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860b0cb6fd39a4575c4673ce4744c671c283fc04	wikidoc	Acetylene	Acetylene # Overview Acetylene (systematic name: ethyne) is a hydrocarbon belonging to the group of alkynes. It is considered to be the simplest of all alkynes as it consists of two hydrogen atoms and two carbon atoms. Acetylene is an unsaturated organic compound because its four atoms are triple bonded through a covalent bond. The carbon-carbon triple bond leaves the carbon atoms with two sp hybrid orbitals for sigma bonding, placing all four atoms in the same straight line, with CCH bond angles of 180°. Acetylene was discovered in 1836 by Edmund Davy who identified it as a "new carburet of hydrogen." It was rediscovered in 1860 by French chemist Marcellin Berthelot, who coined the name "acetylene." The Nobel Laureate Gustaf Dalén was blinded by an acetylene explosion. # Preparation The principal raw materials for acetylene manufacture are calcium carbonate (limestone) and coal. The calcium carbonate is first converted into calcium oxide and the coal into coke, then the two are reacted with each other to form calcium carbide and carbon monoxide: Calcium carbide (or calcium acetylide) and water are then reacted by any of several methods to produce acetylene and calcium hydroxide. This reaction was discovered by Friedrich Wohler in 1862. Calcium carbide synthesis requires an extremely high temperature, ~2000 degrees Celsius, so the reaction is performed in an electric arc furnace. This reaction was an important part of the late-1800s revolution in chemistry enabled by the massive hydroelectric power project at Niagara Falls. Acetylene can also be manufactured by the partial combustion of methane with oxygen, or by the cracking of hydrocarbons. Berthelot was able to prepare acetylene from methyl alcohol, ethyl alcohol, ethylene, or ether, when he passed any one of these as a gas or vapour through a red-hot tube. Berthelot also found acetylene was formed by sparking electricity through mixed cyanogen and hydrogen gases. He was also able to form acetylene directly by combining pure hydrogen with carbon using electrical discharge of a carbon arc. # Reactions - Above 400 °C (673 K), which is quite low for a hydrocarbon, the pyrolysis of acetylene will start. The main products are the dimer vinylacetylene (C4H4) and benzene. At temperatures above 900 °C (1173 K), the main product will be soot. - Using acetylene, Berthelot was the first to show that an aliphatic compound could form an aromatic compound when he heated acetylene in a glass tube to produce benzene with some toluene. Berthelot oxidized acetylene to yield acetic acid and oxalic acid. He found acetylene could be reduced to form ethylene and ethane. - Polymerization of acetylene with Ziegler-Natta catalysts produces polyacetylene films. Polyacetylene, a chain of carbon molecules with alternating single and double bonds, was the first organic semiconductor to be discovered; reaction with iodine produces an extremely conductive material. - In the Kucherov reaction (invented in 1881 by the Russian chemist Mikhail Kucherov) acetylene is hydrated to acetaldehyde with a mercury salt such as mercury(II) bromide. Before the advent of the Wacker process this reaction was conducted on an industrial scale . ## Reppe chemistry Walter Reppe discovered that acetylene can react at high pressures with heavy metal catalysts to give industrially significant chemicals: - Acetylene reacting with alcohols, hydrogen cyanide, hydrogen chloride, or carboxylic acids to give vinyl compounds: File:Reppe-chemnistry-vinylization.png - With aldehydes to give ethynyl diols. File:Reppe-chemistry-endiol.png This is industrially used to produce 1,4-butynediol from formaldehyde and acetylene: - With carbon monoxide to give acrylic acid, or acrylic esters, which can be used to produce acrylic glass. File:Reppe-chemistry-carbonmonoxide-01.png File:Reppe-chemistry-carbonmonoxide-02.png - Cyclicization to give benzene and cyclooctatetraene: File:Reppe-chemistry-benzene.png File:Reppe-chemistry-cyclooctatetraene.png # Uses Approximately 80 percent of the acetylene produced annually in the United States is used in chemical synthesis. The remaining 20 percent is used primarily for oxyacetylene gas welding and cutting due to the high temperature of the flame; combustion of acetylene with oxygen produces a flame of over 3300 °C (6000 °F), releasing 11.8 kJ/g. Oxyacetylene is the hottest burning common fuel gas.. Cyanogen, a more exotic gas, produces a flame of over 4525°C (8180°F) when it burns in oxygen. Acetylene is also used in the acetylene ('carbide') lamp, once used by miners (not to be confused with the Davy lamp), on vintage cars, and still sometimes used by cavers. In this context, the acetylene is generated by dripping water from the upper chamber of the lamp onto calcium carbide (CaC2) pellets in the base of the lamp. In former times a few towns used acetylene for lighting, including Tata in Hungary where it was installed on 24 July 1897, and North Petherton, England in 1898. In modern times acetylene is sometimes used for carburization (that is, hardening) of steel when the object is too large to fit into a furnace. Acetylene has been proposed as a carbon feedstock for molecular manufacturing using nanotechnology. Since it does not occur naturally, using acetylene could limit out-of-control self-replication. Acetylene is used to volatilize carbon in radiocarbon dating. The carbonaceous material in the archeological sample reacted in a small specialized research furnace with lithium metal to form lithium carbide (also known as lithium acetylide). The carbide can then be reacted with water, as usual, to form acetylene gas to be fed into mass spectrometer to sort out the isotopic ratio of carbon 14 to carbon 12. The Future The use of acetylene is expected to continue a gradual increase in the future as new applications are developed. One new application is the conversion of acetylene to ethylene for use in making a variety of polyethylene plastics. In the past, a small amount of acetylene had been generated and wasted as part of the steam cracking process used to make ethylene. A new catalyst developed by Phillips Petroleum allows most of this acetylene to be converted into ethylene for increased yields at a reduced overall cost. # Safety and handling ## Compression Due to the carbon-to-carbon triple bond, acetylene gas is fundamentally unstable, and will decompose in an exothermic reaction if compressed to any great extent. Acetylene can explode with extreme violence if the pressure of the gas exceeds about 100 kPa (≈14.5 psi) as a gas or when in liquid or solid form, so it is shipped and stored dissolved in acetone or dimethylformamide (DMF), contained in a metal cylinder with porous filling (Agamassan), which renders it safe to transport and use. There are strict regulations on the shipment of dangerous gas cylinders throughout the world. The use of dissolved acetylene is decreasing rapidly, due to favourable flameless welding processes. ## Toxic effects Inhaling acetylene may cause dizziness, headache and nausea. It may also contain toxic impurities: the Compressed Gas Association Commodity Specification for acetylene has established a grading system for identifying and quantifying phosphine, arsine, and hydrogen sulfide content in commercial grades of acetylene in order to limit exposure to these impurities. The sulfur, phosphorus and arsenic are carryovers from the synthesis ingredient coke, an impure form of carbon and different, organic impurities would be expected from the thermal cracking of hydrocarbons source. While the impurities in acetylene can be toxic and even fatal, pure acetylene is of a very low toxicity (not counting the "narcotic" effects). Up to 80% percent, (v/v) acetylene has been administered to surgical patients as a general anaesthetic. The trade name for acetylene was "narcylene." It was used a fair amount experimentally in Germany in their impoverished 1920's, perhaps on several thousand patients. Medically, acetylene was considered to be nearly as safe as nitrous oxide and with a slightly higher potency, allowing for the use of higher percentages of oxygen in the blend; it is about 50% more potent. However, the use of acetylene and oxygen mixtures was dropped after several gas explosions inside patients' lungs. The energy of these explosions would be expected to exceed any of the flammable inhalation anesthetics due to the instability of the triple bond (cyclopropane would be nearly as bad). It was suggested that such an internal thorax explosion could not occur with air mixtures (without purified oxygen). Acetylene has been infrequently abused in a manner akin to nitrous oxide abuse up through modern times, according to the literature. Such abuse can result in the death of the abuser due to toxicity of the above mentioned impurities phosphine, arsine, and hydrogen sulfide. Since the gas is charged (absorbed) into tanks soaked with acetone over a solid matrix, some acetone comes out with the gas, further contributing to the poisonings. The driver for this abusive behavior is better understood with the view of acetylene's anesthetic properties and addictive behaviors. Impurities in acetylene are easily detectable by smell. Pure acetylene is a colorless and odorless gas. The characteristic garlic-like odor of technical grade acetylene is attributable to contamination by impurities. Impurities which may be present include: divinyl sulfide, ammonia, oxygen, nitrogen, phosphine, arsine, methane, carbon dioxide, carbon monoxide, hydrogen sulfide, vinyl acetylene, divinyl acetylene, diacetylene, propadiene, hexadiene, butadienyl acetylene, and methyl acetylene. ## Fire hazard Mixtures with air containing between 3% and 82% acetylene are explosive on ignition. The minimum ignition temperature is 335 °C. The majority of acetylene's chemical energy is what is not contained in the carbon-carbon triple bond; that is, it is greater than that of three carbon-carbon bonds spread out, but is disallowed therefrom because of the spaces between its mate carbon and all other carbons likewise shielded in charge. ## Incompatibilities - bromine, chlorine, copper, mercury, silver. # Other meanings Sometimes the plural "acetylenes" may refer to the class of organic chemical compounds known as alkynes which contain the -C≡C- group. # Natural occurrence Acetylene is a moderately common chemical in the universe, often associated with the atmospheres of gas giants. One curious discovery of acetylene is on Enceladus, a moon of Saturn. Natural acetylene is believed to form from either catalytic decomposition of long chain hydrocarbons or at temperatures ≥ 1,770 kelvin. Since such temperatures are highly unlikely on such a small distant body, this discovery is potentially suggestive of catalytic reactions within the moon, making it a promising site to search for prebiotic chemistry.	Acetylene Template:Chembox new # Overview Acetylene (systematic name: ethyne) is a hydrocarbon belonging to the group of alkynes. It is considered to be the simplest of all alkynes as it consists of two hydrogen atoms and two carbon atoms. Acetylene is an unsaturated organic compound because its four atoms are triple bonded through a covalent bond. The carbon-carbon triple bond leaves the carbon atoms with two sp hybrid orbitals for sigma bonding, placing all four atoms in the same straight line, with CCH bond angles of 180°. Acetylene was discovered in 1836 by Edmund Davy who identified it as a "new carburet of hydrogen." It was rediscovered in 1860 by French chemist Marcellin Berthelot, who coined the name "acetylene." The Nobel Laureate Gustaf Dalén was blinded by an acetylene explosion. # Preparation The principal raw materials for acetylene manufacture are calcium carbonate (limestone) and coal. The calcium carbonate is first converted into calcium oxide and the coal into coke, then the two are reacted with each other to form calcium carbide and carbon monoxide: Calcium carbide (or calcium acetylide) and water are then reacted by any of several methods to produce acetylene and calcium hydroxide. This reaction was discovered by Friedrich Wohler in 1862. Calcium carbide synthesis requires an extremely high temperature, ~2000 degrees Celsius, so the reaction is performed in an electric arc furnace. This reaction was an important part of the late-1800s revolution in chemistry enabled by the massive hydroelectric power project at Niagara Falls. Acetylene can also be manufactured by the partial combustion of methane with oxygen, or by the cracking of hydrocarbons. Berthelot was able to prepare acetylene from methyl alcohol, ethyl alcohol, ethylene, or ether, when he passed any one of these as a gas or vapour through a red-hot tube. Berthelot also found acetylene was formed by sparking electricity through mixed cyanogen and hydrogen gases. He was also able to form acetylene directly by combining pure hydrogen with carbon using electrical discharge of a carbon arc. # Reactions - Above 400 °C (673 K), which is quite low for a hydrocarbon, the pyrolysis of acetylene will start. The main products are the dimer vinylacetylene (C4H4) and benzene. At temperatures above 900 °C (1173 K), the main product will be soot. - Using acetylene, Berthelot was the first to show that an aliphatic compound could form an aromatic compound when he heated acetylene in a glass tube to produce benzene with some toluene. Berthelot oxidized acetylene to yield acetic acid and oxalic acid. He found acetylene could be reduced to form ethylene and ethane. - Polymerization of acetylene with Ziegler-Natta catalysts produces polyacetylene films. Polyacetylene, a chain of carbon molecules with alternating single and double bonds, was the first organic semiconductor to be discovered; reaction with iodine produces an extremely conductive material. - In the Kucherov reaction (invented in 1881 by the Russian chemist Mikhail Kucherov) [1] acetylene is hydrated to acetaldehyde with a mercury salt such as mercury(II) bromide. Before the advent of the Wacker process this reaction was conducted on an industrial scale [2]. ## Reppe chemistry Walter Reppe discovered that acetylene can react at high pressures with heavy metal catalysts to give industrially significant chemicals: - Acetylene reacting with alcohols, hydrogen cyanide, hydrogen chloride, or carboxylic acids to give vinyl compounds: File:Reppe-chemnistry-vinylization.png - With aldehydes to give ethynyl diols. File:Reppe-chemistry-endiol.png This is industrially used to produce 1,4-butynediol from formaldehyde and acetylene: - With carbon monoxide to give acrylic acid, or acrylic esters, which can be used to produce acrylic glass. File:Reppe-chemistry-carbonmonoxide-01.png File:Reppe-chemistry-carbonmonoxide-02.png - Cyclicization to give benzene and cyclooctatetraene: File:Reppe-chemistry-benzene.png File:Reppe-chemistry-cyclooctatetraene.png # Uses Approximately 80 percent of the acetylene produced annually in the United States is used in chemical synthesis. The remaining 20 percent is used primarily for oxyacetylene gas welding and cutting due to the high temperature of the flame; combustion of acetylene with oxygen produces a flame of over 3300 °C (6000 °F), releasing 11.8 kJ/g. Oxyacetylene is the hottest burning common fuel gas.[3]. Cyanogen, a more exotic gas, produces a flame of over 4525°C (8180°F) when it burns in oxygen.[4] Acetylene is also used in the acetylene ('carbide') lamp, once used by miners (not to be confused with the Davy lamp), on vintage cars, and still sometimes used by cavers. In this context, the acetylene is generated by dripping water from the upper chamber of the lamp onto calcium carbide (CaC2) pellets in the base of the lamp. In former times a few towns used acetylene for lighting, including Tata in Hungary where it was installed on 24 July 1897, and North Petherton, England in 1898. In modern times acetylene is sometimes used for carburization (that is, hardening) of steel when the object is too large to fit into a furnace.[3] Acetylene has been proposed as a carbon feedstock for molecular manufacturing using nanotechnology. Since it does not occur naturally, using acetylene could limit out-of-control self-replication. Acetylene is used to volatilize carbon in radiocarbon dating. The carbonaceous material in the archeological sample reacted in a small specialized research furnace with lithium metal to form lithium carbide (also known as lithium acetylide). The carbide can then be reacted with water, as usual, to form acetylene gas to be fed into mass spectrometer to sort out the isotopic ratio of carbon 14 to carbon 12. The Future The use of acetylene is expected to continue a gradual increase in the future as new applications are developed. One new application is the conversion of acetylene to ethylene for use in making a variety of polyethylene plastics. In the past, a small amount of acetylene had been generated and wasted as part of the steam cracking process used to make ethylene. A new catalyst developed by Phillips Petroleum allows most of this acetylene to be converted into ethylene for increased yields at a reduced overall cost.[5] # Safety and handling ## Compression Due to the carbon-to-carbon triple bond, acetylene gas is fundamentally unstable, and will decompose in an exothermic reaction if compressed to any great extent. Acetylene can explode with extreme violence if the pressure of the gas exceeds about 100 kPa (≈14.5 psi) as a gas or when in liquid or solid form, so it is shipped and stored dissolved in acetone or dimethylformamide (DMF), contained in a metal cylinder with porous filling (Agamassan), which renders it safe to transport and use. There are strict regulations on the shipment of dangerous gas cylinders throughout the world. The use of dissolved acetylene is decreasing rapidly, due to favourable flameless welding processes. ## Toxic effects Inhaling acetylene may cause dizziness, headache and nausea.[6] It may also contain toxic impurities: the Compressed Gas Association Commodity Specification for acetylene has established a grading system for identifying and quantifying phosphine, arsine, and hydrogen sulfide content in commercial grades of acetylene in order to limit exposure to these impurities. The sulfur, phosphorus and arsenic are carryovers from the synthesis ingredient coke, an impure form of carbon and different, organic impurities would be expected from the thermal cracking of hydrocarbons source. While the impurities in acetylene can be toxic and even fatal, pure acetylene is of a very low toxicity (not counting the "narcotic" effects). Up to 80% percent, (v/v) acetylene has been administered to surgical patients as a general anaesthetic. The trade name for acetylene was "narcylene." It was used a fair amount experimentally in Germany in their impoverished 1920's, perhaps on several thousand patients. Medically, acetylene was considered to be nearly as safe as nitrous oxide and with a slightly higher potency, allowing for the use of higher percentages of oxygen in the blend; it is about 50% more potent. However, the use of acetylene and oxygen mixtures was dropped after several gas explosions inside patients' lungs. The energy of these explosions would be expected to exceed any of the flammable inhalation anesthetics due to the instability of the triple bond (cyclopropane would be nearly as bad). It was suggested that such an internal thorax explosion could not occur with air mixtures (without purified oxygen). Acetylene has been infrequently abused in a manner akin to nitrous oxide abuse up through modern times, according to the literature. Such abuse can result in the death of the abuser due to toxicity of the above mentioned impurities phosphine, arsine, and hydrogen sulfide. Since the gas is charged (absorbed) into tanks soaked with acetone over a solid matrix, some acetone comes out with the gas, further contributing to the poisonings. The driver for this abusive behavior is better understood with the view of acetylene's anesthetic properties and addictive behaviors. Impurities in acetylene are easily detectable by smell. Pure acetylene is a colorless and odorless gas. The characteristic garlic-like odor of technical grade acetylene is attributable to contamination by impurities. Impurities which may be present include: divinyl sulfide, ammonia, oxygen, nitrogen, phosphine, arsine, methane, carbon dioxide, carbon monoxide, hydrogen sulfide, vinyl acetylene, divinyl acetylene, diacetylene, propadiene, hexadiene, butadienyl acetylene, and methyl acetylene. ## Fire hazard Mixtures with air containing between 3% and 82% acetylene are explosive on ignition. The minimum ignition temperature is 335 °C.[6] The majority of acetylene's chemical energy is what is not contained in the carbon-carbon triple bond; that is, it is greater than that of three carbon-carbon bonds spread out, but is disallowed therefrom because of the spaces between its mate carbon and all other carbons likewise shielded in charge. ## Incompatibilities - bromine, chlorine, copper, mercury, silver. # Other meanings Sometimes the plural "acetylenes" may refer to the class of organic chemical compounds known as alkynes which contain the -C≡C- group. # Natural occurrence Acetylene is a moderately common chemical in the universe, often associated with the atmospheres of gas giants.[7] One curious discovery of acetylene is on Enceladus, a moon of Saturn. Natural acetylene is believed to form from either catalytic decomposition of long chain hydrocarbons or at temperatures ≥ 1,770 kelvin. Since such temperatures are highly unlikely on such a small distant body, this discovery is potentially suggestive of catalytic reactions within the moon, making it a promising site to search for prebiotic chemistry.[8][9]	https://www.wikidoc.org/index.php/Acetylene
3981c7e0bc77331072e571f26caaa9c8f0b81318	wikidoc	Acid rain	Acid rain Acid rain is rain or any other form of precipitation that is unusually acidic. It has harmful effects on the environment and on structures. Acid rain is mostly caused by emissions due to human activity of sulfur and nitrogen compounds which react in the atmosphere to produce acids. In recent years, many governments have introduced laws to reduce these emissions. # Definition The term "acid rain" is commonly used to mean the deposition of acidic components in rain, snow, fog, dew, or dry particles. The more accurate term is "acid precipitation." Distilled water, which contains no carbon dioxide, has a neutral pH of 7. Liquids with a pH less than 7 are acidic, and those with a pH greater than 7 are basic. "Clean" or unpolluted rain is slightly acidic, its pH being about 5.6, because carbon dioxide and water in the air react together to form carbonic acid, a weak acid. Carbonic acid then can ionize in water forming low concentrations of hydronium ions: The extra acidity in rain comes from the reaction of primary air pollutants, primarily sulfur oxides and nitrogen oxides, with water in the air to form strong acids (like sulfuric and nitric acid). The main sources of these pollutants are vehicles and industrial and power-generating plants. # History Since the Industrial Revolution, emissions of sulfur dioxide and nitrogen oxides to the atmosphere have increased. Acid rain was first found in Manchester, England. In 1852, Robert Angus Smith found the relationship between acid rain and atmospheric pollution. Though acid rain was discovered in 1852, it wasn't until the late 1960s that scientists began widely observing and studying the phenomenon. Canadian Harold Harvey was among the first to research a "dead" lake. Public awareness of acid rain in the U.S increased in the 1990s after the New York Times promulgated reports from the Hubbard Brook Experimental Forest in New Hampshire of the myriad deleterious environmental effects demonstrated to result from it. Occasional pH readings of well below 2.4 (the acidity of vinegar) have been reported in industrialized areas. Industrial acid rain is a substantial problem in China, Eastern Europe, Russia and areas down-wind from them. These areas all burn sulfur-containing coal to generate heat and electricity. The problem of acid rain not only has increased with population and industrial growth, but has become more widespread. The use of tall smokestacks to reduce local pollution has contributed to the spread of acid rain by releasing gases into regional atmospheric circulation. Often deposition occurs a considerable distance downwind of the emissions, with mountainous regions tending to receive the most (simply because of their higher rainfall). An example of this effect is the low pH of rain (compared to the local emissions) which falls in Scandinavia. # Emissions of chemicals leading to acidification The most important gas which leads to acidification is sulfur dioxide. Emissions of nitrogen oxides which are oxidized to form nitric acid are of increasing importance due to stricter controls on emissions of sulfur containing compounds. 70 Tg(S) per year in the form of SO2 comes from fossil fuel combustion and industry, 2.8 Tg(S) from wildfires and 7-8 Tg(S) per year from volcanoes. ## Natural Phenomena The principal natural phenomena that contribute acid-producing gases to the atmosphere are emissions from volcanoes and those from biological processes that occur on the land, in wetlands, and in the oceans. The major biological source of sulfur containing compounds is dimethyl sulfide. The effects of acidic deposits have been detected in glacial ice thousands of years old in remote parts of the globe. ## Human activity The principal cause of acid rain is sulfur and nitrogen compounds from human sources, such as electricity generation, factories and motor vehicles. Coal power plants are one of the most polluting. The gases can be carried hundreds of kilometres in the atmosphere before they are converted to acids and deposited. In the past, factories had short funnels to let out smoke, but this caused many problems; thus, factories now have longer smoke funnels. However, this causes pollutants to be carried farther, causing greater ecological damage. # Chemical processes ## Gas phase chemistry In the gas phase sulfur dioxide is oxidized by reaction with the hydroxyl radical via a intermolecular reaction: which is followed by: In the presence of water sulfur trioxide (SO3) is converted rapidly to sulfuric acid: Nitric acid is formed by the reaction of OH with Nitrogen dioxide: For more information see Seinfeld and Pandis (1998). ## Chemistry in cloud droplets When clouds are present the loss rate of SO2 is faster than can be explained by gas phase chemistry alone. This is due to reactions in the liquid water droplets Sulfur dioxide dissolves in water and then, like carbon dioxide, hydrolyses in a series of equilibrium reactions: There are a large number of aqueous reactions that oxidize sulfur from S(IV) to S(VI), leading to the formation of sulfuric acid. The most important oxidation reactions are with ozone, hydrogen peroxide and oxygen (reactions with oxygen are catalyzed by iron and manganese in the cloud droplets). For more information see Seinfeld and Pandis (1998). # Acid deposition ## Wet deposition Wet deposition of acids occurs when any form of precipitation (rain, snow, etc) removes acids from the atmosphere and delivers it to the Earth's surface. This can result from the deposition of acids produced in the raindrops (see aqueous phase chemistry above) or by the precipitation removing the acids either in clouds or below clouds. Wet removal of both gases and aerosol are both of importance for wet deposition. ## Dry deposition Acid deposition also occurs via dry deposition in the absence of precipitation. This can be responsible for as much as 20 to 60% of total acid deposition. This occurs when particles and gases stick to the ground, plants or other surfaces. # Adverse effects Acid rain has been shown to have adverse impacts on forests, freshwaters and soils, killing off insect and aquatic lifeforms as well as causing damage to buildings and having possible impacts on human health. ## Surface waters and aquatic animals Both the lower pH and higher aluminum concentrations in surface water that occur as a result of acid rain can cause damage to fish and other aquatic animals. At pHs lower than 5 most fish eggs will not hatch and lower pHs can kill adult fish. As lakes become more acidic biodiversity is reduced. Acid rain has eliminated insect life and some fish species, including the brook trout in some Appalachian streams and creeks. However, there has been some debate on the extent to which acid rain contributes to lake acidity (i.e., that many acid lakes may result primarily from characteristics of the surrounding watershed, and not the rain itself). The EPA's website states: "Of the lakes and streams surveyed, acid rain caused acidity in 75 percent of the acidic lakes and about 50 percent of the acidic streams". ## Soils Soil biology can be seriously damaged by acid rain. Some tropical microbes can quickly consume acids but other microbes are unable to tolerate low pHs and are killed. The enzymes of these microbes are denatured (changed in shape so they no longer function) by the acid. The hydronium ions of acid rain also mobilize toxins and leach away essential nutrients and minerals ## Forests and other vegetation Adverse effects may be indirectly related to acid rain, like the acid's effects on soil (see above) or high concentration of gaseous precursors to acid rain. High altitude forests are especially vulnerable as they are often surrounded by clouds and fog which are more acidic than rain. Other plants can also be damaged by acid rain but the effect on food crops is minimized by the application of fertilizers to replace lost nutrients. In cultivated areas, limestone may also be added to increase the ability of the soil to keep the pH stable, but this tactic is largely unusable in the case of wilderness lands. Acid rain depletes minerals from the soil and then it stunts the growth of the plant. ## Human health Some scientists have suggested direct links to human health, but none have been proven.. However, fine particles, a large fraction of which are formed from the same gases as acid rain (sulfur dioxide and nitrogen dioxide), have been shown to cause illness and premature deaths such as cancer and other deadly diseases For more information on the health effects of aerosol see particulate health effects. ## Other adverse effects Acid rain can also cause damage to certain building materials and historical monuments. This is since the sulfuric acid in the rain chemically reacts with the calcium compounds in the stones (limestone, sandstone, marble and granite) to create gypsum, which then flakes off. This is also commonly seen on old gravestones where the acid rain can cause the inscription to become completely illegible. Acid rain also causes an increased rate of oxidation for iron. Visibility is also reduced by sulfate and nitrate in the atmosphere. # Affected Areas Particularly badly affected places around the globe include most of Europe (particularly Scandinavia with many lakes with acidic water containing no life and many trees dead) many parts of the United States (states like New York are very badly affected) and South Western Canada. Other affected areas include the South Eastern coast of China and Taiwan. ## Potential Problem Areas in the Future Places like much of South Asia (Indonesia, Malaysia and Thailand), Western South Africa (the country), Southern India and Sri Lanka and even West Africa (countries like Ghana, Togo] and Nigeria) could all be prone to acidic rainfall in the future. # Prevention methods ## Technical solutions In the United States, many coal-burning power plants use Flue gas desulfurization (FGD) to remove sulfur-containing gases from their stack gases. An example of FGD is the wet scrubber which is commonly used in the U.S. and many other countries. A wet scrubber is basically a reaction tower equipped with a fan that extracts hot smoke stack gases from a power plant into the tower. Lime or limestone in slurry form is also injected into the tower to mix with the stack gases and combine with the sulfur dioxide present. The calcium carbonate of the limestone produces pH-neutral calcium sulfate that is physically removed from the scrubber. That is, the scrubber turns sulfur pollution into industrial sulfates. In some areas the sulfates are sold to chemical companies as gypsum when the purity of calcium sulfate is high. In others, they are placed in landfill. However, the effects of acid rain can last for generations, as the effects of pH level change can stimulate the continued leaching of undesirable chemicals into otherwise pristine water sources, killing off vulnerable insect and fish species and blocking efforts to restore native life. Automobile emissions control reduces emissions of nitrogen oxides from motor vehicles. ## International treaties A number of international treaties on the long range transport of atmospheric pollutants have been agreed e.g. Sulphur Emissions Reduction Protocol under the Convention on Long-Range Transboundary Air Pollution. ## Emissions trading A more recent regulatory scheme involves emissions trading. In this scheme, every current polluting facility is given an emissions license that becomes part of capital equipment. Operators can then install pollution control equipment, and sell parts of their emissions licenses. The intention of this is to give operators economic incentives to install pollution controls.	Acid rain Template:Pollution Acid rain is rain or any other form of precipitation that is unusually acidic. It has harmful effects on the environment and on structures. Acid rain is mostly caused by emissions due to human activity of sulfur and nitrogen compounds which react in the atmosphere to produce acids. In recent years, many governments have introduced laws to reduce these emissions. # Definition The term "acid rain" is commonly used to mean the deposition of acidic components in rain, snow, fog, dew, or dry particles. The more accurate term is "acid precipitation." Distilled water, which contains no carbon dioxide, has a neutral pH of 7. Liquids with a pH less than 7 are acidic, and those with a pH greater than 7 are basic. "Clean" or unpolluted rain is slightly acidic, its pH being about 5.6, because carbon dioxide and water in the air react together to form carbonic acid, a weak acid.[1] Carbonic acid then can ionize in water forming low concentrations of hydronium ions: The extra acidity in rain comes from the reaction of primary air pollutants, primarily sulfur oxides and nitrogen oxides, with water in the air to form strong acids (like sulfuric and nitric acid). The main sources of these pollutants are vehicles and industrial and power-generating plants. # History Since the Industrial Revolution, emissions of sulfur dioxide and nitrogen oxides to the atmosphere have increased.[2] Acid rain was first found in Manchester, England. In 1852, Robert Angus Smith found the relationship between acid rain and atmospheric pollution.[3] Though acid rain was discovered in 1852, it wasn't until the late 1960s that scientists began widely observing and studying the phenomenon. Canadian Harold Harvey was among the first to research a "dead" lake. Public awareness of acid rain in the U.S increased in the 1990s after the New York Times promulgated reports from the Hubbard Brook Experimental Forest in New Hampshire of the myriad deleterious environmental effects demonstrated to result from it.[4] Occasional pH readings of well below 2.4 (the acidity of vinegar) have been reported in industrialized areas.[2] Industrial acid rain is a substantial problem in China[5], Eastern Europe, Russia and areas down-wind from them. These areas all burn sulfur-containing coal to generate heat and electricity.[6] The problem of acid rain not only has increased with population and industrial growth, but has become more widespread. The use of tall smokestacks to reduce local pollution has contributed to the spread of acid rain by releasing gases into regional atmospheric circulation. Often deposition occurs a considerable distance downwind of the emissions, with mountainous regions tending to receive the most (simply because of their higher rainfall). An example of this effect is the low pH of rain (compared to the local emissions) which falls in Scandinavia.[7] # Emissions of chemicals leading to acidification The most important gas which leads to acidification is sulfur dioxide. Emissions of nitrogen oxides which are oxidized to form nitric acid are of increasing importance due to stricter controls on emissions of sulfur containing compounds. 70 Tg(S) per year in the form of SO2 comes from fossil fuel combustion and industry, 2.8 Tg(S) from wildfires and 7-8 Tg(S) per year from volcanoes.[8] ## Natural Phenomena The principal natural phenomena that contribute acid-producing gases to the atmosphere are emissions from volcanoes and those from biological processes that occur on the land, in wetlands, and in the oceans. The major biological source of sulfur containing compounds is dimethyl sulfide. The effects of acidic deposits have been detected in glacial ice thousands of years old in remote parts of the globe. ## Human activity The principal cause of acid rain is sulfur and nitrogen compounds from human sources, such as electricity generation, factories and motor vehicles. Coal power plants are one of the most polluting. The gases can be carried hundreds of kilometres in the atmosphere before they are converted to acids and deposited. In the past, factories had short funnels to let out smoke, but this caused many problems; thus, factories now have longer smoke funnels. However, this causes pollutants to be carried farther, causing greater ecological damage. # Chemical processes ## Gas phase chemistry In the gas phase sulfur dioxide is oxidized by reaction with the hydroxyl radical via a intermolecular reaction: which is followed by: In the presence of water sulfur trioxide (SO3) is converted rapidly to sulfuric acid: Nitric acid is formed by the reaction of OH with Nitrogen dioxide: For more information see Seinfeld and Pandis (1998).[3] ## Chemistry in cloud droplets When clouds are present the loss rate of SO2 is faster than can be explained by gas phase chemistry alone. This is due to reactions in the liquid water droplets Sulfur dioxide dissolves in water and then, like carbon dioxide, hydrolyses in a series of equilibrium reactions: There are a large number of aqueous reactions that oxidize sulfur from S(IV) to S(VI), leading to the formation of sulfuric acid. The most important oxidation reactions are with ozone, hydrogen peroxide and oxygen (reactions with oxygen are catalyzed by iron and manganese in the cloud droplets). For more information see Seinfeld and Pandis (1998).[3] # Acid deposition ## Wet deposition Wet deposition of acids occurs when any form of precipitation (rain, snow, etc) removes acids from the atmosphere and delivers it to the Earth's surface. This can result from the deposition of acids produced in the raindrops (see aqueous phase chemistry above) or by the precipitation removing the acids either in clouds or below clouds. Wet removal of both gases and aerosol are both of importance for wet deposition. ## Dry deposition Acid deposition also occurs via dry deposition in the absence of precipitation. This can be responsible for as much as 20 to 60% of total acid deposition.[9] This occurs when particles and gases stick to the ground, plants or other surfaces. # Adverse effects Acid rain has been shown to have adverse impacts on forests, freshwaters and soils, killing off insect and aquatic lifeforms as well as causing damage to buildings and having possible impacts on human health. ## Surface waters and aquatic animals Both the lower pH and higher aluminum concentrations in surface water that occur as a result of acid rain can cause damage to fish and other aquatic animals. At pHs lower than 5 most fish eggs will not hatch and lower pHs can kill adult fish. As lakes become more acidic biodiversity is reduced. Acid rain has eliminated insect life and some fish species, including the brook trout in some Appalachian streams and creeks.[10] However, there has been some debate on the extent to which acid rain contributes to lake acidity (i.e., that many acid lakes may result primarily from characteristics of the surrounding watershed, and not the rain itself).[11] The EPA's website states: "Of the lakes and streams surveyed, acid rain caused acidity in 75 percent of the acidic lakes and about 50 percent of the acidic streams".[10] ## Soils Soil biology can be seriously damaged by acid rain. Some tropical microbes can quickly consume acids[12] but other microbes are unable to tolerate low pHs and are killed. The enzymes of these microbes are denatured (changed in shape so they no longer function) by the acid. The hydronium ions of acid rain also mobilize toxins and leach away essential nutrients and minerals[13] ## Forests and other vegetation Adverse effects may be indirectly related to acid rain, like the acid's effects on soil (see above) or high concentration of gaseous precursors to acid rain. High altitude forests are especially vulnerable as they are often surrounded by clouds and fog which are more acidic than rain. Other plants can also be damaged by acid rain but the effect on food crops is minimized by the application of fertilizers to replace lost nutrients. In cultivated areas, limestone may also be added to increase the ability of the soil to keep the pH stable, but this tactic is largely unusable in the case of wilderness lands. Acid rain depletes minerals from the soil and then it stunts the growth of the plant. ## Human health Some scientists have suggested direct links to human health, but none have been proven.[14]. However, fine particles, a large fraction of which are formed from the same gases as acid rain (sulfur dioxide and nitrogen dioxide), have been shown to cause illness and premature deaths such as cancer and other deadly diseases[15] For more information on the health effects of aerosol see particulate health effects. ## Other adverse effects Acid rain can also cause damage to certain building materials and historical monuments. This is since the sulfuric acid in the rain chemically reacts with the calcium compounds in the stones (limestone, sandstone, marble and granite) to create gypsum, which then flakes off. This is also commonly seen on old gravestones where the acid rain can cause the inscription to become completely illegible. Acid rain also causes an increased rate of oxidation for iron.[16] Visibility is also reduced by sulfate and nitrate in the atmosphere.[17] # Affected Areas Particularly badly affected places around the globe include most of Europe (particularly Scandinavia with many lakes with acidic water containing no life and many trees dead) many parts of the United States (states like New York are very badly affected) and South Western Canada. Other affected areas include the South Eastern coast of China and Taiwan. ## Potential Problem Areas in the Future Places like much of South Asia (Indonesia, Malaysia and Thailand), Western South Africa (the country), Southern India and Sri Lanka and even West Africa (countries like Ghana, Togo] and Nigeria) could all be prone to acidic rainfall in the future. # Prevention methods ## Technical solutions In the United States, many coal-burning power plants use Flue gas desulfurization (FGD) to remove sulfur-containing gases from their stack gases. An example of FGD is the wet scrubber which is commonly used in the U.S. and many other countries. A wet scrubber is basically a reaction tower equipped with a fan that extracts hot smoke stack gases from a power plant into the tower. Lime or limestone in slurry form is also injected into the tower to mix with the stack gases and combine with the sulfur dioxide present. The calcium carbonate of the limestone produces pH-neutral calcium sulfate that is physically removed from the scrubber. That is, the scrubber turns sulfur pollution into industrial sulfates. In some areas the sulfates are sold to chemical companies as gypsum when the purity of calcium sulfate is high. In others, they are placed in landfill. However, the effects of acid rain can last for generations, as the effects of pH level change can stimulate the continued leaching of undesirable chemicals into otherwise pristine water sources, killing off vulnerable insect and fish species and blocking efforts to restore native life. Automobile emissions control reduces emissions of nitrogen oxides from motor vehicles. ## International treaties A number of international treaties on the long range transport of atmospheric pollutants have been agreed e.g. Sulphur Emissions Reduction Protocol under the Convention on Long-Range Transboundary Air Pollution. ## Emissions trading A more recent regulatory scheme involves emissions trading. In this scheme, every current polluting facility is given an emissions license that becomes part of capital equipment. Operators can then install pollution control equipment, and sell parts of their emissions licenses. The intention of this is to give operators economic incentives to install pollution controls.	https://www.wikidoc.org/index.php/Acid_Rain
