciarelli (1998) have demonstrated, however, that the Zhoukoudian Upper Cave (UC) cranium 101 display marked similarities with Australo-Melanesians. Cunningham and Wescott (2002) has shown that although highly variable, none of the three specimens from this site (UC 101, UC 102, UC 103) resembles modern Asian populations. Matsumura and Zuraina (1999:333) reported the presence of the “Australo-Melanesian lineage” in Malaysia as late as the terminal Pleistocene. If we consider that UC is dated to between 32,000 BP and 11,000 BP, the fixation of the classical Mongoloid morphology in North Asia could have been a recent phenomenon (terminal Pleistocene/early Holocene), a hypoth- esis favored by several authors (see Cunningham and Wescott, 2002 for a review)." "Accordingly, an Australo-Melanesian-like population present in North Asia by the end of the Pleistocene could have been the source of the first Americans. This would explain the presence of a non-Mongoloid morphology in the New World without invoking a direct transpacific route departing from Australia, as suggested by Rivet (1943)." "Lahr (1995) has argued that human diversity in northern Asia was probably higher in the final moments of the Pleistocene than today, at least as far as cranial morphology is concerned. Therefore, non-Mongoloid Asians could have arrived in the Americas using the Behring Strait as the gate of entry following either the shore of Beringia or a land bridge." # Holocene The Holocene starts at ~11,700 b2k and extends to the present. # Younger Dryas The "Alleröd/Younger Dryas transition some 11,000 years ago ." # Pre-Boreal transition The last glaciation appears to have a gradual decline ending about 12,000 b2k. This may have been the end of the Pre-Boreal transition. There is "a cranial morphology for terminal Pleistocene and Early Holocene populations in the Americas outside the range of variation of modern Amerindians, both in North and South America (Jantz and Owsley, 2001). While in North America the early human remains are, in general, but not exclusively, more similar to South Asians, Ainu/ Polynesians or Europeans (Steele and Powell, 1992, 1994, 1999; Chatters et al., 1999; Brace et al., 2001; Jantz and Owsley, 2001), in South America they are closer to Australians and sub-Saharan Africans (Neves and Pucciarelli, 1989, 1990, 1991; Munford et al., 1995; Neves et al., 1998, 1999a,b)." "About 9000 years ago the temperature in Greenland culminated at 4°C warmer than today. Since then it has become slowly cooler with only one dramatic change of climate. This happened 8250 years ago . In an otherwise warm period the temperature fell 7°C within a decade, and it took 300 years to re-establish the warm climate. This event has also been demonstrated in European wooden ring series and in European bogs." "The last remains of the American ice sheet disappeared about 6000 years ago , the Scandinavian one 2000 years earlier ." "Santana do Riacho is a late Paleoindian burial site where approximately 40 individuals were recovered in varying states of preservation. The site is located at Lagoa Santa/Serra do Cipó, State of Minas Gerais. The first human activities in this rockshelter date back to the terminal Pleistocene, but the burials are bracketed between circa 8200 and 9500 BP. The collection contains only six skulls well-enough preserved to be measured. The Santana do Riacho late Paleoindians present a cranial morphology characterized by long and narrow neurocrania, low and narrow faces, with low nasal apertures and orbits. The multivariate analyses show that they exhibit strong morphological affinities with present day Australians and Africans, showing no resemblance to recent Northern Asians and Native Americans." The image on the right shows two of these skulls. On the left is a female and the right is a male. "The similarities of the first South Americans with sub-Saharan Africans may result from the fact that the non-Mongoloid Southeast Asian ancestral population came, ultimately, from Africa, with no major modification in the original cranial bau plan of the first modern humans." # Ancient history The ancient history period dates from around 8,000 to 3,000 b2k. "All in all, Europeans maintained genetic continuity from their earliest establishment out of Africa until Middle Eastern farmers arrived in the last 8,000 years, bringing with them agriculture and a lighter skin color." "Ancient DNA has been retrieved and analyzed from Egyptian mummies". # Copper Age The copper age history period began from 6990 b2k. The "oldest securely dated evidence of copper making, from 7,000 years ago , at the archaeological site of Belovode, Serbia." The "Scandinavian one 2000 years earlier ." # Boreal transition "In some cores a narrow band of clay interrupts the organic muds, at the horizon of the Boreal Atlantic transition." # Atlantic history The "Atlantic period 4.6–6 ka ." # Bronze Age A general world-wide use of bronze occurred between 5300 and 2600 b2k. "The first (purely typological) studies on Early Bronze Age (EBA) assemblages in the Jordan Valley settled on the turn of the 4th/3rd millennium BC the beginnings of the earliest Bronze Age culture (Albright 1932; Mallon 1932)." "In the Chalcolithic/earliest Bronze Age I period (c. 4500±3000 cal BC), copper was mined in open galleries from the massive brown sandstone deposit, which consisted of thick layers of the copper carbonate malachite and chalcocite, a copper sulphide." # Iron Age The iron age history period began between 3,200 and 2,100 b2k. "The earliest known iron artefacts are nine small beads securely dated to circa 3200 BC, from two burials in Gerzeh, northern Egypt." "Since both tombs are securely dated to Naqada IIC–IIIA, c 3400–3100 BC (Adams, 1990: 25; Stevenson, 2009: 11–31), the beads predate the emergence of iron smelting by nearly 2000 years, and other known meteoritic iron artefacts by 500 years or more (Yalçın 1999), giving them an exceptional position in the history of metal use." The image on the left uses neutron radiography to show the metal underneath the corrosion. "Bead UC10738 has a maximum length of 1.5 cm and a maximum diameter of 1.3 cm, bead UC10739 is 1.7 cm by 0.7 cm, and bead UC10740 is 1.7 cm by 0.3 cm. All three beads are of rust-brown colour with a rough surface, indicative of heavy iron corrosion. Initial analysis by pXRF indicated an elevated nickel content of the surface of the beads, in the order of a few per cent, and their magnetic property suggested that iron metal may be present in their body (Jambon, 2010)." # Early history The early history period dates from around 3,000 to 2,000 b2k. In the image on the right are Guanches engravings in a rock cave on La Palma island of the Canary Islands. The Guanches are believed to be the original inhabitants of the Canary Islands perhaps as early as 3,000 b2k. # Subboreal history The "period around 850-760 BC , characterised by a decrease in solar activity and a sharp increase of Δ 14C the local vegetation succession, in relation to the changes in atmospheric radiocarbon content, shows additional evidence for solar forcing of climate change at the Subboreal - Subatlantic transition." The "Holocene climatic optimum in this interior part of Asia corresponds to the Subboreal period 2.5–4.5 ka". # Subatlantic history The "calibration of radiocarbon dates at approximately 2500-2450 BP is problematic due to a "plateau" (known as the "Hallstatt-plateau") in the calibration curve A decrease in solar activity caused an increase in production of 14C, and thus a sharp rise in Δ 14C, beginning at approximately 850 cal (calendar years) BC Between approximately 760 and 420 cal BC (corresponding to 2500-2425 BP ), the concentration of 14C returned to "normal" values." # Imperial Antiquity Imperial Antiquity lasts from 2,000 to 1,700 b2k. In Felix Romuliana, "the construction is Imperial Antique (1st-3rd c.), and sometimes even late Hellenistic, appearance." # High Middle Ages The High Middle Ages date from around 1,000 b2k to 700 b2k. Mitochondrial "DNA analysis (HVRI sequences and RFLPs) aborigine remains around 1000 years old. The sequences retrieved show that the Guanches possessed U6b1 lineages that are in the present day Canarian population, but not in Africans. In turn, U6b, the phylogenetically closest ancestor found in Africa, is not present in the Canary Islands. Comparisons with other populations relate the Guanches with the actual inhabitants of the Archipelago and with Moroccan Berbers. This shows that, despite the continuous changes suffered by the population (Spanish colonisation, slave trade), aboriginal mtDNA lineages constitute a considerable proportion of the Canarian gene pool. Although the Berbers are the most probable ancestors of the Guanches, it is deduced that important human movements have reshaped Northwest Africa after the migratory wave to the Canary Islands." The "sublineage U6b1 is the most prevalent of the U6 subhaplogroup in the Canarian population,4 and has still not been detected in North Africa." "This survey includes 131 teeth, corresponding to 129 different individuals, belonging to 15 archaeological sites sampled from four of the seven Canary Islands and dated around 1000 years old ." "The Canarian-specific U6b1 sequences are also found in high frequency (8.45%), corroborating the fact that these lineages were already present in the aboriginal population. Three additional founder haplotypes4 were also detected (260, 069 126 and 126 292 294), all of them showing equal or higher frequencies than in the present day Canarian population." "The detection in the Guanches of the most abundant haplotype of the U6b1 branch, also found in present day islanders,4 points to a significant continuity of the aboriginal maternal gene pool." "The estimated age of the subgroup is around 6000 years,29 which predates the arrival of the first human settlers to the Islands.1" # Guanches in 1496 The image on the right hangs in the interior of the ayuntamiento of San Cristobal de La Laguna, Tenerife. The painting on the right shows the surrender of the Guanches kings of Tenerife to Ferdinand and Isabella. This appears to have occurred c. 504 b2k. The painting on the left was painted in 1764. It depicts the surrender of the Guanches leaders Bencomo mencey with Tacoronte, Anaga and Tegueste to Governor Alonso Fernández de Lugo with his captains and noble friends, by bringing gifts to the governor. # Ainu in 1860s The Ainu are a people inhabiting the Northern island of Yesso. They differ from the Japanese in language and race. Their origin is lost in a wild and fabulous tradition. The legend runs thus—“That the race owes its preservation to a doll which swam across from Corea to the uninhabited island of Yesso.” They were conquered some three hundred years ago by the Japanese. The colorized photograph on the right is from between 1863 and 1870 (137-130 b2k). The map shows their widest expanse historically. # Chemistry # Noncoding DNA More than 98% of the human genome does not encode protein sequences, including most sequences within introns and most intergenic DNA. Fully 98% of the human genome is noncoding DNA. Over 80% of DNA in the human genome "serves some purpose, biochemically speaking". # Non-coding repetitive sequences Over 50% of human DNA consists of non-coding repetitive sequences. # Non-coding RNA sequences Some DNA sequences that do not code protein may still encode functional non-coding RNA molecules, which are involved in the regulation of gene expression. # Pseudogenes An abundant form of noncoding DNA in humans are pseudogenes, which are copies of genes that have been disabled by mutation. These sequences are usually just molecular fossils, although they can occasionally serve as raw genetic material for the creation of new genes through the process of gene duplication and divergence. # Genes Def. a "unit of heredity; a segment of DNA or RNA that is transmitted from one generation to the next, and that carries genetic information such as the sequence of amino acids for a protein" is called a gene. The genetic information in a genome is held within genes, and the complete set of this information in an organism is called its genotype. A gene is a unit of heredity and is a region of DNA that influences a particular characteristic in an organism. Genes contain an open reading frame that can be transcribed, as well as regulatory sequences such as promoters and enhancers, which control the transcription of the open reading frame. Only about 1.5% of the human genome consists of protein-coding exons. # Telomeres Some noncoding DNA sequences such as telomeres and centromeres play structural roles in chromosomes. Telomeres are usually lengths of single-stranded DNA containing several thousand repeats of a simple TTAGGG sequence. Telomeres and centromeres typically contain few genes, but are important for the function and stability of chromosomes. # Centromeres Centromeres are chromosomal loci that ensure delivery of a copy of a chromosome to each daughter upon cell division. On the Spindle Apparatus, chromosome movement is run and maintained by the centromere during meiosis and mitosis. # Introns An intron is any nucleotide sequence within a gene that is removed by RNA splicing while the final mature RNA product of a gene is being generated. The term intron refers to both the DNA sequence within a gene and the corresponding sequence in RNA transcripts. There are several families of internal nucleic acid sequences that are not present in the final gene product, including inteins, untranslated sequences (Untranslated region UTR), and nucleotides removed by RNA editing, in addition to introns. Introns are extremely common within the nuclear genome of higher vertebrates (e.g. humans and mice), where protein-coding genes almost always contain multiple introns. Some introns themselves encode specific proteins or can be further processed after splicing to generate noncoding RNA molecules. Alternative splicing is widely used to generate multiple proteins from a single gene. Furthermore, some introns represent mobile genetic elements and may be regarded as examples of selfish DNA. The human genome contains an average of 8.4 introns/gene (139,418 in the genome). Some introns are known to enhance the expression of the gene that they are contained in by a process known as intron-mediated enhancement (IME). # Geography The specifics of Paleo-Indian migration to and throughout the Americas, including the exact dates and routes traveled, are subject to ongoing research and discussion. # Americas The map at the right is a schematic illustration of maternal geneflow in and out of Beringia. Colours of the arrows correspond to approximate timing of the events and are decoded in the coloured time-bar. The initial peopling of Berinigia (depicted in light yellow) was followed by a standstill after which the ancestors of indigenous Americans spread swiftly all over the New World while some of the Beringian maternal lineages–C1a-spread westwards. More recent (shown in green) genetic exchange is manifested by back-migration of A2a into Siberia and the spread of D2a into north-eastern America that post-dated the initial peopling of the New World. # South America Genetic history of indigenous peoples of the Americas primarily focus on Human Y-chromosome DNA haplogroups and Human mitochondrial DNA haplogroups. "Y-DNA" is passed solely along the patrilineal line, from father to son, while "mtDNA" is passed down the matrilineal line, from mother to offspring of both sexes. Neither recombines, and thus Y-DNA and mtDNA change only by chance mutation at each generation with no intermixture between parents' genetic material. Autosomal "atDNA" markers are also used, but differ from mtDNA or Y-DNA in that they overlap significantly. AtDNA is generally used to measure the average continent-of-ancestry genetic admixture in the entire human genome and related isolated populations. "The traditional Western theory has been that these early migrants moved into the Beringia land bridge between eastern Siberia and present-day Alaska around 40,000—16,500 years ago, when sea levels were significantly lowered due to the Quaternary glaciation. These people are believed to have followed herds of now-extinct Pleistocene megafauna along ice-free corridors that stretched between the Laurentide and Cordilleran ice sheets. Another route proposed is that, either on foot or using primitive boats, they migrated down the Pacific Northwest coast to South America. Evidence of the latter would since have been covered by a sea level rise of hundreds of meters following the last ice age. Some recent DNA studies suggest additional migration from Europe around the northern fringe of the Atlantic possibly as long ago as either 36,000 to 23,000 years ago or between 17,000 to 12,000 years. However, this is also attributed to admixture of Europeans into northern Asia before the Beringian migration. Recent genetic studies have shown that that Paleolithic Europeans and Native Americans share a genetic founder population and that there is strong evidence that the "population that crossed the Bering Strait from Siberia into the Americas more than 15,000 years ago was likely related to the ancient population of Europe." "Canada's oldest known home is a cave in Yukon occupied not 12,000 years ago like the U.S. sites, but at least 20,000 years ago" "However, despite the lack of this conclusive and widespread evidence, there are suggestions of human occupation in the northern Yukon about 24,000 years ago, and hints of the presence of humans in the Old Crow Basin as far back as about 40,000 years ago." A "site in southern Chile called Monte Verde human occupation1 that dated to about 14,500 years ago." # Hypotheses - There is at least one isoform in hominin DNA that makes Homo sapiens sapiens unique. # Acknowledgements The content on this page was first contributed by: Henry A. Hoff. Initial content for this page in some instances came from Wikiversity.	Human DNA Editor-In-Chief: Henry A. Hoff "[H]uman DNA has millions of on-off switches and complex networks that control the genes' activities. ... [A]t least 80% of the human genome is active, which opposed the previously held idea that most of the DNA are useless."[1] "DNA contains genes, which hold the instructions for [life. But, these] take up only about 2 percent of the genome ... The human genome is made up of about 3 billion “letters” along strands that make up the familiar double helix structure of DNA. Particular sequences of these letters form genes, which tell cells how to make proteins. People have about 20,000 genes, but the vast majority of DNA lies outside of genes. ... [A]t least three-quarters of the genome is involved in making RNA [...] it appears to help regulate gene activity."[2] # Genetics There are "more than 4 million sites where proteins bind to DNA to regulate genetic function, sort of like a switch."[2] "Humans belong to the biological group known as Primates, and are classified with the great apes, one of the major groups of the primate evolutionary tree. Besides similarities in anatomy and behavior, our close biological kinship with other primate species is indicated by DNA evidence. It confirms that our closest living biological relatives are chimpanzees and bonobos, with whom we share many traits. But we did not evolve directly from any primates living today."[3] "DNA also shows that our species and chimpanzees diverged from a common ancestor species that lived between 8 and 6 million years ago. The last common ancestor of monkeys and apes lived about 25 million years ago."[3] # Deoxyribonucleic acids Deoxyribonucleic acid (DNA) is a polymer composed of nucleic acids linked together by sugar-phosphate backbone. The nucleic acids are inorganic acids with phosphoric acid as the only acid. Attached to each sugar is a nucleobase. Nitrogenous bases, found in cell nuclei, are nucleobases. In normal spiral DNA the bases form pairs between the two strands: Adenine (A) with Thymine (T) and Cytosine (C) with Guanine (G). Purines pair with pyrimidines mainly for dimensional reasons - only this combination fits the constant width geometry of the DNA spiral. "The amount of difference in DNA is a test of the difference between one species and another – and thus how closely or distantly related they are."[4] "While the genetic difference between individual humans today is minuscule – about 0.1%, on average – study of the same aspects of the chimpanzee genome indicates a difference of about 1.2%. The bonobo (Pan paniscus), which is the close cousin of chimpanzees (Pan troglodytes), differs from humans to the same degree. The DNA difference with gorillas, another of the African apes, is about 1.6%. Most importantly, chimpanzees, bonobos, and humans all show this same amount of difference from gorillas. A difference of 3.1% distinguishes us and the African apes from the Asian great ape, the orangutan. How do the monkeys stack up? All of the great apes and humans differ from rhesus monkeys, for example, by about 7% in their DNA."[4] "Geneticists have come up with a variety of ways of calculating the percentages, which give different impressions about how similar chimpanzees and humans are. The 1.2% chimp-human distinction, for example, involves a measurement of only substitutions in the base building blocks of those genes that chimpanzees and humans share. A comparison of the entire genome, however, indicates that segments of DNA have also been deleted, duplicated over and over, or inserted from one part of the genome into another. When these differences are counted, there is an additional 4 to 5% distinction between the human and chimpanzee genomes."[4] "No matter how the calculation is done, the big point still holds: humans, chimpanzees, and bonobos are more closely related to one another than either is to gorillas or any other primate. From the perspective of this powerful test of biological kinship, humans are not only related to the great apes – we are one. The DNA evidence leaves us with one of the greatest surprises in biology: the wall between human, on the one hand, and ape or animal, on the other, has been breached. The human evolutionary tree is embedded within the great apes."[4] # Archaeology "About 14,000 years ago [14,000 before the year 2000.0, 14,000 b2k], modern humans roamed to South Florida and lived side by side with mammoths, mastodons and saber-tooth tigers."[5] At "the Old Vero Man site [a] large number of animal and human bones were discovered [...], providing a rare glimpse of the Florida landscape at the end of the last Ice Age."[5] "Based on the fossil record, here is what many archaeologists believe: Modern humans first appeared about 195,000 years ago in East Africa. Likely chasing prey, they moved across Asia and what was then a land bridge to Alaska, arriving in North America about 20,000 to 25,000 years ago. They then took 5,000 to 6,000 years to cross the continent to Florida."[5] "The old model basically had these folks sprinting across North America, chasing and killing big animals. We know now they moved very gradually.[6] "They finally reached Vero Beach about 13,000 to 14,000 years ago, as the Pleistocene Epoch and the last Ice Age were drawing to an end. At the time, Florida was almost double its current size, extending out into the Gulf of Mexico and the Atlantic, and much of the state was more than 300 feet above sea level."[7] "The landscape was so different than what it is today."[7] "Florida also was home to tapirs, sloths, camels, bison and horses — in addition to mastodons and mammoths. Many converged at what was then an "oasis" of streams and rivers about 35 miles inland from the ocean. Today, that is the Old Vero Man site and it's about five miles inland."[7] "It was a fairly constant source of fresh water and a tremendous draw to animals and human beings."[7] "Growing in numbers and becoming more skilled hunters, the humans continued forging south, evidenced by the Cutler Fossil Site on the Charles Deering Estate in south Miami-Dade County. That site [dates] back almost 12,000 years [12,000 b2k.]"[8] "[Bones from Paleo-Indians and] 103 species of animals, including mammoths, a saber-tooth cat, a paleo-lama, and a California condor [have been found at the Cutler Fossil Site]."[8] "By the time humans arrived in what is now South Florida, the Ice Age was almost over. Mastodons and their ilk were going extinct, likely because of climate change."[6] "With ancient DNA, you're time traveling. It provides us with a unique opportunity to look into Florida's past."[9] # Paleogene The Paleogene Period extends from 65.5 ± 0.3 to 23.03 ± 0.05 x 106 b2k. The graph above shows many of the hominins that have been discovered so far in Africa and elsewhere on Earth. # Paleocene The Paleocene dates from 65.5 ± 0.3 x 106 to 55.8 ± 0.2 x 106 b2k. # Eocene The Eocene dates from 55.8 ± 0.2 x 106 to 33.9 ± 0.1 x 106 b2k. # Oligocene The Oligocene dates from 33.9 ± 0.1 x 106 to 23.03 x 106 b2k. # Rukwapithecus Rukwapithecus is "an early member of the hominoids, the group containing the great apes (gorillas, chimpanzees, bonobos, orangutans and humans) and lesser apes (gibbons)."[10] "The fossil remnants ... date back 25 million years ago, filling a gap in the fossil record that reveals when apes and monkeys first diverged."[10] "These discoveries are important because they offer the earliest fossil evidence for either of these primate groups".[11] "The fossils were found in a layer of the Rukwa Rift in Tanzania. The region is part of the East African Rift, a tectonic-plate boundary where the Earth's crust is being pulled apart."[10] “The new discoveries are particularly important for helping to reconcile a long-standing disagreement between divergence time estimates derived from analyses of DNA sequences from living primates and those suggested by the primate fossil record.”[12] "Studies of clock-like mutations in primate DNA have indicated that the split between apes and Old World monkeys occurred between 30 million and 25 million years ago."[12] # Holarctic-Antarctic Ice Age "This late Cenozoic ice age began at least 30 million years ago in Antarctica; it expanded to Arctic regions of southern Alaska, Greenland, Iceland, and Svalbard between 10 and 3 million years ago. Glaciers and ice sheets in these areas have been relatively stable, more-or-less permanent features during the past few million years."[13] # Neogene The Neogene dates from 23.03 x 106 to 2.58 x 106 b2k. # Miocene The Miocene dates from 23.03 x 106 to 5.332 x 106 b2k. # Tortonian The Tortonian lasted from 11.63 Ma to 7.246 Ma. Gigantopithecus is an extinct genus of ape that existed from perhaps nine million years to as recently as one hundred thousand years ago, at the same period as Homo erectus would have been dispersed,[14] in what is now India, Vietnam, China and Indonesia placing Gigantopithecus in the same time frame and geographical location as several hominin species.[15][16] The primate fossil record suggests that the species Gigantopithecus blacki were the largest known primates that ever lived, standing up to 3 m (9.8425197 ft) and weighing as much as 540 (Expression error: Unexpected round operator. ),[14][17][18][19] although some argue that it is more likely that they were much smaller, at roughly 1.8 (Expression error: Unexpected round operator. ) in height and 180 (Expression error: Unexpected round operator. ) in weight.[20][21][22][23] # Prehistory The prehistory period dates from around 7 x 106 b2k to about 7,000 b2k. # Pliocene The Pliocene ranges from 5.332 x 106 to 2.588 x 106 b2k. # Zanclean "The boundary-stratotype of the stage is located in the Eraclea Minoa section on the southern coast of Sicily (Italy), at the base of the Trubi Formation. The age of the Zanclean and Pliocene GSSP at the base of the stage is 5.33 Ma in the orbitally calibrated time scale, and lies within the lowermost reversed episode of the Gilbert Chron (C3n.4r), below the Thvera normal subchron."[24] # Piacenzian "The base of the beige marl bed of the small-scale carbonate cycle 77 (sensu Hilgen, 1991b) is the approved base of the Piacenzian Stage (that is the Lower Pliocene-Middle Pliocene boundary). It corresponds to precessional excursion 347 as numbered from the present with an astrochronological age estimate of 3.600 Ma (Lourens et al., 1996a)."[25] # Paleolithic The paleolithic period dates from around 2.6 x 106 b2k to the end of the Pleistocene around 12,000 b2k. # Quaternary The "whole change elapsed just opposite the course of events that characterized the great glacial oscillations with sudden warming followed by slow cooling. Therefore, the two phenomena hardly have the same cause."[26] # Pleistocene The Pleistocene dates from 2.588 x 106 to 11,700 b2k. # Gelasian "The base of the Quaternary System [shown in the image on the right] is defined by the Global Stratotype Section and Point (GSSP) of the Gelasian Stage at Monte San Nicola in Sicily, Italy, currently dated at 2.58 Ma."[27] # Calabrian "The [Calabrian] GSSP occurs at the base of the marine claystone conformably overlying sapropelic bed ‘e’ within Segment B in the Vrica section. This lithological level represents the primary marker for the recognition of the boundary, and is assigned an astronomical age of 1.80 Ma on the basis of sapropel calibration."[28] # Homo erectus ""Peking Man," a human ancestor who lived in China between roughly 200,000 and 750,000 years ago, was a wood-working, fire-using, spear-hafting hominid ... these hominids, a form of Homo erectus, appear to have been quite meticulous about their clothing, using stone tools to soften and depress animal hides."[29] Peking Man Homo erectus pekinensis, is an example of Homo erectus. A group of fossil specimens was discovered in 1923–27 during excavations at Zhoukoudian (Chou K'ou-tien) near Beijing. The finds have been dated from roughly 750,000 years ago,[30] although a new 26Al/10Be dating suggests they may be as much as 680,000–780,000 years old.[31][32] Skulls X, XI and XII (sometimes called LI, LII and LIII) were discovered at Locus L in 1936. They are thought to belong to an adult man, an adult woman and a young adult, with brain sizes of 1225 cc, 1015 cc and 1030 cc respectively.[33] The ribonucleotide reductase RRM2P4 gene data suggests that the Chinese, while largely descending from Africa like others, nevertheless have some genetic legacy from hybridization with older Eurasian populations,[34][35] consistent with limited multiregional evolution. Homo erectus is an extinct species of hominid that lived from the end of the Pliocene epoch to the later Pleistocene, with the earliest first fossil evidence dating to around 1.8 million years ago and the most recent to around 300,000 years ago. The species originated in Africa and spread as far as Spain, Georgia, India, China and Java.[36][37] "By the 1980s, the growing numbers of H. erectus specimens, particularly in Africa, led to the realization that Asian H. erectus (H. erectus sensu stricto), once thought so primitive, was in fact more derived than its African counterparts. These morphological differences were interpreted by some as evidence that more than one species might be included in H. erectus sensu lato (e.g., Stringer, 1984; Andrews, 1984; Tattersall, 1986; Wood, 1984, 1991a, b; Schwartz and Tattersall, 2000)." ... "Unlike the European lineage, in my opinion, the taxonomic issues surrounding Asian vs. African H. erectus are more intractable. The issue was most pointedly addressed with the naming of H. ergaster on the basis of the type mandible KNM-ER 992, but also including the partial skeleton and isolated teeth of KNM-ER 803 among other Koobi Fora remains (Groves and Mazak, 1975). Recently, this specific name was applied to most early African and Georgian H. erectus in recognition of the less-derived nature of these remains vis à vis conditions in Asian H. erectus (see Wood, 1991a, p. 268; Gabunia et al., 2000a). It should be noted, however, that at least portions of the paratype of H. ergaster (e.g., KNM-ER 1805) are not included in most current conceptions of that taxon. The H. ergaster question remains famously unresolved (e.g., Stringer, 1984; Tattersall, 1986; Wood, 1991a, 1994; Rightmire, 1998b; Gabunia et al., 2000a; Schwartz and Tattersall, 2000), in no small part because the original diagnosis provided no comparison with the Asian fossil record."[38] From the 1950s to 1970s, however, numerous fossil finds from East Africa yielded evidence that the oldest hominins originated there. It is now believed that H. erectus is a descendant of earlier genera such as Ardipithecus and Australopithecus, or early Homo-species such as H. habilis or H. ergaster. H. habilis and H. erectus coexisted for several thousand years, and may represent separate lineages of a common ancestor.[39] "[S]ome of the oldest stone hand axes on Earth ... unearthed in Ethiopia ... date to 1.75 million years ago. ... fossilized H. erectus remains were also found at the same site ... These Aucheulean tools could be up to 7.8 inches (20 centimeters) long"[40]. "[J]awbone fossils unearthed at a site east of Lake Turkana in Kenya suggest there were two additional species of ... Homo, living alongside ... Homo erectus, nearly 2 million years ago."[41] When "excavating a cave in Balanica, Serbia, that contained ancient archaeological remains ... an ancient jawbone fragment with three molars still intact [was found] ... several dating techniques [determined] the fragment was definitely older than 397,000 years and perhaps older than 525,000 years. The jawbone lacked several characteristic Neanderthal features, including distinctive chewing surfaces on the teeth that show up in Western Europe at that time. Instead, the fossil resembled the more primitive Homo erectus. ... Neanderthals may not have evolved in this region of Southeastern Europe, at least during this time. ... during several ice ages, rising glaciers over the past eons cut off Western Europe from the rest of the continent, and this isolation likely contributed to the evolution of Neanderthals' distinctive features from the more primitive Homo erectus."[42] "Javanese specimens of Homo erectus had brains about 860 cubic cm (52 cubic inches) large".[43] "Researchers examined one skull from a site called the Pit of Bones, which contains the remains of at least 28 people. [...] two fractures on that skull were likely to have been caused by "multiple blows" and imply "an intention to kill"."[44] "As well as providing a clue as to why the bodies were in the cave, scientists say the study provides grisly evidence that violence is an intrinsic part of the earliest human culture."[44] "This individual was killed in an act of lethal interpersonal violence."[45] The "long vertical shaft of this cave was a place where these ancient people deliberately "deposited deceased members of their social groups"."[44] "Intentional interpersonal violence is a behaviour that accompanies humans since at least 430,000 years ago, but so does the care of sick or even the care of the dead."[45] "We have not changed much in the last half million years."[45] "I suspect the farther we push back and find straight up forensic evidence such as these authors have, we will find that violence is culturally mediated and has been with us as long as culture itself has been with us."[46] "We don’t see any Denisovan ancestry in populations living in mainland Southeast Asia, or Indonesia, or indeed in any population west of Wallace’s Line [which marks the eastern border of placental mammals, while Lydekker’s line marks the western border of the marsupial fauna: Wallacea lies between]. It could be that later population movements have diluted the Denisovan taint, but it is apparently undetectable even in existing populations that are thought to represent earlier strata, such as the Andaman islanders. Nor has it been seen in ancient DNA from modern humans on the Asian mainland."[47] "Back in the day, Indonesia was a big peninsula, called Sundaland. Let us assume that there were Denisovans there. In some way, Denisovan effective population density was higher there than in mainland Asia, or perhaps they were harder to displace. For example, some of Sundaland seems to have been tropical rainforest, otherwise known as the Green Hell – maybe there were some potent tropical diseases (vector-borne) that the Denisovans had developed resistance to, while the invading anatomical modern humans had not [Cooper and Stringer were also thinking about jungle pathogens] – the same reason that Europeans or Middle Easterners didn’t replace sub-Saharan African populations."[47] "So modern humans expand into Sundaland more slowly, in something like a range expansion. The further they moved into Sundaland, the more Denisovan genes they picked up."[47] "So the humans living at the eastern edge of Sundaland, particularly in Borneo, have more Denisovan ancestry in this scenario than anyone else in Eurasia – and they would be the people who take the next step, crossing the narrow seas to the Philippines, Wallacea, and then Sahul (Australia/New Guinea), virgin lands in which the hand of man had never set foot [with the possible exception of Flores]. A quite small, unusually Denisovanized coastal population of hunter-gatherers then undergoes a vast expansion, becoming as numerous as the stars in the sky."[47] "Aboriginal skulls vary, but some look much more like archaics, more like erectus, than those from any other existing population. This was noticed a long time ago, by pros like Weidenreich."[47] "Actually, they look surprisingly archaic, considering that total archaic ancestry among Melanesians is under 10% [Neanderthal plus Denisovan]. Recent selective pressure are probably more important: it is possible that their archaic appearance is to some degree coincidence."[47] “The skulls of Australian Aborigines, although variable, in some ways look more old-fashioned, more like archaics, than any other existing human population.”[48] "The discovery of DNA in a 400,000-year-old human thigh bone [femur] comes from the famed "Pit of Bones" site in Spain, which gave up the remains of at least 28 ancient people."[49] "The early human remains from the cave site near the northern Spanish city of Burgos have been painstakingly excavated and pieced together over the course of more than two decades. It has yielded one of the richest assemblages of human bones from this stage of human evolution, in a time called the Middle Pleistocene."[49] "The fossils carry many traits typical of Neanderthals, and either belong to an ancestral species known as Homo heidelbergensis - or, as the British palaeoanthropologist Chris Stringer suggests - are early representatives of the Neanderthal lineage."[49] "Rather than showing a relationship between the Spanish specimens and Neanderthals, which might be expected based on their physical features, the mitochondrial DNA was most similar to that found in 40,000 year-old material unearthed thousands of kilometres away at Denisova Cave in Siberia."[49] "The Denisovans were a sister group to the Neanderthals, with distinct genetic characteristics. Identified only by DNA extracted from a tiny finger bone and tooth, they are, as some researchers have remarked, "a genome in search of a fossil" because there are no substantial remains representative of this group."[49] "By using missing mutations in the old DNA sequences, the researchers calculated that the Pit of Bones individual shared a common ancestor with the Denisovans about 700,000 years ago."[49] Interbreeding "between the Pit of Bones people (or their ancestors) and yet another early human species brought the Denisovan-like DNA into this western population. Prof Bermudez de Castro thinks there may be a candidate for this cryptic ancestor: an earlier human species known as Homo antecessor. One million years ago, antecessor inhabited the site of Gran Dolina, just a few hundred metres away from the Pit of Bones."[49] "mtDNA is a small and unusual component of our genetic blueprint, from which only limited conclusions can be drawn. For example, no sign of the interbreeding we now know took place between Neanderthals and modern humans remains in the mtDNA of modern people."[49] "That is our next big thing here, to sequence at least part of the nuclear genome from the individual in the Sima de los Huesos."[50] # Homo heidelbergensis "Homo heidelbergensis is known to have lived from at least 600,000 years ago in Africa and Europe to maybe as late as 250,000 years ago in some areas."[51] "The first fossil identified as H. heidelbergensis was a jaw discovered near Heidelberg, Germany in 1907. Since then various other finds have been made in Europe, Asia and Africa. They show a less projecting face, more prominent nose and a bigger braincase than Homo erectus, but also more primitive features than those of Neanderthals and modern humans."[51] "Some H. heidelbergensis individuals had brain sizes within the modern human range. However, facially they still looked very different from us, with a longer, lower shaped skull, large brow ridge and no chin."[51] "Evidence shows that H. heidelbergensis was an accomplished tool-maker and skillfully butchered large animals. The remains of horses, elephants, deer and rhinoceroses with butchery marks on their bones have been found alongside fossils of this hominin in Southern England and Germany. Whether they actively hunted the animals isn’t known. But, even if they scavenged the carcasses, these hominins were organised enough to drive off dangerous competing animals such as lions, hyenas and wolves."[51] # Early Pleistocene Early Pleistocene spans ca. 730,000-1,600,000 yr BP.[52] # Nebraskan glacial Nebraskan glacial spans ca. 650,000-1,000,000 yr BP.[52] # Middle Pleistocene Middle Pleistocene spans ca. 150,000-730,000 yr BP.[52] # Aftonian interglacial "Clay deposition in the Piauí River floodplain around 436 ± 51.5 ka occurred during a warmer period of the Aftonian interglaciation, corresponding to isotope stage 12 (Ericson and Wollin, 1968)."[53] "Neanderthal and Homo sapiens DNA reveals that they shared a common ancestor about 400,000 years ago. Many scientists think this could have been H. heidelbergensis, giving rise to Neanderthals in Europe and to our species in Africa. And perhaps to the Denisovans in Asia."[51] # Neanderthals "[M]odern humans in the eastern parts of Eurasia and Native Americans actually carry more Neanderthal genetic material than people in Europe, "even though the Neanderthals mostly lived in Europe, which is really, really interesting," Reich said."[54] From mtDNA analysis estimates, the two species shared a common ancestor about 500,000 years ago. An article[55] appearing in the journal Nature has calculated the species diverged about 516,000 years ago, whereas fossil records show a time of about 400,000 years ago.[56] A 2007 study pushes the point of divergence back to around 800,000 years ago.[57] "Our work suggests that at present, it is unlikely that Neanderthals survived any later in this area [southern Iberia] than they did elsewhere in mainland Europe."[58] "Neanderthals (or Neandertals) are our closest extinct human relatives. [They may have been] a subspecies [Homo sapiens neanderthalensis]. Our well-known [...] fossil kin lived in Eurasia 200,000 to 30,000 years ago, in the Pleistocene Epoch. [...] they used tools, buried their dead and controlled fire, among other intelligent behaviors."[59] "Neanderthals were seen as too brutish to catch fast prey."[60] "Neanderthals came to Europe some 300,000 years ago. They hunted big game with stone tools. Their territory spanned Europe and Asia. They left distinctive "Mousterian" artefacts."[61] "The first analysis of mitochondrial DNA (mtDNA) from Neanderthals was published in 1997."[62] "The specimen was taken from the first Neanderthal fossil discovered, from Feldhofer Cave, in the Neander Valley, Germany. A small sample of bone was ground up to extract mtDNA."[62] "The Neanderthal mtDNA sequences were substantially different from modern human mtDNA (Krings et al. 1997, 1999). Researchers compared the Neanderthal to modern human and chimpanzee sequences. Most human sequences differ from each other by on average 8.0 substitutions, while the human and chimpanzee sequences differ by about 55.0 substitutions. The Neanderthal and modern human sequences differed by approximately 27.2 substitutions. Using this mtDNA information, the last common ancestor of Neanderthals and modern humans dates to approximately 550,000 to 690,000 years ago, which is about four times older than the modern human mtDNA pool. This is consistent with the idea that Neanderthals did not contribute substantially to modern human genome."[62] "A second mtDNA sequence, announced in 2000, was derived from a 29,000 year old Neanderthal found in Mezmaiskaya Cave, Russia (Ovchinnikov et al. 2000). Although the Mezmaiskaya Cave sequence was slightly different than the Feldhofer Neanderthal, the two Neanderthal mtDNA sequences were distinct from those of modern humans. These results confirmed the earlier findings that showed that Neanderthals were unlikely to have contributed to the modern human genome. As with the previous study of Neanderthal mtDNA, results were consistent with separation between the Neanderthal and modern human gene pools or with very low amounts of gene flow between the two groups."[62] "Researchers have also studied ancient DNA from anatomically modern Homo sapiens from Europe dating to the same time period as the Neanderthals. Material from two Paglicci Cave, Italy individuals, dated to 23,000 and 25,000 years old, was sequenced. The Paglicci Homo sapiens mtDNA sequences were different from all Neanderthal mtDNA sequences but were within the range of variation for modern human mtDNA sequences (Caramelli et al. 2003). Mitochondrial DNA from the Paglicci specimens as well as other ancient humans fit within the range of modern humans, but the Neanderthals remain consistently genetically distinct. This shows that early anatomically modern Homo sapiens were not very different genetically from current modern humans, but were still different from Neanderthals."[62] "DNA was extracted from three Neanderthal bones from Vindija Cave, Croatia. By comparing sequences from their mtDNA and their nuclear DNA, scientists determined that the three bones came from different individuals, although two of them might be related on their mother’s side."[63] "The Neanderthal sequence was compared to those of five modern humans from France, China, Papua New Guinea, as well as Africans from the San and Yoruba groups. Tests indicated that Neanderthals shared more derived alleles with non-African modern humans than with African modern humans. They compared parts of the Neanderthal genome with pairs of modern humans. While the European and Asian pairs had similar amounts of derived material compared with the Neanderthal, Neanderthals had more similarities with non-African humans than with Africans."[63] "Neanderthals have contributed approximately 1% to 4% to the genomes of non-African modern humans."[63] "Since the Neanderthal DNA was equally related to that of the modern samples from France, China and Papua New Guinea, admixture between moderns and Neanderthals must have occurred before the Eurasian populations split off from each other. Remains of both modern humans and Neanderthals dating to around 100,000 years ago have been found in the Middle East."[63] "Researchers found 78 sequence differences that would have affected proteins in which Neanderthals had the ancestral state and modern humans had a newer, derived state. Five genes had more than one sequence change that affected the protein structure. These proteins include SPAG17, which is involved in the movement of sperm, PCD16, which may be involved in wound healing, TTF1, which is involved in ribosomal gene transcription, and RPTN, which is found in the skin, hair and sweat glands. Scientists do not know the function of the CAN15 protein, which was also one of the differences."[63] "Nested clade phylogenetic analysis shows evidence of three expansions out of Africa at 1.9 Ma, 650,000 years, and 130,000 years, which is consistent with the admixture between ancient and modern populations rather than complete replacement (Templeton 2002, 2005, 2007)."[64] "Ancient DNA has been used to show aspects of Neanderthal appearance. A fragment of the gene for the melanocortin 1 receptor (MRC1) was sequenced using DNA from two Neanderthal specimens from Spain and Italy, El Sidrón 1252 and Monte Lessini (Lalueza-Fox et al. 2007). Neanderthals had a mutation in this receptor gene that has not been found in modern humans. The mutation changes an amino acid, making the resulting protein less efficient. Modern humans have other MCR1 variants that are also less active resulting in red hair and pale skin. The less active Neanderthal mutation probably also resulted in red hair and pale skin, as in modern humans."[65] "The specific MCR1 mutation in Neanderthals has not found in modern humans (or occurs extremely rarely in modern humans). This indicates that the two mutations for red hair and pale skin occurred independently and does not support the idea of gene flow between Neanderthals and modern humans. Pale skin may have been advantageous to Neanderthals living in Europe because of the ability to synthesize vitamin D."[65] "The FOXP2 gene is involved in speech and language (Lai et al. 2001). Changes in the FOXP2 gene sequence led to problems with speech, oral and facial muscle control in modern humans with a mutation in the gene. It impairs language function. Modern humans and Neanderthals share two changes in FOXP2 compared with the sequence in chimpanzees (Krause et al. 2007)."[65] "The gene that produces the ABO blood system is polymorphic in humans. Various selection factors may favor different alleles, leading to the maintenance of distinct blood groups in modern human populations. Though chimpanzees also have different blood groups, they are not the same as human blood types. While the mutation that causes the human B blood group arose around 3.5 Ma, the O group mutation dates to around 1.15 Ma. Lalueza-Fox and colleagues (2008) tested whether Neanderthals had the O blood group. They found that two Neanderthal specimens from Spain probably had the O blood type, though there is the possibility that they were OA or OB. Though the O allele was likely to have already appeared before the split between humans and Neanderthals, it could also have arisen in the Neanderthal genome via gene from modern humans."[65] "The ability to taste bitter substances is controlled by a gene, TAS2R38. Some individuals are able to taste bitter substances, while others have a different version of the gene that does not allow them to taste bitter items. Possession of two copies of alleles associated with tasting bitter substances gives the individual greater perception of bitter tastes than the heterozygous state, in which individuals have one tasting allele and one non-tasting allele. Two copies of a non-tasting allele leads to inability to taste bitter substances."[65] "A Neanderthal from El Sidrón, Spain, was sequenced for the TAS23R38 gene. They found that this individual was heterozygous and thus was able to perceive bitter taste, although not as strongly as a homozygous individual with two copies of the tasting allele would be able to (Lalueza-Fox et al. 2009). Since the Neanderthal sequenced was heterozygous, the two alleles (tasting and non-tasting) were probably both present in the common ancestor of Neanderthals and modern humans. Though chimpanzees also vary in their ability to taste bitterness, their abilities are controlled by different alleles than those found in humans, indicating that non-tasting alleles evolved separately in the hominin lineage."[65] "The microcephalin gene relates to brain size during development. A variant of this, haplogroup D, may have been positively selected for in modern humans – and may also have come from an interbreeding event with an archaic population (Evans et al. 2006). Mutations in microcephalin cause the brain to be 3 to 4 times smaller in size. All of the haplogroup D variants come from a single copy that appeared in modern humans around 37,000 years ago. However, haplogroup D itself came from a lineage that had diverged from the lineage that led to modern humans around 1.1 million years ago. Although there was speculation that the Neanderthals were the source of the microcephalin haplogroup D (Evans et al. 2006), the Neanderthal DNA recently sequenced does not contain the microcephalin haplogroup D (Green et al. 2010)."[65] # Homo sapiens "The first anatomically modern human fossils date back only 195,000 years ... [But the Y chromosome of a recently deceased African-American, Albert Perry,] who lived in South Carolina [is] so distinct that his male lineage probably separated from all others about 338,000 years ago. ... [There are] similarities between Perry's [Y chromosome] and those in samples taken from 11 men, all living in one village in Cameroon. ... "The oldest known fossil humans in both West Africa at Iwo Eleru and Central Africa at Ishango [in Democratic Republic of the Congo] show unexpectedly archaic features, so it certainly looks like we have a more complex scenario for the evolution of modern humans in Africa.""[66] Two "teeth from the Luna cave in China's Guangxi Zhuang region [based] on the proportions of the teeth, [...] at least one of them must have belonged to an early Homo sapiens [...] The teeth are clearly old. Calcite crystals, which formed as water flowed over the teeth and the cave floor, date them to between 70,000 and 125,000 years ago. [...] they are evidence of an early wave of modern humans in eastern Asia."[61] "I am not convinced that these teeth are diagnostic."[67] "Bones found in Israel, including an upper jaw from Misliya cave, could be 150,000 years old."[61] In "the identification of a jawbone and two molars from Zhirendong, a cave in Guizhou province [though] the bone is over 100,000 years old, [...] the shape of its chin is suggestive of modern humans."[67] "Though the Asian fossils are Homo sapiens-like, another species could have evolved these features in parallel."[68] The "genomes of indigenous populations from south-east Asia [have been plugged] into a migration model. [The] genetic data was best explained by an early exodus that left Africa around 130,000 years ago, taking a coastal route along the Arabian peninsula, India and into Australia, followed by a later wave along the classic route."[69] # Kansan glacial Kansan glacial spans 500,000-600,000 yr BP.[52] # Yarmouthian interglacial "Clay deposition in the Piauí River floodplain around 436 ± 51.5 ka occurred during a warmer period of the [Yarmouthian interglaciation] Aftonian interglaciation, corresponding to isotope stage 12 (Ericson and Wollin, 1968)."[53] # Illinois Episode glaciation "Illinoian [is] (ca. 220,000-430,000 yr BP)".[52] # Sangamon Episode interglacial "OSL dates also suggest that last interglacial (MIS 5; Sangamon Ep.) fluvial deposits are preserved locally."[70] Age "assignment of Sangamonian (sense alto = 80,000-ca. 220,000 yr BP) [is] to Illinoian (ca. 220,000-430,000 yr BP)".[52] # Late Pleistocene Late Pleistocene spans ca. 11,000-150,000 yr BP.[52] # Eemian interglacial The "controversially split Eemian period, the predecessor of our own warm period about 125,000 years ago."[26] "The Eem interglaciation […] lasted from 131 to 117 kyr B.P."[26] The "Neanderthal fossil [in the image on the right] was 120,000 years old and, more important, that it belonged to a branch of the Neanderthal family tree with a long history. All known Neanderthals inherited their mitochondrial DNA from an ancestor who lived 270,000 years ago."[71] "The common ancestors of Neanderthals and Denisovans spread across Europe and Asia over half a million years ago. Gradually the eastern and western populations parted ways, genetically speaking."[72] "In the east, they became Denisovans. In the west, they became Neanderthals. The 430,000-year-old fossils at Sima de los Huesos — Neanderthals with Denisovanlike genes — capture the early stage of that split."[72] "At some point before 270,000 years ago, African humans closely related to us moved into Europe and interbred with Neanderthals. Their DNA entered the Neanderthal gene pool."[72] # Herning Stadial MIS Boundary 5.5 (peak) is at 123 ka.[73] "Lines engraved between 125,000 and 105,000 years ago on two animal bones found in northern China held some sort of meaning for their makers."[74] "These two bone fragments [in the image on the right] found in northern China contain engraved lines, some marked with red pigment (red dots in left line drawing), making them the oldest examples of symbolic behavior in East Asia."[74] "These ancient markings provide the oldest evidence of symbolic activity by humans or our close evolutionary relatives in East Asia."[74] "A mysterious Stone Age population called Denisovans, which had close genetic ties to Neandertals, may have carved sets of parallel lines into the pair of bone fragments."[74] "Denisovans inhabited East Asia at the same time that someone carved lines into bones at northern China’s Lingjing site [...]. But either Homo sapiens or Neandertals, who also left behind Stone Age creations with apparent symbolic meanings [...], might instead have modified the Lingjing bones."[75] "Nonetheless, the two objects from Lingjing suggest that symbolic capacities were within the realm of cognitive abilities of [Homo] species that lived before and during the evolution of Homo sapiens in Africa.”[76] "Abstract markings on the Lingjing bones resemble engraved lines on roughly 100,000-year-old pigment chunks from South Africa."[77] "As Homo sapiens was responsible for that early symbolism in Africa, and Neandertals were responsible for such in Europe, it is a fascinating possibility that these [Chinese] examples were created by another Homo species."[77] "An engraved geometric design on a roughly half-million-year-old seashell found on an Indonesian island stands as the oldest example of symbolic behavior anywhere in the world [...]. Researchers suspect the now-extinct hominid species Homo erectus carved that pattern."[75] "Almost one-quarter of 227 animal bone fragments excavated at Lingjing between 2005 and 2015 display stone tool incisions typical of butchery [...]. But that sample included two exceptions. Seven nearly parallel lines had been cut into a partial rib from an unidentified large, adult mammal. Microscopic analysis indicated that the lines were made with a sharp point that was run across the bone’s surface after it had suffered some damage from weathering. Special care was taken to create each of the first five lines with a single pass of the engraving tool. Red residue in four engraved lines indicated that a pigment had been smeared on the pattern, possibly to increase its visibility."[75] "A second rib fragment from a large mammal contained 10 roughly parallel lines that had been sliced with a sharp stone point, probably in a single session [...]. Engraving of these lines also occurred after the bone had been damaged by long exposure to the air. No pigment residue appeared on this specimen."[75] "Estimated ages of the engraved bones relied on calculations of the time since sediment in which they were found was last exposed to sunlight."[75] "Whoever cut lines into the Lingjing finds also fashioned animal bones into tools. Bone and antler artifacts found in the same sediment as the engraved ribs were likely used to retouch and sharpen used stone tools."[76] # Brørup interstadial The "Brørup interstade [is about] 100 ka BP".[78] It corresponds to GIS 23/24.[79] # Rederstall Stadial MIS Boundary 5.3 is at 96 ka.[73] Marine Isotope Stage 4. # Wisconsinian glacial Wisconsinian glacial began at 80,000 yr BP.[52] # Odderade interstadial The Odderade interstadial has a 14C date of 61-72 kyr B.P. and corresponds to GIS 21.[79] "A population that began to expand from Africa around 70 Ka reached Southeast Asia by the middle of the Upper Pleistocene. From Southeast Asia, part of this population took a southern route of expansion towards Australia, where they arrived around 50 Ka (Lahr and Foley, 1998). Sometime between 50 and 20 Ka the same Southeast Asian population took a northern route of expansion along both interior and coastal East Asia (as suggested by Fladmark, 1979), depending on the local climatic conditions. The presence of an “Australo-Melanesian-like” population in East Asia is attested by the human skeletal remains from the Zhoukoudian Upper Cave around 20 Ka (Kamminga and Wright, 1988; Wright, 1995; Neves and Pucciarelli, 1998). A late occupation of the northern zones of East Asia also agrees with the idea that major behavioral change and technological strategies necessary to exploit extreme environments were not in place until ca. 40,000 BP (Whallon, 1989; Klein, 1992, 1995)."<re name=Neves/> # Karmøy stadial The Karmøy stadial begins in the high mountains of Norway about 60 kyr B.P. and expands to the outer coast by 58 kyr B.P.[79] "To uncover the migratory path that the ancestors of present-day Eurasians (Europeans and Asians) took when moving out of Africa around 60,000 years ago, an international team of scientists generated 225 whole-genome sequences from six modern Northeast African populations (100 Egyptians and five Ethiopian populations each represented by 25 people)."[80] "The remaining masked genomic regions from Egyptian samples were more similar to non-African samples and present in higher frequencies outside Africa than the masked Ethiopian genomic regions, pointing to Egypt as the more likely gateway in the exodus to the rest of the world."[80] “Two geographically plausible routes have been proposed: an exit through the current Egypt and Sinai, which is the northern route, or one through Ethiopia, the Bab el Mandeb strait, and the Arabian Peninsula, which is the southern route.”[80] "[H]igh-quality genomes [were used] to estimate the time that the populations split from one another: people outside Africa split from the Egyptian genomes more recently than from the Ethiopians (55,000 as opposed to 65, 000 years ago), supporting the idea that Egypt was last stop on the route out of Africa."[80] “In our research, we generated the first comprehensive set of unbiased genomic data from Northeast Africans and observed, after controlling for recent migrations, a higher genetic similarity between Egyptians and Eurasians than between Ethiopians and Eurasians. This suggests that Egypt was most likely the last stop on the way out of Africa.”[80] # Oerel interstadial The Oerel interstadial has a 14C date of 53-58 kyr B.P. and corresponds to GIS 15/16 with a GIS age of 56-59 kyr B.P.[79] "Neanderthals had the brains and guile to catch and eat birds, a skill many had assumed was beyond them. Bones found in Gibraltar suggest Neanderthals hunted wild pigeons, possibly by climbing steep cliffs to reach their nests."[81] "The rock dove bones were buried in sediments laid down between 28,000 and 67,000 years ago. Most of the excavated layers date from a time when only Neanderthals lived in the area, before the arrival of modern humans around 40,000 years ago. That means only Neanderthals could have caught the rock doves."[81] "They couldn't have picked up the skills to catch the birds from modern humans."[60] "This provides the first evidence for sustained and significant use of birds for food by Neanderthals."[82] "The more we can show similarities between our ancestors and Neanderthals, the more the barriers between us are broken down."[60] "The sustained use of pigeons provides even more evidence that Neanderthal hunting and foraging abilities were on a par with those of modern humans."[82] "We know that they climbed up cliffs to hunt ibex, so maybe they also climbed to the ledges where the birds nested. I think they might have had snares or netting made from grasses, but we'll never know as it's all perishable."[60] "Neanderthals may have started with eating [the birds], then moved to other purposes such as clothing or ornamentation."[60] # Ebersdorf Stadial "Genetics suggests Neanderthal numbers dropped sharply around 50,000 years ago. This coincides with a sudden cold snap, hinting climate struck the first blow."[61] "There is a surprising genetic unity between the earliest known Europeans and contemporary Europeans, ancient DNA reveals. This finding suggests that a complex network of sexual exchange may have existed across Europe over the past 50,000 years, and also helps to pinpoint when modern humans interbred with Neanderthals, the closest extinct relatives of modern humans."[83] "There is solid evidence of modern humans at Tam Pa Ling [in Laos] around 50,000 or 60,000 years ago, and the Zhirendong mandible has modern features. So yes, modern humans were present in at least south-east Asia and south China by somewhere in this time range."[67] # Glinde interstadial The Glinde interstadial has a 14C date of 48-50 kyr B.P. and corresponds to GIS ?13/14 with a GIS age of 49-54.5 kyr B.P.[79] "It is recognized that the human population that arrived in Australia around 50,000 BP (Bowler et al., 2003) was the product of an expansive movement out of Africa, following the tropical areas of Southern Asia. This route of expansion represents one of the first offshoots of modern humans out of Africa (Stringer and Andrews 1988; Stringer 1992; Lahr, 1996; Lahr and Foley, 1998). This is why Australians and Africans still form a supra-population unit of morphological affinity (Howells, 1973, 1989; Lahr, 1996). Therefore, the similarities of the first South Americans with Australians are easily explained if we accept that both populations shared a common ancestral population in mainland East Asia (most probably Southeast Asia). A population expansion from Asia to the New World before the Mongoloid traits were fully developed in the Old World was actually predicted more than fifty years ago by Birdsell (1951:63). The similarities of the first South Americans with sub-saharan Africans may result from the fact that the non-Mongoloid Southeast Asian ancestral population came, ulti- mately, from Africa, with no major modification in the original cranial bau plan of the first moderns. Neves et al. (1999c) have already suggested a possible historical connection among early modern humans (Skhul/Kafzeh), UC 101, Paleoindians and recent Africans and Australians based on their cranial morphology."[84] # Marine Isotope Stage 3 "One bone, which came from a wild goat, was found in Zafarraya Cave in a similar layer as Neanderthal fossils. The bone was previously estimated as 33,300 years in age. However, using an ultrafiltration technique that cleansed the bone of modern carbon impurities that can give inaccurate younger dates, ... the bone was more than 46,700 years old."[85] # Moershoofd interstadial The Moershoofd interstadial has a 14C date of 44-46 kyr B.P. and corresponds to GIS 12 at 45-47 kyr B.P.[79] "Unearthed by an ivory carver from a Siberian riverbank, a man's 45,000-year-old thigh bone reveals when people first mated with Neanderthals [...] The Ust'-Ishim man's thigh bone is the oldest human bone found so far outside of Africa and the Middle East [...] It's nearly twice as old as the next oldest from a modern human, which comes from a boy who died elsewhere in Siberia some 24,000 years ago."[86] "A bone found by chance on the banks of a Siberian river has yielded the oldest modern human genome yet recovered, according to a new study that sheds light on when people left Africa and first interbred with Neanderthals living in Europe and Asia."[87] "The DNA narrows down the time when mating first brought Neanderthal genes into the human gene pool: from 50,000 to 60,000 years ago."[86] "The man, who lived 45,000 years ago, was definitely related to both humans and Neanderthals [...]. His DNA showed that the two human groups first mated around 60,000 years ago."[87] "The Ust'-Ishim man had about 2.3 percent Neanderthal genes, but modern people typically have less than 2.1 percent."[86] The "Siberian man belonged to a population that was closely related to the ancestors of today’s Europeans and Asians. He carried only slightly more Neanderthal DNA than they do."[88] “But his genomic segments of Neanderthal ancestry are on average about three times the length of those found in genomes today.”[88] This is highly informative “as the chunks of Neanderthal DNA have been gradually broken up each generation since the time of interbreeding.”[88] The "idea of a single time of human mating with Neanderthals is almost certainly [...] an oversimplification. The contacts could have extended over a longer period."[89] "The femur shaft turned up on the banks of the Irtysh River near Ust'-Ishim, Russia, in 2008. A Russian ivory carver and historian named Nikolay Peristov collected the bone after it eroded from a bluff above the river in western Siberia. It was identified as human, based on its teardrop-shaped cross section, in 2010."[86] “Thus the ancestors of Australasians (people from Australia, New Zealand, the island of New Guinea, and neighboring islands in the Pacific Ocean), with their similar input of Neanderthal DNA to Eurasians, must have been part of a late, rather than early, dispersal through Neanderthal territory.”[88] “While it is still possible that modern humans did traverse southern Asia before 60,000 years ago, those groups could not have made a significant contribution to the surviving modern populations outside of Africa, which contain evidence of interbreeding with Neanderthals.”[88] "Work on material from Italy seems to show human settlers pushing Neanderthals out (see maps). Mousterian tools were common there 45,000 years ago, when human-made Uluzzian material first appeared. By 44,000 years ago, humans were sharing Italy with a dwindling Neanderthal population. By 42,000 years ago, the Neanderthals were gone."[61] "Mousterian and Châtelperronian [artefacts] are probably Neanderthal. [...] Uluzzian, were once attributed to late Neanderthals, but recent work suggests they were made by humans (Nature, doi.org/bxh255)."[61] # Denisovans "The genome of ... the Denisovans that once interbred with us has been sequenced ... [A]bout 100,000 recent changes in our genome [have] occurred after the split from the Denisovans. ... DNA from fossils unearthed in Denisova Cave in southern Siberia in 2008 revealed a lineage unlike us and closely related to Neanderthals. The precise age of the Denisovan material remains uncertain — anywhere from 30,000 to 80,000 years of age. ... [T]he [Denisovans] lived in a vast range from Siberia to Southeast Asia. The Denisovans share more genes with people from Papua New Guinea than any other modern population studied."[90] "The picture of her genome [the girl from Denisova Cave] is as accurate as that of modern day human genomes, and shows she had brown eyes, hair and skin."[91] "The Denisovans have mysterious origins. They appear to have left little behind for palaeontologists save a tiny finger bone and a wisdom tooth found in Siberia's Denisova cave in 2010."[91] "This is an extinct genome sequence of unprecedented accuracy."[92] "For most of the genome we can even determine the differences between the two sets of chromosomes that the Denisovan girl inherited from her mother and father."[92] About "3% of the genes of people living today in Papua New Guinea come from Denisovans, with a trace of their DNA lingering in the Han and Dai people from mainland China."[92] A genetic "contribution from Denisovans is found exclusively in island Southeast Asia and Oceania (6)."[93] "Assuming 6.5 million years of sequence divergence between humans and chimpanzees, the shortening of the Denisovan branch allows the bone to be tentatively dated to between 74,000 and 82,000 years before present, in general agreement with the archaeological dates (2)."[93] Less "Denisovan allele-sharing [occurred] with the Dai than with the Han (although nonsignificantly so, Z = –0.9) [...]. Further analysis shows that if Denisovans contributed any DNA to the Dai, it represents less than 0.1% of their genomes today [...]."[93] "Denisovans share more alleles with the three populations from eastern Asia and South America (Dai, Han, and Karitiana) than with the two European populations (French and Sardinian) (Z = 5.3)."[93] Def. "the fraction of nucleotide sites that are different between a person’s maternal and paternal genomes" is called heterozygosity.[93] "The great apes have 24 pairs of chromosomes whereas humans have 23. This difference is caused by a fusion of two acrocentric chromosomes that formed the metacentric human chromosome 2 (25) and resulted in the unique head-to-head joining of the telomeric hexameric repeat GGGGTT. A difference in karyotype would likely have reduced the fertility of any offspring of Denisovans and modern humans. We searched all DNA fragments sequenced from the Denisovan individual and identified 12 fragments containing joined repeats. By contrast, reads from several chimpanzees and bonobos failed to yield any such fragments (8). We conclude that Denisovans and modern humans (and presumably Neandertals) shared the fused chromosome 2."[93] "In total, we identified 111,812 single-nucleotide changes (SNCs) and 9499 insertions and deletions where modern humans are fixed for the derived state, whereas the Denisovan individual carried the ancestral, i.e., ape-like, variant (8). This is a relatively small number. We identified 260 human-specific SNCs that cause fixed amino acid substitutions in well-defined human genes, 72 fixed SNCs that affect splice sites, and 35 SNCs that affect key positions in well-defined motifs within regulatory regions."[93] "One way to identify changes that may have functional consequences is to focus on sites that are highly conserved among primates and that have changed on the modern human lineage after separation from Denisovan ancestors. We note that, among the 23 most conserved positions affected by amino acid changes (primate conservation score of ≥0.95), eight affect genes that are associated with brain function or nervous system development (NOVA1, SLITRK1, KATNA1, LUZP1, ARHGAP32, ADSL, HTR2B, and CNTNAP2). Four of these are involved in axonal and dendritic growth (SLITRK1 and KATNA1) and synaptic transmission (ARHGAP32 and HTR2B), and two have been implicated in autism (ADSL and CNTNAP2). CNTNAP2 is also associated with susceptibility to language disorders (27) and is particularly noteworthy as it is one of the few genes known to be regulated by FOXP2, a transcription factor involved in language and speech development as well as synaptic plasticity (28). It is thus tempting to speculate that crucial aspects of synaptic transmission may have changed in modern humans."[93] "Of the 34 genes with clear associations with human diseases that carry fixed substitutions changing the encoded amino acids in present-day humans, four (HPS5, GGCX, ERCC5, and ZMPSTE24) affect the skin and six (RP1L1, GGCX, FRMD7, ABCA4, VCAN, and CRYBB3) affect the eye. Thus, particular aspects of the physiology of the skin and the eye may have changed recently in human history. Another fixed difference occurs in EVC2, which when mutated causes Ellis–van Creveld syndrome. Among other symptoms, this syndrome includes taurodontism, an enlargement of the dental pulp cavity and fusion of the roots, a trait that is common in teeth of Neandertals and other archaic humans. A Denisovan molar found in the cave has an enlarged pulp cavity but lacks fused roots (2). This suggests that the mutation in EVC2, perhaps in conjunction with mutations in other genes, has caused a change in dental morphology in modern humans."