0b77da7567491ce8fb04e50bf95f2e776938af76	wikidoc	Acitretin	Acitretin # 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 Acitretin is an antipsoriatic that is FDA approved for the treatment of severe psoriasis in adults. There is a Black Box Warning for this drug as shown here. Common adverse reactions include pruritus, arthralgia and paresthesia.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Acitretin is indicated for the treatment of severe psoriasis in adults. - Initial dosage: 25 to 50 mg per day, given as a single dose with the main meal. - Maintenance dosage: 25 to 50 mg per day. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Acitretin in adult patients. ### Non–Guideline-Supported Use - Nonpsoriatic disorder of skin - Lichen planus - Prophylaxis of skin cancers in high-risk renal transplant recipients - Acitretin 30 mg orally daily for 6 months # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness have not been established in pediatric patients ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Acitretin in pediatric patients. ### Non–Guideline-Supported Use - Lichen planus # Contraindications - Pregnancy Category X - Patients with severely impaired liver or kidney function and in patients with chronic abnormally elevated blood lipid values, - An increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate. Consequently, the combination of methotrexate with acitretin is also contraindicated. - Since both acitretin and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated. - In cases of hypersensitivity (e.g., angioedema, urticaria) to the preparation (acitretin or excipients) or to other retinoids. # Warnings - Of the 525 subjects treated in U.S. clinical trials, 2 had clinical jaundice with elevated serum bilirubin and transaminases considered related to treatment with acitretin. Liver function test results in these subjects returned to normal after acitretin was discontinued. Two of the 1,289 subjects treated in European clinical trials developed biopsy-confirmed toxic hepatitis. A second biopsy in one of these subjects revealed nodule formation suggestive of cirrhosis. One subject in a Canadian clinical trial of 63 subjects developed a 3 fold increase of transaminases. A liver biopsy of this subject showed mild lobular disarray, multifocal hepatocyte loss, and mild triaditis of the portal tracts compatible with acute reversible hepatic injury. The subject’s transaminase levels returned to normal 2 months after acitretin was discontinued. - The potential of therapy with acitretin to induce hepatotoxicity was prospectively evaluated using liver biopsies in an open-label trial of 128 subjects. Pretreatment and posttreatment biopsies were available for 87 subjects. A comparison of liver biopsy findings before and after therapy revealed 49 (58%) subjects showed no change, 21 (25%) improved, and 14 (17%) subjects had a worsening of their liver biopsy status. For 6 subjects, the classification changed from class 0 (no pathology) to class I (normal fatty infiltration; nuclear variability and portal inflammation; both mild); for 7 subjects, the change was from class I to class II (fatty infiltration, nuclear variability, portal inflammation, and focal necrosis; all moderate to severe); and for 1 subject, the change was from class II to class IIIb (fibrosis, moderate to severe). No correlation could be found between liver function test result abnormalities and the change in liver biopsy status, and no cumulative dose relationship was found. - Elevations of AST (SGOT), ALT (SGPT), GGT (GGTP), or LDH have occurred in approximately 1 in 3 subjects treated with acitretin. Of the 525 subjects treated in clinical trials in the U.S., treatment was discontinued in 20 (3.8%) due to elevated liver function test results. If hepatotoxicity is suspected during treatment with acitretin, the drug should be discontinued and the etiology further investigated. - Ten of 652 subjects treated in U.S. clinical trials of etretinate, of which acitretin is the active metabolite, had clinical or histologic hepatitis considered to be possibly or probably related to etretinate treatment. - There have been reports of hepatitis-related deaths worldwide; a few of these subjects had received etretinate for a month or less before presenting with hepatic symptoms or signs. # Adverse Reactions ## Clinical Trials Experience During clinical trials with acitretin, 513/525 (98%) of subjects reported a total of 3,545 adverse events. One-hundred sixteen subjects (22%) left trials prematurely, primarily because of adverse experiences involving the mucous membranes and skin. Three subjects died. Two of the deaths were not drug-related (pancreatic adenocarcinoma and lung cancer); the other subject died of an acute myocardial infarction, considered remotely related to drug therapy. In clinical trials, acitretin was associated with elevations in liver function test results or triglyceride levels and hepatitis. The tables below list by body system and frequency the adverse events reported during clinical trials of 525 subjects with psoriasis. Therapy with acitretin induces changes in liver function tests in a significant number of patients. Elevations of AST (SGOT), ALT (SGPT) or LDH were experienced by approximately 1 in 3 subjects treated with acitretin. In most subjects, elevations were slight to moderate and returned to normal either during continuation of therapy or after cessation of treatment. In subjects receiving acitretin during clinical trials, 66% and 33% experienced elevation in triglycerides and cholesterol, respectively. Decreased high density lipoproteins (HDL) occurred in 40%. Transient, usually reversible elevations of alkaline phosphatase have been observed. TABLE 5 lists the laboratory abnormalities reported during clinical trials. ## Postmarketing Experience In addition to the events listed in the tables for the clinical trials, the following adverse events have been identified during postapproval use of acitretin. 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. - Acute myocardial infarction - Thromboembolism, stroke Hypersensitivity, including angioedema and urticaria. - Myopathy - Peripheral neuropathy Both conditions improved with discontinuation of the drug. - Aggressive feelings and/or suicidal thoughts have been reported. - These events, including self-injurious behavior, have been reported in patients taking other systemically administered retinoids, as well as in patients taking acitretin. - Since other factors may have contributed to these events, it is not known if they are related to acitretin. - Vulvo-vaginitis due to Candida albicans. - Thinning of the skin, skin fragility, and scaling may occur all over the body, particularly on the palms and soles; nail fragility is frequently observed. Madarosis and exfoliative dermatitis/erythroderma have been reported. - Capillary leak syndrome # Drug Interactions Clinical evidence has shown that etretinate can be formed with concurrent ingestion of acitretin and ethanol. In a trial of 7 healthy male volunteers, acitretin treatment potentiated the blood glucose-lowering effect of glyburide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects. Repeating the trial with 6 healthy male volunteers in the absence of glyburide did not detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under treatment with acitretin is recommended. It has not been established if there is a pharmacokinetic interaction between acitretin and combined oral contraceptives. However, it has been established that acitretin interferes with the contraceptive effect of microdosed progestin “minipill” preparations. Microdosed “minipill” progestin preparations are not recommended for use with acitretin. It is not known whether other progestational contraceptives, such as implants and injectables, are adequate methods of contraception during acitretin therapy. An increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate. Consequently, the combination of methotrexate with acitretin is also contraindicated. If acitretin is given concurrently with phenytoin, the protein binding of phenytoin may be reduced. Since both acitretin and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated. Concomitant administration of vitamin A and/or other oral retinoids with acitretin must be avoided because of the risk of hypervitaminosis A. There appears to be no pharmacokinetic interaction between acitretin and cimetidine, digoxin, or glyburide. Investigations into the effect of acitretin on the protein binding of anticoagulants of the coumarin type (warfarin) revealed no interaction. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X In a study in which acitretin was administered to male rats only at a dosage of 5 mg/kg/day for 10 weeks (approximate duration of one spermatogenic cycle) prior to and during mating with untreated female rats, no teratogenic effects were observed in the progeny. In rats dosed at 3 mg/kg/day (approximately one-half the maximum recommended therapeutic dose based on a mg/m2 comparison), slightly decreased pup survival and delayed incisor eruption were noted. At the next lowest dose tested, 1 mg/kg/day, no treatment-related adverse effects were observed. Pregnancy Category (AUS): X There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Acitretin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Acitretin during labor and delivery. ### Nursing Mothers Studies on lactating rats have shown that etretinate is excreted in the milk. There is one prospective case report where acitretin is reported to be excreted in human milk. Therefore, nursing mothers should not receive acitretin prior to or during nursing because of the potential for serious adverse reactions in nursing infants. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. No clinical trials have been conducted in pediatric subjects. Ossification of interosseous ligaments and tendons of the extremities, skeletal hyperostoses, decreases in bone mineral density, and premature epiphyseal closure have been reported in children taking other systemic retinoids, including etretinate, a metabolite of acitretin. A causal relationship between these effects and acitretin has not been established. While it is not known that these occurrences are more severe or more frequent in children, there is special concern in pediatric patients because of the implications for growth potential. ### Geriatic Use Clinical trials of acitretin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. 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. A 2 fold increase in acitretin plasma concentrations was seen in healthy elderly subjects compared with young subjects, although the elimination half-life did not change. ### Gender There is no FDA guidance on the use of Acitretin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Acitretin with respect to specific racial populations. ### Renal Impairment Acitretin is contraindicated in patients with severely impaired kidney function ### Hepatic Impairment Acitretin is contraindicated in patients with severely impaired liver function ### Females of Reproductive Potential and Males In a fertility study in rats, the fertility of treated animals was not impaired at the highest dosage of acitretin tested, 3 mg/kg/day (approximately one-half the maximum recommended therapeutic dose based on a mg/m2 comparison). Chronic toxicity studies in dogs revealed testicular changes (reversible mild to moderate spermatogenic arrest and appearance of multinucleated giant cells) in the highest dosage group (50 then 30 mg/kg/day). No decreases in sperm count or concentration and no changes in sperm motility or morphology were noted in 31 men (17 psoriatic subjects, 8 subjects with disorders of keratinization, and 6 healthy volunteers) given 30 to 50 mg/day of acitretin for at least 12 weeks. In these trials, no deleterious effects were seen on either testosterone production, LH, or FSH in any of the 31 men. No deleterious effects were seen on the hypothalamic-pituitary axis in any of the 18 men where it was measured. ### Immunocompromised Patients There is no FDA guidance one the use of Acitretin in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring If significant abnormal laboratory results are obtained, either dosage reduction with careful monitoring or treatment discontinuation is recommended, depending on clinical judgment. # IV Compatibility There is limited information regarding the compatibility of Acitretin and IV administrations. # Overdosage In the event of acute overdosage, acitretin must be withdrawn at once. Symptoms of overdose are identical to acute hypervitaminosis A (e.g., headache and vertigo). The acute oral toxicity (LD50) of acitretin in both mice and rats was greater than 4,000 mg/kg. In one reported case of overdose, a 32-year-old male with Darier’s disease took 21 x 25 mg capsules (525 mg single dose). He vomited several hours later but experienced no other ill effects. All female patients of childbearing potential who have taken an overdose of acitretin must: - Have a pregnancy test at the time of overdose; - Be counseled as per the boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS sections regarding birth defects and contraceptive use for at least 3 years’ duration after the overdose. # Pharmacology ## Mechanism of Action The mechanism of action of acitretin is unknown. ## Structure The structural formula is: ## Pharmacodynamics There is limited information regarding Acitretin Pharmacodynamics in the drug label. ## Pharmacokinetics Oral absorption of acitretin is optimal when given with food. For this reason, acitretin was given with food in all of the following trials. After administration of a single 50 mg oral dose of acitretin to 18 healthy subjects, maximum plasma concentrations ranged from 196 to 728 ng/mL (mean: 416 ng/mL) and were achieved in 2 to 5 hours (mean: 2.7 hours). The oral absorption of acitretin is linear and proportional with increasing doses from 25 to 100 mg. Approximately 72% (range: 47% to 109%) of the administered dose was absorbed after a single 50 mg dose of acitretin was given to 12 healthy subjects. Acitretin is more than 99.9% bound to plasma proteins, primarily albumin. Following oral absorption, acitretin undergoes extensive metabolism and interconversion by simple isomerization to its 13-cis form (cis-acitretin). The formation of cis-acitretin relative to parent compound is not altered by dose or fed/fast conditions of oral administration of acitretin. Both parent compound and isomer are further metabolized into chain-shortened breakdown products and conjugates, which are excreted. Following multiple-dose administration of acitretin, steady-state concentrations of acitretin and cis-acitretin in plasma are achieved within approximately 3 weeks. The chain-shortened metabolites and conjugates of acitretin and cis-acitretin are ultimately excreted in the feces (34% to 54%) and urine (16% to 53%). The terminal elimination half-life of acitretin following multiple-dose administration is 49 hours (range: 33 to 96 hours), and that of cis-acitretin under the same conditions is 63 hours (range: 28 to 157 hours). The accumulation ratio of the parent compound is 1.2; that of cis-acitretin is 6.6. ## Nonclinical Toxicology A carcinogenesis study of acitretin in Wistar rats, at doses up to 2 mg/kg/day administered 7 days/week for 104 weeks, has been completed. There were no neoplastic lesions observed that were considered to have been related to treatment with acitretin. An 80 week carcinogenesis study in mice has been completed with etretinate, the ethyl ester of acitretin. Blood level data obtained during this study demonstrated that etretinate was metabolized to acitretin and that blood levels of acitretin exceeded those of etretinate at all times studied. In the etretinate study, an increased incidence of blood vessel tumors (hemangiomas and hemangiosarcomas at several different sites) was noted in male, but not female, mice at doses approximately one-half the maximum recommended human therapeutic dose based on a mg/m2 comparison. Acitretin was evaluated for mutagenic potential in the Ames test, in the Chinese hamster (V79/HGPRT) assay, in unscheduled DNA synthesis assays using rat hepatocytes and human fibroblasts, and in an in vivo mouse micronucleus assay. No evidence of mutagenicity of acitretin was demonstrated in any of these assays. # Clinical Studies In 2 double-blind, placebo-controlled trials, acitretin was administered once daily to subjects with severe psoriasis (e.g., covering at least 10% to 20% of the body surface area). At 8 weeks (see TABLE 1) subjects treated in Trial A with 50 mg of acitretin per day showed significant improvements (P ≤ 0.05) relative to baseline and to placebo in the physician’s global evaluation and in the mean ratings of severity of psoriasis (scaling, thickness, and erythema). In Trial B, differences from baseline and from placebo were statistically significant (P ≤ 0.05) for all variables at both the 25 mg and 50 mg doses; it should be noted for Trial B that no statistical adjustment for multiplicity was carried out. The efficacy variables consisted of: the mean severity rating of scale, lesion thickness, erythema, and the physician’s global evaluation of the current status of the disease. Ratings of scaling, erythema, and lesion thickness, and the ratings of the global assessments were made using a 7 point scale (0 = none, 1 = trace, 2 = mild, 3 = mild-moderate, 4 = moderate, 5 = moderate-severe, 6 = severe). A subset of 141 subjects from both pivotal Trials A and B continued to receive acitretin in an open fashion for up to 24 weeks. At the end of the treatment period, all efficacy variables, as indicated in TABLE 2, were significantly improved (P ≤ 0.01) from baseline, including extent of psoriasis, mean ratings of psoriasis severity, and physician’s global evaluation. The efficacy variables consisted of: the mean severity rating of scale, lesion thickness, erythema, and the physician’s global evaluation of the current status of the disease. Ratings of scaling, erythema, and lesion thickness, and the ratings of the global assessments were made using a 7 point scale (0 = none, 1 = trace, 2 = mild, 3 = mild-moderate, 4 = moderate, 5 = moderate-severe, 6 = severe). All efficacy variables improved significantly in a subset of 55 subjects from Trial A treated for a second, 6 month maintenance course of therapy (for a total of 12 months of treatment); a small subset of subjects (n = 4) from Trial A continued to improve after a third 6 month course of therapy (for a total of 18 months of treatment). # How Supplied - Acitretin Capsules 10 mg - Bottles of 30 capsules - Acitretin Capsules 17.5 mg - Bottles of 30 capsules - Acitretin Capsules 25 mg - Bottles of 30 capsules ## Storage Store at 20° to 25°C (68° to 77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be advised that a transient worsening of psoriasis is sometimes seen during the initial treatment period. Patients should be advised that they may have to wait 2 to 3 months before they get the full benefit of acitretin, although some patients may achieve significant improvements within the first 8 weeks of treatment as demonstrated in clinical trials. - Decreased night vision has been reported during therapy with acitretin. Patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night. Visual problems should be carefully monitored. Patients should be advised that they may experience decreased tolerance to contact lenses during the treatment period and sometimes after treatment has stopped. - Patients should not donate blood during and for at least 3 years following therapy because acitretin can cause birth defects and women of childbearing potential must not receive blood from patients being treated with acitretin. - Because of the relationship of acitretin to vitamin A, patients should be advised against taking vitamin A supplements in excess of minimum recommended daily allowances to avoid possible additive toxic effects. - Patients should avoid the use of sun lamps and excessive exposure to sunlight (non-medical UV exposure) because the effects of UV light are enhanced by retinoids. # Precautions with Alcohol Alcohol-Acitretin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Soriatane # Look-Alike Drug Names There is limited information regarding Acitretin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Acitretin 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 Acitretin is an antipsoriatic that is FDA approved for the treatment of severe psoriasis in adults. There is a Black Box Warning for this drug as shown here. Common adverse reactions include pruritus, arthralgia and paresthesia.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Acitretin is indicated for the treatment of severe psoriasis in adults. - Initial dosage: 25 to 50 mg per day, given as a single dose with the main meal. - Maintenance dosage: 25 to 50 mg per day. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Acitretin in adult patients. ### Non–Guideline-Supported Use - Nonpsoriatic disorder of skin - Lichen planus - Prophylaxis of skin cancers in high-risk renal transplant recipients - Acitretin 30 mg orally daily for 6 months [1] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness have not been established in pediatric patients ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Acitretin in pediatric patients. ### Non–Guideline-Supported Use - Lichen planus # Contraindications - Pregnancy Category X - Patients with severely impaired liver or kidney function and in patients with chronic abnormally elevated blood lipid values, - An increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate. Consequently, the combination of methotrexate with acitretin is also contraindicated. - Since both acitretin and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated. - In cases of hypersensitivity (e.g., angioedema, urticaria) to the preparation (acitretin or excipients) or to other retinoids. # Warnings - Of the 525 subjects treated in U.S. clinical trials, 2 had clinical jaundice with elevated serum bilirubin and transaminases considered related to treatment with acitretin. Liver function test results in these subjects returned to normal after acitretin was discontinued. Two of the 1,289 subjects treated in European clinical trials developed biopsy-confirmed toxic hepatitis. A second biopsy in one of these subjects revealed nodule formation suggestive of cirrhosis. One subject in a Canadian clinical trial of 63 subjects developed a 3 fold increase of transaminases. A liver biopsy of this subject showed mild lobular disarray, multifocal hepatocyte loss, and mild triaditis of the portal tracts compatible with acute reversible hepatic injury. The subject’s transaminase levels returned to normal 2 months after acitretin was discontinued. - The potential of therapy with acitretin to induce hepatotoxicity was prospectively evaluated using liver biopsies in an open-label trial of 128 subjects. Pretreatment and posttreatment biopsies were available for 87 subjects. A comparison of liver biopsy findings before and after therapy revealed 49 (58%) subjects showed no change, 21 (25%) improved, and 14 (17%) subjects had a worsening of their liver biopsy status. For 6 subjects, the classification changed from class 0 (no pathology) to class I (normal fatty infiltration; nuclear variability and portal inflammation; both mild); for 7 subjects, the change was from class I to class II (fatty infiltration, nuclear variability, portal inflammation, and focal necrosis; all moderate to severe); and for 1 subject, the change was from class II to class IIIb (fibrosis, moderate to severe). No correlation could be found between liver function test result abnormalities and the change in liver biopsy status, and no cumulative dose relationship was found. - Elevations of AST (SGOT), ALT (SGPT), GGT (GGTP), or LDH have occurred in approximately 1 in 3 subjects treated with acitretin. Of the 525 subjects treated in clinical trials in the U.S., treatment was discontinued in 20 (3.8%) due to elevated liver function test results. If hepatotoxicity is suspected during treatment with acitretin, the drug should be discontinued and the etiology further investigated. - Ten of 652 subjects treated in U.S. clinical trials of etretinate, of which acitretin is the active metabolite, had clinical or histologic hepatitis considered to be possibly or probably related to etretinate treatment. - There have been reports of hepatitis-related deaths worldwide; a few of these subjects had received etretinate for a month or less before presenting with hepatic symptoms or signs. # Adverse Reactions ## Clinical Trials Experience During clinical trials with acitretin, 513/525 (98%) of subjects reported a total of 3,545 adverse events. One-hundred sixteen subjects (22%) left trials prematurely, primarily because of adverse experiences involving the mucous membranes and skin. Three subjects died. Two of the deaths were not drug-related (pancreatic adenocarcinoma and lung cancer); the other subject died of an acute myocardial infarction, considered remotely related to drug therapy. In clinical trials, acitretin was associated with elevations in liver function test results or triglyceride levels and hepatitis. The tables below list by body system and frequency the adverse events reported during clinical trials of 525 subjects with psoriasis. Therapy with acitretin induces changes in liver function tests in a significant number of patients. Elevations of AST (SGOT), ALT (SGPT) or LDH were experienced by approximately 1 in 3 subjects treated with acitretin. In most subjects, elevations were slight to moderate and returned to normal either during continuation of therapy or after cessation of treatment. In subjects receiving acitretin during clinical trials, 66% and 33% experienced elevation in triglycerides and cholesterol, respectively. Decreased high density lipoproteins (HDL) occurred in 40%. Transient, usually reversible elevations of alkaline phosphatase have been observed. TABLE 5 lists the laboratory abnormalities reported during clinical trials. ## Postmarketing Experience In addition to the events listed in the tables for the clinical trials, the following adverse events have been identified during postapproval use of acitretin. 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. - Acute myocardial infarction - Thromboembolism, stroke Hypersensitivity, including angioedema and urticaria. - Myopathy - Peripheral neuropathy Both conditions improved with discontinuation of the drug. - Aggressive feelings and/or suicidal thoughts have been reported. - These events, including self-injurious behavior, have been reported in patients taking other systemically administered retinoids, as well as in patients taking acitretin. - Since other factors may have contributed to these events, it is not known if they are related to acitretin. - Vulvo-vaginitis due to Candida albicans. - Thinning of the skin, skin fragility, and scaling may occur all over the body, particularly on the palms and soles; nail fragility is frequently observed. Madarosis and exfoliative dermatitis/erythroderma have been reported. - Capillary leak syndrome # Drug Interactions Clinical evidence has shown that etretinate can be formed with concurrent ingestion of acitretin and ethanol. In a trial of 7 healthy male volunteers, acitretin treatment potentiated the blood glucose-lowering effect of glyburide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects. Repeating the trial with 6 healthy male volunteers in the absence of glyburide did not detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under treatment with acitretin is recommended. It has not been established if there is a pharmacokinetic interaction between acitretin and combined oral contraceptives. However, it has been established that acitretin interferes with the contraceptive effect of microdosed progestin “minipill” preparations. Microdosed “minipill” progestin preparations are not recommended for use with acitretin. It is not known whether other progestational contraceptives, such as implants and injectables, are adequate methods of contraception during acitretin therapy. An increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate. Consequently, the combination of methotrexate with acitretin is also contraindicated. If acitretin is given concurrently with phenytoin, the protein binding of phenytoin may be reduced. Since both acitretin and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated. Concomitant administration of vitamin A and/or other oral retinoids with acitretin must be avoided because of the risk of hypervitaminosis A. There appears to be no pharmacokinetic interaction between acitretin and cimetidine, digoxin, or glyburide. Investigations into the effect of acitretin on the protein binding of anticoagulants of the coumarin type (warfarin) revealed no interaction. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X In a study in which acitretin was administered to male rats only at a dosage of 5 mg/kg/day for 10 weeks (approximate duration of one spermatogenic cycle) prior to and during mating with untreated female rats, no teratogenic effects were observed in the progeny. In rats dosed at 3 mg/kg/day (approximately one-half the maximum recommended therapeutic dose based on a mg/m2 comparison), slightly decreased pup survival and delayed incisor eruption were noted. At the next lowest dose tested, 1 mg/kg/day, no treatment-related adverse effects were observed. Pregnancy Category (AUS): X There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Acitretin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Acitretin during labor and delivery. ### Nursing Mothers Studies on lactating rats have shown that etretinate is excreted in the milk. There is one prospective case report where acitretin is reported to be excreted in human milk. Therefore, nursing mothers should not receive acitretin prior to or during nursing because of the potential for serious adverse reactions in nursing infants. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. No clinical trials have been conducted in pediatric subjects. Ossification of interosseous ligaments and tendons of the extremities, skeletal hyperostoses, decreases in bone mineral density, and premature epiphyseal closure have been reported in children taking other systemic retinoids, including etretinate, a metabolite of acitretin. A causal relationship between these effects and acitretin has not been established. While it is not known that these occurrences are more severe or more frequent in children, there is special concern in pediatric patients because of the implications for growth potential. ### Geriatic Use Clinical trials of acitretin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. 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. A 2 fold increase in acitretin plasma concentrations was seen in healthy elderly subjects compared with young subjects, although the elimination half-life did not change. ### Gender There is no FDA guidance on the use of Acitretin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Acitretin with respect to specific racial populations. ### Renal Impairment Acitretin is contraindicated in patients with severely impaired kidney function ### Hepatic Impairment Acitretin is contraindicated in patients with severely impaired liver function ### Females of Reproductive Potential and Males In a fertility study in rats, the fertility of treated animals was not impaired at the highest dosage of acitretin tested, 3 mg/kg/day (approximately one-half the maximum recommended therapeutic dose based on a mg/m2 comparison). Chronic toxicity studies in dogs revealed testicular changes (reversible mild to moderate spermatogenic arrest and appearance of multinucleated giant cells) in the highest dosage group (50 then 30 mg/kg/day). No decreases in sperm count or concentration and no changes in sperm motility or morphology were noted in 31 men (17 psoriatic subjects, 8 subjects with disorders of keratinization, and 6 healthy volunteers) given 30 to 50 mg/day of acitretin for at least 12 weeks. In these trials, no deleterious effects were seen on either testosterone production, LH, or FSH in any of the 31 men. No deleterious effects were seen on the hypothalamic-pituitary axis in any of the 18 men where it was measured. ### Immunocompromised Patients There is no FDA guidance one the use of Acitretin in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring If significant abnormal laboratory results are obtained, either dosage reduction with careful monitoring or treatment discontinuation is recommended, depending on clinical judgment. # IV Compatibility There is limited information regarding the compatibility of Acitretin and IV administrations. # Overdosage In the event of acute overdosage, acitretin must be withdrawn at once. Symptoms of overdose are identical to acute hypervitaminosis A (e.g., headache and vertigo). The acute oral toxicity (LD50) of acitretin in both mice and rats was greater than 4,000 mg/kg. In one reported case of overdose, a 32-year-old male with Darier’s disease took 21 x 25 mg capsules (525 mg single dose). He vomited several hours later but experienced no other ill effects. All female patients of childbearing potential who have taken an overdose of acitretin must: - Have a pregnancy test at the time of overdose; - Be counseled as per the boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS sections regarding birth defects and contraceptive use for at least 3 years’ duration after the overdose. # Pharmacology ## Mechanism of Action The mechanism of action of acitretin is unknown. ## Structure The structural formula is: ## Pharmacodynamics There is limited information regarding Acitretin Pharmacodynamics in the drug label. ## Pharmacokinetics Oral absorption of acitretin is optimal when given with food. For this reason, acitretin was given with food in all of the following trials. After administration of a single 50 mg oral dose of acitretin to 18 healthy subjects, maximum plasma concentrations ranged from 196 to 728 ng/mL (mean: 416 ng/mL) and were achieved in 2 to 5 hours (mean: 2.7 hours). The oral absorption of acitretin is linear and proportional with increasing doses from 25 to 100 mg. Approximately 72% (range: 47% to 109%) of the administered dose was absorbed after a single 50 mg dose of acitretin was given to 12 healthy subjects. Acitretin is more than 99.9% bound to plasma proteins, primarily albumin. Following oral absorption, acitretin undergoes extensive metabolism and interconversion by simple isomerization to its 13-cis form (cis-acitretin). The formation of cis-acitretin relative to parent compound is not altered by dose or fed/fast conditions of oral administration of acitretin. Both parent compound and isomer are further metabolized into chain-shortened breakdown products and conjugates, which are excreted. Following multiple-dose administration of acitretin, steady-state concentrations of acitretin and cis-acitretin in plasma are achieved within approximately 3 weeks. The chain-shortened metabolites and conjugates of acitretin and cis-acitretin are ultimately excreted in the feces (34% to 54%) and urine (16% to 53%). The terminal elimination half-life of acitretin following multiple-dose administration is 49 hours (range: 33 to 96 hours), and that of cis-acitretin under the same conditions is 63 hours (range: 28 to 157 hours). The accumulation ratio of the parent compound is 1.2; that of cis-acitretin is 6.6. ## Nonclinical Toxicology A carcinogenesis study of acitretin in Wistar rats, at doses up to 2 mg/kg/day administered 7 days/week for 104 weeks, has been completed. There were no neoplastic lesions observed that were considered to have been related to treatment with acitretin. An 80 week carcinogenesis study in mice has been completed with etretinate, the ethyl ester of acitretin. Blood level data obtained during this study demonstrated that etretinate was metabolized to acitretin and that blood levels of acitretin exceeded those of etretinate at all times studied. In the etretinate study, an increased incidence of blood vessel tumors (hemangiomas and hemangiosarcomas at several different sites) was noted in male, but not female, mice at doses approximately one-half the maximum recommended human therapeutic dose based on a mg/m2 comparison. Acitretin was evaluated for mutagenic potential in the Ames test, in the Chinese hamster (V79/HGPRT) assay, in unscheduled DNA synthesis assays using rat hepatocytes and human fibroblasts, and in an in vivo mouse micronucleus assay. No evidence of mutagenicity of acitretin was demonstrated in any of these assays. # Clinical Studies In 2 double-blind, placebo-controlled trials, acitretin was administered once daily to subjects with severe psoriasis (e.g., covering at least 10% to 20% of the body surface area). At 8 weeks (see TABLE 1) subjects treated in Trial A with 50 mg of acitretin per day showed significant improvements (P ≤ 0.05) relative to baseline and to placebo in the physician’s global evaluation and in the mean ratings of severity of psoriasis (scaling, thickness, and erythema). In Trial B, differences from baseline and from placebo were statistically significant (P ≤ 0.05) for all variables at both the 25 mg and 50 mg doses; it should be noted for Trial B that no statistical adjustment for multiplicity was carried out. The efficacy variables consisted of: the mean severity rating of scale, lesion thickness, erythema, and the physician’s global evaluation of the current status of the disease. Ratings of scaling, erythema, and lesion thickness, and the ratings of the global assessments were made using a 7 point scale (0 = none, 1 = trace, 2 = mild, 3 = mild-moderate, 4 = moderate, 5 = moderate-severe, 6 = severe). A subset of 141 subjects from both pivotal Trials A and B continued to receive acitretin in an open fashion for up to 24 weeks. At the end of the treatment period, all efficacy variables, as indicated in TABLE 2, were significantly improved (P ≤ 0.01) from baseline, including extent of psoriasis, mean ratings of psoriasis severity, and physician’s global evaluation. The efficacy variables consisted of: the mean severity rating of scale, lesion thickness, erythema, and the physician’s global evaluation of the current status of the disease. Ratings of scaling, erythema, and lesion thickness, and the ratings of the global assessments were made using a 7 point scale (0 = none, 1 = trace, 2 = mild, 3 = mild-moderate, 4 = moderate, 5 = moderate-severe, 6 = severe). All efficacy variables improved significantly in a subset of 55 subjects from Trial A treated for a second, 6 month maintenance course of therapy (for a total of 12 months of treatment); a small subset of subjects (n = 4) from Trial A continued to improve after a third 6 month course of therapy (for a total of 18 months of treatment). # How Supplied - Acitretin Capsules 10 mg - Bottles of 30 capsules - Acitretin Capsules 17.5 mg - Bottles of 30 capsules - Acitretin Capsules 25 mg - Bottles of 30 capsules ## Storage Store at 20° to 25°C (68° to 77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be advised that a transient worsening of psoriasis is sometimes seen during the initial treatment period. Patients should be advised that they may have to wait 2 to 3 months before they get the full benefit of acitretin, although some patients may achieve significant improvements within the first 8 weeks of treatment as demonstrated in clinical trials. - Decreased night vision has been reported during therapy with acitretin. Patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night. Visual problems should be carefully monitored. Patients should be advised that they may experience decreased tolerance to contact lenses during the treatment period and sometimes after treatment has stopped. - Patients should not donate blood during and for at least 3 years following therapy because acitretin can cause birth defects and women of childbearing potential must not receive blood from patients being treated with acitretin. - Because of the relationship of acitretin to vitamin A, patients should be advised against taking vitamin A supplements in excess of minimum recommended daily allowances to avoid possible additive toxic effects. - Patients should avoid the use of sun lamps and excessive exposure to sunlight (non-medical UV exposure) because the effects of UV light are enhanced by retinoids. # Precautions with Alcohol Alcohol-Acitretin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Soriatane [2] # Look-Alike Drug Names There is limited information regarding Acitretin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Acitretin
67a814f741cb5a11bc0a876d8ea14988e8c8844c	wikidoc	Aconitase	Aconitase Aconitase (aconitate hydratase; EC 4.2.1.3) is an enzyme that catalyses the stereo-specific isomerization of citrate to isocitrate via cis-aconitate in the tricarboxylic acid cycle, a non-redox-active process. - Citric acid - Aconitic acid - Isocitric acid Isocitric acid # Structure Aconitase, displayed in the structures in the right margin of this page, has two slightly different structures, depending on whether it is activated or inactivated. In the inactive form, its structure is divided into four domains. Counting from the N-terminus, only the first three of these domains are involved in close interactions with the cluster, but the active site consists of residues from all four domains, including the larger C-terminal domain. The Fe-S cluster and a SO42− anion also reside in the active site. When the enzyme is activated, it gains an additional iron atom, creating a cluster. However, the structure of the rest of the enzyme is nearly unchanged; the conserved atoms between the two forms are in essentially the same positions, up to a difference of 0.1 angstroms. # Function In contrast with the majority of iron-sulfur proteins that function as electron carriers, the iron-sulfur cluster of aconitase reacts directly with an enzyme substrate. Aconitase has an active 2+ cluster, which may convert to an inactive + form. Three cysteine (Cys) residues have been shown to be ligands of the centre. In the active state, the labile iron ion of the cluster is not coordinated by Cys but by water molecules. The iron-responsive element-binding protein (IRE-BP) and 3-isopropylmalate dehydratase (α-isopropylmalate isomerase; EC 4.2.1.33), an enzyme catalysing the second step in the biosynthesis of leucine, are known aconitase homologues. Iron regulatory elements (IREs) constitute a family of 28-nucleotide, non-coding, stem-loop structures that regulate iron storage, heme synthesis and iron uptake. They also participate in ribosome binding and control the mRNA turnover (degradation). The specific regulator protein, the IRE-BP, binds to IREs in both 5' and 3' regions, but only to RNA in the apo form, without the Fe-S cluster. Expression of IRE-BP in cultured cells has revealed that the protein functions either as an active aconitase, when cells are iron-replete, or as an active RNA-binding protein, when cells are iron-depleted. Mutant IRE-BPs, in which any or all of the three Cys residues involved in Fe-S formation are replaced by serine, have no aconitase activity, but retain RNA-binding properties. Aconitase is inhibited by fluoroacetate, therefore fluoroacetate is poisonous. Fluoroacetate, in the citric acid cycle,can innocently enter as fluorocitrate. However, aconitase cannot bind this substrate and thus the citric acid cycle is halted. The iron sulfur cluster is highly sensitive to oxidation by superoxide. ## Mechanism Aconitase employs a dehydration-hydration mechanism. The catalytic residues involved are His-101 and Ser-642. His-101 protonates the hydroxyl group on C3 of citrate, allowing it to leave as water, and Ser-642 concurrently abstracts the proton on C2, forming a double bond between C2 and C3, forming a cis-aconitate intermediate. At this point, the intermediate is rotated 180°. This rotation is referred to as a "flip." Because of this flip, the intermediate is said to move from a "citrate mode" to a "isocitrate mode." How exactly this flip occurs is debatable. One theory is that, in the rate-limiting step of the mechanism, the cis-aconitate is released from the enzyme, then reattached in the isocitrate mode to complete the reaction. This rate-liming step ensures that the right stereochemistry, specifically (2R,3S), is formed in the final product. Another hypothesis is that cis-aconitate stays bound to the enzyme while it flips from the citrate to the isocitrate mode. In either case, flipping cis-aconitate allows the dehydration and hydration steps to occur on opposite faces of the intermediate. Aconitase catalyzes trans elimination/addition of water, and the flip guarantees that the correct stereochemistry is formed in the product. To complete the reaction, the serine and histidine residues reverse their original catalytic actions: the histidine, now basic, abstracts a proton from water, priming it as a nucleophile to attack at C2, and the protonated serine is deprotonated by the cis-aconitate double bond to complete the hydration, producing isocitrate. # Family members Aconitases are expressed in bacteria to humans. Humans express the following two aconitase isozymes: # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78"..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}	Aconitase Aconitase (aconitate hydratase; EC 4.2.1.3) is an enzyme that catalyses the stereo-specific isomerization of citrate to isocitrate via cis-aconitate in the tricarboxylic acid cycle, a non-redox-active process.[3][4][5] - Citric acid - Aconitic acid - Isocitric acid Isocitric acid # Structure Aconitase, displayed in the structures in the right margin of this page, has two slightly different structures, depending on whether it is activated or inactivated.[6][7] In the inactive form, its structure is divided into four domains.[6] Counting from the N-terminus, only the first three of these domains are involved in close interactions with the [3Fe-4S] cluster, but the active site consists of residues from all four domains, including the larger C-terminal domain.[6] The Fe-S cluster and a SO42− anion also reside in the active site.[6] When the enzyme is activated, it gains an additional iron atom, creating a [4Fe-4S] cluster.[7][8] However, the structure of the rest of the enzyme is nearly unchanged; the conserved atoms between the two forms are in essentially the same positions, up to a difference of 0.1 angstroms.[7] # Function In contrast with the majority of iron-sulfur proteins that function as electron carriers, the iron-sulfur cluster of aconitase reacts directly with an enzyme substrate. Aconitase has an active [Fe4S4]2+ cluster, which may convert to an inactive [Fe3S4]+ form. Three cysteine (Cys) residues have been shown to be ligands of the [Fe4S4] centre. In the active state, the labile iron ion of the [Fe4S4] cluster is not coordinated by Cys but by water molecules. The iron-responsive element-binding protein (IRE-BP) and 3-isopropylmalate dehydratase (α-isopropylmalate isomerase; EC 4.2.1.33), an enzyme catalysing the second step in the biosynthesis of leucine, are known aconitase homologues. Iron regulatory elements (IREs) constitute a family of 28-nucleotide, non-coding, stem-loop structures that regulate iron storage, heme synthesis and iron uptake. They also participate in ribosome binding and control the mRNA turnover (degradation). The specific regulator protein, the IRE-BP, binds to IREs in both 5' and 3' regions, but only to RNA in the apo form, without the Fe-S cluster. Expression of IRE-BP in cultured cells has revealed that the protein functions either as an active aconitase, when cells are iron-replete, or as an active RNA-binding protein, when cells are iron-depleted. Mutant IRE-BPs, in which any or all of the three Cys residues involved in Fe-S formation are replaced by serine, have no aconitase activity, but retain RNA-binding properties. Aconitase is inhibited by fluoroacetate, therefore fluoroacetate is poisonous. Fluoroacetate, in the citric acid cycle,can innocently enter as fluorocitrate. However, aconitase cannot bind this substrate and thus the citric acid cycle is halted. The iron sulfur cluster is highly sensitive to oxidation by superoxide.[9] ## Mechanism Aconitase employs a dehydration-hydration mechanism.[10] The catalytic residues involved are His-101 and Ser-642.[10] His-101 protonates the hydroxyl group on C3 of citrate, allowing it to leave as water, and Ser-642 concurrently abstracts the proton on C2, forming a double bond between C2 and C3, forming a cis-aconitate intermediate.[10][13] At this point, the intermediate is rotated 180°.[10] This rotation is referred to as a "flip."[11] Because of this flip, the intermediate is said to move from a "citrate mode" to a "isocitrate mode."[14] How exactly this flip occurs is debatable. One theory is that, in the rate-limiting step of the mechanism, the cis-aconitate is released from the enzyme, then reattached in the isocitrate mode to complete the reaction.[14] This rate-liming step ensures that the right stereochemistry, specifically (2R,3S), is formed in the final product.[14][15] Another hypothesis is that cis-aconitate stays bound to the enzyme while it flips from the citrate to the isocitrate mode.[10] In either case, flipping cis-aconitate allows the dehydration and hydration steps to occur on opposite faces of the intermediate.[10] Aconitase catalyzes trans elimination/addition of water, and the flip guarantees that the correct stereochemistry is formed in the product.[10][11] To complete the reaction, the serine and histidine residues reverse their original catalytic actions: the histidine, now basic, abstracts a proton from water, priming it as a nucleophile to attack at C2, and the protonated serine is deprotonated by the cis-aconitate double bond to complete the hydration, producing isocitrate.[10] # Family members Aconitases are expressed in bacteria to humans. Humans express the following two aconitase isozymes: # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. [§ 1] - ↑ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}	https://www.wikidoc.org/index.php/Aconitase
a62e3a0eefea33ee291a62167374d94bf58f74be	wikidoc	Acoustics	Acoustics Acoustics is the interdisciplinary science that deals with the study of sound, ultrasound and infrasound (all mechanical waves in gases, liquids, and solids). A scientist who works in the field of acoustics is an acoustician. The application of acoustics in technology is called acoustical engineering. There is often much overlap and interaction between the interests of acousticians and acoustical engineers. Hearing is one of the most crucial means of survival in the animal world, and speech is one of the most distinctive characteristics of human development and culture. So it is no surprise that the science of acoustics spreads across so many facets of our society - music, medicine, architecture, industrial production, warfare and more. Art, craft, science and technology have provoked one another to advance the whole, as in many other fields of knowledge. The word "acoustic" is derived from the ancient Greek word ακουστός, meaning able to be heard (Woodhouse, 1910, 392). The Latin synonym is "sonic". After acousticians had extended their studies to frequencies above and below the audible range, it became conventional to identify these frequency ranges as "ultrasonic" and "infrasonic" respectively, while letting the word "acoustic" refer to the entire frequency range without limit. # History of acoustics ## Early research in acoustics The science of acoustics had its beginnings in the Greek and Roman cultures between the 6th century BCE and 1st century BCE. It began with music, which had been practised as an art for thousands of years, but was not evidently studied in a scientific manner until Pythagoras took an interest in the nature of musical intervals. He wanted to know why some intervals seemed more beautiful than others, and he found answers in terms of numerical ratios. Aristotle (384-322 BC) understood that sound consisted of contractions and expansions of the air "falling upon and striking the air which is next to it...", a very good expression of the nature of wave motion. In about 20 BC, the Roman architect and engineer Vitruvius wrote a treatise on the acoustical properties of theatres including discussion of interference, echoes, and reverberation - the beginnings of architectural acoustics. The physical understanding of acoustical processes advanced rapidly during and after the Scientific Revolution. Galileo (1564-1642) and Mersenne (1588-1648) independently discovered the complete laws of vibrating strings (completing what Pythagoras had started 2000 years earlier). Galileo wrote "Waves are produced by the vibrations of a sonorous body, which spread through the air, bringing to the tympanum of the ear a stimulus which the mind interprets as sound", a remarkable statement that points to the beginnings of physiological and psychological acoustics. Experimental measurements of the speed of sound in air were carried out successfully between 1630 and 1680 by a number of investigators including Mersenne. Meanwhile Newton (1642-1727) derived the relationship for wave velocity in solids, a cornerstone of physical acoustics (Principia, 1687). ## The Age of Enlightenment and onward The eighteenth century saw major advances in acoustics at the hands of the great mathematicians of that era, who applied the new techniques of the calculus to the elaboration of wave propagation theory. In the nineteenth century the giants of acoustics were Helmholtz in Germany, who consolidated the field of physiological acoustics, and Lord Rayleigh in England, who combined the previous knowledge with his own copious contributions to the field in his monumental work "The Theory of Sound". Also in the 19th century, Wheatstone, Ohm, and Henry developed the analog between electricity and acoustics. The twentieth century saw a burgeoning of technological applications of the large body of scientific knowledge that was by then in place. The first such application was Sabine’s groundbreaking work in architectural acoustics, and many others followed. Underwater acoustics was used for detecting submarines in the first World War. Sound recording and the telephone played important roles in a global transformation of society. Sound measurement and analysis reached new levels of accuracy and sophistication through the use of electronics and computing. The ultrasonic frequency range enabled wholly new kinds of application in medicine and industry. New kinds of transducers (generators and receivers of acoustic energy) were invented and put to use. # Fundamental concepts of acoustics The study of acoustics revolves around the generation, propagation and reception of mechanical waves and vibrations. The steps shown in the above diagram can be found in any acoustical event or process. There are many kinds of cause, both natural and volitional. There are many kinds of transduction process that convert energy from some other form into acoustical energy, producing the acoustic wave. There is one fundamental equation that describes acoustic wave propagation, but the phenomena that emerge from it are varied and often complex. The wave carries energy throughout the propagating medium. Eventually this energy is transduced again into other forms, in ways that again may be natural and/or volitionally contrived. The final effect may be purely physical or it may reach far into the biological or volitional domains. The five basic steps are found equally well whether we are talking about an earthquake, a submarine using sonar to locate its foe, or a band playing in a rock concert. The central stage in the acoustical process is wave propagation. This falls within the domain of physical acoustics. In fluids, sound propagates primarily as a pressure wave. In solids, mechanical waves can take many forms including longitudinal waves, transverse waves and surface waves. Acoustics looks first at the pressure levels and frequencies in the sound wave. Transduction processes are also of special importance. ## Wave propagation: pressure levels In fluids such as air and water, sound waves propagate as disturbances in the ambient pressure level. While this disturbance is usually small, it is still noticeable to the human ear. The smallest sound that a person can hear, known as the threshold of hearing, is nine orders of magnitude smaller than the ambient pressure. The loudness of these disturbances is called the sound pressure level, and is measured on a logarithmic scale in decibels. Mathematically, sound pressure level is defined SPL = 20*log_{10}\frac{P}{P_{ref}} where Pref is the threshold of hearing and P is the change in pressure from the ambient pressure. The following table gives a few examples of sounds and their strengths in decibels and Pascals . ## Wave propagation: frequency Physicists and acoustic engineers tend to discuss sound pressure levels in terms of frequencies, partly because this is how our ears interpret sound. What we experience as "higher pitched" or "lower pitched" sounds are pressure vibrations having a higher or lower number of cycles per second. In a common technique of acoustic measurement, acoustic signals are sampled in time, and then presented in more meaningful forms such as octave bands or time frequency plots. Both these popular methods are used to analyze sound and better understand the acoustic phenomenon. The entire spectrum can be divided into three sections: audio, ultrasonic, and infrasonic. The audio range falls between 20 Hz and 20,000 Hz. This range is important because its frequencies can be detected by the human ear. This range has a number of applications, including speech communication and music. The ultrasonic range refers to the very high frequencies: 20,000 Hz and higher. This range has shorter wavelengths which allows better resolution in imaging technologies. Medical applications such as ultrasonography and elastography rely on the ultrasonic frequency range. On the other end of the spectrum, the lowest frequencies are known as the infrasonic range. These frequencies can be used to study geological phenomenon such as earthquakes. ## Transduction in acoustics A transducer is just a device for converting one form of energy into another. In an acoustical context, this usually means converting sound energy into electrical energy (or vice versa). For nearly all acoustic applications, some type of acoustic transducer is necessary. Acoustic transducers include loudspeakers, microphones, hydrophones, sonar projectors, and ultrasound imaging equipment. Most of these are an electromechanical devices that converts an electric signal to or from a sound pressure wave. One common example is a subwoofer used to generate lower notes in speaker audio systems. Subwoofers generate waves using a suspended diaphragm which oscillates, sending off pressure waves. Electret microphones are a common type of microphone which operate using a similar principle. As the sound wave strikes the electret's surface, the surface moves and sends off an electrical signal. # Divisions of acoustics Countless subfields have been created as we have perfected our understanding of the underlying physics of acoustics. The table below shows seventeen major subfields of acoustics established in the PACS classification system. These have been grouped into three domains: physical acoustics, biological acoustics and acoustical engineering.	Acoustics Acoustics is the interdisciplinary science that deals with the study of sound, ultrasound and infrasound (all mechanical waves in gases, liquids, and solids). A scientist who works in the field of acoustics is an acoustician. The application of acoustics in technology is called acoustical engineering. There is often much overlap and interaction between the interests of acousticians and acoustical engineers. Hearing is one of the most crucial means of survival in the animal world, and speech is one of the most distinctive characteristics of human development and culture. So it is no surprise that the science of acoustics spreads across so many facets of our society - music, medicine, architecture, industrial production, warfare and more. Art, craft, science and technology have provoked one another to advance the whole, as in many other fields of knowledge. The word "acoustic" is derived from the ancient Greek word ακουστός, meaning able to be heard (Woodhouse, 1910, 392). The Latin synonym is "sonic". After acousticians had extended their studies to frequencies above and below the audible range, it became conventional to identify these frequency ranges as "ultrasonic" and "infrasonic" respectively, while letting the word "acoustic" refer to the entire frequency range without limit. # History of acoustics ## Early research in acoustics The science of acoustics had its beginnings in the Greek and Roman cultures between the 6th century BCE and 1st century BCE. It began with music, which had been practised as an art for thousands of years, but was not evidently studied in a scientific manner until Pythagoras took an interest in the nature of musical intervals. He wanted to know why some intervals seemed more beautiful than others, and he found answers in terms of numerical ratios. Aristotle (384-322 BC) understood that sound consisted of contractions and expansions of the air "falling upon and striking the air which is next to it...", a very good expression of the nature of wave motion. In about 20 BC, the Roman architect and engineer Vitruvius wrote a treatise on the acoustical properties of theatres including discussion of interference, echoes, and reverberation - the beginnings of architectural acoustics.[1] The physical understanding of acoustical processes advanced rapidly during and after the Scientific Revolution. Galileo (1564-1642) and Mersenne (1588-1648) independently discovered the complete laws of vibrating strings (completing what Pythagoras had started 2000 years earlier). Galileo wrote "Waves are produced by the vibrations of a sonorous body, which spread through the air, bringing to the tympanum of the ear a stimulus which the mind interprets as sound", a remarkable statement that points to the beginnings of physiological and psychological acoustics. Experimental measurements of the speed of sound in air were carried out successfully between 1630 and 1680 by a number of investigators including Mersenne. Meanwhile Newton (1642-1727) derived the relationship for wave velocity in solids, a cornerstone of physical acoustics (Principia, 1687). ## The Age of Enlightenment and onward The eighteenth century saw major advances in acoustics at the hands of the great mathematicians of that era, who applied the new techniques of the calculus to the elaboration of wave propagation theory. In the nineteenth century the giants of acoustics were Helmholtz in Germany, who consolidated the field of physiological acoustics, and Lord Rayleigh in England, who combined the previous knowledge with his own copious contributions to the field in his monumental work "The Theory of Sound". Also in the 19th century, Wheatstone, Ohm, and Henry developed the analog between electricity and acoustics. The twentieth century saw a burgeoning of technological applications of the large body of scientific knowledge that was by then in place. The first such application was Sabine’s groundbreaking work in architectural acoustics, and many others followed. Underwater acoustics was used for detecting submarines in the first World War. Sound recording and the telephone played important roles in a global transformation of society. Sound measurement and analysis reached new levels of accuracy and sophistication through the use of electronics and computing. The ultrasonic frequency range enabled wholly new kinds of application in medicine and industry. New kinds of transducers (generators and receivers of acoustic energy) were invented and put to use. # Fundamental concepts of acoustics The study of acoustics revolves around the generation, propagation and reception of mechanical waves and vibrations. The steps shown in the above diagram can be found in any acoustical event or process. There are many kinds of cause, both natural and volitional. There are many kinds of transduction process that convert energy from some other form into acoustical energy, producing the acoustic wave. There is one fundamental equation that describes acoustic wave propagation, but the phenomena that emerge from it are varied and often complex. The wave carries energy throughout the propagating medium. Eventually this energy is transduced again into other forms, in ways that again may be natural and/or volitionally contrived. The final effect may be purely physical or it may reach far into the biological or volitional domains. The five basic steps are found equally well whether we are talking about an earthquake, a submarine using sonar to locate its foe, or a band playing in a rock concert. The central stage in the acoustical process is wave propagation. This falls within the domain of physical acoustics. In fluids, sound propagates primarily as a pressure wave. In solids, mechanical waves can take many forms including longitudinal waves, transverse waves and surface waves. Acoustics looks first at the pressure levels and frequencies in the sound wave. Transduction processes are also of special importance. ## Wave propagation: pressure levels In fluids such as air and water, sound waves propagate as disturbances in the ambient pressure level. While this disturbance is usually small, it is still noticeable to the human ear. The smallest sound that a person can hear, known as the threshold of hearing, is nine orders of magnitude smaller than the ambient pressure. The loudness of these disturbances is called the sound pressure level, and is measured on a logarithmic scale in decibels. Mathematically, sound pressure level is defined <math>SPL = 20*log_{10}\frac{P}{P_{ref}}</math> where Pref is the threshold of hearing and P is the change in pressure from the ambient pressure. The following table gives a few examples of sounds and their strengths in decibels and Pascals [2]. ## Wave propagation: frequency Physicists and acoustic engineers tend to discuss sound pressure levels in terms of frequencies, partly because this is how our ears interpret sound. What we experience as "higher pitched" or "lower pitched" sounds are pressure vibrations having a higher or lower number of cycles per second. In a common technique of acoustic measurement, acoustic signals are sampled in time, and then presented in more meaningful forms such as octave bands or time frequency plots. Both these popular methods are used to analyze sound and better understand the acoustic phenomenon. The entire spectrum can be divided into three sections: audio, ultrasonic, and infrasonic. The audio range falls between 20 Hz and 20,000 Hz. This range is important because its frequencies can be detected by the human ear. This range has a number of applications, including speech communication and music. The ultrasonic range refers to the very high frequencies: 20,000 Hz and higher. This range has shorter wavelengths which allows better resolution in imaging technologies. Medical applications such as ultrasonography and elastography rely on the ultrasonic frequency range. On the other end of the spectrum, the lowest frequencies are known as the infrasonic range. These frequencies can be used to study geological phenomenon such as earthquakes. ## Transduction in acoustics A transducer is just a device for converting one form of energy into another. In an acoustical context, this usually means converting sound energy into electrical energy (or vice versa). For nearly all acoustic applications, some type of acoustic transducer is necessary. Acoustic transducers include loudspeakers, microphones, hydrophones, sonar projectors, and ultrasound imaging equipment. Most of these are an electromechanical devices that converts an electric signal to or from a sound pressure wave. One common example is a subwoofer used to generate lower notes in speaker audio systems. Subwoofers generate waves using a suspended diaphragm which oscillates, sending off pressure waves. Electret microphones are a common type of microphone which operate using a similar principle. As the sound wave strikes the electret's surface, the surface moves and sends off an electrical signal. # Divisions of acoustics Countless subfields have been created as we have perfected our understanding of the underlying physics of acoustics. The table below shows seventeen major subfields of acoustics established in the PACS classification system. These have been grouped into three domains: physical acoustics, biological acoustics and acoustical engineering.	https://www.wikidoc.org/index.php/Acoustics
5cb180c34b0ded115669eba902fbf7edc1990904	wikidoc	Acrodynia	Acrodynia Acrodynia is characterized by pink discoloration of the hands and feet, irritability, photophobia (sensitivity to light) and polyneuritis (inflamed nerves). It is caused by chronic exposure to mercury. The most common form of exposure in young children is ingesting mercury from a broken thermometer. The signs and symptoms of mercury toxicity may not appear until weeks or months after exposure has occurred. # Signs and Symptoms ## Initial signs - Listlessness, drowsiness, irritability and a tendency to cry - Loss of appetite and subsequent weight loss - More than 50% complain of sensitivity to light - Generalized weakness and painful extremities ## Within 2-4 weeks - Tip of the nose, fingers and toes turn a pinkish color, which progressively darkens and spreads into a net-like pattern. - Hands and feet become painful, cold, cyanotic (blue), erythematous (red) and swollen. - Extreme pain and itchiness in the extremity often leads to thickened scratched skin as the child rubs and scratches the area. - Hyperhidrosis (excessive sweating) with a mouselike smell may occur. This may lead to miliaria and secondary bacterial skin infections. - Inflammation, swelling and gum erosion may occur with subsequent loss of teeth. - Alopecia and nail loss have also been reported. # Clinical Characteristics ## Central nervous system - Irritability - Extreme photophobia (patient burrows head or covers eyes to block out light) ## Cardiovascular - Hypertension - Tachycardia ## Gastrointestinal - Stomatitis with anorexia - Colitis with diarrhea or constipation - Salivation ## Renal - Proteinuria - Nephrotic syndrome progressing to renal failure in extreme cases ## Dermal - Erythema of the palms, soles, and face - Edema and desquamation of the skin of hands and feet - Pruritus ## Muscular/Skeletal - Hypotonia ## Various - Gingivitis - Diaphoresis - Paresthesia - Generalized pain # Treatment The goal of treatment is to remove the mercury and correct any fluid or electrolyte imbalances. - Chelating agents such as meso 2,3-dimercaptosuccinic acid are used to prevent methylmercury uptake by erythrocytes (red blood cells) and hepatocytes (liver cells). - Hemodialysis with and without the addition of L-cysteine as a chelating agent has been used in patients with acute renal failure from mercury toxicity.	Acrodynia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Acrodynia is characterized by pink discoloration of the hands and feet, irritability, photophobia (sensitivity to light) and polyneuritis (inflamed nerves). It is caused by chronic exposure to mercury. The most common form of exposure in young children is ingesting mercury from a broken thermometer. The signs and symptoms of mercury toxicity may not appear until weeks or months after exposure has occurred. # Signs and Symptoms ## Initial signs - Listlessness, drowsiness, irritability and a tendency to cry - Loss of appetite and subsequent weight loss - More than 50% complain of sensitivity to light - Generalized weakness and painful extremities ## Within 2-4 weeks - Tip of the nose, fingers and toes turn a pinkish color, which progressively darkens and spreads into a net-like pattern. - Hands and feet become painful, cold, cyanotic (blue), erythematous (red) and swollen. - Extreme pain and itchiness in the extremity often leads to thickened scratched skin as the child rubs and scratches the area. - Hyperhidrosis (excessive sweating) with a mouselike smell may occur. This may lead to miliaria and secondary bacterial skin infections. - Inflammation, swelling and gum erosion may occur with subsequent loss of teeth. - Alopecia and nail loss have also been reported. # Clinical Characteristics ## Central nervous system - Irritability - Extreme photophobia (patient burrows head or covers eyes to block out light) ## Cardiovascular - Hypertension - Tachycardia ## Gastrointestinal - Stomatitis with anorexia - Colitis with diarrhea or constipation - Salivation ## Renal - Proteinuria - Nephrotic syndrome progressing to renal failure in extreme cases ## Dermal - Erythema of the palms, soles, and face - Edema and desquamation of the skin of hands and feet - Pruritus ## Muscular/Skeletal - Hypotonia ## Various - Gingivitis - Diaphoresis - Paresthesia - Generalized pain # Treatment The goal of treatment is to remove the mercury and correct any fluid or electrolyte imbalances. - Chelating agents such as meso 2,3-dimercaptosuccinic acid are used to prevent methylmercury uptake by erythrocytes (red blood cells) and hepatocytes (liver cells). - Hemodialysis with and without the addition of L-cysteine as a chelating agent has been used in patients with acute renal failure from mercury toxicity. Template:Skin and subcutaneous tissue symptoms and signs Template:Nervous and musculoskeletal system symptoms and signs Template:Urinary system symptoms and signs Template:Cognition, perception, emotional state and behaviour symptoms and signs Template:Speech and voice symptoms and signs Template:General symptoms and signs Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Acrodynia
a791a3632b1037f84f9ec4ebbeedfa1e6664f7c3	wikidoc	Actinides	Actinides The actinoid (according to IUPAC terminology) (previously actinide) series encompasses the 15 chemical elements that lie between actinium and lawrencium included on the periodic table, with atomic numbers 89 - 103. The actinoid series derives its name from the first element in the series, actinium, and ultimately from the Greek ακτις (aktis), "ray," reflecting the elements' radioactivity. The actinoid series (An) is included in some definitions of the rare earth elements. IUPAC is currently recommending the name actinoid rather than actinide, as the suffix "-ide" generally indicates ions (moreover, from Latin, the suffix -ide means "sons of actinium", while -oid means "similar to actinium"). There are alternative arrangements of the periodic table that exclude actinium or lawrencium from appearing together with the other actinoids. The actinoids display less similarity in their chemical properties than the lanthanoid series (Ln), exhibiting a wider range of oxidation states, which initially led to confusion as to whether actinium, thorium, and uranium should be considered d-block elements. All actinoids are radioactive. Only thorium and uranium occur naturally in the earth's crust in anything more than trace quantities. Neptunium and plutonium have been known to show up naturally in trace amounts in uranium ores as a result of decay or bombardment. The remaining actinides were discovered in nuclear fallout, or were synthesized in particle colliders. The latter half of the series possess exceedingly short half-lives. The actinoids are typically placed below the main body of the periodic table (below the lanthanoid series), in the manner of a footnote. The full-width version of the periodic table shows the position of the actinoids more clearly. An organometallic compound of an actinoid is known as an organoactinoid. # History of the actinoid series From the earlier known chemical properties of actinium (89) up to uranium (92), indicating a relation to the transition metals, it was generally assumed that the transuraniums would have similar qualities. During his Manhattan Project research in 1944, Glenn T. Seaborg experienced unexpected difficulty isolating americium (95) and curium (96). He began wondering if these elements more properly belonged to a different series than the transition metals, which would explain why the expected chemical properties of the new elements were different. In 1945, he went against the advice of colleagues and proposed the most significant change to Mendeleev's periodic table to have been accepted universally by the scientific community: the actinide series. In 1945, Seaborg published his actinide concept of heavy element electronic structure, predicting that the actinides would form a transition series analogous to the rare earth series of lanthanoid elements. In 1961, Antoni Przybylski discovered a star that contained unusually high amounts of actinides.	Actinides The actinoid (according to IUPAC terminology) (previously actinide) series encompasses the 15 chemical elements that lie between actinium and lawrencium included on the periodic table, with atomic numbers 89 - 103.[1] [2] The actinoid series derives its name from the first element in the series, actinium, and ultimately from the Greek ακτις (aktis), "ray," reflecting the elements' radioactivity. The actinoid series (An) is included in some definitions of the rare earth elements. IUPAC is currently recommending the name actinoid rather than actinide, as the suffix "-ide" generally indicates ions (moreover, from Latin, the suffix -ide means "sons of actinium", while -oid means "similar to actinium"). There are alternative arrangements of the periodic table that exclude actinium or lawrencium from appearing together with the other actinoids. The actinoids display less similarity in their chemical properties than the lanthanoid series (Ln), exhibiting a wider range of oxidation states, which initially led to confusion as to whether actinium, thorium, and uranium should be considered d-block elements. All actinoids are radioactive. Only thorium and uranium occur naturally in the earth's crust in anything more than trace quantities. Neptunium and plutonium have been known to show up naturally in trace amounts in uranium ores as a result of decay or bombardment. The remaining actinides were discovered in nuclear fallout, or were synthesized in particle colliders. The latter half of the series possess exceedingly short half-lives. The actinoids are typically placed below the main body of the periodic table (below the lanthanoid series), in the manner of a footnote. The full-width version of the periodic table shows the position of the actinoids more clearly. An organometallic compound of an actinoid is known as an organoactinoid. # History of the actinoid series From the earlier known chemical properties of actinium (89) up to uranium (92), indicating a relation to the transition metals, it was generally assumed that the transuraniums would have similar qualities. During his Manhattan Project research in 1944, Glenn T. Seaborg experienced unexpected difficulty isolating americium (95) and curium (96). He began wondering if these elements more properly belonged to a different series than the transition metals, which would explain why the expected chemical properties of the new elements were different. In 1945, he went against the advice of colleagues and proposed the most significant change to Mendeleev's periodic table to have been accepted universally by the scientific community: the actinide series. In 1945, Seaborg published his actinide concept of heavy element electronic structure, predicting that the actinides would form a transition series analogous to the rare earth series of lanthanoid elements. In 1961, Antoni Przybylski discovered a star that contained unusually high amounts of actinides.	https://www.wikidoc.org/index.php/Actinides
232dff1174877f1f3f6fab765b79264a988b4fe0	wikidoc	Protein C	Protein C Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV,:6822 is a zymogen, the activated form of which plays an important role in regulating anticoagulation, inflammation, cell death, and maintaining the permeability of blood vessel walls in humans and other animals. Activated protein C (APC) performs these operations primarily by proteolytically inactivating proteins Factor Va and Factor VIIIa. APC is classified as a serine protease as it contains a residue of serine in its active site.:35 In humans, protein C is encoded by the PROC gene, which is found on chromosome 2. The zymogenic form of protein C is a vitamin K-dependent glycoprotein that circulates in blood plasma. Its structure is that of a two-chain polypeptide consisting of a light chain and a heavy chain connected by a disulfide bond.:4673 The protein C zymogen is activated when it binds to thrombin, another protein heavily involved in coagulation, and protein C's activation is greatly promoted by the presence of thrombomodulin and endothelial protein C receptors (EPCRs). Because of EPCR's role, activated protein C is found primarily near endothelial cells (i.e., those that make up the walls of blood vessels), and it is these cells and leukocytes (white blood cells) that APC affects.:34:3162 Because of the crucial role that protein C plays as an anticoagulant, those with deficiencies in protein C, or some kind of resistance to APC, suffer from a significantly increased risk of forming dangerous blood clots (thrombosis). Research into the clinical use of a recombinant form of human Activated Protein C (rhAPC) known as Drotrecogin alfa-activated, branded Xigris by Eli Lilly and Company, has been surrounded by controversy. Eli Lilly ran an aggressive marketing campaign to promote its use for people with severe sepsis and septic shock, and sponsored the 2004 Surviving Sepsis Campaign Guidelines. However, a 2012 Cochrane review found that its use cannot be recommended as it does not improve survival and increases bleeding risk. In October 2011 Xigris was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults. # History Protein C's anticoagulant role in the human body was first noted by Seegers et al. in 1960, who gave protein C its original name, autoprothrombin II-a.:6822 Protein C was first isolated by Johan Stenflo from bovine plasma in 1976, and Stenflo determined it to be a vitamin K-dependent protein. He named it protein C because it was the third protein ("peak C") that eluted from a DEAE-Sepharose ion-exchange chromotograph. Seegers was, at the time, searching for vitamin K-dependent coagulation factors undetected by clotting assays, which measure global clotting function. Soon after this, Seegers recognised Stenflo's discovery was identical with his own.:6822 Activated protein C was discovered later that year, and in 1977 it was first recognised that APC inactivates Factor Va.:2382 In 1980, Vehar and Davie discovered that APC also inactivates Factor VIIIa, and soon after, Protein S was recognised as a cofactor by Walker. In 1982, a family study by Griffin et al. first associated protein C deficiency with symptoms of venous thrombosis. Homozygous protein C deficiency and the consequent serious health effects were described in 1984 by several scientists.:1214 cDNA cloning of protein C was first performed in 1984 by Beckmann et al. which produced a map of the gene responsible for producing protein C in the liver. In 1987 a seminal experiment was performed (Taylor et al.) whereby it was demonstrated that activated protein C prevented coagulopathy and death in baboons infused with lethal concentrations of E. coli.:2382 In 1993, a heritable resistance to APC was detected by Dahlbäck et al. and associated with familial thrombophilia. In 1994, the relatively common genetic mutation that produces Factor VLeiden was noted (Bertina et al.). Two years later, Gla-domainless APC was imaged at a resolution of 2.8 Ångströms.α Beginning with the PROWESS clinical trial of 2001, it was recognised that many of the symptoms of sepsis may be ameliorated by infusion of APC, and mortality rates of septic patients may be significantly decreased.:3161,6 Near the end of that year, Drotrecogin alfa (activated), a recombinant human activated protein C, became the first drug approved by the U.S. FDA for treating severe sepsis. In 2002, Science published an article that first showed protein C activates protease-activated receptor-1 (PAR-1) and this process accounts for the protein's modulation of the immune system.:2382 # Genetics The biologic instructions for synthesising protein C in humans are encoded in the gene officially named "protein C (inactivator of coagulation factors Va and VIIIa)". The gene's symbol approved by the HUGO Gene Nomenclature Committee is "PROC" from "protein C". It is located on the second chromosome (2q13-q14) and comprises nine exons.:2383 The nucleotide sequence that codes for human protein C is approximately 11,000 bases long.:4675 # Structure Human protein C is a vitamin K-dependent glycoprotein structurally similar to other vitamin K-dependent proteins affecting blood clotting, such as prothrombin, Factor VII, Factor IX and Factor X.:1215 Protein C synthesis occurs in the liver and begins with a single-chain precursor molecule: a 32 amino acid N-terminus signal peptide preceding a propeptide.:S11 Protein C is formed when a dipeptide of Lys198 and Arg199 is removed; this causes the transformation into a heterodimer with N-linked carbohydrates on each chain. The protein has one light chain (21 kDa) and one heavy chain (41 kDa) connected by a disulfide bond between Cys183 and Cys319. Inactive protein C comprises 419 amino acids in multiple domains::2383 one Gla domain (residues 43–88); a helical aromatic segment (89–96); two epidermal growth factor (EGF)-like domains (97–132 and 136–176); an activation peptide (200–211); and a trypsin-like serine protease domain (212–450). The light chain contains the Gla- and EGF-like domains and the aromatic segment. The heavy chain contains the protease domain and the activation petide. It is in this form that 85–90% of protein C circulates in the plasma as a zymogen, waiting to be activated.:6822 The remaining protein C zymogen comprises slightly modified forms of the protein. Activation of the enzyme occurs when a thrombin molecule cleaves away the activation peptide from the N-terminus of the heavy chain.:4673 :S11 The active site contains a catalytic triad typical of serine proteases (His253, Asp299 and Ser402).:2833 The Gla domain is particularly useful for binding to negatively charged phospholipids for anticoagulation and to EPCR for cytoprotection. One particular exosite augments protein C's ability to inactivate Factor Va efficiently. Another is necessary for interacting with thrombomodulin.:2833 # Physiology The activation of protein C is strongly promoted by thrombomodulin and endothelial protein C receptor (EPCR), the latter of which is found primarily on endothelial cells (cells on the inside of blood vessels). The presence of thrombomodulin accelerates activation by several orders of magnitude,:34 and EPCR speeds up activation by a factor of 20. If either of these two proteins is absent in murine specimens, the mouse dies from excessive blood-clotting while still in an embryonic state.:1983:43335 On the endothelium, APC performs a major role in regulating blood clotting, inflammation, and cell death (apoptosis).:28S Because of the accelerating effect of thrombomodulin on the activation of protein C, the protein may be said to be activated not by thrombin but the thrombin–thrombomodulin (or even thrombin–thrombomodulin–EPCR) complex.:2381 Once in active form, APC may or may not remain bound to EPCR, to which it has approximately the same affinity as the protein zymogen.:3162 Protein C in zymogen form is present in normal adult human blood plasma at concentrations between 65–135 IU/dL. Activated protein C is found at levels approximately 2000 times lower than this.:3161 Mild protein C deficiency corresponds to plasma levels above 20 IU/dL, but below the normal range. Moderately severe deficiencies describe blood concentrations between 1 and 20 IU/dL; severe deficiencies yield levels of protein C that are below 1 IU/dL or are undetectable. Protein C levels in a healthy term infant average 40 IU/dL. The concentration of protein C increases until six months, when the mean level is 60 IU/dL; the level stays low through childhood until it reaches adult levels after adolescence.:1216 The half-life of activated protein C is around 15 minutes.:6823 # Pathways The protein C pathways are the specific chemical reactions that control the level of expression of APC and its activity in the body.:34 Protein C is pleiotropic, with two main classes of functions: anticoagulation and cytoprotection (its direct effect on cells). Which function protein C performs depends on whether or not APC remains bound to EPCR after it is activated; the anticoagulative effects of APC occur when it does not. In this case, protein C functions as an anticoagulant by irreversibly proteolytically inactivating Factor Va and Factor VIIIa, turning them into Factor Vi and Factor VIIIi respectively. When still bound to EPCR, activated protein C performs its cytoprotective effects, acting on the effector substrate PAR-1, protease-activated receptor-1. To a degree, APC's anticoagulant properties are independent of its cytoprotective ones, in that expression of one pathway is not affected by the existence of the other.:3162:26S The activity of protein C may be down-regulated by reducing the amount either of available thrombomodulin or of EPCR. This may be done by inflammatory cytokines, such as interleukin-1β (IL-1β ) and tumor necrosis factor-α (TNF-α). Activated leukocytes release these inflammatory mediators during inflammation, inhibiting the creation of both thrombomodulin and EPCR, and inducing their shedding from the endothelial surface. Both of these actions down-regulate protein C activation. Thrombin itself may also have an effect on the levels of EPCR. In addition, proteins released from cells can impede protein C activation, for example eosinophil, which may explain thrombosis in hypereosinophilic heart disease.β Protein C may be up-regulated by platelet factor 4. This cytokine is conjectured to improve activation of protein C by forming an electrostatic bridge from protein C's Gla domain to the glycosaminoglycan (GAG) domain of thrombomodulin, reducing the Michaelis constant (KM) for their reaction.:2386:29S In addition, Protein C is inhibited by protein C inhibitor.:369 ## Anticoagulative effects Protein C is a major component in anticoagulation in the human body. It acts as a serine protease zymogen: APC proteolyses peptide bonds in activated Factor V and Factor VIII (Factor Va and Factor VIIIa), and one of the amino acids in the bond is serine.:2381 These proteins that APC inactivates, Factor Va and Factor VIIIa, are highly procoagulant cofactors in the generation of thrombin, which is a crucial element in blood clotting; together they are part of the prothrombinase complex.:26S Cofactors in the inactivation of Factor Va and Factor VIIIa include protein S, Factor V, high-density lipoprotein, anionic phospholipids and glycosphingolipids.:3161 Factor Va binds to prothrombin and Factor Xa, increasing the rate at which thrombin is produced by four orders of magnitude (10,000x). Inactivation of Factor Va thus practically halts the production of thrombin. Factor VIII, on the other hand, is a cofactor in production of activated Factor X, which in turn converts prothrombin into thrombin. Factor VIIIa augments Factor X activation by a factor of around 200,000. Because of its importance in clotting, Factor VIII is also known as anti-haemophilic factor, and deficiencies of Factor VIII cause haemophilia A.:2382,3 APC inactivates Factor Va by making three cleavages (Arg306, Arg506, Arg679). The cleavages at both Arg306 and Arg506 diminish the molecule's attraction to Factor Xa, and though the first of these sites is slow to be cleaved, it is entirely necessary to the functioning of Factor V. Protein S aids this process by catalysing the proteolysis at Arg306, in which the A2 domain of Factor V is dissociated from the rest of the protein. Protein S also binds to Factor Xa, inhibiting the latter from diminishing APC's inactivation of Factor Va.:2386 The inactivation of Factor VIIIa is not as well understood. The half-life of Factor VIIIa is only around two minutes unless Factor IXa is present to stabilise it. Some have questioned the significance of APC's inactivation of Factor VIIIa, and it is unknown to what degree Factor V and protein S are cofactors in its proteolysis. It is known that APC works on Factor VIIIa by cleaving at two sites, Arg336 and Arg562, either of which is sufficient to disable Factor VIIIa and convert it to Factor VIIIi.:2387 ## Cytoprotective effects When APC is bound to EPCR, it performs a number of important cytoprotective (i.e. cell-protecting) functions, most of which are known to require EPCR and PAR-1. These include regulating gene expression, anti-inflammatory effects, antiapoptotic effects and protecting endothelial barrier function.:3162 Treatment of cells with APC demonstrates that its gene expression modulation effectively controls major pathways for inflammatory and apoptotic behaviour. There are about 20 genes that are up-regulated by protein C, and 20 genes that are down-regulated: the former are generally anti-inflammatory and antiapoptotic pathways, while the latter tend to be proinflammatory and proapoptotic. APC's mechanisms for altering gene expression profiles are not well understood, but it is believed that they at least partly involve an inhibitory effect on transcription factor activity.:3162,4 Important proteins that APC up-regulates include Bcl-2, eNOS and IAP. APC effects significant down-regulation of p53 and Bax.:2388 APC has anti-inflammatory effects on endothelial cells and leukocytes. APC affects endothelial cells by inhibiting inflammatory mediator release and down-regulating vascular adhesion molecules. This reduces leukocyte adhesion and infiltration into tissues, while also limiting damage to underlying tissue. APC supports endothelial barrier function and reduces chemotaxis. APC inhibits the release of inflammatory-response mediators in leukocytes as well as endothelial cells, by reducing cytokine response, and maybe diminishing systemic inflammatory response, such as is seen in sepsis. Studies on both rats and humans have demonstrated that APC reduces endotoxin-induced pulmonary injury and inflammation.:3164 Scientists recognise activated protein C's antiapoptotic effects, but are unclear as to the exact mechanisms by which apoptosis is inhibited. It is known that APC is neuroprotective. APC's antiapoptotic effects are part of the reason that APC is effective in treating sepsis, as reduced levels of apoptosis are correlated with higher survival rates in septic patients.:3165 Antiapoptosis is achieved with diminished activation of caspase 3 and caspase 8, improved Bax/Bcl-2 ratio and down-regulation of p53.:2388 Activated protein C also provides much protection of endothelial barrier function. Endothelial barrier breakdown, and the corresponding increase in endothelial permeability, are associated with swelling, hypotension and inflammation, all problems of sepsis. APC protects endothelial barrier function by inducing PAR-1 dependent sphingosine kinase-1 activation and up-regulating sphingosine-1-phosphate with sphingosine kinase.:3165 Several studies have indicated that the proteolytic activity of APC contributes to the observed cytoprotective properties of APC, but variants that are proteolytically inactive also are able to regulate formation of PAR-activators thrombin and factor Xa and express cytoprotective properties in vitro and in vivo. # Role in disease A genetic protein C deficiency, in its mild form associated with simple heterozygosity, causes a significantly increased risk of venous thrombosis in adults. If a fetus is homozygous or compound heterozygous for the deficiency, there may be a presentation of purpura fulminans, severe disseminated intravascular coagulation and simultaneous venous thromboembolism in the womb;:1214 this is very severe and usually fatal.:211s Deletion of the protein C gene in mice causes fetal death around the time of birth. Fetal mice with no protein C develop normally at first, but experience severe bleeding, coagulopathy, deposition of fibrin and necrosis of the liver.:3161 The frequency of protein C deficiency among asymptomatic individuals is between 1 in 200 and 1 in 500. In contrast, significant symptoms of the deficiency are detectable in 1 in 20,000 individuals. No racial nor ethnic biases have been detected.:1215 Activated protein C resistance occurs when APC is unable to perform its functions. This disease has similar symptoms to protein C deficiency. The most common mutation leading to activated protein C resistance among Caucasians is at the cleavage site in Factor V for APC. There, Arg506 is replaced with Gln, producing Factor V Leiden. This mutation is also called a R506Q.:2382 The mutation leading to the loss of this cleavage site actually stops APC from effectively inactivating both Factor Va and Factor VIIIa. Thus, the person's blood clots too readily, and he is perpetually at an increased risk for thrombosis.:3 Individuals heterozygous for the Factor VLeiden mutation carry a risk of venous thrombosis 5–7 times higher than in the general population. Homozygous subjects have a risk 80 times higher.:40 This mutation is also the most common hereditary risk for venous thrombosis among Caucasians.:2382 Around 5% of APC resistance are not associated with the above mutation and Factor VLeiden. Other genetic mutations cause APC resistance, but none to the extent that Factor VLeiden does. These mutations include various other versions of Factor V, spontaneous generation of autoantibodies targeting Factor V, and dysfunction of any of APC's cofactors.:2387 Also, some acquired conditions may reduce the efficacy of APC in performing its anticoagulative functions.:33 Studies suggest that between 20% and 60% of thrombophilic patients suffer from some form of APC resistance.:37 Warfarin necrosis is an acquired protein C deficiency due to treatment with warfarin, which is a vitamin K antagonist and an anticoagulant itself. However, warfarin treatment may produce paradoxical skin lesions similar to those seen in purpura fulminans. A variant of this response presents as venous limb gangrene when warfarin is used to treat deep vein thrombosis associated with cancer. In these situations, warfarin may be restarted at a low dosage to ensure that the protein C deficiency does not present before the vitamin K coagulation factors II, IX and X are suppressed.:211s Activated protein C cleaves Plasmodium falciparum histones which are released during infection: cleavage of these histones eliminates their pro inflammatory effects. # Role in medicine Protein C levels have long been noted to predict mortality in patients with sepsis. Because of this, and its pleiotropic anticoagulative and cytoprotective effects, protein C has been suggested, along with many other drugs, for use in treating patients with severe sepsis. In November 2001, the Food and Drug Administration approved Drotrecogin alfa-activated (DrotAA) for the clinical treatment of adults suffering from severe sepsis and with a high risk of death.:1332 Drotrecogin alfa-activated is a recombinant form of human activated protein C (rhAPC). It is marketed as Xigris by Eli Lilly and Company,:224 Drotrecogin alfa-activated was the subject of significant controversy while it was approved for clinical use as it was found to increase bleeding and not to reduce mortality. In October 2011 rhAPC (Xigris®) was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults. APC has been studied as way of treating lung injury, after studies showed that in patients with lung injury, reduced APC levels in specific parts of the lungs correlated with worse outcomes.:3167,8 APC also has been considered for use in improving patient outcome in cases of ischemic stroke, a medical emergency in which arterial blockage deprives a region of brain of oxygen, causing tissue death. Promising studies suggest that APC could be coupled with the only currently approved treatment, tissue plasminogen activator (tPA), to protect the brain from tPA's very harmful side effects, in addition to preventing cell death from lack of oxygen (hypoxia).:211 Clinical use of APC has also been proposed for improving the outcome of pancreatic islet transplantation in treating type I diabetes.:2392 # Notes - ^ α: GLA-domainless protein C is produced by selective proteolysis between residues 82 and 83 to remove the N-terminal portion of the protein that includes essentially all of the GLA domain (residues 47–88). The N-terminus was removed in order to make crystallization of the protein easier.:5548 - ^ β: In hypereosinophilia, excess eosinophil-specific granule proteins (such as major basic protein, erythropoietin and eosinophil cationic protein) on the endothelial surface bind to thrombomodulin and inhibit its participation in the activation of protein C by electrostatic interaction on the surface of thrombomodulin.:1728	Protein C Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV,[1]:6822[2] is a zymogen, the activated form of which plays an important role in regulating anticoagulation, inflammation, cell death, and maintaining the permeability of blood vessel walls in humans and other animals. Activated protein C (APC) performs these operations primarily by proteolytically inactivating proteins Factor Va and Factor VIIIa. APC is classified as a serine protease as it contains a residue of serine in its active site.