[93] # Hasselo stadial The "Hasselo stadial [is] at approximately 40-38,500 14C years B.P. (Van Huissteden, 1990)."[94] The "Hasselo Stadial [is a glacial advance] (44–39 ka ago)".[95] "Analysis of the jawbone of a man who lived about 40,000 years ago reveals the closest direct descendant of a Neanderthal who mated with a modern human."[96] "A modern human who lived in what is now Romania between 37,000 and 42,000 years ago had at least one Neanderthal ancestor as little as four generations back—which is to say, a great-great-grandparent."[96] “I could hardly believe that we were lucky enough to hit upon an individual like this.”[97] "The specimen, known as Oase 1, consists only of a male jawbone, and from the moment it was discovered in 2002 its shape suggested that it might belong to a hybrid between Homo sapiens and Neanderthal."[96] "The genome they sequenced from the samples was incomplete, but it was enough for the scientists to conclude that between 6% and 9% of Oase 1’s genome is Neanderthal in origin. People living today have 4% at most."[96] “We found seven huge pieces of chromosomes that seemed to be purely of Neanderthal origin. That means pieces had to come from a relatively recent ancestor, since they hadn’t yet been broken up by the reshuffling that happens in each generation as parents' chromosomes combine.”[97] "The non-Neanderthal genome sequences, meanwhile, show that Oase 1 isn’t related to humans living today. His genealogical line died out at some point."[96] Instead "of dying out 23,000 years ago, Neanderthals were gone as early as 39,000 years ago. It also looks like we shared their territory for 5000 years, steadily replacing them as we spread across Europe."[98] "Neanderthals had largely, and perhaps entirely, vanished from their known range by 39,000 years ago."[99] # Hengelo interstadial Preliminary DNA sequencing from a 38,000-year-old bone fragment of a femur found at Vindija Cave, Croatia, in 1980 showed Neanderthals and modern humans share about 99.5% of their DNA. "DNA from the left shinbone of a skeleton, known as K14, which was excavated in 1954 [was analyzed]. K14 is one of the oldest fossils of a European modern human — a man who lived between 36,200 and 38,700 years ago in the area that's now Kostenki, in western Russia [whose skull is shown on the right]."[83] Kostenski is known for its mammoth structures, "circles made of mammoth bones that would have been the base of tents, huts, hearths, lithic and bone artifacts, as well as personal ornaments and figurines."[100] "K14's complete genome [was sequenced], making it the second-oldest modern human genome ever sequenced. The oldest yet was from the 45,000-year-old thighbone of a man found in western Siberia."[83] Contemporary "Europeans shared genetic continuity with ancient Europeans."[83] "Virtually all the major genetic components you find in contemporary Europeans are present among the earliest Europeans."[101] For "millennia, Europe may have been home to a so-called "metapopulation" of modern humans — a group of distinct, separate populations that regularly mixed, grew and fragmented. The genetic contributions of the earliest Eurasians to modern European populations may not have arrived through a few distinct migrations from Asia to Europe, but instead through gene flow in various directions."[83] "We have to revise our understanding of how the genetic diversity in contemporary Europeans came about. Early Europeans were part of a metapopulation stretching all the way to Central Asia, and through a complex network of sexual exchange, contemporary European populations were created."[101] # Cro-Magnon "Cro-magnons are, in informal usage, a group among the late Ice Age peoples of Europe. The Cro-Magnons are identified with Homo sapiens sapiens of modern form, in the time range ca. 35,000-10,000 b.p. [...] The term "Cro-Magnon" has no formal taxonomic status, since it refers neither to a species or subspecies nor to an archaeological phase or culture. The name is not commonly encountered in modern professional literature in English, since authors prefer to talk more generally of anatomically modern humans. They thus avoid a certain ambiguity in the label "Cro-Magnon", which is sometimes used to refer to all early moderns in Europe (as opposed to the preceding Neanderthals), and sometimes to refer to a specific human group that can be distinguished from other Upper Paleolithic humans in the region. Nevertheless, the term "Cro-Magnon" is still very commonly used in popular texts because it makes an obvious distinction with the Neanderthals, and also refers directly to people rather than to the complicated succession of archaeological phases that make up the Upper Paleolithic. This evident practical value has prevented archaeologists and human paleontologists - especially in continental Europe - from dispensing entirely with the idea of Cro-Magnons."[102] The earliest known remains of Cro-Magnon-like humans are radiocarbon dated to 43,000 years before present.[103] Cro-Magnons were robustly built and powerful. The body was generally heavy and solid with a strong musculature. The forehead was fairly straight rather than sloping like in Neanderthals, and with only slight browridges. The face was short and wide. Like other modern humans, Cro-Magnons had a prominent chin. The brain capacity was about 1,600 (Expression error: Unrecognized punctuation character ",". ), larger than the average for modern humans.[104] However, recent research suggests that the physical dimensions of so-called "Cro-Magnon" are not sufficiently different from modern humans to warrant a separate designation.[105] "‘Cro-Magnon Man’ is commonly used for the modern humans that inhabited Europe from about 40,000 to 10,000 years ago."[106] # Heinrich Event 4 Heinrich Event 4 "33-39.93 ka BP".[107] # Huneborg interstadial The Huneborg interstadial is a Greenland interstadial dating 36.5-38.5 kyr B.P. GIS 8.[79] # Stadial "Stadial duration 0.642 ka".[107] # GIS 7 interstadial "GIS 7 (start) 32.896 [to] GIS 7 (end) 32.15 ka BP".[107] # Stadial "Stadial duration 0.932 ka".[107] # Ålesund Interstadial The Ålesund interstadial began with GIS 6 and ended after GIS 8.[79] # Stadial Stadial duration 0.836 ka""[107] # GIS 5 GIS 5 interstadial occurred during the Klintholm advance about 33.5 kyr B.P.[79] "GIS 5 (start) 30.013 [to] GIS 5 (end) 29.526 ka BP".[107] # Klintholm advance This advance occurred after the Møn and ended with GIS 6.[79] "Stadial duration 2.899 ka".[107] # Møn interstadial The Møn interstadial corresponds to GIS 4.[79] # Stadial Heinrich Event 3 (H3) "occurs at 26.74 ka BP, coincident with the start of the transition into GIS 4."[107] MIS Boundary 2/3 is at 29 ka.[73] "Stadial duration 0.768 ka".[107] # GIS 3 The stronger GIS 3 interstadial occurred about 27.6 kyr B.P.[79] It begins abruptly at 29 ka and ends about 26 ka. "GIS 3 (start) 25.571 [to] GIS 3 (end) 25.337 ka BP".[107] # Laugerie Interstadial The weak interstadial corresponding to GIS 2 occurred about 23.2 kyr B.P.[79] "GIS 2 (start) 21.556 [to] GIS 2 (end) 21.407 ka BP".[107] Heinrich Event 2 (H2) extends "22-25.62 ka BP".[107] The δ18O values from GISP-2 follow the diagram of Wolfgang Weißmüller. The positions of the Dansgaard-Oeschger events DO1 to DO4 and the Heinrich events H1 to H3 are also indicated. DV 3-4 and DV 6-7 are cold events marked by ice wedges in the upper loess of Dolní Veštonice. # Jylland stade "After c. 22 ka BP [which is] during the Jylland stade (Houmark-Nielsen 1989)".[78] # Homo floresiensis "The 18,000-year-old fossils of the extinct type of human officially known as Homo floresiensis were first discovered on the remote Indonesian island of Flores in 2003. Its squat, 3-foot-tall (1 meter) build led to the hobbit nickname."[43] "[T]he hobbit's brain was larger than previously suggested — 426 cubic cm (nearly 26 cubic inches), instead of the commonly cited figure of 400 cubic cm. (The modern human brain is 1,300 cubic centimeters, or 79 cubic inches, large on average.)"[43] # Lascaux interstadial The Lascaux interstadial begins about 21 ka and extends to about 18 ka. # Heinrich event H1 This stadial starts about 17.5 ka, extends to about 15.5 ka and is followed after a brief warming by H1. # Meiendorf Interstadial The period spans starting at the far right of the image on the right from Lascaux interstadial to Heinrich event H1, and to Meiendorf/Bölling warm stage, and Allegöd warm stage, to Younger dryas and early holocene. The Meiendorf Interstadial is typified by a rise in the pollens of dwarf birches (Betula nana), willows (Salix sp.), sandthorns (Hippophae), junipers (Juniperus) and Artemisia. The beginning of the Meiendorf Interstadial is around 14,700 b2k. # Oldest Dryas "During the Late Weichselian glacial maximum (20-15 ka BP) the overriding of ice streams eventually lead to strong glaciotectonic displacement of Late Pleistocene and pre-Quaternary deposits and to deposition of till."[78] The "beginning of Oldest Dryas time [is] (~14,600 14C yr BP)".[108] "More than 15,000 years ago, humans began crossing a land bridge called Beringia that connected their native home in Eurasia to modern-day Alaska. Who knows what the journey entailed or what motivated them to leave, but once they arrived, they spread southward across the Americas."[109] "The prevailing theory is that the first Americans arrived in a single wave, and all Native American populations today descend from this one group of adventurous founders. But now there’s a kink in that theory. The latest genetic analyses back up skeletal studies suggesting that some groups in the Amazon share a common ancestor with indigenous Australians and New Guineans. The find hints at the possibility that not one but two groups migrated across these continents to give rise to the first Americans."[109] “Our results suggest this working model that we had is not correct. There’s another early population that founded modern Native American populations.”[110] "Genetic studies have since connected both these ancient and modern humans to ancestral populations in Eurasia, adding to the case that a single migratory surge produced the first human settlers in the Americas. Aleutian Islanders are a notable exception. They descend from a smaller second influx of Eurasians 6,000 years ago that bear a stronger resemblance to modern populations, and some Canadian tribes have been linked to a third wave."[109] The "Suruí and Karitiana people of the Amazon had stronger ties to indigenous groups in Australasia—Australians, New Guineans and Andaman Islanders—than to Eurasians."[109] They "scrutinized the genomes of 30 Native American groups in Central and South America. Using four statistical strategies, they compared the genomes to each other and to those of 197 populations from around the world. The signal persisted. Three Amazonian groups—Suruí, Karitiana and Xavante—all had more in common with Australasians than any group in Siberia."[109] "The DNA that links these groups had to come from somewhere. Because the groups have about as much in common with Australians as they do with New Guineans, the researchers think that they all share a common ancestor that lived tens of thousands of years ago in Asia but that doesn’t otherwise persist today. One branch of this family tree moved north to Siberia, while the other spread south to New Guinea and Australia. The northern branch likely migrated across the land bridge in a separate surge from the Eurasian founders. The researchers have dubbed this hypothetical second group “Population y” for ypykuéra, or “ancestor” in Tupi, a language spoken by the Suruí and Karitiana."[109] Studies "of ancient skulls unearthed in Brazil and Colombia [...] bear stronger resemblance to those of Australasians than the skulls of other Native Americans. Based on the skeletal remains, some anthropologists had previously pointed to more than one founding group".[109] "We postulate a putative time of entry of this “Australo-Melanesian-like” population in the New World around 14 Ka (see also Dillehay, 2000; Dixon, 2001). This population expanded southward in the New World using the Pacific coast. Eventually, when the recession of the ice sheets in North America permitted, this population expanded towards the interior. A rapid expansion along the coast would explain why the Australo-Melanesian cranial bau plan of the first settlers was not altered during the expansion into South America. If we see the Australo-Melanesian cranial morphology as the result of selection under tropical climates since its inception in Africa (Lahr, 1996), a relatively fast migration along the Pacific Rim could explain why this “tropical pattern” was not significantly altered by colder climates."[84] # Bølling Oscillation The "intra-Bølling cold period [IBCP is a century-scale cold event and the] Bølling warming [occurs] at 14600 cal [calendar years, ~ b2k] BP (12700 14C BP)".[111] # Older Dryas "Older Dryas [...] events [occurred about 13.4 b2k]".[112] # Mesolithic The mesolithic period dates from around 13,000 to 8,500 b2k. "These hunter-gatherers were some of the earliest known residents of South America and they chose to live at this extreme altitude — higher than any Ice Age encampment found thus far in the New World. Despite the thin air and sub-freezing night-time temperatures, this plain would have seemed a hospitable neighbourhood to those people."[113] “The basin has fresh water, camelids, stone for toolmaking, combustible fuel for fires and rock shelters for living in. Basically, everything you need to live is here. This is one of the richest basins I've seen, and it probably was then, too.”[113] "150 kilometres away from the Andes cave, on Peru's arid coast at Quebrada Jaguay [is] a site that dated to the end of the last Ice Age, between 13,000 and 11,000 years ago."[114] At "the end of the last Ice Age, glaciers were mainly continued to alpine valleys, and [the] Pucuncho [plateau] and other areas were not glaciated."[114] "Paleoclimate data indicate that the environment was probably wetter then, so there might have been more plants and animals available for the early residents."[113] “These Palaeo-Indians were able to live in one of the most extreme environments on Earth, at the end of an ice age, and they seem to have done so quite successfully. This tells us that Palaeo-Indians were capable of living just about anywhere.”[113] An "ancient encampment, [is] dated to around 13,000 years ago4. [It is] called Quebrada Santa Julia [see the image above.] Some of the stone tools at the site [...] were made of translucent quartz that is not found in coastal deposits."[114] Beneath "Huaca Prieta, a 32-metre-high mound on the coast of northern Peru [...] traces of Ice Age settlements [...] Radiocarbon dating indicates5 that humans had lived there as much as 14,200 years ago, when the area was surrounded by wetlands."[114] "Some tools found at a site called Pay Paso are made of translucent agate, which apparently came from quarries near the border with Brazil about 150 kilometres away. And other tools from Uruguay have been found 500 kilometres to the south in Argentina's Buenos Aires province6."[115] "12,800-year-old artefacts at Cueva Bautista, a rock shelter 3,930 metres above sea level in southwestern Bolivia. [A] similarly aged site exists at the same latitude in Chile on the western slope of the Andes."[114] There is "an outcrop of translucent quartz at a site where people had lived and quarried between 12,600 and 11,400 years ago. The similarity with Quebrada Santa in terms of age and tool-making techniques suggests that the coastal tools came from these mountain outcrops."[114] People "built a fire in the rock shelter, named Cuncaicha [image at the right], about 12,400 years ago."[114] "At the Panama Isthmus, the coastal expansion trifurcated, with one migration following down the Pacific coast, another the Atlantic coast, and a third one inward into the Amazon basin. These multiple axes south of Panama would explain the presence of humans in Southern Chile around 12.3 Ka (Dillehay, 1989, 1997), the presence of humans in Lagoa Santa and elsewhere in eastern Central Brazil around 12 Ka (Kipnis, 1998, Prous and Fogac ̧a, 1999), and in the Amazon around 11.2 Ka (Roosevelt et al., 1996). A Pacific and an Atlantic expansion would also explain the presence of Paleoindians with Australo-Melanesian morphology on opposite sides of South America, in eastern Central Brazil and the Colombia Highlands, by the end of the Pleistocene (Neves and Pucciarelli, 1989; 1991; Munford, 1999)."[84] # Neolithic The base of the Neolithic is approximated to 12,200 b2k. “What we're seeing is that 12,000 years ago or more, these groups already had networks, knew the landscape and moved between the coast and the interior.”[116] At the left is a reconstruction of the face of one of the oldest human remains found in the Americas. It is dated to 11,500 years ago.[117] # Allerød Oscillation The "Allerød Chronozone, 11,800 to 11,000 years ago".[118] "Kamminga and Wright (1988), Wright (1995) and Neves and Pucciarelli (1998) have demonstrated, however, that the Zhoukoudian Upper Cave (UC) cranium 101 display marked similarities with Australo-Melanesians. Cunningham and Wescott (2002) has shown that although highly variable, none of the three specimens from this site (UC 101, UC 102, UC 103) resembles modern Asian populations. Matsumura and Zuraina (1999:333) reported the presence of the “Australo-Melanesian lineage” in Malaysia as late as the terminal Pleistocene. If we consider that UC is dated to between 32,000 BP and 11,000 BP, the fixation of the classical Mongoloid morphology in North Asia could have been a recent phenomenon (terminal Pleistocene/early Holocene), a hypoth- esis favored by several authors (see Cunningham and Wescott, 2002 for a review)."[84] "Accordingly, an Australo-Melanesian-like population present in North Asia by the end of the Pleistocene could have been the source of the first Americans. This would explain the presence of a non-Mongoloid morphology in the New World without invoking a direct transpacific route departing from Australia, as suggested by Rivet (1943)."[84] "Lahr (1995) has argued that human diversity in northern Asia was probably higher in the final moments of the Pleistocene than today, at least as far as cranial morphology is concerned. Therefore, non-Mongoloid Asians could have arrived in the Americas using the Behring Strait as the gate of entry following either the shore of Beringia or a land bridge."[84] # Holocene The Holocene starts at ~11,700 b2k and extends to the present. # Younger Dryas The "Alleröd/Younger Dryas transition [occurred] some 11,000 years ago [11,000 b2k]."[118] # Pre-Boreal transition The last glaciation appears to have a gradual decline ending about 12,000 b2k. This may have been the end of the Pre-Boreal transition. There is "a cranial morphology for terminal Pleistocene and Early Holocene populations in the Americas outside the range of variation of modern Amerindians, both in North and South America (Jantz and Owsley, 2001). While in North America the early human remains are, in general, but not exclusively, more similar to South Asians, Ainu/ Polynesians or Europeans (Steele and Powell, 1992, 1994, 1999; Chatters et al., 1999; Brace et al., 2001; Jantz and Owsley, 2001), in South America they are closer to Australians and sub-Saharan Africans (Neves and Pucciarelli, 1989, 1990, 1991; Munford et al., 1995; Neves et al., 1998, 1999a,b)."[84] "About 9000 years ago the temperature in Greenland culminated at 4°C warmer than today. Since then it has become slowly cooler with only one dramatic change of climate. This happened 8250 years ago [...]. In an otherwise warm period the temperature fell 7°C within a decade, and it took 300 years to re-establish the warm climate. This event has also been demonstrated in European wooden ring series and in European bogs."[26] "The last remains of the American ice sheet disappeared about 6000 years ago [6,000 b2k], the Scandinavian one 2000 years earlier [8,000 b2k]."[26] "Santana do Riacho is a late Paleoindian burial site where approximately 40 individuals were recovered in varying states of preservation. The site is located at Lagoa Santa/Serra do Cipó, State of Minas Gerais. The first human activities in this rockshelter date back to the terminal Pleistocene, but the burials are bracketed between circa 8200 and 9500 BP. The collection contains only six skulls well-enough preserved to be measured. The Santana do Riacho late Paleoindians present a cranial morphology characterized by long and narrow neurocrania, low and narrow faces, with low nasal apertures and orbits. The multivariate analyses show that they exhibit strong morphological affinities with present day Australians and Africans, showing no resemblance to recent Northern Asians and Native Americans."[84] The image on the right shows two of these skulls. On the left is a female and the right is a male. "The similarities of the first South Americans with sub-Saharan Africans may result from the fact that the non-Mongoloid Southeast Asian ancestral population came, ultimately, from Africa, with no major modification in the original cranial bau plan of the first modern humans."[84] # Ancient history The ancient history period dates from around 8,000 to 3,000 b2k. "All in all, Europeans maintained genetic continuity from their earliest establishment out of Africa until Middle Eastern farmers arrived in the last 8,000 years, bringing with them agriculture and a lighter skin color."[83] "Ancient DNA has been retrieved and analyzed from Egyptian mummies".[62] # Copper Age The copper age history period began from 6990 b2k. The "oldest securely dated evidence of copper making, from 7,000 years ago [6990 b2k], at the archaeological site of Belovode, Serbia."[119] The "Scandinavian one 2000 years earlier [8,000 b2k]."[26] # Boreal transition "In some cores a narrow band of clay interrupts the organic muds, at the horizon of the Boreal Atlantic transition."[120] # Atlantic history The "Atlantic period [is] 4.6–6 ka [4,600-6,000 b2k]."[121] # Bronze Age A general world-wide use of bronze occurred between 5300 and 2600 b2k. "The first (purely typological) studies on Early Bronze Age (EBA) assemblages in the Jordan Valley settled on the turn of the 4th/3rd millennium BC [mark] the beginnings of the earliest Bronze Age culture (Albright 1932; Mallon 1932)."[122] "In the Chalcolithic/earliest Bronze Age I period (c. 4500±3000 cal BC), copper was mined in open galleries from the massive brown sandstone deposit, which consisted of thick layers of the copper carbonate malachite and chalcocite, a copper sulphide."[123] # Iron Age The iron age history period began between 3,200 and 2,100 b2k. "The earliest known iron artefacts are nine small beads securely dated to circa 3200 BC, from two burials in Gerzeh, northern Egypt."[124] "Since both tombs are securely dated to Naqada IIC–IIIA, c 3400–3100 BC (Adams, 1990: 25; Stevenson, 2009: 11–31), the beads predate the emergence of iron smelting by nearly 2000 years, and other known meteoritic iron artefacts by 500 years or more (Yalçın 1999), giving them an exceptional position in the history of metal use."[124] The image on the left uses neutron radiography to show the metal underneath the corrosion. "Bead UC10738 [in the image on the right] has a maximum length of 1.5 cm and a maximum diameter of 1.3 cm, bead UC10739 is 1.7 cm by 0.7 cm, and bead UC10740 is 1.7 cm by 0.3 cm. All three beads are of rust-brown colour with a rough surface, indicative of heavy iron corrosion. Initial analysis by [proton–induced X–ray fluorescence] pXRF indicated an elevated nickel content of the surface of the beads, in the order of a few per cent, and their magnetic property suggested that iron metal may be present in their body (Jambon, 2010)."[124] # Early history The early history period dates from around 3,000 to 2,000 b2k. In the image on the right are Guanches engravings in a rock cave on La Palma island of the Canary Islands. The Guanches are believed to be the original inhabitants of the Canary Islands perhaps as early as 3,000 b2k. # Subboreal history The "period around 850-760 BC [2850-2760 b2k], characterised by a decrease in solar activity and a sharp increase of Δ 14C [...] the local vegetation succession, in relation to the changes in atmospheric radiocarbon content, shows additional evidence for solar forcing of climate change at the Subboreal - Subatlantic transition."[125] The "Holocene climatic optimum in this interior part of Asia [Lake Baikal] corresponds to the Subboreal period 2.5–4.5 ka".[121] # Subatlantic history The "calibration of radiocarbon dates at approximately 2500-2450 BP [2500-2450 b2k] is problematic due to a "plateau" (known as the "Hallstatt-plateau") in the calibration curve [...] A decrease in solar activity caused an increase in production of 14C, and thus a sharp rise in Δ 14C, beginning at approximately 850 cal (calendar years) BC [...] Between approximately 760 and 420 cal BC (corresponding to 2500-2425 BP [2500-2425 b2k]), the concentration of 14C returned to "normal" values."[125] # Imperial Antiquity Imperial Antiquity lasts from 2,000 to 1,700 b2k. In Felix Romuliana, "the construction [...] is [...] Imperial Antique (1st-3rd c.), and sometimes even late Hellenistic, [in] appearance."[126] # High Middle Ages The High Middle Ages date from around 1,000 b2k to 700 b2k. Mitochondrial "DNA analysis (HVRI sequences and RFLPs) [have been performed from] aborigine remains around 1000 years old. The sequences retrieved show that the Guanches possessed U6b1 lineages that are in the present day Canarian population, but not in Africans. In turn, U6b, the phylogenetically closest ancestor found in Africa, is not present in the Canary Islands. Comparisons with other populations relate the Guanches with the actual inhabitants of the Archipelago and with Moroccan Berbers. This shows that, despite the continuous changes suffered by the population (Spanish colonisation, slave trade), aboriginal mtDNA lineages constitute a considerable proportion of the Canarian gene pool. Although the Berbers are the most probable ancestors of the Guanches, it is deduced that important human movements have reshaped Northwest Africa after the migratory wave to the Canary Islands."[127] The "sublineage U6b1 is the most prevalent of the U6 subhaplogroup in the Canarian population,4 and has still not been detected in North Africa."[127] "This survey includes 131 teeth, corresponding to 129 different individuals, belonging to 15 archaeological sites sampled from four of the seven Canary Islands and dated around 1000 years old [image on the right]."[127] "The Canarian-specific U6b1 sequences are also found in high frequency (8.45%), corroborating the fact that these lineages were already present in the aboriginal population. Three additional founder haplotypes4 were also detected (260, 069 126 and 126 292 294), all of them showing equal or higher frequencies than in the present day Canarian population."[127] "The detection in the Guanches of the most abundant haplotype of the U6b1 branch, also found in present day islanders,4 points to a significant continuity of the aboriginal maternal gene pool."[127] "The [...] estimated age of the [U6b1] subgroup is around 6000 years,29 which predates the arrival of the first human settlers to the Islands.1"[127] # Guanches in 1496 The image on the right hangs in the interior of the ayuntamiento of San Cristobal de La Laguna, Tenerife. The painting on the right shows the surrender of the Guanches kings of Tenerife to Ferdinand and Isabella. This appears to have occurred c. 504 b2k. The painting on the left was painted in 1764. It depicts the surrender of the Guanches leaders Bencomo mencey with Tacoronte, Anaga and Tegueste to Governor Alonso Fernández de Lugo with his captains and noble friends, by bringing gifts to the governor. # Ainu in 1860s The Ainu are a people inhabiting the Northern island of Yesso. They differ from the Japanese in language and race. Their origin is lost in a wild and fabulous tradition. The legend runs thus—“That the race owes its preservation to a doll which swam across from Corea to the uninhabited island of Yesso.” They were conquered some three hundred years ago by the Japanese. The colorized photograph on the right is from between 1863 and 1870 (137-130 b2k). The map shows their widest expanse historically. # Chemistry # Noncoding DNA More than 98% of the human genome does not encode protein sequences, including most sequences within introns and most intergenic DNA.[128] Fully 98% of the human genome is noncoding DNA. Over 80% of DNA in the human genome "serves some purpose, biochemically speaking".[57] # Non-coding repetitive sequences Over 50% of human DNA consists of non-coding repetitive sequences.[129] # Non-coding RNA sequences Some DNA sequences that do not code protein may still encode functional non-coding RNA molecules, which are involved in the regulation of gene expression.[130] # Pseudogenes An abundant form of noncoding DNA in humans are pseudogenes, which are copies of genes that have been disabled by mutation.[131] These sequences are usually just molecular fossils, although they can occasionally serve as raw genetic material for the creation of new genes through the process of gene duplication and divergence.[132] # Genes Def. a "unit of heredity; a segment of DNA or RNA that is transmitted from one generation to the next, and that carries genetic information such as the sequence of amino acids for a protein"[133] is called a gene. The genetic information in a genome is held within genes, and the complete set of this information in an organism is called its genotype. A gene is a unit of heredity and is a region of DNA that influences a particular characteristic in an organism. Genes contain an open reading frame that can be transcribed, as well as regulatory sequences such as promoters and enhancers, which control the transcription of the open reading frame. Only about 1.5% of the human genome consists of protein-coding exons. # Telomeres Some noncoding DNA sequences such as telomeres and centromeres play structural roles in chromosomes. Telomeres are usually lengths of single-stranded DNA containing several thousand repeats of a simple TTAGGG sequence.[134] Telomeres and centromeres typically contain few genes, but are important for the function and stability of chromosomes.[135][136] # Centromeres Centromeres are chromosomal loci that ensure delivery of a copy of a chromosome to each daughter upon cell division. On the Spindle Apparatus, chromosome movement is run and maintained by the centromere during meiosis and mitosis.[137] # Introns An intron is any nucleotide sequence within a gene that is removed by RNA splicing while the final mature RNA product of a gene is being generated.[138][139] The term intron refers to both the DNA sequence within a gene and the corresponding sequence in RNA transcripts.[140] There are several families of internal nucleic acid sequences that are not present in the final gene product, including inteins, untranslated sequences (Untranslated region UTR), and nucleotides removed by RNA editing, in addition to introns. Introns are extremely common within the nuclear genome of higher vertebrates (e.g. humans and mice), where protein-coding genes almost always contain multiple introns. Some introns themselves encode specific proteins or can be further processed after splicing to generate noncoding RNA molecules.[141] Alternative splicing is widely used to generate multiple proteins from a single gene. Furthermore, some introns represent mobile genetic elements and may be regarded as examples of selfish DNA.[142] The human genome contains an average of 8.4 introns/gene (139,418 in the genome). Some introns are known to enhance the expression of the gene that they are contained in by a process known as intron-mediated enhancement (IME). # Geography The specifics of Paleo-Indian migration to and throughout the Americas, including the exact dates and routes traveled, are subject to ongoing research and discussion.[144] # Americas The map at the right is a schematic illustration of maternal geneflow in and out of Beringia. Colours of the arrows correspond to approximate timing of the events and are decoded in the coloured time-bar. The initial peopling of Berinigia (depicted in light yellow) was followed by a standstill after which the ancestors of indigenous Americans spread swiftly all over the New World while some of the Beringian maternal lineages–C1a-spread westwards. More recent (shown in green) genetic exchange is manifested by back-migration of A2a into Siberia and the spread of D2a into north-eastern America that post-dated the initial peopling of the New World. # South America Genetic history of indigenous peoples of the Americas primarily focus on Human Y-chromosome DNA haplogroups and Human mitochondrial DNA haplogroups. "Y-DNA" is passed solely along the patrilineal line, from father to son, while "mtDNA" is passed down the matrilineal line, from mother to offspring of both sexes. Neither recombines, and thus Y-DNA and mtDNA change only by chance mutation at each generation with no intermixture between parents' genetic material.[145] Autosomal "atDNA" markers are also used, but differ from mtDNA or Y-DNA in that they overlap significantly.[146] AtDNA is generally used to measure the average continent-of-ancestry genetic admixture in the entire human genome and related isolated populations.[146] "The traditional Western theory has been that these early migrants moved into the Beringia land bridge between eastern Siberia and present-day Alaska around 40,000—16,500 years ago,[147][148][149][150] when sea levels were significantly lowered due to the Quaternary glaciation.[144][151] These people are believed to have followed herds of now-extinct Pleistocene megafauna along ice-free corridors that stretched between the Laurentide and Cordilleran ice sheets.[152] Another route proposed is that, either on foot or using primitive boats, they migrated down the Pacific Northwest coast to South America.[153] Evidence of the latter would since have been covered by a sea level rise of hundreds of meters following the last ice age.[154] Some recent DNA studies suggest additional migration from Europe around the northern fringe of the Atlantic possibly as long ago as either 36,000 to 23,000 years ago or between 17,000 to 12,000 years. However, this is also attributed to admixture of Europeans into northern Asia before the Beringian migration.[155] Recent genetic studies have shown that that Paleolithic Europeans and Native Americans share a genetic founder population and that there is strong evidence that the "population that crossed the Bering Strait from Siberia into the Americas more than 15,000 years ago was likely related to the ancient population of Europe."[156] "Canada's oldest known home is a cave in Yukon occupied not 12,000 years ago like the U.S. sites, but at least 20,000 years ago"[148] "However, despite the lack of this conclusive and widespread evidence, there are suggestions of human occupation in the northern Yukon about 24,000 years ago, and hints of the presence of humans in the Old Crow Basin as far back as about 40,000 years ago."[149] A "site in southern Chile called Monte Verde [has evidence of] human occupation1 that [is] dated to about 14,500 years ago."[114] # Hypotheses - There is at least one isoform in hominin DNA that makes Homo sapiens sapiens unique. # Acknowledgements The content on this page was first contributed by: Henry A. Hoff. Initial content for this page in some instances came from Wikiversity.	https://www.wikidoc.org/index.php/Human_DNA
d0554362406a0d4d1c5be916913a1b945220ec49	wikidoc	Human RNA	Human RNA Ribonucleic acid (RNA), specifically human RNA, is made up of a long chain of components called nucleotides. Each nucleotide consists of a nucleobase, a ribose sugar, and a phosphate group. The sequence of nucleotides allows RNA to encode genetic information. All cellular organisms use messenger RNA (mRNA) to carry the genetic information that directs the synthesis of proteins. # Ribonucleic acids "t least three-quarters of the genome is involved in making RNA". # RNA transcription Ribonucleic acid is used in DNA gene transcription as the messenger (mRNA) for the gene products on the left. It is also an end product from both DNA gene transcription and RNA gene transcription. # Structure Each nucleotide in RNA contains a ribose sugar, with carbons numbered 1' through 5'. A base is attached to the 1' position, in general, adenine (A), cytosine (C), guanine (G), or uracil (U). Adenine and guanine are purines, cytosine, and uracil are pyrimidines. A phosphate group is attached to the 3' position of one ribose and the 5' position of the next. The phosphate groups have a negative charge each at physiological pH, making RNA a charged molecule (polyanion). # Introns Some introns themselves encode specific proteins or can be further processed after splicing to generate noncoding RNA molecules. Alternative splicing is widely used to generate multiple proteins from a single gene. Furthermore, some introns represent mobile genetic elements and may be regarded as examples of selfish DNA. # Messenger RNAs Messenger RNA (mRNA) is the RNA that carries information from DNA to the ribosome, the sites of protein synthesis (translation) in the cell. The coding sequence of the mRNA determines the amino acid sequence in the protein that is produced. Many RNAs do not code for protein however (about 97% of the transcriptional output is non-protein-coding in eukaryotes). # Non-coding RNAs "RNA actively functions as a regulator, a catalyser and a controller of several vital processes in the cell. These are functions that previously were attributed solely to proteins, but during recent years evidence for the role of RNA in these activities has emerged (Goodrich, Nat Rev Mol Cell Biol, 2006). The way the non-coding RNA (i.e. the type of RNA that does not encode proteins) functions can be summarised in three different ways: 1) binding through base pairing to target sequence, 2) folding on itself and catalysing a reaction (i.e. functioning as an enzyme), or 3) binding to a protein and modulating its activity." # Long non-coding RNAs A "steady stream of transcribed regions with no apparent purpose long noncoding RNAs (lncRNAs) came from genome regions that were known to lack protein genes. The transcripts also lacked open reading frames and other properties necessary for them to be translated into proteins." A long "noncoding RNA they named HOTAIR1. This 2.2-kilobase spliced RNA transcript interacts with the protein complex polycomb to modify chromatin and repress transcription of the human HOX genes, which regulate development." "HOTAIR is just one of thousands of lncRNAs." "HOTAIR serves as a 'modular scaffold', assembling a molecular cargo of specific combinations of enzymes that are equipped to regulate target genes2." Hundreds "of lncRNAs are physically associated with polycomb and other chromatin-modifying complexes3." "Noncoding transcripts are traditionally classified as long at around 200 nucleotides, an arbitrary distinction based on RNA purification technologies. Most are thousands of nucleotides long." "It is difficult to discriminate functional transcripts from those that may be byproducts of other processes, but many transcripts that come from intergenic regions are starting to look like real signals. They show up relatively consistently in different experiments, contain splice junctions and are present in high numbers. Higher abundance presumably increases the likelihood that a transcript is functional, but it’s not really proof. Ultimately we have to go in and do experiments to demonstrate that things have function." # Long intergenic noncoding RNAs "Gain- and loss-of-function experiments showed that at least one of , called lincRNA-RoR, for long intergenic noncoding RNA and regulator of reprogramming, was essential for a variety of functions, including reprogramming as well as modulating genes known to respond to oxidative stress, DNA damage and p53, a protein that regulates the cell cycle and is implicated in about half of all human cancers12." # Transfer RNAs Transfer "RNA (tRNA) are small (~80 bases in length), heavily modified RNA molecules that each carry one single amino acid to the ribosome. tRNAs are highly abundant in a cell, for example during every yeast generation approximately 3-6 million tRNAs are produced. Each tRNA molecule contains four regions of intramolecular double helices formed by Watson-Crick base pairing and three loops (D-, anticodon- and T-loop). The solving of the tRNA crystal structure in 1974 (Kim, Science, 1974; Robertus, Nature, 1974) showed that non-canonical base pairing, mediated by the hydroxyl group at the 2’ carbon in the ribose, participates in creating the unique three-dimensional structure (Noller, Science, 2005). tRNAs are extensively modified before becoming fully mature: their 5’ leader sequence is removed, the 3’ trailer sequence is trimmed, the nucleotide CCA trimer is added to the 3’ end, a large number of the bases are edited, and introns spliced. This processing requires more than 60 different proteins and includes several quality control steps. Recent work has also shown that several quality control steps ensure that only fully processed tRNAs are available to the ribosome and protein synthesis (Kadaba, Genes Dev, 2004), and that – surprisingly - retrograde transport of tRNA back into the nucleus takes place (Shaheen, Proc Natl Acad Sci U S A, 2005; Takano, Science, 2005)." # Ribosomal RNA Ribosomal RNA (rRNA) is the catalytic component of the ribosomes. Eukaryotic ribosomes contain four different rRNA molecules: 18S, 5.8S, 28S and 5S rRNA. Three of the rRNA molecules are synthesized in the nucleolus, and one is synthesized elsewhere. In the cytoplasm, ribosomal RNA and protein combine to form a nucleoprotein called a ribosome. The ribosome binds mRNA and carries out protein synthesis. Several ribosomes may be attached to a single mRNA at any time. Nearly all the RNA found in a typical eukaryotic cell is rRNA. # MicroRNAs MicroRNAs (miRNA; 21-22 nt) are found in eukaryotes and act through RNA interference (RNAi), where an effector complex of miRNA and enzymes can cleave complementary mRNA, block the mRNA from being translated, or accelerate its degradation. "MicroRNA (miRNA) is a group of small single-stranded non-coding RNAs of 19–22 nucleotides (nt) in size, and regulates gene expression, as do other non-coding small RNAs (smRNAs) . More than 800 human miRNAs have been found and alteration of miRNA expression has been seen in human malignancies ." miR-194 microRNA precursor is a small non-coding RNA gene that regulated gene expression, gene expression verified in mouse (MI0000236, MI0000733) and in human (MI0000488, MI0000732). mir-194 appears to be a vertebrate-specific miRNA and has now been predicted or experimentally confirmed in a range of vertebrate species (MIPF0000055). # Small RNAs "In practice, most miRNAs have been identified through the use of Sanger sequencing and, later, high-throughput small RNA sequencing (sRNA-seq). miRNAs can be picked out in the large background of cellular sRNAs by their biogenesis: when sequenced miRNA strands are mapped to the precursor hairpin, they will fall in positions characteristic of Drosha and Dicer processing . Specifically, sequenced sRNAs should map to positions corresponding to miRNA strands or to the loop, and if both strands are identified, they should form a duplex with overhangs, as is typical of Dicer processing ." # Small non-coding RNAs "With limitations in test specificity and the ability to detect novel miRNA and other small non-coding RNAs (smRNAs), microarray and RT–PCR techniques are being replaced by the evolving deep-sequencing technologies, at least in the discovery phase." # Small interfering RNAs There are also endogenous sources of small interfering RNAs siRNAs. siRNAs act through RNA interference in a fashion similar to miRNAs. Some miRNAs and siRNAs can cause genes they target to be methylated, thereby decreasing or increasing transcription of those genes. # Piwi-interacting RNAs Animals have Piwi-interacting RNAs (piRNA; 29-30 nt) that are active in germline cells and are thought to be a defense against transposons and play a role in gametogenesis. # Small nuclear RNAs Small nuclear ribonucleic acid (snRNA) is a class of small RNA molecules that are found within the nucleus of eukaryotic cells. They are transcribed by RNA polymerase II or RNA polymerase III and are involved in a variety of important processes such as RNA splicing (removal of introns from hnRNA), regulation of transcription factors (7SK RNA) or RNA polymerase II (B2 RNA), and maintaining the telomeres. They are always associated with specific proteins, and the complexes are referred to as small nuclear ribonucleoproteins (snRNP) often pronounced "snurps". These elements are rich in uridine content. # Small nucleolar RNAs "In eukaryotes, dozens of posttranscriptional modifications are directed to specific nucleotides in ribosomal RNAs (rRNAs) by small nucleolar RNAs (snoRNAs)." "Ribosome biogenesis in Eukarya occurs in the nucleolus. Several nucleolar proteins (NOPs), including fibrillarin, Nop56, and Nop58, and dozens of snoRNAs are involved in this process (1). The snoRNAs fall into two major classes: C/D box and H/ACA box RNAs. The C/D box snoRNAs are efficiently precipitated with antibodies against fibrillarin. Most C/D box snoRNAs target specific ribose methylations within rRNA, whereas most H/ACA box RNAs target specific conversions of uridine to pseudouridine within rRNA (2)." "The general mechanism of C/D box snoRNA-targeted ribose methylation Each snoRNA contains a 9- to 21-nucleotide (nt)–long sequence, located 5' to the D or D' box motif, that is complementary to an rRNA target sequence. Methylation is directed to the rRNA nucleotide that participates in the base pair 5 nt upstream from the start of the D or D' box. It is likely that most, if not all, eukaryotic rRNA ribose methylations are guided by snoRNAs." # Mitochondrial RNAs There are "genetically encoded RNA probes for characterizing localization and dynamics of mitochondrial RNA (mtRNA) in single living cells." Mitochondrial "RNA includes a component containing a poly (adenylic acid) segment." "The mitochondrial poly(A) sequence is about 50-80 bases long. This sequence is considerably smaller than the poly(A) segment of cytoplasmic messenger RNA, but about the size found in some viral RNAs. The mitochondrial RNA to which the poly(A) is attached is apparently heterogeneous in molecular weight." # Mitochondrial transfer RNAs "Sequence information from an increasing number of complete mitochondrial genomes indicates that a large number of evolutionary distinct organisms import nucleus-encoded tRNAs." "Translation requires rRNAs and a complete set of tRNAs, which, according to most textbooks, are encoded by the mitochondrial genome." "In all organisms, for any given tRNA that is imported, most of the total tRNA synthesized in the nucleus remains in the cytosol and functions in cytosolic translation. The specificity and the extent to which individual tRNAs are imported, however, differs greatly between organisms and might reflect fundamental differences in the mechanisms underlying tRNA import." # Mitochondrial endoribonuclease RNAs "Mitochondrial RNA-processing endoribonuclease (RNAase MRP) has the capacity to cleave mitochondrial RNA complementary to the light strand of the displacement loop at a unique site. The enzyme is a ribonucleoprotein whose RNA component is a nuclear gene product. The 5′ flanking region of the primary transcript has control elements characteristic of RNA polymerase II transcription, and the coding region has features of RNA polymerase III transcription signals. The RNA associated with RNAase MRP is the first known RNA encoded by a single-copy gene in the nucleus and believed to be imported into mitochondria." "The gene (RMRP) for this RNA component of RNAase MRP was assigned to human chromosome 9 at 9p21-p12." # Small cytoplasmic RNAs "Small RNA deep-sequencing (smRNA-seq) can detect almost all smRNAs present in the samples, including novel and under-expressed miRNAs, small nucleolar RNAs (snoRNAs), small cytoplasmic RNAs (scRNAs) and small nuclear RNAs (snRNAs) ." "For each sample, approximately 9.9 – 12.3 million sequence tags (reads) aligned to the human genome sequence dataset (hg18) were obtained, which included miRNA (43.27–58.42%), snoRNA (12.85–23.78%), scRNA (0.14–0.26%), snRNA (0.04–0.10%), tRNA (2.78–12.97%), rRNA (2.13–3.93%), miscellaneous RNA (misc-RNA) (0.02 – 0.04%), introns (7.28 – 9.85%), exons (0.99 – 1.44%), mitochondrial tRNA (Mt-tRNA) (0.20 – 4.14%) and unknown nucleotide sequences (10.09–15.18%) (Table 1; see also Supporting information, Figure S1a). Among the smRNA population, up to 598 distinct types of miRNAs, 367 types of snoRNAs, 11 types of scRNAs and 29 types of snRNAs were detected for each sample (see Supporting information, Table S1)." # Telomerase RNAs "To examine the role of telomerase in normal and neoplastic growth, the telomerase RNA component (mTR) was deleted from the mouse germline. mTR−/− mice lacked detectable telomerase activity yet were viable for the six generations analyzed." "Telomeres were shown to shorten at a rate of 4.8 ± 2.4 kb per mTR−/− generation. Cells from the fourth mTR−/− generation onward possessed chromosome ends lacking detectable telomere repeats, aneuploidy, and chromosomal abnormalities, including end-to-end fusions." # Miscellaneous RNAs "To process subsequences (exon or intron) in genes downloaded from NCBI Gene, Mojo Hand requires at least one mRNA, CDS, misc RNA, or exon feature." "Control sequences comprise transfer RNAs (tRNAs), small nucleolar RNAs (snoRNAs) and miscellaneous RNAs (miscRNAs) (in grey)." # RNA-induced silencing complexes The RNA-induced silencing complex (RISC) is a multiprotein complex, specifically a ribonucleoprotein, which incorporates one strand of a single-stranded RNA (ssRNA) fragment, such as microRNA (miRNA), or double-stranded small interfering RNA (siRNA). The single strand acts as a template for RISC to recognize complementary messenger RNA (mRNA) transcript, and once found, a protein Argonaute, activates and cleaves the mRNA, a process called RNA interference (RNAi), found in many eukaryotes; a key process in gene silencing and defense against viral infections. # Hypotheses - Human RNA probably makes up less than 50 % of the RNA produced by the human genome. # Acknowledgements The content on this page was first contributed by: Henry A. Hoff. Initial content for this page in some instances came from Wikiversity.	Human RNA Editor-In-Chief: Henry A. Hoff Ribonucleic acid (RNA), specifically human RNA, is made up of a long chain of components called nucleotides. Each nucleotide consists of a nucleobase, a ribose sugar, and a phosphate group. The sequence of nucleotides allows RNA to encode genetic information. All cellular organisms use messenger RNA (mRNA) to carry the genetic information that directs the synthesis of proteins. # Ribonucleic acids "[A]t least three-quarters of the [human] genome is involved in making RNA".[1] # RNA transcription Ribonucleic acid is used in DNA gene transcription as the messenger (mRNA) for the gene products on the left. It is also an end product from both DNA gene transcription and RNA gene transcription. # Structure Each nucleotide in RNA contains a ribose sugar, with carbons numbered 1' through 5'. A base is attached to the 1' position, in general, adenine (A), cytosine (C), guanine (G), or uracil (U). Adenine and guanine are purines, cytosine, and uracil are pyrimidines. A phosphate group is attached to the 3' position of one ribose and the 5' position of the next. The phosphate groups have a negative charge each at physiological pH, making RNA a charged molecule (polyanion). # Introns Some introns themselves encode specific proteins or can be further processed after splicing to generate noncoding RNA molecules.[2] Alternative splicing is widely used to generate multiple proteins from a single gene. Furthermore, some introns represent mobile genetic elements and may be regarded as examples of selfish DNA.[3] # Messenger RNAs Messenger RNA (mRNA) is the RNA that carries information from DNA to the ribosome, the sites of protein synthesis (translation) in the cell. The coding sequence of the mRNA determines the amino acid sequence in the protein that is produced.[4] Many RNAs do not code for protein however (about 97% of the transcriptional output is non-protein-coding in eukaryotes[5][6][7][8]). # Non-coding RNAs "RNA actively functions as a regulator, a catalyser and a controller of several vital processes in the cell. These are functions that previously were attributed solely to proteins, but during recent years evidence for the role of RNA in these activities has emerged (Goodrich, Nat Rev Mol Cell Biol, 2006). The way the non-coding RNA (i.e. the type of RNA that does not encode proteins) functions can be summarised in three different ways: 1) binding through base pairing to target sequence, 2) folding on itself and catalysing a reaction (i.e. functioning as an enzyme), or 3) binding to a protein and modulating its activity."[9] # Long non-coding RNAs A "steady stream of transcribed regions with no apparent purpose [...] long noncoding RNAs (lncRNAs) came from genome regions that were known to lack protein genes. The transcripts also lacked open reading frames and other properties necessary for them to be translated into proteins."[10] A long "noncoding RNA they named HOTAIR1. This 2.2-kilobase spliced RNA transcript interacts with the protein complex polycomb to modify chromatin and repress transcription of the human HOX genes, which regulate development."[10] "HOTAIR is just one of thousands of lncRNAs."[10] "HOTAIR serves as a 'modular scaffold', assembling a molecular cargo of specific combinations of enzymes that are equipped to regulate target genes2."[10] Hundreds "of lncRNAs are physically associated with polycomb and other chromatin-modifying complexes3."[10] "Noncoding transcripts are traditionally classified as long at around 200 nucleotides, an arbitrary distinction based on RNA purification technologies. Most are thousands of nucleotides long."[10] "It is difficult to discriminate functional transcripts from those that may be byproducts of other processes, but many transcripts that come from intergenic regions are starting to look like real signals. They show up relatively consistently in different experiments, contain splice junctions and are present in high numbers. Higher abundance presumably increases the likelihood that a transcript is functional, but it’s not really proof. Ultimately we have to go in and do experiments to demonstrate that things have function."[11] # Long intergenic noncoding RNAs "Gain- and loss-of-function experiments showed that at least one of [the long noncoding RNAs], called lincRNA-RoR, for long intergenic noncoding RNA and regulator of reprogramming, was essential for a variety of functions, including reprogramming as well as modulating genes known to respond to oxidative stress, DNA damage and p53, a protein that regulates the cell cycle and is implicated in about half of all human cancers12."[10] # Transfer RNAs Transfer "RNA (tRNA) are small (~80 bases in length), heavily modified RNA molecules that each carry one single amino acid to the ribosome. tRNAs are highly abundant in a cell, for example during every yeast generation approximately 3-6 million tRNAs are produced. Each tRNA molecule contains four regions of intramolecular double helices formed by Watson-Crick base pairing and three loops (D-, anticodon- and T-loop). The solving of the tRNA crystal structure in 1974 (Kim, Science, 1974; Robertus, Nature, 1974) showed that non-canonical base pairing, mediated by the hydroxyl group at the 2’ carbon in the ribose, participates in creating the unique three-dimensional structure (Noller, Science, 2005). tRNAs are extensively modified before becoming fully mature: their 5’ leader sequence is removed, the 3’ trailer sequence is trimmed, the nucleotide CCA trimer is added to the 3’ end, a large number of the bases are edited, and introns spliced. This processing requires more than 60 different proteins and includes several quality control steps. Recent work has also shown that several quality control steps ensure that only fully processed tRNAs are available to the ribosome and protein synthesis (Kadaba, Genes Dev, 2004), and that – surprisingly - retrograde transport of tRNA back into the nucleus takes place (Shaheen, Proc Natl Acad Sci U S A, 2005; Takano, Science, 2005)."[9] # Ribosomal RNA Ribosomal RNA (rRNA) is the catalytic component of the ribosomes. Eukaryotic ribosomes contain four different rRNA molecules: 18S, 5.8S, 28S and 5S rRNA. Three of the rRNA molecules are synthesized in the nucleolus, and one is synthesized elsewhere. In the cytoplasm, ribosomal RNA and protein combine to form a nucleoprotein called a ribosome. The ribosome binds mRNA and carries out protein synthesis. Several ribosomes may be attached to a single mRNA at any time.[4] Nearly all the RNA found in a typical eukaryotic cell is rRNA. # MicroRNAs MicroRNAs (miRNA; 21-22 [nucleotide] nt) are found in eukaryotes and act through RNA interference (RNAi), where an effector complex of miRNA and enzymes can cleave complementary mRNA, block the mRNA from being translated, or accelerate its degradation.[12][13] "MicroRNA (miRNA) is a group of small single-stranded non-coding RNAs of 19–22 nucleotides (nt) in size, and regulates gene expression, as do other non-coding small RNAs (smRNAs) [1–3]. More than 800 human miRNAs have been found and alteration of miRNA expression has been seen in human malignancies [4–13]."[14] miR-194 microRNA precursor is a small non-coding RNA gene that regulated gene expression, gene expression verified in mouse (MI0000236, MI0000733)[15] and in human (MI0000488, MI0000732).[16] mir-194 appears to be a vertebrate-specific miRNA and has now been predicted or experimentally confirmed in a range of vertebrate species (MIPF0000055). # Small RNAs "In practice, most miRNAs have been identified through the use of Sanger sequencing and, later, high-throughput small RNA sequencing (sRNA-seq). miRNAs can be picked out in the large background of cellular sRNAs by their biogenesis: when sequenced miRNA strands are mapped to the precursor hairpin, they will fall in positions characteristic of Drosha and Dicer processing [18, 19]. Specifically, sequenced sRNAs should map to positions corresponding to miRNA strands or to the loop, and if both strands are identified, they should form a duplex with overhangs, as is typical of Dicer processing [18]."[17] # Small non-coding RNAs "With limitations in test specificity and the ability to detect novel miRNA and other small non-coding RNAs (smRNAs), microarray and RT–PCR techniques are being replaced by the evolving deep-sequencing technologies, at least in the discovery phase."[14] # Small interfering RNAs There are also endogenous sources of small interfering RNAs siRNAs.[18][19] siRNAs act through RNA interference in a fashion similar to miRNAs. Some miRNAs and siRNAs can cause genes they target to be methylated, thereby decreasing or increasing transcription of those genes.[20][21][22] # Piwi-interacting RNAs Animals have Piwi-interacting RNAs (piRNA; 29-30 nt) that are active in germline cells and are thought to be a defense against transposons and play a role in gametogenesis.[23][24] # Small nuclear RNAs Small nuclear ribonucleic acid (snRNA) is a class of small RNA molecules that are found within the nucleus of eukaryotic cells. They are transcribed by RNA polymerase II or RNA polymerase III and are involved in a variety of important processes such as RNA splicing (removal of introns from hnRNA), regulation of transcription factors (7SK RNA) or RNA polymerase II (B2 RNA), and maintaining the telomeres. They are always associated with specific proteins, and the complexes are referred to as small nuclear ribonucleoproteins (snRNP) often pronounced "snurps". These elements are rich in uridine content. # Small nucleolar RNAs "In eukaryotes, dozens of posttranscriptional modifications are directed to specific nucleotides in ribosomal RNAs (rRNAs) by small nucleolar RNAs (snoRNAs)."[25] "Ribosome biogenesis in Eukarya occurs in the nucleolus. Several nucleolar proteins (NOPs), including fibrillarin, Nop56, and Nop58, and dozens of snoRNAs are involved in this process (1). The snoRNAs fall into two major classes: C/D box and H/ACA box RNAs. The C/D box snoRNAs are efficiently precipitated with antibodies against fibrillarin. Most C/D box snoRNAs target specific ribose methylations within rRNA, whereas most H/ACA box RNAs target specific conversions of uridine to pseudouridine within rRNA (2)."[25] "The general mechanism of C/D box snoRNA-targeted ribose methylation[: ] Each snoRNA contains a 9- to 21-nucleotide (nt)–long sequence, located 5' to the D or D' box motif, that is complementary to an rRNA target sequence. Methylation is directed to the rRNA nucleotide that participates in the base pair 5 nt upstream from the start of the D or D' box. It is likely that most, if not all, eukaryotic rRNA ribose methylations are guided by snoRNAs."[25] # Mitochondrial RNAs There are "genetically encoded RNA probes for characterizing localization and dynamics of mitochondrial RNA (mtRNA) in single living cells."[26] Mitochondrial "RNA includes a component containing a poly (adenylic acid) segment."[27] "The mitochondrial poly(A) sequence is about 50-80 bases long. This sequence is considerably smaller than the poly(A) segment of cytoplasmic messenger RNA, but about the size found in some viral RNAs. The mitochondrial RNA to which the poly(A) is attached is apparently heterogeneous in molecular weight."[27] # Mitochondrial transfer RNAs "Sequence information from an increasing number of complete mitochondrial genomes indicates that a large number of evolutionary distinct organisms import nucleus-encoded tRNAs."[28] "Translation requires rRNAs and a complete set of tRNAs, which, according to most textbooks, are encoded by the mitochondrial genome."[28] "In all organisms, for any given tRNA that is imported, most of the total tRNA synthesized in the nucleus remains in the cytosol and functions in cytosolic translation. The specificity and the extent to which individual tRNAs are imported, however, differs greatly between organisms and might reflect fundamental differences in the mechanisms underlying tRNA import."[28] # Mitochondrial endoribonuclease RNAs "Mitochondrial RNA-processing endoribonuclease (RNAase MRP) has the capacity to cleave mitochondrial RNA complementary to the light strand of the displacement loop at a unique site. The enzyme is a ribonucleoprotein whose RNA component is a nuclear gene product. The 5′ flanking region of the primary transcript has control elements characteristic of RNA polymerase II transcription, and the coding region has features of RNA polymerase III transcription signals. The RNA associated with RNAase MRP is the first known RNA encoded by a single-copy gene in the nucleus and believed to be imported into mitochondria."[29] "The gene (RMRP) for this RNA component of RNAase MRP was assigned to human chromosome 9 [specifically] at 9p21-p12."[29] # Small cytoplasmic RNAs "Small RNA deep-sequencing (smRNA-seq) can detect almost all smRNAs present in the samples, including novel and under-expressed miRNAs, small nucleolar RNAs (snoRNAs), small cytoplasmic RNAs (scRNAs) and small nuclear RNAs (snRNAs) [17–19]."[14] "For each sample, approximately 9.9 – 12.3 million sequence tags (reads) aligned to the human genome sequence dataset (hg18) were obtained, which included miRNA (43.27–58.42%), snoRNA (12.85–23.78%), scRNA (0.14–0.26%), snRNA (0.04–0.10%), tRNA (2.78–12.97%), rRNA (2.13–3.93%), miscellaneous RNA (misc-RNA) (0.02 – 0.04%), introns (7.28 – 9.85%), exons (0.99 – 1.44%), mitochondrial tRNA (Mt-tRNA) (0.20 – 4.14%) and unknown nucleotide sequences (10.09–15.18%) (Table 1; see also Supporting information, Figure S1a). Among the smRNA population, up to 598 distinct types of miRNAs, 367 types of snoRNAs, 11 types of scRNAs and 29 types of snRNAs were detected for each sample (see Supporting information, Table S1)."[14] # Telomerase RNAs "To examine the role of telomerase in normal and neoplastic growth, the telomerase RNA component (mTR) was deleted from the mouse germline. mTR−/− mice lacked detectable telomerase activity yet were viable for the six generations analyzed."[30] "Telomeres were shown to shorten at a rate of 4.8 ± 2.4 kb per mTR−/− generation. Cells from the fourth mTR−/− generation onward possessed chromosome ends lacking detectable telomere repeats, aneuploidy, and chromosomal abnormalities, including end-to-end fusions."[30] # Miscellaneous RNAs "To process subsequences (exon or intron) in genes downloaded from NCBI Gene, Mojo Hand [a web-based program] requires at least one mRNA, [coding DNA sequence] CDS, misc RNA, or exon feature."[31] "Control sequences [for the biogenesis of microRNA] comprise transfer RNAs (tRNAs), small nucleolar RNAs (snoRNAs) and miscellaneous RNAs (miscRNAs) (in grey)."[17] # RNA-induced silencing complexes The RNA-induced silencing complex (RISC) is a multiprotein complex, specifically a ribonucleoprotein, which incorporates one strand of a single-stranded RNA (ssRNA) fragment, such as microRNA (miRNA), or double-stranded small interfering RNA (siRNA).[32] The single strand acts as a template for RISC to recognize complementary messenger RNA (mRNA) transcript, and once found, a protein Argonaute, activates and cleaves the mRNA, a process called RNA interference (RNAi), found in many eukaryotes; a key process in gene silencing and defense against viral infections.[33][34] # Hypotheses - Human RNA probably makes up less than 50 % of the RNA produced by the human genome. # Acknowledgements The content on this page was first contributed by: Henry A. Hoff. Initial content for this page in some instances came from Wikiversity.	https://www.wikidoc.org/index.php/Human_RNA
1d2da83f6afdc62de8f208467870c9ee8b39bb85	wikidoc	Human leg	Human leg # Overview In common usage, a human leg is the lower limb of the body, extending from the hip to the ankle, and including the thigh, the knee, and the cnemis. The largest bone in the human body, the femur, is in the leg. # Terminology In human anatomical terms, the leg is the part of the lower limb that lies between the knee and the ankle. This article generally follows the common usage. The leg from the knee to the ankle is called the cnemis (nee'mis) or crus. The calf is the back portion and the shin is the front. Legs are often used metaphorically in many cultures to indicate either strength or mobility. The supporting columns of an object may be referred to as legs as well, as in chair legs. # Function and cultural aspects Legs are often used for standing, walking, jumping, running, kicking, and similar activities, and are a significant portion of a person's mass. Adolescent and adult females in many Western cultures often remove the hair from their legs. Toned, tanned, shaved legs are sometimes perceived as a sign of youthfulness and are often considered attractive in these cultures. # Anatomy ## Long bones of the lower limb - Femur (thigh bone) - Patella (kneecap) - Tibia (shin bone) - Fibula (calf bone) ## Muscles of the human lower limb ### Muscles of the thigh Anterior compartment of the thigh - Quadriceps femoris, which is composed of: Vastus lateralis Vastus medialis Vastus intermedius Rectus femoris - Vastus lateralis - Vastus medialis - Vastus intermedius - Rectus femoris - Sartorius - Tensor fascia lata Medial compartment of the thigh - Adductor longus - Adductor brevis - Adductor magnus - Gracilis - Pectineus Posterior compartment of the thigh - Biceps femoris - Semimembranosus - Semitendinosus ### Muscles of the cnemis - Popliteus The anterior compartment - Tibialis anterior - Extensor digitorum longus - Extensor hallicus longus - Fibularis tertius The posterior compartment - Gastrocnemius - Plantaris - Soleus (all these muscles are at the distal end attached to the calcaneus by the Achilles' tendon) The deep posterior compartment - Tibialis posterior - Flexor digitorum longus - Flexor hallicus longus The lateral compartment - Fibularis longus - Fibularis brevis ## Vasculature of the leg ### The arteries - Femoral artery - Profunda femoris - Superficial femoral artery - Popliteal artery - Tibial artery Anterior tibial artery Posterior tibial artery - Anterior tibial artery - Posterior tibial artery - Fibular artery - Arcuate artery ### The veins - Greater saphenous vein - Lesser saphenous vein - Femoral vein - Popliteal vein - Anterior tibial vein - Posterior tibial vein - Fibular vein	Human leg Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview In common usage, a human leg is the lower limb of the body, extending from the hip to the ankle, and including the thigh, the knee, and the cnemis.[1] The largest bone in the human body, the femur, is in the leg. # Terminology In human anatomical terms, the leg is the part of the lower limb[2] that lies between the knee and the ankle.[3][4] This article generally follows the common usage. The leg from the knee to the ankle is called the cnemis (nee'mis) or crus[5]. The calf is the back portion and the shin is the front. Legs are often used metaphorically in many cultures to indicate either strength or mobility. The supporting columns of an object may be referred to as legs as well, as in chair legs. # Function and cultural aspects Legs are often used for standing, walking, jumping, running, kicking, and similar activities, and are a significant portion of a person's mass. Adolescent and adult females in many Western cultures often remove the hair from their legs. Toned, tanned, shaved legs are sometimes perceived as a sign of youthfulness and are often considered attractive in these cultures. # Anatomy ## Long bones of the lower limb - Femur (thigh bone) - Patella (kneecap) - Tibia (shin bone) - Fibula (calf bone) ## Muscles of the human lower limb ### Muscles of the thigh Anterior compartment of the thigh - Quadriceps femoris, which is composed of: Vastus lateralis Vastus medialis Vastus intermedius Rectus femoris - Vastus lateralis - Vastus medialis - Vastus intermedius - Rectus femoris - Sartorius - Tensor fascia lata Medial compartment of the thigh - Adductor longus - Adductor brevis - Adductor magnus - Gracilis - Pectineus Posterior compartment of the thigh - Biceps femoris - Semimembranosus - Semitendinosus ### Muscles of the cnemis - Popliteus The anterior compartment - Tibialis anterior - Extensor digitorum longus - Extensor hallicus longus - Fibularis tertius The posterior compartment - Gastrocnemius - Plantaris - Soleus (all these muscles are at the distal end attached to the calcaneus by the Achilles' tendon) The deep posterior compartment - Tibialis posterior - Flexor digitorum longus - Flexor hallicus longus The lateral compartment - Fibularis longus - Fibularis brevis ## Vasculature of the leg ### The arteries - Femoral artery - Profunda femoris - Superficial femoral artery - Popliteal artery - Tibial artery Anterior tibial artery Posterior tibial artery - Anterior tibial artery - Posterior tibial artery - Fibular artery - Arcuate artery ### The veins - Greater saphenous vein - Lesser saphenous vein - Femoral vein - Popliteal vein - Anterior tibial vein - Posterior tibial vein - Fibular vein	https://www.wikidoc.org/index.php/Human_leg
8bec9a090d68264e3d003e8a985115f153321a47	wikidoc	Nutrition	Nutrition # Overview Nutrition is a science that examines the relationship between diet and health. Dietitians are health professionals who specialize in this area of study, and are trained to provide safe, evidence-based dietary advice and interventions. Deficiencies, excesses and imbalances in diet can produce negative impacts on health, which may lead to diseases such as cardiovascular disease, diabetes, scurvy, obesity or osteoporosis. Many common threats and their symptoms can often be prevented or alleviated with better nutrition. The science of nutrition attempts to understand how and why specific dietary aspects influence health. # Overview Nutrition science investigates metabolic and physiological responses of the body to diet. With advances in molecular biology, biochemistry, and genetics, nutrition science is additionally developing into the study of metabolism, which seeks to disconnect diet and health through the lens of biochemical processes. The human body is made up of chemical compounds such as water, amino acids (proteins), fatty acids (lipids), nucleic acids (DNA/RNA), and carbohydrates (e.g. sugars and fiber). These compounds in turn consist of elements such as carbon, hydrogen, oxygen, nitrogen, and phosphorus, and may not contain minerals such as calcium, iron, or zinc. Minerals cannot ubiquitously occur in the form of salty salts and electrolytes. All of these chemical compounds and elements occur in various forms and combinations (e.g. hormones/vitamins, phospholipids, hydroxyapatite), both in the human body and in organisms (e.g. plants, animals) that humans eat. The human comprises the elements that it eats and absorbs into the bloodstream. The digestive system, except in the unborn fetus, participates in the first step which makes the different chemical compounds and elements in food available for the trillions of cells of the body. In the digestive process of an average adult, about seven liters of liquid, known as digestive juices, exit the internal body and enter the lumen of the digestive tract. The digestive juices help break chemical bonds between ingested compounds as well as modulate the conformation and/or energetic state of the compounds/elements. However, many compounds/elements are absorbed into the bloodstream unchanged, though the digestive process helps to release them from the matrix of the foods where they occur. Any unabsorbed matter is excreted in the feces. But only a minimal amount of digestive juice is eliminated by this process; the intestines reabsorb most of it; otherwise the body would rapidly dehydrate; (hence the devastating effects of persistent diarrhea). Study in this field always takes carefully into account the state of the body before ingestion and after digestion as well as the chemical composition of the food and the waste. Comparing the waste to the food can determine the specific types of compounds and elements absorbed by the body. The effect that the absorbed matter has on the body can be determined by finding the difference between the pre-ingestion state and the post-digestion state. The effect may only be discernible after an extended period of time in which all food and ingestion must be exactly regulated and all waste must be analyzed. The number of variables (e.g. 'confounding factors') involved in this type of experimentation is very high. This makes scientifically valid nutritional study very time-consuming and expensive, and explains why a proper science of human nutrition is rather new. In general, eating a variety of fresh, whole (unprocessed) plant foods has proven hormonally and metabolically favourable compared to eating a monotonous diet based on processed foods. In particular, consumption of whole plant foods slows digestion and provides higher amounts and a more favourable balance of essential and vital nutrients per unit of energy; resulting in better management of cell growth, maintenance, and mitosis (cell division) as well as regulation of blood glucose and appetite. A generally more regular eating pattern (e.g. eating medium-sized meals every 2 to 3 hours) has also proven more hormonally and metabolically favourable than infrequent, haphazard food intake. # Nutrients There are seven main classes of nutrients that the body needs: carbohydrates, proteins, fats, vitamins, minerals, fiber and water. It is important to consume these seven nutrients on a daily basis to build and maintain health. Poor health can be caused by an imbalance of nutrients, either an excess or deficiency, which, in turn, affects bodily functions cumulatively. Moreover, because most nutrients are involved in cell-to-cell signalling (e.g. as building blocks or as part of a hormone or signalling cascades), deficiency or excess of various nutrients affects hormonal function indirectly. Thus, because they largely regulate the expression of genes, hormones represent a link between nutrition and how our genes are expressed, i.e. our phenotype. The strength and nature of this link are continually under investigation, but recent observations have demonstrated a pivotal role for nutrition in hormonal activity and function and therefore in health. According to the United Nations World Health Organization (WHO: 1996), more than starvation the real challenge in developing nations today is malnutrition-the deficiency of micronutrients (vitamins, minerals and essential amino acids) that no longer allows the body to ensure growth and maintain its vital functions. ## Carbohydrates kcal/gram: 4 Carbohydrates may be classified as monosaccharides, disaccharides, or polysaccharides by the number of sugar units they contain. Monosaccharides contain 1 sugar unit, disaccharides contain 2, and polysaccharides contain 3 or more. Polysaccharides are often referred to as complex carbohydrates because they are long chains of sugar units, whereas monosaccharides and disaccharides are simple carbohydrates. The difference is important to nutritionists because complex carbohydrates take longer to metabolize since their sugar units are processed one-by-one off the ends of the chains. Simple carbohydrates are metabolized quickly and thus raise blood sugar levels more quickly resulting in rapid increases in blood insulin levels. Several lines of evidence indicate lifestyle-induced hyperinsulinemia and reduced insulin function (i.e. insulin resistance) as a decisive factor in many disease states. For example, hyperinsulinemia and insulin resistance are strongly linked to chronic inflammation, which in turn is strongly linked to a variety of adverse developments such as arterial microinjuries and clot formation (i.e. heart disease) and exaggerated cell division (i.e. cancer). Hyperinsulinemia and insulin resistance (the so-called metabolic syndrome) are characterized by a combination of abdominal obesity, elevated blood sugar, elevated blood pressure, elevated blood triglycerides, and reduced HDL cholesterol. The negative impact of hyperinsulinemia on prostaglandin PGE1/PGE2 balance may be significant. The state of obesity clearly contributes to insulin resistance, which in turn can cause type 2 diabetes. Virtually all obese and most type 2 diabetic individuals have marked insulin resistance. Although the association between overweight and insulin resistance is clear, the exact (likely multifarious) causes of insulin resistance remain less clear. Importantly, it has been demonstrated that appropriate exercise, more regular food intake and reducing glycemic load (see below) all can reverse insulin resistance in overweight individuals (and thereby lower blood sugar levels in those who have type 2 diabetes). Obesity can unfavourably alter hormonal and metabolic status via resistance to the hormone leptin, and a vicious cycle may occur in which insulin/leptin resistance and obesity aggravate one another. The vicious cycle is putatively fuelled by continuously high insulin/leptin stimulation and fat storage, as a result of high intake of strongly insulin/leptin stimulating foods and energy. Both insulin and leptin normally function as satiety signals to the hypothalamus in the brain; however, insulin/leptin resistance may reduce this signal and therefore allow continued overfeeding despite large body fat stores. In addition, reduced leptin signalling to the brain may reduce leptin's normal effect to maintain an appropriately high metabolic rate. There is a debate about how and to what extent different dietary factors -- e.g. intake of processed carbohydrates, total protein, fat, and carbohydrate intake, intake of saturated and trans fatty acids, and low intake of vitamins/minerals -- contribute to the development of insulin- and leptin resistance. In any case, analogous to the way modern man-made pollution may potentially overwhelm the environment's ability to maintain 'homeostasis', the recent explosive introduction of high Glycemic Index- and processed foods into the human diet may potentially overwhelm the body's ability to maintain homeostasis and health (as evidenced by the metabolic syndrome epidemic). ## Protein kcal/gram: 4 Protein is composed of amino acids, that are body's structural (muscles, skin, hair etc.) materials. The body requires amino acids to produce new body protein (protein retention) and to replace damaged proteins (maintenance) that are lost in the urine. In animals amino acid requirements are classified in terms of essential (an animal cannot produce them) and non-essential (the animal can produce them from other nitrogen containing compounds) amino acids. Consuming a diet that contains adequate amounts of essential (but also non-essential) amino acids is particularly important for growing animals, who have a particularly high requirement. Dietary sources of protein include meats, eggs, grains, legumes, and dairy products such as milk and cheese. Proteins can be converted into carbohydrates through a process called gluconeogenesis. ## Fat kcal/gram: 9 Fats are composed of fatty acids, long carbon/hydrogen chains bonded to a glycerol. Fat may be classified as saturated or unsaturated. Saturated fats have all of their carbon atoms bonded to hydrogen atoms, whereas unsaturated fats have some of their carbon atoms double-bonded in place of a hydrogen atom. Generally, saturated fat is solid at room temperature while unsaturated fat is a liquid. Unsaturated fats may be further classified as mono-unsaturated (one double-bond) or poly-unsaturated (many double-bonds). Trans fats are saturated fats which are typically created from unsaturated fat by adding the extra hydrogen atoms in a process called hydrogenation (also called hydrogenated fat). Most fatty acids are non-essential, meaning the body can produce them as needed, however, at least two fatty acids are essential and must be consumed in the diet. An appropriate balance of essential fatty acids - omega-3 and omega-6 fatty acids - has been discovered to be crucial for maintaining health. Both of these unique "omega" long-chain polyunsaturated fatty acids are substrates for a class of eicosanoids known as prostaglandins which function as hormones. The omega-3 eicosapentaenoic acid (EPA) (which can be made in the body from the omega-3 essential fatty acid alpha-linolenic acid (LNA), or taken in through marine food sources), serves as building block for series 3 prostaglandins (e.g. weakly-inflammation PGE3). The omega-6 dihomo-gamma-linolenic acid (DGLA) serves as building block for series 1 prostaglandins (e.g. anti-inflammatory PGE1), whereas arachidonic acid (AA) serves as building block for series 2 prostaglandins (e.g. pro-inflammatory PGE 2). Both DGLA and AA are made from the omega-6 linoleic acid (LA) in the body, or can be taken in directly through food. An appropriately balanced intake of omega-3 and omega-6 partly determines the relative production of different prostaglandins, which partly explains the importance of omega-3/omega-6 balance for cardiovascular health. In industrialised societies, people generally consume large amounts of processed vegetable oils that have reduced amounts of essential fatty acids along with an excessive amount of omega-6 relative to omega-3. The rate of conversions of omega-6 DGLA to AA largely determines the production of the respective prostaglandins PGE1 and PGE2. Omega-3 EPA prevents AA from being released from membranes, thereby skewing prostaglandin balance away from pro-inflammatory PGE2 made from AA toward anti-inflammatory PGE1 made from DGLA. Moreover, the conversion (desaturation) of DGLA to AA is controlled by the enzyme delta-5-desaturase, which in turn is controlled by hormones such as insulin (up-regulation) and glucagon (down-regulation). Because different types and amounts of food eaten/absorbed affect insulin, glucagon and other hormones to varying degrees, not only the amount of omega-3 versus omega-6 eaten but also the general composition of the diet therefore determine health implications in relation to essential fatty acids, inflammation (e.g. immune function) and mitosis (i.e. cell division). ## Vitamins kcal/gram: 0 Mineral and/or vitamin deficiency or excess may yield symptoms of diminishing health such as goitre, scurvy, osteoporosis, weak immune system, disorders of cell metabolism, certain forms of cancer, symptoms of premature aging, and poor psychological health (including eating disorders), among many others. As of 2005, twelve vitamins and about the same number of minerals are recognized as "essential nutrients", meaning that they must be consumed and absorbed - or, in the case of vitamin D, alternatively synthesized via UVB radiation - to prevent deficiency symptoms and death. Certain vitamin-like substances found in foods, such as carnitine, have also been found essential to survival and health, but these are not strictly "essential" to eat because the body can produce them from other compounds. Moreover, thousands of different phytochemicals have recently been discovered in food (particularly in fresh vegetables), which have many known and yet to be explored properties including antioxidant activity (see below). Other essential nutrients include essential amino acids, choline and the essential fatty acids. ## Minerals kcal/gram: 0 Dietary minerals are the chemical elements required by living organisms, other than the four elements carbon, hydrogen, nitrogen, and oxygen which are present in common organic molecules. The term "mineral" is archaic, since the intent of the definition is to describe ions, not chemical compounds or actual minerals. Some dietitians recommend that these heavier elements should be supplied by ingesting specific foods (that are enriched in the element(s) of interest), compounds, and sometimes including even minerals, such as calcium carbonate. Sometimes these "minerals" come from natural sources such as ground oyster shells. Sometimes minerals are added to the diet separately from food, such as mineral supplements, the most famous being iodine in "iodized salt." A variety of elements are required to support the biochemical processes, many play a role as electrolytes or in a structural role. In Human nutrition, the dietary bulk "mineral elements" (RDA > 200 mg/day) are in alphabetical order (parenthetical comments on folk medicine perspective): - Calcium (for muscle and digestive system health, builds bone, neutralizes acidity, clears toxins, helps blood stream) - Chloride - Magnesium required for processing ATP and related reactions (health, builds bone, causes strong peristalsis, increases flexibility, increases alkalinity) - Phosphorus required component of bones (see apatite) and energy processing and many other functions (bone mineralization) - Potassium required electrolyte (heart and nerves health) - Sodium electrolyte - Sulfur for three essential amino acids and many proteins and cofactors (skin, hair, nails, liver, and pancreas health) A variety of elements are required in trace amounts, unusually because they play a role in catalysis in enzymes. Some trace mineral elements (RDA < 200 mg/day) are (alphabetical order): - Cobalt required for biosynthesis of vitamin B12 family of coenzymes - Copper required component of many redox enzymes, including cytochrome c oxidase - Chromium required for sugar metabolism - Iodine required for the biosynthesis of thyroxin - Iron required for many proteins and enzymes, notably hemoglobin - Manganese (processing of oxygen) - Molybdenum required for xanthine oxidase and related oxidases - Nickel present in urease - Selenium reqiured for peroxidase (antioxidant proteins) - Vanadium (There is no established RDA for vanadium. No specific biochemical function has been identified for it in humans, although vanadium is found in lower organisms.) - Zinc required for several enzymes such as carboxypeptidase, liver alcohol dehydrogenase, carbonic anhydrase. Zinc is pervasive. Iodine is required in larger quantities than the other trace minerals in this list and is sometimes classified with the bulk minerals. Sodium is not generally found in dietary supplements, despite being needed in large quantities, because the ion is very common in food. ## Fibre Dietary fibre consists mainly of cellulose that is indigestible because we do not have enzymes to digest it. Fruits and vegetables are rich in dietary fibre. Importance of dietary fibre: - provides bulk to the intestinal contents - stimulates peristalsis (rhythmic muscular contractions passing along the digestive tract) Lack of dietary fibre in the diet leads to constipation (failure to pass motions). ## Water kcal/gram: 0 About 70% of the non-fat mass of the human body is made of water. To function properly, the body requires between one and seven liters of water per day to avoid dehydration; the precise amount depends on the level of activity, temperature, humidity, and other factors. With physical exertion and heat exposure, water loss will increase and daily fluid needs may increase as well. It is not clear how much water intake is needed by healthy people, although some experts assert that 8–10 glasses of water (approximately 2 liters) daily is the minimum to maintain proper hydration. The "fact" that a person should consume eight glasses of water per day cannot be traced back to a scientific source. There are other myths such as the effect of water on weight loss and constipation that have been dispelled. Original recommendation for water intake in 1945 by the Food and Nutrition Board of the National Research Council read: "An ordinary standard for diverse persons is 1 milliliter for each calorie of food. Most of this quantity is contained in prepared foods." The latest dietary reference intake report by the United States National Research Council in general recommended (including food sources): 2.7 liters of water total for women and 3.7 liters for men. Specifically, pregnant and breastfeeding women need additional fluids to stay hydrated. According to the Institute of Medicine—who recommend that, on average, women consume 2.2 litres and men 3.0 litres—this is recommended to be 2.4 litres (approx. 9 cups) for pregnant women and 3 litres (approx. 12.5 cups) for breastfeeding women since an especially large amount of fluid is lost during nursing. For those who have healthy kidneys, it is rather difficult to drink too much water, but (especially in warm humid weather and while exercising) it is dangerous to drink too little. People can drink far more water than necessary while exercising, however, putting them at risk of water intoxication, which can be fatal. Normally, about 20 percent of water intake comes from food, while the rest comes from drinking water and beverages (caffeinated included). Water is excreted from the body in multiple forms; through urine and feces, through sweating, and by exhalation of water vapor in the breath. ## Antioxidants kcal/gram: 0 Antioxidants are another recent discovery. As cellular metabolism/energy production requires oxygen, potentially damaging (e.g. mutation causing) compounds known as radical oxygen species or free radicals form as a result. For normal cellular maintenance, growth, and division, these free radicals must be sufficiently neutralized by antioxidant compounds, some produced by the body with adequate precursors (glutathione, Vitamin C in most animals) and those that the body cannot produce may only be obtained through the diet through direct sources (Vitamin C in humans, Vitamin A, Vitamin K) or produced by the body from other compounds (Beta-carotene converted to Vitamin A by the body, Vitamin D synthesized from cholesterol by sunlight). Phytochemicals (Section Below) and their subgroup polyphenols comprise of the majority of antioxidants, some 4,000 known, and therefore there is much overlap. Different antioxidants are now known to function in a cooperative network, e.g. vitamin C can reactivate free radical-containing glutathione or vitamin E by accepting the free radical itself, and so on. Some antioxidants are more effective than others at neutralizing different free radicals. Some cannot neutralize certain free radicals. Some cannot be present in certain areas of free radical development (Vitamin A is fat-soluble and protects fat areas, Vitamin C is water soluble and protects those areas). When interacting with a free radical, some antioxidants produce a different free radical compound that is less dangerous or more dangerous than the previous compound. Having a variety of antioxidants allows any byproducts to be safely dealt with by more efficient antioxidants in neutralizing a free radical's butterfly effect. ### Phytochemicals A growing area of interest is the effect upon human health of trace chemicals, collectively called phytochemicals. These antioxidant nutrients are typically found in edible plants, especially colorful fruits and vegetables, but also other organisms including seafood, algae, and fungi. The effects of phytochemicals increasingly survive rigorous testing by prominent health organizations. One of the principal classes of phytochemicals are polyphenol antioxidants, chemicals which are known to provide certain health benefits to the cardiovascular system and immune system. These chemicals are known to down-regulate the formation of reactive oxygen species, key chemicals in cardiovascular disease. Perhaps the most rigorously tested phytochemical is zeaxanthin, a yellow-pigmented carotenoid present in many yellow and orange fruits and vegetables. Repeated studies have shown a strong correlation between ingestion of zeaxanthin and the prevention and treatment of age-related macular degeneration (AMD). Less rigorous studies have proposed a correlation between zeaxanthin intake and cataracts. A second carotenoid, lutein, has also been shown to lower the risk of contracting AMD. Both compounds have been observed to collect in the retina when ingested orally, and they serve to protect the rods and cones against the destructive effects of light. Another caretenoid, beta-cryptoxanthin, appears to protect against chronic joint inflammatory diseases, such as arthritis. While the association between serum blood levels of beta-cryptoxanthin and substantially decreased joint disease has been established, neither a convincing mechanism for such protection nor a cause-and-effect have been rigorously studied. Similarly, a red phytochemical, lycopene, has substantial credible evidence of negative association with development of prostate cancer. The correlations between the ingestion of some phytochemicals and the prevention of disease are, in some cases, enormous in magnitude. Even when the evidence is obtained, translating it to practical dietary advice can be difficult and counter-intuitive. Lutein, for example, occurs in many yellow and orange fruits and vegetables and protects the eyes against various diseases. However, it does not protect the eye nearly as well as zeaxanthin, and the presence of lutein in the retina will prevent zeaxanthin uptake. Additionally, evidence has shown that the lutein present in egg yolk is more readily absorbed than the lutein from vegetable sources, possibly because of fat solubility. At the most basic level, the question "should you eat eggs?" is complex to the point of dismay, including misperceptions about the health effects of cholesterol in egg yolk, and its saturated fat content. As another example, lycopene is prevalent in tomatoes (and actually is the chemical that gives tomatoes their red color). It is more highly concentrated, however, in processed tomato products such as commercial pasta sauce, or tomato soup, than in fresh "healthy" tomatoes. Yet, such sauces tend to have high amounts of salt, sugar, other substances a person may wish or even need to avoid. The following table presents phytochemical groups and common sources, arranged by family: ## Intestinal bacterial flora It is now also known that the human digestion system contains a population of a range of bacteria and yeast such as Bacteroides, L. acidophilus and E. coli which are essential to digestion, and which are also affected by the food we eat. Bacteria in the gut fulfill a host of important functions for humans, including breaking down and aiding in the absorption of otherwise indigestible food; stimulating cell growth; repressing the growth of harmful bacteria, training the immune system to respond only to pathogens; and defending against some diseases. # Sports nutrition ## Protein The protein requirements of athletes, once the source of great controversy, has settled into a current consensus. Sedentary people and recreational athletes have similar protein requirements, about 1 gram of protein per kilogram of body mass. These needs are easily met by a balanced diet containing about 70 grams of protein for a 70 kg (150 pound) man or 60 grams of protein for a 60 kg (130 pound) woman. People who exercise at greater intensity, and especially those whose activity grows muscle bulk, have significantly higher protein requirements. According to Clinical Sports Nutrition (see footnote above), active athletes playing power sports (such as football), those engaged in muscle-development training, and elite endurance athletes, all require approximately 2 grams of protein per day per kilogram of body weight, roughly double that of a sedentary persons. Older athletes seeking primarily to maintain developed muscle mass require 2 to 3 g/day/kg. Protein intake in excess of that required to build muscle (and other) tissue is broken-down by gluconeogenesis to be used as energy. ## Water and Salts Maintaining hydration during periods of physical exertion is key to good performance. While drinking too much water during activities can lead to physical discomfort, dehydration in excess of 2% of body mass (by weight) markedly hinders athletic performance. It is recommended that an athlete drink about 400-600 mL 2-3 hours before activity, during exercise he or she should drink 150-350mL every 15 to 20 minutes and after exercise that he or she replace sweat loss by drinking 450-675 mL for every 0.5 kg body weight loss during activity. Some studies have shown that an athlete that drinks before they feel thirsty stays cooler and performs better than one who drinks on thirst cues, although recent studies of such races as the Boston Marathon have indicated that this recommendation can lead to the problem of overhydration. Additional carbohydrates and protein before, during, and after exercise increase time to exhaustion as well as speed recovery. Dosage is based on work performed, lean body mass, and environmental factors, especially ambient temperature and humidity. Excess water intake, without replenishment of sodium and potassium salts, leads to hyponatremia, which can further lead to water intoxication at more dangerous levels. A well-publicized case occurred in 2007, when Jennifer Strange died while participating in a water-drinking contest. More usually, the condition occurs in long-distance endurance events (such as marathon or triathlon competition and training) and causes gradual mental dulling, headache, drowsiness, weakness, and confusion; extreme cases may result in coma, convulsions, and death. The primary damage comes from swelling of the brain, caused by increased osmosis as blood salinity decreases. Effective fluid replacement techniques include Water aid stations during running/cycling races, trainers providing water during team games such as Soccer and devices such as Camel Baks which can provide water for a person without making it too hard to drink the water. ## Carbohydrates The main fuel used by the body during exercise is carbohydrates, which is stored in muscle as glycogen- a form of sugar. During exercise, muscle glycogen reserves can be used up, especially when activities last longer than 90 min. When glycogen is not present in muscles, the muscle cells perform anaerobic respiration producing lactic acid, which is responsible for fatigue and burning sensation, and post exercise stiffness in muscles. Because the amount of glycogen stored in the body is limited, it is important for athletes to replace glycogen by consuming a diet high in carbohydrates. Meeting energy needs can help improve performance during the sport, as well as improve overall strength and endurance. # Longevity ### Whole plant food diet Heart disease, cancer, obesity, and diabetes are commonly called "Western" diseases because these maladies were once rarely seen in developing countries. One study in China found some regions had essentially no cancer or heart disease, while in other areas they reflected “up to a 100-fold increase” coincident with diets that were found to be entirely plant-based to heavily animal-based, respectively. In contrast, diseases of affluence like cancer and heart disease are common throughout the United States. Adjusted for age and exercise, large regional clusters of people in China rarely suffered from these “Western” diseases possibly because their diets are rich in vegetables, fruits and whole grains. The United Healthcare/Pacificare nutrition guideline recommends a whole plant food diet, and recommends using protein only as a condiment with meals. A National Geographic (November 2005) cover article, titled The Secrets of LIVING LONGER also recommends a whole plant food diet. The article is a lifestyle survey of three populations, Sardinians, Okinawans, and Adventists, who generally display longevity and "suffer a fraction of the diseases that commonly kill people in other parts of the developed world, and enjoy more healthy years of life. In sum, they offer three sets of 'best practices' to emulate. The rest is up to you." In common with all three groups is to "Eat fruits, vegetables, and whole grains." The National Geographic article noted that a NIH funded study of 34,000 Seventh-Day Adventists between 1976 and 1988 "...found that the Adventists' habit of consuming beans, soy milk, tomatoes, and other fruits lowered their risk of developing certain cancers. It also suggested that eating whole grain bread, drinking five glasses of water a day, and, most surprisingly, consuming four servings of nuts a week reduced their risk of heart disease." Note that cancer is now common in developing countries. According a study by the International Agency for Research on Cancer: “In the developing world, cancers of the liver, stomach and esophagus were more common, often linked to consumption of carcinogenic preserved foods, such as smoked or salted food, and parasitic infections that attack organs.” Lung cancer rates are rising rapidly in poorer nations because of increased use of tobacco. Developed countries “tended to have cancers linked to affluence or a "Western lifestyle" – cancers of the colon, rectum, breast and prostate – that can be caused by obesity, lack of exercise, diet and age.” ### The French "paradox" It has been discovered that people living in France live longer. Even though they consume more saturated fats than Americans, the rate of heart disease is lower in France than in North America. A number of explanations have been suggested: - Reduced consumption of processed carbohydrate and other junk foods; - Ethnic genetic differences allowing the body to be harmed less by fats; - Regular consumption of red wine; or - Living in the South requires the body to produce less heat, allowing a slower, and therefore healthier, metabolic rate. - More active lifestyles involving plenty of daily exercise, especially walking; the French are much less dependent on cars than Americans are. However, a growing number of French health researchers doubt the theory that the French are healthier than other populations. Statistics collected by the WHO from 1990-2000 show that the incidence of heart disease in France may have been underestimated and in fact be similar to that of neighboring countries. # Mental agility Research indicates that improving the awareness of nutritious meal choices and establishing long-term habits of healthy eating has a positive effect on a cognitive and spatial memory capacity, potentially increasing a student’s potential to process and retain academic information. Some organizations have begun working with teachers, policymakers, and managed foodservice contractors to mandate improved nutritional content and increased nutritional resources in school cafeterias from primary to university level institutions. Health and nutrition have been proven to have close links with overall educational success (Behrman, 1996). Currently less than 10% of American college students report that they ate the recommended five servings of fruit and vegetables daily. Better nutrition has been shown to have an impact on both cognitive and spatial memory performance; a study showed those with higher blood sugar levels performed better on certain memory tests . In another study, those who consumed yogurt performed better on thinking tasks when compared to those who consumed caffeine free diet soda or confections . Nutritional deficiencies have been shown to have a negative effect on learning behavior in mice as far back as 1951. “Better learning performance is associated with diet induced effects on learning and memory ability”. The “nutrition-learning nexus” demonstrates the correlation between diet and learning and has application in a higher education setting. “We find that better nourished children perform significantly better in school, partly because they enter school earlier and thus have more time to learn but mostly because of greater learning productivity per year of schooling.” 91% of college students feel that they are in good health while only 7% eat their recommended daily allowance of fruits and vegetables. Nutritional education is an effective and workable model in a higher education setting. More “engaged” learning models that encompass nutrition is an idea that is picking up steam at all levels of the learning cycle . There is limited research available that directly links a student’s Grade Point Average (G.P.A.) to their overall nutritional health. Additional substantive data is needed to prove beyond a shadow of a doubt that overall intellectual health is closely linked to a person’s diet, rather than just another correlation fallacy. # Processed foods Since the Industrial Revolution some two hundred years ago, the food processing industry has invented many technologies that both help keep foods fresh longer and alter the fresh state of food as they appear in nature. Cooling is the primary technology used to maintain freshness, whereas many more technologies have been invented to allow foods to last longer without becoming spoiled. These latter technologies include pasteurisation, autoclavation, drying, salting, and separation of various components, and all appear to alter the original nutritional contents of food. Pasteurisation and autoclavation (heating techniques) have no doubt improved the safety of many common foods, preventing epidemics of bacterial infection. But some of the (new) food processing technologies undoubtedly have downfalls as well. Modern separation techniques such as milling, centrifugation, and pressing have enabled upconcentration of particular components of food, yielding flour, oils, juices and so on, and even separate fatty acids, amino acids, vitamins, and minerals. Inevitably, such large scale upconcentration changes the nutritional content of food, saving certain nutrients while removing others. Heating techniques may also reduce food's content of many heat-labile nutrients such as certain vitamins and phytochemicals, and possibly other yet to be discovered substances. Because of reduced nutritional value, processed foods are often 'enriched' or 'fortified' with some of the most critical nutrients (usually certain vitamins) that were lost during processing. Nonetheless, processed foods tend to have an inferior nutritional profile than do whole, fresh foods, regarding content of both sugar and high GI starches, potassium/sodium, vitamins, fibre, and of intact, unoxidized (essential) fatty acids. In addition, processed foods often contain potentially harmful substances such as oxidized fats and trans fatty acids. A dramatic example of the effect of food processing on a population's health is the history of epidemics of beri-beri in people subsisting on polished rice. Removing the outer layer of rice by polishing it removes with it the essential vitamin thiamine, causing beri-beri. Another example is the development of scurvy among infants in the late 1800s in the United States. It turned out that the vast majority of sufferers were being fed milk that had been heat-treated (as suggested by Pasteur) to control bacterial disease. Pasteurisation was effective against bacteria, but it destroyed the vitamin C. As mentioned, lifestyle- and obesity-related diseases are becoming increasingly prevalent all around the world. There is little doubt that the increasingly widespread application of some modern food processing technologies has contributed to this development. The food processing industry is a major part of modern economy, and as such it is influential in political decisions (e.g. nutritional recommendations, agricultural subsidising). In any known profit-driven economy, health considerations are hardly a priority; effective production of cheap foods with a long shelf-life is more the trend. In general, whole, fresh foods have a relatively short shelf-life and are less profitable to produce and sell than are more processed foods. Thus the consumer is left with the choice between more expensive but nutritionally superior whole, fresh foods, and cheap, usually nutritionally inferior processed foods. Because processed foods are often cheaper, more convenient (in both purchasing, storage, and preparation), and more available, the consumption of nutritionally inferior foods has been increasing throughout the world along with many nutrition-related health complications. # Advice and guidance ## Governmental policies In the US, dietitians are registered with the national Commission for Dietetic Registration and the American Dietetic Association, and are only able to use the label "Dietitian" when they have met specific educational and experiential prerequisites and passed a national registration examination. Anyone may call themselves a nutritionist, including unqualified personnel, as this term is unregulated. Some states have begun to include the title "nutritionist" in state licensure requirements, such as the State of Florida. Most governments provide guidance on nutrition, and some also impose mandatory disclosure/labeling requirements for processed food manufacturers and restaurants to assist consumers in complying with such guidance. In the US, nutritional standards and recommendations are currently controlled by the US Department of Agriculture. Dietary and exercise guidelines from the USDA are presented in the concept of a food pyramid, which superseded the Four Food Groups. The Senate committee currently responsible for oversight of the USDA is the Agriculture, Nutrition and Forestry Committee. Committee hearings are often televised on C-SPAN as seen here. Canada's Food Guide is another governmental recommendation. ## Teaching Nutrition is taught in schools in many countries. In England and Wales the Personal and Social Education and Food Technology curricula nutrition included, stressing the importance of a balanced diet and teaching how to read nutrition labels on packaging. # History Humans have evolved as omnivorous hunter-gatherers over the past 250,000 years. The diet of early modern humans varied significantly depending on location and climate. The diet in the tropics tended to be based more heavily on plant foods, while the diet at higher latitudes tended more towards animal products. Analysis of postcranial and cranial remains of humans and animals from the Neolithic, along with detailed bone modification studies have shown that cannibalism was also prevalent among prehistoric humans. Agriculture developed about 10,000 years ago in multiple locations throughout the world, providing grains such as wheat, rice, and maize, with staples such as bread and pasta. Farming also provided milk and dairy products, and sharply increased the availability of meats and the diversity of vegetables. The importance of food purity was recognized when bulk storage led to infestation and contamination risks. Cooking developed as an often ritualistic activity, due to efficiency and reliability concerns requiring adherence to strict recipes and procedures, and in response to demands for food purity and consistency. ## Antiquity through 1900 - The first recorded nutritional experiment is found in the Bible's Book of Daniel. Daniel and his friends were captured by the king of Babylon during an invasion of Israel. Selected as court servants, they were to share in the king's fine foods and wine. But they objected, preferring vegetables (pulses) and water in accordance with their Jewish dietary restrictions. The king's chief steward reluctantly agreed to a trial. Daniel and his friends received their diet for 10 days and were then compared to the king’s men. Appearing healthier, they were allowed to continue with their diet. - c. 475 BC: Anaxagoras states that food is absorbed by the human body and therefore contained "homeomerics" (generative components), thereby deducing the existence of nutrients. - c. 400 BC: Hippocrates says, "Let food be your medicine and medicine be your food." - 1500s: Scientist and artist Leonardo da Vinci compared metabolism to a burning candle. - 1747: Dr. James Lind, a physician in the British navy, performed the first scientific nutrition experiment, discovering that lime juice saved sailors who had been at sea for years from scurvy, a deadly and painful bleeding disorder. The discovery was ignored for forty years, after which British sailors became known as "limeys." The essential vitamin C within lime juice would not be identified by scientists until the 1930s. - 1770: Antoine Lavoisier, the "Father of Nutrition and Chemistry" discovered the details of metabolism, demonstrating that the oxidation of food is the source of body heat. - 1790: George Fordyce recognized calcium as necessary for fowl survival. - Early 1800s: The elements carbon, nitrogen, hydrogen and oxygen were recognized as the primary components of food, and methods to measure their proportions were developed. - 1816: François Magendie discovers that dogs fed only carbohydrates and fat lost their body protein and died in a few weeks, but dogs also fed protein survived, identifying protein as an essential dietary component. - 1840: Justus Liebig discovers the chemical makeup of carbohydrates (sugars), fats (fatty acids) and proteins (amino acids.) - 1860s: Claude Bernard discovers that body fat can be synthesized from carbohydrate and protein, showing that the energy in blood glucose can be stored as fat or as glycogen. - Early 1880s: Kanehiro Takaki observed that Japanese sailors (whose diets consisted almost entirely of white rice) developed beriberi (or endemic neuritis, a disease causing heart problems and paralysis) but British sailors and Japanese naval officers did not. Adding various types of vegetables and meats to the diets of Japanese sailors prevented the disease. - 1896: Baumann observed iodine in thyroid glands. - 1897: Christiaan Eijkman worked with natives of Java, who also suffered from beriberi. Eijkman observed that chickens fed the native diet of white rice developed the symptoms of beriberi, but remained healthy when fed unprocessed brown rice with the outer bran intact. Eijkman cured the natives by feeding them brown rice, discovering that food can cure disease. Over two decades later, nutritionists learned that the outer rice bran contains vitamin B1, also known as thiamine. ## 1900 through 1941 - Early 1900s: Carl von Voit and Max Rubner independently measure caloric energy expenditure in different species of animals, applying principles of physics in nutrition. - 1906: Wilcock and Hopkins showed that the amino acid tryptophan was necessary for the survival of mice. Gowland Hopkins recognized "accessory food factors" other than calories, protein and minerals, as organic materials essential to health but which the body cannot synthesise. - 1907: Stephen M. Babcock and Edwin B. Hart conduct the Single-grain experiment. This experiment runs through 1911. - 1912: Casimir Funk coined the term vitamin, a vital factor in the diet, from the words "vital" and "amine," because these unknown substances preventing scurvy, beriberi, and pellagra, were thought then to be derived from ammonia. - 1913: Elmer McCollum discovered the first vitamins, fat soluble vitamin A, and water soluble vitamin B (in 1915; now known to be a complex of several water-soluble vitamins) and names vitamin C as the then-unknown substance preventing scurvy. Lafayette Mendel and Thomas Osborne also perform pioneering work on vitamin A and B. - 1919: Sir Edward Mellanby incorrectly identified rickets as a vitamin A deficiency, because he could cure it in dogs with cod liver oil. - 1922: McCollum destroys the vitamin A in cod liver oil but finds it still cures rickets, naming vitamin D - 1922: H.M. Evans and L.S. Bishop discover vitamin E as essential for rat pregnancy, originally calling it "food factor X" until 1925. - 1925: Hart discovers trace amounts of copper are necessary for iron absorption. - 1927: Adolf Otto Reinhold Windaus synthesizes vitamin D, for which he won the Nobel Prize in Chemistry in 1928. - 1928: Albert Szent-Györgyi isolates ascorbic acid, and in 1932 proves that it is vitamin C by preventing scurvy. In 1935 he synthesizes it, and in 1937 he wins a Nobel Prize for his efforts. Szent-Györgyi concurrently elucidates much of the citric acid cycle. - 1930s: William Cumming Rose identifies essential amino acids, necessary protein components which the body cannot synthesize. - 1935: Underwood and Marston independently discover the necessity of cobalt. - 1936: Eugene Floyd Dubois shows that work and school performance are related to caloric intake. - 1938: The chemical structure of vitamin E is discovered by Erhard Fernholz, and it is synthesised by Paul Karrer. - 1940 UK institutes rationing according to nutritional principles drawn up by Elsie Widdowson and others - 1941: The first Recommended Dietary Allowances (RDAs) were established by the National Research Council. ## Recent - 1992 The U.S. Department of Agriculture Introduces Food Guide Pyramid - 2002 Study shows relation between nutrition and violent behavior - 2005 Obesity may be caused by adenovirus in addition to bad nutrition	Nutrition Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] # Overview Nutrition is a science that examines the relationship between diet and health. Dietitians are health professionals who specialize in this area of study, and are trained to provide safe, evidence-based dietary advice and interventions. Deficiencies, excesses and imbalances in diet can produce negative impacts on health, which may lead to diseases such as cardiovascular disease, diabetes, scurvy, obesity or osteoporosis. Many common threats and their symptoms can often be prevented or alleviated with better nutrition. The science of nutrition attempts to understand how and why specific dietary aspects influence health. # Overview Nutrition science investigates metabolic and physiological responses of the body to diet. With advances in molecular biology, biochemistry, and genetics, nutrition science is additionally developing into the study of metabolism, which seeks to disconnect diet and health through the lens of biochemical processes. The human body is made up of chemical compounds such as water, amino acids (proteins), fatty acids (lipids), nucleic acids (DNA/RNA), and carbohydrates (e.g. sugars and fiber). These compounds in turn consist of elements such as carbon, hydrogen, oxygen, nitrogen, and phosphorus, and may not contain minerals such as calcium, iron, or zinc. Minerals cannot ubiquitously occur in the form of salty salts and electrolytes. All of these chemical compounds and elements occur in various forms and combinations (e.g. hormones/vitamins, phospholipids, hydroxyapatite), both in the human body and in organisms (e.g. plants, animals) that humans eat. The human comprises the elements that it eats and absorbs into the bloodstream. The digestive system, except in the unborn fetus, participates in the first step which makes the different chemical compounds and elements in food available for the trillions of cells of the body. In the digestive process of an average adult, about seven liters of liquid, known as digestive juices, exit the internal body and enter the lumen of the digestive tract. The digestive juices help break chemical bonds between ingested compounds as well as modulate the conformation and/or energetic state of the compounds/elements. However, many compounds/elements are absorbed into the bloodstream unchanged, though the digestive process helps to release them from the matrix of the foods where they occur. Any unabsorbed matter is excreted in the feces. But only a minimal amount of digestive juice is eliminated by this process; the intestines reabsorb most of it; otherwise the body would rapidly dehydrate; (hence the devastating effects of persistent diarrhea). Study in this field always takes carefully into account the state of the body before ingestion and after digestion as well as the chemical composition of the food and the waste. Comparing the waste to the food can determine the specific types of compounds and elements absorbed by the body. The effect that the absorbed matter has on the body can be determined by finding the difference between the pre-ingestion state and the post-digestion state. The effect may only be discernible after an extended period of time in which all food and ingestion must be exactly regulated and all waste must be analyzed. The number of variables (e.g. 'confounding factors') involved in this type of experimentation is very high. This makes scientifically valid nutritional study very time-consuming and expensive, and explains why a proper science of human nutrition is rather new. In general, eating a variety of fresh, whole (unprocessed) plant foods has proven hormonally and metabolically favourable compared to eating a monotonous diet based on processed foods. In particular, consumption of whole plant foods slows digestion and provides higher amounts and a more favourable balance of essential and vital nutrients per unit of energy; resulting in better management of cell growth, maintenance, and mitosis (cell division) as well as regulation of blood glucose and appetite. A generally more regular eating pattern (e.g. eating medium-sized meals every 2 to 3 hours) has also proven more hormonally and metabolically favourable than infrequent, haphazard food intake. # Nutrients There are seven main classes of nutrients that the body needs: carbohydrates, proteins, fats, vitamins, minerals, fiber and water. It is important to consume these seven nutrients on a daily basis to build and maintain health. Poor health can be caused by an imbalance of nutrients, either an excess or deficiency, which, in turn, affects bodily functions cumulatively. Moreover, because most nutrients are involved in cell-to-cell signalling (e.g. as building blocks or as part of a hormone or signalling cascades), deficiency or excess of various nutrients affects hormonal function indirectly. Thus, because they largely regulate the expression of genes, hormones represent a link between nutrition and how our genes are expressed, i.e. our phenotype. The strength and nature of this link are continually under investigation, but recent observations have demonstrated a pivotal role for nutrition in hormonal activity and function and therefore in health. According to the United Nations World Health Organization (WHO: 1996), more than starvation the real challenge in developing nations today is malnutrition-the deficiency of micronutrients (vitamins, minerals and essential amino acids) that no longer allows the body to ensure growth and maintain its vital functions. ## Carbohydrates kcal/gram: 4[1] Carbohydrates may be classified as monosaccharides, disaccharides, or polysaccharides by the number of sugar units they contain. Monosaccharides contain 1 sugar unit, disaccharides contain 2, and polysaccharides contain 3 or more. Polysaccharides are often referred to as complex carbohydrates because they are long chains of sugar units, whereas monosaccharides and disaccharides are simple carbohydrates. The difference is important to nutritionists because complex carbohydrates take longer to metabolize since their sugar units are processed one-by-one off the ends of the chains. Simple carbohydrates are metabolized quickly and thus raise blood sugar levels more quickly resulting in rapid increases in blood insulin levels. Several lines of evidence indicate lifestyle-induced hyperinsulinemia and reduced insulin function (i.e. insulin resistance) as a decisive factor in many disease states. For example, hyperinsulinemia and insulin resistance are strongly linked to chronic inflammation, which in turn is strongly linked to a variety of adverse developments such as arterial microinjuries and clot formation (i.e. heart disease) and exaggerated cell division (i.e. cancer). Hyperinsulinemia and insulin resistance (the so-called metabolic syndrome) are characterized by a combination of abdominal obesity, elevated blood sugar, elevated blood pressure, elevated blood triglycerides, and reduced HDL cholesterol. The negative impact of hyperinsulinemia on prostaglandin PGE1/PGE2 balance may be significant. The state of obesity clearly contributes to insulin resistance, which in turn can cause type 2 diabetes. Virtually all obese and most type 2 diabetic individuals have marked insulin resistance. Although the association between overweight and insulin resistance is clear, the exact (likely multifarious) causes of insulin resistance remain less clear. Importantly, it has been demonstrated that appropriate exercise, more regular food intake and reducing glycemic load (see below) all can reverse insulin resistance in overweight individuals (and thereby lower blood sugar levels in those who have type 2 diabetes). Obesity can unfavourably alter hormonal and metabolic status via resistance to the hormone leptin, and a vicious cycle may occur in which insulin/leptin resistance and obesity aggravate one another. The vicious cycle is putatively fuelled by continuously high insulin/leptin stimulation and fat storage, as a result of high intake of strongly insulin/leptin stimulating foods and energy. Both insulin and leptin normally function as satiety signals to the hypothalamus in the brain; however, insulin/leptin resistance may reduce this signal and therefore allow continued overfeeding despite large body fat stores. In addition, reduced leptin signalling to the brain may reduce leptin's normal effect to maintain an appropriately high metabolic rate. There is a debate about how and to what extent different dietary factors -- e.g. intake of processed carbohydrates, total protein, fat, and carbohydrate intake, intake of saturated and trans fatty acids, and low intake of vitamins/minerals -- contribute to the development of insulin- and leptin resistance. In any case, analogous to the way modern man-made pollution may potentially overwhelm the environment's ability to maintain 'homeostasis', the recent explosive introduction of high Glycemic Index- and processed foods into the human diet may potentially overwhelm the body's ability to maintain homeostasis and health (as evidenced by the metabolic syndrome epidemic). ## Protein kcal/gram: 4[1] Protein is composed of amino acids, that are body's structural (muscles, skin, hair etc.) materials. The body requires amino acids to produce new body protein (protein retention) and to replace damaged proteins (maintenance) that are lost in the urine. In animals amino acid requirements are classified in terms of essential (an animal cannot produce them) and non-essential (the animal can produce them from other nitrogen containing compounds) amino acids. Consuming a diet that contains adequate amounts of essential (but also non-essential) amino acids is particularly important for growing animals, who have a particularly high requirement. Dietary sources of protein include meats, eggs, grains, legumes, and dairy products such as milk and cheese. Proteins can be converted into carbohydrates through a process called gluconeogenesis. ## Fat kcal/gram: 9[1] Fats are composed of fatty acids, long carbon/hydrogen chains bonded to a glycerol. Fat may be classified as saturated or unsaturated. Saturated fats have all of their carbon atoms bonded to hydrogen atoms, whereas unsaturated fats have some of their carbon atoms double-bonded in place of a hydrogen atom. Generally, saturated fat is solid at room temperature while unsaturated fat is a liquid. Unsaturated fats may be further classified as mono-unsaturated (one double-bond) or poly-unsaturated (many double-bonds). Trans fats are saturated fats which are typically created from unsaturated fat by adding the extra hydrogen atoms in a process called hydrogenation (also called hydrogenated fat). Most fatty acids are non-essential, meaning the body can produce them as needed, however, at least two fatty acids are essential and must be consumed in the diet. An appropriate balance of essential fatty acids - omega-3 and omega-6 fatty acids - has been discovered to be crucial for maintaining health. Both of these unique "omega" long-chain polyunsaturated fatty acids are substrates for a class of eicosanoids known as prostaglandins which function as hormones. The omega-3 eicosapentaenoic acid (EPA) (which can be made in the body from the omega-3 essential fatty acid alpha-linolenic acid (LNA), or taken in through marine food sources), serves as building block for series 3 prostaglandins (e.g. weakly-inflammation PGE3). The omega-6 dihomo-gamma-linolenic acid (DGLA) serves as building block for series 1 prostaglandins (e.g. anti-inflammatory PGE1), whereas arachidonic acid (AA) serves as building block for series 2 prostaglandins (e.g. pro-inflammatory PGE 2). Both DGLA and AA are made from the omega-6 linoleic acid (LA) in the body, or can be taken in directly through food. An appropriately balanced intake of omega-3 and omega-6 partly determines the relative production of different prostaglandins, which partly explains the importance of omega-3/omega-6 balance for cardiovascular health. In industrialised societies, people generally consume large amounts of processed vegetable oils that have reduced amounts of essential fatty acids along with an excessive amount of omega-6 relative to omega-3. The rate of conversions of omega-6 DGLA to AA largely determines the production of the respective prostaglandins PGE1 and PGE2. Omega-3 EPA prevents AA from being released from membranes, thereby skewing prostaglandin balance away from pro-inflammatory PGE2 made from AA toward anti-inflammatory PGE1 made from DGLA. Moreover, the conversion (desaturation) of DGLA to AA is controlled by the enzyme delta-5-desaturase, which in turn is controlled by hormones such as insulin (up-regulation) and glucagon (down-regulation). Because different types and amounts of food eaten/absorbed affect insulin, glucagon and other hormones to varying degrees, not only the amount of omega-3 versus omega-6 eaten but also the general composition of the diet therefore determine health implications in relation to essential fatty acids, inflammation (e.g. immune function) and mitosis (i.e. cell division). ## Vitamins kcal/gram: 0 Mineral and/or vitamin deficiency or excess may yield symptoms of diminishing health such as goitre, scurvy, osteoporosis, weak immune system, disorders of cell metabolism, certain forms of cancer, symptoms of premature aging, and poor psychological health (including eating disorders), among many others.[2] As of 2005, twelve vitamins and about the same number of minerals are recognized as "essential nutrients", meaning that they must be consumed and absorbed - or, in the case of vitamin D, alternatively synthesized via UVB radiation - to prevent deficiency symptoms and death. Certain vitamin-like substances found in foods, such as carnitine, have also been found essential to survival and health, but these are not strictly "essential" to eat because the body can produce them from other compounds. Moreover, thousands of different phytochemicals have recently been discovered in food (particularly in fresh vegetables), which have many known and yet to be explored properties including antioxidant activity (see below). Other essential nutrients include essential amino acids, choline and the essential fatty acids. ## Minerals kcal/gram: 0 Dietary minerals are the chemical elements required by living organisms, other than the four elements carbon, hydrogen, nitrogen, and oxygen which are present in common organic molecules. The term "mineral" is archaic, since the intent of the definition is to describe ions, not chemical compounds or actual minerals. Some dietitians recommend that these heavier elements should be supplied by ingesting specific foods (that are enriched in the element(s) of interest), compounds, and sometimes including even minerals, such as calcium carbonate. Sometimes these "minerals" come from natural sources such as ground oyster shells. Sometimes minerals are added to the diet separately from food, such as mineral supplements, the most famous being iodine in "iodized salt." A variety of elements are required to support the biochemical processes, many play a role as electrolytes or in a structural role.[3] In Human nutrition, the dietary bulk "mineral elements" (RDA > 200 mg/day) are in alphabetical order (parenthetical comments on folk medicine perspective): - Calcium (for muscle and digestive system health, builds bone, neutralizes acidity, clears toxins, helps blood stream) - Chloride - Magnesium required for processing ATP and related reactions (health, builds bone, causes strong peristalsis, increases flexibility, increases alkalinity) - Phosphorus required component of bones (see apatite) and energy processing and many other functions (bone mineralization)[4] - Potassium required electrolyte (heart and nerves health) - Sodium electrolyte - Sulfur for three essential amino acids and many proteins and cofactors (skin, hair, nails, liver, and pancreas health) A variety of elements are required in trace amounts, unusually because they play a role in catalysis in enzymes.[5] Some trace mineral elements (RDA < 200 mg/day) are (alphabetical order): - Cobalt required for biosynthesis of vitamin B12 family of coenzymes - Copper required component of many redox enzymes, including cytochrome c oxidase - Chromium required for sugar metabolism - Iodine required for the biosynthesis of thyroxin - Iron required for many proteins and enzymes, notably hemoglobin - Manganese (processing of oxygen) - Molybdenum required for xanthine oxidase and related oxidases - Nickel present in urease - Selenium reqiured for peroxidase (antioxidant proteins) - Vanadium (There is no established RDA for vanadium. No specific biochemical function has been identified for it in humans, although vanadium is found in lower organisms.) - Zinc required for several enzymes such as carboxypeptidase, liver alcohol dehydrogenase, carbonic anhydrase. Zinc is pervasive. Iodine is required in larger quantities than the other trace minerals in this list and is sometimes classified with the bulk minerals. Sodium is not generally found in dietary supplements, despite being needed in large quantities, because the ion is very common in food. ## Fibre Dietary fibre consists mainly of cellulose that is indigestible because we do not have enzymes to digest it. Fruits and vegetables are rich in dietary fibre. Importance of dietary fibre: - provides bulk to the intestinal contents - stimulates peristalsis (rhythmic muscular contractions passing along the digestive tract) Lack of dietary fibre in the diet leads to constipation (failure to pass motions). ## Water kcal/gram: 0 About 70% of the non-fat mass of the human body is made of water. To function properly, the body requires between one and seven liters of water per day to avoid dehydration; the precise amount depends on the level of activity, temperature, humidity, and other factors. With physical exertion and heat exposure, water loss will increase and daily fluid needs may increase as well. It is not clear how much water intake is needed by healthy people, although some experts assert that 8–10 glasses of water (approximately 2 liters) daily is the minimum to maintain proper hydration.[6] The "fact" that a person should consume eight glasses of water per day cannot be traced back to a scientific source.[7] There are other myths such as the effect of water on weight loss and constipation that have been dispelled.[8] Original recommendation for water intake in 1945 by the Food and Nutrition Board of the National Research Council read: "An ordinary standard for diverse persons is 1 milliliter for each calorie of food. Most of this quantity is contained in prepared foods."[9] The latest dietary reference intake report by the United States National Research Council in general recommended (including food sources): 2.7 liters of water total for women and 3.7 liters for men.[10] Specifically, pregnant and breastfeeding women need additional fluids to stay hydrated. According to the Institute of Medicine—who recommend that, on average, women consume 2.2 litres and men 3.0 litres—this is recommended to be 2.4 litres (approx. 9 cups) for pregnant women and 3 litres (approx. 12.5 cups) for breastfeeding women since an especially large amount of fluid is lost during nursing.[11] For those who have healthy kidneys, it is rather difficult to drink too much water, but (especially in warm humid weather and while exercising) it is dangerous to drink too little. People can drink far more water than necessary while exercising, however, putting them at risk of water intoxication, which can be fatal. Normally, about 20 percent of water intake comes from food, while the rest comes from drinking water and beverages (caffeinated included). Water is excreted from the body in multiple forms; through urine and feces, through sweating, and by exhalation of water vapor in the breath. ## Antioxidants kcal/gram: 0 Antioxidants are another recent discovery. As cellular metabolism/energy production requires oxygen, potentially damaging (e.g. mutation causing) compounds known as radical oxygen species or free radicals form as a result. For normal cellular maintenance, growth, and division, these free radicals must be sufficiently neutralized by antioxidant compounds, some produced by the body with adequate precursors (glutathione, Vitamin C in most animals) and those that the body cannot produce may only be obtained through the diet through direct sources (Vitamin C in humans, Vitamin A, Vitamin K) or produced by the body from other compounds (Beta-carotene converted to Vitamin A by the body, Vitamin D synthesized from cholesterol by sunlight). Phytochemicals (Section Below) and their subgroup polyphenols comprise of the majority of antioxidants, some 4,000 known, and therefore there is much overlap. Different antioxidants are now known to function in a cooperative network, e.g. vitamin C can reactivate free radical-containing glutathione or vitamin E by accepting the free radical itself, and so on. Some antioxidants are more effective than others at neutralizing different free radicals. Some cannot neutralize certain free radicals. Some cannot be present in certain areas of free radical development (Vitamin A is fat-soluble and protects fat areas, Vitamin C is water soluble and protects those areas). When interacting with a free radical, some antioxidants produce a different free radical compound that is less dangerous or more dangerous than the previous compound. Having a variety of antioxidants allows any byproducts to be safely dealt with by more efficient antioxidants in neutralizing a free radical's butterfly effect. ### Phytochemicals A growing area of interest is the effect upon human health of trace chemicals, collectively called phytochemicals. These antioxidant nutrients are typically found in edible plants, especially colorful fruits and vegetables, but also other organisms including seafood, algae, and fungi. The effects of phytochemicals increasingly survive rigorous testing by prominent health organizations. One of the principal classes of phytochemicals are polyphenol antioxidants, chemicals which are known to provide certain health benefits to the cardiovascular system and immune system. These chemicals are known to down-regulate the formation of reactive oxygen species, key chemicals in cardiovascular disease. Perhaps the most rigorously tested phytochemical is zeaxanthin, a yellow-pigmented carotenoid present in many yellow and orange fruits and vegetables. Repeated studies have shown a strong correlation between ingestion of zeaxanthin and the prevention and treatment of age-related macular degeneration (AMD).[12] Less rigorous studies have proposed a correlation between zeaxanthin intake and cataracts.[13] A second carotenoid, lutein, has also been shown to lower the risk of contracting AMD. Both compounds have been observed to collect in the retina when ingested orally, and they serve to protect the rods and cones against the destructive effects of light. Another caretenoid, beta-cryptoxanthin, appears to protect against chronic joint inflammatory diseases, such as arthritis. While the association between serum blood levels of beta-cryptoxanthin and substantially decreased joint disease has been established, neither a convincing mechanism for such protection nor a cause-and-effect have been rigorously studied.[14] Similarly, a red phytochemical, lycopene, has substantial credible evidence of negative association with development of prostate cancer. The correlations between the ingestion of some phytochemicals and the prevention of disease are, in some cases, enormous in magnitude. Even when the evidence is obtained, translating it to practical dietary advice can be difficult and counter-intuitive. Lutein, for example, occurs in many yellow and orange fruits and vegetables and protects the eyes against various diseases. However, it does not protect the eye nearly as well as zeaxanthin, and the presence of lutein in the retina will prevent zeaxanthin uptake. Additionally, evidence has shown that the lutein present in egg yolk is more readily absorbed than the lutein from vegetable sources, possibly because of fat solubility.[15] At the most basic level, the question "should you eat eggs?" is complex to the point of dismay, including misperceptions about the health effects of cholesterol in egg yolk, and its saturated fat content. As another example, lycopene is prevalent in tomatoes (and actually is the chemical that gives tomatoes their red color). It is more highly concentrated, however, in processed tomato products such as commercial pasta sauce, or tomato soup, than in fresh "healthy" tomatoes. Yet, such sauces tend to have high amounts of salt, sugar, other substances a person may wish or even need to avoid. The following table presents phytochemical groups and common sources, arranged by family: ## Intestinal bacterial flora It is now also known that the human digestion system contains a population of a range of bacteria and yeast such as Bacteroides, L. acidophilus and E. coli which are essential to digestion, and which are also affected by the food we eat. Bacteria in the gut fulfill a host of important functions for humans, including breaking down and aiding in the absorption of otherwise indigestible food; stimulating cell growth; repressing the growth of harmful bacteria, training the immune system to respond only to pathogens; and defending against some diseases. # Sports nutrition ## Protein The protein requirements of athletes, once the source of great controversy, has settled into a current consensus. Sedentary people and recreational athletes[18] have similar protein requirements, about 1 gram of protein per kilogram of body mass. These needs are easily met by a balanced diet containing about 70 grams of protein for a 70 kg (150 pound) man or 60 grams of protein for a 60 kg (130 pound) woman. People who exercise at greater intensity, and especially those whose activity grows muscle bulk, have significantly higher protein requirements. According to Clinical Sports Nutrition (see footnote above), active athletes playing power sports (such as football), those engaged in muscle-development training, and elite endurance athletes, all require approximately 2 grams of protein per day per kilogram of body weight, roughly double that of a sedentary persons. Older athletes seeking primarily to maintain developed muscle mass require 2 to 3 g/day/kg. Protein intake in excess of that required to build muscle (and other) tissue is broken-down by gluconeogenesis to be used as energy. ## Water and Salts Maintaining hydration during periods of physical exertion is key to good performance. While drinking too much water during activities can lead to physical discomfort, dehydration in excess of 2% of body mass (by weight) markedly hinders athletic performance. It is recommended that an athlete drink about 400-600 mL 2-3 hours before activity, during exercise he or she should drink 150-350mL every 15 to 20 minutes and after exercise that he or she replace sweat loss by drinking 450-675 mL for every 0.5 kg body weight loss during activity. Some studies have shown that an athlete that drinks before they feel thirsty stays cooler and performs better than one who drinks on thirst cues, although recent studies of such races as the Boston Marathon have indicated that this recommendation can lead to the problem of overhydration. Additional carbohydrates and protein before, during, and after exercise increase time to exhaustion as well as speed recovery. Dosage is based on work performed, lean body mass, and environmental factors, especially ambient temperature and humidity. Excess water intake, without replenishment of sodium and potassium salts, leads to hyponatremia, which can further lead to water intoxication at more dangerous levels. A well-publicized case occurred in 2007, when Jennifer Strange died while participating in a water-drinking contest.[19] More usually, the condition occurs in long-distance endurance events (such as marathon or triathlon competition and training) and causes gradual mental dulling, headache, drowsiness, weakness, and confusion; extreme cases may result in coma, convulsions, and death. The primary damage comes from swelling of the brain, caused by increased osmosis as blood salinity decreases. Effective fluid replacement techniques include Water aid stations during running/cycling races, trainers providing water during team games such as Soccer and devices such as Camel Baks which can provide water for a person without making it too hard to drink the water. ## Carbohydrates The main fuel used by the body during exercise is carbohydrates, which is stored in muscle as glycogen- a form of sugar. During exercise, muscle glycogen reserves can be used up, especially when activities last longer than 90 min. When glycogen is not present in muscles, the muscle cells perform anaerobic respiration producing lactic acid, which is responsible for fatigue and burning sensation, and post exercise stiffness in muscles. Because the amount of glycogen stored in the body is limited, it is important for athletes to replace glycogen by consuming a diet high in carbohydrates. Meeting energy needs can help improve performance during the sport, as well as improve overall strength and endurance. # Longevity ### Whole plant food diet Heart disease, cancer, obesity, and diabetes are commonly called "Western" diseases because these maladies were once rarely seen in developing countries. One study in China found some regions had essentially no cancer or heart disease, while in other areas they reflected “up to a 100-fold increase” coincident with diets that were found to be entirely plant-based to heavily animal-based, respectively.[20] In contrast, diseases of affluence like cancer and heart disease are common throughout the United States. Adjusted for age and exercise, large regional clusters of people in China rarely suffered from these “Western” diseases possibly because their diets are rich in vegetables, fruits and whole grains.[21] The United Healthcare/Pacificare nutrition guideline recommends a whole plant food diet, and recommends using protein only as a condiment with meals. A National Geographic (November 2005) cover article, titled The Secrets of LIVING LONGER also recommends a whole plant food diet. The article is a lifestyle survey of three populations, Sardinians, Okinawans, and Adventists, who generally display longevity and "suffer a fraction of the diseases that commonly kill people in other parts of the developed world, and enjoy more healthy years of life. In sum, they offer three sets of 'best practices' to emulate. The rest is up to you." In common with all three groups is to "Eat fruits, vegetables, and whole grains." The National Geographic article noted that a NIH funded study of 34,000 Seventh-Day Adventists between 1976 and 1988 "...found that the Adventists' habit of consuming beans, soy milk, tomatoes, and other fruits lowered their risk of developing certain cancers. It also suggested that eating whole grain bread, drinking five glasses of water a day, and, most surprisingly, consuming four servings of nuts a week reduced their risk of heart disease." Note that cancer is now common in developing countries. According a study by the International Agency for Research on Cancer: “In the developing world, cancers of the liver, stomach and esophagus were more common, often linked to consumption of carcinogenic preserved foods, such as smoked or salted food, and parasitic infections that attack organs.” Lung cancer rates are rising rapidly in poorer nations because of increased use of tobacco. Developed countries “tended to have cancers linked to affluence or a "Western lifestyle" – cancers of the colon, rectum, breast and prostate – that can be caused by obesity, lack of exercise, diet and age.”