[3]:35 In humans, protein C is encoded by the PROC gene, which is found on chromosome 2.[4] The zymogenic form of protein C is a vitamin K-dependent glycoprotein that circulates in blood plasma. Its structure is that of a two-chain polypeptide consisting of a light chain and a heavy chain connected by a disulfide bond.[4]:4673 The protein C zymogen is activated when it binds to thrombin, another protein heavily involved in coagulation, and protein C's activation is greatly promoted by the presence of thrombomodulin and endothelial protein C receptors (EPCRs). Because of EPCR's role, activated protein C is found primarily near endothelial cells (i.e., those that make up the walls of blood vessels), and it is these cells and leukocytes (white blood cells) that APC affects.[3]:34[5]:3162 Because of the crucial role that protein C plays as an anticoagulant, those with deficiencies in protein C, or some kind of resistance to APC, suffer from a significantly increased risk of forming dangerous blood clots (thrombosis). Research into the clinical use of a recombinant form of human Activated Protein C (rhAPC) known as Drotrecogin alfa-activated, branded Xigris by Eli Lilly and Company, has been surrounded by controversy. Eli Lilly ran an aggressive marketing campaign to promote its use for people with severe sepsis and septic shock, and sponsored the 2004 Surviving Sepsis Campaign Guidelines.[6] However, a 2012 Cochrane review found that its use cannot be recommended as it does not improve survival and increases bleeding risk.[7] In October 2011 Xigris was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults.[8] # History Protein C's anticoagulant role in the human body was first noted by Seegers et al. in 1960,[9] who gave protein C its original name, autoprothrombin II-a.[1]:6822 Protein C was first isolated by Johan Stenflo from bovine plasma in 1976, and Stenflo determined it to be a vitamin K-dependent protein.[10] He named it protein C because it was the third protein ("peak C") that eluted from a DEAE-Sepharose ion-exchange chromotograph. Seegers was, at the time, searching for vitamin K-dependent coagulation factors undetected by clotting assays, which measure global clotting function. Soon after this, Seegers recognised Stenflo's discovery was identical with his own.[1]:6822 Activated protein C was discovered later that year,[11] and in 1977 it was first recognised that APC inactivates Factor Va.[12]:2382[13] In 1980, Vehar and Davie discovered that APC also inactivates Factor VIIIa,[14] and soon after, Protein S was recognised as a cofactor by Walker.[15] In 1982, a family study by Griffin et al. first associated protein C deficiency with symptoms of venous thrombosis.[16] Homozygous protein C deficiency and the consequent serious health effects were described in 1984 by several scientists.[17]:1214 cDNA cloning of protein C was first performed in 1984 by Beckmann et al. which produced a map of the gene responsible for producing protein C in the liver.[18] In 1987 a seminal experiment was performed (Taylor et al.) whereby it was demonstrated that activated protein C prevented coagulopathy and death in baboons infused with lethal concentrations of E. coli.[12]:2382[19] In 1993, a heritable resistance to APC was detected by Dahlbäck et al. and associated with familial thrombophilia.[20] In 1994, the relatively common genetic mutation that produces Factor VLeiden was noted (Bertina et al.).[21] Two years later, Gla-domainless APC was imaged at a resolution of 2.8 Ångströms.α[›][1] Beginning with the PROWESS clinical trial of 2001,[22] it was recognised that many of the symptoms of sepsis may be ameliorated by infusion of APC, and mortality rates of septic patients may be significantly decreased.[5]:3161,6 Near the end of that year, Drotrecogin alfa (activated), a recombinant human activated protein C, became the first drug approved by the U.S. FDA for treating severe sepsis.[23] In 2002, Science published an article that first showed protein C activates protease-activated receptor-1 (PAR-1) and this process accounts for the protein's modulation of the immune system.[12]:2382[24] # Genetics The biologic instructions for synthesising protein C in humans are encoded in the gene officially named "protein C (inactivator of coagulation factors Va and VIIIa)". The gene's symbol approved by the HUGO Gene Nomenclature Committee is "PROC" from "protein C". It is located on the second chromosome (2q13-q14) and comprises nine exons.[4][12]:2383 The nucleotide sequence that codes for human protein C is approximately 11,000 bases long.[4]:4675 # Structure Human protein C is a vitamin K-dependent glycoprotein structurally similar to other vitamin K-dependent proteins affecting blood clotting,[25] such as prothrombin, Factor VII, Factor IX and Factor X.[17]:1215 Protein C synthesis occurs in the liver and begins with a single-chain precursor molecule: a 32 amino acid N-terminus signal peptide preceding a propeptide.[26]:S11 Protein C is formed when a dipeptide of Lys198 and Arg199 is removed; this causes the transformation into a heterodimer with N-linked carbohydrates on each chain. The protein has one light chain (21 kDa) and one heavy chain (41 kDa) connected by a disulfide bond between Cys183 and Cys319. Inactive protein C comprises 419 amino acids in multiple domains:[12]:2383 one Gla domain (residues 43–88); a helical aromatic segment (89–96); two epidermal growth factor (EGF)-like domains (97–132 and 136–176); an activation peptide (200–211); and a trypsin-like serine protease domain (212–450). The light chain contains the Gla- and EGF-like domains and the aromatic segment. The heavy chain contains the protease domain and the activation petide. It is in this form that 85–90% of protein C circulates in the plasma as a zymogen, waiting to be activated.[1]:6822 The remaining protein C zymogen comprises slightly modified forms of the protein. Activation of the enzyme occurs when a thrombin molecule cleaves away the activation peptide from the N-terminus of the heavy chain.[4]:4673 [26]:S11 The active site contains a catalytic triad typical of serine proteases (His253, Asp299 and Ser402).[12]:2833 The Gla domain is particularly useful for binding to negatively charged phospholipids for anticoagulation and to EPCR for cytoprotection. One particular exosite augments protein C's ability to inactivate Factor Va efficiently. Another is necessary for interacting with thrombomodulin.[12]:2833 # Physiology The activation of protein C is strongly promoted by thrombomodulin and endothelial protein C receptor (EPCR), the latter of which is found primarily on endothelial cells (cells on the inside of blood vessels). The presence of thrombomodulin accelerates activation by several orders of magnitude,[3]:34 and EPCR speeds up activation by a factor of 20. If either of these two proteins is absent in murine specimens, the mouse dies from excessive blood-clotting while still in an embryonic state.[27]:1983[28]:43335 On the endothelium, APC performs a major role in regulating blood clotting, inflammation, and cell death (apoptosis).[29]:28S Because of the accelerating effect of thrombomodulin on the activation of protein C, the protein may be said to be activated not by thrombin but the thrombin–thrombomodulin (or even thrombin–thrombomodulin–EPCR) complex.[12]:2381 Once in active form, APC may or may not remain bound to EPCR, to which it has approximately the same affinity as the protein zymogen.[5]:3162 Protein C in zymogen form is present in normal adult human blood plasma at concentrations between 65–135 IU/dL. Activated protein C is found at levels approximately 2000 times lower than this.[5]:3161 Mild protein C deficiency corresponds to plasma levels above 20 IU/dL, but below the normal range. Moderately severe deficiencies describe blood concentrations between 1 and 20 IU/dL; severe deficiencies yield levels of protein C that are below 1 IU/dL or are undetectable. Protein C levels in a healthy term infant average 40 IU/dL. The concentration of protein C increases until six months, when the mean level is 60 IU/dL; the level stays low through childhood until it reaches adult levels after adolescence.[17]:1216 The half-life of activated protein C is around 15 minutes.[1]:6823 # Pathways The protein C pathways are the specific chemical reactions that control the level of expression of APC and its activity in the body.[3]:34 Protein C is pleiotropic, with two main classes of functions: anticoagulation and cytoprotection (its direct effect on cells). Which function protein C performs depends on whether or not APC remains bound to EPCR after it is activated; the anticoagulative effects of APC occur when it does not. In this case, protein C functions as an anticoagulant by irreversibly proteolytically inactivating Factor Va and Factor VIIIa, turning them into Factor Vi and Factor VIIIi respectively. When still bound to EPCR, activated protein C performs its cytoprotective effects, acting on the effector substrate PAR-1, protease-activated receptor-1. To a degree, APC's anticoagulant properties are independent of its cytoprotective ones, in that expression of one pathway is not affected by the existence of the other.[5]:3162[29]:26S The activity of protein C may be down-regulated by reducing the amount either of available thrombomodulin or of EPCR. This may be done by inflammatory cytokines, such as interleukin-1β (IL-1β ) and tumor necrosis factor-α (TNF-α). Activated leukocytes release these inflammatory mediators during inflammation, inhibiting the creation of both thrombomodulin and EPCR, and inducing their shedding from the endothelial surface. Both of these actions down-regulate protein C activation. Thrombin itself may also have an effect on the levels of EPCR. In addition, proteins released from cells can impede protein C activation, for example eosinophil, which may explain thrombosis in hypereosinophilic heart disease.β[›] Protein C may be up-regulated by platelet factor 4. This cytokine is conjectured to improve activation of protein C by forming an electrostatic bridge from protein C's Gla domain to the glycosaminoglycan (GAG) domain of thrombomodulin, reducing the Michaelis constant (KM) for their reaction.[12]:2386[29]:29S In addition, Protein C is inhibited by protein C inhibitor.[30]:369 ## Anticoagulative effects Protein C is a major component in anticoagulation in the human body. It acts as a serine protease zymogen: APC proteolyses peptide bonds in activated Factor V and Factor VIII (Factor Va and Factor VIIIa), and one of the amino acids in the bond is serine.[12]:2381 These proteins that APC inactivates, Factor Va and Factor VIIIa, are highly procoagulant cofactors in the generation of thrombin, which is a crucial element in blood clotting; together they are part of the prothrombinase complex.[29]:26S Cofactors in the inactivation of Factor Va and Factor VIIIa include protein S, Factor V, high-density lipoprotein, anionic phospholipids and glycosphingolipids.[5]:3161 Factor Va binds to prothrombin and Factor Xa, increasing the rate at which thrombin is produced by four orders of magnitude (10,000x). Inactivation of Factor Va thus practically halts the production of thrombin. Factor VIII, on the other hand, is a cofactor in production of activated Factor X, which in turn converts prothrombin into thrombin. Factor VIIIa augments Factor X activation by a factor of around 200,000. Because of its importance in clotting, Factor VIII is also known as anti-haemophilic factor, and deficiencies of Factor VIII cause haemophilia A.[12]:2382,3 APC inactivates Factor Va by making three cleavages (Arg306, Arg506, Arg679). The cleavages at both Arg306 and Arg506 diminish the molecule's attraction to Factor Xa, and though the first of these sites is slow to be cleaved, it is entirely necessary to the functioning of Factor V. Protein S aids this process by catalysing the proteolysis at Arg306, in which the A2 domain of Factor V is dissociated from the rest of the protein.[31] Protein S also binds to Factor Xa, inhibiting the latter from diminishing APC's inactivation of Factor Va.[12]:2386 The inactivation of Factor VIIIa is not as well understood. The half-life of Factor VIIIa is only around two minutes unless Factor IXa is present to stabilise it. Some have questioned the significance of APC's inactivation of Factor VIIIa, and it is unknown to what degree Factor V and protein S are cofactors in its proteolysis. It is known that APC works on Factor VIIIa by cleaving at two sites, Arg336 and Arg562, either of which is sufficient to disable Factor VIIIa and convert it to Factor VIIIi.[12]:2387 ## Cytoprotective effects When APC is bound to EPCR, it performs a number of important cytoprotective (i.e. cell-protecting) functions, most of which are known to require EPCR and PAR-1. These include regulating gene expression, anti-inflammatory effects, antiapoptotic effects and protecting endothelial barrier function.[5]:3162 Treatment of cells with APC demonstrates that its gene expression modulation effectively controls major pathways for inflammatory and apoptotic behaviour. There are about 20 genes that are up-regulated by protein C, and 20 genes that are down-regulated: the former are generally anti-inflammatory and antiapoptotic pathways, while the latter tend to be proinflammatory and proapoptotic. APC's mechanisms for altering gene expression profiles are not well understood, but it is believed that they at least partly involve an inhibitory effect on transcription factor activity.[5]:3162,4 Important proteins that APC up-regulates include Bcl-2, eNOS and IAP. APC effects significant down-regulation of p53 and Bax.[12]:2388 APC has anti-inflammatory effects on endothelial cells and leukocytes. APC affects endothelial cells by inhibiting inflammatory mediator release and down-regulating vascular adhesion molecules. This reduces leukocyte adhesion and infiltration into tissues, while also limiting damage to underlying tissue. APC supports endothelial barrier function and reduces chemotaxis. APC inhibits the release of inflammatory-response mediators in leukocytes as well as endothelial cells, by reducing cytokine response, and maybe diminishing systemic inflammatory response, such as is seen in sepsis. Studies on both rats and humans have demonstrated that APC reduces endotoxin-induced pulmonary injury and inflammation.[5]:3164 Scientists recognise activated protein C's antiapoptotic effects, but are unclear as to the exact mechanisms by which apoptosis is inhibited. It is known that APC is neuroprotective. APC's antiapoptotic effects are part of the reason that APC is effective in treating sepsis, as reduced levels of apoptosis are correlated with higher survival rates in septic patients.[5]:3165 Antiapoptosis is achieved with diminished activation of caspase 3 and caspase 8, improved Bax/Bcl-2 ratio and down-regulation of p53.[12]:2388 Activated protein C also provides much protection of endothelial barrier function. Endothelial barrier breakdown, and the corresponding increase in endothelial permeability, are associated with swelling, hypotension and inflammation, all problems of sepsis. APC protects endothelial barrier function by inducing PAR-1 dependent sphingosine kinase-1 activation and up-regulating sphingosine-1-phosphate with sphingosine kinase.[5]:3165 Several studies have indicated that the proteolytic activity of APC contributes to the observed cytoprotective properties of APC, but variants that are proteolytically inactive also are able to regulate formation of PAR-activators thrombin and factor Xa and express cytoprotective properties in vitro and in vivo.[32][33] # Role in disease A genetic protein C deficiency, in its mild form associated with simple heterozygosity, causes a significantly increased risk of venous thrombosis in adults. If a fetus is homozygous or compound heterozygous for the deficiency, there may be a presentation of purpura fulminans, severe disseminated intravascular coagulation and simultaneous venous thromboembolism in the womb;[17]:1214 this is very severe and usually fatal.[34]:211s Deletion of the protein C gene in mice causes fetal death around the time of birth. Fetal mice with no protein C develop normally at first, but experience severe bleeding, coagulopathy, deposition of fibrin and necrosis of the liver.[5]:3161 The frequency of protein C deficiency among asymptomatic individuals is between 1 in 200 and 1 in 500. In contrast, significant symptoms of the deficiency are detectable in 1 in 20,000 individuals. No racial nor ethnic biases have been detected.[17]:1215 Activated protein C resistance occurs when APC is unable to perform its functions. This disease has similar symptoms to protein C deficiency. The most common mutation leading to activated protein C resistance among Caucasians is at the cleavage site in Factor V for APC. There, Arg506 is replaced with Gln, producing Factor V Leiden. This mutation is also called a R506Q.[12]:2382 The mutation leading to the loss of this cleavage site actually stops APC from effectively inactivating both Factor Va and Factor VIIIa. Thus, the person's blood clots too readily, and he is perpetually at an increased risk for thrombosis.[35]:3 Individuals heterozygous for the Factor VLeiden mutation carry a risk of venous thrombosis 5–7 times higher than in the general population. Homozygous subjects have a risk 80 times higher.[3]:40 This mutation is also the most common hereditary risk for venous thrombosis among Caucasians.[12]:2382 Around 5% of APC resistance are not associated with the above mutation and Factor VLeiden. Other genetic mutations cause APC resistance, but none to the extent that Factor VLeiden does. These mutations include various other versions of Factor V, spontaneous generation of autoantibodies targeting Factor V, and dysfunction of any of APC's cofactors.[12]:2387 Also, some acquired conditions may reduce the efficacy of APC in performing its anticoagulative functions.[3]:33 Studies suggest that between 20% and 60% of thrombophilic patients suffer from some form of APC resistance.[3]:37 Warfarin necrosis is an acquired protein C deficiency due to treatment with warfarin, which is a vitamin K antagonist and an anticoagulant itself. However, warfarin treatment may produce paradoxical skin lesions similar to those seen in purpura fulminans. A variant of this response presents as venous limb gangrene when warfarin is used to treat deep vein thrombosis associated with cancer. In these situations, warfarin may be restarted at a low dosage to ensure that the protein C deficiency does not present before the vitamin K coagulation factors II, IX and X are suppressed.[34]:211s Activated protein C cleaves Plasmodium falciparum histones which are released during infection: cleavage of these histones eliminates their pro inflammatory effects.[36] # Role in medicine Protein C levels have long been noted to predict mortality in patients with sepsis. Because of this, and its pleiotropic anticoagulative and cytoprotective effects, protein C has been suggested, along with many other drugs, for use in treating patients with severe sepsis. In November 2001, the Food and Drug Administration approved Drotrecogin alfa-activated (DrotAA) for the clinical treatment of adults suffering from severe sepsis and with a high risk of death.[37]:1332 Drotrecogin alfa-activated is a recombinant form of human activated protein C (rhAPC). It is marketed as Xigris by Eli Lilly and Company,[23]:224 Drotrecogin alfa-activated was the subject of significant controversy while it was approved for clinical use as it was found to increase bleeding and not to reduce mortality.[38] In October 2011 rhAPC (Xigris®) was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults.[8][38] APC has been studied as way of treating lung injury, after studies showed that in patients with lung injury, reduced APC levels in specific parts of the lungs correlated with worse outcomes.[5]:3167,8 APC also has been considered for use in improving patient outcome in cases of ischemic stroke, a medical emergency in which arterial blockage deprives a region of brain of oxygen, causing tissue death. Promising studies suggest that APC could be coupled with the only currently approved treatment, tissue plasminogen activator (tPA), to protect the brain from tPA's very harmful side effects, in addition to preventing cell death from lack of oxygen (hypoxia).[39]:211 Clinical use of APC has also been proposed for improving the outcome of pancreatic islet transplantation in treating type I diabetes.[12]:2392 # Notes - ^ α: GLA-domainless protein C is produced by selective proteolysis between residues 82 and 83 to remove the N-terminal portion of the protein that includes essentially all of the GLA domain (residues 47–88). The N-terminus was removed in order to make crystallization of the protein easier.[40]:5548 - ^ β: In hypereosinophilia, excess eosinophil-specific granule proteins (such as major basic protein, erythropoietin and eosinophil cationic protein) on the endothelial surface bind to thrombomodulin and inhibit its participation in the activation of protein C by electrostatic interaction on the surface of thrombomodulin.[41]:1728	https://www.wikidoc.org/index.php/Activated_protein_C
2bb1f4a937d601067732f98016a144171904bc52	wikidoc	Enteritis	Enteritis Please help WikiDoc by adding content here. It's easy! Click here to learn about editing. # Overview Enteritis is the inflammation of the small intestine (inflammation of the large intestine is termed colitis, while enterocolitis refers to an inflammation of both the large and small intestine.). # Historical Perspective # Classification # Pathophysiology # Causes # Differentiating Enteritis from Other Diseases # Epidemiology and Demographics # Risk Factors # Screening # Natural History, Complications, and Prognosis ## Natural History ## Complications ## Prognosis # Diagnosis ## Diagnostic Criteria ## History and Symptoms Symptoms may include abdominal pain, diarrhea, abdominal distension and hematochezia. If there is vomiting, gastroenteritis is the more correct diagnosis. Generally a good history is the most important tool in distinguishing serious cases of enteritis from self-limiting ones. The presence of blood in the faeces, dehydration, cutaneous eruptions, presumed link with food exposure, as well as recent travel to endemic areas can prompt further investigation. Acute enteritis is usually due to bacteria or viruses. When food is involved, foodborne illness is to be suspected. If other family members or members of the household are affected, this may signify infectious causes. Chronic enteritis can be due to Crohn's disease, giardiasis, tuberculosis, coeliac disease, or rarely due to Whipple's disease. ## Physical Examination ## Laboratory Findings ## Imaging Findings ## Other Diagnostic Studies # Treatment ## Medical Therapy Viral diarrhea is usually self-limiting and is treated with rehydration. When bacterial causes are suspected (recent travel, food poisoning), antibiotics can be considered. Chronic enteritides are treated according to the diagnosis (please refer to individual articles). ## Surgery ## Prevention	Enteritis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Please help WikiDoc by adding content here. It's easy! Click here to learn about editing. # Overview Enteritis is the inflammation of the small intestine (inflammation of the large intestine is termed colitis, while enterocolitis refers to an inflammation of both the large and small intestine.). # Historical Perspective # Classification # Pathophysiology # Causes # Differentiating Enteritis from Other Diseases # Epidemiology and Demographics # Risk Factors # Screening # Natural History, Complications, and Prognosis ## Natural History ## Complications ## Prognosis # Diagnosis ## Diagnostic Criteria ## History and Symptoms Symptoms may include abdominal pain, diarrhea, abdominal distension and hematochezia. If there is vomiting, gastroenteritis is the more correct diagnosis. Generally a good history is the most important tool in distinguishing serious cases of enteritis from self-limiting ones. The presence of blood in the faeces, dehydration, cutaneous eruptions, presumed link with food exposure, as well as recent travel to endemic areas can prompt further investigation. Acute enteritis is usually due to bacteria or viruses. When food is involved, foodborne illness is to be suspected. If other family members or members of the household are affected, this may signify infectious causes. Chronic enteritis can be due to Crohn's disease, giardiasis, tuberculosis, coeliac disease, or rarely due to Whipple's disease. ## Physical Examination ## Laboratory Findings ## Imaging Findings ## Other Diagnostic Studies # Treatment ## Medical Therapy Viral diarrhea is usually self-limiting and is treated with rehydration. When bacterial causes are suspected (recent travel, food poisoning), antibiotics can be considered. Chronic enteritides are treated according to the diagnosis (please refer to individual articles). ## Surgery ## Prevention	https://www.wikidoc.org/index.php/Acute_enteritis
8bb2ba371a03dab6c57d1b4854863141ef7be1ff	wikidoc	Adapalene	Adapalene # 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 Adapalene is a retinoid that is FDA approved for the treatment of acne vulgaris. Common adverse reactions include dry skin, erythema and Scaly skin. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ## Acne Vulgaris Dosing information - DIFFERIN Gel should be applied once a day to affected areas after washing in the evening before retiring. A thin film of the gel should be applied, avoiding eyes, lips, and mucous membranes. - During the early weeks of therapy, an apparent exacerbation of acne may occur. This is due to the action of the medication on previously unseen lesions and should not be considered a reason to discontinue therapy. Therapeutic results should be noticed after eight to twelve weeks of treatment. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Adapalene in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Adapalene in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness in pediatric patients below the age of 12 have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Adapalene in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Adapalene in pediatric patients. # Contraindications - DIFFERIN Gel should not be administered to individuals who are hypersensitive to adapalene or any of the components in the vehicle gel. # Warnings - Use of DIFFERIN Gel should be discontinued if hypersensitivity to any of the ingredients is noted. Patients with sunburn should be advised not to use the product until fully recovered. ## PRECAUTIONS: ### General: - If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. Exposure to sunlight, including sunlamps, should be minimized during the use of adapalene. Patients who normally experience high levels of sun exposure, and those with inherent sensitivity to sun, should be warned to exercise caution. Use of sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with adapalene. - Avoid contact with the eyes, lips, angles of the nose, and mucous membranes. The product should not be applied to cuts, abrasions, eczematous skin, or sunburned skin. - Certain cutaneous signs and symptoms such as erythema, dryness, scaling, burning, or pruritus may be experienced during treatment. These are most likely to occur during the first two to four weeks and will usually lessen with continued use of the medication. Depending upon the severity of adverse events, patients should be instructed to reduce the frequency of application or discontinue use. # Adverse Reactions ## Clinical Trials Experience Some adverse effects such as erythema, scaling, dryness, pruritus, and burning will occur in 10-40% of patients. Pruritus or burning immediately after application also occurs in approximately 20% of patients. The following additional adverse experiences were reported in approximately 1% or less of patients: skin irritation, burning/stinging, erythema, sunburn, and acne flares. These are most commonly seen during the first month of therapy and decrease in frequency and severity thereafter. All adverse effects with use of DIFFERIN Gel during clinical trials were reversible upon discontinuation of therapy. ## Postmarketing Experience - FDA Package Insert for Adapalene contains no information regarding postmarketing experience. # Drug Interactions - As DIFFERIN Gel has the potential to produce local irritation in some patients, concomitant use of other potentially irritating topical products (medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices, or lime) should be approached with caution. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid in combination with DIFFERIN Gel. If these preparations have been used, it is advisable not to start therapy with DIFFERIN Gel until the effects of such preparations in the skin have subsided. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Teratogenic Effects. Pregnancy Category C. No teratogenic effects were seen in rats at oral doses of adapalene 0.15 to 5.0 mg/kg/day, up to 120 times the maximal daily human topical dose. Cutaneous route teratology studies conducted in rats and rabbits at doses of 0.6, 2.0, and 6.0 mg/kg/day, up to 150 times the maximal daily human topical dose exhibited no fetotoxicity and only minimal increases in supernumerary ribs in rats. There are no adequate and well-controlled studies in pregnant women. Adapalene should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Adapalene in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Adapalene during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when DIFFERIN Gel is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients below the age of 12 have not been established. ### Geriatic Use There is no FDA guidance on the use of Adapalene in geriatric settings. ### Gender There is no FDA guidance on the use of Adapalene with respect to specific gender populations. ### Race There is no FDA guidance on the use of Adapalene with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Adapalene in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Adapalene in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Adapalene in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Adapalene in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring - There is limited information about the Drug Monitoring. # IV Compatibility - There is limited information about the IV Compatibility. # Overdosage - DIFFERIN Gel is intended for cutaneous use only. If the medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. The acute oral toxicity of DIFFERIN Gel in mice and rats is greater than 10 mL/kg. Chronic ingestion of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A. # Pharmacology ## Mechanism of Action - Mechanistically, adapalene binds to specific retinoic acid nuclear receptors but does not bind to the cytosolic receptor protein. Although the exact mode of action of adapalene is unknown, it is suggested that topical adapalene may normalize the differentiation of follicular epithelial cells resulting in decreased microcomedone formation. ## Structure - DIFFERIN® Gel, containing adapalene, is used for the topical treatment of acne vulgaris. Each gram of DIFFERIN Gel contains adapalene 0.1% (1 mg) in a vehicle consisting of carbomer 940, edetate disodium, methylparaben, poloxamer 182, propylene glycol, purified water and sodium hydroxide. May contain hydrochloric acid to adjust pH. - The chemical name of adapalene is 6--2-naphthoic acid. Adapalene is a white to off-white powder which is soluble in tetrahydrofuran, sparingly soluble in ethanol, and practically insoluble in water. The molecular formula is C28H28O3 and molecular weight is 412.52. Adapalene is represented by the following structural formula: ## Pharmacodynamics - FDA Package Insert for Adapalene contains no information regarding Pharmacodynamics. ## Pharmacokinetics - Absorption of adapalene through human skin is low. Only trace amounts (<0.25 ng/mL) of parent substance have been found in the plasma of acne patients following chronic topical application of adapalene in controlled clinical trials. Excretion appears to be primarily by the biliary route. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility: - Carcinogenicity studies with adapalene have been conducted in mice at topical doses of 0.3, 0.9, and 2.6 mg/kg/day and in rats at oral doses of 0.15, 0.5, and 1.5 mg/kg/day, approximately 4-75 times the maximal daily human topical dose. In the oral study, positive linear trends were observed in the incidence of follicular cell adenomas and carcinomas in the thyroid glands of female rats, and in the incidence of benign and malignant pheochromocytomas in the adrenal medullas of male rats. - No photocarcinogenicity studies were conducted. Animal studies have shown an increased tumorigenic risk with the use of pharmacologically similar drugs (e.g., retinoids) when exposed to UV irradiation in the laboratory or to sunlight. Although the significance of these studies to human use is not clear, patients should be advised to avoid or minimize exposure to either sunlight or artificial UV irradiation sources. - In a series of in vivo and in vitro studies, adapalene did not exhibit mutagenic or genotoxic activities. # Clinical Studies - FDA Package Insert for Adapalene contains no information regarding Clinical studies. # How Supplied - DIFFERIN (adapalene gel) Gel, 0.1% is supplied in the following size: - 45 g laminate tube - NDC 0299-5910-45 ## Storage - Store at controlled room temperature 68° - 77°F (20° - 25°C), excursions permitted between 59° and 86°F (15° - 30°C). Protect from freezing. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - There is limited information about the Patient Counseling Information. # Precautions with Alcohol - Alcohol-Adapalene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Differin # Look-Alike Drug Names - There is limited information about the look alike drug names. # Drug Shortage Status # Price	Adapalene Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Kiran Singh, M.D. [3] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Adapalene is a retinoid that is FDA approved for the treatment of acne vulgaris. Common adverse reactions include dry skin, erythema and Scaly skin. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ## Acne Vulgaris Dosing information - DIFFERIN Gel should be applied once a day to affected areas after washing in the evening before retiring. A thin film of the gel should be applied, avoiding eyes, lips, and mucous membranes. - During the early weeks of therapy, an apparent exacerbation of acne may occur. This is due to the action of the medication on previously unseen lesions and should not be considered a reason to discontinue therapy. Therapeutic results should be noticed after eight to twelve weeks of treatment. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Adapalene in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Adapalene in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness in pediatric patients below the age of 12 have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Adapalene in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Adapalene in pediatric patients. # Contraindications - DIFFERIN Gel should not be administered to individuals who are hypersensitive to adapalene or any of the components in the vehicle gel. # Warnings - Use of DIFFERIN Gel should be discontinued if hypersensitivity to any of the ingredients is noted. Patients with sunburn should be advised not to use the product until fully recovered. ## PRECAUTIONS: ### General: - If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. Exposure to sunlight, including sunlamps, should be minimized during the use of adapalene. Patients who normally experience high levels of sun exposure, and those with inherent sensitivity to sun, should be warned to exercise caution. Use of sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with adapalene. - Avoid contact with the eyes, lips, angles of the nose, and mucous membranes. The product should not be applied to cuts, abrasions, eczematous skin, or sunburned skin. - Certain cutaneous signs and symptoms such as erythema, dryness, scaling, burning, or pruritus may be experienced during treatment. These are most likely to occur during the first two to four weeks and will usually lessen with continued use of the medication. Depending upon the severity of adverse events, patients should be instructed to reduce the frequency of application or discontinue use. # Adverse Reactions ## Clinical Trials Experience Some adverse effects such as erythema, scaling, dryness, pruritus, and burning will occur in 10-40% of patients. Pruritus or burning immediately after application also occurs in approximately 20% of patients. The following additional adverse experiences were reported in approximately 1% or less of patients: skin irritation, burning/stinging, erythema, sunburn, and acne flares. These are most commonly seen during the first month of therapy and decrease in frequency and severity thereafter. All adverse effects with use of DIFFERIN Gel during clinical trials were reversible upon discontinuation of therapy. ## Postmarketing Experience - FDA Package Insert for Adapalene contains no information regarding postmarketing experience. # Drug Interactions - As DIFFERIN Gel has the potential to produce local irritation in some patients, concomitant use of other potentially irritating topical products (medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices, or lime) should be approached with caution. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid in combination with DIFFERIN Gel. If these preparations have been used, it is advisable not to start therapy with DIFFERIN Gel until the effects of such preparations in the skin have subsided. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Teratogenic Effects. Pregnancy Category C. No teratogenic effects were seen in rats at oral doses of adapalene 0.15 to 5.0 mg/kg/day, up to 120 times the maximal daily human topical dose. Cutaneous route teratology studies conducted in rats and rabbits at doses of 0.6, 2.0, and 6.0 mg/kg/day, up to 150 times the maximal daily human topical dose exhibited no fetotoxicity and only minimal increases in supernumerary ribs in rats. There are no adequate and well-controlled studies in pregnant women. Adapalene should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Adapalene in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Adapalene during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when DIFFERIN Gel is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients below the age of 12 have not been established. ### Geriatic Use There is no FDA guidance on the use of Adapalene in geriatric settings. ### Gender There is no FDA guidance on the use of Adapalene with respect to specific gender populations. ### Race There is no FDA guidance on the use of Adapalene with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Adapalene in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Adapalene in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Adapalene in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Adapalene in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring - There is limited information about the Drug Monitoring. # IV Compatibility - There is limited information about the IV Compatibility. # Overdosage - DIFFERIN Gel is intended for cutaneous use only. If the medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. The acute oral toxicity of DIFFERIN Gel in mice and rats is greater than 10 mL/kg. Chronic ingestion of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A. # Pharmacology ## Mechanism of Action - Mechanistically, adapalene binds to specific retinoic acid nuclear receptors but does not bind to the cytosolic receptor protein. Although the exact mode of action of adapalene is unknown, it is suggested that topical adapalene may normalize the differentiation of follicular epithelial cells resulting in decreased microcomedone formation. ## Structure - DIFFERIN® Gel, containing adapalene, is used for the topical treatment of acne vulgaris. Each gram of DIFFERIN Gel contains adapalene 0.1% (1 mg) in a vehicle consisting of carbomer 940, edetate disodium, methylparaben, poloxamer 182, propylene glycol, purified water and sodium hydroxide. May contain hydrochloric acid to adjust pH. - The chemical name of adapalene is 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid. Adapalene is a white to off-white powder which is soluble in tetrahydrofuran, sparingly soluble in ethanol, and practically insoluble in water. The molecular formula is C28H28O3 and molecular weight is 412.52. Adapalene is represented by the following structural formula: ## Pharmacodynamics - FDA Package Insert for Adapalene contains no information regarding Pharmacodynamics. ## Pharmacokinetics - Absorption of adapalene through human skin is low. Only trace amounts (<0.25 ng/mL) of parent substance have been found in the plasma of acne patients following chronic topical application of adapalene in controlled clinical trials. Excretion appears to be primarily by the biliary route. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility: - Carcinogenicity studies with adapalene have been conducted in mice at topical doses of 0.3, 0.9, and 2.6 mg/kg/day and in rats at oral doses of 0.15, 0.5, and 1.5 mg/kg/day, approximately 4-75 times the maximal daily human topical dose. In the oral study, positive linear trends were observed in the incidence of follicular cell adenomas and carcinomas in the thyroid glands of female rats, and in the incidence of benign and malignant pheochromocytomas in the adrenal medullas of male rats. - No photocarcinogenicity studies were conducted. Animal studies have shown an increased tumorigenic risk with the use of pharmacologically similar drugs (e.g., retinoids) when exposed to UV irradiation in the laboratory or to sunlight. Although the significance of these studies to human use is not clear, patients should be advised to avoid or minimize exposure to either sunlight or artificial UV irradiation sources. - In a series of in vivo and in vitro studies, adapalene did not exhibit mutagenic or genotoxic activities. # Clinical Studies - FDA Package Insert for Adapalene contains no information regarding Clinical studies. # How Supplied - DIFFERIN (adapalene gel) Gel, 0.1% is supplied in the following size: - 45 g laminate tube - NDC 0299-5910-45 ## Storage - Store at controlled room temperature 68° - 77°F (20° - 25°C), excursions permitted between 59° and 86°F (15° - 30°C). Protect from freezing. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - There is limited information about the Patient Counseling Information. # Precautions with Alcohol - Alcohol-Adapalene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Differin # Look-Alike Drug Names - There is limited information about the look alike drug names. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Adapalene