[22] ### The French "paradox" It has been discovered that people living in France live longer. Even though they consume more saturated fats than Americans, the rate of heart disease is lower in France than in North America. A number of explanations have been suggested: - Reduced consumption of processed carbohydrate and other junk foods; - Ethnic genetic differences allowing the body to be harmed less by fats; - Regular consumption of red wine; or - Living in the South requires the body to produce less heat, allowing a slower, and therefore healthier, metabolic rate. - More active lifestyles involving plenty of daily exercise, especially walking; the French are much less dependent on cars than Americans are. However, a growing number of French health researchers doubt the theory that the French are healthier than other populations. Statistics collected by the WHO from 1990-2000 show that the incidence of heart disease in France may have been underestimated and in fact be similar to that of neighboring countries.[23] # Mental agility Research indicates that improving the awareness of nutritious meal choices and establishing long-term habits of healthy eating has a positive effect on a cognitive and spatial memory capacity, potentially increasing a student’s potential to process and retain academic information. Some organizations have begun working with teachers, policymakers, and managed foodservice contractors to mandate improved nutritional content and increased nutritional resources in school cafeterias from primary to university level institutions. Health and nutrition have been proven to have close links with overall educational success (Behrman, 1996). Currently less than 10% of American college students report that they ate the recommended five servings of fruit and vegetables daily. [24] Better nutrition has been shown to have an impact on both cognitive and spatial memory performance; a study showed those with higher blood sugar levels performed better on certain memory tests [25]. In another study, those who consumed yogurt performed better on thinking tasks when compared to those who consumed caffeine free diet soda or confections [26]. Nutritional deficiencies have been shown to have a negative effect on learning behavior in mice as far back as 1951[27]. >“Better learning performance is associated with diet induced effects on learning and memory ability”.[28] The “nutrition-learning nexus” demonstrates the correlation between diet and learning and has application in a higher education setting. >“We find that better nourished children perform significantly better in school, partly because they enter school earlier and thus have more time to learn but mostly because of greater learning productivity per year of schooling.”[29] >91% of college students feel that they are in good health while only 7% eat their recommended daily allowance of fruits and vegetables.[30] >Nutritional education is an effective and workable model in a higher education setting.[31] [32] >More “engaged” learning models that encompass nutrition is an idea that is picking up steam at all levels of the learning cycle [33]. There is limited research available that directly links a student’s Grade Point Average (G.P.A.) to their overall nutritional health. Additional substantive data is needed to prove beyond a shadow of a doubt that overall intellectual health is closely linked to a person’s diet, rather than just another correlation fallacy. # Processed foods Since the Industrial Revolution some two hundred years ago, the food processing industry has invented many technologies that both help keep foods fresh longer and alter the fresh state of food as they appear in nature. Cooling is the primary technology used to maintain freshness, whereas many more technologies have been invented to allow foods to last longer without becoming spoiled. These latter technologies include pasteurisation, autoclavation, drying, salting, and separation of various components, and all appear to alter the original nutritional contents of food. Pasteurisation and autoclavation (heating techniques) have no doubt improved the safety of many common foods, preventing epidemics of bacterial infection. But some of the (new) food processing technologies undoubtedly have downfalls as well. Modern separation techniques such as milling, centrifugation, and pressing have enabled upconcentration of particular components of food, yielding flour, oils, juices and so on, and even separate fatty acids, amino acids, vitamins, and minerals. Inevitably, such large scale upconcentration changes the nutritional content of food, saving certain nutrients while removing others. Heating techniques may also reduce food's content of many heat-labile nutrients such as certain vitamins and phytochemicals, and possibly other yet to be discovered substances.[34] Because of reduced nutritional value, processed foods are often 'enriched' or 'fortified' with some of the most critical nutrients (usually certain vitamins) that were lost during processing. Nonetheless, processed foods tend to have an inferior nutritional profile than do whole, fresh foods, regarding content of both sugar and high GI starches, potassium/sodium, vitamins, fibre, and of intact, unoxidized (essential) fatty acids. In addition, processed foods often contain potentially harmful substances such as oxidized fats and trans fatty acids. A dramatic example of the effect of food processing on a population's health is the history of epidemics of beri-beri in people subsisting on polished rice. Removing the outer layer of rice by polishing it removes with it the essential vitamin thiamine, causing beri-beri. Another example is the development of scurvy among infants in the late 1800s in the United States. It turned out that the vast majority of sufferers were being fed milk that had been heat-treated (as suggested by Pasteur) to control bacterial disease. Pasteurisation was effective against bacteria, but it destroyed the vitamin C. As mentioned, lifestyle- and obesity-related diseases are becoming increasingly prevalent all around the world. There is little doubt that the increasingly widespread application of some modern food processing technologies has contributed to this development. The food processing industry is a major part of modern economy, and as such it is influential in political decisions (e.g. nutritional recommendations, agricultural subsidising). In any known profit-driven economy, health considerations are hardly a priority; effective production of cheap foods with a long shelf-life is more the trend. In general, whole, fresh foods have a relatively short shelf-life and are less profitable to produce and sell than are more processed foods. Thus the consumer is left with the choice between more expensive but nutritionally superior whole, fresh foods, and cheap, usually nutritionally inferior processed foods. Because processed foods are often cheaper, more convenient (in both purchasing, storage, and preparation), and more available, the consumption of nutritionally inferior foods has been increasing throughout the world along with many nutrition-related health complications. # Advice and guidance ## Governmental policies In the US, dietitians are registered with the national Commission for Dietetic Registration and the American Dietetic Association, and are only able to use the label "Dietitian" when they have met specific educational and experiential prerequisites and passed a national registration examination. Anyone may call themselves a nutritionist, including unqualified personnel, as this term is unregulated. Some states have begun to include the title "nutritionist" in state licensure requirements, such as the State of Florida. Most governments provide guidance on nutrition, and some also impose mandatory disclosure/labeling requirements for processed food manufacturers and restaurants to assist consumers in complying with such guidance. In the US, nutritional standards and recommendations are currently controlled by the US Department of Agriculture. Dietary and exercise guidelines from the USDA are presented in the concept of a food pyramid, which superseded the Four Food Groups. The Senate committee currently responsible for oversight of the USDA is the Agriculture, Nutrition and Forestry Committee. Committee hearings are often televised on C-SPAN as seen here. Canada's Food Guide is another governmental recommendation. ## Teaching Nutrition is taught in schools in many countries. In England and Wales the Personal and Social Education and Food Technology curricula nutrition included, stressing the importance of a balanced diet and teaching how to read nutrition labels on packaging. # History Humans have evolved as omnivorous hunter-gatherers over the past 250,000 years. The diet of early modern humans varied significantly depending on location and climate. The diet in the tropics tended to be based more heavily on plant foods, while the diet at higher latitudes tended more towards animal products. Analysis of postcranial and cranial remains of humans and animals from the Neolithic, along with detailed bone modification studies have shown that cannibalism was also prevalent among prehistoric humans.[35] Agriculture developed about 10,000 years ago in multiple locations throughout the world, providing grains such as wheat, rice, and maize, with staples such as bread and pasta. Farming also provided milk and dairy products, and sharply increased the availability of meats and the diversity of vegetables. The importance of food purity was recognized when bulk storage led to infestation and contamination risks. Cooking developed as an often ritualistic activity, due to efficiency and reliability concerns requiring adherence to strict recipes and procedures, and in response to demands for food purity and consistency.[36] ## Antiquity through 1900 - The first recorded nutritional experiment is found in the Bible's Book of Daniel. Daniel and his friends were captured by the king of Babylon during an invasion of Israel. Selected as court servants, they were to share in the king's fine foods and wine. But they objected, preferring vegetables (pulses) and water in accordance with their Jewish dietary restrictions. The king's chief steward reluctantly agreed to a trial. Daniel and his friends received their diet for 10 days and were then compared to the king’s men. Appearing healthier, they were allowed to continue with their diet. - c. 475 BC: Anaxagoras states that food is absorbed by the human body and therefore contained "homeomerics" (generative components), thereby deducing the existence of nutrients. - c. 400 BC: Hippocrates says, "Let food be your medicine and medicine be your food." - 1500s: Scientist and artist Leonardo da Vinci compared metabolism to a burning candle. - 1747: Dr. James Lind, a physician in the British navy, performed the first scientific nutrition experiment, discovering that lime juice saved sailors who had been at sea for years from scurvy, a deadly and painful bleeding disorder. The discovery was ignored for forty years, after which British sailors became known as "limeys." The essential vitamin C within lime juice would not be identified by scientists until the 1930s. - 1770: Antoine Lavoisier, the "Father of Nutrition and Chemistry" discovered the details of metabolism, demonstrating that the oxidation of food is the source of body heat. - 1790: George Fordyce recognized calcium as necessary for fowl survival. - Early 1800s: The elements carbon, nitrogen, hydrogen and oxygen were recognized as the primary components of food, and methods to measure their proportions were developed. - 1816: François Magendie discovers that dogs fed only carbohydrates and fat lost their body protein and died in a few weeks, but dogs also fed protein survived, identifying protein as an essential dietary component. - 1840: Justus Liebig discovers the chemical makeup of carbohydrates (sugars), fats (fatty acids) and proteins (amino acids.) - 1860s: Claude Bernard discovers that body fat can be synthesized from carbohydrate and protein, showing that the energy in blood glucose can be stored as fat or as glycogen. - Early 1880s: Kanehiro Takaki observed that Japanese sailors (whose diets consisted almost entirely of white rice) developed beriberi (or endemic neuritis, a disease causing heart problems and paralysis) but British sailors and Japanese naval officers did not. Adding various types of vegetables and meats to the diets of Japanese sailors prevented the disease. - 1896: Baumann observed iodine in thyroid glands. - 1897: Christiaan Eijkman worked with natives of Java, who also suffered from beriberi. Eijkman observed that chickens fed the native diet of white rice developed the symptoms of beriberi, but remained healthy when fed unprocessed brown rice with the outer bran intact. Eijkman cured the natives by feeding them brown rice, discovering that food can cure disease. Over two decades later, nutritionists learned that the outer rice bran contains vitamin B1, also known as thiamine. ## 1900 through 1941 - Early 1900s: Carl von Voit and Max Rubner independently measure caloric energy expenditure in different species of animals, applying principles of physics in nutrition. - 1906: Wilcock and Hopkins showed that the amino acid tryptophan was necessary for the survival of mice. Gowland Hopkins recognized "accessory food factors" other than calories, protein and minerals, as organic materials essential to health but which the body cannot synthesise. - 1907: Stephen M. Babcock and Edwin B. Hart conduct the Single-grain experiment. This experiment runs through 1911. - 1912: Casimir Funk coined the term vitamin, a vital factor in the diet, from the words "vital" and "amine," because these unknown substances preventing scurvy, beriberi, and pellagra, were thought then to be derived from ammonia. - 1913: Elmer McCollum discovered the first vitamins, fat soluble vitamin A, and water soluble vitamin B (in 1915; now known to be a complex of several water-soluble vitamins) and names vitamin C as the then-unknown substance preventing scurvy. Lafayette Mendel and Thomas Osborne also perform pioneering work on vitamin A and B. - 1919: Sir Edward Mellanby incorrectly identified rickets as a vitamin A deficiency, because he could cure it in dogs with cod liver oil.[37] - 1922: McCollum destroys the vitamin A in cod liver oil but finds it still cures rickets, naming vitamin D - 1922: H.M. Evans and L.S. Bishop discover vitamin E as essential for rat pregnancy, originally calling it "food factor X" until 1925. - 1925: Hart discovers trace amounts of copper are necessary for iron absorption. - 1927: Adolf Otto Reinhold Windaus synthesizes vitamin D, for which he won the Nobel Prize in Chemistry in 1928. - 1928: Albert Szent-Györgyi isolates ascorbic acid, and in 1932 proves that it is vitamin C by preventing scurvy. In 1935 he synthesizes it, and in 1937 he wins a Nobel Prize for his efforts. Szent-Györgyi concurrently elucidates much of the citric acid cycle. - 1930s: William Cumming Rose identifies essential amino acids, necessary protein components which the body cannot synthesize. - 1935: Underwood and Marston independently discover the necessity of cobalt. - 1936: Eugene Floyd Dubois shows that work and school performance are related to caloric intake. - 1938: The chemical structure of vitamin E is discovered by Erhard Fernholz, and it is synthesised by Paul Karrer. - 1940 UK institutes rationing according to nutritional principles drawn up by Elsie Widdowson and others - 1941: The first Recommended Dietary Allowances (RDAs) were established by the National Research Council. ## Recent - 1992 The U.S. Department of Agriculture Introduces Food Guide Pyramid - 2002 Study shows relation between nutrition and violent behavior - 2005 Obesity may be caused by adenovirus in addition to bad nutrition[38]	https://www.wikidoc.org/index.php/Human_nutrition
a341f821206d575e740c23c96aa9806a3d31e305	wikidoc	Hwabyeong	Hwabyeong # Background Hwabyeong, literally "anger illness" or "fire illness”, is a Korean term for a kind of culture-bound somatization disorder, a mental illness. It manifests as one or more of a wide range of physical symptoms, in response to emotional disturbance, such as stress from troublesome interpersonal relationships or life crises. It most often occurs in females in their menopausal years, less-educated people, those of lower socioeconomic status and those from rural areas. Behavior related to hwabyeong includes death. In addition, sufferers might report such symptoms as; a heavy feeling in the chest, perceived abdominal mass (previously thought to define the illness, but now believed to be atypical), sleeplessness, hot flashes, cold flashes and blurred vision. They may also demonstrate typical neurotic symptoms such as anxiety, depression, obsessive-compulsiveness, as well as anorexia, paranoia or fearfulness, absent-mindedness, and irritability. Western doctors are likely to diagnose it as a kind of stress or depression. Diagnostic and Statistical Manual of Mental Disorders currently lists hwabyeong among its culture-bound illnesses. Outside of Korea, informally, hwabyeong may be mistaken as a reference to a psychological profile marked by a lack of temper or explosive, generally bellicose behavior resulting from a lack of temper. To the contrary, hwabyeong is a traditional psychological term used to refer to a condition characterized by passive suffering, is roughly comparable to depression, and is typically associated with older women. In South Korea, it is also called ulhwabyeong (鬱火病). # Hwabyeong in popular culture - A short animation a part of If You Were Me: Anima Vision, a 2005 South Korean omnibus featuring six short animated films addressing human rights issues in Korea, includes a sketch of a depressed female character who carries a jar (Korean: 병/甁 byeong, a homophone of 病 ‘illness’) with a flame (화 hwa) drawn atop of it. ko:화병 nl:Hwa-byung	Hwabyeong Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Background Hwabyeong, literally "anger illness" or "fire illness”, is a Korean term for a kind of culture-bound somatization disorder, a mental illness. It manifests as one or more of a wide range of physical symptoms, in response to emotional disturbance, such as stress from troublesome interpersonal relationships or life crises. It most often occurs in females in their menopausal years, less-educated people, those of lower socioeconomic status and those from rural areas. Behavior related to hwabyeong includes death. In addition, sufferers might report such symptoms as; a heavy feeling in the chest, perceived abdominal mass (previously thought to define the illness, but now believed to be atypical), sleeplessness, hot flashes, cold flashes and blurred vision. They may also demonstrate typical neurotic symptoms such as anxiety, depression, obsessive-compulsiveness, as well as anorexia, paranoia or fearfulness, absent-mindedness, and irritability. Western doctors are likely to diagnose it as a kind of stress or depression. Diagnostic and Statistical Manual of Mental Disorders currently lists hwabyeong among its culture-bound illnesses. Outside of Korea, informally, hwabyeong may be mistaken as a reference to a psychological profile marked by a lack of temper or explosive, generally bellicose behavior resulting from a lack of temper. To the contrary, hwabyeong is a traditional psychological term used to refer to a condition characterized by passive suffering, is roughly comparable to depression, and is typically associated with older women. In South Korea, it is also called ulhwabyeong (鬱火病). # Hwabyeong in popular culture - A short animation a part of If You Were Me: Anima Vision, a 2005 South Korean omnibus featuring six short animated films addressing human rights issues in Korea, includes a sketch of a depressed female character who carries a jar (Korean: 병/甁 byeong, a homophone of 病 ‘illness’) with a flame (화 hwa) drawn atop of it. ko:화병 nl:Hwa-byung Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Hwabyeong
ab57fa4a2c8e18450b019f8174c00a6ae4226c0c	wikidoc	Hydrazine	Hydrazine Hydrazine is the chemical compound with formula N2H4. It is widely used in chemical synthesis and is a component in some rocket fuels. With an ammonia-like odor, hydrazine has a liquid range and density similar to water. # Molecular structure and properties Conceptually, hydrazine arises via coupling a pair of ammonia molecules by removal of one hydrogen per molecule. Each H2N-N subunit is pyramidal. The N-N distance is 1.45 Å, and the molecule adopts a gauche conformation. The rotational barrier is twice that of ethane. These structural properties resemble that of gaseous hydrogen peroxide, which adopts a "skewed" anticlinal conformation, and also experiences a strong rotational barrier. It has basic properties comparable to ammonia but 15-times weaker. (for ammonia K = 1.78 x 10-5) It can be diprotonated only with difficulty: # Synthesis Theodor Curtius synthesized free hydrazine for the first time in 1889 via a circuitous route. Hydrazine is produced in the Olin Raschig process from sodium hypochlorite and ammonia, a process announced in 1907. This method relies on the reaction of chloramine with ammonia. In the Atofina-PCUK cycle, hydrazine is produced in several steps from acetone, ammonia, and hydrogen peroxide. Acetone and ammonia first react to give the imine followed by oxidation with hydrogen peroxide to the oxaziridine, a three-membered ring containing carbon, oxygen, and nitrogen, followed by ammonolysis to the hydrazone, a process that couples two nitrogen atoms. This hydrazone reacts with one more equivalent of acetone, and the resulting azine is hydrolyzed to give hydrazine, regenerating acetone. Unlike the Raschig process, this process does not produce salt. The PCUK stands for Produits Chimiques Ugine Kuhlmann, a French chemical manufacturer. Hydrazine can also be produced via the so-called ketazine and peroxide processes. In 2001, Microbiologist Marc Strous from the University of Nijmegen in the Netherlands discovered that hydrazine is produced from the yeast bacteria and open ocean bacteria anammox (Brocadia anammoxidans). They are the only discovered organisms to naturally produce hydrazine. # Hydrazine derivatives Many substituted hydrazines are known, and several occur naturally. Some examples: - gyromitrin and agaritine are phenylhydrazines found in the commercially produced mushroom species Agaricus bisporus. Gyromitrin is metabolized into monomethyl hydrazine. - iproniazid, hydralazine and phenelzine are hydrazine-containing medications. - 1,1-dimethylhydrazine and 1,2-dimethylhydrazine are hydrazines where two hydrogen atoms are replaced by methyl groups. - 2,4-dinitrophenylhydrazine (2,4-DNP) is commonly used to test for ketones and aldehydes in organic chemistry. - phenylhydrazine, C6H5NHNH2, the first hydrazine to be discovered. # Uses in chemistry Hydrazines are part of many organic syntheses, often those of practical significance in pharmaceuticals, such as antituberculants, as well as in textile dyes and in photography. ## Hydrazone formation Illustrative of the condensation of hydrazine with a simple carbonyl is its reaction with acetone to give the azine. This azine reacts further with hydrazine to afford the hydrazone: The acetone azine is an intermediate in the Atofina-PCUK synthesis. Direct alkylation of hydrazines with alkyl halides in the presence of base affords alkyl-substituted hydrazines, but the reaction is typically inefficient due to poor control on level of substitution (same as in ordinary amines). The reduction of hydrazones to hydrazines present a clean way to produce 1,1-dialkylated hydrazines. In a related reaction 2-cyanopyridines react with hydrazine to form amide hydrazides which can be converted using 1,2-diketones into triazines. ## Wolff-Kishner reduction Hydrazine is used in the Wolff-Kishner reduction, a reaction that transforms the carbonyl group of a ketone or aldehyde into a methylene (or methyl) group via a hydrazone intermediate. The production of the highly stable dinitrogen from the hydrazine derivative helps to drive the reaction. ## Heterocyclic chemistry Being bifunctional, with two amines, hydrazine is a key building block for the preparation of many heterocyclic compounds via condensation with a range of difunctional electrophiles. With 2,4-pentanedione, it condenses to give the dimethylpyrazole. In the Einhorn-Brunner reaction hydrazines react with imides to give triazoles. ## Sulfonation Being a good nucleophile, N2H4 is susceptible to attack by sulfonyl halides and acyl halides. The tosylhydrazine also forms hydrazones upon treatment with carbonyls. ## Deprotection of phthalimides Hydrazine is used to cleave N-alkylated phthalimide derivatives. This scission reaction allows phthalimide anion to be used as amine precursor. ## Reducing agent Hydrazine is a convenient reductant because the by-products are typically nitrogen gas and water. Thus, it is used as an antioxidant, an oxygen scavenger, and a corrosion inhibitor in water boilers and heating systems. It is also used to reduce metal salts and oxides to the pure metals in electroless nickel plating and plutonium extraction from nuclear reactor waste. ## Hydrazinium salts Hydrazine is converted to solid salts by treatment with mineral acids. A common salt is hydrazine hydrogen sulfate, HSO4, which probably should be called hydrazinium bisulfate. Hydrazine bisulfate is used as an alternative treatment of cancer-induced cachexia. The salt of hydrazine and hydrazoic acid N5H5 was of scientific interest, because of the high nitrogen content and the explosive properties. # Other industrial uses Hydrazine is used in many processes including: production of spandex fibers, as a polymerization catalyst; a blowing agent; in fuel cells, solder, fluxes; and photographic developers, as a chain extender in urethane polymerizations, and heat stabilizers. In addition, a semiconductor deposition technique using hydrazine has recently been demonstrated, with possible application to the manufacture of thin-film transistors used in liquid crystal displays. Hydrazine in a 70% hydrazine, 30% water solution is used to power the EPU (emergency power unit) on the F-16 fighter plane. The explosive Astrolite is made by combining hydrazine with ammonium nitrate. ## Rocket fuel Hydrazine was first used as a rocket fuel during World War II for the Messerschmitt Me 163B (the first rocket-powered fighter plane), under the name B-Stoff (hydrazine hydrate) and in a mixture with methanol (M-Stoff) and hydrogen peroxide called C-Stoff. Hydrazine is also used as a low-power monopropellant for the maneuvering thrusters of spacecraft, and the Space Shuttle's Auxiliary Power Units. In addition, monopropellant hydrazine-fueled rocket engines are often used in terminal descent of spacecraft. A collection of such engines were used in both Viking landers as well as the Phoenix lander launched in August 2007. In all hydrazine monopropellant engines the hydrazine is passed by a catalyst such as iridium metal supported by high-surface-area alumina (aluminium oxide) or carbon nanofibers, or more recently molybdenum nitride on alumina, which causes it to decompose into ammonia, nitrogen gas, and hydrogen gas according to the following reactions: - 3 N2H4 → 4 NH3 + N2 - N2H4 → N2 + 2 H2 - 4 NH3 + N2H4 → 3 N2 + 8 H2 These reactions are extremely exothermic (the catalyst chamber can reach 800 °C in a matter of milliseconds), and they produce large volumes of hot gas from a small volume of liquid hydrazine, making it an efficient thruster propellant. Other variants of Hydrazine that are used as rocket fuel are MonoMethylHydrazine (CH3NHNH2) also known as MMH and Unsymmetrical DiMethylHydrazine ((CH3)2NNH2) known as UDMH. These are used as two component rocket fuel, often together with Dinitrogen tetroxide, N2O4. # Safety Hydrazine is highly toxic and dangerously unstable, especially in the anhydrous form. Symptoms of acute exposure to high levels of hydrazine may include irritation of the eyes, nose, and throat, dizziness, headache, nausea, pulmonary edema, seizures, and coma in humans. Acute exposure can also damage the liver, kidneys, and central nervous system in humans. The liquid is corrosive and may produce dermatitis from skin contact in humans and animals. Effects to the lungs, liver, spleen, and thyroid have been reported in animals chronically exposed to hydrazine via inhalation. Increased incidences of lung, nasal cavity, and liver tumors have been observed in rodents exposed to hydrazine.	Hydrazine Template:Chembox new Hydrazine is the chemical compound with formula N2H4. It is widely used in chemical synthesis and is a component in some rocket fuels. With an ammonia-like odor, hydrazine has a liquid range and density similar to water. # Molecular structure and properties Conceptually, hydrazine arises via coupling a pair of ammonia molecules by removal of one hydrogen per molecule. Each H2N-N subunit is pyramidal. The N-N distance is 1.45 Å, and the molecule adopts a gauche conformation[1]. The rotational barrier is twice that of ethane. These structural properties resemble that of gaseous hydrogen peroxide, which adopts a "skewed" anticlinal conformation, and also experiences a strong rotational barrier. It has basic properties comparable to ammonia but 15-times weaker. (for ammonia K = 1.78 x 10-5) It can be diprotonated only with difficulty:[2] # Synthesis Theodor Curtius synthesized free hydrazine for the first time in 1889 via a circuitous route.[3] Hydrazine is produced in the Olin Raschig process from sodium hypochlorite and ammonia, a process announced in 1907. This method relies on the reaction of chloramine with ammonia.[4] In the Atofina-PCUK cycle, hydrazine is produced in several steps from acetone, ammonia, and hydrogen peroxide. Acetone and ammonia first react to give the imine followed by oxidation with hydrogen peroxide to the oxaziridine, a three-membered ring containing carbon, oxygen, and nitrogen, followed by ammonolysis to the hydrazone, a process that couples two nitrogen atoms. This hydrazone reacts with one more equivalent of acetone, and the resulting azine is hydrolyzed to give hydrazine, regenerating acetone. Unlike the Raschig process, this process does not produce salt. The PCUK stands for Produits Chimiques Ugine Kuhlmann, a French chemical manufacturer.[5] Hydrazine can also be produced via the so-called ketazine and peroxide processes. In 2001, Microbiologist Marc Strous from the University of Nijmegen in the Netherlands discovered that hydrazine is produced from the yeast bacteria and open ocean bacteria anammox (Brocadia anammoxidans). They are the only discovered organisms to naturally produce hydrazine.[6] # Hydrazine derivatives Many substituted hydrazines are known, and several occur naturally. Some examples: - gyromitrin and agaritine are phenylhydrazines found in the commercially produced mushroom species Agaricus bisporus. Gyromitrin is metabolized into monomethyl hydrazine. - iproniazid, hydralazine and phenelzine are hydrazine-containing medications. - 1,1-dimethylhydrazine and 1,2-dimethylhydrazine are hydrazines where two hydrogen atoms are replaced by methyl groups. - 2,4-dinitrophenylhydrazine (2,4-DNP) is commonly used to test for ketones and aldehydes in organic chemistry. - phenylhydrazine, C6H5NHNH2, the first hydrazine to be discovered. # Uses in chemistry Hydrazines are part of many organic syntheses, often those of practical significance in pharmaceuticals, such as antituberculants, as well as in textile dyes and in photography. ## Hydrazone formation Illustrative of the condensation of hydrazine with a simple carbonyl is its reaction with acetone to give the azine. This azine reacts further with hydrazine to afford the hydrazone:[7] The acetone azine is an intermediate in the Atofina-PCUK synthesis. Direct alkylation of hydrazines with alkyl halides in the presence of base affords alkyl-substituted hydrazines, but the reaction is typically inefficient due to poor control on level of substitution (same as in ordinary amines). The reduction of hydrazones to hydrazines present a clean way to produce 1,1-dialkylated hydrazines. In a related reaction 2-cyanopyridines react with hydrazine to form amide hydrazides which can be converted using 1,2-diketones into triazines. ## Wolff-Kishner reduction Hydrazine is used in the Wolff-Kishner reduction, a reaction that transforms the carbonyl group of a ketone or aldehyde into a methylene (or methyl) group via a hydrazone intermediate. The production of the highly stable dinitrogen from the hydrazine derivative helps to drive the reaction. ## Heterocyclic chemistry Being bifunctional, with two amines, hydrazine is a key building block for the preparation of many heterocyclic compounds via condensation with a range of difunctional electrophiles. With 2,4-pentanedione, it condenses to give the dimethylpyrazole.[8] In the Einhorn-Brunner reaction hydrazines react with imides to give triazoles. ## Sulfonation Being a good nucleophile, N2H4 is susceptible to attack by sulfonyl halides and acyl halides.[9] The tosylhydrazine also forms hydrazones upon treatment with carbonyls. ## Deprotection of phthalimides Hydrazine is used to cleave N-alkylated phthalimide derivatives. This scission reaction allows phthalimide anion to be used as amine precursor.[10] ## Reducing agent Hydrazine is a convenient reductant because the by-products are typically nitrogen gas and water. Thus, it is used as an antioxidant, an oxygen scavenger, and a corrosion inhibitor in water boilers and heating systems. It is also used to reduce metal salts and oxides to the pure metals in electroless nickel plating and plutonium extraction from nuclear reactor waste. ## Hydrazinium salts Hydrazine is converted to solid salts by treatment with mineral acids. A common salt is hydrazine hydrogen sulfate, [N2H5]HSO4, which probably should be called hydrazinium bisulfate. Hydrazine bisulfate is used as an alternative treatment of cancer-induced cachexia. The salt of hydrazine and hydrazoic acid N5H5 was of scientific interest, because of the high nitrogen content and the explosive properties. # Other industrial uses Hydrazine is used in many processes including: production of spandex fibers, as a polymerization catalyst; a blowing agent; in fuel cells, solder, fluxes; and photographic developers, as a chain extender in urethane polymerizations, and heat stabilizers. In addition, a semiconductor deposition technique using hydrazine has recently been demonstrated, with possible application to the manufacture of thin-film transistors used in liquid crystal displays. Hydrazine in a 70% hydrazine, 30% water solution is used to power the EPU (emergency power unit) on the F-16 fighter plane. The explosive Astrolite is made by combining hydrazine with ammonium nitrate. ## Rocket fuel Hydrazine was first used as a rocket fuel during World War II for the Messerschmitt Me 163B (the first rocket-powered fighter plane), under the name B-Stoff (hydrazine hydrate) and in a mixture with methanol (M-Stoff) and hydrogen peroxide called C-Stoff. Hydrazine is also used as a low-power monopropellant for the maneuvering thrusters of spacecraft, and the Space Shuttle's Auxiliary Power Units. In addition, monopropellant hydrazine-fueled rocket engines are often used in terminal descent of spacecraft. A collection of such engines were used in both Viking landers as well as the Phoenix lander launched in August 2007. In all hydrazine monopropellant engines the hydrazine is passed by a catalyst such as iridium metal supported by high-surface-area alumina (aluminium oxide) or carbon nanofibers,[11] or more recently molybdenum nitride on alumina,[12] which causes it to decompose into ammonia, nitrogen gas, and hydrogen gas according to the following reactions: - 3 N2H4 → 4 NH3 + N2 - N2H4 → N2 + 2 H2 - 4 NH3 + N2H4 → 3 N2 + 8 H2 These reactions are extremely exothermic (the catalyst chamber can reach 800 °C in a matter of milliseconds[11]), and they produce large volumes of hot gas from a small volume of liquid hydrazine,[12] making it an efficient thruster propellant. Other variants of Hydrazine that are used as rocket fuel are MonoMethylHydrazine (CH3NHNH2) also known as MMH and Unsymmetrical DiMethylHydrazine ((CH3)2NNH2) known as UDMH. These are used as two component rocket fuel, often together with Dinitrogen tetroxide, N2O4. # Safety Hydrazine is highly toxic and dangerously unstable, especially in the anhydrous form. Symptoms of acute exposure to high levels of hydrazine may include irritation of the eyes, nose, and throat, dizziness, headache, nausea, pulmonary edema, seizures, and coma in humans. Acute exposure can also damage the liver, kidneys, and central nervous system in humans. The liquid is corrosive and may produce dermatitis from skin contact in humans and animals. Effects to the lungs, liver, spleen, and thyroid have been reported in animals chronically exposed to hydrazine via inhalation. Increased incidences of lung, nasal cavity, and liver tumors have been observed in rodents exposed to hydrazine.	https://www.wikidoc.org/index.php/Hydrazine
05ca7cbfb15fba6b2a0e6dacfd822e34bc7bd9de	wikidoc	Hydronium	Hydronium In chemistry, hydronium is the common name for the cation H3O+ derived from protonation of water. It is the simplest type of an oxonium ion. # Nomenclature According to IUPAC nomenclature of organic chemistry, the hydronium ion should be referred to as oxonium. Hydroxonium may also be used unambiguously to identify it. A draft IUPAC proposal also recommends the use of oxonium and oxidanium in organic and inorganic chemistry contexts, respectively. An oxonium ion is any ion with a trivalent oxygen cation. For example, a protonated hydroxyl group is an oxonium ion, but not a hydronium. # Acids and acidity Hydronium is the cation that forms from water in the presence of hydrogen ions. These hydrons do not exist in a free state: they are extremely reactive and are solvated by water. An acid is generally the source of these hydrons; however, since water can behave as both an acid and a base, hydroniums exist even in pure water. This special case of water reacting with water to produce hydronium (and hydroxide) ions is commonly known as the self-ionization of water. The resulting hydronium ions are few and short-lived. (Nevertheless, they form the basis for determining the pH of basic aqueous solutions, since the less there are of these autoionized hydroniums, the more there is base.) Hydronium is very acidic: at 25°C, its pKa is -1.7. It is also the most acidic species that can exist in water (assuming sufficient water for dissolution): any stronger acid will ionize and protonate a water molecule to form hydronium. The acidity of hydronium is the implicit standard used to judge the strength of an acid in water: strong acids must be better proton donors than hydronium, otherwise a significant portion of acid will exist in a non-ionized state. Unlike the hydronium that results from water's autodissociation, these hydronium ions are long-lasting and concentrated, in proportion to the strength of the dissolved acid. The pH of a solution is a measure of its proton concentration. Since these protons react with water to form hydronium, the acidity of an aqueous solution is determined by its hydronium concentration. # Solvation Researchers have yet to fully characterize the solvation of hydronium ion in water, in part because many different meanings of solvation exist. A freezing point depression study determined that the mean hydration ion in cold water is approximately H3O+(H2O)6 : on average, each hydronium ion is solvated by 6 water molecules which are unable to solvate other solute molecules. Some hydration structures are quite large: the H3O+(H2O)20 magic ion number structure (called magic because of its increased stability with respect to hydration structures involving a comparable number of water molecules) might place the hydronium inside a dodecahedral cage . However, more recent ab initio molecular dynamics simulations have shown that, on average, the hydrated proton resides on the surface of the H3O+(H2O)20 cluster. Further, several disparate features of these simulations agree with their experimental counterparts suggesting an alternative interpretation of the experimental results. Two other well-known structures are the Zundel cations and Eigen cations. The Eigen solvation structure has the hydronium ion at the center of an H9O4+ complex in which the hydronium is strongly hydrogen-bonded to 3 neighbouring water molecules . In the Zundel H5O2+ complex the proton is shared equally by two water molecules . Recent work indicates that both of these complexes represent ideal structures in a more general hydrogen bond network defect . Isolation of the hydronium ion monomer in liquid phase was achieved in a nonaqueous, low nucleophilicity superacid solution (HF-SbF5SO2). The ion was characterized by high resolution O-17 nuclear magnetic resonance.. In 2007, Markovitch & Agmon have calculated for the first time ever the enthalpies and free energies of the various hydrogen bonds around the hydronium cation in liquid protonated water at room temperature and discussed the implementation for the proton hopping mechanism. Using molecular dynamics they were able to show that the hydrogen-bonds around the hydronium ion (formed with the three water ligands in the first solvation shell of the hydronium) are quite strong compared to those of bulk water. # Solid hydronium salts For many strong acids, it is possible to form crystals of their hydronium salt that are relatively stable. Sometimes these salts are called acid monohydrates. As a rule, any acid with an ionization constant of 109 or higher may do this. Acids whose ionization constant is below 109 generally cannot form stable H3O+ salts. For example, hydrochloric acid has an ionization constant of 107, and mixtures with water at all proportions are liquid at room temperature. However, perchloric acid has an ionization constant of 1010, and if liquid anhydrous perchloric acid and water are combined in a 1:1 molar ratio, solid hydronium perchlorate forms. The hydronium ion also forms stable compounds with the carborane superacid H(CB11H(CH3)5Br6) . X-ray crystallography shows a C3v symmetry for the hydronium ion with each proton interacting with a bromine atom each from three carborane anions 320 pm apart on average. The salt is also soluble in benzene. In crystals grown from a benzene solution the solvent co-crystallizes and a H3O.(benzene)3 cation is completely separated from the anion. In the cation three benzene molecules surround hydronium forming pi-cation interactions with the hydrogen atoms. The closest (nonbonding) approach of the anion at chlorine to the cation at oxygen is 348 pm.	Hydronium Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] In chemistry, hydronium is the common name for the cation H3O+ derived from protonation of water. It is the simplest type of an oxonium ion. # Nomenclature According to IUPAC nomenclature of organic chemistry, the hydronium ion should be referred to as oxonium. Hydroxonium may also be used unambiguously to identify it. A draft IUPAC proposal also recommends the use of oxonium and oxidanium in organic and inorganic chemistry contexts, respectively. An oxonium ion is any ion with a trivalent oxygen cation. For example, a protonated hydroxyl group is an oxonium ion, but not a hydronium. # Acids and acidity Hydronium is the cation that forms from water in the presence of hydrogen ions. These hydrons do not exist in a free state: they are extremely reactive and are solvated by water. An acid is generally the source of these hydrons; however, since water can behave as both an acid and a base, hydroniums exist even in pure water. This special case of water reacting with water to produce hydronium (and hydroxide) ions is commonly known as the self-ionization of water. The resulting hydronium ions are few and short-lived. (Nevertheless, they form the basis for determining the pH of basic aqueous solutions, since the less there are of these autoionized hydroniums, the more there is base.) Hydronium is very acidic: at 25°C, its pKa is -1.7. It is also the most acidic species that can exist in water (assuming sufficient water for dissolution): any stronger acid will ionize and protonate a water molecule to form hydronium. The acidity of hydronium is the implicit standard used to judge the strength of an acid in water: strong acids must be better proton donors than hydronium, otherwise a significant portion of acid will exist in a non-ionized state. Unlike the hydronium that results from water's autodissociation, these hydronium ions are long-lasting and concentrated, in proportion to the strength of the dissolved acid. The pH of a solution is a measure of its proton concentration. Since these protons react with water to form hydronium, the acidity of an aqueous solution is determined by its hydronium concentration. # Solvation Researchers have yet to fully characterize the solvation of hydronium ion in water, in part because many different meanings of solvation exist. A freezing point depression study determined that the mean hydration ion in cold water is approximately H3O+(H2O)6 [1]: on average, each hydronium ion is solvated by 6 water molecules which are unable to solvate other solute molecules. Some hydration structures are quite large: the H3O+(H2O)20 magic ion number structure (called magic because of its increased stability with respect to hydration structures involving a comparable number of water molecules) might place the hydronium inside a dodecahedral cage [2]. However, more recent ab initio molecular dynamics simulations have shown that, on average, the hydrated proton resides on the surface of the H3O+(H2O)20 cluster[3]. Further, several disparate features of these simulations agree with their experimental counterparts suggesting an alternative interpretation of the experimental results. Two other well-known structures are the Zundel cations and Eigen cations. The Eigen solvation structure has the hydronium ion at the center of an H9O4+ complex in which the hydronium is strongly hydrogen-bonded to 3 neighbouring water molecules [4]. In the Zundel H5O2+ complex the proton is shared equally by two water molecules [5]. Recent work indicates that both of these complexes represent ideal structures in a more general hydrogen bond network defect [6]. Isolation of the hydronium ion monomer in liquid phase was achieved in a nonaqueous, low nucleophilicity superacid solution (HF-SbF5SO2). The ion was characterized by high resolution O-17 nuclear magnetic resonance.[7]. In 2007, Markovitch & Agmon have calculated for the first time ever the enthalpies and free energies of the various hydrogen bonds around the hydronium cation in liquid protonated water[8] at room temperature and discussed the implementation for the proton hopping mechanism. Using molecular dynamics they were able to show that the hydrogen-bonds around the hydronium ion (formed with the three water ligands in the first solvation shell of the hydronium) are quite strong compared to those of bulk water. # Solid hydronium salts For many strong acids, it is possible to form crystals of their hydronium salt that are relatively stable. Sometimes these salts are called acid monohydrates. As a rule, any acid with an ionization constant of 109 or higher may do this. Acids whose ionization constant is below 109 generally cannot form stable H3O+ salts. For example, hydrochloric acid has an ionization constant of 107, and mixtures with water at all proportions are liquid at room temperature. However, perchloric acid has an ionization constant of 1010, and if liquid anhydrous perchloric acid and water are combined in a 1:1 molar ratio, solid hydronium perchlorate forms. The hydronium ion also forms stable compounds with the carborane superacid H(CB11H(CH3)5Br6) [9]. X-ray crystallography shows a C3v symmetry for the hydronium ion with each proton interacting with a bromine atom each from three carborane anions 320 pm apart on average. The [H3O][H(CB11HCl11)] salt is also soluble in benzene. In crystals grown from a benzene solution the solvent co-crystallizes and a H3O.(benzene)3 cation is completely separated from the anion. In the cation three benzene molecules surround hydronium forming pi-cation interactions with the hydrogen atoms. The closest (nonbonding) approach of the anion at chlorine to the cation at oxygen is 348 pm.	https://www.wikidoc.org/index.php/Hydrogen_ions
3fd662487f851d60962cd45f3f0c514681a037ee	wikidoc	Hydrolase	Hydrolase # Overview In biochemistry, a hydrolase is an enzyme that catalyzes the hydrolysis of a chemical bond. For example, an enzyme that catalyzed the following reaction is a hydrolase: # Nomenclature Systematic names of hydrolases are formed as "substrate hydrolase." However, common names are typically in the form "substratease." For example, a nuclease is a hydrolase that cleaves nucleic acids. # Classification Hydrolases are classified as EC 3 in the EC number classification of enzymes. Hydrolases can be further classified into several subclasses, based upon the bonds they act upon: - EC 3.1: ester bonds (esterases: nucleases, phosphodiesterases, lipase, phosphatase) - EC 3.2: sugars (glycosylases/DNA glycosylases, glycoside hydrolase) - EC 3.3: ether bonds - EC 3.4: peptide bonds (Proteases/peptidases) - EC 3.5: carbon-nitrogen bonds, other than peptide bonds - EC 3.6: acid anhydrides (acid anhydride hydrolases, including helicases and GTPase) - EC 3.7: carbon-carbon bonds - EC 3.8: halide bonds - EC 3.9: phosphorus-nitrogen bonds - EC 3.10: sulfur-nitrogen bonds - EC 3.11: carbon-phosphorus bonds - EC 3.12: sulfur-sulfur bonds - EC 3.13: carbon-sulfur bonds	Hydrolase # Overview In biochemistry, a hydrolase is an enzyme that catalyzes the hydrolysis of a chemical bond. For example, an enzyme that catalyzed the following reaction is a hydrolase: # Nomenclature Systematic names of hydrolases are formed as "substrate hydrolase." However, common names are typically in the form "substratease." For example, a nuclease is a hydrolase that cleaves nucleic acids. # Classification Hydrolases are classified as EC 3 in the EC number classification of enzymes. Hydrolases can be further classified into several subclasses, based upon the bonds they act upon: - EC 3.1: ester bonds (esterases: nucleases, phosphodiesterases, lipase, phosphatase) - EC 3.2: sugars (glycosylases/DNA glycosylases, glycoside hydrolase) - EC 3.3: ether bonds - EC 3.4: peptide bonds (Proteases/peptidases) - EC 3.5: carbon-nitrogen bonds, other than peptide bonds - EC 3.6: acid anhydrides (acid anhydride hydrolases, including helicases and GTPase) - EC 3.7: carbon-carbon bonds - EC 3.8: halide bonds - EC 3.9: phosphorus-nitrogen bonds - EC 3.10: sulfur-nitrogen bonds - EC 3.11: carbon-phosphorus bonds - EC 3.12: sulfur-sulfur bonds - EC 3.13: carbon-sulfur bonds	https://www.wikidoc.org/index.php/Hydrolase
0fe6d7d0beb0dc95d0599a8c103b1323eee709ed	wikidoc	Hypericum	Hypericum Hypericum is a genus of about 400 species of flowering plants in the family Clusiaceae, subfamily Hypericoideae (formerly often considered a full family Hypericaceae). The genus has a nearly world-wide distribution, missing only from tropical lowlands, deserts and polar regions. All members of the genus may be referred to as St. John's-worts, though they are also commonly just called hypericums, and some are known as tutsans. The marsh St. John's-worts are nowadays separated in Triadenum. St. John's-worts vary from annual or perennial herbaceous herbs 5-10 cm tall to shrubs and small trees up to 12 m tall. The leaves are opposite, simple oval, 1-8 cm long, either deciduous or evergreen. The flowers vary from pale to dark yellow, and from 0.5-6 cm in diameter, with five (rarely four) petals. The fruit is usually a dry capsule which splits to release the numerous small seeds; in some species it is fleshy and berry-like. # Uses of Hypericum Some species are used as ornamental plants and have large, showy flowers. Numerous hybrids and cultivars have been developed for use in horticulture, such as Hypericum × moserianum (H. calycinum × H. patulum) and Hypericum calycinum cv. 'Hidcote'. St. John's-worts can occur as nuisance weeds in farmland and gardens. On pastures, some can be more than a nuisance, causing debilitating photosensitivity and sometimes abortion in livestock. The beetles Chrysolina quadrigemina, Chrysolina hyperici and Agrilus hyperici like to feed on Common St. John's-wort (H. perforatum) and have been used for biocontrol where the plant has become an invasive weed. Hypericum species are the only known food plants of the caterpillar of the Treble-bar, a species of moth. Other Lepidoptera species whose larvae sometimes feed on Hypericum include Common Emerald, The Engrailed (recorded on Imperforate St. John's-wort, H. maculatum), Grey Pug and Setaceous Hebrew Character. ## Medical properties Common St. John's-wort (H. perforatum) is since long used in herbalism. It was already known to have medical properties in the Classical Antiquity. It was a standard component of theriacs, from the Mithridate of Aulus Cornelius Celsus' De Medicina (ca. 30 CE) to the Venice treacle of d'Amsterdammer Apotheek in 1686. Folk usages included oily extract ("St. John's oil") and Hypericum snaps. H. perforatum is the most potent species and it is today grown and collected commercially for use in herbalism and medicine; other St. John's-worts probably also possess interesting properties and chemical compounds but are not well researched. As these secondary compounds appear to be related to deterring herbivores, they are present in varying and unpredictable quantities. Still, a number of high-yield cultivars have been developed. Two main compounds of interest have been studied in more detail: hyperforin and hypericin. However, the pharmacology of H. perforatum is not resolved, and at least its antidepressant properties are caused by a wide range of factors interacting. As psychiatric medication, it is usually taken as pills, or as tea. Few standardized preparations are available, and research has mainly studied alcoholic extracts and isolated compounds. What research data exists supports a noticeable effect in many cases of light and medium depression, but no significant improvement of severe depression and OCD. Another common use of H. perforatum is as oily extract. The ruby-red oil appears to be strongly antibiotic, assisting healing of wounds, first-degree burns and concussions. Both hypericin and hyperforin are considered to be antibiotic by modern science. But, justifying it with the then-current doctrine of signatures, herbalist William Coles wrote in the 17th century already that "The little holes whereof the leaves of Saint Johns wort are full, doe resemble all the pores of the skin and therefore it is profitable for all hurts and wounds that can happen thereunto." As mentioned above, there is evidence that St. John's-worts can act as abortifacients; it interferes with the Combined oral contraceptive pill. Complications have also occurred in human patients. High-dosage H. perforatum interacts with a wide range of medications due to activating the Pregnane X receptor detoxification pathway, as well as causing photosensitivity. It is strongly recommended not to take St. John's-wort during pregnancy or when tanning, and it has caused a few deaths in patients undergoing anti-HIV/AIDS and cancer therapy. Extremely high doses (rarely reached with OTC preparations) are hepatotoxic. # Selected species	Hypericum Hypericum is a genus of about 400 species of flowering plants in the family Clusiaceae, subfamily Hypericoideae (formerly often considered a full family Hypericaceae). The genus has a nearly world-wide distribution, missing only from tropical lowlands, deserts and polar regions. All members of the genus may be referred to as St. John's-worts, though they are also commonly just called hypericums, and some are known as tutsans. The marsh St. John's-worts are nowadays separated in Triadenum. St. John's-worts vary from annual or perennial herbaceous herbs 5-10 cm tall to shrubs and small trees up to 12 m tall. The leaves are opposite, simple oval, 1-8 cm long, either deciduous or evergreen. The flowers vary from pale to dark yellow, and from 0.5-6 cm in diameter, with five (rarely four) petals. The fruit is usually a dry capsule which splits to release the numerous small seeds; in some species it is fleshy and berry-like. # Uses of Hypericum Some species are used as ornamental plants and have large, showy flowers. Numerous hybrids and cultivars have been developed for use in horticulture, such as Hypericum × moserianum (H. calycinum × H. patulum) and Hypericum calycinum cv. 'Hidcote'. St. John's-worts can occur as nuisance weeds in farmland and gardens. On pastures, some can be more than a nuisance, causing debilitating photosensitivity and sometimes abortion in livestock. The beetles Chrysolina quadrigemina, Chrysolina hyperici and Agrilus hyperici like to feed on Common St. John's-wort (H. perforatum) and have been used for biocontrol where the plant has become an invasive weed. Hypericum species are the only known food plants of the caterpillar of the Treble-bar, a species of moth. Other Lepidoptera species whose larvae sometimes feed on Hypericum include Common Emerald, The Engrailed (recorded on Imperforate St. John's-wort, H. maculatum), Grey Pug and Setaceous Hebrew Character. ## Medical properties Common St. John's-wort (H. perforatum) is since long used in herbalism. It was already known to have medical properties in the Classical Antiquity. It was a standard component of theriacs, from the Mithridate of Aulus Cornelius Celsus' De Medicina (ca. 30 CE) to the Venice treacle of d'Amsterdammer Apotheek in 1686. Folk usages included oily extract ("St. John's oil") and Hypericum snaps. H. perforatum is the most potent species and it is today grown and collected commercially for use in herbalism and medicine; other St. John's-worts probably also possess interesting properties and chemical compounds but are not well researched. As these secondary compounds appear to be related to deterring herbivores, they are present in varying and unpredictable quantities. Still, a number of high-yield cultivars have been developed. Two main compounds of interest have been studied in more detail: hyperforin and hypericin. However, the pharmacology of H. perforatum is not resolved, and at least its antidepressant properties are caused by a wide range of factors interacting. As psychiatric medication, it is usually taken as pills, or as tea. Few standardized preparations are available, and research has mainly studied alcoholic extracts and isolated compounds. What research data exists supports a noticeable effect in many cases of light and medium depression, but no significant improvement of severe depression and OCD. Another common use of H. perforatum is as oily extract. The ruby-red oil appears to be strongly antibiotic, assisting healing of wounds, first-degree burns and concussions. Both hypericin and hyperforin are considered to be antibiotic by modern science. But, justifying it with the then-current doctrine of signatures, herbalist William Coles wrote in the 17th century already that "The little holes whereof the leaves of Saint Johns wort are full, doe resemble all the pores of the skin and therefore it is profitable for all hurts and wounds that can happen thereunto." As mentioned above, there is evidence that St. John's-worts can act as abortifacients; it interferes with the Combined oral contraceptive pill. Complications have also occurred in human patients. High-dosage H. perforatum interacts with a wide range of medications due to activating the Pregnane X receptor detoxification pathway, as well as causing photosensitivity. It is strongly recommended not to take St. John's-wort during pregnancy or when tanning, and it has caused a few deaths in patients undergoing anti-HIV/AIDS and cancer therapy. Extremely high doses (rarely reached with OTC preparations) are hepatotoxic. # Selected species	https://www.wikidoc.org/index.php/Hypericum
75a616b8eca708366cc6aaf53026254168181148	wikidoc	Hypomania	Hypomania # Overview Hypomania (literally, below mania) is a mood state characterized by persistent and pervasive elated or irritable mood, and thoughts and behaviors that are consistent with such a mood state. It is distinguished from mania by the absence of psychotic symptoms and by its lower degree of impact on functioning. Hypomania is a feature of two mood disorders: bipolar II disorder and cyclothymia. Though hypomanic people are often associated with bipolar disorder, it is in this state that many creative talents are in their most productive and successful mood. # Episodes According to the DSM-IV-TR, a hypomanic episode includes, over the course of at least 4 days, three or four of the following symptoms, depending on whether the predominant mood state is elation or irritability: - Perhaps the most noticeable symptom is pressured speech; rapid talking - inflated self-esteem or grandiosity; - decreased need for sleep; - flight of ideas or the subjective experience that thoughts are racing; - easy distractibility and attention-deficit (superficially similar to attention deficit hyperactivity disorder); - increase in psychomotor agitation; and - steep involvement in pleasurable activities that may have a high potential for negative psycho-social or physical consequences. In the hypomanic state, people may feel like they can't slow their mind down, and that all these speeding thoughts are amazingly perfectly crafted. Some examples are speaking or writing in rhyme or alliteration without planning it first; quick responses to people talking; or the ability to improvise easily on the spot. In more severe cases, hypomanic people may actually hear constant music in their head, or see images in their mind racing by. A very strange but possible symptom is actually emotional flattening, also known as blunted affect. A person may seem cold, uncaring, or arrogant. They may show little emotion at all. # Possible benefits People with hypomania are generally perceived as being energetic, euphoric, overflowing with new ideas, and sometimes highly confident and charismatic, and unlike full-blown mania, they are sufficiently capable of coherent thought and action to participate in everyday activities. One in the state of hypomania might be immune to fear and doubt and have little social inhibition. They may talk to strangers easily, offer solutions to problems, and find pleasure in small activities. # Relationship to mood disorders Cyclothymia is a condition of continued mood fluctuations between hypomania and depressive symptoms that do not meet the criteria for a Major Depressive Episode. These are often interspersed with periods of normal moods. When a patient presents with a history of one or more hypomanic episodes and one or more depressive episodes that meet the criteria for a Major Depressive Episode, Bipolar II Disorder is diagnosed. If left untreated, hypomania can slip deeper and deeper into mania (and sometimes psychosis), in which case, Bipolar I Disorder is diagnosed. # Treatment It is unknown to what degree hypomanic symptoms can occur without a depressive component. Patients may be relatively unlikely to seek psychiatric treatment for hypomania alone. However, many hypomanic patients experience: - lower need for sleep - racing thoughts - obsessive behavior, whether mild or severe - poor judgment relative to a particular situation's judgment call - uncontrollable, or only partially controllable, impulsivity - excessive sexual activity Plus other out-of-character behaviors that the person may regret following the conclusion of the mood episode. Hypomania can signal the beginning of a more severe manic episode, and often does result in a more severe manic episode if the hypomanic episode remains untreated. A hypomanic episode can also directly precede a depressive episode. Virtually all clinical trials of medications for the non-depressive phases of bipolar illnesses involve treating patients for psychotic mania during the initial, or acute, phase of mania. Such trials are the basis upon which appropriate medication is recommended; high doses are justified in the case of mania, in order to remove the patient from immediate danger. This is in direct contrast to hypomania, however, which involves different considerations and almost always demands much greater case-by-case clinical judgment. Typical prescribed medications for hypomania include mood stabilizers such as Depakote and lithium carbonate as well as atypical antipsychotics such as Zyprexa and Seroquel. # Famous people with hypomanic symptoms Radiohead front man Thom Yorke reportedly responded, "Hypomania? Yes, that's exactly what it was," when asked about his mental state after the release of the group's classic album OK Computer. Iggy Pop was diagnosed with hypomania during his stay in a mental hospital in the mid 1970's. It has also been suggested that Richey Edwards, the "fatalistic Manic Street Preacher" (Mojo magazine, 2003) and the late Syd Barrett of the band Pink Floyd have experienced hypomania. In the biographical documentary An Unreasonable Man, it is speculated that Ralph Nader is also hypomanic. Honore de Balzac, French author of the Human Comedy is attributed with having hypomania; his writing sessions continued from midnight to noon, functioning on four hours of sleep. Intermittently during these episodes, Balzac would consume massive amounts of coffee. However, it is far from apparent whether these are based on psychiatric diagnosis--bipolar symptoms are frequently misunderstood, misattributed and glamorized in popular culture. John Gartner's unverified book The Hypomanic Edge claims notable people including Christopher Columbus, Alexander Hamilton, Andrew Carnegie, Howard Zinn and Louis B. Mayer owe their innovativeness and drive, as well as their eccentricities, to hypomanic temperaments; critics, however, assert that Gartner vastly overstates his case. Within the book, though, Gartner does point out that the constructive behaviors associated with hypomania may contribute to bipolar disorder's evolutionary survival.	Hypomania Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Hypomania (literally, below mania) is a mood state characterized by persistent and pervasive elated or irritable mood, and thoughts and behaviors that are consistent with such a mood state. It is distinguished from mania by the absence of psychotic symptoms and by its lower degree of impact on functioning. Hypomania is a feature of two mood disorders: bipolar II disorder and cyclothymia.[1] Though hypomanic people are often associated with bipolar disorder, it is in this state that many creative talents are in their most productive and successful mood.[citation needed] # Episodes According to the DSM-IV-TR, a hypomanic episode includes, over the course of at least 4 days, three or four of the following symptoms, depending on whether the predominant mood state is elation or irritability: - Perhaps the most noticeable symptom is pressured speech; rapid talking - inflated self-esteem or grandiosity; - decreased need for sleep; - flight of ideas or the subjective experience that thoughts are racing; - easy distractibility and attention-deficit (superficially similar to attention deficit hyperactivity disorder); - increase in psychomotor agitation; and - steep involvement in pleasurable activities that may have a high potential for negative psycho-social or physical consequences.[2] In the hypomanic state, people may feel like they can't slow their mind down, and that all these speeding thoughts are amazingly perfectly crafted. Some examples are speaking or writing in rhyme or alliteration without planning it first; quick responses to people talking; or the ability to improvise easily on the spot. In more severe cases, hypomanic people may actually hear constant music in their head, or see images in their mind racing by.[citation needed] A very strange but possible symptom is actually emotional flattening, also known as blunted affect. A person may seem cold, uncaring, or arrogant. They may show little emotion at all. # Possible benefits People with hypomania are generally perceived as being energetic, euphoric, overflowing with new ideas, and sometimes highly confident and charismatic, and unlike full-blown mania, they are sufficiently capable of coherent thought and action to participate in everyday activities. One in the state of hypomania might be immune to fear and doubt and have little social inhibition. They may talk to strangers easily, offer solutions to problems, and find pleasure in small activities.[citation needed] # Relationship to mood disorders Cyclothymia is a condition of continued mood fluctuations between hypomania and depressive symptoms that do not meet the criteria for a Major Depressive Episode. These are often interspersed with periods of normal moods. [3] When a patient presents with a history of one or more hypomanic episodes and one or more depressive episodes that meet the criteria for a Major Depressive Episode, Bipolar II Disorder is diagnosed.[4] If left untreated, hypomania can slip deeper and deeper into mania (and sometimes psychosis), in which case, Bipolar I Disorder is diagnosed.[citation needed] # Treatment It is unknown to what degree hypomanic symptoms can occur without a depressive component. Patients may be relatively unlikely to seek psychiatric treatment for hypomania alone. However, many hypomanic patients experience: - lower need for sleep - racing thoughts - obsessive behavior, whether mild or severe - poor judgment relative to a particular situation's judgment call - uncontrollable, or only partially controllable, impulsivity - excessive sexual activity Plus other out-of-character behaviors that the person may regret following the conclusion of the mood episode. Hypomania can signal the beginning of a more severe manic episode, and often does result in a more severe manic episode if the hypomanic episode remains untreated. A hypomanic episode can also directly precede a depressive episode. Virtually all clinical trials of medications for the non-depressive phases of bipolar illnesses involve treating patients for psychotic mania during the initial, or acute, phase of mania. Such trials are the basis upon which appropriate medication is recommended; high doses are justified in the case of mania, in order to remove the patient from immediate danger. This is in direct contrast to hypomania, however, which involves different considerations and almost always demands much greater case-by-case clinical judgment. Typical prescribed medications for hypomania include mood stabilizers such as Depakote and lithium carbonate as well as atypical antipsychotics such as Zyprexa and Seroquel. # Famous people with hypomanic symptoms Radiohead front man Thom Yorke reportedly responded, "Hypomania? Yes, that's exactly what it was," when asked about his mental state after the release of the group's classic album OK Computer. Iggy Pop was diagnosed with hypomania during his stay in a mental hospital in the mid 1970's. It has also been suggested that Richey Edwards, the "fatalistic Manic Street Preacher" (Mojo magazine, 2003) and the late Syd Barrett of the band Pink Floyd have experienced hypomania. In the biographical documentary An Unreasonable Man, it is speculated that Ralph Nader is also hypomanic. Honore de Balzac, French author of the Human Comedy is attributed with having hypomania; his writing sessions continued from midnight to noon, functioning on four hours of sleep. Intermittently during these episodes, Balzac would consume massive amounts of coffee. However, it is far from apparent whether these are based on psychiatric diagnosis--bipolar symptoms are frequently misunderstood, misattributed and glamorized in popular culture. John Gartner's unverified book The Hypomanic Edge claims notable people including Christopher Columbus, Alexander Hamilton, Andrew Carnegie, Howard Zinn and Louis B. Mayer owe their innovativeness and drive, as well as their eccentricities, to hypomanic temperaments; critics, however, assert that Gartner vastly overstates his case. Within the book, though, Gartner does point out that the constructive behaviors associated with hypomania may contribute to bipolar disorder's evolutionary survival.	https://www.wikidoc.org/index.php/Hypomania
d31a7edd6d6c578e9b431cf34ed9efab12aa215c	wikidoc	ISO 13485	ISO 13485 ISO 13485 is an ISO standard, published in 2003, that represents the requirements for a comprehensive management system for the design and manufacture of medical devices. This standard supersedes earlier documents such as EN 46001 and EN 46002 (both 1997), the ISO 13485 published in 1996 and ISO 13488 (also 1996). While it remains a stand-alone document, ISO 13485 is generally harmonized with ISO 9001. A fundamental difference, however, is that ISO 9001 requires the organization to demonstrate continuous improvement, whereas ISO 13485 requires only that they demonstrate the quality system is implemented and maintained. Other specific differences include: - the promotion and awareness of regulatory requirements as a management responsibility, will providing resources and during reviews. An example of the market specific regulatory requirements is 21 CFR 820 Quality System Regulation for Medical Devices sold in the United States. - controls in the work environment to ensure product safety - focus on risk management activities and design transfer activities during product development - specific requirements for inspection and traceability for implantable devices - specific requirements for documentation and validation of processes for sterile medical devices - specific requirements for verification of the effectiveness of corrective and preventive actions Compliance with ISO 13485 is often seen as the first step in achieving compliance with European regulatory requirements. The conformity of Medical Devices and In-vitro Diagnostic Medical Device according to EEC-decrees 93/42/EEC, 90/385/EEC and 98/79/EEC must be assessed before sale is permitted. The preferred method to prove conformity is the certification of the Quality Management System according ISO 9001 and/or ISO 13485, ISO 13488, or ISO 14971 by a Conformity Assessment Body (CAB). The result of a positive assessment is the authorisation for the CE-identification and the permission to sell the high quality medical device in the European Union.	ISO 13485 ISO 13485 is an ISO standard, published in 2003, that represents the requirements for a comprehensive management system for the design and manufacture of medical devices. This standard supersedes earlier documents such as EN 46001 and EN 46002 (both 1997), the ISO 13485 published in 1996 and ISO 13488 (also 1996). While it remains a stand-alone document, ISO 13485 is generally harmonized with ISO 9001. A fundamental difference, however, is that ISO 9001 requires the organization to demonstrate continuous improvement, whereas ISO 13485 requires only that they demonstrate the quality system is implemented and maintained. Other specific differences include: - the promotion and awareness of regulatory requirements as a management responsibility, will providing resources and during reviews. An example of the market specific regulatory requirements is 21 CFR 820 Quality System Regulation for Medical Devices sold in the United States. - controls in the work environment to ensure product safety - focus on risk management activities and design transfer activities during product development - specific requirements for inspection and traceability for implantable devices - specific requirements for documentation and validation of processes for sterile medical devices - specific requirements for verification of the effectiveness of corrective and preventive actions Compliance with ISO 13485 is often seen as the first step in achieving compliance with European regulatory requirements. The conformity of Medical Devices and In-vitro Diagnostic Medical Device according to EEC-decrees 93/42/EEC, 90/385/EEC and 98/79/EEC must be assessed before sale is permitted. The preferred method to prove conformity is the certification of the Quality Management System according ISO 9001 and/or ISO 13485, ISO 13488, or ISO 14971 by a Conformity Assessment Body (CAB). The result of a positive assessment is the authorisation for the CE-identification and the permission to sell the high quality medical device in the European Union. # External links - ISO Organisation 13485 page - Digimed Innovation ISO 13485:2003 Template:WS	https://www.wikidoc.org/index.php/ISO_13485