e0b1147b45ddc1284f97b16c0e7c083a976a7cb9	wikidoc	Adaptogen	Adaptogen The term adaptogen is used by herbalists to refer to a natural herb product that is proposed to increase the body's resistance to stress, trauma, anxiety and fatigue. In the past, they have been called rejuvenating herbs, qi tonics, rasayanas, or restoratives. All adaptogens contain antioxidants, but antioxidants are not necessarily adaptogens and that is not proposed to be their primary mode of action. The concept of adaptogens dates back thousands of years to ancient India and China, but modern study did not begin until the late 1940s. In 1947, Nikolai Lazarev defined an adaptogen as an agent that allows the body to counter adverse physical, chemical, or biological stressors by raising nonspecific resistance toward such stress, thus allowing the organism to "adapt" to the stressful circumstances. In 1968, Israel I. Brekhman , PhD, and I. V. Dardymov formally gave adaptogens a functional definition, as follows: - An adaptogen is nontoxic to the recipient. - An adaptogen produces a nonspecific response in the body—an increase in the power of resistance against multiple stressors including physical, chemical, or biological agents. - An adaptogen has a normalizing influence on physiology, irrespective of the direction of change from physiological norms caused by the stressor. Under this definition, adaptogens would be nontoxic in normal doses, produce a general defensive response against stress, and have a normalizing influence on the body. It is claimed that adaptogenic herbs are unique from other substances in their ability to balance endocrine hormones and the immune system, and they help the body to maintain optimal homeostasis. Adaptogens are proposed to have a normalizing effect on the body and to be capable of either toning down the activity of hyperfunctioning systems or strengthening the activity of hypofunctioning systems. However, they are also proposed to be functional at the level of allostasis, which is a more dynamic reaction to long term stress, lacking the fixed reference points of homeostasis. # Adaptogenic herbs and other organisms Most herbal adaptogens that have been identified have long been used in either Ayurveda or Traditional Chinese Medicine (TCM). Some of the more commonly used herbs described as adaptogens include: Possible adaptogens with less scientific research include: Panax ginseng is an example of an adaptogen that has demonstrated an "overall normalizing effect." Among the active ingredients found in Panax Ginseng are substances called ginsenosides. The herb contains ginsenosides Rg1, which can stimulate the nervous system, and ginsenosides Rb1, which calms it. However ginsenosides alone do not determine the active strength of ginseng and some preparations with higher ginsenosides have lower activity, indicating that cofactors are necessary to potentiate the adaptogenic properties of ginseng. # Constituents common to adaptogens It can be difficult to determine which constituents are active ingredients in plants with as diffuse an effect as adaptogens. According to adaptogen researcher Panossian and medical botanist and herbalist Robyn Klein, adaptogens tend to have the following consitituents: Triterpenes (mevalonate pathway) - Triterpenoid saponins: dammarane triterpene saponins, cucurbitacins - Phytosterols: beta-sitosterol - Phytoecdysteroids: 20-ecdysone, turkesterone Phenylpropanes (shikimate pathway) - Flavonoids: glucopyranosides, prenylated flavonoids, flavan glycosides - Lignans: schizandrin, sesamin, syringaresinol Oxylipins (acetate pathway) - Hydroxylated fatty acids: octadecadienoic acid Triterpenoid saponins have been the focus of most studies of adaptogen constituents. Saponins include ginsenoside from Panax ginseng, gypenosides from Gynostemma and eleutherosides from Eleutherococcus. The lipophilic properties of ginsenosides, for instance, favor binding to intracellular steroid hormone receptors. Triterpenes also include phytosterols and phytoecdysteroids, both of which are thought to have adaptogenic roles in mammals. Phytosterols have been studied more in food science than phytotherapy but are known to have immune function. Phytoecdysteroids are in common use by athletes and weight lifters for the anabolic effects they produce. Rhaponticum carthamoides is notable for these compounds. Oxylipins are fatty acids that have been oxidized and display prostaglandin-like activity due to a shape similar to leukotrienes. Examples are the hydroxylated fatty acids in licorice, Glycyrrhiza glabra. In addition to the above constituents, many adaptogens contain polysaccharides that have been reported to stimulate immune system components and have immune system enhancing benefits. Polysaccharide-rich plants have a long history of use in traditional practices such as Chinese medicine. In addition to stimulating the immune system, they are used to increase vital energy and considered qi tonics. Adaptogens that contain polysaccharides include: American ginseng, Asian ginseng, astragalus, cordyceps, eleuthero, licorice, lycium, prince seng, reishi, rhaponticum, and shatavari. # Notes - ↑ Jump up to: 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Winston, David & Maimes, Steven. “Adaptogens: Herbs for Strength, Stamina, and Stress Relief,” Healing Arts Press, 2007. - ↑ Robyn Klein."Allostasis Theory and Adaptogenic Plant Remedies" 2004 - ↑ Saleeby, J. P. "Wonder Herbs: A Guide to Three Adaptogens", Xlibris, 2006. (Three chapters on adaptogens Rhodiola rosea, Eleuthero & Jiaogulan.) - ↑ Hobbs, Christopher "Medicinal mushrooms: The history, chemistry, pharmacology and folk uses for modern times" Botanica Press, 1987. - ↑ April 2005 MMS Newsletter "PubMed Home". www.ncbi.nlm.nih.gov. Retrieved 2008-03-06..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} - ↑ Search term "licorice" instead of scientific name. The search term also brought up some other similar species. - ↑ It seems there may be more papers under a synonym for the plant. - ↑ 0 PubMed results listed under the name Ashphaltum bitumen + 0 under "Shilajit" - ↑ 44 PubMed results found under the name Asparagus racemosus + 0 results under synonym Asparagus rigidulus + 0 results under synonym Protasparagus racemosus - ↑ 342 PubMed results under the name Astragalus membranaceus + 151 under the synonym Radix astragali = 493. This is assuming both terms do not appear in the same paper - ↑ 30 PubMed results listed under the name Bacopa monnieri - ↑ 96 results for PubMed search under the name Phyllanthus emblica + 122 results under the name Emblica officinalis = 218. This is assuming bother terms do not appear in the same paper - ↑ 0 PubMed results found - ↑ 12 results under the name Pfaffia paniculata - ↑ 66 PubMed results under the name Polygonum multiflorum - ↑ 17 PubMed results under the name Pseudostellaria heterophylla - ↑ 17 PubMed results under the name Rhaponticum carthamoides - ↑ Panossian, Alexander G., 2003. Adaptogens: a historical overview and perspective. Natural Pharmacy, 7(4), 1, 19- - ↑ Robyn Klein Masters Thesis Paper, May 2004, Montana State University, Dept Plant Sciences & Plant Pathology: Phylogenetic and phytochemical characteristics of plant species with adaptogenic properties - ↑ Bouic, Patrick J.D., 2002. Sterols and sterolins: new drugs for the immune system? Drug Discovery Today, 7(14), - ↑ Panossian, Alexander G., 2003. Adaptogens: a historical overview and perspective. Natural Pharmacy, 7(4), 1, 19- - ↑ Robyn Klein Masters Thesis Paper, May 2004, Montana State University, Dept Plant Sciences & Plant Pathology: Phylogenetic and phytochemical characteristics of plant species with adaptogenic properties # Further reading - Adaptogens.org - David Winston & Steven Maimes. “Adaptogens: Herbs for Strength, Stamina, and Stress Relief,” Healing Arts Press, 2007. The definitive guide to adaptogenic herbs. Includes overview, history, actions, health benefits, 21 monographs; and chapters on adaptogens as food and adaptogens for animals. - Adaptogens in America ca:Adaptogen cs:Adaptogen de:Adaptogen lt:Adaptogenas fi:Adaptogeeni sv:Adaptogen	Adaptogen Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4] The term adaptogen is used by herbalists to refer to a natural herb product that is proposed to increase the body's resistance to stress, trauma, anxiety and fatigue. In the past, they have been called rejuvenating herbs, qi tonics, rasayanas, or restoratives. All adaptogens contain antioxidants, but antioxidants are not necessarily adaptogens and that is not proposed to be their primary mode of action.[1] The concept of adaptogens dates back thousands of years to ancient India and China, but modern study did not begin until the late 1940s. In 1947, Nikolai Lazarev defined an adaptogen as an agent that allows the body to counter adverse physical, chemical, or biological stressors by raising nonspecific resistance toward such stress, thus allowing the organism to "adapt" to the stressful circumstances.[1] In 1968, Israel I. Brekhman , PhD, and I. V. Dardymov formally gave adaptogens a functional definition, as follows: - An adaptogen is nontoxic to the recipient. - An adaptogen produces a nonspecific response in the body—an increase in the power of resistance against multiple stressors including physical, chemical, or biological agents. - An adaptogen has a normalizing influence on physiology, irrespective of the direction of change from physiological norms caused by the stressor. Under this definition, adaptogens would be nontoxic in normal doses, produce a general defensive response against stress, and have a normalizing influence on the body.[1] It is claimed that adaptogenic herbs are unique from other substances in their ability to balance endocrine hormones and the immune system, and they help the body to maintain optimal homeostasis.[1] Adaptogens are proposed to have a normalizing effect on the body and to be capable of either toning down the activity of hyperfunctioning systems or strengthening the activity of hypofunctioning systems. However, they are also proposed to be functional at the level of allostasis, which is a more dynamic reaction to long term stress, lacking the fixed reference points of homeostasis.[2] # Adaptogenic herbs and other organisms Most herbal adaptogens that have been identified have long been used in either Ayurveda or Traditional Chinese Medicine (TCM). Some of the more commonly used herbs described as adaptogens include:[1][3][4][5] Possible adaptogens with less scientific research include: Panax ginseng is an example of an adaptogen that has demonstrated an "overall normalizing effect." Among the active ingredients found in Panax Ginseng are substances called ginsenosides. The herb contains ginsenosides Rg1, which can stimulate the nervous system, and ginsenosides Rb1, which calms it.[1] However ginsenosides alone do not determine the active strength of ginseng and some preparations with higher ginsenosides have lower activity, indicating that cofactors are necessary to potentiate the adaptogenic properties of ginseng. # Constituents common to adaptogens It can be difficult to determine which constituents are active ingredients in plants with as diffuse an effect as adaptogens. According to adaptogen researcher Panossian and medical botanist and herbalist Robyn Klein, adaptogens tend to have the following consitituents:[19][20] Triterpenes (mevalonate pathway) - Triterpenoid saponins: dammarane triterpene saponins, cucurbitacins - Phytosterols: beta-sitosterol - Phytoecdysteroids: 20-ecdysone, turkesterone Phenylpropanes (shikimate pathway) - Flavonoids: glucopyranosides, prenylated flavonoids, flavan glycosides - Lignans: schizandrin, sesamin, syringaresinol Oxylipins (acetate pathway) - Hydroxylated fatty acids: octadecadienoic acid Triterpenoid saponins have been the focus of most studies of adaptogen constituents. Saponins include ginsenoside from Panax ginseng, gypenosides from Gynostemma and eleutherosides from Eleutherococcus. The lipophilic properties of ginsenosides, for instance, favor binding to intracellular steroid hormone receptors. Triterpenes also include phytosterols and phytoecdysteroids, both of which are thought to have adaptogenic roles in mammals. Phytosterols have been studied more in food science than phytotherapy but are known to have immune function.[21] Phytoecdysteroids are in common use by athletes and weight lifters for the anabolic effects they produce. Rhaponticum carthamoides is notable for these compounds. Oxylipins are fatty acids that have been oxidized and display prostaglandin-like activity due to a shape similar to leukotrienes. Examples are the hydroxylated fatty acids in licorice, Glycyrrhiza glabra.[22][23] In addition to the above constituents, many adaptogens contain polysaccharides that have been reported to stimulate immune system components and have immune system enhancing benefits. Polysaccharide-rich plants have a long history of use in traditional practices such as Chinese medicine. In addition to stimulating the immune system, they are used to increase vital energy and considered qi tonics. Adaptogens that contain polysaccharides include: American ginseng, Asian ginseng, astragalus, cordyceps, eleuthero, licorice, lycium, prince seng, reishi, rhaponticum, and shatavari.[1] # Notes - ↑ Jump up to: 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Winston, David & Maimes, Steven. “Adaptogens: Herbs for Strength, Stamina, and Stress Relief,” Healing Arts Press, 2007. - ↑ [1]Robyn Klein."Allostasis Theory and Adaptogenic Plant Remedies" 2004 - ↑ Saleeby, J. P. "Wonder Herbs: A Guide to Three Adaptogens", Xlibris, 2006. (Three chapters on adaptogens Rhodiola rosea, Eleuthero & Jiaogulan.) - ↑ Hobbs, Christopher "Medicinal mushrooms: The history, chemistry, pharmacology and folk uses for modern times" Botanica Press, 1987. - ↑ April 2005 MMS Newsletter - ↑ "PubMed Home". www.ncbi.nlm.nih.gov. Retrieved 2008-03-06..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} - ↑ Search term "licorice" instead of scientific name. The search term also brought up some other similar species. - ↑ It seems there may be more papers under a synonym for the plant. - ↑ 0 PubMed results listed under the name Ashphaltum bitumen + 0 under "Shilajit" - ↑ 44 PubMed results found under the name Asparagus racemosus + 0 results under synonym Asparagus rigidulus + 0 results under synonym Protasparagus racemosus - ↑ 342 PubMed results under the name Astragalus membranaceus + 151 under the synonym Radix astragali = 493. This is assuming both terms do not appear in the same paper - ↑ 30 PubMed results listed under the name Bacopa monnieri - ↑ 96 results for PubMed search under the name Phyllanthus emblica + 122 results under the name Emblica officinalis = 218. This is assuming bother terms do not appear in the same paper - ↑ 0 PubMed results found - ↑ 12 results under the name Pfaffia paniculata - ↑ 66 PubMed results under the name Polygonum multiflorum - ↑ 17 PubMed results under the name Pseudostellaria heterophylla - ↑ 17 PubMed results under the name Rhaponticum carthamoides - ↑ Panossian, Alexander G., 2003. Adaptogens: a historical overview and perspective. Natural Pharmacy, 7(4), 1, 19- 20. - ↑ [2]Robyn Klein Masters Thesis Paper, May 2004, Montana State University, Dept Plant Sciences & Plant Pathology: Phylogenetic and phytochemical characteristics of plant species with adaptogenic properties - ↑ Bouic, Patrick J.D., 2002. Sterols and sterolins: new drugs for the immune system? Drug Discovery Today, 7(14), 775-778 - ↑ Panossian, Alexander G., 2003. Adaptogens: a historical overview and perspective. Natural Pharmacy, 7(4), 1, 19- 20. - ↑ [3]Robyn Klein Masters Thesis Paper, May 2004, Montana State University, Dept Plant Sciences & Plant Pathology: Phylogenetic and phytochemical characteristics of plant species with adaptogenic properties # Further reading - Adaptogens.org - David Winston & Steven Maimes. “Adaptogens: Herbs for Strength, Stamina, and Stress Relief,” Healing Arts Press, 2007. The definitive guide to adaptogenic herbs. Includes overview, history, actions, health benefits, 21 monographs; and chapters on adaptogens as food and adaptogens for animals. - Adaptogens in America ca:Adaptogen cs:Adaptogen de:Adaptogen lt:Adaptogenas fi:Adaptogeeni sv:Adaptogen Template:WH Template:WS	https://www.wikidoc.org/index.php/Adaptogen
879c54cf19650331926129a1bc6a73699d3929de	wikidoc	Addiction	Addiction # Overview Addiction was a term used to describe a devotion, attachment, dedication, inclination, etc. Nowadays, however, the term addiction is used to describe a recurring compulsion by an individual to engage in some specific activity, despite harmful consequences to the individual's health, mental state or social life. The term is often reserved for drug addictions but it is sometimes applied to other compulsions, such as problem gambling, and compulsive overeating. Factors that have been suggested as causes of addiction include genetic, biological/pharmacological and social factors. # Terminology and usage Decades ago addiction was a pharmacological term that clearly referred to the use of a tolerance-inducing drug in sufficient quantity as to cause tolerance (the requirement that greater dosages of a given drug be used to produce an identical effect as time passes). With that definition, humans (and indeed all mammals) can become addicted to various drugs quickly. Almost at the same time, a lay definition of addiction developed. This definition referred to individuals who continued to use a given drug despite their own best interest. This latter definition is now thought of as a disease state by the medical community. Physical dependence, abuse of, and withdrawal from drugs and other miscellaneous substances is outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV TR). Terminology has become quite complicated in the field. To wit, pharmacologists continue to speak of addiction from a physiologic standpoint (some call this a physical dependence); psychiatrists refer to the disease state as dependence; most other physicians refer to the disease as addiction. The field of psychiatry is now considering, as they move from DSM-IV to DSM-V, transitioning from "dependence" to "addiction" as terminology for the disease state. The medical community now makes a careful theoretical distinction between physical dependence (characterized by symptoms of withdrawal) and psychological dependence (or simply addiction). Addiction is now narrowly defined as "uncontrolled, compulsive use"; if there is no harm being suffered by, or damage done to, the patient or another party, then clinically it may be considered compulsive, but to the definition of some it is not categorized as "addiction". In practice, the two kinds of addiction are not always easy to distinguish. Addictions often have both physical and psychological components. There is also a lesser known situation called pseudo-addiction.(Weissman and Haddox, 1989) A patient will exhibit drug-seeking behavior reminiscent of psychological addiction, but they tend to have genuine pain or other symptoms that have been undertreated. Unlike true psychological addiction, these behaviors tend to stop when the pain is adequately treated. The obsolete term physical addiction is deprecated, because of its connotations. In modern pain management with opioids physical dependence is nearly universal. While opiates are essential in the treatment of acute pain, the benefit of this class of medication in chronic pain is not well proven. Clearly, there are those who would not function well without opiate treatment; on the other hand, many states are noting significant increases in non-intentional deaths related to opiate use. High-quality, long-term studies are needed to better delineate the risks and benefits of chronic opiate use. Not all doctors agree on what addiction or dependency is. Traditionally, addiction has been defined as being possible only to a psychoactive substance (for example alcohol, tobacco and other drugs) which ingested cross the blood-brain barrier, altering the natural chemical behavior of the brain temporarily. However, "Studies on phenomenology, family history, and response to treatment suggest that intermittent explosive disorder, kleptomania, pathological gambling, pyromania, and trichotillomania may be related to mood disorders, alcohol and psychoactive substance abuse, and anxiety disorders (especially obsessive-compulsive disorder). It is generally accepted that addiction is a disease, a state of physiological or psychological dependence or devotion to something manifesting as a condition in which medically significant symptoms liable to have a damaging effect are present. Many people, both psychology professionals and laypersons, now feel that there should be accommodation made to include psychological dependency on such things as gambling, food, sex, pornography, computers, work, exercise, cutting, shopping, and religion so these behaviours count as diseases as well and don't cause guilt, shame, fear, hopelessness, failure, rejection,anxiety, or humiliation symptoms associated with, among other medical conditions, depression,epilepsy, and hyperreligiosity In depression related to religious addiction "The religious addict seeks to avoid pain and overcome shame by becoming involved in a belief system which offers security through its rigidity and its absolute values." While religion and spirituality may play a key role in psychotherapeutic support and recovery, it can also be a source of pain, guilt and exclusion, and religious themes may also play a negative role in psychopathology. Although, the above mentioned are things or tasks which, when used or performed, do not fit into the traditional view of addiction and may be better defined as an obsessive-compulsive disorder,withdrawal symptoms may occur with abatement of such behaviors. It is said by those who adhere to a traditionalist view that these withdrawal-like symptoms are not strictly reflective of an addiction, but rather of a behavioral disorder. However, understanding of neural science, the brain, the nervous system, human behavior, and affective disorders has revealed "the impact of molecular biology in the mechanisms underlying developmental processes and in the pathogenesis of disease". The use of thyroid hormones as an effective adjunct treatment for affective disorders has been studied over the past three decades and has been confirmed repeatedly. In spite of traditionalist protests and warnings that overextension of definitions may cause the wrong treatment to be used (thus failing the person with the behavioral problem), popular media, and some members of the field, do represent the aforementioned behavioral examples as addictions. Recently, some have modeled addiction using the tools of Economics, for instance, by calculating the elasticity of addictive goods and determining to what extent present income and consumption has on future consumption. # Varied forms of addiction ## Physical dependency Physical dependence on a substance is defined by the appearance of characteristic withdrawal symptoms when the substance is suddenly discontinued. Opiates, benzodiazepines, barbiturates, alcohol and nicotine induce physical dependence. On the other hand, some categories of substances share this property and are still not considered addictive: cortisone, beta-blockers and most antidepressants are examples. So, while physical dependency can be a major factor in the psychology of addiction and most often becomes a primary motivator in the continuation of an addiction, the initial primary attribution of an addictive substance is usually its ability to induce pleasure, although with continued use the goal is not so much to induce pleasure as it is to relieve the anxiety caused by the absence of a given addictive substance, causing it to become used compulsively. An example of this is nicotine; A cigarette can be described as pleasurable, but is in fact fulfilling the physical addiction of the user, and therefore, is achieving pleasurable feelings relative to his/her previous state of physical withdrawal. Further, the physical dependency of the nicotine addict on the substance itself becomes an overwhelming factor in the continuation of use. Some substances induce physical dependence or physiological tolerance - but not addiction - for example many laxatives, which are not psychoactive; nasal decongestants, which can cause rebound congestion if used for more than a few days in a row; and some antidepressants, most notably venlafaxine, paroxetine and sertraline, as they have quite short half-lives, so stopping them abruptly causes a more rapid change in the neurotransmitter balance in the brain than many other antidepressants. Many non-addictive prescription drugs should not be suddenly stopped, so a doctor should be consulted before abruptly discontinuing them. The speed with which a given individual becomes addicted to various substances varies with the substance, the frequency of use, the means of ingestion, the intensity of pleasure or euphoria, and the individual's genetic and psychological susceptibility. Some people may exhibit alcoholic tendencies from the moment of first intoxication, while most people can drink socially without ever becoming addicted. Opioid dependent individuals have different responses to even low doses of opioids than the majority of people, although this may be due to a variety of other factors, as opioid use heavily stimulates pleasure-inducing neurotransmitters in the brain. Nonetheless, because of these variations, in addition to the adoption and twin studies that have been well replicated, much of the medical community is satisfied that addiction is in part genetically moderated. That is, one's genetic makeup may regulate how susceptible one is to a substance and how easily one may become psychologically attached to a pleasurable routine. Eating disorders are complicated pathological mental illnesses and thus are not the same as addictions described in this article. Eating disorders, which some argue are not addictions at all, are driven by a multitude of factors, most of which are highly different than the factors behind addictions described in this article. ## Psychological dependency Psychological dependency is a dependency of the mind, and leads to psychological withdrawal symptoms (such as cravings, irritability, insomnia, depression, anorexia etc). Addiction can in theory be derived from any rewarding behavior, and is believed to be strongly associated with the dopaminergic system of the brain's reward system (as in the case of cocaine and amphetamines). Some claim that it is a [[Habit habitual means to avoid undesired activity, but typically it is only so to a clinical level in individuals who have emotional, social, or psychological dysfunctions (psychological addiction is defined as such), replacing normal positive stimuli not otherwise attained. It is considered possible to be both psychologically and physically dependent at the same time. Some doctors make little distinction between the two types of addiction, since the result, substance abuse, is the same. However, the cause and characteristics of each of the two types of addiction is quite different, as is the type of treatment preferred. Psychological dependence does not have to be limited only to substances; even activities and behavioral patterns can be considered addictions, if they become uncontrollable, e.g. gambling, Internet addiction, computer addiction, sexual addiction/pornography addiction, eating, self-harm, vandalism or work addiction. # Addiction and drug control legislation Most countries have legislation which brings various drugs and drug-like substances under the control of licensing systems. Typically this legislation covers any or all of the opiates, amphetamines, cannabinoids, cocaine, barbiturates, hallucinogens (tryptamines, LSD, phencyclidine(PCP), psilocybin) and a variety of more modern synthetic drugs, and unlicensed production, supply or possession may be a criminal offense. Usually, however, drug classification under such legislation is not related simply to addictiveness. The substances covered often have very different addictive properties. Some are highly prone to cause physical dependency, whilst others rarely cause any form of compulsive need whatsoever. Typically nicotine (in the form of tobacco) is regulated extremely loosely, if at all, although it is well-known as one of the most addictive substances ever discovered. Also, although the legislation may be justifiable on moral grounds to some, it can make addiction or dependency a much more serious issue for the individual. Reliable supplies of a drug become difficult to secure as illegally produced substances may have contaminants. Withdrawal from the substances or associated contaminants can cause additional health issues and the individual becomes vulnerable to both criminal abuse and legal punishment. Criminal elements that can be involved in the profitable trade of such substances can also cause physical harm to users. # Methods of care Early editions of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM) described addiction as a physical dependency to a substance that resulted in withdrawal symptoms in its absence. Recent editions, including DSM-IV, have moved toward a diagnostic instrument that classifies such conditions as dependency, rather than addiction. The American Society of Addiction Medicine recommends treatment for people with chemical dependency based on patient placement criteria (currently listed in PPC-2), which attempt to match levels of care according to clinical assessments in six areas, including: - Acute intoxication and/or withdrawal potential - Biomedical conditions or complications - Emotional/behavioral conditions or complications - Treatment acceptance/resistance - Relapse potential - Recovery environment Some medical systems, including those of at least 15 states of the United States, refer to an Addiction Severity Index to assess the severity of problems related to substance use. The index assesses problems in six areas: medical, employment/support, alcohol and other drug use, legal, family/social, and psychiatric. While addiction or dependency is related to seemingly uncontrollable urges, and arguably could have roots in genetic predispositions, treatment of dependency is conducted by a wide range of medical and allied professionals, including Addiction Medicine specialists, psychiatrists, and appropriately trained nurses, social workers, and counselors. Early treatment of acute withdrawal often includes medical detoxification, which can include doses of anxiolytics or narcotics to reduce symptoms of withdrawal. An experimental drug, ibogaine, is also proposed to treat withdrawal and craving. Alternatives to medical detoxification include acupuncture detoxification. In chronic opiate addiction, a surrogate drug such as methadone is sometimes offered as a form of opiate replacement therapy. But treatment approaches universal focus on the individual's ultimate choice to pursue an alternate course of action. Therapists often classify patients with chemical dependencies as either interested or not interested in changing. Treatments usually involve planning for specific ways to avoid the addictive stimulus, and therapeutic interventions intended to help a client learn healthier ways to find satisfaction. Clinical leaders in recent years have attempted to tailor intervention approaches to specific influences that affect addictive behavior, using therapeutic interviews in an effort to discover factors that led a person to embrace unhealthy, addictive sources of pleasure or relief from pain. From the applied behavior analysis literature and the behavioral psychology literature several evidenced based intervention programs have emerged (1) behavioral maritial therapy (2) community reinforcement approach (3) cue exposure therapy and (4) contingency management stategies (see O'Donohue, W., Ferguson, K.E. (2006) Evidence-Based Practice in Psychology and Behavior Analysis. The Behavior Analyst Today. vol 7(3). pp.335-350 and Chambless, D. L. et al. (1996). An update on empirically validated therapies. Clinical Psychology, 49, 5-14 ). In addition, the same author suggest that Social skills training adjunctive to inpatient treatment of alcohol dependence is probably efficacious. # Diverse explanations Several explanations (or "models") have been presented to explain addiction. These divide, more or less, into the models which stress biological or genetic causes for addiction, and those which stress social or purely psychological causes. Of course there are also many models which attempt to see addiction as both a physiological and a psycho-social phenomenon. - The disease model of addiction holds that addiction is a disease, coming about as a result of either the impairment of neurochemical or behavioral processes, or of some combination of the two. Within this model, addictive disease is treated by specialists in Addiction Medicine. Within the field of medicine, the American Medical Association, National Association of Social Workers, and American Psychological Association all have policies which are predicated on the theory that addictive processes represent a disease state. Most treatment approaches, as well, are based on the idea that dependencies are behavioral dysfunctions, and, therefore, contain, at least to some extent, elements of physical or mental disease. Organizations such as the American Society of Addiction Medicine believe the research-based evidence for addiction's status as a disease is overwhelming. - The genetic model posits a genetic predisposition to certain behaviors. It is frequently noted that certain addictions "run in the family," and while researchers continue to explore the extent of genetic influence, many researchers argue that there is strong evidence that genetic predisposition is often a factor in dependency. - The experiential model devised by Stanton Peele argues that addictions occur with regard to experiences generated by various involvements, whether drug-induced or not. This model is in opposition to the disease, genetic, and neurobiological approaches. Among other things, it proposes that addiction is both more temporary or situational than the disease model claims, and is often outgrown through natural processes. - The opponent-process model generated by Richard Soloman states that for every psychological event A will be followed by its opposite psychological event B. For example, the pleasure one experiences from heroin is followed by an opponent process of withdrawal, or the terror of jumping out of an airplane is rewarded with intense pleasure when the parachute opens. This model is related to the opponent process color theory. If you look at the color red then quickly look at a gray area you will see green. There are many examples of opponent processes in the nervous system including taste, motor movement, touch, vision, and hearing. Opponent-processes occurring at the sensory level may translate "down-stream" into addictive or habit-forming behavior. - The allostatic(stability through change) model generated by George Koob and Michel LeMoal is a modification of the opponent process theory where continued use of a drug leads to a spiralling of uncontrolled use, negative emotional states and withdrawal and a shift into use to new allostatic set point which is lower than that maintained before use of the drug (Koob and LeMoal, 2001; Koob and LeMoal, 2006). - The cultural model recognizes that the influence of culture is a strong determinant of whether or not individuals fall prey to certain addictions. For example, alcoholism is rare among Saudi Arabians, where obtaining alcohol is difficult and using alcohol is prohibited. In North America, on the other hand, the incidence of gambling addictions soared in the last two decades of the 20th century, mirroring the growth of the gaming industry. Half of all patients diagnosed as alcoholic are born into families where alcohol is used heavily, suggesting that familiar influence, genetic factors, or more likely both, play a role in the development of addiction. What also needs to be noted is that when people don't gain a sense of moderation through their development they can be just as likely, if not more, to abuse substances than people born into alcoholic families. - The moral model states that addictions are the result of human weakness, and are defects of character. Those who advance this model do not accept that there is any biological basis for addiction. They often have scant sympathy for people with serious addictions, believing either that a person with greater moral strength could have the force of will to break an addiction, or that the addict demonstrated a great moral failure in the first place by starting the addiction. The moral model is widely applied to dependency on illegal substances, perhaps purely for social or political reasons, but is no longer widely considered to have any therapeutic value. Elements of the moral model, especially a focus on individual choices, have found enduring roles in other approaches to the treatment of dependencies. - The habit model proposed by Thomas Szasz questions the very concept of "addiction." He argues that addiction is a metaphor, and that the only reason to make the distinction between habit and addiction "is to persecute somebody." (Szasz, 1973). Cf also the life-process model of addiction. - Finally, the blended model attempts to consider elements of all other models in developing a therapeutic approach to dependency. It holds that the mechanism of dependency is different for different individuals, and that each case must be considered on its own merits. # Neurobiological basis The development of addiction is thought to involve a simultaneous process of 1) increased focus on and engagement in a particular behavior and 2) the attenuation or "shutting down" of other behaviors. For example, under certain experimental circumstances such as social deprivation and boredom, animals allowed the unlimited ability to self-administer certain psychoactive drugs will show such a strong preference that they will forgo food, sleep, and sex for continued access. The neuro-anatomical correlate of this is that the brain regions involved in driving goal-directed behavior grow increasingly selective for particular motivating stimuli and rewards, to the point that the brain regions involved in the inhibition of behavior can no longer effectively send "stop" signals. A good analogy is to imagine flooring the gas pedal in a car with very bad brakes. In this case, the limbic system is thought to be the major "driving force" and the orbitofrontal cortex is the substrate of the top-down inhibition. A specific portion of the limbic circuit known as the mesolimbic dopaminergic system is hypothesized to play an important role in translation of motivation to motor behavior- and reward-related learning in particular. It is typically defined as the ventral tegmental area (VTA), the nucleus accumbens, and the bundle of dopamine-containing fibers that are connecting them. This system is commonly implicated in the seeking out and consumption of rewarding stimuli or events, such as sweet-tasting foods or sexual interaction. However, its importance to addiction research goes beyond its role in "natural" motivation: while the specific site or mechanism of action may differ, all known drugs of abuse have the common effect in that they elevate the level of dopamine in the nucleus accumbens. This may happen directly, such as through blockade of the dopamine re-uptake mechanism (see cocaine). It may also happen indirectly, such as through stimulation of the dopamine-containing neurons of the VTA that synapse onto neurons in the accumbens (see opiates). The euphoric effects of drugs of abuse are thought to be a direct result of the acute increase in accumbal dopamine. The human body has a natural tendency to maintain homeostasis, and the central nervous system is no exception. Chronic elevation of dopamine will result in a decrease in the number of dopamine receptors available in a process known as downregulation. The decreased number of receptors changes the permeability of the cell membrane located post-synaptically, such that the post-synaptic neuron is less excitable- i.e.: less able to respond to chemical signaling with an electrical impulse, or action potential. It is hypothesized that this dulling of the responsiveness of the brain's reward pathways contributes to the inability to feel pleasure, known as anhedonia, often observed in addicts. The increased requirement for dopamine to maintain the same electrical activity is the basis of both physiological tolerance and withdrawal associated with addiction. Downregulation can be classically conditioned. If a behavior consistently occurs in the same environment or contingently with a particular cue, the brain will adjust to the presence of the conditioned cues by decreasing the number of available receptors in the absence of the behavior. It is thought that many drug overdoses are not the result of a user taking a higher dose than is typical, but rather that the user is administering the same dose in a new environment. In cases of physical dependency on depressants of the central nervous system such as opioids, barbiturates, or alcohol, the absence of the substance can lead to symptoms of severe physical discomfort. Withdrawal from alcohol or sedatives such as barbiturates or benzodiazepines (valium-family) can result in seizures and even death. By contrast, withdrawal from opioids, which can be extremely uncomfortable, is rarely if ever life-threatening. In cases of dependence and withdrawal, the body has become so dependent on high concentrations of the particular chemical that it has stopped producing its own natural versions (endogenous ligands) and instead produces opposing chemicals. When the addictive substance is withdrawn, the effects of the opposing chemicals can become overwhelming. For example, chronic use of sedatives (alcohol, barbiturates, or benzodiazepines) results in higher chronic levels of stimulating neurotransmitters such as glutamate. Very high levels of glutamate kill nerve cells, a phenomenon called excitatory neurotoxicity. # Criticism Levi Bryant has criticized the term and concept of addiction as counterproductive in psychotherapy as it defines a patient's identity and makes it harder to become a non-addict. "The signifier 'addict' doesn't simply describe what I am, but initiates a way of relating to myself that informs how I relate to others." A stronger form of criticism comes from Thomas Szasz, who denies that addiction is a psychiatric problem. In many of his works, he argues that addiction is a choice, and that a drug addict is one who simply prefers a socially taboo substance rather than, say, a low risk lifestyle. In Our Right to Drugs, Szasz cites the biography of Malcolm X to corroborate his economic views towards addiction: Malcolm claimed that quitting cigarettes was harder than shaking his heroin addiction. Szasz postulates that humans always have a choice, and it is foolish to call someone an 'addict' just because they prefer a drug induced euphoria to a more popular and socially welcome lifestyle.Therefore, being 'addicted' to a substance is no different from being 'addicted' to a job at which you work everyday. Szasz and Bryant are not alone in questioning the standard view of addiction. Professor John Booth Davies at the University of Strathclyde has argued in his book The Myth of Addiction that 'people take drugs because they want to and because it makes sense for them to do so given the choices available' as opposed to the view that 'they are compelled to by the pharmacology of the drugs they take'. . He uses an adaption of attribution theory (what he calls the theory of functional attributions) to argue that the statement 'I am addicted to drugs' is functional, rather than veridical. Stanton Peele has put forward similar views. Experimentally, Bruce K. Alexander used the classic experiment of Rat Park to show that 'addicted' behaviour in rats only occurred when the rats had no other options. When other options and behavioural opportunities were put in place, the rats soon showed far more complex behaviours. # Casual addiction The word addiction is also sometimes used colloquially to refer to something for which a person has a passion, such as books, chocolate, work, the web, running, or eating.	Addiction Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Addiction was a term used to describe a devotion, attachment, dedication, inclination, etc. Nowadays, however, the term addiction is used to describe a recurring compulsion by an individual to engage in some specific activity, despite harmful consequences to the individual's health, mental state or social life. The term is often reserved for drug addictions but it is sometimes applied to other compulsions, such as problem gambling, and compulsive overeating. Factors that have been suggested as causes of addiction include genetic, biological/pharmacological and social factors. # Terminology and usage Decades ago addiction was a pharmacological term that clearly referred to the use of a tolerance-inducing drug in sufficient quantity as to cause tolerance (the requirement that greater dosages of a given drug be used to produce an identical effect as time passes). With that definition, humans (and indeed all mammals) can become addicted to various drugs quickly. Almost at the same time, a lay definition of addiction developed. This definition referred to individuals who continued to use a given drug despite their own best interest. This latter definition is now thought of as a disease state by the medical community. Physical dependence, abuse of, and withdrawal from drugs and other miscellaneous substances is outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV TR). Terminology has become quite complicated in the field. To wit, pharmacologists continue to speak of addiction from a physiologic standpoint (some call this a physical dependence); psychiatrists refer to the disease state as dependence; most other physicians refer to the disease as addiction. The field of psychiatry is now considering, as they move from DSM-IV to DSM-V, transitioning from "dependence" to "addiction" as terminology for the disease state. The medical community now makes a careful theoretical distinction between physical dependence (characterized by symptoms of withdrawal) and psychological dependence (or simply addiction). Addiction is now narrowly defined as "uncontrolled, compulsive use"; if there is no harm being suffered by, or damage done to, the patient or another party, then clinically it may be considered compulsive, but to the definition of some it is not categorized as "addiction". In practice, the two kinds of addiction are not always easy to distinguish. Addictions often have both physical and psychological components. There is also a lesser known situation called pseudo-addiction.(Weissman and Haddox, 1989) A patient will exhibit drug-seeking behavior reminiscent of psychological addiction, but they tend to have genuine pain or other symptoms that have been undertreated. Unlike true psychological addiction, these behaviors tend to stop when the pain is adequately treated. The obsolete term physical addiction is deprecated, because of its connotations. In modern pain management with opioids physical dependence is nearly universal. While opiates are essential in the treatment of acute pain, the benefit of this class of medication in chronic pain is not well proven. Clearly, there are those who would not function well without opiate treatment; on the other hand, many states are noting significant increases in non-intentional deaths related to opiate use. High-quality, long-term studies are needed to better delineate the risks and benefits of chronic opiate use. Not all doctors agree on what addiction or dependency is. Traditionally, addiction has been defined as being possible only to a psychoactive substance (for example alcohol, tobacco and other drugs) which ingested cross the blood-brain barrier, altering the natural chemical behavior of the brain temporarily. However, "Studies on phenomenology, family history, and response to treatment suggest that intermittent explosive disorder, kleptomania, pathological gambling, pyromania, and trichotillomania may be related to mood disorders, alcohol and psychoactive substance abuse, and anxiety disorders (especially obsessive-compulsive disorder).[2] It is generally accepted that addiction is a disease, a state of physiological or psychological dependence or devotion to something manifesting as a condition in which medically significant symptoms liable to have a damaging effect are present[3]. Many people, both psychology professionals and laypersons, now feel that there should be accommodation made to include psychological dependency on such things as gambling, food, sex, pornography, computers, work, exercise, cutting, shopping, and religion[4] so these behaviours count as diseases as well and don't cause guilt, shame, fear, hopelessness, failure, rejection,anxiety, or humiliation symptoms associated with, among other medical conditions, depression[5],epilepsy, [6] and hyperreligiosity[7] In depression related to religious addiction "The religious addict seeks to avoid pain and overcome shame by becoming involved in a belief system which offers security through its rigidity and its absolute values."[8] While religion and spirituality may play a key role in psychotherapeutic support and recovery, it can also be a source of pain, guilt and exclusion, and religious themes may also play a negative role in psychopathology.[9] Although, the above mentioned are things or tasks which, when used or performed, do not fit into the traditional view of addiction and may be better defined as an obsessive-compulsive disorder,withdrawal symptoms may occur with abatement of such behaviors. It is said by those who adhere to a traditionalist view that these withdrawal-like symptoms are not strictly reflective of an addiction, but rather of a behavioral disorder. However, understanding of neural science, the brain, the nervous system, human behavior, and affective disorders has revealed "the impact of molecular biology in the mechanisms underlying developmental processes and in the pathogenesis of disease".[10] The use of thyroid hormones as an effective adjunct treatment for affective disorders has been studied over the past three decades and has been confirmed repeatedly.[11] In spite of traditionalist protests and warnings that overextension of definitions may cause the wrong treatment to be used (thus failing the person with the behavioral problem), popular media, and some members of the field, do represent the aforementioned behavioral examples as addictions. Recently, some have modeled addiction using the tools of Economics, for instance, by calculating the elasticity of addictive goods and determining to what extent present income and consumption has on future consumption. [1] # Varied forms of addiction ## Physical dependency Physical dependence on a substance is defined by the appearance of characteristic withdrawal symptoms when the substance is suddenly discontinued. Opiates, benzodiazepines, barbiturates, alcohol and nicotine induce physical dependence. On the other hand, some categories of substances share this property and are still not considered addictive: cortisone, beta-blockers and most antidepressants are examples. So, while physical dependency can be a major factor in the psychology of addiction and most often becomes a primary motivator in the continuation of an addiction, the initial primary attribution of an addictive substance is usually its ability to induce pleasure, although with continued use the goal is not so much to induce pleasure as it is to relieve the anxiety caused by the absence of a given addictive substance, causing it to become used compulsively. An example of this is nicotine; A cigarette can be described as pleasurable, but is in fact fulfilling the physical addiction of the user, and therefore, is achieving pleasurable feelings relative to his/her previous state of physical withdrawal. Further, the physical dependency of the nicotine addict on the substance itself becomes an overwhelming factor in the continuation of use. Some substances induce physical dependence or physiological tolerance - but not addiction - for example many laxatives, which are not psychoactive; nasal decongestants, which can cause rebound congestion if used for more than a few days in a row; and some antidepressants, most notably venlafaxine, paroxetine and sertraline, as they have quite short half-lives, so stopping them abruptly causes a more rapid change in the neurotransmitter balance in the brain than many other antidepressants. Many non-addictive prescription drugs should not be suddenly stopped, so a doctor should be consulted before abruptly discontinuing them. The speed with which a given individual becomes addicted to various substances varies with the substance, the frequency of use, the means of ingestion, the intensity of pleasure or euphoria, and the individual's genetic and psychological susceptibility. Some people may exhibit alcoholic tendencies from the moment of first intoxication, while most people can drink socially without ever becoming addicted. Opioid dependent individuals have different responses to even low doses of opioids than the majority of people, although this may be due to a variety of other factors, as opioid use heavily stimulates pleasure-inducing neurotransmitters in the brain. Nonetheless, because of these variations, in addition to the adoption and twin studies that have been well replicated, much of the medical community is satisfied that addiction is in part genetically moderated. That is, one's genetic makeup may regulate how susceptible one is to a substance and how easily one may become psychologically attached to a pleasurable routine. Eating disorders are complicated pathological mental illnesses and thus are not the same as addictions described in this article. Eating disorders, which some argue are not addictions at all, are driven by a multitude of factors, most of which are highly different than the factors behind addictions described in this article. ## Psychological dependency Psychological dependency is a dependency of the mind, and leads to psychological withdrawal symptoms (such as cravings, irritability, insomnia, depression, anorexia etc). Addiction can in theory be derived from any rewarding behavior, and is believed to be strongly associated with the dopaminergic system of the brain's reward system (as in the case of cocaine and amphetamines). Some claim that it is a [[Habit habitual means to avoid undesired activity, but typically it is only so to a clinical level in individuals who have emotional, social, or psychological dysfunctions (psychological addiction is defined as such), replacing normal positive stimuli not otherwise attained. It is considered possible to be both psychologically and physically dependent at the same time. Some doctors make little distinction between the two types of addiction, since the result, substance abuse, is the same. However, the cause and characteristics of each of the two types of addiction is quite different, as is the type of treatment preferred. Psychological dependence does not have to be limited only to substances; even activities and behavioral patterns can be considered addictions, if they become uncontrollable, e.g. gambling, Internet addiction, computer addiction, sexual addiction/pornography addiction, eating, self-harm, vandalism or work addiction. # Addiction and drug control legislation Most countries have legislation which brings various drugs and drug-like substances under the control of licensing systems. Typically this legislation covers any or all of the opiates, amphetamines, cannabinoids, cocaine, barbiturates, hallucinogens (tryptamines, LSD, phencyclidine(PCP), psilocybin) and a variety of more modern synthetic drugs, and unlicensed production, supply or possession may be a criminal offense. Usually, however, drug classification under such legislation is not related simply to addictiveness. The substances covered often have very different addictive properties. Some are highly prone to cause physical dependency, whilst others rarely cause any form of compulsive need whatsoever. Typically nicotine (in the form of tobacco) is regulated extremely loosely, if at all, although it is well-known as one of the most addictive substances ever discovered. Also, although the legislation may be justifiable on moral grounds to some, it can make addiction or dependency a much more serious issue for the individual. Reliable supplies of a drug become difficult to secure as illegally produced substances may have contaminants. Withdrawal from the substances or associated contaminants can cause additional health issues and the individual becomes vulnerable to both criminal abuse and legal punishment. Criminal elements that can be involved in the profitable trade of such substances can also cause physical harm to users. # Methods of care Early editions of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM) described addiction as a physical dependency to a substance that resulted in withdrawal symptoms in its absence. Recent editions, including DSM-IV, have moved toward a diagnostic instrument that classifies such conditions as dependency, rather than addiction. The American Society of Addiction Medicine recommends treatment for people with chemical dependency based on patient placement criteria (currently listed in PPC-2), which attempt to match levels of care according to clinical assessments in six areas, including: - Acute intoxication and/or withdrawal potential - Biomedical conditions or complications - Emotional/behavioral conditions or complications - Treatment acceptance/resistance - Relapse potential - Recovery environment Some medical systems, including those of at least 15 states of the United States, refer to an Addiction Severity Index to assess the severity of problems related to substance use. The index assesses problems in six areas: medical, employment/support, alcohol and other drug use, legal, family/social, and psychiatric. While addiction or dependency is related to seemingly uncontrollable urges, and arguably could have roots in genetic predispositions, treatment of dependency is conducted by a wide range of medical and allied professionals, including Addiction Medicine specialists, psychiatrists, and appropriately trained nurses, social workers, and counselors. Early treatment of acute withdrawal often includes medical detoxification, which can include doses of anxiolytics or narcotics to reduce symptoms of withdrawal. An experimental drug, ibogaine, is also proposed to treat withdrawal and craving. Alternatives to medical detoxification include acupuncture detoxification. In chronic opiate addiction, a surrogate drug such as methadone is sometimes offered as a form of opiate replacement therapy. But treatment approaches universal focus on the individual's ultimate choice to pursue an alternate course of action. Therapists often classify patients with chemical dependencies as either interested or not interested in changing. Treatments usually involve planning for specific ways to avoid the addictive stimulus, and therapeutic interventions intended to help a client learn healthier ways to find satisfaction. Clinical leaders in recent years have attempted to tailor intervention approaches to specific influences that affect addictive behavior, using therapeutic interviews in an effort to discover factors that led a person to embrace unhealthy, addictive sources of pleasure or relief from pain. From the applied behavior analysis literature and the behavioral psychology literature several evidenced based intervention programs have emerged (1) behavioral maritial therapy (2) community reinforcement approach (3) cue exposure therapy and (4) contingency management stategies (see O'Donohue, W., Ferguson, K.E. (2006) Evidence-Based Practice in Psychology and Behavior Analysis. The Behavior Analyst Today. vol 7(3). pp.335-350 http://www.behavior-analyst-today.com/VOL-7/BAT-7-3.PDF and Chambless, D. L. et al. (1996). An update on empirically validated therapies. Clinical Psychology, 49, 5-14 ). In addition, the same author suggest that Social skills training adjunctive to inpatient treatment of alcohol dependence is probably efficacious. # Diverse explanations Several explanations (or "models") have been presented to explain addiction. These divide, more or less, into the models which stress biological or genetic causes for addiction, and those which stress social or purely psychological causes. Of course there are also many models which attempt to see addiction as both a physiological and a psycho-social phenomenon. - The disease model of addiction holds that addiction is a disease, coming about as a result of either the impairment of neurochemical or behavioral processes, or of some combination of the two. Within this model, addictive disease is treated by specialists in Addiction Medicine. Within the field of medicine, the American Medical Association, National Association of Social Workers, and American Psychological Association all have policies which are predicated on the theory that addictive processes represent a disease state. Most treatment approaches, as well, are based on the idea that dependencies are behavioral dysfunctions, and, therefore, contain, at least to some extent, elements of physical or mental disease. Organizations such as the American Society of Addiction Medicine believe the research-based evidence for addiction's status as a disease is overwhelming. - The genetic model posits a genetic predisposition to certain behaviors. It is frequently noted that certain addictions "run in the family," and while researchers continue to explore the extent of genetic influence, many researchers argue that there is strong evidence that genetic predisposition is often a factor in dependency. - The experiential model devised by Stanton Peele argues that addictions occur with regard to experiences generated by various involvements, whether drug-induced or not. This model is in opposition to the disease, genetic, and neurobiological approaches. Among other things, it proposes that addiction is both more temporary or situational than the disease model claims, and is often outgrown through natural processes. - The opponent-process model generated by Richard Soloman states that for every psychological event A will be followed by its opposite psychological event B. For example, the pleasure one experiences from heroin is followed by an opponent process of withdrawal, or the terror of jumping out of an airplane is rewarded with intense pleasure when the parachute opens. This model is related to the opponent process color theory. If you look at the color red then quickly look at a gray area you will see green. There are many examples of opponent processes in the nervous system including taste, motor movement, touch, vision, and hearing. Opponent-processes occurring at the sensory level may translate "down-stream" into addictive or habit-forming behavior. - The allostatic(stability through change) model generated by George Koob and Michel LeMoal is a modification of the opponent process theory where continued use of a drug leads to a spiralling of uncontrolled use, negative emotional states and withdrawal and a shift into use to new allostatic set point which is lower than that maintained before use of the drug (Koob and LeMoal, 2001; Koob and LeMoal, 2006). - The cultural model recognizes that the influence of culture is a strong determinant of whether or not individuals fall prey to certain addictions. For example, alcoholism is rare among Saudi Arabians, where obtaining alcohol is difficult and using alcohol is prohibited. In North America, on the other hand, the incidence of gambling addictions soared in the last two decades of the 20th century, mirroring the growth of the gaming industry. Half of all patients diagnosed as alcoholic are born into families where alcohol is used heavily, suggesting that familiar influence, genetic factors, or more likely both, play a role in the development of addiction. What also needs to be noted is that when people don't gain a sense of moderation through their development they can be just as likely, if not more, to abuse substances than people born into alcoholic families. - The moral model states that addictions are the result of human weakness, and are defects of character. Those who advance this model do not accept that there is any biological basis for addiction. They often have scant sympathy for people with serious addictions, believing either that a person with greater moral strength could have the force of will to break an addiction, or that the addict demonstrated a great moral failure in the first place by starting the addiction. The moral model is widely applied to dependency on illegal substances, perhaps purely for social or political reasons, but is no longer widely considered to have any therapeutic value. Elements of the moral model, especially a focus on individual choices, have found enduring roles in other approaches to the treatment of dependencies. - The habit model proposed by Thomas Szasz questions the very concept of "addiction." He argues that addiction is a metaphor, and that the only reason to make the distinction between habit and addiction "is to persecute somebody." (Szasz, 1973). Cf also the life-process model of addiction. - Finally, the blended model attempts to consider elements of all other models in developing a therapeutic approach to dependency. It holds that the mechanism of dependency is different for different individuals, and that each case must be considered on its own merits. # Neurobiological basis The development of addiction is thought to involve a simultaneous process of 1) increased focus on and engagement in a particular behavior and 2) the attenuation or "shutting down" of other behaviors. For example, under certain experimental circumstances such as social deprivation and boredom, animals allowed the unlimited ability to self-administer certain psychoactive drugs will show such a strong preference that they will forgo food, sleep, and sex for continued access. The neuro-anatomical correlate of this is that the brain regions involved in driving goal-directed behavior grow increasingly selective for particular motivating stimuli and rewards, to the point that the brain regions involved in the inhibition of behavior can no longer effectively send "stop" signals. A good analogy is to imagine flooring the gas pedal in a car with very bad brakes. In this case, the limbic system is thought to be the major "driving force" and the orbitofrontal cortex is the substrate of the top-down inhibition. A specific portion of the limbic circuit known as the mesolimbic dopaminergic system is hypothesized to play an important role in translation of motivation to motor behavior- and reward-related learning in particular. It is typically defined as the ventral tegmental area (VTA), the nucleus accumbens, and the bundle of dopamine-containing fibers that are connecting them. This system is commonly implicated in the seeking out and consumption of rewarding stimuli or events, such as sweet-tasting foods or sexual interaction. However, its importance to addiction research goes beyond its role in "natural" motivation: while the specific site or mechanism of action may differ, all known drugs of abuse have the common effect in that they elevate the level of dopamine in the nucleus accumbens. This may happen directly, such as through blockade of the dopamine re-uptake mechanism (see cocaine). It may also happen indirectly, such as through stimulation of the dopamine-containing neurons of the VTA that synapse onto neurons in the accumbens (see opiates). The euphoric effects of drugs of abuse are thought to be a direct result of the acute increase in accumbal dopamine. The human body has a natural tendency to maintain homeostasis, and the central nervous system is no exception. Chronic elevation of dopamine will result in a decrease in the number of dopamine receptors available in a process known as downregulation. The decreased number of receptors changes the permeability of the cell membrane located post-synaptically, such that the post-synaptic neuron is less excitable- i.e.: less able to respond to chemical signaling with an electrical impulse, or action potential. It is hypothesized that this dulling of the responsiveness of the brain's reward pathways contributes to the inability to feel pleasure, known as anhedonia, often observed in addicts. The increased requirement for dopamine to maintain the same electrical activity is the basis of both physiological tolerance and withdrawal associated with addiction. Downregulation can be classically conditioned. If a behavior consistently occurs in the same environment or contingently with a particular cue, the brain will adjust to the presence of the conditioned cues by decreasing the number of available receptors in the absence of the behavior. It is thought that many drug overdoses are not the result of a user taking a higher dose than is typical, but rather that the user is administering the same dose in a new environment. In cases of physical dependency on depressants of the central nervous system such as opioids, barbiturates, or alcohol, the absence of the substance can lead to symptoms of severe physical discomfort. Withdrawal from alcohol or sedatives such as barbiturates or benzodiazepines (valium-family) can result in seizures and even death. By contrast, withdrawal from opioids, which can be extremely uncomfortable, is rarely if ever life-threatening. In cases of dependence and withdrawal, the body has become so dependent on high concentrations of the particular chemical that it has stopped producing its own natural versions (endogenous ligands) and instead produces opposing chemicals. When the addictive substance is withdrawn, the effects of the opposing chemicals can become overwhelming. For example, chronic use of sedatives (alcohol, barbiturates, or benzodiazepines) results in higher chronic levels of stimulating neurotransmitters such as glutamate. Very high levels of glutamate kill nerve cells, a phenomenon called excitatory neurotoxicity. # Criticism Levi Bryant has criticized the term and concept of addiction as counterproductive in psychotherapy as it defines a patient's identity and makes it harder to become a non-addict. "The signifier 'addict' doesn't simply describe what I am, but initiates a way of relating to myself that informs how I relate to others." A stronger form of criticism comes from Thomas Szasz, who denies that addiction is a psychiatric problem. In many of his works, he argues that addiction is a choice, and that a drug addict is one who simply prefers a socially taboo substance rather than, say, a low risk lifestyle. In Our Right to Drugs, Szasz cites the biography of Malcolm X to corroborate his economic views towards addiction: Malcolm claimed that quitting cigarettes was harder than shaking his heroin addiction. Szasz postulates that humans always have a choice, and it is foolish to call someone an 'addict' just because they prefer a drug induced euphoria to a more popular and socially welcome lifestyle.Therefore, being 'addicted' to a substance is no different from being 'addicted' to a job at which you work everyday. Szasz and Bryant are not alone in questioning the standard view of addiction. Professor John Booth Davies at the University of Strathclyde has argued in his book The Myth of Addiction that 'people take drugs because they want to and because it makes sense for them to do so given the choices available' as opposed to the view that 'they are compelled to by the pharmacology of the drugs they take'. [12]. He uses an adaption of attribution theory (what he calls the theory of functional attributions) to argue that the statement 'I am addicted to drugs' is functional, rather than veridical. Stanton Peele has put forward similar views. Experimentally, Bruce K. Alexander used the classic experiment of Rat Park to show that 'addicted' behaviour in rats only occurred when the rats had no other options. When other options and behavioural opportunities were put in place, the rats soon showed far more complex behaviours. # Casual addiction The word addiction is also sometimes used colloquially to refer to something for which a person has a passion, such as books, chocolate, work, the web, running, or eating.	https://www.wikidoc.org/index.php/Addiction
1b11c3fd1f2ee6f3f4f8df19f362e47b1a4b5a37	wikidoc	Addressin	Addressin Addressin also known as mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) is a protein that in humans is encoded by the MADCAM1 gene. Addressin is an extracellular protein of the endothelium of venules. Addressins are the ligands to the homing receptors of lymphocytes. The task of these ligands and their receptors is to determine which tissue the lymphocyte will enter next. They carry carbohydrates in order to be recognized by L-selectin. # Function The protein encoded by this gene is an endothelial cell adhesion molecule that interacts preferentially with the leukocyte beta7 integrin LPAM-1 (alpha4 / beta7), L-selectin, and VLA-4 (alpha4 / beta1) on myeloid cells to direct leukocytes into mucosal and inflamed tissues. It is a member of the immunoglobulin superfamily and is similar to ICAM-1 and VCAM-1. In terms of migration, MADCAM is selectively expressed on mucosal endothelial cells, driving memory T-cell re-circulation through mucosal tissues. In contrast, and indeed the main difference between the two molecules, ICAM molecules are involved with naive T-cell re-circulation. Whereas MADCAM is selectively expressed, ICAM is broadly expressed on inflamed endothelium.	Addressin Addressin also known as mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) is a protein that in humans is encoded by the MADCAM1 gene.[1][2][3] Addressin is an extracellular protein of the endothelium of venules. Addressins are the ligands to the homing receptors of lymphocytes.[4] The task of these ligands and their receptors is to determine which tissue the lymphocyte will enter next. They carry carbohydrates in order to be recognized by L-selectin. # Function The protein encoded by this gene is an endothelial cell adhesion molecule that interacts preferentially with the leukocyte beta7 integrin LPAM-1 (alpha4 / beta7), L-selectin, and VLA-4 (alpha4 / beta1) on myeloid cells to direct leukocytes into mucosal and inflamed tissues. It is a member of the immunoglobulin superfamily and is similar to ICAM-1 and VCAM-1.[1] In terms of migration, MADCAM is selectively expressed on mucosal endothelial cells, driving memory T-cell re-circulation through mucosal tissues. In contrast, and indeed the main difference between the two molecules, ICAM molecules are involved with naive T-cell re-circulation. Whereas MADCAM is selectively expressed, ICAM is broadly expressed on inflamed endothelium.	https://www.wikidoc.org/index.php/Addressin
ca0e5f549d5e9cc8001e1ba361bd55c270238a34	wikidoc	Adenosine	Adenosine # 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 Adenosine is an adenosine receptor agonist and antiarrhythmic that is FDA approved for the {{{indicationType}}} of paroxysmal supraventricular tachycardia (PSVT), including that associated with accessory bypass tracts (Wolff-Parkinson-White syndrome).. Common adverse reactions include chest discomfort, flushing, abdominal discomfort, pain of head and neck region, dizziness, headache, and dyspnea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Adenocard (adenosine injection) should be given as a rapid bolus by the peripheral intravenous route. To be certain the solution reaches the systemic circulation, it should be administered either directly into a vein or, if given into an IV line, it should be given as close to the patient as possible and followed by a rapid saline flush. - The dose recommendation is based on clinical studies with peripheral venous bolus dosing. Central venous (CVP or other) administration of Adenocard has not been systematically studied. - Dosing Information - Initial dose: 6 mg given as a rapid intravenous bolus (administered over a 1-2 second period). - Repeat administration: If the first dose does not result in elimination of the supraventricular tachycardia within 1-2 minutes, 12 mg should be given as a rapid intravenous bolus. This 12 mg dose may be repeated a second time if required. - Dosing Information - Give 0.05 to 0.1 mg/kg as a rapid IV bolus given either centrally or peripherally. A saline flush should follow. - Repeat administration: If conversion of PSVT does not occur within 1-2 minutes, additional bolus injections of adenosine can be administered at incrementally higher doses, increasing the amount given by 0.05 to 0.1 mg/kg. Follow each bolus with a saline flush. This process should continue until sinus rhythm is established or a maximum single dose of 0.3 mg/kg is used. - Administer the adult dose. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Developed by: ACCF/AHA - Class of Recommendation: Class I - Strength of Evidence: Category B - Dosing Information - 6 mg, followed by 12 mg as needed ### Non–Guideline-Supported Use - Dosing Information - Intraoperative administration of blood cardioplegia containing containing 0.5–2 mM adenosine. Patients receiving adenosine cardioplegia were also given an infusion of adenosine (200 microg/kg/min) 10 minutes before and 15 minutes after removal of the aortic crossclamp. - Dosing Information - 20 mg in 50 milliliters (mL) saline infused at a rate of 2 mg/minute # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Adenosine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - Developed by: ACCF/AHA - Class of Recommendation: Class IIa - Strength of Evidence: Category B - Dosing Information - 0.05–0.3 mg/kg ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Adenosine in pediatric patients. # Contraindications - Second- or third-degree A-V block (except in patients with a functioning artificial pacemaker) - Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with a functioning artificial pacemaker) - Hypersensitivity to adenosine # Warnings - Heart Block - Adenocard (adenosine injection) exerts its effect by decreasing conduction through the A-V node and may produce a short lasting first-, second- or third-degree heart block. Appropriate therapy should be instituted as needed. Patients who develop high-level block on one dose of Adenocard should not be given additional doses. Because of the very short half-life of adenosine, these effects are generally self-limiting. Appropriate resuscitative measures should be available. - Transient or prolonged episodes of asystole have been reported with fatal outcomes in some cases. Rarely, ventricular fibrillation has been reported following Adenocard administration, including both resuscitated and fatal events. In most instances, these cases were associated with the concomitant use of digoxin and, less frequently with digoxin and verapamil. Although no causal relationship or drug-drug interaction has been established, Adenocard should be used with caution in patients receiving digoxin or digoxin and verapamil in combination. - Arrhythmias at Time of Conversion - At the time of conversion to normal sinus rhythm, a variety of new rhythms may appear on the electrocardiogram. They generally last only a few seconds without intervention, and may take the form of premature ventricular contractions, atrial premature contractions, atrial fibrillation, sinus bradycardia, sinus tachycardia, skipped beats, and varying degrees of A-V nodal block. Such findings were seen in 55% of patients. - Bronchoconstriction - Adenocard (adenosine injection) is a respiratory stimulant (probably through activation of carotid body chemoreceptors) and intravenous administration in man has been shown to increase minute ventilation (Ve) and reduce arterial PCO2 causing respiratory alkalosis. - Adenosine administered by inhalation has been reported to cause bronchoconstriction in asthmatic patients, presumably due to mast cell degranulation and histamine release. These effects have not been observed in normal subjects. Adenocard has been administered to a limited number of patients with asthma and mild to moderate exacerbation of their symptoms has been reported. Respiratory compromise has occurred during adenosine infusion in patients with obstructive pulmonary disease. Adenocard should be used with caution in patients with obstructive lung disease not associated with bronchoconstriction (e.g., emphysema, bronchitis, etc.) and should be avoided in patients with bronchoconstriction or bronchospasm (e.g., asthma). Adenocard should be discontinued in any patient who develops severe respiratory difficulties. # Adverse Reactions ## Clinical Trials Experience Facial flushing (18%), headache (2%), sweating, palpitations, chest pain, hypotension (less than 1%). Nausea (3%), metallic taste, tightness in throat, pressure in groin (less than 1%). Lightheadedness (2%), dizziness, tingling in arms, numbness (1%), apprehension, blurred vision, burning sensation, heaviness in arms, neck and back pain (less than 1%). Shortness of breath/dyspnea (12%), chest pressure (7%), hyperventilation, head pressure (less than 1%). ## Postmarketing Experience Prolonged asystole, ventricular tachycardia, ventricular fibrillation, transient increase in blood pressure, bradycardia, atrial fibrillation, and Torsade de Pointes Seizure activity, including tonic clonic (grand mal) seizures, and loss of consciousness. Bronchospasm # Drug Interactions - Intravenous Adenocard (adenosine injection) has been effectively administered in the presence of other cardioactive drugs, such as quinidine, beta-adrenergic blocking agents, calcium channel blocking agents, and angiotensin converting enzyme inhibitors, without any change in the adverse reaction profile. Digoxin and verapamil use may be rarely associated with ventricular fibrillation when combined with Adenocard (see Warnings). Because of the potential for additive or synergistic depressant effects on the SA and AV nodes, however, Adenocard should be used with caution in the presence of these agents. The use of Adenocard in patients receiving digitalis may be rarely associated with ventricular fibrillation. - The effects of adenosine are antagonized by methylxanthines such as caffeine and theophylline. In the presence of these methylxanthines, larger doses of adenosine may be required or adenosine may not be effective. Adenosine effects are potentiated by dipyridamole. Thus, smaller doses of adenosine may be effective in the presence of dipyridamole. Carbamazepine has been reported to increase the degree of heart block produced by other agents. As the primary effect of adenosine is to decrease conduction through the A-V node, higher degrees of heart block may be produced in the presence of carbamazepine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Animal reproduction studies have not been conducted with adenosine; nor have studies been performed in pregnant women. As adenosine is a naturally occurring material, widely dispersed throughout the body, no fetal effects would be anticipated. However, since it is not known whether Adenocard can cause fetal harm when administered to pregnant women, Adenocard should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Adenosine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Adenosine during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Adenosine with respect to nursing mothers. ### Pediatric Use - No controlled studies have been conducted in pediatric patients to establish the safety and efficacy of Adenocard for the conversion of paroxysmal supraventricular tachycardia (PSVT). However, intravenous adenosine has been used for the treatment of PSVT in neonates, infants, children and adolescents. ### Geriatic Use - Clinical studies of Adenocard did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, Adenocard in geriatric patients should be used with caution since this population may have a diminished cardiac function, nodal dysfunction, concomitant diseases or drug therapy that may alter hemodynamic function and produce severe bradycardia or AV block. ### Gender There is no FDA guidance on the use of Adenosine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Adenosine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Adenosine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Adenosine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Adenosine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Adenosine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Adenosine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Adenosine in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - The half-life of Adenocard (adenosine injection) is less than 10 seconds. Thus, adverse effects are generally rapidly self-limiting. ### Management - Treatment of any prolonged adverse effects should be individualized and be directed toward the specific effect. Methylxanthines, such as caffeine and theophylline, are competitive antagonists of adenosine. ## Chronic Overdose There is limited information regarding Chronic Overdose of Adenosine in the drug label. # Pharmacology ## Mechanism of Action - Adenocard (adenosine injection) slows conduction time through the AV node, can interrupt the reentry pathways through the AV node, and can restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardia (PSVT), including PSVT associated with Wolff-Parkinson-White syndrome. - Adenocard is antagonized competitively by methylxanthines such as caffeine and theophylline, and potentiated by blockers of nucleoside transport such as dipyridamole. Adenocard is not blocked by atropine. ## Structure - Adenosine is an endogenous nucleoside occurring in all cells of the body. It is chemically 6-amino-9-β-D-ribofuranosyl-9-H-purine and has the following structural formula: - Adenosine is a white crystalline powder. It is soluble in water and practically insoluble in alcohol. Solubility increases by warming and lowering the pH. Adenosine is not chemically related to other antiarrhythmic drugs. Adenocard® (adenosine injection) is a sterile, nonpyrogenic solution for rapid bolus intravenous injection. Each mL contains 3 mg adenosine and 9 mg sodium chloride in Water for Injection. The pH of the solution is between 4.5 and 7.5. - The Ansyr® plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. - Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material. ## Pharmacodynamics - The intravenous bolus dose of 6 or 12 mg Adenocard (adenosine injection) usually has no systemic hemodynamic effects. When larger doses are given by infusion, adenosine decreases blood pressure by decreasing peripheral resistance. ## Pharmacokinetics - Intravenously administered adenosine is rapidly cleared from the circulation via cellular uptake, primarily by erythrocytes and vascular endothelial cells. This process involves a specific transmembrane nucleoside carrier system that is reversible, nonconcentrative, and bidirectionally symmetrical. Intracellular adenosine is rapidly metabolized either via phosphorylation to adenosine monophosphate by adenosine kinase, or via deamination to inosine by adenosine deaminase in the cytosol. Since adenosine kinase has a lower Km and Vmax than adenosine deaminase, deamination plays a significant role only when cytosolic adenosine saturates the phosphorylation pathway. Inosine formed by deamination of adenosine can leave the cell intact or can be degraded to hypoxanthine, xanthine, and ultimately uric acid. Adenosine monophosphate formed by phosphorylation of adenosine is incorporated into the high-energy phosphate pool. While extracellular adenosine is primarily cleared by cellular uptake with a half-life of less than 10 seconds in whole blood, excessive amounts may be deaminated by an ecto-form of adenosine deaminase. As Adenocard requires no hepatic or renal function for its activation or inactivation, hepatic and renal failure would not be expected to alter its effectiveness or tolerability. ## Nonclinical Toxicology - Carcinogenesis, Mutagenesis, Impairment of Fertility - Studies in animals have not been performed to evaluate the carcinogenic potential of Adenocard (adenosine injection). Adenosine was negative for genotoxic potential in the Salmonella (Ames Test) and Mammalian Microsome Assay. - Adenosine, however, like other nucleosides at millimolar concentrations present for several doubling times of cells in culture, is known to produce a variety of chromosomal alterations. Fertility studies in animals have not been conducted with adenosine. # Clinical Studies - In controlled studies in the United States, bolus doses of 3, 6, 9, and 12 mg were studied. A cumulative 60% of patients with paroxysmal supraventricular tachycardia had converted to normal sinus rhythm within one minute after an intravenous bolus dose of 6 mg Adenocard (some converted on 3 mg and failures were given 6 mg), and a cumulative 92% converted after a bolus dose of 12 mg. Seven to sixteen percent of patients converted after 1-4 placebo bolus injections. Similar responses were seen in a variety of patient subsets, including those using or not using digoxin, those with Wolff-Parkinson-White syndrome, males, females, blacks, Caucasians, and Hispanics. - Adenosine is not effective in converting rhythms other than PSVT, such as atrial flutter, atrial fibrillation, or ventricular tachycardia, to normal sinus rhythm. # How Supplied - Adenocard® (adenosine injection) is supplied as a sterile non-pyrogenic solution in normal saline. - Store at controlled room temperature 15º-30ºC (59º-86ºF). - DO NOT REFRIGERATE as crystallization may occur. If crystallization has occurred, dissolve crystals by warming to room temperature. The solution must be clear at the time of use. - Contains no preservatives. Discard unused portion. - May require needle or blunt. To prevent needle-stick injuries, needles should not be recapped, purposely bent or broken by hand. ## Storage There is limited information regarding Adenosine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Adenosine in the drug label. # Precautions with Alcohol - Alcohol-Adenosine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Adenocard® # Look-Alike Drug Names - N/A # Drug Shortage Status # Price	Adenosine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi # 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 Adenosine is an adenosine receptor agonist and antiarrhythmic that is FDA approved for the {{{indicationType}}} of paroxysmal supraventricular tachycardia (PSVT), including that associated with accessory bypass tracts (Wolff-Parkinson-White syndrome).. Common adverse reactions include chest discomfort, flushing, abdominal discomfort, pain of head and neck region, dizziness, headache, and dyspnea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Adenocard (adenosine injection) should be given as a rapid bolus by the peripheral intravenous route. To be certain the solution reaches the systemic circulation, it should be administered either directly into a vein or, if given into an IV line, it should be given as close to the patient as possible and followed by a rapid saline flush. - The dose recommendation is based on clinical studies with peripheral venous bolus dosing. Central venous (CVP or other) administration of Adenocard has not been systematically studied. - Dosing Information - Initial dose: 6 mg given as a rapid intravenous bolus (administered over a 1-2 second period). - Repeat administration: If the first dose does not result in elimination of the supraventricular tachycardia within 1-2 minutes, 12 mg should be given as a rapid intravenous bolus. This 12 mg dose may be repeated a second time if required. - Dosing Information - Give 0.05 to 0.1 mg/kg as a rapid IV bolus given either centrally or peripherally. A saline flush should follow. - Repeat administration: If conversion of PSVT does not occur within 1-2 minutes, additional bolus injections of adenosine can be administered at incrementally higher doses, increasing the amount given by 0.05 to 0.1 mg/kg. Follow each bolus with a saline flush. This process should continue until sinus rhythm is established or a maximum single dose of 0.3 mg/kg is used. - Administer the adult dose. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Developed by: ACCF/AHA - Class of Recommendation: Class I - Strength of Evidence: Category B - Dosing Information - 6 mg, followed by 12 mg as needed[1] ### Non–Guideline-Supported Use - Dosing Information - Intraoperative administration of blood cardioplegia containing containing 0.5–2 mM adenosine. Patients receiving adenosine cardioplegia were also given an infusion of adenosine (200 microg/kg/min) 10 minutes before and 15 minutes after removal of the aortic crossclamp.