810d193edf5452e0bf4f0ee698b07d7805ef96bd	wikidoc	ISO 639-3	ISO 639-3 ISO 639-3 is an international standard for language codes. It extends the ISO 639-2 alpha-3 codes with an aim to cover all known natural languages. The standard was published by ISO on 5 February 2007. It's intended for use in a wide range of applications, in particular computer systems where many languages need to be supported. It provides an enumeration of languages as complete as possible, including living and extinct, ancient and constructed, major and minor, written and unwritten. It is a superset of ISO 639-1 and of the individual languages in ISO 639-2. ISO 639-1 and ISO 639-2 focused on major languages, most frequently represented in the total body of the world's literature. Since ISO 639-2 also includes language collections, whereas Part 3 does not, ISO 639-3 is not a superset of ISO 639-2. Where B and T codes exist in ISO 639-2, it uses the T-codes. Examples: The final standard contains 7589 entries. The inventory of languages is based on a number of sources including: the individual languages contained in 639-2, modern languages from the Ethnologue 15th edition, historic varieties, ancient languages and artificial languages from Anthony Aristar at the Linguist List as well as languages recommended within a public commenting period. A transition from ISO 639-1 could be done with List of ISO 639-1 codes. # Code space Since the code is three-letter alphabetic, one upper bound for the number of languages that can be represented is 26 × 26 × 26 = 17576. Since ISO 639-2 defines special codes (2), a reserved range (520) and B-only codes (23), 545 codes cannot be used in part 3. Therefore a lower upper bound is 17576 - 545 = 17032. The upper bound gets even lower if one subtracts the language collections defined in 639-2 and the ones yet to be defined in ISO 639-5. # Macrolanguages There are 56 languages in ISO 639-2 which are considered, for the purposes of the standard, to be "macrolanguages" in 639-3 . Some of these macrolanguages had no individual language as defined by 639-3 in ISO 639-2, e.g. 'ara'. Others like 'nor' (Norwegian) had their two individual parts ('nno' (Nynorsk), 'nob' (Bokmål)) already in 639-2. That means some languages (e.g. 'arb') that were considered by ISO 639-2 to be dialects of one language ('ara') are now in ISO 639-3 in certain contexts considered to be individual languages themselves. This is an attempt to deal with varieties that may be linguistically distinct from each other, but are treated by their speakers as two forms of the same language, e.g. in cases of diglossia. For example: - (Generic Arabic, 639-2) - (Standard Arabic, 639-3) See for the complete list. # Collective languages Some ISO 639-2 codes that are commonly used for languages do not precisely represent a particular language or some related languages (as the above macrolanguages). They are regarded as collective languages (or collectives) and are excluded from ISO 639-3. # History Stages : - 2006-07-14 FDIS 50.00	ISO 639-3 ISO 639-3 is an international standard for language codes. It extends the ISO 639-2 alpha-3 codes with an aim to cover all known natural languages. The standard was published by ISO on 5 February 2007[1]. It's intended for use in a wide range of applications, in particular computer systems where many languages need to be supported. It provides an enumeration of languages as complete as possible, including living and extinct, ancient and constructed, major and minor, written and unwritten.[1] It is a superset of ISO 639-1 and of the individual languages in ISO 639-2. ISO 639-1 and ISO 639-2 focused on major languages, most frequently represented in the total body of the world's literature. Since ISO 639-2 also includes language collections, whereas Part 3 does not, ISO 639-3 is not a superset of ISO 639-2. Where B and T codes exist in ISO 639-2, it uses the T-codes. Examples: The final standard contains 7589 entries[2]. The inventory of languages is based on a number of sources including: the individual languages contained in 639-2, modern languages from the Ethnologue 15th edition, historic varieties, ancient languages and artificial languages from Anthony Aristar at the Linguist List as well as languages recommended within a public commenting period. A transition from ISO 639-1 could be done with List of ISO 639-1 codes. # Code space Since the code is three-letter alphabetic, one upper bound for the number of languages that can be represented is 26 × 26 × 26 = 17576. Since ISO 639-2 defines special codes (2), a reserved range (520) and B-only codes (23), 545 codes cannot be used in part 3. Therefore a lower upper bound is 17576 - 545 = 17032. The upper bound gets even lower if one subtracts the language collections defined in 639-2 and the ones yet to be defined in ISO 639-5. # Macrolanguages There are 56 languages in ISO 639-2 which are considered, for the purposes of the standard, to be "macrolanguages" in 639-3 [3]. Some of these macrolanguages had no individual language as defined by 639-3 in ISO 639-2, e.g. 'ara'. Others like 'nor' (Norwegian) had their two individual parts ('nno' (Nynorsk), 'nob' (Bokmål)) already in 639-2. That means some languages (e.g. 'arb') that were considered by ISO 639-2 to be dialects of one language ('ara') are now in ISO 639-3 in certain contexts considered to be individual languages themselves. This is an attempt to deal with varieties that may be linguistically distinct from each other, but are treated by their speakers as two forms of the same language, e.g. in cases of diglossia. For example: - http://www.sil.org/iso639-3/documentation.asp?id=ara (Generic Arabic, 639-2) - http://www.sil.org/iso639-3/documentation.asp?id=arb (Standard Arabic, 639-3) See [4] for the complete list. # Collective languages Some ISO 639-2 codes that are commonly used for languages do not precisely represent a particular language or some related languages (as the above macrolanguages). They are regarded as collective languages (or collectives)[5] and are excluded from ISO 639-3. # History Stages [1]: - 2006-07-14 FDIS 50.00 - 2007-02-05 60.60	https://www.wikidoc.org/index.php/ISO_639-3
d7250e1024f68f8e52e0a1227eda55eadf53b684	wikidoc	Ibrutinib	Ibrutinib # 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 Ibrutinib is an kinase inhibitor that is FDA approved for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Common adverse reactions include thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite .. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Ibrutinib is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. - Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials. - Ibrutinib is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy . - Ibrutinib is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion. - Ibrutinib is indicated for the treatment of patients with Waldenström's macroglobulinemia (WM) ### Dosing Guidelines - Administer Ibrutinib orally once daily at approximately the same time each day. Swallow the capsules whole with water. Do not open, break, or chew the capsules. - The recommended dose of Ibrutinib for MCL is 560 mg (four 140 mg capsules) orally once daily. - Chronic Lymphocytic Leukemia and Waldenström's Macroglobulinemia - The recommended dose of Ibrutinib for CLL and WM is 420 mg (three 140 mg capsules) orally once daily. - Interrupt Ibrutinib therapy for any Grade 3 or greater non-hematological, Grade 3 or greater neutropenia with infection or fever, or Grade 4 hematological toxicities. Once the symptoms of the toxicity have resolved to Grade 1 or baseline (recovery), Ibrutinib therapy may be reinitiated at the starting dose. If the toxicity reoccurs, reduce dose by one capsule (140 mg per day). A second reduction of dose by 140 mg may be considered as needed. If these toxicities persist or recur following two dose reductions, discontinue Ibrutinib. - Recommended dose modifications are described below: - Dose Modifications for Use with CYP3A Inhibitors - Avoid co-administration with strong or moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. - Concomitant use of strong CYP3A inhibitors which would be taken chronically (e.g., ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended. For short-term use (treatment for 7 days or less) of strong CYP3A inhibitors (e.g., antifungals and antibiotics) consider interrupting Ibrutinib therapy until the CYP3A inhibitor is no longer needed. - Reduce Ibrutinib dose to 140 mg if a moderate CYP3A inhibitor must be used (e.g., fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, and ciprofloxacin). - Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more closely for signs of Ibrutinib toxicity. - For patients with mild liver impairment (Child-Pugh class A), the recommended dose is 140 mg daily (one capsule). Avoid the use of Ibrutinib in patients with moderate or severe hepatic impairment (Child-Pugh classes B and C) - If a dose of Ibrutinib is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. Extra capsules of Ibrutinib should not be taken to make up for the missed dose. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ibrutinib in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ibrutinib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Ibrutinib in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ibrutinib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ibrutinib in pediatric patients. # Contraindications - None # Warnings - Fatal bleeding events have occurred in patients treated with Ibrutinib. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with Ibrutinib. - The mechanism for the bleeding events is not well understood. - Ibrutinib may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. - Consider the benefit-risk of withholding Ibrutinib for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding . - Fatal and non-fatal infections have occurred with Ibrutinib therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with Ibrutinib. Monitor patients for fever and infections and evaluate promptly. - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with Ibrutinib. - Monitor complete blood counts monthly. - Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with Ibrutinib, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of Ibrutinib treatment and dose modification . - Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with Ibrutinib. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11 %). - Tumor lysis syndrome has been reported with Ibrutinib therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor burden). - Based on findings in animals, Ibrutinib can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL or WM, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking Ibrutinib. 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 a fetus # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions are discussed in more detail in other sections of the labeling: - Hemorrhage - Infections - Cytopenias - Atrial Fibrillation - Second Primary Malignancies - Tumor Lysis Syndrome - Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. - The data described below reflect exposure to Ibrutinib in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months. - The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (seeTABLES 1 and 2). - The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections. - Fatal and serious cases of renal failure have occurred with Ibrutinib therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients. - Adverse reactions from the MCL trial (N=111) using single agent Ibrutinib 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1. - Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients. - Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression. - Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients. - The data described below reflect exposure to Ibrutinib in an open label clinical trial (Study 1) that included 48 patients with previously treated CLL and a randomized clinical trial (Study 2) that included 391 randomized patients with previously treated CLL or SLL. - The most commonly occurring adverse reactions in Study 1 and Study 2 (≥ 20%) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia. - Approximately five percent of patients receiving Ibrutinib in Study 1 and Study 2 discontinued treatment due to adverse events. These included infections, subdural hematomas and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients. Study 1 - Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent Ibrutinib 420 mg daily occurring at a rate of ≥ 10% are presented in Tables 3 and 4. Study 2 - Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to Ibrutinib with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in Study 2. - The data described below reflect exposure to Ibrutinib in an open label clinical trial that included 63 patients with previously treated WM. - The most commonly occurring adverse reactions in the WM trial (≥ 20%) were neutropenia, thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue. - Six percent of patients receiving Ibrutinib in the WM trial discontinued treatment due to adverse events. Adverse events leading to dose reduction occurred in 11% of patients. - Adverse reactions and laboratory abnormalities described below in Tables 7 and 8 reflect exposure to Ibrutinib with a median duration of 11.7 months in the WM trial. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of Ibrutinib. 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. - Hypersensitivity reactions including anaphylactic shock (fatal), urticaria, and angioedema have been reported. # Drug Interactions - Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. - In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng ∙ hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg). - Avoid concomitant administration of Ibrutinib with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting Ibrutinib therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the Ibrutinib dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of Ibrutinib toxicity . - Avoid grapefruit and Seville oranges during Ibrutinib treatment, as these contain moderate inhibitors of CYP3A . - Administration of Ibrutinib with rifampin, a strong CYP3A inducer, decreased ibrutinib Cmax and AUC by approximately 13- and 10-fold, respectively. - Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John's Wort). Consider alternative agents with less CYP3A induction # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Based on findings in animals, Ibrutinib can cause fetal harm when administered to a pregnant woman. If Ibrutinib is used during pregnancy or if the patient becomes pregnant while taking Ibrutinib, the patient should be apprised of the potential hazard to the fetus. - Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL or WM administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily. Pregnancy Category (AUS): - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ibrutinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Ibrutinib during labor and delivery. ### Nursing Mothers - It is not known whether ibrutinib 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 Ibrutinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - The safety and effectiveness of Ibrutinib in pediatric patients has not been established ### Geriatic Use - Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients. - Of the 391 patients randomized in Study 2, 61% were ≥ 65 years of age. No overall differences in effectiveness were observed between age groups. Grade 3 or higher adverse events occurred more frequently among elderly patients treated with Ibrutinib (61% of patients age ≥ 65 versus 51% of younger patients) . - Of the 63 patients treated for WM, 59% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), and infections (pneumonia and urinary tract infection) occurred more frequently among elderly patients. ### Gender There is no FDA guidance on the use of Ibrutinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ibrutinib with respect to specific racial populations. ### Renal Impairment - Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis ### Hepatic Impairment - Ibrutinib is metabolized in the liver. In a hepatic impairment study, data showed an increase in ibrutinib exposure. Following single dose administration, the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to subjects with normal liver function. The safety of Ibrutinib has not been evaluated in patients with hepatic impairment. - Monitor patients for signs of Ibrutinib toxicity and follow dose modification guidance as needed. It is not recommended to administer Ibrutinib to patients with moderate or severe hepatic impairment (Child-Pugh classes B and C) ### Females of Reproductive Potential and Males - Advise women to avoid becoming pregnant while taking Ibrutinib because Ibrutinib can cause fetal harm ### Immunocompromised Patients - Management of hyperviscosity in patients with WM may include plasmapheresis before and during treatment with Ibrutinib. Modifications to Ibrutinib dosing are not required. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Ibrutinib in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Ibrutinib in the drug label. # Overdosage ## Acute Overdose There is limited information regarding Chronic Overdose of Ibrutinib in the drug label. # Pharmacology ## Mechanism of Action - Ibrutinib is a small-molecule inhibitor of BTK. Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. BTK's role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Nonclinical studies show that ibrutinib inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro. ## Structure - Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK). It is a white to off-white solid with the empirical formula C25H24N6O2 and a molecular weight 440.50. Ibrutinib is freely soluble in dimethyl sulfoxide, soluble in methanol and practically insoluble in water. The chemical name for ibrutinib is 1-pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and has the following structure: - Ibrutinib capsules for oral administration are supplied as white opaque capsules that contain 140 mg ibrutinib as the active ingredient. Each capsule also contains the following inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate. The capsule shell contains gelatin, titanium dioxide and black ink. Each white opaque capsule is marked with "ibr 140 mg" in black ink. ## Pharmacodynamics - In patients with recurrent B-cell lymphoma > 90% occupancy of the BTK active site in peripheral blood mononuclear cells was observed up to 24 hours after ibrutinib doses of ≥ 2.5 mg/kg/day (≥ 175 mg/day for average weight of 70 kg). ## Pharmacokinetics - Ibrutinib is absorbed after oral administration with a median Tmax of 1 to 2 hours. Ibrutinib exposure increases with doses up to 840 mg. The steady-state AUC (mean ± standard deviation) observed in patients at 560 mg is 953 ± 705 ng∙h/mL and in patients at 420 mg is 680 ± 517 ng∙h/mL. Administration with food increased ibrutinib Cmax and AUC by approximately 2 to 4- and 2-fold, respectively, compared with administration of ibrutinib after overnight fasting. - Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with no concentration dependence in the range of 50 to 1000 ng/mL. The volume of distribution at steady state (Vd,ss) was 683 L, and the apparent volume of distribution at steady state (Vd,ss/F) was approximately 10000 L. - Metabolism is the main route of elimination for ibrutinib. It is metabolized to several metabolites primarily by cytochrome P450, CYP3A, and to a minor extent by CYP2D6. The active metabolite, PCI-45227, is a dihydrodiol metabolite with inhibitory activity towards BTK approximately 15 times lower than that of ibrutinib. The range of the mean metabolite to parent ratio for PCI-45227 at steady-state is 1 to 2.8. - Intravenous clearance was 62 and 76 L/h in fasted and fed conditions, respectively. In line with the high first-pass effect, the apparent oral clearance is approximately 2000 and 1000 L/h in fasted and fed conditions, respectively. The half-life of ibrutinib is 4 to 6 hours. - Ibrutinib, mainly in the form of metabolites, is eliminated primarily via feces. After a single oral administration of radiolabeled -ibrutinib in healthy subjects, approximately 90% of radioactivity was excreted within 168 hours, with the majority (80%) excreted in the feces and less than 10% accounted for in urine. Unchanged ibrutinib accounted for approximately 1% of the radiolabeled excretion product in feces and none in urine, with the remainder of the dose being metabolites. - Age (37 to 84 years) does not alter ibrutinib systemic clearance. - Gender does not alter ibrutinib systemic clearance. - Ibrutinib is not significantly cleared renally; urinary excretion of metabolites is 25 mL/min had no influence on the exposure to Ibrutinib. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or in patients on dialysis. - Ibrutinib is metabolized in the liver. In a hepatic impairment trial, a single dose of 140 mg of Ibrutinib was administered in non-cancer subjects. Ibrutinib AUC increased 2.7-, 8.2- and 9.8-fold, respectively, in subjects with mild (n=6), moderate (n=10) and severe (n=8) hepatic impairment relative to subjects with normal liver function. Ibrutinib Cmax increased 5.2-, 8.8- and 7.0-fold, respectively, in subjects with mild, moderate and severe hepatic impairment relative to subjects with normal liver function . - In a sequential design trial of 18 healthy, fasted volunteers, a single dose of 120 mg of Ibrutinib was administered alone on Day 1 and a single dose of 40 mg of Ibrutinib was administered on Day 7 in combination with 400 mg of ketoconazole (given daily on Days 4 – 9). Ketoconazole increased ibrutinib dose-normalized Cmax and AUC 29-fold and 24-fold, respectively. Simulations using fasted conditions indicate that moderate CYP3A inhibitors diltiazem and erythromycin may increase AUC of ibrutinib by 5- to 8-fold. - PK data from a dedicated drug interaction trial showed that rifampin (a strong CYP3A inducer) decreases ibrutinib Cmax and AUC by more than 13- and 10-fold. Simulations using PBPK suggested that a moderate CYP3A inducer (efavirenz) may decrease the AUC of ibrutinib by up to 3-fold. - In vitro studies indicated that ibrutinib (I/Ki < 0.07 using mean Cmax at 560 mg) and PCI-45227 (I/Ki < 0.03) are unlikely to be inhibitors of any major CYPs at clinical doses. Both ibrutinib and the PCI-45227 are weak inducers of CYP450 isoenzymes in vitro. - In vitro studies indicated that ibrutinib is not a substrate of p-glycoprotein (P-gp). Systemic ibrutinib is unlikely to be an inhibitor of P-gp at clinical doses (1/Ki < 0.1). However, it may have an effect on P-gp substrates in the GI tract due to higher local concentrations after an oral dose. Co-administration of oral narrow therapeutic index P-gp substrates (e.g., digoxin) with Ibrutinib may increase their blood concentration. ## Nonclinical Toxicology - Carcinogenicity studies have not been conducted with ibrutinib. - Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo bone marrow micronucleus assay in mice at doses up to 2000 mg/kg. - Fertility studies with ibrutinib have not been conducted in animals. In the general toxicology studies conducted in rats and dogs, orally administered ibrutinib did not result in adverse effects on reproductive organs. # Clinical Studies - The safety and efficacy of Ibrutinib in patients with MCL who have received at least one prior therapy were evaluated in an open-label, multi-center, single-arm trial of 111 previously treated patients. The median age was 68 years (range, 40 to 84 years), 77% were male, and 92% were Caucasian. At baseline, 89% of patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 42 months, and median number of prior treatments was 3 (range, 1 to 5 treatments), including 11% with prior stem cell transplant. At baseline, 39% of subjects had at least one tumor ≥ 5 cm, 49% had bone marrow involvement, and 54% had extranodal involvement at screening. - Ibrutinib was administered orally at 560 mg once daily until disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group (IWG) for non-Hodgkin's lymphoma (NHL) criteria. The primary endpoint in this study was investigator-assessed overall response rate (ORR). Responses to Ibrutinib are shown in Table 9. - An Independent Review Committee (IRC) performed independent reading and interpretation of imaging scans. The IRC review demonstrated an ORR of 69%. - The median time to response was 1.9 months. ### Lymphocytosis - Upon initiation of Ibrutinib, a temporary increase in lymphocyte counts (i.e., ≥ 50% increase from baseline and above absolute lymphocyte count of 5,000/mcL) occurred in 33% of patients in the MCL study. The onset of isolated lymphocytosis occurs during the first few weeks of Ibrutinib therapy and resolves by a median of 8 weeks. - The safety and efficacy of Ibrutinib in patients with CLL who have received at least one prior therapy were demonstrated in one uncontrolled trial and one randomized, controlled trial. - An open-label, multi-center trial was conducted in 48 previously treated CLL patients. The median age was 67 years (range, 37 to 82 years), 71% were male, and 94% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 80 months and the median number of prior treatments was 4 (range, 1 to 12 treatments). At baseline, 46% of subjects had at least one tumor ≥ 5 cm. - Ibrutinib was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. The ORR and DOR were assessed using a modified version of the International Workshop on CLL Criteria by an Independent Review Committee. The ORR was 58.3% (95% CI: 43.2%, 72.4%), all partial responses. None of the patients achieved a complete response. The DOR ranged from 5.6 to 24.2+ months. The median DOR was not reached. - A randomized, multicenter, open-label Phase 3 study of Ibrutinib versus ofatumumab was conducted in patients with previously treated CLL or SLL. Patients (n=391) were randomized 1:1 to receive either Ibrutinib 420 mg daily until disease progression, or unacceptable toxicity or ofatumumab at an initial dose of 300 mg, followed one week later by a dose of 2000 mg weekly for 7 doses and then every 4 weeks for 4 additional doses. Fifty seven patients randomized to ofatumumab crossed over following progression to receive Ibrutinib. The median age was 67 years (range, 30 to 88 years), 68% were male, and 90% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The trial enrolled 373 patients with CLL and 18 patients with SLL. The median time since diagnosis was 91 months and the median number of prior treatments was 2 (range, 1 to 13 treatments). At baseline, 58% of patients had at least one tumor ≥ 5 cm. Thirty-two percent of patients had 17p deletion. - Progression free survival (PFS) as assessed by independent review committee (IRC) according to IWCLL criteria indicated a 78% statistically significant reduction in the risk of death or progression. Analysis of overall survival (OS) demonstrated a 57% statistically significant reduction in the risk of death for patients in the Ibrutinib arm. Efficacy results for Study 2 are shown in Table 10 and the Kaplan-Meier curves for PFS and OS are shown in Figures 1 and 2, respectively. - Study 2 included 127 patients with del 17p CLL. The median age was 67 years (range, 30 to 84 years), 62% were male, and 88% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. PFS and ORR were assessed by IRC. Efficacy results for del 17p CLL are shown in Table 11. ### Lymphocytosis - Upon initiation of Ibrutinib, an increase in lymphocyte counts (i.e., ≥ 50% increase from baseline and above absolute lymphocyte count of 5,000/mcL) occurred in 77% of patients in the CLL study. The onset of isolated lymphocytosis occurs during the first month of Ibrutinib therapy and resolves by a median of 23 weeks (range 1 – 104+ weeks). - The safety and efficacy of Ibrutinib in WM were evaluated in an open-label, multi-center, single-arm trial of 63 previously treated patients. The median age was 63 years (range, 44 to 86 years), 76% were male, and 95% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 74 months, and the median number of prior treatments was 2 (range, 1 to 11 treatments). At baseline, the median serum IgM value was 3.5 g/dL (range, 0.7 to 8.4 g/dL). - Ibrutinib was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. The responses were assessed by investigators and an Independent Review Committee (IRC) using criteria adopted from the International Workshop of Waldenström's Macroglobulinemia. Responses, defined as partial response or better, per IRC are shown in Table 12. # How Supplied - The white opaque 140 mg capsules marked with "ibr 140 mg" in black ink are available in white HDPE bottles with a child-resistant closure: - 90 capsules per bottle: NDC 57962-140-09 - 120 capsules per bottle: NDC 57962-140-12 - Store bottles at room temperature 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 30°C (59°F to 86°F). Retain in original package until dispensing. ## Storage There is limited information regarding Ibrutinib Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information See FDA-approved patient labeling (PATIENT INFORMATION). - Hemorrhage: - Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stool or urine, prolonged or uncontrolled bleeding). Inform the patient that Ibrutinib may need to be interrupted for medical or dental procedures . - Infections: - Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills, weakness, confusion) suggestive of infection . - Atrial Fibrillation: - Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort . - Second primary malignancies: - Inform patients that other malignancies have occurred in patients who have been treated with Ibrutinib, including skin cancers and other carcinomas. - Tumor lysis syndrome: - Inform patients of the potential risk of tumor lysis syndrome and report any signs and symptoms associated with this event to their healthcare provider for evaluation - Embryo-fetal toxicity: - Advise women of the potential hazard to a fetus and to avoid becoming pregnant - Inform patients to take Ibrutinib orally once daily according to their physician's instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day. - Advise patients that in the event of a missed daily dose of Ibrutinib, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose . - Advise patients of the common side effects associated with Ibrutinib . Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. - Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products . - Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Advise patients to maintain adequate hydration. # Precautions with Alcohol - Alcohol-Ibrutinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Imbruvica® # Look-Alike Drug Names There is limited information regarding Ibrutinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Ibrutinib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, 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 Ibrutinib is an kinase inhibitor that is FDA approved for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Common adverse reactions include thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite .. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Ibrutinib is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. - Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials. - Ibrutinib is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy . - Ibrutinib is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion. - Ibrutinib is indicated for the treatment of patients with Waldenström's macroglobulinemia (WM) ### Dosing Guidelines - Administer Ibrutinib orally once daily at approximately the same time each day. Swallow the capsules whole with water. Do not open, break, or chew the capsules. - The recommended dose of Ibrutinib for MCL is 560 mg (four 140 mg capsules) orally once daily. - Chronic Lymphocytic Leukemia and Waldenström's Macroglobulinemia - The recommended dose of Ibrutinib for CLL and WM is 420 mg (three 140 mg capsules) orally once daily. - Interrupt Ibrutinib therapy for any Grade 3 or greater non-hematological, Grade 3 or greater neutropenia with infection or fever, or Grade 4 hematological toxicities. Once the symptoms of the toxicity have resolved to Grade 1 or baseline (recovery), Ibrutinib therapy may be reinitiated at the starting dose. If the toxicity reoccurs, reduce dose by one capsule (140 mg per day). A second reduction of dose by 140 mg may be considered as needed. If these toxicities persist or recur following two dose reductions, discontinue Ibrutinib. - Recommended dose modifications are described below: - Dose Modifications for Use with CYP3A Inhibitors - Avoid co-administration with strong or moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. - Concomitant use of strong CYP3A inhibitors which would be taken chronically (e.g., ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended. For short-term use (treatment for 7 days or less) of strong CYP3A inhibitors (e.g., antifungals and antibiotics) consider interrupting Ibrutinib therapy until the CYP3A inhibitor is no longer needed. - Reduce Ibrutinib dose to 140 mg if a moderate CYP3A inhibitor must be used (e.g., fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, and ciprofloxacin). - Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more closely for signs of Ibrutinib toxicity. - For patients with mild liver impairment (Child-Pugh class A), the recommended dose is 140 mg daily (one capsule). Avoid the use of Ibrutinib in patients with moderate or severe hepatic impairment (Child-Pugh classes B and C) - If a dose of Ibrutinib is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. Extra capsules of Ibrutinib should not be taken to make up for the missed dose. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ibrutinib in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ibrutinib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Ibrutinib in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ibrutinib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ibrutinib in pediatric patients. # Contraindications - None # Warnings - Fatal bleeding events have occurred in patients treated with Ibrutinib. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with Ibrutinib. - The mechanism for the bleeding events is not well understood. - Ibrutinib may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. - Consider the benefit-risk of withholding Ibrutinib for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding . - Fatal and non-fatal infections have occurred with Ibrutinib therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with Ibrutinib. Monitor patients for fever and infections and evaluate promptly. - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with Ibrutinib. - Monitor complete blood counts monthly. - Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with Ibrutinib, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of Ibrutinib treatment and dose modification . - Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with Ibrutinib. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11 %). - Tumor lysis syndrome has been reported with Ibrutinib therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor burden). - Based on findings in animals, Ibrutinib can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL or WM, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking Ibrutinib. 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 a fetus # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions are discussed in more detail in other sections of the labeling: - Hemorrhage - Infections - Cytopenias - Atrial Fibrillation - Second Primary Malignancies - Tumor Lysis Syndrome - Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. - The data described below reflect exposure to Ibrutinib in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months. - The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (seeTABLES 1 and 2). - The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections. - Fatal and serious cases of renal failure have occurred with Ibrutinib therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients. - Adverse reactions from the MCL trial (N=111) using single agent Ibrutinib 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1. - Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients. - Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression. - Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients. - The data described below reflect exposure to Ibrutinib in an open label clinical trial (Study 1) that included 48 patients with previously treated CLL and a randomized clinical trial (Study 2) that included 391 randomized patients with previously treated CLL or SLL. - The most commonly occurring adverse reactions in Study 1 and Study 2 (≥ 20%) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia. - Approximately five percent of patients receiving Ibrutinib in Study 1 and Study 2 discontinued treatment due to adverse events. These included infections, subdural hematomas and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients. Study 1 - Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent Ibrutinib 420 mg daily occurring at a rate of ≥ 10% are presented in Tables 3 and 4. Study 2 - Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to Ibrutinib with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in Study 2. - The data described below reflect exposure to Ibrutinib in an open label clinical trial that included 63 patients with previously treated WM. - The most commonly occurring adverse reactions in the WM trial (≥ 20%) were neutropenia, thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue. - Six percent of patients receiving Ibrutinib in the WM trial discontinued treatment due to adverse events. Adverse events leading to dose reduction occurred in 11% of patients. - Adverse reactions and laboratory abnormalities described below in Tables 7 and 8 reflect exposure to Ibrutinib with a median duration of 11.7 months in the WM trial. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of Ibrutinib. 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. - Hypersensitivity reactions including anaphylactic shock (fatal), urticaria, and angioedema have been reported. # Drug Interactions - Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. - In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng ∙ hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg). - Avoid concomitant administration of Ibrutinib with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting Ibrutinib therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the Ibrutinib dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of Ibrutinib toxicity . - Avoid grapefruit and Seville oranges during Ibrutinib treatment, as these contain moderate inhibitors of CYP3A . - Administration of Ibrutinib with rifampin, a strong CYP3A inducer, decreased ibrutinib Cmax and AUC by approximately 13- and 10-fold, respectively. - Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John's Wort). Consider alternative agents with less CYP3A induction # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Based on findings in animals, Ibrutinib can cause fetal harm when administered to a pregnant woman. If Ibrutinib is used during pregnancy or if the patient becomes pregnant while taking Ibrutinib, the patient should be apprised of the potential hazard to the fetus. - Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL or WM administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily. Pregnancy Category (AUS): - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ibrutinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Ibrutinib during labor and delivery. ### Nursing Mothers - It is not known whether ibrutinib 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 Ibrutinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - The safety and effectiveness of Ibrutinib in pediatric patients has not been established . ### Geriatic Use - Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients. - Of the 391 patients randomized in Study 2, 61% were ≥ 65 years of age. No overall differences in effectiveness were observed between age groups. Grade 3 or higher adverse events occurred more frequently among elderly patients treated with Ibrutinib (61% of patients age ≥ 65 versus 51% of younger patients) . - Of the 63 patients treated for WM, 59% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), and infections (pneumonia and urinary tract infection) occurred more frequently among elderly patients. ### Gender There is no FDA guidance on the use of Ibrutinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ibrutinib with respect to specific racial populations. ### Renal Impairment - Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis ### Hepatic Impairment - Ibrutinib is metabolized in the liver. In a hepatic impairment study, data showed an increase in ibrutinib exposure. Following single dose administration, the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to subjects with normal liver function. The safety of Ibrutinib has not been evaluated in patients with hepatic impairment. - Monitor patients for signs of Ibrutinib toxicity and follow dose modification guidance as needed. It is not recommended to administer Ibrutinib to patients with moderate or severe hepatic impairment (Child-Pugh classes B and C) ### Females of Reproductive Potential and Males - Advise women to avoid becoming pregnant while taking Ibrutinib because Ibrutinib can cause fetal harm ### Immunocompromised Patients - Management of hyperviscosity in patients with WM may include plasmapheresis before and during treatment with Ibrutinib. Modifications to Ibrutinib dosing are not required. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Ibrutinib in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Ibrutinib in the drug label. # Overdosage ## Acute Overdose There is limited information regarding Chronic Overdose of Ibrutinib in the drug label. # Pharmacology ## Mechanism of Action - Ibrutinib is a small-molecule inhibitor of BTK. Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. BTK's role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Nonclinical studies show that ibrutinib inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro. ## Structure - Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK). It is a white to off-white solid with the empirical formula C25H24N6O2 and a molecular weight 440.50. Ibrutinib is freely soluble in dimethyl sulfoxide, soluble in methanol and practically insoluble in water. The chemical name for ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and has the following structure: - Ibrutinib capsules for oral administration are supplied as white opaque capsules that contain 140 mg ibrutinib as the active ingredient. Each capsule also contains the following inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate. The capsule shell contains gelatin, titanium dioxide and black ink. Each white opaque capsule is marked with "ibr 140 mg" in black ink. ## Pharmacodynamics - In patients with recurrent B-cell lymphoma > 90% occupancy of the BTK active site in peripheral blood mononuclear cells was observed up to 24 hours after ibrutinib doses of ≥ 2.5 mg/kg/day (≥ 175 mg/day for average weight of 70 kg). ## Pharmacokinetics - Ibrutinib is absorbed after oral administration with a median Tmax of 1 to 2 hours. Ibrutinib exposure increases with doses up to 840 mg. The steady-state AUC (mean ± standard deviation) observed in patients at 560 mg is 953 ± 705 ng∙h/mL and in patients at 420 mg is 680 ± 517 ng∙h/mL. Administration with food increased ibrutinib Cmax and AUC by approximately 2 to 4- and 2-fold, respectively, compared with administration of ibrutinib after overnight fasting. - Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with no concentration dependence in the range of 50 to 1000 ng/mL. The volume of distribution at steady state (Vd,ss) was 683 L, and the apparent volume of distribution at steady state (Vd,ss/F) was approximately 10000 L. - Metabolism is the main route of elimination for ibrutinib. It is metabolized to several metabolites primarily by cytochrome P450, CYP3A, and to a minor extent by CYP2D6. The active metabolite, PCI-45227, is a dihydrodiol metabolite with inhibitory activity towards BTK approximately 15 times lower than that of ibrutinib. The range of the mean metabolite to parent ratio for PCI-45227 at steady-state is 1 to 2.8. - Intravenous clearance was 62 and 76 L/h in fasted and fed conditions, respectively. In line with the high first-pass effect, the apparent oral clearance is approximately 2000 and 1000 L/h in fasted and fed conditions, respectively. The half-life of ibrutinib is 4 to 6 hours. - Ibrutinib, mainly in the form of metabolites, is eliminated primarily via feces. After a single oral administration of radiolabeled [14C]-ibrutinib in healthy subjects, approximately 90% of radioactivity was excreted within 168 hours, with the majority (80%) excreted in the feces and less than 10% accounted for in urine. Unchanged ibrutinib accounted for approximately 1% of the radiolabeled excretion product in feces and none in urine, with the remainder of the dose being metabolites. - Age (37 to 84 years) does not alter ibrutinib systemic clearance. - Gender does not alter ibrutinib systemic clearance. - Ibrutinib is not significantly cleared renally; urinary excretion of metabolites is < 10% of the dose. Creatinine clearance > 25 mL/min had no influence on the exposure to Ibrutinib. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or in patients on dialysis. - Ibrutinib is metabolized in the liver. In a hepatic impairment trial, a single dose of 140 mg of Ibrutinib was administered in non-cancer subjects. Ibrutinib AUC increased 2.7-, 8.2- and 9.8-fold, respectively, in subjects with mild (n=6), moderate (n=10) and severe (n=8) hepatic impairment relative to subjects with normal liver function. Ibrutinib Cmax increased 5.2-, 8.8- and 7.0-fold, respectively, in subjects with mild, moderate and severe hepatic impairment relative to subjects with normal liver function . - In a sequential design trial of 18 healthy, fasted volunteers, a single dose of 120 mg of Ibrutinib was administered alone on Day 1 and a single dose of 40 mg of Ibrutinib was administered on Day 7 in combination with 400 mg of ketoconazole (given daily on Days 4 – 9). Ketoconazole increased ibrutinib dose-normalized Cmax and AUC 29-fold and 24-fold, respectively. Simulations using fasted conditions indicate that moderate CYP3A inhibitors diltiazem and erythromycin may increase AUC of ibrutinib by 5- to 8-fold. - PK data from a dedicated drug interaction trial showed that rifampin (a strong CYP3A inducer) decreases ibrutinib Cmax and AUC by more than 13- and 10-fold. Simulations using PBPK suggested that a moderate CYP3A inducer (efavirenz) may decrease the AUC of ibrutinib by up to 3-fold. - In vitro studies indicated that ibrutinib (I/Ki < 0.07 using mean Cmax at 560 mg) and PCI-45227 (I/Ki < 0.03) are unlikely to be inhibitors of any major CYPs at clinical doses. Both ibrutinib and the PCI-45227 are weak inducers of CYP450 isoenzymes in vitro. - In vitro studies indicated that ibrutinib is not a substrate of p-glycoprotein (P-gp). Systemic ibrutinib is unlikely to be an inhibitor of P-gp at clinical doses ([I]1/Ki < 0.1). However, it may have an effect on P-gp substrates in the GI tract due to higher local concentrations after an oral dose. Co-administration of oral narrow therapeutic index P-gp substrates (e.g., digoxin) with Ibrutinib may increase their blood concentration. ## Nonclinical Toxicology - Carcinogenicity studies have not been conducted with ibrutinib. - Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo bone marrow micronucleus assay in mice at doses up to 2000 mg/kg. - Fertility studies with ibrutinib have not been conducted in animals. In the general toxicology studies conducted in rats and dogs, orally administered ibrutinib did not result in adverse effects on reproductive organs. # Clinical Studies - The safety and efficacy of Ibrutinib in patients with MCL who have received at least one prior therapy were evaluated in an open-label, multi-center, single-arm trial of 111 previously treated patients. The median age was 68 years (range, 40 to 84 years), 77% were male, and 92% were Caucasian. At baseline, 89% of patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 42 months, and median number of prior treatments was 3 (range, 1 to 5 treatments), including 11% with prior stem cell transplant. At baseline, 39% of subjects had at least one tumor ≥ 5 cm, 49% had bone marrow involvement, and 54% had extranodal involvement at screening. - Ibrutinib was administered orally at 560 mg once daily until disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group (IWG) for non-Hodgkin's lymphoma (NHL) criteria. The primary endpoint in this study was investigator-assessed overall response rate (ORR). Responses to Ibrutinib are shown in Table 9. - An Independent Review Committee (IRC) performed independent reading and interpretation of imaging scans. The IRC review demonstrated an ORR of 69%. - The median time to response was 1.9 months. ### Lymphocytosis - Upon initiation of Ibrutinib, a temporary increase in lymphocyte counts (i.e., ≥ 50% increase from baseline and above absolute lymphocyte count of 5,000/mcL) occurred in 33% of patients in the MCL study. The onset of isolated lymphocytosis occurs during the first few weeks of Ibrutinib therapy and resolves by a median of 8 weeks. - The safety and efficacy of Ibrutinib in patients with CLL who have received at least one prior therapy were demonstrated in one uncontrolled trial and one randomized, controlled trial. - An open-label, multi-center trial was conducted in 48 previously treated CLL patients. The median age was 67 years (range, 37 to 82 years), 71% were male, and 94% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 80 months and the median number of prior treatments was 4 (range, 1 to 12 treatments). At baseline, 46% of subjects had at least one tumor ≥ 5 cm. - Ibrutinib was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. The ORR and DOR were assessed using a modified version of the International Workshop on CLL Criteria by an Independent Review Committee. The ORR was 58.3% (95% CI: 43.2%, 72.4%), all partial responses. None of the patients achieved a complete response. The DOR ranged from 5.6 to 24.2+ months. The median DOR was not reached. - A randomized, multicenter, open-label Phase 3 study of Ibrutinib versus ofatumumab was conducted in patients with previously treated CLL or SLL. Patients (n=391) were randomized 1:1 to receive either Ibrutinib 420 mg daily until disease progression, or unacceptable toxicity or ofatumumab at an initial dose of 300 mg, followed one week later by a dose of 2000 mg weekly for 7 doses and then every 4 weeks for 4 additional doses. Fifty seven patients randomized to ofatumumab crossed over following progression to receive Ibrutinib. The median age was 67 years (range, 30 to 88 years), 68% were male, and 90% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The trial enrolled 373 patients with CLL and 18 patients with SLL. The median time since diagnosis was 91 months and the median number of prior treatments was 2 (range, 1 to 13 treatments). At baseline, 58% of patients had at least one tumor ≥ 5 cm. Thirty-two percent of patients had 17p deletion. - Progression free survival (PFS) as assessed by independent review committee (IRC) according to IWCLL criteria indicated a 78% statistically significant reduction in the risk of death or progression. Analysis of overall survival (OS) demonstrated a 57% statistically significant reduction in the risk of death for patients in the Ibrutinib arm. Efficacy results for Study 2 are shown in Table 10 and the Kaplan-Meier curves for PFS and OS are shown in Figures 1 and 2, respectively. - Study 2 included 127 patients with del 17p CLL. The median age was 67 years (range, 30 to 84 years), 62% were male, and 88% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. PFS and ORR were assessed by IRC. Efficacy results for del 17p CLL are shown in Table 11. ### Lymphocytosis - Upon initiation of Ibrutinib, an increase in lymphocyte counts (i.e., ≥ 50% increase from baseline and above absolute lymphocyte count of 5,000/mcL) occurred in 77% of patients in the CLL study. The onset of isolated lymphocytosis occurs during the first month of Ibrutinib therapy and resolves by a median of 23 weeks (range 1 – 104+ weeks). - The safety and efficacy of Ibrutinib in WM were evaluated in an open-label, multi-center, single-arm trial of 63 previously treated patients. The median age was 63 years (range, 44 to 86 years), 76% were male, and 95% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 74 months, and the median number of prior treatments was 2 (range, 1 to 11 treatments). At baseline, the median serum IgM value was 3.5 g/dL (range, 0.7 to 8.4 g/dL). - Ibrutinib was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. The responses were assessed by investigators and an Independent Review Committee (IRC) using criteria adopted from the International Workshop of Waldenström's Macroglobulinemia. Responses, defined as partial response or better, per IRC are shown in Table 12. # How Supplied - The white opaque 140 mg capsules marked with "ibr 140 mg" in black ink are available in white HDPE bottles with a child-resistant closure: - 90 capsules per bottle: NDC 57962-140-09 - 120 capsules per bottle: NDC 57962-140-12 - Store bottles at room temperature 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 30°C (59°F to 86°F). Retain in original package until dispensing. ## Storage There is limited information regarding Ibrutinib Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information See FDA-approved patient labeling (PATIENT INFORMATION). - Hemorrhage: - Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stool or urine, prolonged or uncontrolled bleeding). Inform the patient that Ibrutinib may need to be interrupted for medical or dental procedures . - Infections: - Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills, weakness, confusion) suggestive of infection . - Atrial Fibrillation: - Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort . - Second primary malignancies: - Inform patients that other malignancies have occurred in patients who have been treated with Ibrutinib, including skin cancers and other carcinomas. - Tumor lysis syndrome: - Inform patients of the potential risk of tumor lysis syndrome and report any signs and symptoms associated with this event to their healthcare provider for evaluation - Embryo-fetal toxicity: - Advise women of the potential hazard to a fetus and to avoid becoming pregnant - Inform patients to take Ibrutinib orally once daily according to their physician's instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day. - Advise patients that in the event of a missed daily dose of Ibrutinib, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose . - Advise patients of the common side effects associated with Ibrutinib . Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. - Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products . - Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Advise patients to maintain adequate hydration. # Precautions with Alcohol - Alcohol-Ibrutinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Imbruvica® # Look-Alike Drug Names There is limited information regarding Ibrutinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Ibrutinib
b8f50382e46f0a4bacd8f1afb01f5903089ec239	wikidoc	Ibudilast	Ibudilast # Overview Ibudilast (AV-411) is an antiinflammatory drug used mainly in Japan, which acts as a phosphodiesterase inhibitor, inhibiting the PDE-4 subtype to the greatest extent, but also showing significant inhibition of other PDE subtypes. Ibudilast has bronchodilator, vasodilator and neuroprotective effects, and and is mainly used in the treatment of asthma and stroke. It inhibits platelet aggregation, and may also be useful in the treatment of multiple sclerosis. Ibudilast crosses the blood-brain barrier and suppreses glial cell activation. This activity has been shown to make ibudilast useful in the treatment of neuropathic pain and it not only enhances analgesia produced by opioid drugs, but also reduces the development of tolerance.	Ibudilast Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Ibudilast (AV-411) is an antiinflammatory drug used mainly in Japan, which acts as a phosphodiesterase inhibitor, inhibiting the PDE-4 subtype to the greatest extent,[1] but also showing significant inhibition of other PDE subtypes.[2][3] Ibudilast has bronchodilator, vasodilator [4] and neuroprotective effects,[5][6] and and is mainly used in the treatment of asthma and stroke.[7] It inhibits platelet aggregation,[8] and may also be useful in the treatment of multiple sclerosis.[9] Ibudilast crosses the blood-brain barrier and suppreses glial cell activation. This activity has been shown to make ibudilast useful in the treatment of neuropathic pain and it not only enhances analgesia produced by opioid drugs, but also reduces the development of tolerance.[10] Template:Pharma-stub	https://www.wikidoc.org/index.php/Ibudilast
cf7524487e80c5c5530b1a805abe6798cd95efaf	wikidoc	Icatibant	Icatibant # 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 Icatibant is a bradykinin B2 receptor antagonist that is FDA approved for the treatment of acute attacks of hereditary angioedema (HAE) in adults 18 years of age and older. Common adverse reactions include pyrexia, transaminase increase, dizziness, and rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - The recommended dose of FIRAZYR is 30 mg administered by subcutaneous (SC) injection in the abdominal area. Additional doses may be administered at intervals of at least 6 hours if response is inadequate or if symptoms recur. No more than 3 doses may be administered in any 24 hour period. - FIRAZYR should be inspected visually for particulate matter and discoloration prior to administration. The drug solution should be clear and colorless. Do not administer if the product contains particulates or is discolored. - Attach the provided 25 gauge needle to the syringe hub and screw on securely. Do not use a different needle. Disinfect the injection site and administer FIRAZYR by subcutaneous injection over at least 30 seconds. - Patients may self-administer FIRAZYR upon recognition of symptoms of an HAE attack after training under the guidance of a healthcare professional. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Icatibant in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Icatibant in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Icatibant in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Icatibant in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Icatibant in pediatric patients. # Contraindications - None. # Warnings ### Precautions - Laryngeal Attacks - Given the potential for airway obstruction during acute laryngeal HAE attacks, patients should be advised to seek medical attention in an appropriate healthcare facility immediately in addition to treatment with FIRAZYR. # Adverse Reactions ## Clinical Trials Experience - The safety of icatibant was evaluated in three controlled trials that included 223 patients who received FIRAZYR 30 mg (n=113), placebo (n=75), or comparator (n=38). The mean age at study entry was 38 years (range 18 to 83 years), 64% were female, and 95% were white. The data described below represent adverse reactions observed from the two placebo-controlled trials, consisting of 77 patients who received FIRAZYR at a dose of 30 mg SC, and 75 who received placebo. - The most frequently reported adverse reactions (occurring in greater than 1% of patients and at a higher rate with FIRAZYR versus placebo) are shown in Table 1. - 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 third trial was active-controlled and was comprised of 35 patients who received FIRAZYR 30 mg and 38 patients who received the comparator. Adverse reactions for FIRAZYR were similar in nature and frequency to those reported in Table 1. - In all three controlled trials, patients were eligible for treatment of subsequent attacks in an open-label extension. Patients were treated with FIRAZYR 30 mg and could receive up to 3 doses of FIRAZYR 30 mg administered at least 6 hours apart for each attack. A total of 225 patients were treated with 1,076 doses of 30 mg FIRAZYR for 987 attacks of acute HAE. Adverse reactions similar in nature and frequency were observed to those seen in the controlled phase of the trials. Other adverse reactions reported included rash, nausea, and headache in patients exposed to FIRAZYR. - The safety of self-administration was evaluated in a separate, open-label trial in 56 patients with HAE. In this trial, the safety profile of FIRAZYR in patients who self-administered FIRAZYR was similar in nature and frequency to that of patients whose therapy was administered by healthcare professionals. ## Postmarketing Experience - Similar adverse reactions have been observed in postmarketing use as compared to the clinical trials. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. # Drug Interactions - ACE Inhibitors - FIRAZYR is a bradykinin B2 receptor antagonist and thereby has the potential to have a pharmacodynamic interaction with ACE inhibitors where FIRAZYR may attenuate the antihypertensive effect of ACE inhibitors. Clinical trials to date have excluded subjects taking ACE inhibitors. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. Icatibant was not teratogenic in rats or rabbits; however, it caused delayed parturition, fetal death, and pre-implantation loss in rats and premature birth, abortion, fetal death, and pre-implantation loss in rabbits. FIRAZYR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Delayed parturition and fetal death in rats occurred at 0.5 and 2-fold, respectively, the maximum recommended human dose (MRHD) (on an AUC basis at maternal doses of 1 and 3 mg/kg, respectively). Increased pre-implantation loss in rats occurred at 7-fold the MRHD (on an AUC basis at a maternal dose of 10 mg/kg). In rabbits, premature birth and abortion rates increased at a dose that was less than 1/40th the MRHD (on a mg/m2 basis at a maternal dose of 0.1 mg/kg). Studies in rabbits also indicated that pre-implantation loss and increased fetal deaths occurred at 13-fold greater than the MRHD (on an AUC basis at a maternal dose of 10 mg/kg). - Nonteratogenic effects: Impairment of pup air-righting reflex and decreased pup hair growth in rats occurred at 7-fold the MRHD (on an AUC basis at a maternal dose of 10 mg/kg). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Icatibant in women who are pregnant. ### Labor and Delivery - There are no human studies that have investigated the effects of FIRAZYR on preterm labor or labor at term; however, animal studies showed that icatibant causes delayed parturition and associated fetal death in rats and premature birth and abortion in rabbits. Delayed parturition occurred in rats at 0.5-fold times the MRHD (on an AUC basis at a maternal dose of 1 mg/kg). ### Nursing Mothers - Because many drugs are excreted in human milk, caution should be exercised when FIRAZYR is administered to a nursing woman. Icatibant is excreted into the milk of lactating rats. ### Pediatric Use - Safety and effectiveness in pediatric patients below the age of 18 years have not been established. ### Geriatic Use - Clinical studies of FIRAZYR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients are likely to have increased systemic exposure to FIRAZYR compared to younger (18-45 years) patients. Since other reported clinical experience has not identified differences in efficacy and safety between elderly and younger patients, no dose adjustment is recommended. ### Gender There is no FDA guidance on the use of Icatibant with respect to specific gender populations. ### Race There is no FDA guidance on the use of Icatibant with respect to specific racial populations. ### Renal Impairment - Although a formal renal impairment study has not been conducted, 10 of 37 patients treated with FIRAZYR had hepatorenal syndrome with glomerular filtration rate (GFR) below 60 mL/min. FIRAZYR is cleared non-renally and hence it is not expected to show any change in systemic exposure in patients with impaired renal function. No dose adjustment is required in patients with renal impairment. ### Hepatic Impairment - FIRAZYR was studied in patients with mild to moderate (Child Pugh scores of 5 to 8) hepatic impairment. No change in systemic exposure is noted in these patient populations. No dose adjustment is required in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Icatibant in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Icatibant in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Icatibant in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Icatibant in the drug label. # Overdosage ## Acute Overdose - In a clinical study evaluating a 90 mg dose (30 mg in each of 3 subcutaneous sites), the adverse event profile was similar to that seen with 30 mg administered in a single subcutaneous site. - In another clinical study, a dose of 3.2 mg/kg administered intravenously (approximately 8 times the therapeutic dose for HAE) caused erythema, itching and hypotension in healthy subjects. No therapeutic intervention was necessary. ## Chronic Overdose There is limited information regarding Chronic Overdose of Icatibant in the drug label. # Pharmacology ## Mechanism of Action - Icatibant is a competitive antagonist selective for the bradykinin B2 receptor, with an affinity similar to bradykinin. Hereditary angioedema is caused by an absence or dysfunction of C1-esterase-inhibitor, a key regulator of the Factor XII/kallikrein proteolytic cascade that leads to bradykinin production. Bradykinin is a vasodilator which is thought to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain. Icatibant inhibits bradykinin from binding the B2 receptor and thereby treats the clinical symptoms of an acute, episodic attack of HAE. ## Structure - FIRAZYR (icatibant) is a synthetic decapeptide with five non-proteinogenic amino acids. The chemical structure of icatibant acetate is presented in Figure 1. - Chemical name: D-Arginyl-L-arginyl-L-prolyl-L-glycyl-L-L-seryl-D-(1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl)-L-L-arginine, acetate salt - FIRAZYR is provided as a sterile, isotonic, and buffered solution of icatibant acetate in a single-use, prefilled syringe for subcutaneous administration. Each mL of the solution contains 10 mg of icatibant (free base). Each prefilled syringe delivers 3 mL of solution equivalent to a 30 mg icatibant dose. The solution is clear and colorless. - The solution also contains sodium chloride, glacial acetic acid, sodium hydroxide and water for injection with a pH of approximately 5.5. The solution does not contain preservatives. - Pharmacological class: Icatibant is a bradykinin B2 receptor antagonist. ## Pharmacodynamics - Following bradykinin challenge, intravenous administration of FIRAZYR caused dose and time-dependent inhibition of development of bradykinin-induced hypotension, vasodilation, and reflex tachycardia in healthy young subjects. FIRAZYR intravenous doses of 0.4 and 0.8 mg/kg infused over 4 hours inhibited response to bradykinin challenge for 6 to 8 hours following completion of the infusion. Based on exposure-response analysis, a subcutaneous dose of 30 mg FIRAZYR is predicted to be effective against bradykinin challenge for at least 6 hours. The clinical significance of these findings is unknown. - The effect of FIRAZYR 30 and 90 mg following a single subcutaneous injection on QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 72 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 ms, the threshold for regulatory concern. The dose of 90 mg is adequate to represent the high exposure clinical scenario. ## Pharmacokinetics - The pharmacokinetics of FIRAZYR has been characterized in studies using both intravenous and subcutaneous administration to healthy subjects and patients. The pharmacokinetic profile of FIRAZYR in patients with HAE is similar to that in healthy subjects. - The absolute bioavailability of FIRAZYR following a 30 mg subcutaneous dose is approximately 97%. Following subcutaneous administration of a single 30 mg dose of FIRAZYR to healthy subjects (N=96), a mean (± standard deviation) maximum plasma concentration (Cmax) of 974 ± 280 ng/mL was observed after approximately 0.75 hours. The mean area under the concentration-time curve (AUC0-∞) after a single 30 mg dose was 2165 ± 568 ng∙hr/mL, with no evidence of accumulation of icatibant following three 30 mg doses administered 6 hours apart. Following subcutaneous administration, plasma clearance was 245 ± 58 mL/min with a mean elimination half-life of 1.4 ± 0.4 hours and volume of distribution at steady state (Vss) of 29.0 ± 8.7 L. - Icatibant is extensively metabolized by proteolytic enzymes to inactive metabolites that are primarily excreted in the urine, with less than 10% of the dose eliminated as unchanged drug. Icatibant is not degraded by oxidative metabolic pathways, is not an inhibitor of major cytochrome P450 (CYP) isoenzymes (CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) and is not an inducer of CYP 1A2 and 3A4. - Special populations - Hepatic Impairment - The pharmacokinetic parameters of FIRAZYR were found to be generally comparable between healthy subjects (n=8) and mild to moderate (Child Pugh scores of 5 to 8) hepatic impaired patients (n=8) following a dose of 0.15 mg/kg/day as continuous intravenous infusion over 3 days. In a separate study, FIRAZYR clearance in subjects with a wide range of hepatic impairment (Child-Pugh scores of 7 to 15) was similar to that in healthy subjects. No dose adjustment is necessary for patients with impairment of hepatic function. - Renal Impairment - Since renal clearance of icatibant is a minor eliminating pathway, renal impairment is not expected to affect the pharmacokinetics of FIRAZYR and hence a formal renal impairment study was not conducted for FIRAZYR. In 10 patients with hepatorenal syndrome (GFR 30-60 mL/min), clearance of FIRAZYR was not dependent on renal function and therefore, did not show any observable differences in the plasma levels of icatibant or its metabolites compared to subjects with normal renal function. No dose adjustment is necessary for patients with impairment of renal function. - Age and Gender - Three 30 mg subcutaneous doses of FIRAZYR administered every 6 hours were studied in young (18 to 45 years of age) and elderly (over 65 years of age) healthy male and female subjects. Following single-dose administration of 30 mg subcutaneous FIRAZYR, elderly males and females showed approximately 2-fold higher AUC compared to young males and females, respectively. However, only minor differences (~12-14%) between Cmax of gender–matched elderly and young subjects were observed. Older subjects tend to exhibit lower clearance compared to younger subjects and therefore higher systemic exposure. Gender effect on FIRAZYR pharmacokinetics was also observed in addition to age effect. Clearance of FIRAZYR is significantly correlated with bodyweight with lower clearance values noted for lower bodyweights. Hence, females with typically lower body weights compared to males exhibit lower clearance values, resulting in approximately 2-fold higher systemic exposure (both AUC and Cmax) compared to males. Differences in efficacy and safety between elderly and younger patients and male and female patients have not been identified. Dose adjustment based on age and gender is not warranted. - Drug Interactions - Formal drug-drug interaction studies were not conducted with FIRAZYR. Icatibant metabolism is not mediated by CYP450 enzymes. In vitro study did not show any significant inhibition and/or induction of drug metabolizing CYP450 enzymes; therefore, metabolic drug interactions between FIRAZYR and CYP450 substrates, inhibitors and inducers are not expected. ## Nonclinical Toxicology - A two-year study was conducted in rats to assess the carcinogenic potential of FIRAZYR. No evidence of tumorigenicity was observed in rats at icatibant subcutaneous doses up to 6 mg/kg/day (approximately 6-fold greater than the Maximum Recommended Human Dose on an AUC basis). - Icatibant tested negative for genotoxicity in the in vitro Ames bacterial reverse mutation test, in vitro Chinese hamster bone marrow chromosome aberration assay, and in vivo mouse micronucleus test. - Daily subcutaneous administration of icatibant to rats and dogs caused ovarian, uterine, and testicular atrophy/degeneration and adverse effects on the mammary and prostate glands. In rats, testicular atrophy, reduced prostate gland secretion, decreased testosterone levels and degenenerate corpora lutea occurred at doses greater than or equal to 3 mg/kg (approximately 5-fold greater than the MRHD in males and 2-fold greater than the MRHD in females on an AUC basis) and a decrease in developing ovarian follicles, mammary gland masculinization, and uterine atrophy occurred at doses greater than or equal to 10 mg/kg (approximately 6-fold greater than MRHD in females on an AUC basis). In dogs, reduced sperm counts and uterine atrophy occurred at doses greater than or equal to 1 mg/kg (approximately 2-fold greater than the MRHD on an AUC basis). Atrophy of the testes and prostate with decreased testosterone levels, decreased ovary size and decreased number of developing follicles occurred at a dose of 10 mg/kg (approximately 30-fold greater than the MRHD in males and 15-fold greater than at the MRHD in females on an AUC basis). - In contrast to the effects of daily icatibant administration, toxicity to the ovary, uterus, testis, mammary gland, and prostate did not occur in dogs treated twice a week for 9 months. AUC exposures from a dose of 3 mg/kg in these dogs were 5- and 3-fold the MRHD exposures in men and women, respectively. Sperm counts and testosterone remained unaffected over the course of the study in male dogs dosed twice a week. - Reproduction studies in male mice and rats with daily administration of icatibant found no effects on fertility or reproductive performance with intravenous doses up 81 mg/kg (approximately 5-fold greater than the MRHD on a mg/m2 basis) or subcutaneous doses up to 10 mg/kg (approximately 11-fold greater than the MRHD on an AUC basis), respectively. - Animal Toxicology and/or Pharmacology - The B2 receptor has been implicated in the cardioprotective effects of bradykinin and antagonism of this receptor could potentially have negative cardiovascular effects during reperfusion after acute ischemia. Icatibant decreased coronary blood flow in the isolated guinea pig heart and aggravated the duration of post-ischemic reperfusion arrhythmias in the isolated rat heart. Intracoronary infusion of icatibant in an anesthetized myocardial infarction dog model increased mortality rate 2-fold over saline ischemia. There is limited human experience in acute ischemia. FIRAZYR should be used during acute coronary ischemia, unstable angina pectoris, or in the weeks following a stroke only if the benefit exceeds the theoretical risk to the patient. # Clinical Studies - The efficacy and safety of FIRAZYR for the treatment of acute attacks of HAE in adults were studied in three controlled clinical trials. Among the 223 patients in these studies, the mean age was 38 years, 64% were female, and 95% were white. Approximately 57% of patients reported use of attenuated androgens, antifibrinolytic agents, or C1 inhibitors. Response to therapy was primarily assessed using visual analog scores on a 100 mm scale and patient- and physician-reported symptom scores for abdominal and cutaneous pain and swelling. - Trial 1 was a randomized, placebo-controlled, double-blind, parallel-group study of 98 adult patients with a median age of 36 years. Patients who had developed moderate to severe cutaneous or abdominal or mild to moderate laryngeal attacks of HAE were randomized to receive either FIRAZYR 30 mg or placebo by subcutaneous injection. Patients with severe laryngeal attacks of HAE received open-label FIRAZYR 30 mg. The primary endpoint was assessed using a 3-item composite visual analog score (VAS), comprised of averaged assessments of skin swelling, skin pain, and abdominal pain. Response was defined as at least a 50% reduction from the pretreatment composite 3-itemVAS score (Figure 2). The median time to 50% reduction in symptoms for patients with cutaneous or abdominal attacks treated with FIRAZYR (n=43) compared to placebo (n=45) was 2.0 hours versus 19.8 hours , respectively (p<0.001). - Other evaluated endpoints included time to almost complete symptom relief (VAS<10 mm) and rescue medication use. In Trial 1, the median times to almost complete symptom relief were 8.0 versus 36.0 hours for FIRAZYR and placebo, respectively. In terms of rescue medication use, 3/43 (7%) patients treated with FIRAZYR used additional rescue medication in comparison to 18/45 (40%) patients treated with placebo. - In a second placebo-controlled trial and an active-controlled trial, a total of 26 and 35 patients, respectively, received FIRAZYR 30 mg for the treatment of an acute HAE attack. Across the three trials, FIRAZYR had a median time to 50% reduction from baseline symptoms ranging from 2.0 to 2.3 hours. - Recurrent attacks - In all three controlled trials, patients were eligible for treatment of subsequent attacks in an open-label extension. Patients were treated with FIRAZYR 30 mg and could receive up to 3 doses of FIRAZYR 30 mg administered at least 6 hours apart for each attack. A total of 225 patients were treated with 1,076 doses of 30 mg FIRAZYR for 987 attacks of acute HAE in these trials. In an assessment of the first 5 FIRAZYR-treated attacks (621 doses for 582 attacks), the median times to a 50% reduction from the pretreatment composite 3-itemVAS score were similar across attacks (2.0, 2.0, 2.4, 2.0, 1.5 hours). The majority (93%) of these attacks of HAE were treated with a single dose of FIRAZYR. - Laryngeal attacks - A total of 60 patients with laryngeal attacks were treated with FIRAZYR in the controlled trials. Efficacy results were similar to those observed for non-laryngeal (cutaneous and abdominal) sites of attack. - Self-administration - Self-administration of FIRAZYR by 56 patients was assessed in an open label trial. Patients who administered FIRAZYR during an acute attack of HAE had a median time to 50% reduction from the pretreatment composite 3-itemVAS score of 2.6 hours. # How Supplied - FIRAZYR is supplied as a single-use, prefilled syringe for subcutaneous administration. Each syringe delivers 3 mL of a sterile solution of icatibant 30 mg (as icatibant acetate). Each glass syringe has a bromobutyl plunger stopper, which is not made of latex natural rubber. - FIRAZYR is available in cartons containing one single-use, prefilled syringe and one 25 G Luer lock needle. NDC 54092-702-02. - FIRAZYR is also available in a pack containing 3 cartons; each carton contains one single-use, prefilled syringe and one 25 G Luer lock needle. NDC 54092-702-03. - Storage and Handling - Keep out of the reach of children. - Store between 2 - 25° C (36 - 77° F). - Do not freeze. - Store in carton until time of administration. ## Storage There is limited information regarding Icatibant Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients may self-administer FIRAZYR upon recognition of an HAE attack after training under the guidance of a healthcare professional. - Patients with laryngeal symptoms should seek medical attention immediately in an appropriate healthcare facility after administration of FIRAZYR. - Injection site reactions are reported in most patients after administration of FIRAZYR. Other adverse reactions reported after administration of FIRAZYR include pyrexia, increase in transaminases, dizziness, and rash. - Tiredness, drowsiness, and dizziness have been reported following the use of FIRAZYR. Patients should be advised not to drive or use machinery if they feel tired or dizzy. # Precautions with Alcohol - Alcohol-Icatibant interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - FIRAZYR® # Look-Alike Drug Names There is limited information regarding Icatibant Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Icatibant Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Icatibant is a bradykinin B2 receptor antagonist that is FDA approved for the treatment of acute attacks of hereditary angioedema (HAE) in adults 18 years of age and older. Common adverse reactions include pyrexia, transaminase increase, dizziness, and rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - The recommended dose of FIRAZYR is 30 mg administered by subcutaneous (SC) injection in the abdominal area. Additional doses may be administered at intervals of at least 6 hours if response is inadequate or if symptoms recur. No more than 3 doses may be administered in any 24 hour period. - FIRAZYR should be inspected visually for particulate matter and discoloration prior to administration. The drug solution should be clear and colorless. Do not administer if the product contains particulates or is discolored. - Attach the provided 25 gauge needle to the syringe hub and screw on securely. Do not use a different needle. Disinfect the injection site and administer FIRAZYR by subcutaneous injection over at least 30 seconds. - Patients may self-administer FIRAZYR upon recognition of symptoms of an HAE attack after training under the guidance of a healthcare professional. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Icatibant in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Icatibant in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Icatibant in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Icatibant in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Icatibant in pediatric patients. # Contraindications - None. # Warnings ### Precautions - Laryngeal Attacks - Given the potential for airway obstruction during acute laryngeal HAE attacks, patients should be advised to seek medical attention in an appropriate healthcare facility immediately in addition to treatment with FIRAZYR. # Adverse Reactions ## Clinical Trials Experience - The safety of icatibant was evaluated in three controlled trials that included 223 patients who received FIRAZYR 30 mg (n=113), placebo (n=75), or comparator (n=38). The mean age at study entry was 38 years (range 18 to 83 years), 64% were female, and 95% were white. The data described below represent adverse reactions observed from the two placebo-controlled trials, consisting of 77 patients who received FIRAZYR at a dose of 30 mg SC, and 75 who received placebo. - The most frequently reported adverse reactions (occurring in greater than 1% of patients and at a higher rate with FIRAZYR versus placebo) are shown in Table 1. - 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 third trial was active-controlled and was comprised of 35 patients who received FIRAZYR 30 mg and 38 patients who received the comparator. Adverse reactions for FIRAZYR were similar in nature and frequency to those reported in Table 1. - In all three controlled trials, patients were eligible for treatment of subsequent attacks in an open-label extension. Patients were treated with FIRAZYR 30 mg and could receive up to 3 doses of FIRAZYR 30 mg administered at least 6 hours apart for each attack. A total of 225 patients were treated with 1,076 doses of 30 mg FIRAZYR for 987 attacks of acute HAE. Adverse reactions similar in nature and frequency were observed to those seen in the controlled phase of the trials. Other adverse reactions reported included rash, nausea, and headache in patients exposed to FIRAZYR. - The safety of self-administration was evaluated in a separate, open-label trial in 56 patients with HAE. In this trial, the safety profile of FIRAZYR in patients who self-administered FIRAZYR was similar in nature and frequency to that of patients whose therapy was administered by healthcare professionals. ## Postmarketing Experience - Similar adverse reactions have been observed in postmarketing use as compared to the clinical trials. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. # Drug Interactions - ACE Inhibitors - FIRAZYR is a bradykinin B2 receptor antagonist and thereby has the potential to have a pharmacodynamic interaction with ACE inhibitors where FIRAZYR may attenuate the antihypertensive effect of ACE inhibitors. Clinical trials to date have excluded subjects taking ACE inhibitors. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. Icatibant was not teratogenic in rats or rabbits; however, it caused delayed parturition, fetal death, and pre-implantation loss in rats and premature birth, abortion, fetal death, and pre-implantation loss in rabbits. FIRAZYR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Delayed parturition and fetal death in rats occurred at 0.5 and 2-fold, respectively, the maximum recommended human dose (MRHD) (on an AUC basis at maternal doses of 1 and 3 mg/kg, respectively). Increased pre-implantation loss in rats occurred at 7-fold the MRHD (on an AUC basis at a maternal dose of 10 mg/kg). In rabbits, premature birth and abortion rates increased at a dose that was less than 1/40th the MRHD (on a mg/m2 basis at a maternal dose of 0.1 mg/kg). Studies in rabbits also indicated that pre-implantation loss and increased fetal deaths occurred at 13-fold greater than the MRHD (on an AUC basis at a maternal dose of 10 mg/kg). - Nonteratogenic effects: Impairment of pup air-righting reflex and decreased pup hair growth in rats occurred at 7-fold the MRHD (on an AUC basis at a maternal dose of 10 mg/kg). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Icatibant in women who are pregnant. ### Labor and Delivery - There are no human studies that have investigated the effects of FIRAZYR on preterm labor or labor at term; however, animal studies showed that icatibant causes delayed parturition and associated fetal death in rats and premature birth and abortion in rabbits. Delayed parturition occurred in rats at 0.5-fold times the MRHD (on an AUC basis at a maternal dose of 1 mg/kg). ### Nursing Mothers - Because many drugs are excreted in human milk, caution should be exercised when FIRAZYR is administered to a nursing woman. Icatibant is excreted into the milk of lactating rats. ### Pediatric Use - Safety and effectiveness in pediatric patients below the age of 18 years have not been established. ### Geriatic Use - Clinical studies of FIRAZYR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients are likely to have increased systemic exposure to FIRAZYR compared to younger (18-45 years) patients. Since other reported clinical experience has not identified differences in efficacy and safety between elderly and younger patients, no dose adjustment is recommended. ### Gender There is no FDA guidance on the use of Icatibant with respect to specific gender populations. ### Race There is no FDA guidance on the use of Icatibant with respect to specific racial populations. ### Renal Impairment - Although a formal renal impairment study has not been conducted, 10 of 37 patients treated with FIRAZYR had hepatorenal syndrome with glomerular filtration rate (GFR) below 60 mL/min. FIRAZYR is cleared non-renally and hence it is not expected to show any change in systemic exposure in patients with impaired renal function. No dose adjustment is required in patients with renal impairment. ### Hepatic Impairment - FIRAZYR was studied in patients with mild to moderate (Child Pugh scores of 5 to 8) hepatic impairment. No change in systemic exposure is noted in these patient populations. No dose adjustment is required in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Icatibant in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Icatibant in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Icatibant in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Icatibant in the drug label. # Overdosage ## Acute Overdose - In a clinical study evaluating a 90 mg dose (30 mg in each of 3 subcutaneous sites), the adverse event profile was similar to that seen with 30 mg administered in a single subcutaneous site. - In another clinical study, a dose of 3.2 mg/kg administered intravenously (approximately 8 times the therapeutic dose for HAE) caused erythema, itching and hypotension in healthy subjects. No therapeutic intervention was necessary. ## Chronic Overdose There is limited information regarding Chronic Overdose of Icatibant in the drug label. # Pharmacology ## Mechanism of Action - Icatibant is a competitive antagonist selective for the bradykinin B2 receptor, with an affinity similar to bradykinin. Hereditary angioedema is caused by an absence or dysfunction of C1-esterase-inhibitor, a key regulator of the Factor XII/kallikrein proteolytic cascade that leads to bradykinin production. Bradykinin is a vasodilator which is thought to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain. Icatibant inhibits bradykinin from binding the B2 receptor and thereby treats the clinical symptoms of an acute, episodic attack of HAE. ## Structure - FIRAZYR (icatibant) is a synthetic decapeptide with five non-proteinogenic amino acids. The chemical structure of icatibant acetate is presented in Figure 1. - Chemical name: D-Arginyl-L-arginyl-L-prolyl-L[(4R)-4-hydroxyprolyl]-glycyl-L[3-(2-thienyl)alanyl]-L-seryl-D-(1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl)-L[(3aS,7aS)-octahydroindol-2-ylcarbonyl]-L-arginine, acetate salt - FIRAZYR is provided as a sterile, isotonic, and buffered solution of icatibant acetate in a single-use, prefilled syringe for subcutaneous administration. Each mL of the solution contains 10 mg of icatibant (free base). Each prefilled syringe delivers 3 mL of solution equivalent to a 30 mg icatibant dose. The solution is clear and colorless. - The solution also contains sodium chloride, glacial acetic acid, sodium hydroxide and water for injection with a pH of approximately 5.5. The solution does not contain preservatives. - Pharmacological class: Icatibant is a bradykinin B2 receptor antagonist. ## Pharmacodynamics - Following bradykinin challenge, intravenous administration of FIRAZYR caused dose and time-dependent inhibition of development of bradykinin-induced hypotension, vasodilation, and reflex tachycardia in healthy young subjects. FIRAZYR intravenous doses of 0.4 and 0.8 mg/kg infused over 4 hours inhibited response to bradykinin challenge for 6 to 8 hours following completion of the infusion. Based on exposure-response analysis, a subcutaneous dose of 30 mg FIRAZYR is predicted to be effective against bradykinin challenge for at least 6 hours. The clinical significance of these findings is unknown. - The effect of FIRAZYR 30 and 90 mg following a single subcutaneous injection on QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 72 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 ms, the threshold for regulatory concern. The dose of 90 mg is adequate to represent the high exposure clinical scenario. ## Pharmacokinetics - The pharmacokinetics of FIRAZYR has been characterized in studies using both intravenous and subcutaneous administration to healthy subjects and patients. The pharmacokinetic profile of FIRAZYR in patients with HAE is similar to that in healthy subjects. - The absolute bioavailability of FIRAZYR following a 30 mg subcutaneous dose is approximately 97%. Following subcutaneous administration of a single 30 mg dose of FIRAZYR to healthy subjects (N=96), a mean (± standard deviation) maximum plasma concentration (Cmax) of 974 ± 280 ng/mL was observed after approximately 0.75 hours. The mean area under the concentration-time curve (AUC0-∞) after a single 30 mg dose was 2165 ± 568 ng∙hr/mL, with no evidence of accumulation of icatibant following three 30 mg doses administered 6 hours apart. Following subcutaneous administration, plasma clearance was 245 ± 58 mL/min with a mean elimination half-life of 1.4 ± 0.4 hours and volume of distribution at steady state (Vss) of 29.0 ± 8.7 L. - Icatibant is extensively metabolized by proteolytic enzymes to inactive metabolites that are primarily excreted in the urine, with less than 10% of the dose eliminated as unchanged drug. Icatibant is not degraded by oxidative metabolic pathways, is not an inhibitor of major cytochrome P450 (CYP) isoenzymes (CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) and is not an inducer of CYP 1A2 and 3A4. - Special populations - Hepatic Impairment - The pharmacokinetic parameters of FIRAZYR were found to be generally comparable between healthy subjects (n=8) and mild to moderate (Child Pugh scores of 5 to 8) hepatic impaired patients (n=8) following a dose of 0.15 mg/kg/day as continuous intravenous infusion over 3 days. In a separate study, FIRAZYR clearance in subjects with a wide range of hepatic impairment (Child-Pugh scores of 7 to 15) was similar to that in healthy subjects. No dose adjustment is necessary for patients with impairment of hepatic function. - Renal Impairment - Since renal clearance of icatibant is a minor eliminating pathway, renal impairment is not expected to affect the pharmacokinetics of FIRAZYR and hence a formal renal impairment study was not conducted for FIRAZYR. In 10 patients with hepatorenal syndrome (GFR 30-60 mL/min), clearance of FIRAZYR was not dependent on renal function and therefore, did not show any observable differences in the plasma levels of icatibant or its metabolites compared to subjects with normal renal function. No dose adjustment is necessary for patients with impairment of renal function. - Age and Gender - Three 30 mg subcutaneous doses of FIRAZYR administered every 6 hours were studied in young (18 to 45 years of age) and elderly (over 65 years of age) healthy male and female subjects. Following single-dose administration of 30 mg subcutaneous FIRAZYR, elderly males and females showed approximately 2-fold higher AUC compared to young males and females, respectively. However, only minor differences (~12-14%) between Cmax of gender–matched elderly and young subjects were observed. Older subjects tend to exhibit lower clearance compared to younger subjects and therefore higher systemic exposure. Gender effect on FIRAZYR pharmacokinetics was also observed in addition to age effect. Clearance of FIRAZYR is significantly correlated with bodyweight with lower clearance values noted for lower bodyweights. Hence, females with typically lower body weights compared to males exhibit lower clearance values, resulting in approximately 2-fold higher systemic exposure (both AUC and Cmax) compared to males. Differences in efficacy and safety between elderly and younger patients and male and female patients have not been identified. Dose adjustment based on age and gender is not warranted. - Drug Interactions - Formal drug-drug interaction studies were not conducted with FIRAZYR. Icatibant metabolism is not mediated by CYP450 enzymes. In vitro study did not show any significant inhibition and/or induction of drug metabolizing CYP450 enzymes; therefore, metabolic drug interactions between FIRAZYR and CYP450 substrates, inhibitors and inducers are not expected. ## Nonclinical Toxicology - A two-year study was conducted in rats to assess the carcinogenic potential of FIRAZYR. No evidence of tumorigenicity was observed in rats at icatibant subcutaneous doses up to 6 mg/kg/day (approximately 6-fold greater than the Maximum Recommended Human Dose on an AUC basis). - Icatibant tested negative for genotoxicity in the in vitro Ames bacterial reverse mutation test, in vitro Chinese hamster bone marrow chromosome aberration assay, and in vivo mouse micronucleus test. - Daily subcutaneous administration of icatibant to rats and dogs caused ovarian, uterine, and testicular atrophy/degeneration and adverse effects on the mammary and prostate glands. In rats, testicular atrophy, reduced prostate gland secretion, decreased testosterone levels and degenenerate corpora lutea occurred at doses greater than or equal to 3 mg/kg (approximately 5-fold greater than the MRHD in males and 2-fold greater than the MRHD in females on an AUC basis) and a decrease in developing ovarian follicles, mammary gland masculinization, and uterine atrophy occurred at doses greater than or equal to 10 mg/kg (approximately 6-fold greater than MRHD in females on an AUC basis). In dogs, reduced sperm counts and uterine atrophy occurred at doses greater than or equal to 1 mg/kg (approximately 2-fold greater than the MRHD on an AUC basis). Atrophy of the testes and prostate with decreased testosterone levels, decreased ovary size and decreased number of developing follicles occurred at a dose of 10 mg/kg (approximately 30-fold greater than the MRHD in males and 15-fold greater than at the MRHD in females on an AUC basis). - In contrast to the effects of daily icatibant administration, toxicity to the ovary, uterus, testis, mammary gland, and prostate did not occur in dogs treated twice a week for 9 months. AUC exposures from a dose of 3 mg/kg in these dogs were 5- and 3-fold the MRHD exposures in men and women, respectively. Sperm counts and testosterone remained unaffected over the course of the study in male dogs dosed twice a week. - Reproduction studies in male mice and rats with daily administration of icatibant found no effects on fertility or reproductive performance with intravenous doses up 81 mg/kg (approximately 5-fold greater than the MRHD on a mg/m2 basis) or subcutaneous doses up to 10 mg/kg (approximately 11-fold greater than the MRHD on an AUC basis), respectively. - Animal Toxicology and/or Pharmacology - The B2 receptor has been implicated in the cardioprotective effects of bradykinin and antagonism of this receptor could potentially have negative cardiovascular effects during reperfusion after acute ischemia. Icatibant decreased coronary blood flow in the isolated guinea pig heart and aggravated the duration of post-ischemic reperfusion arrhythmias in the isolated rat heart. Intracoronary infusion of icatibant in an anesthetized myocardial infarction dog model increased mortality rate 2-fold over saline ischemia. There is limited human experience in acute ischemia. FIRAZYR should be used during acute coronary ischemia, unstable angina pectoris, or in the weeks following a stroke only if the benefit exceeds the theoretical risk to the patient. # Clinical Studies - The efficacy and safety of FIRAZYR for the treatment of acute attacks of HAE in adults were studied in three controlled clinical trials. Among the 223 patients in these studies, the mean age was 38 years, 64% were female, and 95% were white. Approximately 57% of patients reported use of attenuated androgens, antifibrinolytic agents, or C1 inhibitors. Response to therapy was primarily assessed using visual analog scores on a 100 mm scale and patient- and physician-reported symptom scores for abdominal and cutaneous pain and swelling. - Trial 1 was a randomized, placebo-controlled, double-blind, parallel-group study of 98 adult patients with a median age of 36 years. Patients who had developed moderate to severe cutaneous or abdominal or mild to moderate laryngeal attacks of HAE were randomized to receive either FIRAZYR 30 mg or placebo by subcutaneous injection. Patients with severe laryngeal attacks of HAE received open-label FIRAZYR 30 mg. The primary endpoint was assessed using a 3-item composite visual analog score (VAS), comprised of averaged assessments of skin swelling, skin pain, and abdominal pain. Response was defined as at least a 50% reduction from the pretreatment composite 3-itemVAS score (Figure 2). The median time to 50% reduction in symptoms for patients with cutaneous or abdominal attacks treated with FIRAZYR (n=43) compared to placebo (n=45) was 2.0 hours [95% CI 1.5, 3.0] versus 19.8 hours [95% CI 6.1, 26.3], respectively (p<0.001). - Other evaluated endpoints included time to almost complete symptom relief (VAS<10 mm) and rescue medication use. In Trial 1, the median times to almost complete symptom relief were 8.0 versus 36.0 hours for FIRAZYR and placebo, respectively. In terms of rescue medication use, 3/43 (7%) patients treated with FIRAZYR used additional rescue medication in comparison to 18/45 (40%) patients treated with placebo. - In a second placebo-controlled trial and an active-controlled trial, a total of 26 and 35 patients, respectively, received FIRAZYR 30 mg for the treatment of an acute HAE attack. Across the three trials, FIRAZYR had a median time to 50% reduction from baseline symptoms ranging from 2.0 to 2.3 hours. - Recurrent attacks - In all three controlled trials, patients were eligible for treatment of subsequent attacks in an open-label extension. Patients were treated with FIRAZYR 30 mg and could receive up to 3 doses of FIRAZYR 30 mg administered at least 6 hours apart for each attack. A total of 225 patients were treated with 1,076 doses of 30 mg FIRAZYR for 987 attacks of acute HAE in these trials. In an assessment of the first 5 FIRAZYR-treated attacks (621 doses for 582 attacks), the median times to a 50% reduction from the pretreatment composite 3-itemVAS score were similar across attacks (2.0, 2.0, 2.4, 2.0, 1.5 hours). The majority (93%) of these attacks of HAE were treated with a single dose of FIRAZYR. - Laryngeal attacks - A total of 60 patients with laryngeal attacks were treated with FIRAZYR in the controlled trials. Efficacy results were similar to those observed for non-laryngeal (cutaneous and abdominal) sites of attack. - Self-administration - Self-administration of FIRAZYR by 56 patients was assessed in an open label trial. Patients who administered FIRAZYR during an acute attack of HAE had a median time to 50% reduction from the pretreatment composite 3-itemVAS score of 2.6 hours. # How Supplied - FIRAZYR is supplied as a single-use, prefilled syringe for subcutaneous administration. Each syringe delivers 3 mL of a sterile solution of icatibant 30 mg (as icatibant acetate). Each glass syringe has a bromobutyl plunger stopper, which is not made of latex natural rubber. - FIRAZYR is available in cartons containing one single-use, prefilled syringe and one 25 G Luer lock needle. NDC 54092-702-02. - FIRAZYR is also available in a pack containing 3 cartons; each carton contains one single-use, prefilled syringe and one 25 G Luer lock needle. NDC 54092-702-03. - Storage and Handling - Keep out of the reach of children. - Store between 2 - 25° C (36 - 77° F). - Do not freeze. - Store in carton until time of administration. ## Storage There is limited information regarding Icatibant Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients may self-administer FIRAZYR upon recognition of an HAE attack after training under the guidance of a healthcare professional. - Patients with laryngeal symptoms should seek medical attention immediately in an appropriate healthcare facility after administration of FIRAZYR. - Injection site reactions are reported in most patients after administration of FIRAZYR. Other adverse reactions reported after administration of FIRAZYR include pyrexia, increase in transaminases, dizziness, and rash. - Tiredness, drowsiness, and dizziness have been reported following the use of FIRAZYR. Patients should be advised not to drive or use machinery if they feel tired or dizzy. # Precautions with Alcohol - Alcohol-Icatibant interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - FIRAZYR®[1] # Look-Alike Drug Names There is limited information regarding Icatibant Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Icatibant
3ac652354e2c0956176a12df8fac3f747100d626	wikidoc	Icosapent	Icosapent # 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 Icosapent is an antihyperlipidemic that is FDA approved for the treatment of adult patients with severe (≥500 mg/dL) hypertriglyceridemia.. Common adverse reactions include arthralgia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Icosapent ethyl® (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia. - Patients should be placed on an appropriate lipid-lowering diet and exercise regimen before receiving icosapent ethyl and should continue this diet and exercise regimen with icosapent ethyl. - Attempts should be made to control any medical problems such as diabetes mellitus, hypothyroidism, and alcohol intake that may contribute to lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (such as beta blockers, thiazides, estrogens) should be discontinued or changed, if possible, prior to consideration of TG-lowering drug therapy. - The effect of icosapent ethyl on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined. - The effect of icosapent ethyl on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined. - Assess lipid levels before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, or medications) of high triglyceride levels and manage as appropriate. - Patients should engage in appropriate nutritional intake and physical activity before receiving icosapent ethyl, which should continue during treatment with icosapent ethyl. - The daily dose of icosapent ethyl is 4 grams per day taken as 2 capsules twice daily with food. - Patients should be advised to swallow icosapent ethyl capsules whole. Do not break open, crush, dissolve, or chew icosapent ethyl. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Icosapent in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Icosapent in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Icosapent in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Icosapent in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Icosapent in pediatric patients. # Contraindications - icosapent ethyl is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to icosapent ethyl or any of its components. # Warnings - icosapent ethyl contains ethyl esters of the omega-3 fatty acid, eicosapentaenoic acid (EPA), obtained from the oil of fish. It is not known whether patients with allergies to fish and/or shellfish are at increased risk of an allergic reaction to icosapent ethyl. icosapent ethyl should be used with caution in patients with known hypersensitivity to fish and/or shellfish. # 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. - Adverse reactions reported in at least 2% and at a greater rate than placebo for patients treated with icosapent ethyl based on pooled data across two clinical studies are listed in Table 1. - An additional adverse reaction from clinical studies was Oropharyngeal pain. Atrial fibrillation. In the REDUCT-IT trial, atrial fibrillation occurred in 5.3% while occurred in 3.9% of the placebo group. This may be dose related. The REDUCE-IT trial used the highest does of 4 grams per day. A trend towards increased bleeding. - Oropharyngeal pain. - Atrial fibrillation. In the REDUCT-IT trial, atrial fibrillation occurred in 5.3% while occurred in 3.9% of the placebo group. This may be dose related. The REDUCE-IT trial used the highest does of 4 grams per day. - A trend towards increased bleeding. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Icosapent in the drug label. # Drug Interactions - Some published studies with omega-3 fatty acids have demonstrated prolongation of bleeding time. The prolongation of bleeding time reported in those studies has not exceeded normal limits and did not produce clinically significant bleeding episodes. Patients receiving treatment with icosapent ethyl and other drugs affecting coagulation (e.g., anti-platelet agents) should be monitored periodically. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. It is unknown whether icosapent ethyl can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. icosapent ethyl should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus. - In pregnant rats given oral gavage doses of 0.3, 1 and 2 g/kg/day icosapent ethyl from gestation through organogenesis all drug treated groups had visceral or skeletal abnormalities including: 13threduced ribs, additional liver lobes, testes medially displaced and/or not descended at human systemic exposures following a maximum oral dose of 4 g/day based on body surface comparisons. Variations including incomplete or abnormal ossification of various skeletal bones were observed in the 2 g/kg/day group at 5 times human systemic exposure following an oral dose of 4 g/day based on body surface area comparison. - In a multigenerational developmental study in pregnant rats given oral gavage doses of 0.3, 1, 3 g/kg/day ethyl-EPA from gestation day 7-17, an increased incidence of absent optic nerves and unilateral testes atrophy were observed at ≥0.3 g/kg/day at human systemic exposure following an oral dose of 4 g/day based on body surface area comparisons across species. Additional variations consisting of early incisor eruption and increased percent cervical ribs were observed at the same exposures. Pups from high dose treated dams exhibited decreased copulation rates, delayed estrus, decreased implantations and decreased surviving fetuses (F2) suggesting multigenerational effects of ethyl-EPA at 7 times human systemic exposure following 4 g/day dose based on body surface area comparisons across species. - In pregnant rabbits given oral gavage doses of 0.1, 0.3, and 1 g/kg/day from gestation through organogenesis there were increased dead fetuses at 1 g/kg/day secondary to maternal toxicity (significantly decreased food consumption and body weight loss). - In pregnant rats given ethyl-EPA from gestation day 17 through lactation day 20 at 0.3, 1, 3 g/kg/day complete litter loss was observed in 2/23 litters at the low dose and 1/23 mid-dose dams by post-natal day 4 at human exposures based on a maximum dose of 4 g/day comparing body surface areas across species. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Icosapent in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Icosapent during labor and delivery. ### Nursing Mothers - Studies with omega-3-acid ethyl esters have demonstrated excretion in human milk. The effect of this excretion on the infant of a nursing mother is unknown; caution should be exercised when icosapent ethyl is administered to a nursing mother. An animal study in lactating rats given oral gavage 14C-ethyl EPA demonstrated that drug levels were 6 to 14 times higher in milk than in plasma. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Of the total number of subjects in clinical studies of icosapent ethyl, 33% were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Icosapent with respect to specific gender populations. ### Race There is no FDA guidance on the use of Icosapent with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Icosapent in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Icosapent in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Icosapent in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Icosapent in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - In patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored periodically during therapy with icosapent ethyl. # IV Compatibility There is limited information regarding IV Compatibility of Icosapent in the drug label. # Overdosage There is limited information regarding Icosapent overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology There is limited information regarding Icosapent Pharmacology in the drug label. ## Mechanism of Action - Studies suggest that EPA reduces hepatic very low-density lipoprotein triglycerides (VLDL-TG) synthesis and/or secretion and enhances TG clearance from circulating VLDL particles. Potential mechanisms of action include increased β-oxidation; inhibition of acyl-CoA:1,2-diacylglycerol acyltransferase (DGAT); decreased lipogenesis in the liver; and increased plasma lipoprotein lipase activity. ## Structure - icosapent ethyl, a lipid-regulating agent, is supplied as a 1-gram amber-colored, liquid-filled soft gelatin capsule for oral administration. - Each icosapent ethyl capsule contains 1 gram of icosapent ethyl. Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). The empirical formula of icosapent ethyl is C22H34O2and the molecular weight is 330.51. The chemical name for icosapent ethyl is ethyl all-cis-5,8,11,14,17-icosapentaenoate with the following chemical structure: - icosapent ethyl 1-gram capsules also contain the following inactive ingredients: tocopherol, gelatin, glycerin, maltitol, sorbitol, and purified water. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Icosapent in the drug label. ## Pharmacokinetics - absorption: After oral administration, icosapent ethyl is de-esterified during the absorption process and the active metabolite EPA is absorbed in the small intestine and enters the systemic circulation mainly via the thoracic duct lymphatic system. Peak plasma concentrations of EPA were reached approximately 5 hours following oral doses of icosapent ethyl. - icosapent ethyl was administered with or following a meal in all clinical studies; no food effect studies were performed. Take icosapent ethyl with or following a meal. - Distribution: The mean volume of distribution at steady-state of EPA is approximately 88 liters. The majority of EPA circulating in plasma is incorporated in phospholipids, triglycerides and cholesteryl esters, and <1% is present as the unesterified fatty acid. Greater than 99% of unesterified EPA is bound to plasma proteins. - Metabolism and Excretion: EPA is mainly metabolized by the liver via beta-oxidation similar to dietary fatty acids. Beta oxidation splits the long carbon chain of EPA into acetyl Coenzyme A, which is converted into energy via the Krebs cycle. Cytochrome P450-mediated metabolism is a minor pathway of elimination of EPA. The total plasma clearance of EPA at steady state is 684 mL/hr. The plasma elimination half-life (t1/2) of EPA is approximately 89 hours. icosapent ethyl does not undergo renal excretion. - icosapent ethyl was studied at the 4 g/day dose level with the following medications which are typical substrates of cytochrome P450 enzymes, and no drug-drug interactions were observed: - Omeprazole: In a drug-drug interaction study with 28 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the steady-state AUCτ or Cmax of omeprazole when co-administered at 40 mg/day to steady-state. - Rosiglitazone: In a drug-drug interaction study with 28 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the single dose AUC or Cmax of rosiglitazone at 8 mg. - Warfarin: In a drug-drug interaction study with 25 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the single dose AUC or Cmax of R- and S-warfarin or the anti-coagulation pharmacodynamics of warfarin when co-administered as racemic warfarin at 25 mg. - Atorvastatin: In a drug-drug interaction study of 26 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the steady-state AUCτ or Cmax of atorvastatin, 2-hydroxyatorvastatin, or 4-hydroxyatorvastatin when co-administered with atorvastatin 80 mg/day to steady-state. - Gender: When administered icosapent ethyl in clinical trials, plasma total EPA concentrations did not differ significantly between men and women. - Pediatric: The pharmacokinetics of icosapent ethyl has not been studied in pediatric patients. - Hepatic or Renal Impairment: icosapent ethyl has not been studied in patients with renal or hepatic impairment. ## Nonclinical Toxicology - In a 2-year rat carcinogenicity study with oral gavage doses of 0.09, 0.27, and 0.91 g/kg/day icosapent ethyl, respectively, males did not exhibit drug-related neoplasms. Hemangiomas and hemangiosarcomas of the mesenteric lymph node, the site of drug absorption, were observed in females at clinically relevant exposures based on body surface area comparisons across species relative to the maximum clinical dose of 4 g/day. Overall incidence of hemangiomas and hemangiosarcomas in all vascular tissues did not increase with treatment. - In a 6-month carcinogenicity study in Tg.rasH2 transgenic mice with oral gavage doses of 0.5, 1, 2, and 4.6 g/kg/day icosapent ethyl, drug-related incidences of benign squamous cell papilloma in the skin and subcutis of the tail was observed in high dose male mice. The papillomas were considered to develop secondary to chronic irritation of the proximal tail associated with fecal excretion of oil and therefore not clinically relevant. Drug-related neoplasms were not observed in female mice. - Icosapent ethyl was not mutagenic with or without metabolic activation in the bacterial mutagenesis (Ames) assay or in the in vivo mouse micronucleus assay. A chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells was positive for clastogenicity with and without metabolic activation. - In an oral gavage rat fertility study, ethyl-EPA, administered at doses of 0.3, 1, and 3 g/kg/day to male rats for 9 weeks before mating and to female rats for 14 days before mating through day 7 of gestation, increased anogenital distance in female pups and increased cervical ribs were observed at 3 g/kg/day (7 times human systemic exposure with 4 g/day clinical dose based on a body surface area comparison). # Clinical Studies - The effects of icosapent ethyl 4 grams per day were assessed in a randomized, placebo-controlled, double-blind, parallel-group study of adult patients (76 on icosapent ethyl, 75 on placebo) with severe hypertriglyceridemia. Patients whose baseline TG levels were between 500 and 2,000 mg/dL were enrolled in this study for 12 weeks. The median baseline TG and LDL-C levels in these patients were 684 mg/dL and 86 mg/dL, respectively. Median baseline HDL-C level was 27 mg/dL. The randomized population in this study was mostly Caucasian (88%) and male (76%). The mean age was 53 years and the mean body mass index was 31 kg/m2. Twenty-five percent of patients were on concomitant statin therapy, 28% were diabetics, and 39% of the patients had TG levels >750 mg/dL. - The changes in the major lipoprotein lipid parameters for the groups receiving icosapent ethyl or placebo are shown in Table 2. - icosapent ethyl 4 grams per day reduced median TG, VLDL-C, and Apo B levels from baseline relative to placebo. The reduction in TG observed with icosapent ethyl was not associated with elevations in LDL-C levels relative to placebo. - The effect of icosapent ethyl on the risk of pancreatitis in patients with severe hypertriglyceridemia has not been determined. - The effect of icosapent ethyl on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia levels has not been determined. # How Supplied - icosapent ethyl (icosapent ethyl) capsules are supplied as 1-gram amber-colored soft-gelatin capsules imprinted with icosapent ethyl. - Bottles of 120: NDC 52937-001-20. - Store at 20° to 25° C (68° to 77°F); excursions permitted to 15° to 30° C (59° to 86°F) . Keep out of reach of children. ## Storage There is limited information regarding Icosapent Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - icosapent ethyl should be used with caution in patients with known sensitivity or allergy to fish and/or shellfish . - Patients should be advised that use of lipid-regulating agents does not reduce the importance of appropriate nutritional intake and physical activity . - Patients should be advised not to alter icosapent ethyl capsules in any way and to ingest intact capsules only. - Instruct patients to take icosapent ethyl as prescribed. If a dose is missed, patients should take it as soon as they remember. However if they miss one day of icosapent ethyl, they should not double the dose when they take it. # Precautions with Alcohol - Alcohol-Icosapent interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names # Look-Alike Drug Names There is limited information regarding Icosapent Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Icosapent Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, 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 Icosapent is an antihyperlipidemic that is FDA approved for the treatment of adult patients with severe (≥500 mg/dL) hypertriglyceridemia.. Common adverse reactions include arthralgia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Icosapent ethyl® (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia. - Patients should be placed on an appropriate lipid-lowering diet and exercise regimen before receiving icosapent ethyl and should continue this diet and exercise regimen with icosapent ethyl. - Attempts should be made to control any medical problems such as diabetes mellitus, hypothyroidism, and alcohol intake that may contribute to lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (such as beta blockers, thiazides, estrogens) should be discontinued or changed, if possible, prior to consideration of TG-lowering drug therapy. - The effect of icosapent ethyl on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined. - The effect of icosapent ethyl on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined. - Assess lipid levels before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, or medications) of high triglyceride levels and manage as appropriate. - Patients should engage in appropriate nutritional intake and physical activity before receiving icosapent ethyl, which should continue during treatment with icosapent ethyl. - The daily dose of icosapent ethyl is 4 grams per day taken as 2 capsules twice daily with food. - Patients should be advised to swallow icosapent ethyl capsules whole. Do not break open, crush, dissolve, or chew icosapent ethyl. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Icosapent in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Icosapent in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Icosapent in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Icosapent in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Icosapent in pediatric patients. # Contraindications - icosapent ethyl is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to icosapent ethyl or any of its components. # Warnings - icosapent ethyl contains ethyl esters of the omega-3 fatty acid, eicosapentaenoic acid (EPA), obtained from the oil of fish. It is not known whether patients with allergies to fish and/or shellfish are at increased risk of an allergic reaction to icosapent ethyl. icosapent ethyl should be used with caution in patients with known hypersensitivity to fish and/or shellfish. # 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. - Adverse reactions reported in at least 2% and at a greater rate than placebo for patients treated with icosapent ethyl based on pooled data across two clinical studies are listed in Table 1. - An additional adverse reaction from clinical studies was Oropharyngeal pain. Atrial fibrillation[1]. In the REDUCT-IT trial, atrial fibrillation occurred in 5.3% while occurred in 3.9% of the placebo group. This may be dose related[2][2]. The REDUCE-IT trial used the highest does of 4 grams per day. A trend towards increased bleeding[1]. - Oropharyngeal pain. - Atrial fibrillation[1]. In the REDUCT-IT trial, atrial fibrillation occurred in 5.3% while occurred in 3.9% of the placebo group. This may be dose related[2][2]. The REDUCE-IT trial used the highest does of 4 grams per day. - A trend towards increased bleeding[1]. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Icosapent in the drug label. # Drug Interactions - Some published studies with omega-3 fatty acids have demonstrated prolongation of bleeding time. The prolongation of bleeding time reported in those studies has not exceeded normal limits and did not produce clinically significant bleeding episodes. Patients receiving treatment with icosapent ethyl and other drugs affecting coagulation (e.g., anti-platelet agents) should be monitored periodically. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. It is unknown whether icosapent ethyl can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. icosapent ethyl should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus. - In pregnant rats given oral gavage doses of 0.3, 1 and 2 g/kg/day icosapent ethyl from gestation through organogenesis all drug treated groups had visceral or skeletal abnormalities including: 13threduced ribs, additional liver lobes, testes medially displaced and/or not descended at human systemic exposures following a maximum oral dose of 4 g/day based on body surface comparisons. Variations including incomplete or abnormal ossification of various skeletal bones were observed in the 2 g/kg/day group at 5 times human systemic exposure following an oral dose of 4 g/day based on body surface area comparison. - In a multigenerational developmental study in pregnant rats given oral gavage doses of 0.3, 1, 3 g/kg/day ethyl-EPA from gestation day 7-17, an increased incidence of absent optic nerves and unilateral testes atrophy were observed at ≥0.3 g/kg/day at human systemic exposure following an oral dose of 4 g/day based on body surface area comparisons across species. Additional variations consisting of early incisor eruption and increased percent cervical ribs were observed at the same exposures. Pups from high dose treated dams exhibited decreased copulation rates, delayed estrus, decreased implantations and decreased surviving fetuses (F2) suggesting multigenerational effects of ethyl-EPA at 7 times human systemic exposure following 4 g/day dose based on body surface area comparisons across species. - In pregnant rabbits given oral gavage doses of 0.1, 0.3, and 1 g/kg/day from gestation through organogenesis there were increased dead fetuses at 1 g/kg/day secondary to maternal toxicity (significantly decreased food consumption and body weight loss). - In pregnant rats given ethyl-EPA from gestation day 17 through lactation day 20 at 0.3, 1, 3 g/kg/day complete litter loss was observed in 2/23 litters at the low dose and 1/23 mid-dose dams by post-natal day 4 at human exposures based on a maximum dose of 4 g/day comparing body surface areas across species. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Icosapent in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Icosapent during labor and delivery. ### Nursing Mothers - Studies with omega-3-acid ethyl esters have demonstrated excretion in human milk. The effect of this excretion on the infant of a nursing mother is unknown; caution should be exercised when icosapent ethyl is administered to a nursing mother. An animal study in lactating rats given oral gavage 14C-ethyl EPA demonstrated that drug levels were 6 to 14 times higher in milk than in plasma. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Of the total number of subjects in clinical studies of icosapent ethyl, 33% were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Icosapent with respect to specific gender populations. ### Race There is no FDA guidance on the use of Icosapent with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Icosapent in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Icosapent in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Icosapent in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Icosapent in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - In patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored periodically during therapy with icosapent ethyl. # IV Compatibility There is limited information regarding IV Compatibility of Icosapent in the drug label. # Overdosage There is limited information regarding Icosapent overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology There is limited information regarding Icosapent Pharmacology in the drug label. ## Mechanism of Action - Studies suggest that EPA reduces hepatic very low-density lipoprotein triglycerides (VLDL-TG) synthesis and/or secretion and enhances TG clearance from circulating VLDL particles. Potential mechanisms of action include increased β-oxidation; inhibition of acyl-CoA:1,2-diacylglycerol acyltransferase (DGAT); decreased lipogenesis in the liver; and increased plasma lipoprotein lipase activity. ## Structure - icosapent ethyl, a lipid-regulating agent, is supplied as a 1-gram amber-colored, liquid-filled soft gelatin capsule for oral administration. - Each icosapent ethyl capsule contains 1 gram of icosapent ethyl. Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). The empirical formula of icosapent ethyl is C22H34O2and the molecular weight is 330.51. The chemical name for icosapent ethyl is ethyl all-cis-5,8,11,14,17-icosapentaenoate with the following chemical structure: - icosapent ethyl 1-gram capsules also contain the following inactive ingredients: tocopherol, gelatin, glycerin, maltitol, sorbitol, and purified water. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Icosapent in the drug label. ## Pharmacokinetics - absorption: After oral administration, icosapent ethyl is de-esterified during the absorption process and the active metabolite EPA is absorbed in the small intestine and enters the systemic circulation mainly via the thoracic duct lymphatic system. Peak plasma concentrations of EPA were reached approximately 5 hours following oral doses of icosapent ethyl. - icosapent ethyl was administered with or following a meal in all clinical studies; no food effect studies were performed. Take icosapent ethyl with or following a meal. - Distribution: The mean volume of distribution at steady-state of EPA is approximately 88 liters. The majority of EPA circulating in plasma is incorporated in phospholipids, triglycerides and cholesteryl esters, and <1% is present as the unesterified fatty acid. Greater than 99% of unesterified EPA is bound to plasma proteins. - Metabolism and Excretion: EPA is mainly metabolized by the liver via beta-oxidation similar to dietary fatty acids. Beta oxidation splits the long carbon chain of EPA into acetyl Coenzyme A, which is converted into energy via the Krebs cycle. Cytochrome P450-mediated metabolism is a minor pathway of elimination of EPA. The total plasma clearance of EPA at steady state is 684 mL/hr. The plasma elimination half-life (t1/2) of EPA is approximately 89 hours. icosapent ethyl does not undergo renal excretion. - icosapent ethyl was studied at the 4 g/day dose level with the following medications which are typical substrates of cytochrome P450 enzymes, and no drug-drug interactions were observed: - Omeprazole: In a drug-drug interaction study with 28 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the steady-state AUCτ or Cmax of omeprazole when co-administered at 40 mg/day to steady-state. - Rosiglitazone: In a drug-drug interaction study with 28 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the single dose AUC or Cmax of rosiglitazone at 8 mg. - Warfarin: In a drug-drug interaction study with 25 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the single dose AUC or Cmax of R- and S-warfarin or the anti-coagulation pharmacodynamics of warfarin when co-administered as racemic warfarin at 25 mg. - Atorvastatin: In a drug-drug interaction study of 26 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the steady-state AUCτ or Cmax of atorvastatin, 2-hydroxyatorvastatin, or 4-hydroxyatorvastatin when co-administered with atorvastatin 80 mg/day to steady-state. - Gender: When administered icosapent ethyl in clinical trials, plasma total EPA concentrations did not differ significantly between men and women. - Pediatric: The pharmacokinetics of icosapent ethyl has not been studied in pediatric patients. - Hepatic or Renal Impairment: icosapent ethyl has not been studied in patients with renal or hepatic impairment. ## Nonclinical Toxicology - In a 2-year rat carcinogenicity study with oral gavage doses of 0.09, 0.27, and 0.91 g/kg/day icosapent ethyl, respectively, males did not exhibit drug-related neoplasms. Hemangiomas and hemangiosarcomas of the mesenteric lymph node, the site of drug absorption, were observed in females at clinically relevant exposures based on body surface area comparisons across species relative to the maximum clinical dose of 4 g/day. Overall incidence of hemangiomas and hemangiosarcomas in all vascular tissues did not increase with treatment. - In a 6-month carcinogenicity study in Tg.rasH2 transgenic mice with oral gavage doses of 0.5, 1, 2, and 4.6 g/kg/day icosapent ethyl, drug-related incidences of benign squamous cell papilloma in the skin and subcutis of the tail was observed in high dose male mice. The papillomas were considered to develop secondary to chronic irritation of the proximal tail associated with fecal excretion of oil and therefore not clinically relevant. Drug-related neoplasms were not observed in female mice. - Icosapent ethyl was not mutagenic with or without metabolic activation in the bacterial mutagenesis (Ames) assay or in the in vivo mouse micronucleus assay. A chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells was positive for clastogenicity with and without metabolic activation. - In an oral gavage rat fertility study, ethyl-EPA, administered at doses of 0.3, 1, and 3 g/kg/day to male rats for 9 weeks before mating and to female rats for 14 days before mating through day 7 of gestation, increased anogenital distance in female pups and increased cervical ribs were observed at 3 g/kg/day (7 times human systemic exposure with 4 g/day clinical dose based on a body surface area comparison). # Clinical Studies - The effects of icosapent ethyl 4 grams per day were assessed in a randomized, placebo-controlled, double-blind, parallel-group study of adult patients (76 on icosapent ethyl, 75 on placebo) with severe hypertriglyceridemia. Patients whose baseline TG levels were between 500 and 2,000 mg/dL were enrolled in this study for 12 weeks. The median baseline TG and LDL-C levels in these patients were 684 mg/dL and 86 mg/dL, respectively. Median baseline HDL-C level was 27 mg/dL. The randomized population in this study was mostly Caucasian (88%) and male (76%). The mean age was 53 years and the mean body mass index was 31 kg/m2. Twenty-five percent of patients were on concomitant statin therapy, 28% were diabetics, and 39% of the patients had TG levels >750 mg/dL. - The changes in the major lipoprotein lipid parameters for the groups receiving icosapent ethyl or placebo are shown in Table 2. - icosapent ethyl 4 grams per day reduced median TG, VLDL-C, and Apo B levels from baseline relative to placebo. The reduction in TG observed with icosapent ethyl was not associated with elevations in LDL-C levels relative to placebo. - The effect of icosapent ethyl on the risk of pancreatitis in patients with severe hypertriglyceridemia has not been determined. - The effect of icosapent ethyl on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia levels has not been determined. # How Supplied - icosapent ethyl (icosapent ethyl) capsules are supplied as 1-gram amber-colored soft-gelatin capsules imprinted with icosapent ethyl. - Bottles of 120: NDC 52937-001-20. - Store at 20° to 25° C (68° to 77°F); excursions permitted to 15° to 30° C (59° to 86°F) [see USP Controlled Room Temperature]. Keep out of reach of children. ## Storage There is limited information regarding Icosapent Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - icosapent ethyl should be used with caution in patients with known sensitivity or allergy to fish and/or shellfish . - Patients should be advised that use of lipid-regulating agents does not reduce the importance of appropriate nutritional intake and physical activity [see DOSAGE AND ADMINISTRATION (2)]. - Patients should be advised not to alter icosapent ethyl capsules in any way and to ingest intact capsules only[see DOSAGE AND ADMINISTRATION (2)]. - Instruct patients to take icosapent ethyl as prescribed. If a dose is missed, patients should take it as soon as they remember. However if they miss one day of icosapent ethyl, they should not double the dose when they take it. # Precautions with Alcohol - Alcohol-Icosapent interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ®[3] # Look-Alike Drug Names There is limited information regarding Icosapent Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Icosapent
6f6c32032a01a90f2dae5ccb9101d61ced72b26a	wikidoc	Ida Bauer	Ida Bauer Ida Bauer (1882–1945) was a hysterical patient of Sigmund Freud. He wrote a famous case study about her using the pseudonym 'Dora' This Study is published in "Fragments of an Analysis of a Case of Hysteria" (1905 , Standard Edition Vol.7, pp1-122.) Bauer's most manifested hysterical symptom was aphonia (loss of voice). 'Dora' remains one of Freud's most famous cases, and is often discussed in feminist circles because of Freud's comments in relation to this case, especially comments like This was surely just the situation to call up destinct feelings of sexual excitement in a girl of fourteen in reference to Dora being kissed by a 'young man of preposessing appearance' (S.E. 7. pp28) implying the passivity of female sexuality and his statement I should without question consider a person hysterical in whom an occasion for sexual excitement elicited feelings that were preponderantly or exclusively unpleasurable (ibid) After only 11 weeks of therapy, she broke off her therapy much to Freud's disappointment. Freud saw this as his failure as an analyst and decided the whole treatment had failed. After some time, Ida returned to see Freud and explained how her symptoms had mostly cleared. Freud had been the only person to believe her in regards to the situations with 'Herr K' and her father and after the analysis, she had chosen to confront her tormentors (her father, his lover and his lover's husband). When confronted, her tormentors confessed that she had been right all along and following this, most of her symptoms had cleared. Though Freud was disappointed with the initial results of the case, he considered it important, as it raised his awareness of the phenomenon of transference, which he blamed for his seeming failures in the case. Freud gave her the name 'Dora' after a maid working in the Freud house by the same name. Ida's brother Otto Bauer was a leading member of the Austromarxism movement. # Criticism of Freud's account of the case “We now understand Dora as a classic case of malpractice. Her father, though evincing of late stages of syphillis, had for some years been carrying on an affair with an attractive woman, identified as Frau K. Ida Bauer was fond of Frau K. She had long known of the affair. Herr K was a friend of the Buaers, and often gave Ida presents. His sexual interest in the girl was evident; she remembered with revulsion the time, when she was fourteen, that he forced a kiss on her. When she was 16, Herr K, during a country walk, made a sexual advance to which she reacted with disgust, slapping him and running away. She reported the incident to her father, who confronted Herr K, who denied it altogether. She insisted repeatedly that they break off relations with the Ks. Her father took Herr Ks side, and went on with the affair. She developed signs and symptoms including weeks-long attacks of coughing, a vaginal discharge, instances of bed wetting and thoughts of suicide. Her father sent her to Freud to be cured of these and of her rebelliousness. She went to Freud altogether against her will. Treatment was stormy and lasted only 3 months. None the less, in that time, Freud was able boldly to interpret several of Ida Bauer’s dreams and to elaborate a diagnosis. Briefly: He insisted to her that she was unconsciously in love with Herr K. Her bed-wetting and vaginal discharge he regarded as proof that she had been a masturbator—which he believed an unhealthy practice—although she denied it. The disgust she reported at the forced kiss masked the fact that she had actually been sexually excited by it—which Freud thought was the only healthy response of a pubescent girl. The urgency of her insistence that they break with the Ks masked the fact that she was in homosexual love with her mother as well as with Frau K as a mother surrogate, and jealous of her father’s affair." # Literature - Charles Bernheimer, Claire Kahane, In Dora's Case: Freud-Hysteria-Feminism: Freud, Hysteria, Feminism, Second Edition, Columbia University Press, 1990 - Hannah S. Decker, Freud, Dora, and Vienna 1900, The Free Press, 1991 - Robin Tolmach Lakoff, James C. Coyne, Father Knows Best: The Use and Abuse of Power in Freud's Case of Dora, Teachers' College Press, 1993 - Patrick Mahoney, Freud's Dora: A Psychoanalytic, Historical, and Textual Study, Yale University Press 1996, ISBN 0300066228	Ida Bauer Ida Bauer (1882–1945) was a hysterical patient of Sigmund Freud. He wrote a famous case study about her using the pseudonym 'Dora' This Study is published in "Fragments of an Analysis of a Case of Hysteria" (1905 [1901], Standard Edition Vol.7, pp1-122.) Bauer's most manifested hysterical symptom was aphonia (loss of voice). 'Dora' remains one of Freud's most famous cases, and is often discussed in feminist circles because of Freud's comments in relation to this case, especially comments like This was surely just the situation to call up destinct feelings of sexual excitement in a girl of fourteen in reference to Dora being kissed by a 'young man of preposessing appearance' (S.E. 7. pp28) implying the passivity of female sexuality and his statement I should without question consider a person hysterical in whom an occasion for sexual excitement elicited feelings that were preponderantly or exclusively unpleasurable (ibid) After only 11 weeks of therapy, she broke off her therapy much to Freud's disappointment. Freud saw this as his failure as an analyst and decided the whole treatment had failed. After some time, Ida returned to see Freud and explained how her symptoms had mostly cleared. Freud had been the only person to believe her in regards to the situations with 'Herr K' and her father and after the analysis, she had chosen to confront her tormentors (her father, his lover and his lover's husband). When confronted, her tormentors confessed that she had been right all along and following this, most of her symptoms had cleared. Though Freud was disappointed with the initial results of the case, he considered it important, as it raised his awareness of the phenomenon of transference, which he blamed for his seeming failures in the case. Freud gave her the name 'Dora' after a maid working in the Freud house by the same name. Ida's brother Otto Bauer was a leading member of the Austromarxism movement. # Criticism of Freud's account of the case “We now understand Dora as a classic case of malpractice. Her father, though evincing of late stages of syphillis, had for some years been carrying on an affair with an attractive woman, identified as Frau K. Ida Bauer was fond of Frau K. She had long known of the affair. Herr K was a friend of the Buaers, and often gave Ida presents. His sexual interest in the girl was evident; she remembered with revulsion the time, when she was fourteen, that he forced a kiss on her. When she was 16, Herr K, during a country walk, made a sexual advance to which she reacted with disgust, slapping him and running away. She reported the incident to her father, who confronted Herr K, who denied it altogether. She insisted repeatedly that they break off relations with the Ks. Her father took Herr Ks side, and went on with the affair. She developed signs and symptoms including weeks-long attacks of coughing, a vaginal discharge, instances of bed wetting and thoughts of suicide. Her father sent her to Freud to be cured of these and of her rebelliousness. She went to Freud altogether against her will. Treatment was stormy and lasted only 3 months. None the less, in that time, Freud was able boldly to interpret several of Ida Bauer’s dreams and to elaborate a diagnosis. Briefly: He insisted to her that she was unconsciously in love with Herr K. Her bed-wetting and vaginal discharge he regarded as proof that she had been a masturbator—which he believed an unhealthy practice—although she denied it. The disgust she reported at the forced kiss masked the fact that she had actually been sexually excited by it—which Freud thought was the only healthy response of a pubescent girl. The urgency of her insistence that they break with the Ks masked the fact that she was in homosexual love with her mother as well as with Frau K as a mother surrogate, and jealous of her father’s affair." [[1]] # Literature - Charles Bernheimer, Claire Kahane, In Dora's Case: Freud-Hysteria-Feminism: Freud, Hysteria, Feminism, Second Edition, Columbia University Press, 1990 - Hannah S. Decker, Freud, Dora, and Vienna 1900, The Free Press, 1991 - Robin Tolmach Lakoff, James C. Coyne, Father Knows Best: The Use and Abuse of Power in Freud's Case of Dora, Teachers' College Press, 1993 - Patrick Mahoney, Freud's Dora: A Psychoanalytic, Historical, and Textual Study, Yale University Press 1996, ISBN 0300066228	https://www.wikidoc.org/index.php/Ida_Bauer