[2][3][4] - Dosing Information - 20 mg in 50 milliliters (mL) saline infused at a rate of 2 mg/minute[5] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Adenosine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - Developed by: ACCF/AHA - Class of Recommendation: Class IIa - Strength of Evidence: Category B - Dosing Information - 0.05–0.3 mg/kg[6][7][8][9] ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Adenosine in pediatric patients. # Contraindications - Second- or third-degree A-V block (except in patients with a functioning artificial pacemaker) - Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with a functioning artificial pacemaker) - Hypersensitivity to adenosine # Warnings - Heart Block - Adenocard (adenosine injection) exerts its effect by decreasing conduction through the A-V node and may produce a short lasting first-, second- or third-degree heart block. Appropriate therapy should be instituted as needed. Patients who develop high-level block on one dose of Adenocard should not be given additional doses. Because of the very short half-life of adenosine, these effects are generally self-limiting. Appropriate resuscitative measures should be available. - Transient or prolonged episodes of asystole have been reported with fatal outcomes in some cases. Rarely, ventricular fibrillation has been reported following Adenocard administration, including both resuscitated and fatal events. In most instances, these cases were associated with the concomitant use of digoxin and, less frequently with digoxin and verapamil. Although no causal relationship or drug-drug interaction has been established, Adenocard should be used with caution in patients receiving digoxin or digoxin and verapamil in combination. - Arrhythmias at Time of Conversion - At the time of conversion to normal sinus rhythm, a variety of new rhythms may appear on the electrocardiogram. They generally last only a few seconds without intervention, and may take the form of premature ventricular contractions, atrial premature contractions, atrial fibrillation, sinus bradycardia, sinus tachycardia, skipped beats, and varying degrees of A-V nodal block. Such findings were seen in 55% of patients. - Bronchoconstriction - Adenocard (adenosine injection) is a respiratory stimulant (probably through activation of carotid body chemoreceptors) and intravenous administration in man has been shown to increase minute ventilation (Ve) and reduce arterial PCO2 causing respiratory alkalosis. - Adenosine administered by inhalation has been reported to cause bronchoconstriction in asthmatic patients, presumably due to mast cell degranulation and histamine release. These effects have not been observed in normal subjects. Adenocard has been administered to a limited number of patients with asthma and mild to moderate exacerbation of their symptoms has been reported. Respiratory compromise has occurred during adenosine infusion in patients with obstructive pulmonary disease. Adenocard should be used with caution in patients with obstructive lung disease not associated with bronchoconstriction (e.g., emphysema, bronchitis, etc.) and should be avoided in patients with bronchoconstriction or bronchospasm (e.g., asthma). Adenocard should be discontinued in any patient who develops severe respiratory difficulties. # Adverse Reactions ## Clinical Trials Experience Facial flushing (18%), headache (2%), sweating, palpitations, chest pain, hypotension (less than 1%). Nausea (3%), metallic taste, tightness in throat, pressure in groin (less than 1%). Lightheadedness (2%), dizziness, tingling in arms, numbness (1%), apprehension, blurred vision, burning sensation, heaviness in arms, neck and back pain (less than 1%). Shortness of breath/dyspnea (12%), chest pressure (7%), hyperventilation, head pressure (less than 1%). ## Postmarketing Experience Prolonged asystole, ventricular tachycardia, ventricular fibrillation, transient increase in blood pressure, bradycardia, atrial fibrillation, and Torsade de Pointes Seizure activity, including tonic clonic (grand mal) seizures, and loss of consciousness. Bronchospasm # Drug Interactions - Intravenous Adenocard (adenosine injection) has been effectively administered in the presence of other cardioactive drugs, such as quinidine, beta-adrenergic blocking agents, calcium channel blocking agents, and angiotensin converting enzyme inhibitors, without any change in the adverse reaction profile. Digoxin and verapamil use may be rarely associated with ventricular fibrillation when combined with Adenocard (see Warnings). Because of the potential for additive or synergistic depressant effects on the SA and AV nodes, however, Adenocard should be used with caution in the presence of these agents. The use of Adenocard in patients receiving digitalis may be rarely associated with ventricular fibrillation. - The effects of adenosine are antagonized by methylxanthines such as caffeine and theophylline. In the presence of these methylxanthines, larger doses of adenosine may be required or adenosine may not be effective. Adenosine effects are potentiated by dipyridamole. Thus, smaller doses of adenosine may be effective in the presence of dipyridamole. Carbamazepine has been reported to increase the degree of heart block produced by other agents. As the primary effect of adenosine is to decrease conduction through the A-V node, higher degrees of heart block may be produced in the presence of carbamazepine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Animal reproduction studies have not been conducted with adenosine; nor have studies been performed in pregnant women. As adenosine is a naturally occurring material, widely dispersed throughout the body, no fetal effects would be anticipated. However, since it is not known whether Adenocard can cause fetal harm when administered to pregnant women, Adenocard should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Adenosine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Adenosine during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Adenosine with respect to nursing mothers. ### Pediatric Use - No controlled studies have been conducted in pediatric patients to establish the safety and efficacy of Adenocard for the conversion of paroxysmal supraventricular tachycardia (PSVT). However, intravenous adenosine has been used for the treatment of PSVT in neonates, infants, children and adolescents. ### Geriatic Use - Clinical studies of Adenocard did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, Adenocard in geriatric patients should be used with caution since this population may have a diminished cardiac function, nodal dysfunction, concomitant diseases or drug therapy that may alter hemodynamic function and produce severe bradycardia or AV block. ### Gender There is no FDA guidance on the use of Adenosine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Adenosine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Adenosine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Adenosine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Adenosine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Adenosine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Adenosine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Adenosine in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - The half-life of Adenocard (adenosine injection) is less than 10 seconds. Thus, adverse effects are generally rapidly self-limiting. ### Management - Treatment of any prolonged adverse effects should be individualized and be directed toward the specific effect. Methylxanthines, such as caffeine and theophylline, are competitive antagonists of adenosine. ## Chronic Overdose There is limited information regarding Chronic Overdose of Adenosine in the drug label. # Pharmacology ## Mechanism of Action - Adenocard (adenosine injection) slows conduction time through the AV node, can interrupt the reentry pathways through the AV node, and can restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardia (PSVT), including PSVT associated with Wolff-Parkinson-White syndrome. - Adenocard is antagonized competitively by methylxanthines such as caffeine and theophylline, and potentiated by blockers of nucleoside transport such as dipyridamole. Adenocard is not blocked by atropine. ## Structure - Adenosine is an endogenous nucleoside occurring in all cells of the body. It is chemically 6-amino-9-β-D-ribofuranosyl-9-H-purine and has the following structural formula: - Adenosine is a white crystalline powder. It is soluble in water and practically insoluble in alcohol. Solubility increases by warming and lowering the pH. Adenosine is not chemically related to other antiarrhythmic drugs. Adenocard® (adenosine injection) is a sterile, nonpyrogenic solution for rapid bolus intravenous injection. Each mL contains 3 mg adenosine and 9 mg sodium chloride in Water for Injection. The pH of the solution is between 4.5 and 7.5. - The Ansyr® plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. - Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material. ## Pharmacodynamics - The intravenous bolus dose of 6 or 12 mg Adenocard (adenosine injection) usually has no systemic hemodynamic effects. When larger doses are given by infusion, adenosine decreases blood pressure by decreasing peripheral resistance. ## Pharmacokinetics - Intravenously administered adenosine is rapidly cleared from the circulation via cellular uptake, primarily by erythrocytes and vascular endothelial cells. This process involves a specific transmembrane nucleoside carrier system that is reversible, nonconcentrative, and bidirectionally symmetrical. Intracellular adenosine is rapidly metabolized either via phosphorylation to adenosine monophosphate by adenosine kinase, or via deamination to inosine by adenosine deaminase in the cytosol. Since adenosine kinase has a lower Km and Vmax than adenosine deaminase, deamination plays a significant role only when cytosolic adenosine saturates the phosphorylation pathway. Inosine formed by deamination of adenosine can leave the cell intact or can be degraded to hypoxanthine, xanthine, and ultimately uric acid. Adenosine monophosphate formed by phosphorylation of adenosine is incorporated into the high-energy phosphate pool. While extracellular adenosine is primarily cleared by cellular uptake with a half-life of less than 10 seconds in whole blood, excessive amounts may be deaminated by an ecto-form of adenosine deaminase. As Adenocard requires no hepatic or renal function for its activation or inactivation, hepatic and renal failure would not be expected to alter its effectiveness or tolerability. ## Nonclinical Toxicology - Carcinogenesis, Mutagenesis, Impairment of Fertility - Studies in animals have not been performed to evaluate the carcinogenic potential of Adenocard (adenosine injection). Adenosine was negative for genotoxic potential in the Salmonella (Ames Test) and Mammalian Microsome Assay. - Adenosine, however, like other nucleosides at millimolar concentrations present for several doubling times of cells in culture, is known to produce a variety of chromosomal alterations. Fertility studies in animals have not been conducted with adenosine. # Clinical Studies - In controlled studies in the United States, bolus doses of 3, 6, 9, and 12 mg were studied. A cumulative 60% of patients with paroxysmal supraventricular tachycardia had converted to normal sinus rhythm within one minute after an intravenous bolus dose of 6 mg Adenocard (some converted on 3 mg and failures were given 6 mg), and a cumulative 92% converted after a bolus dose of 12 mg. Seven to sixteen percent of patients converted after 1-4 placebo bolus injections. Similar responses were seen in a variety of patient subsets, including those using or not using digoxin, those with Wolff-Parkinson-White syndrome, males, females, blacks, Caucasians, and Hispanics. - Adenosine is not effective in converting rhythms other than PSVT, such as atrial flutter, atrial fibrillation, or ventricular tachycardia, to normal sinus rhythm. # How Supplied - Adenocard® (adenosine injection) is supplied as a sterile non-pyrogenic solution in normal saline. - Store at controlled room temperature 15º-30ºC (59º-86ºF). - DO NOT REFRIGERATE as crystallization may occur. If crystallization has occurred, dissolve crystals by warming to room temperature. The solution must be clear at the time of use. - Contains no preservatives. Discard unused portion. - May require needle or blunt. To prevent needle-stick injuries, needles should not be recapped, purposely bent or broken by hand. ## Storage There is limited information regarding Adenosine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Adenosine in the drug label. # Precautions with Alcohol - Alcohol-Adenosine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Adenocard®[10] # Look-Alike Drug Names - N/A[11] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Adenosine
5c28892f37a6e497b241f67fd7a7221c8315586f	wikidoc	Adipiplon	Adipiplon Adipiplon (NG2-73) is an anxiolytic drug developed by Neurogen Corporation. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic. Adipiplon is a subtype selective GABAA partial agonist, which binds preferentially to the α3 subtype. This is significant as while several previous nonbenzodiazepine drugs have been developed that are selective for α2/3 over the other subtypes, adipiplon is one of the first drugs selected for clinical development which is able to discriminate between α2 and α3, as well as showing little affinity for the α1 or α5 subtypes - alpidem is selective for α3 over α2, but still has moderate affinity to α1, whereas adipiplon is highly α3-selective with little affinity for either α1, α2 or α5. Adipiplon is being researched as a potential medication for the treatment of anxiety and insomnia, and is currently (as of 2008) in Phase IIb trials.	Adipiplon Adipiplon (NG2-73) is an anxiolytic drug developed by Neurogen Corporation. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic. Adipiplon is a subtype selective GABAA partial agonist, which binds preferentially to the α3 subtype. This is significant as while several previous nonbenzodiazepine drugs have been developed that are selective for α2/3 over the other subtypes, adipiplon is one of the first drugs selected for clinical development which is able to discriminate between α2 and α3, as well as showing little affinity for the α1 or α5 subtypes - alpidem is selective for α3 over α2, but still has moderate affinity to α1, whereas adipiplon is highly α3-selective with little affinity for either α1, α2 or α5. Adipiplon is being researched as a potential medication for the treatment of anxiety and insomnia, and is currently (as of 2008) in Phase IIb trials.[1][2][3] Template:Pharmacology-stub	https://www.wikidoc.org/index.php/Adipiplon
c2656e617bd1ff0ef6e2e1ff14dbd971149bacd5	wikidoc	Adipocyte	Adipocyte # Overview Adipocytes are the cells that primarily compose adipose tissue, specialized in storing energy as fat. # Description There are two types of adipose tissue, white adipose tissue (WAT) and brown adipose tissue (BAT), which are also known as white fat and brown fat, respectively, and comprise two types of fat cells: - White fat cells (also known as Unilocular Cells) contain a large lipid droplet surrounded by a ring of cytoplasm. The nucleus is flattened and located on the periphery. The fat stored is in a semi-liquid state, and is composed primarily of triglycerides and cholesterol ester. White fat cells secrete resistin, adiponectin, and leptin. - Brown fat cells (also known as Multilocular Cells) are polygonal in shape. Unlike white fat cells, these cells have considerable cytoplasm, with lipid droplets scattered throughout. The nucleus is round, and, although eccentrically located, it is not in the periphery of the cell. The brown color comes from the large quantity of mitochondria. Brown fat, also known as "baby fat," is used to generate heat. # Lineage Although the lineage of adipocytes is still unclear, Preadipocytes are undifferentiated fibroblasts that can be stimulated to form adipocytes. Mesenchymal stem cells can differentiate into adipocytes, connective tissue, muscle or bone. Areolar connective tissue is composed of adipocytes.	Adipocyte # Overview Adipocytes are the cells that primarily compose adipose tissue, specialized in storing energy as fat. # Description There are two types of adipose tissue, white adipose tissue (WAT) and brown adipose tissue (BAT), which are also known as white fat and brown fat, respectively, and comprise two types of fat cells: - White fat cells (also known as Unilocular Cells) contain a large lipid droplet surrounded by a ring of cytoplasm. The nucleus is flattened and located on the periphery. The fat stored is in a semi-liquid state, and is composed primarily of triglycerides and cholesterol ester. White fat cells secrete resistin, adiponectin, and leptin. - Brown fat cells (also known as Multilocular Cells) are polygonal in shape. Unlike white fat cells, these cells have considerable cytoplasm, with lipid droplets scattered throughout. The nucleus is round, and, although eccentrically located, it is not in the periphery of the cell. The brown color comes from the large quantity of mitochondria. Brown fat, also known as "baby fat," is used to generate heat. # Lineage Although the lineage of adipocytes is still unclear, Preadipocytes are undifferentiated fibroblasts that can be stimulated to form adipocytes. Mesenchymal stem cells can differentiate into adipocytes, connective tissue, muscle or bone. Areolar connective tissue is composed of adipocytes. # External links - Histology image: 08201loa – Histology Learning System at Boston University - "Connective Tissue: unilocular (white) adipocytes " - Histology image: 04901lob – Histology Learning System at Boston University - "Connective Tissue: multilocular (brown) adipocytes" Template:WH Template:WS Template:Jb1 cs:Tuková buňka de:Adipozyt it:Adipocita sk:Tuková bunka sr:Адипоцит fi:Rasvasolu sv:Fettcell	https://www.wikidoc.org/index.php/Adipocyte
6fcba3a1c72e48a5cc92d7490011f83ef955cd03	wikidoc	Adipokine	Adipokine The adipokines or adipocytokines are a group of cytokines (cell-to-cell signalling proteins) secreted by adipose tissue. Members include: - adiponectin - chemerin - interleukin-6 (IL-6) - leptin (Ob ligand) - plasminogen activator inhibitor-1 (PAI-1) - resistin - retinol binding protein 4 (RBP4) - tumor necrosis factor-alpha (TNFα) - visfatin Their relative roles in modifying appetite, insulin resistance and atherosclerosis are the subjects of intense research, as they may be modifyable causes of morbidity in people with obesity. # Notes - ↑ MacDougald1, Ormond A. and Burant, Charles F. (September 2007) "The Rapidly Expanding Family of Adipokines" Cell Metabolism 6: pp. 159-161 - ↑ Monzillo, Lais U. (2003) "Effect of Lifestyle Modification on Adipokine Levels in Obese Subjects with Insulin Resistance" Obesity Research 11(9): pp. 1048-1054 - ↑ Matsuzawa, Yuji; Funahashi, Tohru and Nakamura, Tadashi (1999) "Molecular Mechanism of Metabolic Syndrome X: Contribution of Adipocytokines - Adipocyte-derived Bioactive Substances" Annals of the New York Academy of Sciences 892: pp. 146-54 Abstract - ↑ Funahashi, T. et al. (1999) "Role of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity" Internal Medicine (Japan) 38: pp. 202-206 Abstract	Adipokine Template:Mergeto The adipokines or adipocytokines are a group of cytokines (cell-to-cell signalling proteins) secreted by adipose tissue. Members include: - adiponectin - chemerin[1] - interleukin-6 (IL-6)[2] - leptin (Ob ligand) - plasminogen activator inhibitor-1 (PAI-1) - resistin - retinol binding protein 4 (RBP4) - tumor necrosis factor-alpha (TNFα) - visfatin Their relative roles in modifying appetite, insulin resistance and atherosclerosis are the subjects of intense research, as they may be modifyable causes of morbidity in people with obesity.[3][4] # Notes - ↑ MacDougald1, Ormond A. and Burant, Charles F. (September 2007) "The Rapidly Expanding Family of Adipokines" Cell Metabolism 6: pp. 159-161 - ↑ Monzillo, Lais U. (2003) "Effect of Lifestyle Modification on Adipokine Levels in Obese Subjects with Insulin Resistance" Obesity Research 11(9): pp. 1048-1054 - ↑ Matsuzawa, Yuji; Funahashi, Tohru and Nakamura, Tadashi (1999) "Molecular Mechanism of Metabolic Syndrome X: Contribution of Adipocytokines - Adipocyte-derived Bioactive Substances" Annals of the New York Academy of Sciences 892: pp. 146-54 Abstract - ↑ Funahashi, T. et al. (1999) "Role of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity" Internal Medicine (Japan) 38: pp. 202-206 Abstract	https://www.wikidoc.org/index.php/Adipocytokine
965d2c4a67eb1b9005bec89b3e71f738d95e39bb	wikidoc	Adrafinil	Adrafinil # Overview Adrafinil (Olmifon) is a wakefulness-promoting agent (or eugeroic) used to relieve excessive sleepiness and inattention. It is also used off-label by individuals wishing to avoid fatigue, such as night workers or others who need to stay awake and alert for long periods of time. Adrafinil is a prodrug; it is primarily metabolized in vivo to modafinil, resulting in nearly identical pharmacological effects. Unlike modafinil, however, it takes time for the metabolite to accumulate to active levels in the bloodstream. Effects usually are apparent within 45–60 minutes when taken orally on an empty stomach. Adrafinil does not currently have FDA approval and is thus unregulated in the United States. It was marketed in France and elsewhere in Europe under the trade name Olmifon until September 2011 when France's FDA-equivalent reassessed the drug and withdrew marketing permission, citing known adverse reactions and an unsatisfactory risk to benefit ratio. # History Adrafinil was discovered in the late 1970s by scientists working with the French pharmaceutical company Group Lafon. First offered in France in 1986 as an experimental treatment for narcolepsy, Lafon later developed modafinil, the primary metabolite of adrafinil. Even though the exact mechanism of action is unclear, "most investigators assume that adrafinil and modafinil both serve as α1-adrenergic receptor agonists." The evidence in support of this hypothesis is, however, weak and other mechanisms of action are probable. Modafinil possesses greater selective α1-adrenergic activity than adrafinil, without many of adrafinil's common side effects (stomach pain, skin irritation, anxiety and (with prolonged use) elevated liver enzymes). This makes it important to monitor the liver of an individual using adrafinil for prolonged periods. As of September 2011, Cephalon has discontinued Olmifon, its adrafinil product. # Legal status ## Athletic doping Adrafinil and its active metabolite modafinil were added to the list of substances prohibited for athletic competition according to World Anti-Doping Agency in 2004. ## United States In the United States, adrafinil is currently unregulated. It has not been approved for any clinical uses by the U.S. Food and Drug Administration. Unlike modafinil, adrafinil is not classified as a controlled substance and does not fall under DEA jurisdiction; in particular, it is not illegal to possess without a prescription and can be imported privately by citizens. ## Canada In Canada adrafinil is unregulated and can be legally purchased within the country as a research chemical, or imported privately by citizens. ## New Zealand In 2005 a Medical Classification Committee in New Zealand recommended to MEDSAFE NZ that adrafinil be classified as a prescription medicine. "Adrafinil had been referred to the MCC for classification as a prescription medicine by the Medicines Control section of Medsafe following growing concern about increased imports and potential abuse of this substance as a party drug. Evidence of misuse was supplied in support of the request for classification. Adrafinil is not scheduled in New Zealand but is chemically related to modafinil which is a prescription medicine taken orally for mental function impairment in the elderly. All participants agreed that adrafinil should be classified as a prescription medicine."	Adrafinil Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Adrafinil (Olmifon) is a wakefulness-promoting agent (or eugeroic) used to relieve excessive sleepiness and inattention. It is also used off-label by individuals wishing to avoid fatigue, such as night workers or others who need to stay awake and alert for long periods of time. Adrafinil is a prodrug; it is primarily metabolized in vivo to modafinil, resulting in nearly identical pharmacological effects. Unlike modafinil, however, it takes time for the metabolite to accumulate to active levels in the bloodstream. Effects usually are apparent within 45–60 minutes when taken orally on an empty stomach. Adrafinil does not currently have FDA approval and is thus unregulated in the United States. It was marketed in France and elsewhere in Europe under the trade name Olmifon until September 2011 when France's FDA-equivalent reassessed the drug and withdrew marketing permission, citing known adverse reactions and an unsatisfactory risk to benefit ratio. # History Adrafinil was discovered in the late 1970s by scientists working with the French pharmaceutical company Group Lafon. First offered in France in 1986 as an experimental treatment for narcolepsy, Lafon later developed modafinil, the primary metabolite of adrafinil. Even though the exact mechanism of action is unclear, "most investigators assume that adrafinil and modafinil both serve as α1-adrenergic receptor agonists."[1] The evidence in support of this hypothesis is, however, weak and other mechanisms of action are probable.[1] Modafinil possesses greater selective α1-adrenergic activity than adrafinil, without many of adrafinil's common side effects (stomach pain, skin irritation, anxiety and (with prolonged use) elevated liver enzymes).[2] This makes it important to monitor the liver of an individual using adrafinil for prolonged periods. As of September 2011, Cephalon has discontinued Olmifon, its adrafinil product. # Legal status ## Athletic doping Adrafinil and its active metabolite modafinil were added to the list of substances prohibited for athletic competition according to World Anti-Doping Agency in 2004.[3] ## United States In the United States, adrafinil is currently[update] unregulated. It has not been approved for any clinical uses by the U.S. Food and Drug Administration. Unlike modafinil, adrafinil is not classified as a controlled substance and does not fall under DEA jurisdiction; in particular, it is not illegal to possess without a prescription and can be imported privately by citizens. ## Canada In Canada adrafinil is unregulated and can be legally purchased within the country as a research chemical, or imported privately by citizens. ## New Zealand In 2005 a Medical Classification Committee in New Zealand recommended to MEDSAFE NZ that adrafinil be classified as a prescription medicine. "Adrafinil had been referred to the MCC for classification as a prescription medicine by the Medicines Control section of Medsafe following growing concern about increased imports and potential abuse of this substance as a party drug. Evidence of misuse was supplied in support of the request for classification. Adrafinil is not scheduled in New Zealand but is chemically related to modafinil which is a prescription medicine taken orally for mental function impairment in the elderly. All participants agreed that adrafinil should be classified as a prescription medicine."[4]	https://www.wikidoc.org/index.php/Adrafinil
637eec35b748da67beeb81bb0f916f42762ca7a7	wikidoc	Aeromonas	Aeromonas Aeromonas is a gram-negative, facultative anaerobic rod that morphologically resembles members of the family Enterobacteriaceae. Fourteen species of Aeromonas have been described, most of which have been associated with human diseases. The most important pathogens are A. hydrophila, A. caviae, and A. veronii biovar sobria. The organisms are ubiquitous in fresh and brackish water. Two major diseases associated with Aeromonas are gastroenteritis and wound infections, with or without bacteremia. Gastroenteritis typically occurs after the ingestion of contaminated water or food, whereas wound infections result from exposure to contaminated water. Although some potential virulence factors (e.g. endotoxins, hemolysins, enterotoxins, adherence factors) have been identified, their precise role is unknown. Aeromonas species cause: 1) opportunistic systemic disease in immunocompromised patients, 2) diarrheal disease in otherwise healthy individuals, and 3) wound infections. # Gastroenteritis Gastrointestinal disease in children is usually an acute, severe illness, whereas that in adults tends to be chronic diarrhea. Severe Aeromonas gastroenteritis resembles shigellosis, with blood and leukocytes in the stool. Acute diarrheal disease is self limited, and only supportive care is indicated in affected patients. # Antimicrobial Therapy Is necessary for patients with chronic diarrheal disease or systemic infection. Aeromonas species are resistant to penicillins, most cephalosporins, and erythromycin. Ciprofloxacin is consistently active against their strains in the U.S. and Europe, but resistant cases has been reported in Asia. de:Aeromonas	Aeromonas Aeromonas is a gram-negative, facultative anaerobic rod that morphologically resembles members of the family Enterobacteriaceae. Fourteen species of Aeromonas have been described, most of which have been associated with human diseases. The most important pathogens are A. hydrophila, A. caviae, and A. veronii biovar sobria. The organisms are ubiquitous in fresh and brackish water. Two major diseases associated with Aeromonas are gastroenteritis and wound infections, with or without bacteremia. Gastroenteritis typically occurs after the ingestion of contaminated water or food, whereas wound infections result from exposure to contaminated water. Although some potential virulence factors (e.g. endotoxins, hemolysins, enterotoxins, adherence factors) have been identified, their precise role is unknown. Aeromonas species cause: 1) opportunistic systemic disease in immunocompromised patients, 2) diarrheal disease in otherwise healthy individuals, and 3) wound infections. # Gastroenteritis Gastrointestinal disease in children is usually an acute, severe illness, whereas that in adults tends to be chronic diarrhea. Severe Aeromonas gastroenteritis resembles shigellosis, with blood and leukocytes in the stool. Acute diarrheal disease is self limited, and only supportive care is indicated in affected patients. # Antimicrobial Therapy Is necessary for patients with chronic diarrheal disease or systemic infection. Aeromonas species are resistant to penicillins, most cephalosporins, and erythromycin. Ciprofloxacin is consistently active against their strains in the U.S. and Europe, but resistant cases has been reported in Asia. de:Aeromonas Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Aeromonas
c06b34b739308a884746eab3e8011592e3ce652f	wikidoc	Affection	Affection # Overview Affection is defined by the Random House Dictionary as "disposition or state of mind or body." It has given rise to a number of branches of meaning concerning: emotion (popularly: love, devotion etc); disease; influence; state of being (philosophy) ; and state of mind (psychology) Affect (psychology). # Usage "Affection" is popularly used to denote a feeling or type of love, amounting to more than goodwill or friendship. Writers on ethics generally use the word to refer to distinct states of feeling, both lasting and spasmodic. Some contrast it with passion as being free from the distinctively sensual element. More specifically the word has been restricted to emotional states the object of which is a person. In the former sense, it is the Greek "pathos" and as such it appears in the writings of French philosopher René Descartes, Dutch philosopher Baruch Spinoza, and most of the writings of early British ethicists. However, on various grounds (e.g., that it does not involve anxiety or excitement and that it is comparatively inert and compatible with the entire absence of the sensuous element), it is generally and usefully distinguished from passion. In this narrower sense the word has played a great part in ethical systems, which have spoken of the social or parental affections as in some sense a part of moral obligation. For a consideration of these and similar problems, which depend ultimately on the degree in which the affections are regarded as voluntary, see H. Sidgwick, Methods of Ethics pp. 345–349. # Affectionate Behavior Numerous behaviors are used by people to express affection. Some theories suggest that affectionate behavior evolved from parental nurturing behavior due to its associations with hormonal rewards with research verifying that expressions of affection, although commonly evaluated positively, can be considered negative if they pose implied threats to one's well being. Furthermore, affectionate behavior in positively valenced relationships may be associated with numerous health benefits. Other, more loving type gestures of affectionate behavior include obvious signs of liking a person. Many cases of a boy liking a girl or a girl liking a boy is called a crush. # Psychology In psychology the terms affection and affective are of great importance. As all intellectual phenomena have by experimentalists been reduced to sensation, so all emotion has been and is regarded as reducible to simple mental affection, the element of which all emotional manifestations are ultimately composed. The nature of this element is a problem which has been provisionally, but not conclusively, solved by many psychologists; the method is necessarily experimental, and all experiments on feeling are peculiarly difficult. The solutions proposed are two. In the first, all affection phenomena are primarily divisible into those which are pleasurable and those which are the reverse. The main objections to this are that it does not explain the infinite variety of phenomena, and that it disregards the distinction which most philosophers admit between higher and lower pleasures. The second solution is that every sensation has its specific affective quality, though by reason of the poverty of language many of these have no name. W. Wundt, Outlines of Psychology (trans. C. H. Judd, Leipzig, 1897), maintains that we may group under three main affective directions, each with its negative, all the infinite varieties in question; these are (a) pleasure, or rather pleasantness, and displeasure, (b) tension and relaxation, (c) excitement and depression. These two views are antithetic and no solution has been discovered. American psychologist Henry Murray (1893–1988) developed a theory of personality that was organized in terms of motives, presses, and needs. According to Murray, these psychogenic needs function mostly on the unconscious level, but play a major role in our personality. Murray classified five affection needs: - Affiliation: Spending time with other people. - Nurturance: Taking care of another person. - Play: Having fun with others. - Rejection: Rejecting other people. - Succorance: Being helped or protected by others Two methods of experiment on affection have been tried: - The first, introduced by A. Mosso, the Italian psychologist, consists in recording the physical phenomena which are observed to accompany modifications of the affective consciousness. Thus it is found that the action of the heart is accelerated by pleasant, and retarded by unpleasant, stimuli; again, changes of weight and volume are found to accompany modifications of affection—and so on. Apart altogether from the facts that this investigation is still in its infancy and that the conditions of experiment are insufficiently understood, its ultimate success is rendered highly problematical by the essential fact that real scientific results can be achieved only by data recorded in connection with a perfectly normal subject; a conscious or interested subject introduces variable factors which are probably incalculable. - The second is Fechner's method; it consists of recording the changes in feeling-tone produced in a subject by bringing him in contact with a series of conditions, objects or stimuli graduated according to a scientific plan and presented singly in pairs or in groups. The result is a comparative table of likes and dislikes. Mention should also be made of a third method which has hardly yet been tried, namely, that of endeavouring to isolate one of the three directions by the method of suggestion or even hypnotic trance observations. # Books For a contemporary text regarding the expression of affection, see: - K. Floyd, "Communicating Affection: Interpersonal Behavior and Social Context," Cambridge University Press, 2006 For the subject of emotion in general see modern textbooks of psychology, e.g. those of - J. Sully - W. James - G. T. Fechner - O. Kulpe; Angelo Mosso, La Paura (Milan, 1884, 1900 Eng. trans. E. Lough and F. Kiesow, Lond. 1896) - E. B. Titchener, Experimental Psychology (1905); art. "Psychology" and works there quoted.	Affection Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Affection is defined by the Random House Dictionary as "disposition or state of mind or body." [2] It has given rise to a number of branches of meaning concerning: emotion (popularly: love, devotion etc); disease; influence; state of being (philosophy) [3]; and state of mind (psychology) Affect (psychology). Template:Emotion # Usage "Affection" is popularly used to denote a feeling or type of love, amounting to more than goodwill or friendship. Writers on ethics generally use the word to refer to distinct states of feeling, both lasting and spasmodic. Some contrast it with passion as being free from the distinctively sensual element. More specifically the word has been restricted to emotional states the object of which is a person. In the former sense, it is the Greek "pathos" and as such it appears in the writings of French philosopher René Descartes, Dutch philosopher Baruch Spinoza, and most of the writings of early British ethicists. However, on various grounds (e.g., that it does not involve anxiety or excitement and that it is comparatively inert and compatible with the entire absence of the sensuous element), it is generally and usefully distinguished from passion. In this narrower sense the word has played a great part in ethical systems, which have spoken of the social or parental affections as in some sense a part of moral obligation. For a consideration of these and similar problems, which depend ultimately on the degree in which the affections are regarded as voluntary, see H. Sidgwick, Methods of Ethics pp. 345–349. # Affectionate Behavior Numerous behaviors are used by people to express affection. Some theories[1] suggest that affectionate behavior evolved from parental nurturing behavior due to its associations with hormonal rewards with research verifying that expressions of affection, although commonly evaluated positively, can be considered negative if they pose implied threats to one's well being. Furthermore, affectionate behavior in positively valenced relationships may be associated with numerous health benefits. Other, more loving type gestures of affectionate behavior include obvious signs of liking a person. Many cases of a boy liking a girl or a girl liking a boy is called a crush. # Psychology In psychology the terms affection and affective are of great importance. As all intellectual phenomena have by experimentalists been reduced to sensation, so all emotion has been and is regarded as reducible to simple mental affection, the element of which all emotional manifestations are ultimately composed. The nature of this element is a problem which has been provisionally, but not conclusively, solved by many psychologists; the method is necessarily experimental, and all experiments on feeling are peculiarly difficult. The solutions proposed are two. In the first, all affection phenomena are primarily divisible into those which are pleasurable and those which are the reverse. The main objections to this are that it does not explain the infinite variety of phenomena, and that it disregards the distinction which most philosophers admit between higher and lower pleasures. The second solution is that every sensation has its specific affective quality, though by reason of the poverty of language many of these have no name. W. Wundt, Outlines of Psychology (trans. C. H. Judd, Leipzig, 1897), maintains that we may group under three main affective directions, each with its negative, all the infinite varieties in question; these are (a) pleasure, or rather pleasantness, and displeasure, (b) tension and relaxation, (c) excitement and depression. These two views are antithetic and no solution has been discovered. American psychologist Henry Murray (1893–1988) developed a theory of personality that was organized in terms of motives, presses, and needs. According to Murray, these psychogenic needs function mostly on the unconscious level, but play a major role in our personality. Murray classified five affection needs: - Affiliation: Spending time with other people. - Nurturance: Taking care of another person. - Play: Having fun with others. - Rejection: Rejecting other people. - Succorance: Being helped or protected by others Two methods of experiment on affection have been tried: - The first, introduced by A. Mosso, the Italian psychologist, consists in recording the physical phenomena which are observed to accompany modifications of the affective consciousness. Thus it is found that the action of the heart is accelerated by pleasant, and retarded by unpleasant, stimuli; again, changes of weight and volume are found to accompany modifications of affection—and so on. Apart altogether from the facts that this investigation is still in its infancy and that the conditions of experiment are insufficiently understood, its ultimate success is rendered highly problematical by the essential fact that real scientific results can be achieved only by data recorded in connection with a perfectly normal subject; a conscious or interested subject introduces variable factors which are probably incalculable. - The second is Fechner's method; it consists of recording the changes in feeling-tone produced in a subject by bringing him in contact with a series of conditions, objects or stimuli graduated according to a scientific plan and presented singly in pairs or in groups. The result is a comparative table of likes and dislikes. Mention should also be made of a third method which has hardly yet been tried, namely, that of endeavouring to isolate one of the three directions by the method of suggestion or even hypnotic trance observations. # Books For a contemporary text regarding the expression of affection, see: - K. Floyd, "Communicating Affection: Interpersonal Behavior and Social Context," Cambridge University Press, 2006 For the subject of emotion in general see modern textbooks of psychology, e.g. those of - J. Sully - W. James - G. T. Fechner - O. Kulpe; Angelo Mosso, La Paura (Milan, 1884, 1900 Eng. trans. E. Lough and F. Kiesow, Lond. 1896) - E. B. Titchener, Experimental Psychology (1905); art. "Psychology" and works there quoted.	https://www.wikidoc.org/index.php/Affection