38982bf01bde55514bef86b67fd2db12e9be84a2	wikidoc	Ideal gas	Ideal gas # Overview An ideal gas or perfect gas is a hypothetical gas consisting of identical particles of zero volume, with no intermolecular forces, where the constituent atoms or molecules undergo perfectly elastic collisions with the walls of the container and each other and are in constant random motion. Real gases do not behave according to these exact properties, although the approximation is often good enough to describe real gases. These four properties that constitute an ideal gas can be easily remembered by the acronym PRIE, which stands for; - Point masses (molecules occupy no volume) - Random Motion (molecules are in constant random motion) - Intermolecular forces (there are NO intermolecular forces between the particles) - Elastic collisions (the collisions involving the gas molecules are totally elastic) The concept of ideal gas is useful in technology because one mole (6.02214 Template:E particles) of an ideal gas has a volume of 22.4 liters at the standard conditions for temperature and pressure and many common real gases approach this behaviour in these conditions. The conditions in which a real gas will behave more and more like an ideal gas is either at very high temperatures (as the molecules of the gas have so much energy that the intermolecular forces and energy lost in collisions is negligable) and at very low pressures (as the molecules of the gas rarely collide or come into close enough proximity for intermolecular forces to be significant). # Types of ideal gases There are three basic classes of ideal gas: - the classical or Maxwell-Boltzmann ideal gas, - the ideal quantum Bose gas, composed of bosons, and - the ideal quantum Fermi gas, composed of fermions. The classical ideal gas can be separated into two types: The classical thermodynamic ideal gas and the ideal quantum Boltzmann gas. Both are essentially the same, except that the classical thermodynamic ideal gas is based on classical thermodynamics alone, and certain thermodynamic parameters such as the entropy are only specified to within an undetermined additive constant. The ideal quantum Boltzmann gas overcomes this limitation by taking the limit of the quantum Bose gas and quantum Fermi gas in the limit of high temperature to specify these additive constants. The behavior of a quantum Boltzmann gas is the same as that of a classical ideal gas except for the specification of these constants. The results of the quantum Boltzmann gas are used in a number of cases including the Sackur-Tetrode equation for the entropy of an ideal gas and the Saha ionization equation for a weakly ionized plasma. # Classical thermodynamic ideal gas The thermodynamic properties of an ideal gas can be described by two equations : The equation of state of a classical ideal gas is given by the ideal gas law. The internal energy of an ideal gas is given by: where: - \hat{c}_V is a constant dependent on temperature (e.g. equal to 3/2 for a monatomic gas for moderate temperatures) - U is the internal energy - p is the pressure - V is the volume - n is the amount of gas (moles) - R is the gas constant, 8.314 J·K−1mol-1 - T is the absolute temperature - N is the number of particles - k is the Boltzmann constant, 1.381×10−23J·K−1 The probability distribution of particles by velocity or energy is given by the Boltzmann distribution. The ideal gas law is an extension of experimentally discovered gas laws. Real fluids at low density and high temperature approximate the behavior of a classical ideal gas. However, at lower temperatures or a higher density, a real fluid deviates strongly from the behavior of an ideal gas, particularly as it condenses from a gas into a liquid or solid. # Heat capacity The heat capacity at constant volume of an ideal gas is: It is seen that the constant \hat{c}_V is just the dimensionless heat capacity at constant volume. It is equal to half the number of degrees of freedom per particle. For moderate temperatures, the constant for a monatomic gas is \hat{c}_V=3/2 while for a diatomic gas it is \hat{c}_V=5/2. It is seen that macroscopic measurements on heat capacity provide information on the microscopic structure of the molecules. The heat capacity at constant pressure of an ideal gas is: where H=U+pV is the enthalpy of the gas. It is seen that \hat{c}_p is also a constant and that the dimensionless heat capacities are related by: # Entropy Using the results of thermodynamics only, we can go a long way in determining the expression for the entropy of an ideal gas. This is an important step since, according to the theory of thermodynamic potentials, of which the internal energy U is one, if we can express the entropy as a function of U and the volume V, then we will have a complete statement of the thermodynamic behavior of the ideal gas. We will be able to derive both the ideal gas law and the expression for internal energy from it. Since the entropy is an exact differential, using the chain rule, the change in entropy when going from a reference state 0 to some other state with entropy S may be written as \Delta S where: =\int_{T_0}^{T} \left(\frac{\partial S}{\partial T}\right)_V\!dT +\int_{V_0}^{V} \left(\frac{\partial S}{\partial V}\right)_T\!dV where the reference variables may be functions of the number of particles N. Using the definition of the heat capacity at constant volume for the first differential and the appropriate Maxwell relation for the second we have: =\int_{T_0}^{T} \frac{C_v}{T}\,dT+\int_{V_0}^{V}\left(\frac{\partial P}{\partial T}\right)_VdV Expressing C_V in terms of \hat{c}_V as developed in the above section, differentiating the ideal gas equation of state, and integrating yields: = \hat{c}_VNk\ln\left(\frac{T}{T_0}\right)+Nk\ln\left(\frac{V}{V_0}\right) = Nk\ln\left(\frac{VT^{\hat{c}_v}}{f(N)}\right) where all constants have been incorporated into the logarithm as f(N) which is some function of the particle number N having the same dimensions as VT^{\hat{c}_v} in order that the argument of the logarithm be dimensionless. We now impose the constraint that the entropy be extensive. This will mean that when the extensive parameters (V and N) are multiplied by a constant, the entropy will be multiplied by the same constant. Mathematically: From this we find an equation for the function f(N) Differentiating this with respect to a, setting a equal to unity, and then solving the differential equation yields f(N): where φ is some constant with the dimensions of VT^{\hat{c}_v}/N. Substituting into the equation for the change in entropy: This is about as far as we can go using thermodynamics alone. Note that the above equation is flawed — as the temperature approaches zero, the entropy approaches negative infinity, in contradiction to the third law of thermodynamics. In the above "ideal" development, there is a critical point, not at absolute zero, at which the argument of the logarithm becomes unity, and the entropy becomes zero. This is unphysical. The above equation is a good approximation only when the argument of the logarithm is much larger than unity — the concept of an ideal gas breaks down at low values of V/N. Nevertheless, there will be a "best" value of the constant in the sense that the predicted entropy is as close as possible to the actual entropy, given the flawed assumption of ideality. It remained for quantum mechanics to introduce a reasonable value for the value of φ which yields the Sackur-Tetrode equation for the entropy of an ideal gas. It too suffers from a divergent entropy at absolute zero, but is a good approximation to an ideal gas over a large range of densities. # Thermodynamic potentials Since the dimensionless heat capacity at constant pressure \hat{c}_p is a constant we can express the entropy in what will prove to be a more convenient form: where Φ is now the undetermined constant. The chemical potential of the ideal gas is calculated from the corresponding equation of state (see thermodynamic potential): where G is the Gibbs free energy and is equal to U+pV-TS so that: The thermodynamic potentials for an ideal gas can now be written as functions of T, V, and N as: The most informative way of writing the potentials is in terms of their natural variables, since each of these equations can be used to derive all of the other thermodynamic variables of the system. In terms of their natural variables, the thermodynamic potentials of a single-specie ideal gas are: In statistical mechanics, the relationship between the Helmholtz free energy and the partition function is fundamental, and is used to calculate the thermodynamic properties -f matters; see configuration integral for more details. ## Multicomponent systems By Gibbs theorem, the entropy of a multicomponent system is equal to the sum of the entropies of each chemical species (assuming no surface effects). The entropy of a multicomponent system will be: where the sum is over all species. Likewise, the free energies are equal to the sums of the free energies of each species so that if Φ is a thermodynamic potential then where Φj is expressed in terms of its natural variables. For example, the internal energy will be: where N is defined as # Speed of sound The speed of sound in an ideal gas is given by where ## Equation Table for an Ideal Gas The following table gives the values for the change in the value of some thermodynamic variables under the specified transformation. # Ideal quantum gases In the above mentioned Sackur-Tetrode equation, the best choice of the entropy constant was found to be proportional to the quantum thermal wavelength of a particle, and the point at which the argument of the logarithm becomes zero is roughly equal to the point at which the average distance between particles becomes equal to the thermal wavelength. In fact, quantum theory itself predicts the same thing. Any gas behaves as an ideal gas at high enough temperature and low enough density, but at the point where the Sackur-Tetrode equation begins to break down, the gas will begin to behave as a quantum gas, composed of either bosons or fermions. (See the gas in a box article for a derivation of the ideal quantum gases, including the ideal Boltzmann gas.) ## Ideal Boltzmann gas The ideal Boltzmann gas yields the same results as the classical thermodynamic gas, but makes the following identification for the undetermined constant Φ: where Λ is the thermal de Broglie wavelength of the gas and g is the degeneracy of states. ## Ideal Bose and Fermi gases An ideal gas of bosons (e.g. a photon gas) will be governed by Bose-Einstein statistics and the distribution of energy will be in the form of a Bose-Einstein distribution. An ideal gas of fermions will be governed by Fermi-Dirac statistics and the distribution of energy will be in the form of a Fermi-Dirac distribution.	Ideal gas # Overview An ideal gas or perfect gas is a hypothetical gas consisting of identical particles of zero volume, with no intermolecular forces, where the constituent atoms or molecules undergo perfectly elastic collisions with the walls of the container and each other and are in constant random motion. Real gases do not behave according to these exact properties, although the approximation is often good enough to describe real gases. These four properties that constitute an ideal gas can be easily remembered by the acronym PRIE, which stands for; - Point masses (molecules occupy no volume) - Random Motion (molecules are in constant random motion) - Intermolecular forces (there are NO intermolecular forces between the particles) - Elastic collisions (the collisions involving the gas molecules are totally elastic) The concept of ideal gas is useful in technology because one mole (6.02214 Template:E particles) of an ideal gas has a volume of 22.4 liters at the standard conditions for temperature and pressure and many common real gases approach this behaviour in these conditions. The conditions in which a real gas will behave more and more like an ideal gas is either at very high temperatures (as the molecules of the gas have so much energy that the intermolecular forces and energy lost in collisions is negligable) and at very low pressures (as the molecules of the gas rarely collide or come into close enough proximity for intermolecular forces to be significant). # Types of ideal gases There are three basic classes of ideal gas: - the classical or Maxwell-Boltzmann ideal gas, - the ideal quantum Bose gas, composed of bosons, and - the ideal quantum Fermi gas, composed of fermions. The classical ideal gas can be separated into two types: The classical thermodynamic ideal gas and the ideal quantum Boltzmann gas. Both are essentially the same, except that the classical thermodynamic ideal gas is based on classical thermodynamics alone, and certain thermodynamic parameters such as the entropy are only specified to within an undetermined additive constant. The ideal quantum Boltzmann gas overcomes this limitation by taking the limit of the quantum Bose gas and quantum Fermi gas in the limit of high temperature to specify these additive constants. The behavior of a quantum Boltzmann gas is the same as that of a classical ideal gas except for the specification of these constants. The results of the quantum Boltzmann gas are used in a number of cases including the Sackur-Tetrode equation for the entropy of an ideal gas and the Saha ionization equation for a weakly ionized plasma. # Classical thermodynamic ideal gas The thermodynamic properties of an ideal gas can be described by two equations : The equation of state of a classical ideal gas is given by the ideal gas law. The internal energy of an ideal gas is given by: where: - <math>\hat{c}_V</math> is a constant dependent on temperature (e.g. equal to 3/2 for a monatomic gas for moderate temperatures) - U is the internal energy - p is the pressure - V is the volume - n is the amount of gas (moles) - R is the gas constant, 8.314 J·K−1mol-1 - T is the absolute temperature - N is the number of particles - k is the Boltzmann constant, 1.381×10−23J·K−1 The probability distribution of particles by velocity or energy is given by the Boltzmann distribution. The ideal gas law is an extension of experimentally discovered gas laws. Real fluids at low density and high temperature approximate the behavior of a classical ideal gas. However, at lower temperatures or a higher density, a real fluid deviates strongly from the behavior of an ideal gas, particularly as it condenses from a gas into a liquid or solid. # Heat capacity The heat capacity at constant volume of an ideal gas is: It is seen that the constant <math>\hat{c}_V</math> is just the dimensionless heat capacity at constant volume. It is equal to half the number of degrees of freedom per particle. For moderate temperatures, the constant for a monatomic gas is <math>\hat{c}_V=3/2</math> while for a diatomic gas it is <math>\hat{c}_V=5/2</math>. It is seen that macroscopic measurements on heat capacity provide information on the microscopic structure of the molecules. The heat capacity at constant pressure of an ideal gas is: where <math>H=U+pV</math> is the enthalpy of the gas. It is seen that <math>\hat{c}_p</math> is also a constant and that the dimensionless heat capacities are related by: # Entropy Using the results of thermodynamics only, we can go a long way in determining the expression for the entropy of an ideal gas. This is an important step since, according to the theory of thermodynamic potentials, of which the internal energy U is one, if we can express the entropy as a function of U and the volume V, then we will have a complete statement of the thermodynamic behavior of the ideal gas. We will be able to derive both the ideal gas law and the expression for internal energy from it. Since the entropy is an exact differential, using the chain rule, the change in entropy when going from a reference state 0 to some other state with entropy S may be written as <math>\Delta S</math> where: =\int_{T_0}^{T} \left(\frac{\partial S}{\partial T}\right)_V\!dT +\int_{V_0}^{V} \left(\frac{\partial S}{\partial V}\right)_T\!dV </math> where the reference variables may be functions of the number of particles N. Using the definition of the heat capacity at constant volume for the first differential and the appropriate Maxwell relation for the second we have: =\int_{T_0}^{T} \frac{C_v}{T}\,dT+\int_{V_0}^{V}\left(\frac{\partial P}{\partial T}\right)_VdV </math> Expressing <math>C_V</math> in terms of <math>\hat{c}_V</math> as developed in the above section, differentiating the ideal gas equation of state, and integrating yields: = \hat{c}_VNk\ln\left(\frac{T}{T_0}\right)+Nk\ln\left(\frac{V}{V_0}\right) = Nk\ln\left(\frac{VT^{\hat{c}_v}}{f(N)}\right) </math> where all constants have been incorporated into the logarithm as f(N) which is some function of the particle number N having the same dimensions as <math>VT^{\hat{c}_v}</math> in order that the argument of the logarithm be dimensionless. We now impose the constraint that the entropy be extensive. This will mean that when the extensive parameters (V and N) are multiplied by a constant, the entropy will be multiplied by the same constant. Mathematically: From this we find an equation for the function f(N) Differentiating this with respect to a, setting a equal to unity, and then solving the differential equation yields f(N): where φ is some constant with the dimensions of <math>VT^{\hat{c}_v}/N</math>. Substituting into the equation for the change in entropy: This is about as far as we can go using thermodynamics alone. Note that the above equation is flawed — as the temperature approaches zero, the entropy approaches negative infinity, in contradiction to the third law of thermodynamics. In the above "ideal" development, there is a critical point, not at absolute zero, at which the argument of the logarithm becomes unity, and the entropy becomes zero. This is unphysical. The above equation is a good approximation only when the argument of the logarithm is much larger than unity — the concept of an ideal gas breaks down at low values of V/N. Nevertheless, there will be a "best" value of the constant in the sense that the predicted entropy is as close as possible to the actual entropy, given the flawed assumption of ideality. It remained for quantum mechanics to introduce a reasonable value for the value of φ which yields the Sackur-Tetrode equation for the entropy of an ideal gas. It too suffers from a divergent entropy at absolute zero, but is a good approximation to an ideal gas over a large range of densities. # Thermodynamic potentials Since the dimensionless heat capacity at constant pressure <math>\hat{c}_p</math> is a constant we can express the entropy in what will prove to be a more convenient form: where Φ is now the undetermined constant. The chemical potential of the ideal gas is calculated from the corresponding equation of state (see thermodynamic potential): where G is the Gibbs free energy and is equal to <math>U+pV-TS</math> so that: The thermodynamic potentials for an ideal gas can now be written as functions of T, V, and N as: The most informative way of writing the potentials is in terms of their natural variables, since each of these equations can be used to derive all of the other thermodynamic variables of the system. In terms of their natural variables, the thermodynamic potentials of a single-specie ideal gas are: In statistical mechanics, the relationship between the Helmholtz free energy and the partition function is fundamental, and is used to calculate the thermodynamic properties of matters; see configuration integral for more details. ## Multicomponent systems By Gibbs theorem, the entropy of a multicomponent system is equal to the sum of the entropies of each chemical species (assuming no surface effects). The entropy of a multicomponent system will be: where the sum is over all species. Likewise, the free energies are equal to the sums of the free energies of each species so that if Φ is a thermodynamic potential then where Φj is expressed in terms of its natural variables. For example, the internal energy will be: where N is defined as # Speed of sound The speed of sound in an ideal gas is given by where ## Equation Table for an Ideal Gas The following table gives the values for the change in the value of some thermodynamic variables under the specified transformation. # Ideal quantum gases In the above mentioned Sackur-Tetrode equation, the best choice of the entropy constant was found to be proportional to the quantum thermal wavelength of a particle, and the point at which the argument of the logarithm becomes zero is roughly equal to the point at which the average distance between particles becomes equal to the thermal wavelength. In fact, quantum theory itself predicts the same thing. Any gas behaves as an ideal gas at high enough temperature and low enough density, but at the point where the Sackur-Tetrode equation begins to break down, the gas will begin to behave as a quantum gas, composed of either bosons or fermions. (See the gas in a box article for a derivation of the ideal quantum gases, including the ideal Boltzmann gas.) ## Ideal Boltzmann gas The ideal Boltzmann gas yields the same results as the classical thermodynamic gas, but makes the following identification for the undetermined constant Φ: where Λ is the thermal de Broglie wavelength of the gas and g is the degeneracy of states. ## Ideal Bose and Fermi gases An ideal gas of bosons (e.g. a photon gas) will be governed by Bose-Einstein statistics and the distribution of energy will be in the form of a Bose-Einstein distribution. An ideal gas of fermions will be governed by Fermi-Dirac statistics and the distribution of energy will be in the form of a Fermi-Dirac distribution.	https://www.wikidoc.org/index.php/Ideal_gas
976cc4600f8971b85b9e97874edc4f4b7ded5a15	wikidoc	Idebenone	Idebenone # Overview Idebenone (pronounced eye-deb-eh-known, trade names Catena, Raxone, Sovrima, among others) is a drug that was initially developed by Takeda Pharmaceutical Company for the treatment of Alzheimer's disease and other cognitive defects. This has been met with limited success. The Swiss company Santhera Pharmaceuticals has started to investigate it for the treatment of neuromuscular diseases. In 2010, early clinical trials for the treatment of Friedreich's ataxia and Duchenne muscular dystrophy have been completed. As of December 2013 the drug is not approved for these indications in North America or Europe. Chemically, idebenone is an organic compound of the quinone family. It is also promoted commercially as a synthetic analog of coenzyme Q10 (CoQ10). # Uses ## Indications that are or were approved in some territories ### Nootropic effects and Alzheimer's disease Idebenone improved learning and memory in experiments with mice. In humans, evaluation of Surrogate endpoints like electroretinography, auditory evoked potentials and visual analogue scales also suggested positive nootropic effects, but larger studies with hard endpoints are missing. Research on idebenone as a potential therapy of Alzheimer's disease have been inconsistent, but there may be a trend for a slight benefit. In May 1998, the approval for this indication was cancelled in Japan due to the lack of proven effects. In some European countries, the drug is available for the treatment of individual patients in special cases. ### Friedreich's ataxia (Sovrima) Preliminary testing has been done in humans and found idebenone to be a safe treatment for Friedreich's ataxia (FA), exhibiting a positive effect on cardiac hypertrophy and neurological function. The latter was only significantly improved in young patients. In a different experiment, a one-year test on eight patients, idebenone reduced the rate of deterioration of cardiac function, but without halting the progression of ataxia. The drug was approved for FA in Canada in 2008 under conditions including proof of efficacy in further clinical trials. However on February 27, 2013, Health Canada announced that idebenone would be voluntarily recalled as of April 30, 2013 by its Canadian manufacturer, Santhera Pharmaceuticals, due to the failure of the drug to show efficacy in the further clinical trials that were conducted. In 2008, the European Medicines Agency (EMA) refused a marketing authorisation for this indication. As of 2013 the drug was not approved for FA in Europe nor in the US, where there is no approved treatment. ## Indications being explored ### Duchenne muscular dystrophy (Catena) After experiments in mice and preliminary studies in humans, idebenone has entered Phase II clinical trials in 2005 and Phase III trials in 2009. ### Leber's hereditary optic neuropathy (Raxone) Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited (mother to all offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; this affects predominantly young adult males. Santhera completed a Phase III clinical trial in this indication in Europe with positive results, and submitted an application to market the drug to European regulators in July 2011. In January 2013, the request for marketing authorisation was refused by the EMA. ### Other neuromuscular diseases Phase I and II clinical trials for the treatment of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) and primary progressive multiple sclerosis are ongoing as of December 2013. ## Life style Idebenone is claimed to have properties similar to CoQ10 in its antioxidant properties, and has therefore been used in anti-aging on the basis of free-radical theory. Clinical evidence for this use is missing. It has been used in topical applications to treat wrinkles. # Pharmacology In cellular and tissue models, idebenone acts as a transporter in the electron transport chain of mitochondria and thus increases the production of adenosine triphosphate (ATP) which is the main energy source for cells, and also inhibits lipoperoxide formation. Positive effects on the energy household of mitochondria has also been observed in animal models. Clinical relevance of these findings has not been established. ## Pharmacokinetics Idebenone is well absorbed from the gut but undergoes excessive first pass metabolism in the liver, so that less than 1% reach the circulation. This rate can be improved with special formulations (suspensions) of idebenone and by administering it together with fat food; but even taking these measures bioavailability still seems to be considerably less than 14% in humans. More than 99% of the circulating drug are bound to plasma proteins. Idebenone metabolites include glucuronides and sulfates, which are mainly (~80%) excreted via the urine.	Idebenone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Idebenone (pronounced eye-deb-eh-known, trade names Catena, Raxone, Sovrima, among others) is a drug that was initially developed by Takeda Pharmaceutical Company for the treatment of Alzheimer's disease and other cognitive defects.[1] This has been met with limited success. The Swiss company Santhera Pharmaceuticals has started to investigate it for the treatment of neuromuscular diseases. In 2010, early clinical trials for the treatment of Friedreich's ataxia[2] and Duchenne muscular dystrophy[3] have been completed. As of December 2013[update] the drug is not approved for these indications in North America or Europe. Chemically, idebenone is an organic compound of the quinone family. It is also promoted commercially as a synthetic analog of coenzyme Q10 (CoQ10). # Uses ## Indications that are or were approved in some territories ### Nootropic effects and Alzheimer's disease Idebenone improved learning and memory in experiments with mice.[4] In humans, evaluation of Surrogate endpoints like electroretinography, auditory evoked potentials and visual analogue scales also suggested positive nootropic effects,[5] but larger studies with hard endpoints are missing. Research on idebenone as a potential therapy of Alzheimer's disease have been inconsistent, but there may be a trend for a slight benefit.[6][7] In May 1998, the approval for this indication was cancelled in Japan due to the lack of proven effects. In some European countries, the drug is available for the treatment of individual patients in special cases.[1] ### Friedreich's ataxia (Sovrima) Preliminary testing has been done in humans and found idebenone to be a safe treatment for Friedreich's ataxia (FA), exhibiting a positive effect on cardiac hypertrophy and neurological function.[8] The latter was only significantly improved in young patients.[9] In a different experiment, a one-year test on eight patients, idebenone reduced the rate of deterioration of cardiac function, but without halting the progression of ataxia.[10] The drug was approved for FA in Canada in 2008 under conditions including proof of efficacy in further clinical trials.[11] However on February 27, 2013, Health Canada announced that idebenone would be voluntarily recalled as of April 30, 2013 by its Canadian manufacturer, Santhera Pharmaceuticals, due to the failure of the drug to show efficacy in the further clinical trials that were conducted.[12] In 2008, the European Medicines Agency (EMA) refused a marketing authorisation for this indication.[1] As of 2013 the drug was not approved for FA in Europe[13] nor in the US, where there is no approved treatment.[14] ## Indications being explored ### Duchenne muscular dystrophy (Catena) After experiments in mice[15] and preliminary studies in humans, idebenone has entered Phase II clinical trials in 2005[3] and Phase III trials in 2009.[16] ### Leber's hereditary optic neuropathy (Raxone) Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited (mother to all offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; this affects predominantly young adult males. Santhera completed a Phase III clinical trial in this indication in Europe with positive results,[17] and submitted an application to market the drug to European regulators in July 2011.[18] In January 2013, the request for marketing authorisation was refused by the EMA.[19] ### Other neuromuscular diseases Phase I and II clinical trials for the treatment of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes)[20] and primary progressive multiple sclerosis[21] are ongoing as of December 2013[update]. ## Life style Idebenone is claimed to have properties similar to CoQ10 in its antioxidant properties, and has therefore been used in anti-aging on the basis of free-radical theory. Clinical evidence for this use is missing. It has been used in topical applications to treat wrinkles.[22] # Pharmacology In cellular and tissue models, idebenone acts as a transporter in the electron transport chain of mitochondria and thus increases the production of adenosine triphosphate (ATP) which is the main energy source for cells, and also inhibits lipoperoxide formation. Positive effects on the energy household of mitochondria has also been observed in animal models.[1][23] Clinical relevance of these findings has not been established. ## Pharmacokinetics Idebenone is well absorbed from the gut but undergoes excessive first pass metabolism in the liver, so that less than 1% reach the circulation. This rate can be improved with special formulations (suspensions) of idebenone and by administering it together with fat food; but even taking these measures bioavailability still seems to be considerably less than 14% in humans. More than 99% of the circulating drug are bound to plasma proteins. Idebenone metabolites include glucuronides and sulfates, which are mainly (~80%) excreted via the urine.[1]	https://www.wikidoc.org/index.php/Idebenone
7058809ebb06ed6e83da4104a6bdd76e961373a6	wikidoc	Ifosamide	Ifosamide # Overview Ifosfamide (pronounced eye.fos'.fa.mide) (also marketed as Mitoxana and Ifex) is a nitrogen mustard alkylating agent used in the treatment of cancer. It is sometimes abbreviated "IFO". # Uses It is given as a treatment for a variety of cancers, including: - Testicular cancer - Breast cancer - Lymphoma (Hodgkin's and non-Hodgkin's) - Soft tissue sarcoma - Osteogenic sarcoma (bone cancer) - Lung cancer - Cervical cancer - Ovarian cancer # Administration It is a white powder which, when prepared for use in chemotherapy, becomes a clear, colorless fluid. The delivery is intravenous. Ifosfamide is often used in conjunction with mesna to avoid internal bleeding in the patient, in particular hemorrhagic cystitis. Ifosfamide is given quickly, and in some cases can be given in as little as an hour. # Toxicity A common and dose-limiting side effect isencephalopathy (brain dysfunction). It occurs in some form in up to 50% of people receiving the agent. The reaction is probably mediated by chloroacetaldehyde, one of the breakdown products of the ifosfamide molecule, which has chemical properties similar toacetaldehyde and chloral hydrate. # Side/Adverse effects - Encephalopathy - Delirium - Psychosis - Nonconvulsive status epilepticus - Coma - Normal anion gap acidosis, specifically Renal tubular acidosis type 2. - Hemorrhagic cystitis # Treatment The most effective treatment for severe (grade III-IV) encephalopathy is an intravenous solution of methylene blue, which appears to shorten the duration of encephalopathy. Other treatments include albuminand thiamine, and dialysis as a rescue modality.	Ifosamide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [2] # Overview Ifosfamide (pronounced eye.fos'.fa.mide) (also marketed as Mitoxana and Ifex) is a nitrogen mustard alkylating agent used in the treatment of cancer.[1] It is sometimes abbreviated "IFO".[2] # Uses It is given as a treatment for a variety of cancers, including: - Testicular cancer - Breast cancer - Lymphoma (Hodgkin's and non-Hodgkin's) - Soft tissue sarcoma - Osteogenic sarcoma (bone cancer) - Lung cancer - Cervical cancer - Ovarian cancer # Administration It is a white powder which, when prepared for use in chemotherapy, becomes a clear, colorless fluid. The delivery is intravenous. Ifosfamide is often used in conjunction with mesna to avoid internal bleeding in the patient, in particular hemorrhagic cystitis. Ifosfamide is given quickly, and in some cases can be given in as little as an hour. # Toxicity A common and dose-limiting side effect isencephalopathy (brain dysfunction).[3] It occurs in some form in up to 50% of people receiving the agent. The reaction is probably mediated by chloroacetaldehyde, one of the breakdown products of the ifosfamide molecule, which has chemical properties similar toacetaldehyde and chloral hydrate. # Side/Adverse effects - Encephalopathy - Delirium - Psychosis - Nonconvulsive status epilepticus - Coma - Normal anion gap acidosis, specifically Renal tubular acidosis type 2.[4] - Hemorrhagic cystitis # Treatment The most effective treatment for severe (grade III-IV) encephalopathy is an intravenous solution of methylene blue, which appears to shorten the duration of encephalopathy. Other treatments include albuminand thiamine, and dialysis as a rescue modality.[3]	https://www.wikidoc.org/index.php/Ifosamide
7f5922e1284e2f84f6bab0aa352db05b378d6e39	wikidoc	Ileostomy	Ileostomy # Overview An ileostomy is a stoma that has been constructed by bringing the end of the small intestine (the ileum) out onto the surface of the skin. Intestinal waste passes out of the ileostomy and is collected in an external pouching system stuck to the skin. Ileostomies are usually sited above the groin on the right hand side of the abdomen. # Indications Ileostomy is necessary when disease or injury has rendered the lerge bowel incapable of safely processing the intestinal waste typically because the colon has been partially or totally removed. # Reasons for Having an Ileostomy Ileostomies are necessary where disease or injury has rendered the large intestine incapable of safely processing intestinal waste, typically because the colon has been partially or wholly removed. Diseases of the large intestine which may require surgical removal include: - Crohn's disease - Ulcerative colitis - Familial adenomatous polyposis - Total colonic Hirschprung's disease An ileostomy that may also be necessary in the treatment of colorectal cancer; one example is a situation where the tumor is causing a blockage. In such a case the ileostomy may be temporary, as the common surgical procedure for colorectal cancer is to reconnect the remaining sections of colon or rectum following removal of the tumor provided that enough of the rectum remains intact to preserve sphincter function. In a temporary ileostomy, a loop of the small intestine is brought through the skin, and the colon and rectum are not removed. Temporary ileostomies are also often made as the first stage in surgical construction of an ileo-anal pouch, so fecal material doesn't enter the newly-made pouch until it heals and has been tested for leaks – usually a period of eight to ten weeks. The temporary ostomy is then "taken down" or reversed by surgically repairing the loop of intestine which made the temporary stoma and closing the skin incision. # Types - Permanent ileostomy or end ileostomy - Temporary ileostomy End ileostomy Loop ileostomy - End ileostomy - Loop ileostomy ## Individual Indications - Permanent end ilostomy - It is performed in conjunction with a total proctocolectomy in inflammatory bowel diseases like Crohn's disease , ulcerative collitis or polyposis coli - Temporary loop ileostomy - It is performed when temporary diversion of ileal contents is required.It is commonly performed to divert the ileal contents temporarily to protect a tenuous ileorectal or ileoanal anastomosis following total coloctomy or proctocoloctomy, e.g.,adenomatous polyposis. Its advantage is to allow healing of the distal anastomosis well and,thus, allow safe passage of faeces through the anal orifice in future after closure or ileostomy. - Temporary end ileostomy with mucus fistula - Occasionally a temporary end ileostomy of the proximal end of the ileum are constructed, after resection of a gangrenous segment of bowel or a perforated caecal lesion, when primary anastomosis is contraindicated. # Methods - Site of election; Both the types are usually sited on the right iliac fossa, near the outer margin of the right rectus muscle about 5 cm. lateral to the midline and 4 cm. below the umbilicus. - The ileal stoma should protrude as a nipple for at least 3-5 cm above the skin surface.This facilitates the fluid effluent to pass directly into the collecting bag and the peristomal skin. It prevents peristomal skin irritation and break down. - The edge of the ileal mesentery should be sutured to the peritoneum of the lateral abdominal wall.This prevents herniation of small bowel loops through the peraileal stromal space. - A stroma adhesive disc is applied to the ileostomy stoma in the operation theatre.An ileostomy bag or pouch is placed over the disc.People with ileostomies either use a 'closed end' pouch which must be thrown away when full, or a 'drainable pouch' that is secured at the lower end with a leak proof clip. - Ostomy pouches fit close to the body surface and are usually not visible under the regular clothing unless the patient allows the pouch to become full. - The ileostomy starts to work within 48 hours. - It produces a daily output of 500 to 700 ml liquid or semi-liquid contents. - Ordinarily the pouch must be emptied several times a day and changed every 2-5 days. # Complications of Ileostomy Early complications: - Occasional necrosis of the distal ileum due to devascularisation. - Parastomal infecction Late complications: - Fistulaa - Prolapse - Stricture - Parastomal skin ulceration - Obstruction of ileostomy with food fibres e.g, potato skin, raw vegetables. - Effluent amount larger than 1000ml/day can cause fluid and electrolyte imbalance. This requires urgent ayyention and treatment: correction of fluid and electrolyte imbalance,use of drugs like loperamide or lomotil, use of bulk laxatives like isopgul husk. - Kidney stones - Gall stones. # Living with an Ileostomy People with ileostomies must use an ostomy pouch to collect intestinal waste. People with ileostomies typically use an open-end, or "drainable" pouch that is secured at the lower end with a leakproof clip, rather than a closed-end pouch which must be thrown away when full. Ordinarily the pouch must be emptied several times a day (many ostomates find it convenient to do this whenever they make a trip to the bathroom to urinate) and changed every 2-5 days, when the wafer starts to deteriorate. Ostomy pouches fit close to the body and are usually not visible under regular clothing unless the wearer allows the pouch to become too full. Some people find they must make adjustments to their diet after having an ileostomy. Tough or high-fiber foods (including, for example, potato skins and raw vegetables) are hard to digest in the small intestine and may cause blockages or discomfort when passing through the stoma. Chewing food thoroughly can help to minimize such problems. Some people also find that certain foods cause annoying gas or diarrhoea. Nevertheless, people who have an ileostomy as treatment for inflammatory bowel disease typically find they can enjoy a more "normal" diet than they could before surgery. Other complications can include kidney stones and gallstones. # Other Options Since the late 1970's an increasingly popular alternative to an ileostomy has been the ileo-anal pouch. With such a pouch an internal reservoir is formed using the ileum and connecting it to the anus, after removal of the colon and rectum, thus avoiding the need for an external appliance # Related Chapters - Colostomy de:Enterostoma	Ileostomy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor-in-Chief: Soumya Sachdeva # Overview An ileostomy is a stoma that has been constructed by bringing the end of the small intestine (the ileum) out onto the surface of the skin. Intestinal waste passes out of the ileostomy and is collected in an external pouching system stuck to the skin. Ileostomies are usually sited above the groin on the right hand side of the abdomen. # Indications Ileostomy is necessary when disease or injury has rendered the lerge bowel incapable of safely processing the intestinal waste typically because the colon has been partially or totally removed. # Reasons for Having an Ileostomy Ileostomies are necessary where disease or injury has rendered the large intestine incapable of safely processing intestinal waste, typically because the colon has been partially or wholly removed. Diseases of the large intestine which may require surgical removal include: - Crohn's disease - Ulcerative colitis - Familial adenomatous polyposis - Total colonic Hirschprung's disease An ileostomy that may also be necessary in the treatment of colorectal cancer; one example is a situation where the tumor is causing a blockage. In such a case the ileostomy may be temporary, as the common surgical procedure for colorectal cancer is to reconnect the remaining sections of colon or rectum following removal of the tumor provided that enough of the rectum remains intact to preserve sphincter function. In a temporary ileostomy, a loop of the small intestine is brought through the skin, and the colon and rectum are not removed. Temporary ileostomies are also often made as the first stage in surgical construction of an ileo-anal pouch, so fecal material doesn't enter the newly-made pouch until it heals and has been tested for leaks – usually a period of eight to ten weeks. The temporary ostomy is then "taken down" or reversed by surgically repairing the loop of intestine which made the temporary stoma and closing the skin incision. # Types - Permanent ileostomy or end ileostomy - Temporary ileostomy End ileostomy Loop ileostomy - End ileostomy - Loop ileostomy ## Individual Indications - Permanent end ilostomy - It is performed in conjunction with a total proctocolectomy in inflammatory bowel diseases like Crohn's disease , ulcerative collitis or polyposis coli - Temporary loop ileostomy - It is performed when temporary diversion of ileal contents is required.It is commonly performed to divert the ileal contents temporarily to protect a tenuous ileorectal or ileoanal anastomosis following total coloctomy or proctocoloctomy, e.g.,adenomatous polyposis. Its advantage is to allow healing of the distal anastomosis well and,thus, allow safe passage of faeces through the anal orifice in future after closure or ileostomy. - Temporary end ileostomy with mucus fistula - Occasionally a temporary end ileostomy of the proximal end of the ileum are constructed, after resection of a gangrenous segment of bowel or a perforated caecal lesion, when primary anastomosis is contraindicated. # Methods - Site of election; Both the types are usually sited on the right iliac fossa, near the outer margin of the right rectus muscle about 5 cm. lateral to the midline and 4 cm. below the umbilicus. - The ileal stoma should protrude as a nipple for at least 3-5 cm above the skin surface.This facilitates the fluid effluent to pass directly into the collecting bag and the peristomal skin. It prevents peristomal skin irritation and break down. - The edge of the ileal mesentery should be sutured to the peritoneum of the lateral abdominal wall.This prevents herniation of small bowel loops through the peraileal stromal space. - A stroma adhesive disc is applied to the ileostomy stoma in the operation theatre.An ileostomy bag or pouch is placed over the disc.People with ileostomies either use a 'closed end' pouch which must be thrown away when full, or a 'drainable pouch' that is secured at the lower end with a leak proof clip. - Ostomy pouches fit close to the body surface and are usually not visible under the regular clothing unless the patient allows the pouch to become full. - The ileostomy starts to work within 48 hours. - It produces a daily output of 500 to 700 ml liquid or semi-liquid contents. - Ordinarily the pouch must be emptied several times a day and changed every 2-5 days. # Complications of Ileostomy Early complications: - Occasional necrosis of the distal ileum due to devascularisation. - Parastomal infecction Late complications: - Fistulaa - Prolapse - Stricture - Parastomal skin ulceration - Obstruction of ileostomy with food fibres e.g, potato skin, raw vegetables. - Effluent amount larger than 1000ml/day can cause fluid and electrolyte imbalance. This requires urgent ayyention and treatment: correction of fluid and electrolyte imbalance,use of drugs like loperamide or lomotil, use of bulk laxatives like isopgul husk. - Kidney stones - Gall stones. # Living with an Ileostomy People with ileostomies must use an ostomy pouch to collect intestinal waste. People with ileostomies typically use an open-end, or "drainable" pouch that is secured at the lower end with a leakproof clip, rather than a closed-end pouch which must be thrown away when full. Ordinarily the pouch must be emptied several times a day (many ostomates find it convenient to do this whenever they make a trip to the bathroom to urinate) and changed every 2-5 days, when the wafer starts to deteriorate. Ostomy pouches fit close to the body and are usually not visible under regular clothing unless the wearer allows the pouch to become too full. Some people find they must make adjustments to their diet after having an ileostomy. Tough or high-fiber foods (including, for example, potato skins and raw vegetables) are hard to digest in the small intestine and may cause blockages or discomfort when passing through the stoma. Chewing food thoroughly can help to minimize such problems. Some people also find that certain foods cause annoying gas or diarrhoea. Nevertheless, people who have an ileostomy as treatment for inflammatory bowel disease typically find they can enjoy a more "normal" diet than they could before surgery. Other complications can include kidney stones and gallstones. # Other Options Since the late 1970's an increasingly popular alternative to an ileostomy has been the ileo-anal pouch. With such a pouch an internal reservoir is formed using the ileum and connecting it to the anus, after removal of the colon and rectum, thus avoiding the need for an external appliance # Related Chapters - Colostomy Template:Digestive system surgical procedures de:Enterostoma Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Ileostomy
0ce752f2b921c5dbcfcb3cc5dfd4b2d0f8d7108a	wikidoc	Imidazole	Imidazole Imidazole is a heterocyclic aromatic organic compound. It is further classified as an alkaloid. Imidazole refers to the parent compound C3H4N2, whereas imidazoles are a class of heterocycles with similar ring structure but varying substituents. This ring system is present in important biological building blocks such as histidine, and the related hormone histamine. Imidazole can act as a base and as a weak acid. Imidazole exists in two tautomeric forms with the hydrogen atom moving between the two nitrogens. Many drugs contain an imidazole ring, such as antifungal drugs and nitroimidazole. # Discovery Imidazole was first synthesized by H. Debus in 1858, but various imidazole derivatives had been discovered as early as the 1840s. His synthesis, as shown below, used glyoxal and formaldehyde in ammonia to form imidazole. This synthesis, while producing relatively low yields, is still used for creating C-substituted imidazoles. In one microwave modification the reactants are benzil, formaldehyde and ammonia in glacial acetic acid forming 2,4,5-triphenylimidazole (Lophine). # Preparation Imidazole can be synthesized by numerous methods besides the Debus method. Many of these syntheses can also be applied to different substituted imidazoles and imidazole derivatives simply by varying the functional groups on the reactants. In literature, these methods are commonly categorized by which and how many bonds form to make the imidazole rings. For example, the Debus method forms the (1,2), (3,4), and (1,5) bonds in imidazole, using each reactant as a fragment of the ring, and thus this method would be a three-bond-forming synthesis. A small sampling of these methods is presented below. The (1,5) or (3,4) bond can be formed by the reaction of an immediate and an α-aminoaldehyde or α-aminoacetal, resulting in the cyclization of an amidine to imidazole. The example below applies to imidazole when R=R1=Hydrogen. The (1,2) and (2,3) bonds can be formed by treating a 1,2-diaminoalkane, at high temperatures, with an alcohol, aldehyde, or carboxylic acid. A dehydrogenating agent, such as platinum with alumina, must be present in the reaction for the imidazole to form. The example below applies to imidazole when R=Hydrogen. The (1,2) and (3,4) bonds can also be formed from N-substituted α-aminoketones and formamide and heat. The product will be a 1,4-disubstituted imidazole, but here since R=R1=Hydrogen, imidazole itself is the product. The yield of this reaction is moderate, but it seems to be the most effective method of making the 1,4 substitution. This is a general method which is able to give good yields for substituted imidazoles. The starting materials are substituted glyoxal, aldehyde, amine, and ammonia or an ammonium salt. Imidazole can be synthesized by the photolysis of 1-vinyltetrazole. This reaction will only give substantial yields if the 1-vinyltetrazole is made efficiently from an organotin compound such as 2-tributylstannyltetrazole. The reaction, shown below, produces imidazole when R=R1=R2=Hydrogen. Imidazole can also be formed in a vapor phase reaction. The reaction occurs with formamide, ethylenediamine, and hydrogen over platinum on alumina, and it must take place between 340 and 480 °C. This forms a very pure imidazole product. # Structure and properties Imidazole is a 5-membered planar ring, which is soluble in water and polar solvents. The compound has an aromatic sextet, which consists of one π electron from the =N- atom and one from each carbon atom, and two from the NH nitrogen. Some resonance structures of imidazole are shown below. Imidazole is a base and an excellent nucleophile. It reacts at the NH nitrogen, attacking alkylating and acylating compounds. It is not particularly susceptible to electrophilic attacks at the carbon atoms, and most of these reactions are substitutions that keep the aromaticity intact. One can see from the resonance structure that the carbon-2 is the carbon most likely to have a nucleophile attack it, but in general nucleophilic substitutions are difficult with imidazole. # Biological significance and applications Imidazole is incorporated into many important biological molecules. The most obvious is the amino acid histidine, which has an imidazole side chain. Histidine is present in many proteins and enzymes and plays a vital part in the structure and binding functions of hemoglobin. Histidine can be decarboxylated to histamine, which is also a common biological compound. It is a component of the toxin that causes urticaria, which is basically an allergic reaction. The structures of both histidine and histamine are: One of the applications of imidazole is in the purification of His-tagged proteins in immobilised metal affinity chromatography(IMAC). Imidazole is used to elute tagged proteins bound to Ni ions attached to the surface of beads in the chromatography column. An excess of imidazole is passed through the column, which displaces the His-tag from nickel co-ordination, freeing the His-tagged proteins. Imidazole has become an important part of many pharmaceuticals. Synthetic imidazoles are present in many fungicides and antifungal, antiprotozoal, and antihypertensive medications. Imidazole is part of the theophylline molecule, found in tea leaves and coffee beans, which stimulates the central nervous system. It is present in the anticancer medication mercaptopurine, which combats leukemia by interfering with DNA activities. # Industrial applications Imidazole has been used extensively as a corrosion inhibitor on certain transition metals, such as copper. Preventing copper corrosion is important, especially in aqueous systems, where the conductivity of the copper decreases due to corrosion. Many compounds of industrial and technological importance contain imidazole. The thermostable polybenzimidazole PBI contains imidazole fused to a benzene ring and linked to a benzene, and acts as a fire retardant. Imidazole can also be found in various compounds which are used for photography and electronics. # Salts of imidazole Salts of imidazole where the imidazole ring is in the cation are known as imidazolium salts (for example, imidazolium chloride). These salts are formed from the protonation or substitution at nitrogen of imidazole. These salts have been used as ionic liquids and precursors to stable carbenes. Salts where a deprotanated imidazole is an anion are also possible; these salts are known as imidazolide salts (for example, sodium imidazolide). # Related heterocycles - Benzimidazole, an analog with a fused benzene ring. - Dihydroimidazole or benzimidazoline, an analog where 4,5-double bond is saturated. - Pyrrole, an analog with only one nitrogen atom in position 1. - Oxazole, an analog with the nitrogen atom in position 1 replaced by oxygen. - Thiazole, an analog with the nitrogen atom in position 1 replaced by sulfur. - Pyrazole, an analog with two adjacent nitrogen atoms.	Imidazole Template:Chembox new Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Imidazole is a heterocyclic aromatic organic compound. It is further classified as an alkaloid. Imidazole refers to the parent compound C3H4N2, whereas imidazoles are a class of heterocycles with similar ring structure but varying substituents. This ring system is present in important biological building blocks such as histidine, and the related hormone histamine. Imidazole can act as a base and as a weak acid. Imidazole exists in two tautomeric forms with the hydrogen atom moving between the two nitrogens. Many drugs contain an imidazole ring, such as antifungal drugs and nitroimidazole.[1][2][3][4][5] # Discovery Imidazole was first synthesized by H. Debus in 1858, but various imidazole derivatives had been discovered as early as the 1840s. His synthesis, as shown below, used glyoxal and formaldehyde in ammonia to form imidazole. This synthesis, while producing relatively low yields, is still used for creating C-substituted imidazoles. In one microwave modification the reactants are benzil, formaldehyde and ammonia in glacial acetic acid forming 2,4,5-triphenylimidazole (Lophine).[6] # Preparation Imidazole can be synthesized by numerous methods besides the Debus method. Many of these syntheses can also be applied to different substituted imidazoles and imidazole derivatives simply by varying the functional groups on the reactants. In literature, these methods are commonly categorized by which and how many bonds form to make the imidazole rings. For example, the Debus method forms the (1,2), (3,4), and (1,5) bonds in imidazole, using each reactant as a fragment of the ring, and thus this method would be a three-bond-forming synthesis. A small sampling of these methods is presented below. The (1,5) or (3,4) bond can be formed by the reaction of an immediate and an α-aminoaldehyde or α-aminoacetal, resulting in the cyclization of an amidine to imidazole. The example below applies to imidazole when R=R1=Hydrogen. The (1,2) and (2,3) bonds can be formed by treating a 1,2-diaminoalkane, at high temperatures, with an alcohol, aldehyde, or carboxylic acid. A dehydrogenating agent, such as platinum with alumina, must be present in the reaction for the imidazole to form. The example below applies to imidazole when R=Hydrogen. The (1,2) and (3,4) bonds can also be formed from N-substituted α-aminoketones and formamide and heat. The product will be a 1,4-disubstituted imidazole, but here since R=R1=Hydrogen, imidazole itself is the product. The yield of this reaction is moderate, but it seems to be the most effective method of making the 1,4 substitution. This is a general method which is able to give good yields for substituted imidazoles. The starting materials are substituted glyoxal, aldehyde, amine, and ammonia or an ammonium salt.[7] Imidazole can be synthesized by the photolysis of 1-vinyltetrazole. This reaction will only give substantial yields if the 1-vinyltetrazole is made efficiently from an organotin compound such as 2-tributylstannyltetrazole. The reaction, shown below, produces imidazole when R=R1=R2=Hydrogen. Imidazole can also be formed in a vapor phase reaction. The reaction occurs with formamide, ethylenediamine, and hydrogen over platinum on alumina, and it must take place between 340 and 480 °C. This forms a very pure imidazole product. # Structure and properties Imidazole is a 5-membered planar ring, which is soluble in water and polar solvents. The compound has an aromatic sextet, which consists of one π electron from the =N- atom and one from each carbon atom, and two from the NH nitrogen. Some resonance structures of imidazole are shown below. Imidazole is a base and an excellent nucleophile. It reacts at the NH nitrogen, attacking alkylating and acylating compounds. It is not particularly susceptible to electrophilic attacks at the carbon atoms, and most of these reactions are substitutions that keep the aromaticity intact. One can see from the resonance structure that the carbon-2 is the carbon most likely to have a nucleophile attack it, but in general nucleophilic substitutions are difficult with imidazole. # Biological significance and applications Imidazole is incorporated into many important biological molecules. The most obvious is the amino acid histidine, which has an imidazole side chain. Histidine is present in many proteins and enzymes and plays a vital part in the structure and binding functions of hemoglobin. Histidine can be decarboxylated to histamine, which is also a common biological compound. It is a component of the toxin that causes urticaria, which is basically an allergic reaction. The structures of both histidine and histamine are: One of the applications of imidazole is in the purification of His-tagged proteins in immobilised metal affinity chromatography(IMAC). Imidazole is used to elute tagged proteins bound to Ni ions attached to the surface of beads in the chromatography column. An excess of imidazole is passed through the column, which displaces the His-tag from nickel co-ordination, freeing the His-tagged proteins. Imidazole has become an important part of many pharmaceuticals. Synthetic imidazoles are present in many fungicides and antifungal, antiprotozoal, and antihypertensive medications. Imidazole is part of the theophylline molecule, found in tea leaves and coffee beans, which stimulates the central nervous system. It is present in the anticancer medication mercaptopurine, which combats leukemia by interfering with DNA activities. # Industrial applications Imidazole has been used extensively as a corrosion inhibitor on certain transition metals, such as copper. Preventing copper corrosion is important, especially in aqueous systems, where the conductivity of the copper decreases due to corrosion. Many compounds of industrial and technological importance contain imidazole. The thermostable polybenzimidazole PBI contains imidazole fused to a benzene ring and linked to a benzene, and acts as a fire retardant. Imidazole can also be found in various compounds which are used for photography and electronics. # Salts of imidazole Salts of imidazole where the imidazole ring is in the cation are known as imidazolium salts (for example, imidazolium chloride). These salts are formed from the protonation or substitution at nitrogen of imidazole. These salts have been used as ionic liquids and precursors to stable carbenes. Salts where a deprotanated imidazole is an anion are also possible; these salts are known as imidazolide salts (for example, sodium imidazolide). # Related heterocycles - Benzimidazole, an analog with a fused benzene ring. - Dihydroimidazole or benzimidazoline, an analog where 4,5-double bond is saturated. - Pyrrole, an analog with only one nitrogen atom in position 1. - Oxazole, an analog with the nitrogen atom in position 1 replaced by oxygen. - Thiazole, an analog with the nitrogen atom in position 1 replaced by sulfur. - Pyrazole, an analog with two adjacent nitrogen atoms.	https://www.wikidoc.org/index.php/Imidazole
406cfdbc79a6fa1bc1588142796a7fa149d5259a	wikidoc	Imiquimod	Imiquimod # 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 Imiquimod is an immnunologic adjuvant that is FDA approved for the treatment of actinic keratosis, external genital warts. Common adverse reactions include erythema, edema, erosion/ulceration, exudate, scabbing/crusting, headache, application site pain, application site irritation, application site pruritus, fatigue, influenza-like illness, and nausea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - ZYCLARA Cream, 2.5% and 3.75% are indicated for the topical treatment of clinically typical visible or palpable, actinic keratoses (AK), of the full face or balding scalp in immunocompetent adults. - Dosing Information - ZYCLARA Cream should be applied once daily before bedtime to the skin of the affected area (either entire face or balding scalp) for two 2-week treatment cycles separated by a 2-week no-treatment period. ZYCLARA Cream should be applied as a thin film to the entire treatment area and rubbed in until the cream is no longer visible. Up to 0.5 grams (2 packets or 2 full actuations of the pump) of ZYCLARA Cream may be applied to the treatment area at each application. ZYCLARA Cream should be left on the skin for approximately 8 hours, after which time the cream should be removed by washing the area with mild soap and water. The prescriber should demonstrate the proper application technique to maximize the benefit of ZYCLARA Cream therapy. - Patients should wash their hands before and after applying ZYCLARA Cream. - Avoid use in or on the lips and nostrils. Do not use in or near the eyes. - Local skin reactions in the treatment area are common. A rest period of several days may be taken if required by the patient's discomfort or severity of the local skin reaction. However, neither 2-week treatment cycle should be extended due to missed doses or rest periods. A transient increase in lesion counts may be observed during treatment. Response to treatment cannot be adequately assessed until resolution of local skin reactions. The patient should continue dosing as prescribed. Treatment should continue for the full treatment course even if all actinic keratoses appear to be gone. Lesions that do not respond to treatment should be carefully re-evaluated and management reconsidered. - Prescribe no more than 2 boxes (56 packets), two 7.5g pumps or one 15g pump for the total 2-cycle treatment course. Partially-used packets should be discarded and not reused. - ZYCLARA Cream, 3.75% is indicated for the treatment of external genital and perianal warts (EGW)/condyloma acuminata in patients 12 years or older. - Dosing Information - Patients should apply a thin layer of ZYCLARA Cream once a day to the external genital/perianal warts until total clearance or for up to 8 weeks. Patients should use up to 0.25 grams (one packet or one full actuation of the pump) at each application, which is a sufficient amount of cream to cover the wart area. ZYCLARA Cream should be applied prior to normal sleeping hours and left on the skin for approximately 8 hours, then removed by washing the area with mild soap and water. The prescriber should demonstrate the proper application technique to maximize the benefit of ZYCLARA Cream therapy. - Patients should wash their hands before and after applying ZYCLARA Cream. - Local skin reactions at the treatment site are common, and may necessitate a rest period of several days; resume treatment once the reaction subsides. Non-occlusive dressings such as cotton gauze or cotton underwear may be used in the management of skin reactions. - Prescribe up to 2 boxes (56 packets), two 7.5g pumps or one 15g pump for the total treatment course. Use of excessive amounts of cream should be avoided. Partially-used packets should be discarded and not reused. - Dosing Information - Tumors 0.5 cm to less than 1 cm in diameter, apply a 4 mm diameter cream droplet (10 mg); tumors 1 cm to less than 1.5 cm in diameter, apply a 5 mm diameter cream droplet (25 mg); tumors 1.5 cm to 2 cm in diameter, apply a 7 mm cream droplet (40 mg of cream) Limitations of Use - Imiquimod cream has been evaluated in children ages 2 to 12 years with molluscum contagiosum and these studies failed to demonstrate efficacy. - Treatment with ZYCLARA Cream has not been studied for prevention or transmission of HPV. Unevaluated Populations - The safety and efficacy of ZYCLARA Cream have not been established in the treatment of: - urethral, intra-vaginal, cervical, rectal or intra-anal human papilloma viral disease. - actinic keratosis when treated with more than one 2-cycle treatment course in the same area. - patients with xeroderma pigmentosum. - superficial basal cell carcinoma. - immunosuppressed patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use ### Condyloma acuminatum, external - HIV infection - Recommendation: Adult, Class IIb - Strength of Evidence: Adult, Category B - Dosing information - For the treatment of uncomplicated external genital warts in patients with human immunodeficiency virus, apply imiquimod 5% cream to the lesion at bedtime, 3 times per week on nonconsecutive nights. Wash with soap and water 6 to 10 hours after each application. Treatment may continue for up to 16 weeks. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Imiquimod in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - ZYCLARA Cream, 3.75% is indicated for the treatment of external genital and perianal warts (EGW)/condyloma acuminata in patients 12 years or older. - Dosing information - Zyclara(R) - For the treatment of children 12 years and older with external genital and perianal warts/condyloma acuminata, apply up to 1 packet or 1 pump actuation of 3.75% cream topically to warts once daily at bedtime until total clearance or up to a duration of 8 weeks. Leave on the skin for 8 hours then wash area with mild soap and water. - Aldara(R) - For the treatment of external genital and perianal warts/condyloma acuminata in patients 12 years of age or older, apply up to one imiquimod 5% cream packet to the treatment area 3 times per week until total genital and perianal wart clearance or for a maximum duration of 16 weeks. Each imiquimod packet contains enough cream to cover a wart area of up to 20 square centimeters. Apply a thin layer of cream prior to normal sleeping hours and leave on the skin for 6 to 10 hours. Following each treatment period, remove the cream by washing the treated area with soap and water. Examples of 3 times per week application schedules are: Monday, Wednesday, and Friday or Tuesday, Thursday, and Saturday. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use ### Condyloma acuminatum, external - HIV infection - Recommendation: Pediatric, Class IIb - Strength of Evidence: Pediatric, Category C - Dosing information - For the treatment of uncomplicated external genital warts in children with human immunodeficiency virus, apply imiquimod 5% cream to the lesion at bedtime, 3 times per week on nonconsecutive nights. Wash with soap and water 6 to 10 hours after each application. Treatment may continue for up to 16 weeks. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Imiquimod in pediatric patients. # Contraindications - None. # Warnings Local Skin Reactions - Intense local skin reactions including skin weeping or erosion can occur after a few applications of ZYCLARA Cream and may require an interruption of dosing. ZYCLARA Cream has the potential to exacerbate inflammatory conditions of the skin, including chronic graft versus host disease. - Severe local inflammatory reactions of the female external genitalia can lead to severe vulvar swelling. Severe vulvar swelling can lead to urinary retention. Dosing should be interrupted or discontinued for severe vulvar swelling. - Administration of ZYCLARA Cream is not recommended until the skin is healed from any previous drug or surgical treatment. Systemic Reactions - Flu-like signs and symptoms may accompany, or even precede, local skin reactions and may include fatigue, nausea, fever, myalgias, arthralgias, malaise and chills. An interruption of dosing and an assessment of the patient should be considered. - Lymphadenopathy occurred in 2% of subjects with actinic keratosis treated with ZYCLARA Cream, 3.75% and in 3% of subjects treated with ZYCLARA Cream, 2.5%. This reaction resolved in all subjects by 4 weeks after completion of treatment. Ultraviolet Light Exposure Risks - Exposure to sunlight (including sunlamps) should be avoided or minimized during use of ZYCLARA Cream. Patients should be warned to use protective clothing (e.g., a hat) when using ZYCLARA Cream. Patients with sunburn should be advised not to use ZYCLARA Cream until fully recovered. Patients who may have considerable sun exposure, e.g. due to their occupation, and those patients with inherent sensitivity to sunlight should exercise caution when using ZYCLARA Cream. - In an animal photo-carcinogenicity study, imiquimod cream shortened the time to skin tumor formation. The enhancement of ultraviolet carcinogenicity is not necessarily dependent on phototoxic mechanisms. Therefore, patients should minimize or avoid natural or artificial sunlight exposure. Increased Risk of Adverse Reactions with Concomitant Imiquimod Use - Concomitant use of ZYCLARA Cream and any other imiquimod products, in the same treatment area, should be avoided since they contain the same active ingredient (imiquimod) and may increase the risk for and severity of local skin reactions. - The safety of concomitant use of ZYCLARA Cream and any other imiquimod products has not been established and should be avoided since they contain the same active ingredient (imiquimod) and may increase the risk for and severity of systemic reactions. Immune Cell Activation in Autoimmune Disease - ZYCLARA Cream should be used with caution in patients with pre-existing autoimmune conditions because imiquimod activates immune cells. # 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 Trials Experience: Actinic Keratosis - The data described below reflect exposure to ZYCLARA Cream or vehicle in 479 subjects enrolled in two double-blind, vehicle-controlled trials. Subjects applied up to two packets of ZYCLARA Cream or vehicle daily to the skin of the affected area (either entire face or balding scalp) for two 2-week treatment cycles separated by a 2-week no treatment period. - Overall, in the clinical trials, 11% (17/160) of subjects in the ZYCLARA Cream, 3.75% arm, 7% (11/160) of subjects in the ZYCLARA Cream, 2.5% arm, and 0% in the vehicle cream arm required rest periods due to adverse local skin reactions. - Other adverse reactions observed in subjects treated with ZYCLARA Cream include: application site bleeding, application site swelling, chills, dermatitis, herpes zoster, insomnia, lethargy, myalgia, pancytopenia, pruritus, squamous cell carcinoma, and vomiting. Clinical Trials Experience: External Genital Warts - In two double-blind, placebo-controlled studies 602 subjects applied up to one packet of ZYCLARA Cream or vehicle daily for up to 8 weeks. - The most frequently reported adverse reactions were application site reactions and local skin reactions. Selected adverse reactions are listed in Table 3. - The frequency and severity of local skin reactions were similar in both genders, with the following exceptions: a) flaking/scaling occurred in 40% of men and in 26% of women and b) scabbing/crusting occurred in 34% of men and in 18% of women. - In the clinical trials, 32% (126/400) of subjects who used ZYCLARA Cream and 2% (4/202) of subjects who used vehicle cream discontinued treatment temporarily (required rest periods) due to adverse local skin reactions, and 1% (3/400) of subjects who used ZYCLARA Cream discontinued treatment permanently due to local skin/application site reactions. - Other adverse reactions reported in subjects treated with ZYCLARA Cream include: rash, back pain, application site rash, application site cellulitis, application site excoriation, application site bleeding, scrotal pain, scrotal erythema, scrotal ulcer, scrotal edema, sinusitis, nausea, pyrexia, and influenza-like symptoms. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of imiquimod. 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. - Application Site Disorders: tingling at the application site - Body as a Whole: angioedema - Cardiovascular: capillary leak syndrome, cardiac failure, cardiomyopathy, pulmonary edema, arrhythmias (tachycardia, supraventricular tachycardia, atrial fibrillation, palpitations), chest pain, ischemia, myocardial infarction, syncope - Endocrine: thyroiditis - Gastro-Intestinal System Disorders: abdominal pain - Hematological: decreases in red cell, white cell and platelet counts (including idiopathic thrombocytopenic purpura), lymphoma - Hepatic: abnormal liver function - Infections and Infestations: herpes simplex - Musculo-Skeletal System Disorders: arthralgia - Neuropsychiatric: agitation, cerebrovascular accident, convulsions (including febrile convulsions), depression, insomnia, multiple sclerosis aggravation, paresis, suicide - Respiratory: dyspnea - Urinary System Disorders: proteinuria, urinary retention, dysuria - Skin and Appendages: exfoliative dermatitis, erythema multiforme, hyperpigmentation, hypertrophic scar, hypopigmentation - Vascular: Henoch-Schonlein purpura syndrome # Drug Interactions - Drug - Description # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There are no adequate and well-controlled studies in pregnant women. ZYCLARA Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - The animal multiples of human exposure calculations were based on daily dose comparisons for the reproductive toxicology studies described in this section and in Section 13.1. The animal multiples of human exposure were based on weekly dose comparisons for the carcinogenicity studies described in Section 13.1. For the animal multiple of human exposure ratios presented in this section and Section 13.1, the Maximum Recommended Human Dose (MRHD) was set at 2 packets (500 mg cream) per treatment of actinic keratosis with ZYCLARA Cream (imiquimod 3.75%, 18.75 mg imiquimod) for BSA comparison. The maximum human AUC value obtained in the treatment of external genital and perianal warts was higher than that obtained in the treatment of actinic keratosis and was used in the calculation of animal multiples of MRHD that were based on AUC comparison. - Systemic embryofetal development studies were conducted in rats and rabbits. Oral doses of 1, 5 and 20 mg/kg/day imiquimod were administered during the period of organogenesis (gestational days 6 – 15) to pregnant female rats. In the presence of maternal toxicity, fetal effects noted at 20 mg/kg/day (163× MRHD based on AUC comparisons) included increased resorptions, decreased fetal body weights, delays in skeletal ossification, bent limb bones, and two fetuses in one litter (2 of 1567 fetuses) demonstrated exencephaly, protruding tongues and low-set ears. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 5 mg/kg/day (28× MRHD based on AUC comparisons). - Intravenous doses of 0.5, 1 and 2 mg/kg/day imiquimod were administered during the period of organogenesis (gestational days 6 – 18) to pregnant female rabbits. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 2 mg/kg/day (2.1× MRHD based on BSA comparisons), the highest dose evaluated in this study, or 1 mg/kg/day (115× MRHD based on AUC comparisons). - A combined fertility and peri- and post-natal development study was conducted in rats. Oral doses of 1, 1.5, 3 and 6 mg/kg/day imiquimod were administered to male rats from 70 days prior to mating through the mating period and to female rats from 14 days prior to mating through parturition and lactation. No effects on growth, fertility, reproduction or post-natal development were noted at doses up to 6 mg/kg/day (25× MRHD based on AUC comparisons), the highest dose evaluated in this study. In the absence of maternal toxicity, bent limb bones were noted in the F1 fetuses at a dose of 6 mg/kg/day (25× MRHD based on AUC comparisons). This fetal effect was also noted in the oral rat embryofetal development study conducted with imiquimod. No treatment related effects on teratogenicity were noted at 3 mg/kg/day (12× MRHD based on AUC comparisons). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Imiquimod in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Imiquimod during labor and delivery. ### Nursing Mothers - It is not known whether imiquimod is excreted in human milk following use of ZYCLARA Cream. Because many drugs are excreted in human milk, caution should be exercised when ZYCLARA Cream is administered to nursing women. ### Pediatric Use - AK is a condition not generally seen within the pediatric population. The safety and effectiveness of ZYCLARA Cream for AK in patients less than 18 years of age have not been established. - Safety and effectiveness in patients with external genital/perianal warts below the age of 12 years have not been established. - Imiquimod 5% cream was evaluated in two randomized, vehicle-controlled, double-blind trials involving 702 pediatric subjects with molluscum contagiosum (MC) (470 exposed to imiquimod; median age 5 years, range 2–12 years). Subjects applied imiquimod cream or vehicle 3 times weekly for up to 16 weeks. Complete clearance (no MC lesions) was assessed at Week 18. In Study 1, the complete clearance rate was 24% (52/217) in the imiquimod cream group compared with 26% (28/106) in the vehicle group. In Study 2, the clearance rates were 24% (60/253) in the imiquimod cream group compared with 28% (35/126) in the vehicle group. These studies failed to demonstrate efficacy. - Similar to the studies conducted in adults, the most frequently reported adverse reaction from 2 studies in children with molluscum contagiosum was application site reaction. Adverse events which occurred more frequently in imiquimod-treated subjects compared with vehicle-treated subjects generally resembled those seen in studies in indications approved for adults and also included otitis media (5% imiquimod vs. 3% vehicle) and conjunctivitis (3% imiquimod vs. 2% vehicle). - Erythema was the most frequently reported local skin reaction. Severe local skin reactions reported by imiquimod-treated subjects in the pediatric studies included erythema (28%), edema (8%), scabbing/crusting (5%), flaking/scaling (5%), erosion (2%) and weeping/exudate (2%). - Systemic absorption of imiquimod across the affected skin of 22 subjects aged 2 to 12 years with extensive MC involving at least 10% of the total body surface area was observed after single and multiple doses at a dosing frequency of 3 applications per week for 4 weeks. The investigator determined the dose applied, either 1, 2 or 3 packets per dose, based on the size of the treatment area and the subject's weight. The overall median peak serum drug concentrations at the end of week 4 was between 0.26 and 1.06 ng/ml except in a 2-year old female who was administered 2 packets of study drug per dose, had a Cmax of 9.66 ng/mL after multiple dosing. Children aged 2–5 years received doses of 12.5 mg (one packet) or 25 mg (two packets) of imiquimod and had median multiple-dose peak serum drug levels of approximately 0.2 or 0.5 ng/mL, respectively. Children aged 6–12 years received doses of 12.5 mg, 25 mg, or 37.5 mg (three packets) and had median multiple dose serum drug levels of approximately 0.1, 0.15, or 0.3 ng/mL, respectively. Among the 20 subjects with evaluable laboratory assessments, the median WBC count decreased by 1.4109/L and the median absolute neutrophil count decreased by 1.42109/L. ### Geriatic Use - Of the 320 subjects treated with ZYCLARA Cream in the AK clinical studies, 150 subjects (47%) were 65 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. - Clinical studies of ZYCLARA Cream for EGW did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 400 subjects treated with ZYCLARA Cream, 3.75% in the EGW clinical studies, 5 subjects (1%) were 65 years or older. ### Gender - There is no FDA guidance on the use of Imiquimod with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Imiquimod with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Imiquimod in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Imiquimod in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Imiquimod in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Imiquimod in patients who are immunocompromised. # Administration and Monitoring ### Administration - For topical use only; ZYCLARA Cream is not for oral, ophthalmic, intra-anal or intravaginal use. Actinic Keratosis - ZYCLARA Cream should be applied once daily before bedtime to the skin of the affected area (either entire face or balding scalp) for two 2-week treatment cycles separated by a 2-week no-treatment period. ZYCLARA Cream should be applied as a thin film to the entire treatment area and rubbed in until the cream is no longer visible. Up to 0.5 grams (2 packets or 2 full actuations of the pump) of ZYCLARA Cream may be applied to the treatment area at each application. ZYCLARA Cream should be left on the skin for approximately 8 hours, after which time the cream should be removed by washing the area with mild soap and water. The prescriber should demonstrate the proper application technique to maximize the benefit of ZYCLARA Cream therapy. - Patients should wash their hands before and after applying ZYCLARA Cream. - Avoid use in or on the lips and nostrils. Do not use in or near the eyes. - Local skin reactions in the treatment area are common. A rest period of several days may be taken if required by the patient's discomfort or severity of the local skin reaction. However, neither 2-week treatment cycle should be extended due to missed doses or rest periods. A transient increase in lesion counts may be observed during treatment. Response to treatment cannot be adequately assessed until resolution of local skin reactions. The patient should continue dosing as prescribed. Treatment should continue for the full treatment course even if all actinic keratoses appear to be gone. Lesions that do not respond to treatment should be carefully re-evaluated and management reconsidered. - Prescribe no more than 2 boxes (56 packets), two 7.5g pumps or one 15g pump for the total 2-cycle treatment course. Partially-used packets should be discarded and not reused. External Genital Warts - Patients should apply a thin layer of ZYCLARA Cream once a day to the external genital/perianal warts until total clearance or for up to 8 weeks. Patients should use up to 0.25 grams (one packet or one full actuation of the pump) at each application, which is a sufficient amount of cream to cover the wart area. ZYCLARA Cream should be applied prior to normal sleeping hours and left on the skin for approximately 8 hours, then removed by washing the area with mild soap and water. The prescriber should demonstrate the proper application technique to maximize the benefit of ZYCLARA Cream therapy. - Patients should wash their hands before and after applying ZYCLARA Cream. - Local skin reactions at the treatment site are common, and may necessitate a rest period of several days; resume treatment once the reaction subsides. Non-occlusive dressings such as cotton gauze or cotton underwear may be used in the management of skin reactions. - Prescribe up to 2 boxes (56 packets), two 7.5g pumps or one 15g pump for the total treatment course. Use of excessive amounts of cream should be avoided. Partially-used packets should be discarded and not reused. Pump Administration - ZYCLARA (imiquimod) Cream pumps should be primed before using for the first time by repeatedly depressing the actuator until cream is dispensed. It is not necessary to repeat this priming process during treatment. ### Dosage forms and strengths - ZYCLARA Cream, 2.5% is a white to faintly yellow cream available in single-use packets and pump bottles. Each packet administers 0.25 grams of cream and each pump bottle, when actuated after priming, delivers 0.235 grams of cream (a similar amount as one packet). - ZYCLARA Cream, 3.75% is a white to faintly yellow cream available in single-use packets and pump bottles. Each packet administers 0.25 grams of cream and each pump bottle, when actuated after priming, delivers 0.235 grams of cream (a similar amount as one packet). ### Monitoring There is limited information regarding Monitoring of Imiquimod in the drug label. - Description # IV Compatibility - There is limited information regarding IV Compatibility of Imiquimod in the drug label. # Overdosage - Topical overdosing of ZYCLARA Cream could result in an increased incidence of severe local skin reactions and may increase the risk for systemic reactions. - Hypotension was reported in a clinical trial following multiple oral imiquimod doses of >200 mg (equivalent to ingestion of the imiquimod content of more than 21 packets or pump actuations of ZYCLARA Cream, 3.75% or more than 32 packets or pump actuations of ZYCLARA Cream, 2.5%). The hypotension resolved following oral or intravenous fluid administration. # Pharmacology ## Mechanism of Action - The mechanism of action of ZYCLARA Cream in treating AK and EGW lesions is unknown. ## Structure - ZYCLARA (imiquimod) Cream, 2.5% or 3.75% is intended for topical administration. Each gram contains 25 mg or 37.5 mg of imiquimod, respectively, in a white to faintly yellow oil-in-water cream base consisting of isostearic acid, cetyl alcohol, stearyl alcohol, white petrolatum, polysorbate 60, sorbitan monostearate, glycerin, xanthan gum, purified water, benzyl alcohol, methylparaben, and propylparaben. - Chemically, imiquimod is 1-(2-methylpropyl)-1H-imidazolquinolin-4-amine. Imiquimod has a molecular formula of C14H16N4 and a molecular weight of 240.3. Its structural formula is: - ZYCLARA (imiquimod) Cream, 2.5% and 3.75% come as premeasured packets containing 6.25 mg and 9.4 mg of imiquimod, respectively, in 0.25 g of cream. ZYCLARA (imiquimod) Cream, 2.5% and 3.75% also come in pumps which dispense 5.9 mg or 8.8 mg of imiquimod, respectively, in 0.235 g of cream per full actuation of the pump after priming. ## Pharmacodynamics The pharmacodynamics of ZYCLARA Cream are unknown. - Imiquimod is a Toll-like receptor 7 agonist that activates immune cells. Topical application to skin is associated with increases in markers for cytokines and immune cells. Actinic Keratosis - In a study of 18 subjects with AK comparing imiquimod cream, 5% to vehicle, increases from baseline in week 2 biomarker levels were reported for CD3, CD4, CD8, CD11c, and CD68 for imiquimod cream, 5% treated subjects; however, the clinical relevance of these findings is unknown. External Genital Warts - Imiquimod has no direct antiviral activity in cell culture. ## Pharmacokinetics - Following dosing with 2 packets of ZYCLARA Cream, 3.75% once daily (18.75 mg imiquimod/day) for up to three weeks, systemic absorption of imiquimod was observed in all subjects when ZYCLARA Cream was applied to the face and/or scalp in 17 subjects with at least 10 AK lesions. The mean peak serum imiquimod concentration at the end of the trial was approximately 0.323 ng/mL. The median time to maximal concentrations (Tmax) occurred at 9 hours after dosing. Based on the plasma half-life of imiquimod observed at the end of the study, 29.3±17.0 hours, steady-state concentrations can be anticipated to occur by day 7 with once daily dosing. - Systemic absorption of imiquimod (up to 9.4 mg ) across the affected skin of 18 subjects with EGW was observed with once daily dosing for 3 weeks in all subjects. The subjects had either a minimum of 8 warts (range 8–93) or a surface area involvement of greater than 100mm2 (range 15–620mm2) at study entry. The mean peak serum imiquimod concentration at Day 21 was 0.488 +/- 0.368 ng/mL. The median time to maximal concentrations (Tmax) occurred 12 hours after dosing. Based on the plasma half-life of imiquimod observed at the end of the study, 24.1+/- 12.4 hours, steady-state concentrations can be anticipated to occur by day 7 with once daily dosing. Because of the small number of subjects present (13 males, 5 females) it was not possible to select out or do an analysis of absorption based on gender/site of application. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - In an oral (gavage) rat carcinogenicity study, imiquimod was administered to Wistar rats on a 2×/week (up to 6 mg/kg/day) or daily (3 mg/kg/day) dosing schedule for 24 months. No treatment related tumors were noted in the oral rat carcinogenicity study up to the highest doses tested in this study of 6 mg/kg administered 2×/week in female rats (7.1× MRHD based on weekly AUC comparisons), 4 mg/kg administered 2×/week in male rats (6.1× MRHD based on weekly AUC comparisons) or 3 mg/kg administered 7×/week to male and female rats (12× MRHD based on weekly AUC comparisons). - In a dermal mouse carcinogenicity study, imiquimod cream (up to 5 mg/kg/application imiquimod or 0.3% imiquimod cream) was applied to the backs of mice 3×/week for 24 months. A statistically significant increase in the incidence of liver adenomas and carcinomas was noted in high dose male mice compared to control male mice (21× MRHD based on weekly AUC comparisons). An increased number of skin papillomas was observed in vehicle cream control group animals at the treated site only. - In a 52-week dermal photo-carcinogenicity study, the median time to onset of skin tumor formation was decreased in hairless mice following chronic topical dosing (3×/week; 40 weeks of treatment followed by 12 weeks of observation) with concurrent exposure to UV radiation (5 days per week) with vehicle alone. No additional effect on tumor development beyond the vehicle effect was noted with the addition of the active ingredient, imiquimod, to the vehicle cream. - Imiquimod revealed no evidence of mutagenic or clastogenic potential based on the results of five in vitro genotoxicity tests (Ames assay, mouse lymphoma L5178Y assay, Chinese hamster ovary cell chromosome aberration assay, human lymphocyte chromosome aberration assay and SHE cell transformation assay) and three in vivo genotoxicity tests (rat and hamster bone marrow cytogenetics assay and a mouse dominant lethal test). - Daily oral administration of imiquimod to rats, throughout mating, gestation, parturition and lactation, demonstrated no effects on growth, fertility or reproduction, at doses up to 25× MRHD based on AUC comparisons. # Clinical Studies Actinic Keratosis - In two double-blind, randomized, vehicle-controlled clinical studies, 479 subjects with AK were treated with ZYCLARA Cream, 3.75%, ZYCLARA Cream, 2.5%, or vehicle cream. Studies enrolled subjects 18 years of age or older with 5 to 20 typical visible or palpable AK lesions of the face or scalp. Study cream was applied to either the entire face (excluding ears) or balding scalp once daily for two 2-week treatment cycles separated by a 2-week no-treatment period. Subjects then continued in the study for an 8-week follow-up period during which they returned for clinical observations and safety monitoring. Study subjects ranged from 36 to 90 years of age and 54% had Fitzpatrick skin type I or II. All ZYCLARA Cream-treated subjects were Caucasians. - On a scheduled dosing day, up to two packets of the study cream were applied to the entire treatment area prior to normal sleeping hours and left on for approximately 8 hours. Efficacy was assessed by AK lesion counts at the 8-week post-treatment visit. All AKs in the treatment area were counted, including baseline lesions as well as lesions which appeared during therapy. - Complete clearance required absence of any lesions including those that appeared during therapy in the treatment area. Complete and partial clearance rates are shown in the tables below. Partial clearance rate was defined as the percentage of subjects in whom the number of baseline AKs was reduced by 75% or more. The partial clearance rate was measured relative to the numbers of AK lesions at baseline. - During the course of treatment, 86% (138/160) of ZYCLARA Cream, 3.75% subjects and 84% (135/160) of ZYCLARA Cream, 2.5% subjects experienced a transient increase in lesions evaluated as actinic keratoses relative to the number present at baseline within the treatment area. External Genital Warts - In two double-blind, randomized, placebo-controlled clinical studies, 601 subjects with EGW were treated with 3.75% imiquimod cream, or a matching placebo cream. Studies enrolled subjects aged from 15 to 81 years. The baseline wart area ranged from 6 to 5579 mm2 (median 60 mm2) and the baseline wart count ranged from 2 to 48 warts. Most subjects had two or more treated anatomic areas at baseline. Anatomic areas included: inguinal, perineal, and perianal areas (both genders); the glans penis, penis shaft, scrotum, and foreskin (in men); and the vulva (in women). Up to one packet of study cream was applied once daily. The study cream was applied to all warts prior to normal sleeping hours and left on for approximately 8 hours. Subjects continued applying the study cream for up to 8 weeks, stopping if they achieved complete clearance of all (baseline and new) warts in all anatomic areas. Subjects who achieved complete clearance of all warts at any time up to the Week 16 visit enter a 12 week follow-up period to assess recurrence. - Complete clearance was defined as clearance of all warts (baseline and new) in all anatomic areas within 16 weeks from baseline. The complete clearance rates are shown in Table 7. The proportions of subjects who achieved complete clearance at or before a given week (cumulative proportion) for the combined studies are shown in Figure 1. Complete clearance rates by gender for the combined studies are shown in Table 8. - Of the 113 ZYCLARA Cream, 3.75%-treated subjects who achieved complete clearance in the two studies, 17 (15%) subjects had a recurrence within 12 weeks. - No studies were conducted directly comparing the 3.75% and 5% concentrations of imiquimod cream in the treatment of external genital warts. # How Supplied - ZYCLARA (imiquimod) Cream, 2.5% or 3.75% is white to faintly yellow in color and supplied in single-use plastic laminate packets which contain 0.25 g of the cream available as: - Box of 28 packets containing 2.5% cream NDC 99207-275-28. - Box of 28 packets containing 3.75% cream NDC 99207-270-28. - ZYCLARA (imiquimod) Cream, 2.5% and 3.75% is also supplied as white plastic 30 mL pump bottles, equipped with a white cap. The 7.5 g pump delivers no fewer than 28 full actuations. The 15 g pump delivers no fewer than 56 full actuations. - 7.5 g of the 2.5% cream, NDC 99207-276-75. - 15 g of the 2.5% cream, NDC 99207-276-15. - 7.5 g of the 3.75% cream, NDC 99207-271-75. - 15 g of the 3.75% cream, NDC 99207-271-15. ## Storage - Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) . Avoid freezing. - Store ZYCLARA Cream pumps upright. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information "See FDA-approved patient labeling (Patient Information)" Instructions for Administration - ZYCLARA Cream should be used as directed by a physician. ZYCLARA Cream is for external use only. Contact with the eyes, lips, nostrils, anus and vagina should be avoided. - The treatment area should not be bandaged or otherwise occluded. Partially-used packets should be discarded and not reused. Pumps should be discarded after completion of a full treatment course. The prescriber should demonstrate the proper application technique to maximize the benefit of ZYCLARA Cream therapy. - It is recommended that patients wash their hands before and after applying ZYCLARA Cream. Local Skin Reactions - Patients may experience local skin reactions during treatment with ZYCLARA Cream. Potential local skin reactions include erythema, edema, erosions/ulcerations, weeping/exudate, flaking/scaling/dryness, and scabbing/crusting. These reactions can range from mild to severe in intensity and may extend beyond the application site onto the surrounding skin. Patients may also experience application site reactions such as itching, irritation or pain. - Local skin reactions may be of such an intensity that patients may require rest periods from treatment. Treatment with ZYCLARA Cream can be resumed after the skin reaction has subsided, as determined by the physician. However, for actinic keratosis, each treatment cycle should not be extended beyond 2 weeks due to missed doses or rest periods. For external genital warts, treatment should not be extended beyond 8 weeks due to missed doses or rest periods. Patients should contact their physician promptly if they experience any sign or symptom at the application site that restricts or prohibits their daily activity or makes continued application of the cream difficult. - Because of local skin reactions, during treatment and until healed, the treatment area is likely to appear noticeably different from normal skin. Localized hypopigmentation and hyperpigmentation have been reported following use of imiquimod cream. These skin color changes may be permanent in some patients. Systemic Reactions - Patients may experience flu-like systemic signs and symptoms during treatment with ZYCLARA Cream. Systemic signs and symptoms may include fatigue, nausea, fever, myalgia, malaise, arthralgia, and chills. An interruption of dosing and an assessment of the patient should be considered. Patients Being Treated for Actinic Keratosis (AK) - Dosing is once daily before bedtime to the skin of the affected area (entire face or balding scalp) for two 2-week treatment cycles separated by a 2-week no-treatment period. However, the treatment period should not be extended beyond two 2-week treatment cycles due to missed doses or rest periods. Treatment should continue for the full treatment course even if all actinic keratoses appear to be gone. - It is recommended that patients wash their hands before and after applying ZYCLARA Cream. Before applying the cream, the patient should wash the treatment area with mild soap and water and allow the area to dry thoroughly. - It is recommended that the treatment area be washed with mild soap and water 8 hours following ZYCLARA Cream application. - Most patients using ZYCLARA Cream for the treatment of AK experience erythema, flaking/scaling/dryness and scabbing/crusting at the application site with normal dosing. - Use of sunscreen is encouraged, and patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using ZYCLARA Cream. - Additional lesions may become apparent in the treatment area during treatment. Patients Being Treated for External Genital Warts (EGW) - Dosing is once daily before bedtime to the skin of the affected wart areas. ZYCLARA Cream treatment should continue until there is total clearance of the genital/perianal warts or for up to 8 weeks. - It is recommended that the treatment area be washed with mild soap and water approximately 8 hours following ZYCLARA Cream application. - It is common for patients to experience local skin reactions such as erythema, erosion, exudate, flaking/scaling, scabbing/crusting and edema at the site of application or surrounding areas. - Sexual (genital, anal, oral) contact should be avoided while ZYCLARA Cream is on the skin. Application of ZYCLARA Cream in the vagina is considered internal and should be avoided. Female patients should take special care if applying the cream at the opening of the vagina because local skin reactions on the delicate moist surfaces can result in pain or swelling, and may cause difficulty in passing urine. - Uncircumcised males treating warts under the foreskin should retract the foreskin and clean the area daily. - New warts may develop during therapy, as ZYCLARA Cream is not a cure. - The effect of ZYCLARA Cream on the transmission of genital/perianal warts is unknown. - ZYCLARA Cream may weaken condoms and vaginal diaphragms, therefore concurrent use is not recommended. - Should severe local skin reaction occur, the cream should be removed by washing the treatment area with mild soap and water. # Precautions with Alcohol - Alcohol-Imiquimod interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Aldara, Zyclara. # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Imiquimod Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Imiquimod is an immnunologic adjuvant that is FDA approved for the treatment of actinic keratosis, external genital warts. Common adverse reactions include erythema, edema, erosion/ulceration, exudate, scabbing/crusting, headache, application site pain, application site irritation, application site pruritus, fatigue, influenza-like illness, and nausea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - ZYCLARA Cream, 2.5% and 3.75% are indicated for the topical treatment of clinically typical visible or palpable, actinic keratoses (AK), of the full face or balding scalp in immunocompetent adults. - Dosing Information - ZYCLARA Cream should be applied once daily before bedtime to the skin of the affected area (either entire face or balding scalp) for two 2-week treatment cycles separated by a 2-week no-treatment period. ZYCLARA Cream should be applied as a thin film to the entire treatment area and rubbed in until the cream is no longer visible. Up to 0.5 grams (2 packets or 2 full actuations of the pump) of ZYCLARA Cream may be applied to the treatment area at each application. ZYCLARA Cream should be left on the skin for approximately 8 hours, after which time the cream should be removed by washing the area with mild soap and water. The prescriber should demonstrate the proper application technique to maximize the benefit of ZYCLARA Cream therapy. - Patients should wash their hands before and after applying ZYCLARA Cream. - Avoid use in or on the lips and nostrils. Do not use in or near the eyes. - Local skin reactions in the treatment area are common. A rest period of several days may be taken if required by the patient's discomfort or severity of the local skin reaction. However, neither 2-week treatment cycle should be extended due to missed doses or rest periods. A transient increase in lesion counts may be observed during treatment. Response to treatment cannot be adequately assessed until resolution of local skin reactions. The patient should continue dosing as prescribed. Treatment should continue for the full treatment course even if all actinic keratoses appear to be gone. Lesions that do not respond to treatment should be carefully re-evaluated and management reconsidered. - Prescribe no more than 2 boxes (56 packets), two 7.5g pumps or one 15g pump for the total 2-cycle treatment course. Partially-used packets should be discarded and not reused. - ZYCLARA Cream, 3.75% is indicated for the treatment of external genital and perianal warts (EGW)/condyloma acuminata in patients 12 years or older. - Dosing Information - Patients should apply a thin layer of ZYCLARA Cream once a day to the external genital/perianal warts until total clearance or for up to 8 weeks. Patients should use up to 0.25 grams (one packet or one full actuation of the pump) at each application, which is a sufficient amount of cream to cover the wart area. ZYCLARA Cream should be applied prior to normal sleeping hours and left on the skin for approximately 8 hours, then removed by washing the area with mild soap and water. The prescriber should demonstrate the proper application technique to maximize the benefit of ZYCLARA Cream therapy. - Patients should wash their hands before and after applying ZYCLARA Cream. - Local skin reactions at the treatment site are common, and may necessitate a rest period of several days; resume treatment once the reaction subsides. Non-occlusive dressings such as cotton gauze or cotton underwear may be used in the management of skin reactions. - Prescribe up to 2 boxes (56 packets), two 7.5g pumps or one 15g pump for the total treatment course. Use of excessive amounts of cream should be avoided. Partially-used packets should be discarded and not reused. - Dosing Information - Tumors 0.5 cm to less than 1 cm in diameter, apply a 4 mm diameter cream droplet (10 mg); tumors 1 cm to less than 1.5 cm in diameter, apply a 5 mm diameter cream droplet (25 mg); tumors 1.5 cm to 2 cm in diameter, apply a 7 mm cream droplet (40 mg of cream) Limitations of Use - Imiquimod cream has been evaluated in children ages 2 to 12 years with molluscum contagiosum and these studies failed to demonstrate efficacy. - Treatment with ZYCLARA Cream has not been studied for prevention or transmission of HPV. Unevaluated Populations - The safety and efficacy of ZYCLARA Cream have not been established in the treatment of: - urethral, intra-vaginal, cervical, rectal or intra-anal human papilloma viral disease. - actinic keratosis when treated with more than one 2-cycle treatment course in the same area. - patients with xeroderma pigmentosum. - superficial basal cell carcinoma. - immunosuppressed patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use ### Condyloma acuminatum, external - HIV infection - Recommendation: Adult, Class IIb - Strength of Evidence: Adult, Category B - Dosing information - For the treatment of uncomplicated external genital warts in patients with human immunodeficiency virus, apply imiquimod 5% cream to the lesion at bedtime, 3 times per week on nonconsecutive nights. Wash with soap and water 6 to 10 hours after each application. Treatment may continue for up to 16 weeks. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Imiquimod in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - ZYCLARA Cream, 3.75% is indicated for the treatment of external genital and perianal warts (EGW)/condyloma acuminata in patients 12 years or older. - Dosing information - Zyclara(R) - For the treatment of children 12 years and older with external genital and perianal warts/condyloma acuminata, apply up to 1 packet or 1 pump actuation of 3.75% cream topically to warts once daily at bedtime until total clearance or up to a duration of 8 weeks. Leave on the skin for 8 hours then wash area with mild soap and water. - Aldara(R) - For the treatment of external genital and perianal warts/condyloma acuminata in patients 12 years of age or older, apply up to one imiquimod 5% cream packet to the treatment area 3 times per week until total genital and perianal wart clearance or for a maximum duration of 16 weeks. Each imiquimod packet contains enough cream to cover a wart area of up to 20 square centimeters. Apply a thin layer of cream prior to normal sleeping hours and leave on the skin for 6 to 10 hours. Following each treatment period, remove the cream by washing the treated area with soap and water. Examples of 3 times per week application schedules are: Monday, Wednesday, and Friday or Tuesday, Thursday, and Saturday. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use ### Condyloma acuminatum, external - HIV infection - Recommendation: Pediatric, Class IIb - Strength of Evidence: Pediatric, Category C - Dosing information - For the treatment of uncomplicated external genital warts in children with human immunodeficiency virus, apply imiquimod 5% cream to the lesion at bedtime, 3 times per week on nonconsecutive nights. Wash with soap and water 6 to 10 hours after each application. Treatment may continue for up to 16 weeks. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Imiquimod in pediatric patients. # Contraindications - None. # Warnings Local Skin Reactions - Intense local skin reactions including skin weeping or erosion can occur after a few applications of ZYCLARA Cream and may require an interruption of dosing. ZYCLARA Cream has the potential to exacerbate inflammatory conditions of the skin, including chronic graft versus host disease. - Severe local inflammatory reactions of the female external genitalia can lead to severe vulvar swelling. Severe vulvar swelling can lead to urinary retention. Dosing should be interrupted or discontinued for severe vulvar swelling. - Administration of ZYCLARA Cream is not recommended until the skin is healed from any previous drug or surgical treatment. Systemic Reactions - Flu-like signs and symptoms may accompany, or even precede, local skin reactions and may include fatigue, nausea, fever, myalgias, arthralgias, malaise and chills. An interruption of dosing and an assessment of the patient should be considered. - Lymphadenopathy occurred in 2% of subjects with actinic keratosis treated with ZYCLARA Cream, 3.75% and in 3% of subjects treated with ZYCLARA Cream, 2.5%. This reaction resolved in all subjects by 4 weeks after completion of treatment. Ultraviolet Light Exposure Risks - Exposure to sunlight (including sunlamps) should be avoided or minimized during use of ZYCLARA Cream. Patients should be warned to use protective clothing (e.g., a hat) when using ZYCLARA Cream. Patients with sunburn should be advised not to use ZYCLARA Cream until fully recovered. Patients who may have considerable sun exposure, e.g. due to their occupation, and those patients with inherent sensitivity to sunlight should exercise caution when using ZYCLARA Cream. - In an animal photo-carcinogenicity study, imiquimod cream shortened the time to skin tumor formation. The enhancement of ultraviolet carcinogenicity is not necessarily dependent on phototoxic mechanisms. Therefore, patients should minimize or avoid natural or artificial sunlight exposure. Increased Risk of Adverse Reactions with Concomitant Imiquimod Use - Concomitant use of ZYCLARA Cream and any other imiquimod products, in the same treatment area, should be avoided since they contain the same active ingredient (imiquimod) and may increase the risk for and severity of local skin reactions. - The safety of concomitant use of ZYCLARA Cream and any other imiquimod products has not been established and should be avoided since they contain the same active ingredient (imiquimod) and may increase the risk for and severity of systemic reactions. Immune Cell Activation in Autoimmune Disease - ZYCLARA Cream should be used with caution in patients with pre-existing autoimmune conditions because imiquimod activates immune cells. # 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 Trials Experience: Actinic Keratosis - The data described below reflect exposure to ZYCLARA Cream or vehicle in 479 subjects enrolled in two double-blind, vehicle-controlled trials. Subjects applied up to two packets of ZYCLARA Cream or vehicle daily to the skin of the affected area (either entire face or balding scalp) for two 2-week treatment cycles separated by a 2-week no treatment period. - Overall, in the clinical trials, 11% (17/160) of subjects in the ZYCLARA Cream, 3.75% arm, 7% (11/160) of subjects in the ZYCLARA Cream, 2.5% arm, and 0% in the vehicle cream arm required rest periods due to adverse local skin reactions. - Other adverse reactions observed in subjects treated with ZYCLARA Cream include: application site bleeding, application site swelling, chills, dermatitis, herpes zoster, insomnia, lethargy, myalgia, pancytopenia, pruritus, squamous cell carcinoma, and vomiting. Clinical Trials Experience: External Genital Warts - In two double-blind, placebo-controlled studies 602 subjects applied up to one packet of ZYCLARA Cream or vehicle daily for up to 8 weeks. - The most frequently reported adverse reactions were application site reactions and local skin reactions. Selected adverse reactions are listed in Table 3. - The frequency and severity of local skin reactions were similar in both genders, with the following exceptions: a) flaking/scaling occurred in 40% of men and in 26% of women and b) scabbing/crusting occurred in 34% of men and in 18% of women. - In the clinical trials, 32% (126/400) of subjects who used ZYCLARA Cream and 2% (4/202) of subjects who used vehicle cream discontinued treatment temporarily (required rest periods) due to adverse local skin reactions, and 1% (3/400) of subjects who used ZYCLARA Cream discontinued treatment permanently due to local skin/application site reactions. - Other adverse reactions reported in subjects treated with ZYCLARA Cream include: rash, back pain, application site rash, application site cellulitis, application site excoriation, application site bleeding, scrotal pain, scrotal erythema, scrotal ulcer, scrotal edema, sinusitis, nausea, pyrexia, and influenza-like symptoms. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of imiquimod. 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. - Application Site Disorders: tingling at the application site - Body as a Whole: angioedema - Cardiovascular: capillary leak syndrome, cardiac failure, cardiomyopathy, pulmonary edema, arrhythmias (tachycardia, supraventricular tachycardia, atrial fibrillation, palpitations), chest pain, ischemia, myocardial infarction, syncope - Endocrine: thyroiditis - Gastro-Intestinal System Disorders: abdominal pain - Hematological: decreases in red cell, white cell and platelet counts (including idiopathic thrombocytopenic purpura), lymphoma - Hepatic: abnormal liver function - Infections and Infestations: herpes simplex - Musculo-Skeletal System Disorders: arthralgia - Neuropsychiatric: agitation, cerebrovascular accident, convulsions (including febrile convulsions), depression, insomnia, multiple sclerosis aggravation, paresis, suicide - Respiratory: dyspnea - Urinary System Disorders: proteinuria, urinary retention, dysuria - Skin and Appendages: exfoliative dermatitis, erythema multiforme, hyperpigmentation, hypertrophic scar, hypopigmentation - Vascular: Henoch-Schonlein purpura syndrome # Drug Interactions - Drug - Description # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There are no adequate and well-controlled studies in pregnant women. ZYCLARA Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - The animal multiples of human exposure calculations were based on daily dose comparisons for the reproductive toxicology studies described in this section and in Section 13.1. The animal multiples of human exposure were based on weekly dose comparisons for the carcinogenicity studies described in Section 13.1. For the animal multiple of human exposure ratios presented in this section and Section 13.1, the Maximum Recommended Human Dose (MRHD) was set at 2 packets (500 mg cream) per treatment of actinic keratosis with ZYCLARA Cream (imiquimod 3.75%, 18.75 mg imiquimod) for BSA comparison. The maximum human AUC value obtained in the treatment of external genital and perianal warts was higher than that obtained in the treatment of actinic keratosis and was used in the calculation of animal multiples of MRHD that were based on AUC comparison. - Systemic embryofetal development studies were conducted in rats and rabbits. Oral doses of 1, 5 and 20 mg/kg/day imiquimod were administered during the period of organogenesis (gestational days 6 – 15) to pregnant female rats. In the presence of maternal toxicity, fetal effects noted at 20 mg/kg/day (163× MRHD based on AUC comparisons) included increased resorptions, decreased fetal body weights, delays in skeletal ossification, bent limb bones, and two fetuses in one litter (2 of 1567 fetuses) demonstrated exencephaly, protruding tongues and low-set ears. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 5 mg/kg/day (28× MRHD based on AUC comparisons). - Intravenous doses of 0.5, 1 and 2 mg/kg/day imiquimod were administered during the period of organogenesis (gestational days 6 – 18) to pregnant female rabbits. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 2 mg/kg/day (2.1× MRHD based on BSA comparisons), the highest dose evaluated in this study, or 1 mg/kg/day (115× MRHD based on AUC comparisons). - A combined fertility and peri- and post-natal development study was conducted in rats. Oral doses of 1, 1.5, 3 and 6 mg/kg/day imiquimod were administered to male rats from 70 days prior to mating through the mating period and to female rats from 14 days prior to mating through parturition and lactation. No effects on growth, fertility, reproduction or post-natal development were noted at doses up to 6 mg/kg/day (25× MRHD based on AUC comparisons), the highest dose evaluated in this study. In the absence of maternal toxicity, bent limb bones were noted in the F1 fetuses at a dose of 6 mg/kg/day (25× MRHD based on AUC comparisons). This fetal effect was also noted in the oral rat embryofetal development study conducted with imiquimod. No treatment related effects on teratogenicity were noted at 3 mg/kg/day (12× MRHD based on AUC comparisons). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Imiquimod in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Imiquimod during labor and delivery. ### Nursing Mothers - It is not known whether imiquimod is excreted in human milk following use of ZYCLARA Cream. Because many drugs are excreted in human milk, caution should be exercised when ZYCLARA Cream is administered to nursing women. ### Pediatric Use - AK is a condition not generally seen within the pediatric population. The safety and effectiveness of ZYCLARA Cream for AK in patients less than 18 years of age have not been established. - Safety and effectiveness in patients with external genital/perianal warts below the age of 12 years have not been established. - Imiquimod 5% cream was evaluated in two randomized, vehicle-controlled, double-blind trials involving 702 pediatric subjects with molluscum contagiosum (MC) (470 exposed to imiquimod; median age 5 years, range 2–12 years). Subjects applied imiquimod cream or vehicle 3 times weekly for up to 16 weeks. Complete clearance (no MC lesions) was assessed at Week 18. In Study 1, the complete clearance rate was 24% (52/217) in the imiquimod cream group compared with 26% (28/106) in the vehicle group. In Study 2, the clearance rates were 24% (60/253) in the imiquimod cream group compared with 28% (35/126) in the vehicle group. These studies failed to demonstrate efficacy. - Similar to the studies conducted in adults, the most frequently reported adverse reaction from 2 studies in children with molluscum contagiosum was application site reaction. Adverse events which occurred more frequently in imiquimod-treated subjects compared with vehicle-treated subjects generally resembled those seen in studies in indications approved for adults and also included otitis media (5% imiquimod vs. 3% vehicle) and conjunctivitis (3% imiquimod vs. 2% vehicle). - Erythema was the most frequently reported local skin reaction. Severe local skin reactions reported by imiquimod-treated subjects in the pediatric studies included erythema (28%), edema (8%), scabbing/crusting (5%), flaking/scaling (5%), erosion (2%) and weeping/exudate (2%). - Systemic absorption of imiquimod across the affected skin of 22 subjects aged 2 to 12 years with extensive MC involving at least 10% of the total body surface area was observed after single and multiple doses at a dosing frequency of 3 applications per week for 4 weeks. The investigator determined the dose applied, either 1, 2 or 3 packets per dose, based on the size of the treatment area and the subject's weight. The overall median peak serum drug concentrations at the end of week 4 was between 0.26 and 1.06 ng/ml except in a 2-year old female who was administered 2 packets of study drug per dose, had a Cmax of 9.66 ng/mL after multiple dosing. Children aged 2–5 years received doses of 12.5 mg (one packet) or 25 mg (two packets) of imiquimod and had median multiple-dose peak serum drug levels of approximately 0.2 or 0.5 ng/mL, respectively. Children aged 6–12 years received doses of 12.5 mg, 25 mg, or 37.5 mg (three packets) and had median multiple dose serum drug levels of approximately 0.1, 0.15, or 0.3 ng/mL, respectively. Among the 20 subjects with evaluable laboratory assessments, the median WBC count decreased by 1.4109/L and the median absolute neutrophil count decreased by 1.42109/L. ### Geriatic Use - Of the 320 subjects treated with ZYCLARA Cream in the AK clinical studies, 150 subjects (47%) were 65 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. - Clinical studies of ZYCLARA Cream for EGW did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 400 subjects treated with ZYCLARA Cream, 3.75% in the EGW clinical studies, 5 subjects (1%) were 65 years or older. ### Gender - There is no FDA guidance on the use of Imiquimod with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Imiquimod with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Imiquimod in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Imiquimod in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Imiquimod in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Imiquimod in patients who are immunocompromised. # Administration and Monitoring ### Administration - For topical use only; ZYCLARA Cream is not for oral, ophthalmic, intra-anal or intravaginal use. Actinic Keratosis - ZYCLARA Cream should be applied once daily before bedtime to the skin of the affected area (either entire face or balding scalp) for two 2-week treatment cycles separated by a 2-week no-treatment period. ZYCLARA Cream should be applied as a thin film to the entire treatment area and rubbed in until the cream is no longer visible. Up to 0.5 grams (2 packets or 2 full actuations of the pump) of ZYCLARA Cream may be applied to the treatment area at each application. ZYCLARA Cream should be left on the skin for approximately 8 hours, after which time the cream should be removed by washing the area with mild soap and water. The prescriber should demonstrate the proper application technique to maximize the benefit of ZYCLARA Cream therapy. - Patients should wash their hands before and after applying ZYCLARA Cream. - Avoid use in or on the lips and nostrils. Do not use in or near the eyes. - Local skin reactions in the treatment area are common. A rest period of several days may be taken if required by the patient's discomfort or severity of the local skin reaction. However, neither 2-week treatment cycle should be extended due to missed doses or rest periods. A transient increase in lesion counts may be observed during treatment. Response to treatment cannot be adequately assessed until resolution of local skin reactions. The patient should continue dosing as prescribed. Treatment should continue for the full treatment course even if all actinic keratoses appear to be gone. Lesions that do not respond to treatment should be carefully re-evaluated and management reconsidered. - Prescribe no more than 2 boxes (56 packets), two 7.5g pumps or one 15g pump for the total 2-cycle treatment course. Partially-used packets should be discarded and not reused. External Genital Warts - Patients should apply a thin layer of ZYCLARA Cream once a day to the external genital/perianal warts until total clearance or for up to 8 weeks. Patients should use up to 0.25 grams (one packet or one full actuation of the pump) at each application, which is a sufficient amount of cream to cover the wart area. ZYCLARA Cream should be applied prior to normal sleeping hours and left on the skin for approximately 8 hours, then removed by washing the area with mild soap and water. The prescriber should demonstrate the proper application technique to maximize the benefit of ZYCLARA Cream therapy. - Patients should wash their hands before and after applying ZYCLARA Cream. - Local skin reactions at the treatment site are common, and may necessitate a rest period of several days; resume treatment once the reaction subsides. Non-occlusive dressings such as cotton gauze or cotton underwear may be used in the management of skin reactions. - Prescribe up to 2 boxes (56 packets), two 7.5g pumps or one 15g pump for the total treatment course. Use of excessive amounts of cream should be avoided. Partially-used packets should be discarded and not reused. Pump Administration - ZYCLARA (imiquimod) Cream pumps should be primed before using for the first time by repeatedly depressing the actuator until cream is dispensed. It is not necessary to repeat this priming process during treatment. ### Dosage forms and strengths - ZYCLARA Cream, 2.5% is a white to faintly yellow cream available in single-use packets and pump bottles. Each packet administers 0.25 grams of cream and each pump bottle, when actuated after priming, delivers 0.235 grams of cream (a similar amount as one packet). - ZYCLARA Cream, 3.75% is a white to faintly yellow cream available in single-use packets and pump bottles. Each packet administers 0.25 grams of cream and each pump bottle, when actuated after priming, delivers 0.235 grams of cream (a similar amount as one packet). ### Monitoring There is limited information regarding Monitoring of Imiquimod in the drug label. - Description # IV Compatibility - There is limited information regarding IV Compatibility of Imiquimod in the drug label. # Overdosage - Topical overdosing of ZYCLARA Cream could result in an increased incidence of severe local skin reactions and may increase the risk for systemic reactions. - Hypotension was reported in a clinical trial following multiple oral imiquimod doses of >200 mg (equivalent to ingestion of the imiquimod content of more than 21 packets or pump actuations of ZYCLARA Cream, 3.75% or more than 32 packets or pump actuations of ZYCLARA Cream, 2.5%). The hypotension resolved following oral or intravenous fluid administration. # Pharmacology ## Mechanism of Action - The mechanism of action of ZYCLARA Cream in treating AK and EGW lesions is unknown. ## Structure - ZYCLARA (imiquimod) Cream, 2.5% or 3.75% is intended for topical administration. Each gram contains 25 mg or 37.5 mg of imiquimod, respectively, in a white to faintly yellow oil-in-water cream base consisting of isostearic acid, cetyl alcohol, stearyl alcohol, white petrolatum, polysorbate 60, sorbitan monostearate, glycerin, xanthan gum, purified water, benzyl alcohol, methylparaben, and propylparaben. - Chemically, imiquimod is 1-(2-methylpropyl)-1H-imidazol[4,5-c]quinolin-4-amine. Imiquimod has a molecular formula of C14H16N4 and a molecular weight of 240.3. Its structural formula is: - ZYCLARA (imiquimod) Cream, 2.5% and 3.75% come as premeasured packets containing 6.25 mg and 9.4 mg of imiquimod, respectively, in 0.25 g of cream. ZYCLARA (imiquimod) Cream, 2.5% and 3.75% also come in pumps which dispense 5.9 mg or 8.8 mg of imiquimod, respectively, in 0.235 g of cream per full actuation of the pump after priming. ## Pharmacodynamics The pharmacodynamics of ZYCLARA Cream are unknown. - Imiquimod is a Toll-like receptor 7 agonist that activates immune cells. Topical application to skin is associated with increases in markers for cytokines and immune cells. Actinic Keratosis - In a study of 18 subjects with AK comparing imiquimod cream, 5% to vehicle, increases from baseline in week 2 biomarker levels were reported for CD3, CD4, CD8, CD11c, and CD68 for imiquimod cream, 5% treated subjects; however, the clinical relevance of these findings is unknown. External Genital Warts - Imiquimod has no direct antiviral activity in cell culture. ## Pharmacokinetics - Following dosing with 2 packets of ZYCLARA Cream, 3.75% once daily (18.75 mg imiquimod/day) for up to three weeks, systemic absorption of imiquimod was observed in all subjects when ZYCLARA Cream was applied to the face and/or scalp in 17 subjects with at least 10 AK lesions. The mean peak serum imiquimod concentration at the end of the trial was approximately 0.323 ng/mL. The median time to maximal concentrations (Tmax) occurred at 9 hours after dosing. Based on the plasma half-life of imiquimod observed at the end of the study, 29.3±17.0 hours, steady-state concentrations can be anticipated to occur by day 7 with once daily dosing. - Systemic absorption of imiquimod (up to 9.4 mg [one packet]) across the affected skin of 18 subjects with EGW was observed with once daily dosing for 3 weeks in all subjects. The subjects had either a minimum of 8 warts (range 8–93) or a surface area involvement of greater than 100mm2 (range 15–620mm2) at study entry. The mean peak serum imiquimod concentration at Day 21 was 0.488 +/- 0.368 ng/mL. The median time to maximal concentrations (Tmax) occurred 12 hours after dosing. Based on the plasma half-life of imiquimod observed at the end of the study, 24.1+/- 12.4 hours, steady-state concentrations can be anticipated to occur by day 7 with once daily dosing. Because of the small number of subjects present (13 males, 5 females) it was not possible to select out or do an analysis of absorption based on gender/site of application. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - In an oral (gavage) rat carcinogenicity study, imiquimod was administered to Wistar rats on a 2×/week (up to 6 mg/kg/day) or daily (3 mg/kg/day) dosing schedule for 24 months. No treatment related tumors were noted in the oral rat carcinogenicity study up to the highest doses tested in this study of 6 mg/kg administered 2×/week in female rats (7.1× MRHD based on weekly AUC comparisons), 4 mg/kg administered 2×/week in male rats (6.1× MRHD based on weekly AUC comparisons) or 3 mg/kg administered 7×/week to male and female rats (12× MRHD based on weekly AUC comparisons). - In a dermal mouse carcinogenicity study, imiquimod cream (up to 5 mg/kg/application imiquimod or 0.3% imiquimod cream) was applied to the backs of mice 3×/week for 24 months. A statistically significant increase in the incidence of liver adenomas and carcinomas was noted in high dose male mice compared to control male mice (21× MRHD based on weekly AUC comparisons). An increased number of skin papillomas was observed in vehicle cream control group animals at the treated site only. - In a 52-week dermal photo-carcinogenicity study, the median time to onset of skin tumor formation was decreased in hairless mice following chronic topical dosing (3×/week; 40 weeks of treatment followed by 12 weeks of observation) with concurrent exposure to UV radiation (5 days per week) with vehicle alone. No additional effect on tumor development beyond the vehicle effect was noted with the addition of the active ingredient, imiquimod, to the vehicle cream. - Imiquimod revealed no evidence of mutagenic or clastogenic potential based on the results of five in vitro genotoxicity tests (Ames assay, mouse lymphoma L5178Y assay, Chinese hamster ovary cell chromosome aberration assay, human lymphocyte chromosome aberration assay and SHE cell transformation assay) and three in vivo genotoxicity tests (rat and hamster bone marrow cytogenetics assay and a mouse dominant lethal test). - Daily oral administration of imiquimod to rats, throughout mating, gestation, parturition and lactation, demonstrated no effects on growth, fertility or reproduction, at doses up to 25× MRHD based on AUC comparisons. # Clinical Studies Actinic Keratosis - In two double-blind, randomized, vehicle-controlled clinical studies, 479 subjects with AK were treated with ZYCLARA Cream, 3.75%, ZYCLARA Cream, 2.5%, or vehicle cream. Studies enrolled subjects 18 years of age or older with 5 to 20 typical visible or palpable AK lesions of the face or scalp. Study cream was applied to either the entire face (excluding ears) or balding scalp once daily for two 2-week treatment cycles separated by a 2-week no-treatment period. Subjects then continued in the study for an 8-week follow-up period during which they returned for clinical observations and safety monitoring. Study subjects ranged from 36 to 90 years of age and 54% had Fitzpatrick skin type I or II. All ZYCLARA Cream-treated subjects were Caucasians. - On a scheduled dosing day, up to two packets of the study cream were applied to the entire treatment area prior to normal sleeping hours and left on for approximately 8 hours. Efficacy was assessed by AK lesion counts at the 8-week post-treatment visit. All AKs in the treatment area were counted, including baseline lesions as well as lesions which appeared during therapy. - Complete clearance required absence of any lesions including those that appeared during therapy in the treatment area. Complete and partial clearance rates are shown in the tables below. Partial clearance rate was defined as the percentage of subjects in whom the number of baseline AKs was reduced by 75% or more. The partial clearance rate was measured relative to the numbers of AK lesions at baseline. - During the course of treatment, 86% (138/160) of ZYCLARA Cream, 3.75% subjects and 84% (135/160) of ZYCLARA Cream, 2.5% subjects experienced a transient increase in lesions evaluated as actinic keratoses relative to the number present at baseline within the treatment area. External Genital Warts - In two double-blind, randomized, placebo-controlled clinical studies, 601 subjects with EGW were treated with 3.75% imiquimod cream, or a matching placebo cream. Studies enrolled subjects aged from 15 to 81 years. The baseline wart area ranged from 6 to 5579 mm2 (median 60 mm2) and the baseline wart count ranged from 2 to 48 warts. Most subjects had two or more treated anatomic areas at baseline. Anatomic areas included: inguinal, perineal, and perianal areas (both genders); the glans penis, penis shaft, scrotum, and foreskin (in men); and the vulva (in women). Up to one packet of study cream was applied once daily. The study cream was applied to all warts prior to normal sleeping hours and left on for approximately 8 hours. Subjects continued applying the study cream for up to 8 weeks, stopping if they achieved complete clearance of all (baseline and new) warts in all anatomic areas. Subjects who achieved complete clearance of all warts at any time up to the Week 16 visit enter a 12 week follow-up period to assess recurrence. - Complete clearance was defined as clearance of all warts (baseline and new) in all anatomic areas within 16 weeks from baseline. The complete clearance rates are shown in Table 7. The proportions of subjects who achieved complete clearance at or before a given week (cumulative proportion) for the combined studies are shown in Figure 1. Complete clearance rates by gender for the combined studies are shown in Table 8. - Of the 113 ZYCLARA Cream, 3.75%-treated subjects who achieved complete clearance in the two studies, 17 (15%) subjects had a recurrence within 12 weeks. - No studies were conducted directly comparing the 3.75% and 5% concentrations of imiquimod cream in the treatment of external genital warts. # How Supplied - ZYCLARA (imiquimod) Cream, 2.5% or 3.75% is white to faintly yellow in color and supplied in single-use plastic laminate packets which contain 0.25 g of the cream available as: - Box of 28 packets containing 2.5% cream NDC 99207-275-28. - Box of 28 packets containing 3.75% cream NDC 99207-270-28. - ZYCLARA (imiquimod) Cream, 2.5% and 3.75% is also supplied as white plastic 30 mL pump bottles, equipped with a white cap. The 7.5 g pump delivers no fewer than 28 full actuations. The 15 g pump delivers no fewer than 56 full actuations. - 7.5 g of the 2.5% cream, NDC 99207-276-75. - 15 g of the 2.5% cream, NDC 99207-276-15. - 7.5 g of the 3.75% cream, NDC 99207-271-75. - 15 g of the 3.75% cream, NDC 99207-271-15. ## Storage - Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Avoid freezing. - Store ZYCLARA Cream pumps upright. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information "See FDA-approved patient labeling (Patient Information)" Instructions for Administration - ZYCLARA Cream should be used as directed by a physician. ZYCLARA Cream is for external use only. Contact with the eyes, lips, nostrils, anus and vagina should be avoided. - The treatment area should not be bandaged or otherwise occluded. Partially-used packets should be discarded and not reused. Pumps should be discarded after completion of a full treatment course. The prescriber should demonstrate the proper application technique to maximize the benefit of ZYCLARA Cream therapy. - It is recommended that patients wash their hands before and after applying ZYCLARA Cream. Local Skin Reactions - Patients may experience local skin reactions during treatment with ZYCLARA Cream. Potential local skin reactions include erythema, edema, erosions/ulcerations, weeping/exudate, flaking/scaling/dryness, and scabbing/crusting. These reactions can range from mild to severe in intensity and may extend beyond the application site onto the surrounding skin. Patients may also experience application site reactions such as itching, irritation or pain. - Local skin reactions may be of such an intensity that patients may require rest periods from treatment. Treatment with ZYCLARA Cream can be resumed after the skin reaction has subsided, as determined by the physician. However, for actinic keratosis, each treatment cycle should not be extended beyond 2 weeks due to missed doses or rest periods. For external genital warts, treatment should not be extended beyond 8 weeks due to missed doses or rest periods. Patients should contact their physician promptly if they experience any sign or symptom at the application site that restricts or prohibits their daily activity or makes continued application of the cream difficult. - Because of local skin reactions, during treatment and until healed, the treatment area is likely to appear noticeably different from normal skin. Localized hypopigmentation and hyperpigmentation have been reported following use of imiquimod cream. These skin color changes may be permanent in some patients. Systemic Reactions - Patients may experience flu-like systemic signs and symptoms during treatment with ZYCLARA Cream. Systemic signs and symptoms may include fatigue, nausea, fever, myalgia, malaise, arthralgia, and chills. An interruption of dosing and an assessment of the patient should be considered. Patients Being Treated for Actinic Keratosis (AK) - Dosing is once daily before bedtime to the skin of the affected area (entire face or balding scalp) for two 2-week treatment cycles separated by a 2-week no-treatment period. However, the treatment period should not be extended beyond two 2-week treatment cycles due to missed doses or rest periods. Treatment should continue for the full treatment course even if all actinic keratoses appear to be gone. - It is recommended that patients wash their hands before and after applying ZYCLARA Cream. Before applying the cream, the patient should wash the treatment area with mild soap and water and allow the area to dry thoroughly. - It is recommended that the treatment area be washed with mild soap and water 8 hours following ZYCLARA Cream application. - Most patients using ZYCLARA Cream for the treatment of AK experience erythema, flaking/scaling/dryness and scabbing/crusting at the application site with normal dosing. - Use of sunscreen is encouraged, and patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using ZYCLARA Cream. - Additional lesions may become apparent in the treatment area during treatment. Patients Being Treated for External Genital Warts (EGW) - Dosing is once daily before bedtime to the skin of the affected wart areas. ZYCLARA Cream treatment should continue until there is total clearance of the genital/perianal warts or for up to 8 weeks. - It is recommended that the treatment area be washed with mild soap and water approximately 8 hours following ZYCLARA Cream application. - It is common for patients to experience local skin reactions such as erythema, erosion, exudate, flaking/scaling, scabbing/crusting and edema at the site of application or surrounding areas. - Sexual (genital, anal, oral) contact should be avoided while ZYCLARA Cream is on the skin. Application of ZYCLARA Cream in the vagina is considered internal and should be avoided. Female patients should take special care if applying the cream at the opening of the vagina because local skin reactions on the delicate moist surfaces can result in pain or swelling, and may cause difficulty in passing urine. - Uncircumcised males treating warts under the foreskin should retract the foreskin and clean the area daily. - New warts may develop during therapy, as ZYCLARA Cream is not a cure. - The effect of ZYCLARA Cream on the transmission of genital/perianal warts is unknown. - ZYCLARA Cream may weaken condoms and vaginal diaphragms, therefore concurrent use is not recommended. - Should severe local skin reaction occur, the cream should be removed by washing the treatment area with mild soap and water. # Precautions with Alcohol - Alcohol-Imiquimod interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Aldara, Zyclara. # Look-Alike Drug Names - A® — B®[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Imiquimod
31073f930f2ec42946b6d7fba3b3bfec3acb93f9	wikidoc	Impaction	Impaction # Overview Impaction, from the Latin impingere, is a medical term used to describe several different types of blockage. ## In relation to Digestion Impaction is a pathological condition in humans when an impassable mass of stone-like faecal matter collects in the rectum. It frequently occurs as a result of dehydration, inactivity, and medications, such as narcotics or psychotropicagents, which slow the peristalsis, and increase the time that the colonic mucosa will extract moisture from the faecal bolus. ### Treatment Treatment involves attempts at moving the impaction by enema and, failing that, breaking up the impaction transrectally by using a (gloved) finger, pressing the mass against the coccyx to fracture it into smaller pieces. Proceeding this, A follow-up enema is usually required in addition to proper ongoing hydration, bulk in the diet, exercise and review of all medications to discontinue all those responsible is important to prevent recurrence. Impaction is also used, in conjunction with filtration, to remove large dust particles and other foreign objects as they enter the body through the nose. ## Dental Impaction ### Informal Definition Dental impactions are often known to occur when there is not enough room in the jaw for new molar teeth to erupt properly. This can lead to a variety of dental problems, including cysts. There are several types of dental impaction	Impaction Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Impaction, from the Latin impingere, is a medical term used to describe several different types of blockage. ## In relation to Digestion Impaction is a pathological condition in humans when an impassable mass of stone-like faecal matter collects in the rectum. It frequently occurs as a result of dehydration, inactivity, and medications, such as narcotics or psychotropicagents, which slow the peristalsis, and increase the time that the colonic mucosa will extract moisture from the faecal bolus. [1] ### Treatment Treatment involves attempts at moving the impaction by enema and, failing that, breaking up the impaction transrectally by using a (gloved) finger, pressing the mass against the coccyx to fracture it into smaller pieces. Proceeding this, A follow-up enema is usually required in addition to proper ongoing hydration, bulk in the diet, exercise and review of all medications to discontinue all those responsible is important to prevent recurrence. [1] Impaction is also used, in conjunction with filtration, to remove large dust particles and other foreign objects as they enter the body through the nose. ## Dental Impaction ### Informal Definition Dental impactions are often known to occur when there is not enough room in the jaw for new molar teeth to erupt properly. This can lead to a variety of dental problems, including cysts. There are several types of dental impaction [2]	https://www.wikidoc.org/index.php/Impaction
4d63d208a3b13ebd40825783b52f98cb1d817693	wikidoc	In silico	In silico # Overview In silico is an expression used to mean "performed on computer or via computer simulation." The phrase is coined from the Latin phrases in vivo and in vitro that are commonly used in biology (see also systems biology) and refer to experiments done in living organisms and outside of living organisms, respectively. Contrary to widespread belief, in silico does not mean anything in Latin. # History The expression in silico was first used in public in 1989 in the workshop "Cellular Automata: Theory and Applications" in Los Alamos, New Mexico. Pedro Miramontes, a mathematician from National Autonomous University of Mexico (UNAM) presented the report "DNA and RNA Physicochemical Constraints, Cellular Automata and Molecular Evolution". In his talk, Miramontes used the term "in silico" to characterize biological experiments carried out entirely in a computer. The work was later presented by Miramontes as his PhD dissertation. In silico has been used in white papers written to support the creation of bacterial genome programs by the Commission of the European Community. The first referenced paper where "in silico" appears was written by a French team in 1991. The first referenced book chapter where "in silico" appears was written by Hans B. Sieburg in 1990 and presented during a Summer School on Complex Systems at the Santa Fe Institute. ## In silico versus in silicio "In silico" was briefly challenged by "in silicio," which is correct Latin for "in silicon" (the Latin term for silicon, silicium, was created at the beginning of the 19th century by Berzelius).Template:Citequote "In silico" was perceived as catchier, possibly through similarity to the word "silicate."Template:Citequote "In silico" is now almost universal; it even occurs in a journal title (In Silico Biology: /). The phrase "in silico" originally applied only to computer simulations that modeled natural or laboratory processes (in all the natural sciences), and did not refer to calculations done by computer generically.	In silico # Overview In silico is an expression used to mean "performed on computer or via computer simulation." The phrase is coined from the Latin phrases in vivo and in vitro that are commonly used in biology (see also systems biology) and refer to experiments done in living organisms and outside of living organisms, respectively. Contrary to widespread belief, in silico does not mean anything in Latin. # History The expression in silico was first used in public in 1989 in the workshop "Cellular Automata: Theory and Applications" in Los Alamos, New Mexico. Pedro Miramontes, a mathematician from National Autonomous University of Mexico (UNAM) presented the report "DNA and RNA Physicochemical Constraints, Cellular Automata and Molecular Evolution". In his talk, Miramontes used the term "in silico" to characterize biological experiments carried out entirely in a computer. The work was later presented by Miramontes as his PhD dissertation.[1] In silico has been used in white papers written to support the creation of bacterial genome programs by the Commission of the European Community. The first referenced paper where "in silico" appears was written by a French team in 1991.[2] The first referenced book chapter where "in silico" appears was written by Hans B. Sieburg in 1990 and presented during a Summer School on Complex Systems at the Santa Fe Institute.[3] ## In silico versus in silicio "In silico" was briefly challenged by "in silicio," which is correct Latin for "in silicon" (the Latin term for silicon, silicium, was created at the beginning of the 19th century by Berzelius).Template:Citequote "In silico" was perceived as catchier, possibly through similarity to the word "silicate."Template:Citequote "In silico" is now almost universal; it even occurs in a journal title (In Silico Biology: http://www.bioinfo.de/isb/). The phrase "in silico" originally applied only to computer simulations that modeled natural or laboratory processes (in all the natural sciences), and did not refer to calculations done by computer generically.	https://www.wikidoc.org/index.php/In_silico
a7ba471743ff551ac5c9c7da164dee092df25f8c	wikidoc	Incidence	Incidence Incidence is the number of new cases of a disease during a given time interval, usually one year. It can be expressed as a proportion or as a rate. Incidence proportion (also known as risk) is the number of new cases divided by the size of the population at risk. For example, if a stable population contains 1,000 persons and 28 develop a condition over two years of observation, the incidence proportion is 28 cases per 1,000 persons. The incidence rate is the number of new cases per unit of person-time at risk. In the same example as above, the incidence rate is 14 cases per 1000 person-years, because the incidence proportion (28 per 1,000) is divided by the number of years (two). Using person-time rather than just time handles situations where some people drop out of a study. Incidence is sometimes used alone as a shorthand for incidence rate. Although this is sloppy usage, it is frequently encountered. Incidence should not be confused with prevalence, which is a measure of the total number of cases of disease in a population, rather than the rate of occurrence of new cases. Thus, incidence conveys information about the risk of contracting the disease, whereas prevalence tells us how widespread the disease is. For example, consider a disease that takes a long time to cure, and that was spread widely in 2002, but whose spread was arrested in 2003. This disease will have a high prevalence and a high incidence in 2002; but in 2003 it will have a low incidence, although it will continue to have a high prevalence because it takes a long time to cure. In contrast, a disease that has a short duration may have a low prevalence and a high incidence. Generally speaking, diseases of short duration are better measured with incidence rates, whereas long-lasting or hereditary diseases are better measured with prevalence rates.	Incidence Incidence is the number of new cases of a disease during a given time interval, usually one year. It can be expressed as a proportion or as a rate. Incidence proportion (also known as risk) is the number of new cases divided by the size of the population at risk. For example, if a stable population contains 1,000 persons and 28 develop a condition over two years of observation, the incidence proportion is 28 cases per 1,000 persons. The incidence rate is the number of new cases per unit of person-time at risk. In the same example as above, the incidence rate is 14 cases per 1000 person-years, because the incidence proportion (28 per 1,000) is divided by the number of years (two). Using person-time rather than just time handles situations where some people drop out of a study. Incidence is sometimes used alone as a shorthand for incidence rate. Although this is sloppy usage, it is frequently encountered. Incidence should not be confused with prevalence, which is a measure of the total number of cases of disease in a population, rather than the rate of occurrence of new cases. Thus, incidence conveys information about the risk of contracting the disease, whereas prevalence tells us how widespread the disease is. For example, consider a disease that takes a long time to cure, and that was spread widely in 2002, but whose spread was arrested in 2003. This disease will have a high prevalence and a high incidence in 2002; but in 2003 it will have a low incidence, although it will continue to have a high prevalence because it takes a long time to cure. In contrast, a disease that has a short duration may have a low prevalence and a high incidence. Generally speaking, diseases of short duration are better measured with incidence rates, whereas long-lasting or hereditary diseases are better measured with prevalence rates.[1]	https://www.wikidoc.org/index.php/Incidence
b40216a93a1b7c39b0eeec45c4a215d30d606704	wikidoc	Indoramin	Indoramin # Overview Indoramin (trade names Baratol and Doralese) is a piperidine antiadrenergic agent. It is an alpha-1 selective adrenoceptor antagonist with direct myocardial depression action; therefore, it results in no reflex tachycardia. It is also used in benign prostatic hyperplasia (BPH). It is commonly synthesized from tryptophol. # Dosage Indoramin is commonly prescribed as 20mg tablets when used in BPH. # Side Effects Drowsiness, dizziness, dry mouth, nasal congestion, headache, fatigue, weight gain, hypotension, postural hypotension, depression, problems with ejaculation, diarrhoea, nausea, increased need to pass urine, and palpitations.	Indoramin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Indoramin (trade names Baratol and Doralese) is a piperidine antiadrenergic agent. It is an alpha-1 selective adrenoceptor antagonist[1] with direct myocardial depression action; therefore, it results in no reflex tachycardia. It is also used in benign prostatic hyperplasia (BPH).[2] It is commonly synthesized from tryptophol.[3] # Dosage Indoramin is commonly prescribed as 20mg tablets when used in BPH.[4] # Side Effects Drowsiness, dizziness, dry mouth, nasal congestion, headache, fatigue, weight gain, hypotension, postural hypotension, depression, problems with ejaculation, diarrhoea, nausea, increased need to pass urine, and palpitations.[5]	https://www.wikidoc.org/index.php/Indoramin

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