99ad75ed281d1ddc0513033878d9c3c17b8fea8c	wikidoc	Aflatoxin	Aflatoxin # Overview Aflatoxins are naturally occurring mycotoxins that are produced by many species of Aspergillus, a fungus, most notably Aspergillus flavus and Aspergillus parasiticus. Aflatoxins are toxic and among the most carcinogenic substances known. After entering the body, aflatoxins are metabolized by the liver to a reactive intermediate, aflatoxin M1, an epoxide. Aflatoxin is frequently misspelled as "aflotoxin" and "alfatoxin", which could be confused with alpha toxin. # Contamination conditions Aflatoxin-producing members of Aspergillus are common and widespread in nature. They can colonize and contaminate grain before harvest or during storage. Host crops are particularly susceptible to infection by Aspergillus following prolonged exposure to a high humidity environment or damage from stressful conditions such as drought, a condition which lowers the barrier to entry. The native habitat of Aspergillus is in soil, decaying vegetation, hay, and grains undergoing microbiological deterioration and it invades all types of organic substrates whenever conditions are favorable for its growth. Favorable conditions include high moisture content (at least 7%) and high temperature. Crops which are frequently affected include cereals (maize, sorghum, pearl millet, rice, wheat), oilseeds (peanut, soybean, sunflower, cotton), spices (chile peppers, black pepper, coriander, turmeric, ginger), and tree nuts (almond, pistachio, walnut, coconut, brazil nut). The toxin can also be found in the milk of animals which are fed contaminated feed. Virtually all sources of commercial peanut butter contain minute quantities of aflatoxin, but it is usually far below the US Food and Drug Administration's (FDA) recommended safe level. The Food and Drug Administration (FDA) has established action levels for aflatoxin present in food or feed to protect human and animal health. Levels must not exceed: # Pathology High-level aflatoxin exposure produces an acute hepatic necrosis, resulting later in cirrhosis, and/or carcinoma of the liver. Acute hepatic failure is manifested by hemorrhage, edema, alteration in digestion, and absorption and/or metabolism of nutrients and mental changes and/or coma. No animal species is immune to the acute toxic effects of aflatoxins including humans; however, humans have an extraordinarily high tolerance for aflatoxin exposure and rarely succumb to acute aflatoxicosis. Chronic, subclinical exposure does not lead to symptoms as dramatic as acute aflatoxicosis. Children, however, are particularly affected by aflatoxin exposure which leads to stunted growth and delayed development. Chronic exposure also leads to a high risk of developing liver cancer, as the metabolite aflatoxin M1 can intercalate into DNA and alkylate the bases through its epoxide moiety. This is thought to cause mutations in the p53 gene, an important gene in preventing cell cycle progression when there are DNA mutations. The Aflatoxin acts as a DNA mutatory, not only mutating DNA randomly, but has a selection for mutating the p53 DNA specifically at base 249 to cause liver tumors (249 is an arginine residue, thus extremely important for interacting with DNA. Slight mutations affecting this charge relationship between the positive Arginine and negative DNA can severely hamper the tumor suppressing effects of p53 and its role in apoptosis). Medical research indicates that a regular diet including apiaceous vegetables such as carrots, parsnips, celery and parsley, reduces the carcinogenic effects of aflatoxin. # Detection in humans There are two principal techniques that have been used most often to detect levels of aflatoxin in humans. The first method is measuring the AFB1-guanine adduct in the urine of subjects. Presence of this breakdown product indicates exposure to aflatoxin B1 in the past 24 hours. However, this technique only measures recent exposure, and due to the half-life of this metabolite, the level of AFB1-guanine measured can vary from day to day, based on diet, and thus is not ideal for assessing long term exposure. Another technique that has been used is a measurement of the AFB1-albumin adduct level in the blood serum. This approach provides a more integrated measure of exposure over several weeks/months. # Pets Aflatoxin in dry dog food manufactured by Diamond Pet Foods was responsible for at least 23 dog deaths due to liver failure between Dec 2005 and early 2006. In an April 12, 2006 letter FedEx'd from the Department of Health and Human Resources to a manufacturing plant, the FDA warned Gary Schell, president of Schell and Kampeter Inc. of Missouri that independent testing of three samples of incoming corn to their processing plant showed between 90 and 1851 ppb, while paperwork on three (of four samples) showed aflatoxins levels <20 ppb, and other sample was not recorded. The results of this letter are unknown. # Major types of aflatoxins and their metabolites At least 13 different types of aflatoxin are produced in nature. Aflatoxin B1 is considered the most toxic and is produced by both Aspergillus flavus and Aspergillus parasiticus. Aflatoxin G1 and G2 are produced exclusively by A. parasiticus. While the presence of Aspergillus in food products does not always indicate harmful levels of aflatoxin are also present, it does imply a significant risk in consumption Aflatoxins M1, M2 were originally discovered in the milk of cows which fed on moldy grain. These compounds are products of a conversion process in the animal's liver. However, aflatoxin M1 is present in the fermentation broth of Aspergillus parasiticus. - Aflatoxin B1 & B2 : produced by Aspergillus flavus and A. parasiticus. - Aflatoxin G1 & G2 : produced by Aspergillus parasiticus. - Aflatoxin M1 : metabolite of aflatoxin B1 in humans and animals (exposure in ng can come from mother's milk). - Aflatoxin M2 : metabolite of aflatoxin B2 in milk of cattle fed on contaminated foods. - Aflatoxicol. # Interaction with the Hepatitis B virus Studies have shown that concurrent infection with the Hepatitis B virus (HBV) during aflatoxin exposure increases the risk of hepatocellular carcinoma (HCC). As HBV interferes with the ability of hepatocytes to metabolize aflatoxins, an aflatoxin M1-DNA conjugate exists for a longer period of time in the liver, increasing the probability of damage to tumor suppressor genes such as p53. This effect is synergistic with the resulting damage far greater than just the sum of aflatoxin and HBV . (Williams, 2004) Decreasing HBV infection levels through vaccination is an effective and simple approach that can be taken to reduce these harmful synergistic effects, thus decreasing the impact of chronic aflatoxin exposure. This strategy may prove to be highly effective – many regions of the world which have high aflatoxin rates, such as western Africa and China, also have high HBV infection rates. # Manufacturers As of May 2008, there are but three primary manufacturers (as distinguished from re-packers and re-sellers) of pure aflatoxins known: - Biopure Referenzsubstanzen GmbH part of Romer Labs Group produces fully isotope labeled 13C Aflatoxin (Patented) - Sigma-Aldrich - Fermentek, the only one that produces aflatoxin M2 Customers use these compounds for instance as internal standard when monitoring foodstuffs for aflatoxin contaminants.	Aflatoxin # Overview Aflatoxins are naturally occurring mycotoxins that are produced by many species of Aspergillus, a fungus, most notably Aspergillus flavus and Aspergillus parasiticus. Aflatoxins are toxic and among the most carcinogenic substances known.[1] After entering the body, aflatoxins are metabolized by the liver to a reactive intermediate, aflatoxin M1, an epoxide. Aflatoxin is frequently misspelled as "aflotoxin" and "alfatoxin", which could be confused with alpha toxin. # Contamination conditions Aflatoxin-producing members of Aspergillus are common and widespread in nature. They can colonize and contaminate grain before harvest or during storage. Host crops are particularly susceptible to infection by Aspergillus following prolonged exposure to a high humidity environment or damage from stressful conditions such as drought, a condition which lowers the barrier to entry. The native habitat of Aspergillus is in soil, decaying vegetation, hay, and grains undergoing microbiological deterioration and it invades all types of organic substrates whenever conditions are favorable for its growth. Favorable conditions include high moisture content (at least 7%) and high temperature. Crops which are frequently affected include cereals (maize, sorghum, pearl millet, rice, wheat), oilseeds (peanut, soybean, sunflower, cotton), spices (chile peppers, black pepper, coriander, turmeric, ginger), and tree nuts (almond, pistachio, walnut, coconut, brazil nut). The toxin can also be found in the milk of animals which are fed contaminated feed. Virtually all sources of commercial peanut butter contain minute quantities of aflatoxin,[2] but it is usually far below the US Food and Drug Administration's (FDA) recommended safe level. The Food and Drug Administration (FDA) has established action levels for aflatoxin present in food or feed to protect human and animal health. [3] Levels must not exceed: # Pathology High-level aflatoxin exposure produces an acute hepatic necrosis, resulting later in cirrhosis, and/or carcinoma of the liver. Acute hepatic failure is manifested by hemorrhage, edema, alteration in digestion, and absorption and/or metabolism of nutrients and mental changes and/or coma. No animal species is immune to the acute toxic effects of aflatoxins including humans; however, humans have an extraordinarily high tolerance for aflatoxin exposure and rarely succumb to acute aflatoxicosis. Chronic, subclinical exposure does not lead to symptoms as dramatic as acute aflatoxicosis. Children, however, are particularly affected by aflatoxin exposure which leads to stunted growth and delayed development.[4] Chronic exposure also leads to a high risk of developing liver cancer, as the metabolite aflatoxin M1 can intercalate into DNA and alkylate the bases through its epoxide moiety. This is thought to cause mutations in the p53 gene, an important gene in preventing cell cycle progression when there are DNA mutations. The Aflatoxin acts as a DNA mutatory, not only mutating DNA randomly, but has a selection for mutating the p53 DNA specifically at base 249 to cause liver tumors (249 is an arginine residue, thus extremely important for interacting with DNA. Slight mutations affecting this charge relationship between the positive Arginine and negative DNA can severely hamper the tumor suppressing effects of p53 and its role in apoptosis). Medical research indicates that a regular diet including apiaceous vegetables such as carrots, parsnips, celery and parsley, reduces the carcinogenic effects of aflatoxin.[5] # Detection in humans There are two principal techniques that have been used most often to detect levels of aflatoxin in humans. The first method is measuring the AFB1-guanine adduct in the urine of subjects. Presence of this breakdown product indicates exposure to aflatoxin B1 in the past 24 hours. However, this technique only measures recent exposure, and due to the half-life of this metabolite, the level of AFB1-guanine measured can vary from day to day, based on diet, and thus is not ideal for assessing long term exposure. Another technique that has been used is a measurement of the AFB1-albumin adduct level in the blood serum. This approach provides a more integrated measure of exposure over several weeks/months. # Pets Aflatoxin in dry dog food manufactured by Diamond Pet Foods was responsible for at least 23 dog deaths due to liver failure between Dec 2005 and early 2006. In an April 12, 2006 letter FedEx'd from the Department of Health and Human Resources to a manufacturing plant,[6][7] the FDA warned Gary Schell, president of Schell and Kampeter Inc. of Missouri that independent testing of three samples of incoming corn to their processing plant showed between 90 and 1851 ppb, while paperwork on three (of four samples) showed aflatoxins levels <20 ppb, and other sample was not recorded. The results of this letter are unknown. # Major types of aflatoxins and their metabolites At least 13 different types of aflatoxin are produced in nature. Aflatoxin B1 is considered the most toxic and is produced by both Aspergillus flavus and Aspergillus parasiticus. Aflatoxin G1 and G2 are produced exclusively by A. parasiticus. While the presence of Aspergillus in food products does not always indicate harmful levels of aflatoxin are also present, it does imply a significant risk in consumption Aflatoxins M1, M2 were originally discovered in the milk of cows which fed on moldy grain. These compounds are products of a conversion process in the animal's liver. However, aflatoxin M1 is present in the fermentation broth of Aspergillus parasiticus. - Aflatoxin B1 & B2 : produced by Aspergillus flavus and A. parasiticus. - Aflatoxin G1 & G2 : produced by Aspergillus parasiticus. - Aflatoxin M1 : metabolite of aflatoxin B1 in humans and animals (exposure in ng can come from mother's milk). - Aflatoxin M2 : metabolite of aflatoxin B2 in milk of cattle fed on contaminated foods.[8] - Aflatoxicol. # Interaction with the Hepatitis B virus Studies have shown that concurrent infection with the Hepatitis B virus (HBV) during aflatoxin exposure increases the risk of hepatocellular carcinoma (HCC). As HBV interferes with the ability of hepatocytes to metabolize aflatoxins, an aflatoxin M1-DNA conjugate exists for a longer period of time in the liver, increasing the probability of damage to tumor suppressor genes such as p53. This effect is synergistic with the resulting damage far greater than just the sum of aflatoxin and HBV . (Williams, 2004) Decreasing HBV infection levels through vaccination is an effective and simple approach that can be taken to reduce these harmful synergistic effects, thus decreasing the impact of chronic aflatoxin exposure. This strategy may prove to be highly effective – many regions of the world which have high aflatoxin rates, such as western Africa and China, also have high HBV infection rates[9]. # Manufacturers As of May 2008, there are but three primary manufacturers (as distinguished from re-packers and re-sellers) of pure aflatoxins known: - Biopure Referenzsubstanzen GmbH part of Romer Labs Group [10] produces fully isotope labeled 13C Aflatoxin (Patented) - Sigma-Aldrich [11] - Fermentek, the only one that produces aflatoxin M2 Customers use these compounds for instance as internal standard when monitoring foodstuffs for aflatoxin contaminants.	https://www.wikidoc.org/index.php/Aflatoxin
2cfb06c39e43785a41ac3e2d108b365bc2b30814	wikidoc	Afterlife	Afterlife The terms afterlife or life after death refer to the continuation of existence of the soul, spirit or mind of a human (or animal) after physical death, sometimes in a spiritual or ghostlike afterworld. Deceased persons are usually believed to go to a specific region or plane of existence in the next life, often depending on the rightness of their actions during life. Some believe the afterlife can be another life in this world (reincarnation). The major views on the afterlife derive from religion, esotericism and metaphysics. There are those who are skeptical of the existence of the afterlife, or believe that it is absolutely impossible, such as the materialist-reductionists, who state that the topic is supernatural, therefore does not really exist or is unknowable. # Types of views on the afterlife There are two fundamentally different types of views on the afterlife: views claiming to be scientific and religious views. - The first type claims to be based on some form of an observation by a human or an instrument (for example a radio or a voice recorder, which are used in EVP)Template:Clarifyme. These observations come from reincarnation research, near death experiences, out-of-body experiences, astral projection, electronic voice phenomena, mediumship, various forms of photography etcetera. They are studied by survivalism. The work of people like Bruce Moen and Robert Monroe are also of this type. Also scientific research into near death experiences based on observation, for example the work of Pim van Lommel. - The second type is based on some form of faith, usually faith in the stories that are told by ancestors or faith in religious books like the Bible, the Qur'an, the Talmud, the Vedas, the Tripitaka et cetera. This article is mainly about this second type. # The afterlife in different metaphysical models In metaphysical models, theists generally believe some sort of afterlife awaits people when they die. Atheists generally do not believe that there is an afterlife. Members of some generally non-theistic religions such as Buddhism, tend to believe in an afterlife like reincarnation but without reference to God. Agnostics generally hold the position that like the existence of God, the existence of supernatural phenomena, such as souls or life after death, is unverifiable and therefore unknowable. Some philosophies (i.e. posthumanism, Humanism, and often empiricism) generally hold that there is not an afterlife. Many religions, whether they believe in the soul’s existence in another world like Christianity, Islam and many pagan belief systems, or in reincarnation like many forms of Hinduism and Buddhism, believe that one’s status in the afterlife is a reward or punishment for their conduct during life. # Afterlife research in the early 20th century Science, in general, either describes the universe and human beings without reference to a soul or to an afterlife, or tends to remain mute on the issue. A notable exception is a famous study conducted in 1901 by physician Duncan MacDougall, who sought to measure the weight purportedly lost by a human body when the soul departed the body upon death. MacDougall weighed dying patients in an attempt to prove that the soul was material, tangible and thus measurable. These experiments are widely considered to have had little if any scientific merit, and although MacDougall's results varied considerably from "21 grams," for some people this figure has become synonymous with the measure of a soul's mass. The title of the 2003 movie 21 Grams is a reference to MacDougall's findings. # Afterlife in modern science Some, such as Francis Crick in 1994, have attempted a ‘scientific search for the soul’. Frank Tipler has argued that physics can explain immortality, though such arguments are not falsifiable and thus do not qualify as science. Some investigations have been conducted which failed to find evidence that “out-of-body” experiences transcend the confines of the brain. For example, one hospital placed an LED marquee above its patients’ beds which displayed a hidden message that could only be read if one were looking down from above. As of 2001, no one who claimed near-death experience or out-of-body experience within that hospital had reported having seen the hidden message. # Afterlife in Ancient Egyptian religion The afterlife played an important role in Ancient Egyptian religion, and its belief system is one of the earliest known. When the body died, parts of its soul known as ka (body double) and the ba (personality) would go to the Kingdom of the Dead. While the soul dwelt in the Fields of Aaru, Osiris demanded work as payback for the protection he provided. Statues were placed in the tombs to serve as substitutes for the deceased. Arriving at one's reward in afterlife was a demanding ordeal, requiring a sin-free heart and the ability to recite the spells, passwords, and formulae of the Book of the Dead. In the Hall of Two Truths, the deceased's heart was weighed against the Shu feather of truth and justice taken from the headdress of the goddess Ma'at. If the heart was lighter than the feather, they could pass on, but if it were heavier they would be devoured by the demon Ammit. Egyptians also believed that being mummified was the only way to have an afterlife. Only if the corpse had been properly embalmed and entombed in a mastaba, could the dead live again in the Fields of Yalu and accompany the Sun on its daily ride. Due to the dangers the afterlife posed, the Book of the Dead was placed in the tomb with the body. # Afterlife in Zoroastrianism Zoroaster, who lived in Iran around 1000 BCE, teaches that the dead will be swallowed by terror and purified to live in a perfected material world at the end of time. The Pahlavi text Dadestan-i Denig ("Religious Decisions") from about 900 CE, describes the particular judgment of the soul three days after death, with each soul sent to heaven, hell, or a neutral place (hamistagan) to await Judgment Day. # Afterlife in ancient Greek and Roman religion In the Odyssey, Homer refers to the dead as "burnt-out wraiths." An afterlife of eternal bliss exists in Elysium, but is reserved for Zeus's mortal descendants. In his Myth of Er, Plato describes souls being judged immediately after death and sent either to the heavens for a reward or underground for punishment. After their respective judgments have been enjoyed or suffered, the souls are reincarnated. The Greek god Hades is known in Greek mythology as the king of the underworld, a bleak place in between the place of torment and the place of rest, where most souls live after death. Some heroes of Greek legend are allowed to visit the underworld. The Romans had a similar belief system about the afterlife, with Hades becoming known as Pluto. The Trojan prince Aeneas, who founds the nation that would later become Rome, visits the underworld according to the epic poem Aeneid. # Afterlife in Norse religion The Poetic and Prose Eddas, the oldest sources for information on the Norse concept of the afterlife, vary in their description of the several realms that are described as falling under this topic. The most well-known are: - Valhalla: (lit. "Hall of the Slain" i.e. "the Chosen Ones") This heavenly abode, somewhat analogous to the Greek Elysium, is reserved for those brave warriors who die heroically in battle. - Hel: (lit. "The Covered Hall") This abode is somewhat like Hades from Ancient Greek religion: there, something not unlike the Asphodel Meadows can be found, and people who have neither excelled in that which is good nor excelled in that which is bad can expect to go there after they die and be reunited with their loved ones. - Niflhel: (lit. "The Dark" or "Misty Hel") This realm is roughly analogous to Greek Tartarus. It is the deeper level beneath Hel, and those who break oaths, abduct and rape women, and other vile things will be sent there to be among their kind to suffer some pretty harsh punishments. # Afterlife in Abrahamic religions ## Judaism Writing that would later be incorporated into the Hebrew Bible names sheol as the afterlife, a gloomy place where all are destined to go after death. The Book of Numbers identifies sheol as literally underground (Template:Niv), in the Biblical account of the destruction of the rebellious Korah, Dathan and Abiram and their 250 followers, although it is speculated that this passage should be read literally, signifying an earthquake or split in the earth. The Talmud offers a number of thoughts relating to the afterlife. After death, the soul is brought for judgment. Those who have lead pristine lives enter immediately into the "World to Come." Most do not enter the World to Come immediately, but now experience a period of review of their earthly actions and they are made aware of what they have done wrong. Some view this period as being a "re-schooling", with the soul gaining wisdom as one's errors are reviewed. Others view this period to include punishment for past wrongs. At the end of this period, approximately one year, the soul then takes its place in the World to Come. Although punishments are made part of certain Jewish conceptions of the afterlife, the concept of "eternal damnation," so prevalent in other religions, is not a central tenet of the Jewish afterlife. According to the Talmud, eternal punishment is reserved for a much smaller group of malicious and evil leaders, either whose deeds go way beyond norms, or who lead large groups of people to evil. In the Talmud, completed by 500 CE, eternal damnation is reserved for the Caesar of Rome, for example, along with other individuals who led many to evil. The modern-day example of someone who would merit eternal damnation in Jewish thought would be Hitler. The Book of Enoch describes sheol as divided into four compartments for four types of the dead: the faithful saints who await resurrection in Paradise, the merely virtuous who await their reward, the wicked who await punishment, and the wicked who have already been punished and will not be resurrected on Judgment Day. It should be noted that the Book of Enoch is considered apocryphal by most denominations of Christianity and all denominations of Judaism. The book of 2 Maccabees gives a clear account of the dead awaiting a future resurrection and judgment, plus prayers and offerings for the dead to remove the burden of sin. Maimonides describes the Olam Haba ("World to Come") in spiritual terms, relegating the prophesied physical resurrection to the status of a future miracle, unrelated to the afterlife or the Messianic era. According to Maimonides, an afterlife continues for the soul of every human being, a soul now separated from the body in which it was "housed" during its earthly existence. The Zohar describes Gehenna not as a place of punishment for the wicked but as a place of spiritual purification for the souls of almost all mortals. ## Christianity ### The Early Church: 1st century Jesus and the New Testament writers of the Bible books mention notions of an afterlife and resurrection that involve ideas like heaven and hell. The author of Luke recounts the story of Lazarus and the rich man, which shows people in Hades awaiting the resurrection either in comfort or torment. The author of the Book of Revelation writes about God and the angels versus Satan and demons in an epic battle at the end of times when all souls are judged. There is mention of ghostly bodies of past prophets, and the transfiguration. ### The Early Church: 2nd and 3rd century The non-canonical Acts of Paul and Thecla speak of the efficacy of prayer for the dead, so that they might be "translated to a state of happiness." Hippolytus of Rome pictures Hades as a place where the righteous dead, awaiting in the bosom of Abraham their resurrection, rejoice at their future prospect, while the unrighteous are tormented at the sight of the "lake of unquenchable fire" into which they are destined to be cast. ### The Early Church: 4th and 5th century Gregory of Nyssa discusses the long-before believed possibility of purification of souls after death. Saint Augustine counters Pelagius, arguing that original sin means that the unbaptized go to hell, including infants, albeit with less suffering than is experienced by those guilty of actual sins. ### Medieval Christianity Pope Gregory I repeats the concept, articulated over a century earlier by Gregory of Nyssa that the saved suffer purification after death, in connection with which he wrote of "purgatorial flames". The noun "purgatorium" (Latin: place of cleansing) is used for the first time to describe a state of painful purification of the saved after life. The same word in adjectival form (purgatorius -a -um, cleansing), which appears also in non-religious writing, was already used by Christians such as Augustine of Hippo and Pope Gregory I to refer to an after-death cleansing. ### The Protestant Reformation Martin Luther denounces the doctrine of particular judgment, professing instead the belief that the soul sleeps until Judgment Day. John Calvin denounces Luther's doctrine, writing instead that the souls of the elect rest in blessedness while awaiting the resurrection of the dead. ### Swedenborg and the Enlightenment During the Age of Enlightenment, theologians and philosophers presented various philosophies and beliefs. A notable example is Emanuel Swedenborg who wrote some 18 theological works which describe in detail the nature of the afterlife according to his claimed spiritual experiences, the most famous of which is Heaven and Hell. On the other hand, the enlightenment produced more rationalist philosophies such as deism. Many deist freethinkers held that belief in an afterlife with reward and punishment was a necessity of reason and good moral order. ### Afterlife in Latter-Day Saints (Mormonism) President Joseph F. Smith of The Church of Jesus Christ of Latter-day Saints presents an elaborate vision of the Afterlife. It is revealed as the scene of an extensive missionary effort by righteous spirits to redeem those still in darkness - a spirit prison or "hell" where the spirits of the dead remain until judgement. It is divided into two parts: Spirit Prison and Paradise. Together these are also known as the Spirit World (also Abraham's Bosom; see Luke 16:19-25). They believe that Christ visited spirit prison (1 Peter 3:18-20) and opened the gate for those who repent to cross over to Paradise. This is similar to the Harrowing of Hell doctrine of some mainstream Christian faiths. Both Spirit Prison and Paradise are temporary according to Latter-day Saint beliefs. After the resurrection spirits are assigned "permanently" to three degrees of heavenly glory (1 Cor 15:44-42; Doctrine and Covenants, Section 76) or are cast with Satan into Outer Darkness. (See Doctrine and Covenants, Section 76.) This continues to be the belief system of most Mormons. ### Salvation, faith, and merit from ancient to modern Christianity Most Christians deny that entry into Heaven can be properly earned, rather it is a gift that is solely God's to give through his unmerited grace. This belief follows the theology of St. Paul: For it is by grace you have been saved, through faith--and this not from yourselves, it is the gift of God, not by works, so that no one can boast. The Augustinian, Thomist, Lutheran, and Calvinist theological traditions all emphasize the necessity of God's undeserved grace for salvation, and reject so-called Pelagianism, which would make man earn salvation through good works. Not all Christian sects accept this doctrine, leading many controversies on grace and free will, and the idea of predestination. In particular, the belief that heaven is a reward for good behavior is a common folk belief in Christian societies, even among members of churches which reject that belief. Christian theologians Thomas Aquinas and Jonathan Edwards wrote that the saved in heaven will delight in the suffering of the damned. Hell, however, doesn't fit modern, humanitarian concepts of punishment because it can't deter the unbeliever nor rehabilitate the damned, this however, does not affect the Christian belief which places Biblical teaching above the ideas of society. Some Christian believers have come to downplay the punishment of hell. Universalists teach that salvation is for all. Jehovah's Witnesses and Seventh-day Adventists, though they have among the strictest rules on how to conduct their lives, teach that sinners are destroyed rather than tortured forever. ### The dead as Angels in Heaven In the informal folk beliefs of many Christians, the souls of virtuous people ascend to Heaven and are converted into angels. More formal Christian theology makes a sharp distinction between angels, who were created by God before the creation of humanity, and saints, who are people who have received immortality from the grace of God through faith in the Son of God Jesus (John 3:16). ### Universalists Some sects, such as the Universalists, believe in universalism which holds that all will eventually be rewarded regardless of what they have done or believed. ### Jehovah's Witnesses Jehovah's Witnesses understand Ecclesiastes 9:5 to preclude an afterlife: For the living are conscious that they will die; but as for the dead, they are conscious of nothing at all, neither do they any more have wages, because the remembrance of them has been forgotten. They believe that following Armageddon a resurrection in the flesh to an Edenic Earth will be rewarded to both righteous and unrighteous (but not wicked) dead. Acts 24:15 states, "“I have hope toward God . . . that there is going to be a resurrection of both the righteous and the unrighteous.” Eternal death (non-existence) is the punishment for sin lacking repentance after Armageddon. Although those who are not dead when Armageddon occurs will be judged and possibly slain during Armageddon because of their potential regretless sins. They believe that death is the price for sinning (that is why most dead will be resurrected - they paid the price already). ### The Modern Catholic Church In the 1990s, the Catechism of the Catholic Church defined hell not as punishment imposed on the sinner but rather as the sinner's self-exclusion from God. ## Islam The Islamic belief in the afterlife as stated in the Qur'an is unique, its official description is more detailed. The word used to describe Paradise in Islam is referred to as jannat and to describe Hell is jahannam. Jannat and Jahannam both have different levels. Souls will not get there until after the Judgment Day, but their level of comfort while in the grave depends on their belief in The God and hereafter, as well as their deeds during this life. The levels are 7 for Jannat and 5 for Hell. Islam teaches that the purpose of Mans creation is to worship the Creator of the Heavens and Earth, Allah, the Arabic word used to refer to The One and Only God of the Abrahamic Tradition. Islam teaches that life lived on this Earth is a test for man to determine each individuals ultimate Reward or Punishment in the Afterlife, which is eternal and everlasting. According to the Qur’an, the basic criteria for salvation in afterlife is: 1. The belief in one and only God 2. To believe in the afterlife, resurrection and Last Judgment 3. Performing good deeds and abstaining from bad actions 4. To believe in ALL the seen and unseen messengers of Allah: All of the Angels (i.e. Gabriel and Michael); All of the Prophets including Adam, Noah, Abraham, Jesus (including his miraculous birth and Second Coming), as well as believing that Muhammad is the last messenger of God, Peace and Blessings upon all of them. When one holds these to be true, then they are considered to be a Muslim, or one who submits to Allah, and should formally declare their Islam at their local masjid. # Afterlife as reincarnation An afterlife concept that is found among Hindus, Rosicrucians, Spiritists, and Wicca is reincarnation, as evolving humans life after life in the physical world, that is, acquiring a superior grade of consciousness and altruism by means of successive reincarnations. This succession is conceived to lead toward an eventual liberation or spiritual rebirth as spiritual beings. Some practitioners of eastern religions follow a different concept called metempsychosis which purposes that human beings can transmigrate into animals, vegetables, or even minerals. One consequence of the Hindu and Spiritist beliefs is that our current lives are also an afterlife. According to those beliefs events in our current life are consequences of actions taken in previous lives, or Karma. ### Eastern Religions The Upanishads describe reincarnation, or samsara. The Bhagavad Gita, an important book for Hinduism talks extensively about the afterlife. Here, the Lord Krishna says that just as a man discards his old clothes and wears new ones; similarly the soul discards the old body and takes on a new one. In Hinduism, the belief is that the body is but a shell, the soul inside is immutable and indestructible and takes on different lives in a cycle of birth and death. The end of this cycle is Moksha or salvation. However, not all Hindus believe in reincarnation. Buddhists believe that rebirth takes place without a self (similar to soul) and that the process of rebirth is simply a continuation of the previous life. The process of being reborn as any other being is based on your karma. From a Buddhist perspective, the current life is a continuation of the past life. If one dies with a peaceful state of mind, this will cause fortunate karma to ripen and a fortunate rebirth as a human or god will follow. If one dies with a negative state of mind, this will ripen negative karma and a lower rebirth such as an animal, ghost, or hell-being will follow. In Tibetan Buddhism the Tibetan Book of the Dead explains the intermediate state of humans between death and reincarnation. The deceased will find the bright light of wisdom, which shows a straightforward path to move upward and leave the cycle of reincarnation. There are various reasons why the deceased do not follow that light. Some had no briefing about the intermediate state in the former life. Others only used to follow their basic instincts like animals. And some have fear, which results from foul deeds in the former life or from insistent haughtiness. In the intermediate state the awareness is very flexible, so it is important to be virtuous, adopt a positive attitude, and avoid negative ideas. Ideas which are rising from subconsciousness can cause extreme tempers and cowing visions. In this situation they have to understand, that these manifestations are just reflections of the inner thoughts. No one can really hurt them, because they have no more material body. The deceased get help from different Buddhas who show them the path to the bright light. The ones who do not follow the path after all will get hints for a better reincarnation. They have to release the things and beings on which or whom they still hang from the life before. It is recommended to choose a family where the parents trust in the Dharma and to reincarnate with the will to care for the welfare of all beings. Sikhs also believe in reincarnation. They believe that the soul belongs to the spiritual universe which has its origins in God. It is like a see-saw, the amount of good done in life will store up blessings, thus uniting with God. A soul may need to live many lives before it is one with God. But there is more to it than this; there are four classes that are included in this belief...Above these four classes is God "Waheguru" and you can stay with him if you like or take another step and go to your people and serve them. Below these four classes are non humans such as plants and viruses. You move up and down according to your deeds, a good life and death moves you up to a higher class and a bad life and death results in going down a class.Bolo satnam waheguru. ### Other believers in reincarnation Rosicrucians, in the same way of those who have had near-death experiences, speak of a life review period occurring immediately after death and before entering the afterlife's planes of existence (before the silver cord is broken), followed by a judgment, more akin to a Final Review or End Report over one's life. Some Neopagans believe in personal reincarnation, whereas some believe that the energy of one's soul reintegrates with a continuum of such energy which is recycled into other living things as they are born. Many Wiccans, though not all, profess a belief in an afterlife called the Summerland, a peaceful and sunny place where the souls of the newly dead are sent. Here, souls rest, recuperate from life, and reflect on the experiences they had during their lives. After a period of rest, the souls are reincarnated, and the memory of their previous lives is erased. Shi'a Muslims believe to Raj'a that can be understood as a limited reincarnation.	Afterlife The terms afterlife or life after death refer to the continuation of existence of the soul, spirit or mind of a human (or animal) after physical death, sometimes in a spiritual or ghostlike afterworld. Deceased persons are usually believed to go to a specific region or plane of existence in the next life, often depending on the rightness of their actions during life. Some believe the afterlife can be another life in this world (reincarnation). The major views on the afterlife derive from religion, esotericism and metaphysics. There are those who are skeptical of the existence of the afterlife, or believe that it is absolutely impossible, such as the materialist-reductionists, who state that the topic is supernatural, therefore does not really exist or is unknowable. # Types of views on the afterlife There are two fundamentally different types of views on the afterlife: views claiming to be scientific and religious views. - The first type claims to be based on some form of an observation by a human or an instrument (for example a radio or a voice recorder, which are used in EVP)Template:Clarifyme. These observations come from reincarnation research, near death experiences, out-of-body experiences, astral projection, electronic voice phenomena, mediumship, various forms of photography etcetera. They are studied by survivalism. The work of people like Bruce Moen and Robert Monroe are also of this type. Also scientific research into near death experiences based on observation, for example the work of Pim van Lommel. [1] - The second type is based on some form of faith, usually faith in the stories that are told by ancestors or faith in religious books like the Bible, the Qur'an, the Talmud, the Vedas, the Tripitaka et cetera. This article is mainly about this second type. # The afterlife in different metaphysical models In metaphysical models, theists generally believe some sort of afterlife awaits people when they die. Atheists generally do not believe that there is an afterlife. Members of some generally non-theistic religions such as Buddhism, tend to believe in an afterlife like reincarnation but without reference to God. Agnostics generally hold the position that like the existence of God, the existence of supernatural phenomena, such as souls or life after death, is unverifiable and therefore unknowable. Some philosophies (i.e. posthumanism, Humanism, and often empiricism) generally hold that there is not an afterlife. Many religions, whether they believe in the soul’s existence in another world like Christianity, Islam and many pagan belief systems, or in reincarnation like many forms of Hinduism and Buddhism, believe that one’s status in the afterlife is a reward or punishment for their conduct during life. # Afterlife research in the early 20th century Science, in general, either describes the universe and human beings without reference to a soul or to an afterlife, or tends to remain mute on the issue. A notable exception is a famous study conducted in 1901 by physician Duncan MacDougall, who sought to measure the weight purportedly lost by a human body when the soul departed the body upon death.[2] MacDougall weighed dying patients in an attempt to prove that the soul was material, tangible and thus measurable. These experiments are widely considered to have had little if any scientific merit, and although MacDougall's results varied considerably from "21 grams," for some people this figure has become synonymous with the measure of a soul's mass.[3] The title of the 2003 movie 21 Grams is a reference to MacDougall's findings. # Afterlife in modern science Some, such as Francis Crick in 1994, have attempted a ‘scientific search for the soul’.[4] Frank Tipler has argued that physics can explain immortality, though such arguments are not falsifiable and thus do not qualify as science.[5] Some investigations have been conducted which failed to find evidence that “out-of-body” experiences transcend the confines of the brain. For example, one hospital placed an LED marquee above its patients’ beds which displayed a hidden message that could only be read if one were looking down from above. As of 2001, no one who claimed near-death experience or out-of-body experience within that hospital had reported having seen the hidden message. [6] # Afterlife in Ancient Egyptian religion The afterlife played an important role in Ancient Egyptian religion, and its belief system is one of the earliest known. When the body died, parts of its soul known as ka (body double) and the ba (personality) would go to the Kingdom of the Dead. While the soul dwelt in the Fields of Aaru, Osiris demanded work as payback for the protection he provided. Statues were placed in the tombs to serve as substitutes for the deceased. Arriving at one's reward in afterlife was a demanding ordeal, requiring a sin-free heart and the ability to recite the spells, passwords, and formulae of the Book of the Dead. In the Hall of Two Truths, the deceased's heart was weighed against the Shu feather of truth and justice taken from the headdress of the goddess Ma'at.[7] If the heart was lighter than the feather, they could pass on, but if it were heavier they would be devoured by the demon Ammit. Egyptians also believed that being mummified was the only way to have an afterlife. Only if the corpse had been properly embalmed and entombed in a mastaba, could the dead live again in the Fields of Yalu and accompany the Sun on its daily ride. Due to the dangers the afterlife posed, the Book of the Dead was placed in the tomb with the body. # Afterlife in Zoroastrianism Zoroaster, who lived in Iran around 1000 BCE, teaches that the dead will be swallowed by terror and purified to live in a perfected material world at the end of time. The Pahlavi text Dadestan-i Denig ("Religious Decisions") from about 900 CE, describes the particular judgment of the soul three days after death, with each soul sent to heaven, hell, or a neutral place (hamistagan) to await Judgment Day. # Afterlife in ancient Greek and Roman religion In the Odyssey, Homer refers to the dead as "burnt-out wraiths." An afterlife of eternal bliss exists in Elysium, but is reserved for Zeus's mortal descendants. In his Myth of Er, Plato describes souls being judged immediately after death and sent either to the heavens for a reward or underground for punishment. After their respective judgments have been enjoyed or suffered, the souls are reincarnated. The Greek god Hades is known in Greek mythology as the king of the underworld, a bleak place in between the place of torment and the place of rest, where most souls live after death. Some heroes of Greek legend are allowed to visit the underworld. The Romans had a similar belief system about the afterlife, with Hades becoming known as Pluto. The Trojan prince Aeneas, who founds the nation that would later become Rome, visits the underworld according to the epic poem Aeneid. # Afterlife in Norse religion The Poetic and Prose Eddas, the oldest sources for information on the Norse concept of the afterlife, vary in their description of the several realms that are described as falling under this topic. The most well-known are: - Valhalla: (lit. "Hall of the Slain" i.e. "the Chosen Ones") This heavenly abode, somewhat analogous to the Greek Elysium, is reserved for those brave warriors who die heroically in battle. - Hel: (lit. "The Covered Hall") This abode is somewhat like Hades from Ancient Greek religion: there, something not unlike the Asphodel Meadows can be found, and people who have neither excelled in that which is good nor excelled in that which is bad can expect to go there after they die and be reunited with their loved ones. - Niflhel: (lit. "The Dark" or "Misty Hel") This realm is roughly analogous to Greek Tartarus. It is the deeper level beneath Hel, and those who break oaths, abduct and rape women, and other vile things will be sent there to be among their kind to suffer some pretty harsh punishments. # Afterlife in Abrahamic religions ## Judaism Writing that would later be incorporated into the Hebrew Bible names sheol as the afterlife, a gloomy place where all are destined to go after death. The Book of Numbers identifies sheol as literally underground (Template:Niv), in the Biblical account of the destruction of the rebellious Korah, Dathan and Abiram and their 250 followers, although it is speculated that this passage should be read literally, signifying an earthquake or split in the earth. The Talmud offers a number of thoughts relating to the afterlife. After death, the soul is brought for judgment. Those who have lead pristine lives enter immediately into the "World to Come." Most do not enter the World to Come immediately, but now experience a period of review of their earthly actions and they are made aware of what they have done wrong. Some view this period as being a "re-schooling", with the soul gaining wisdom as one's errors are reviewed. Others view this period to include punishment for past wrongs. At the end of this period, approximately one year, the soul then takes its place in the World to Come. Although punishments are made part of certain Jewish conceptions of the afterlife, the concept of "eternal damnation," so prevalent in other religions, is not a central tenet of the Jewish afterlife. According to the Talmud, eternal punishment is reserved for a much smaller group of malicious and evil leaders, either whose deeds go way beyond norms, or who lead large groups of people to evil. In the Talmud, completed by 500 CE, eternal damnation is reserved for the Caesar of Rome, for example, along with other individuals who led many to evil. The modern-day example of someone who would merit eternal damnation in Jewish thought would be Hitler. The Book of Enoch describes sheol as divided into four compartments for four types of the dead: the faithful saints who await resurrection in Paradise, the merely virtuous who await their reward, the wicked who await punishment, and the wicked who have already been punished and will not be resurrected on Judgment Day.[8] It should be noted that the Book of Enoch is considered apocryphal by most denominations of Christianity and all denominations of Judaism. The book of 2 Maccabees gives a clear account of the dead awaiting a future resurrection and judgment, plus prayers and offerings for the dead to remove the burden of sin. Maimonides describes the Olam Haba ("World to Come") in spiritual terms, relegating the prophesied physical resurrection to the status of a future miracle, unrelated to the afterlife or the Messianic era. According to Maimonides, an afterlife continues for the soul of every human being, a soul now separated from the body in which it was "housed" during its earthly existence. The Zohar describes Gehenna not as a place of punishment for the wicked but as a place of spiritual purification for the souls of almost all mortals.[1] ## Christianity ### The Early Church: 1st century Jesus and the New Testament writers of the Bible books mention notions of an afterlife and resurrection that involve ideas like heaven and hell. The author of Luke recounts the story of Lazarus and the rich man, which shows people in Hades awaiting the resurrection either in comfort or torment. The author of the Book of Revelation writes about God and the angels versus Satan and demons in an epic battle at the end of times when all souls are judged. There is mention of ghostly bodies of past prophets, and the transfiguration. ### The Early Church: 2nd and 3rd century The non-canonical Acts of Paul and Thecla speak of the efficacy of prayer for the dead, so that they might be "translated to a state of happiness."[9] Hippolytus of Rome pictures Hades as a place where the righteous dead, awaiting in the bosom of Abraham their resurrection, rejoice at their future prospect, while the unrighteous are tormented at the sight of the "lake of unquenchable fire" into which they are destined to be cast. ### The Early Church: 4th and 5th century Gregory of Nyssa discusses the long-before believed possibility of purification of souls after death.[10] Saint Augustine counters Pelagius, arguing that original sin means that the unbaptized go to hell, including infants, albeit with less suffering than is experienced by those guilty of actual sins. ### Medieval Christianity Pope Gregory I repeats the concept, articulated over a century earlier by Gregory of Nyssa that the saved suffer purification after death, in connection with which he wrote of "purgatorial flames". The noun "purgatorium" (Latin: place of cleansing[11]) is used for the first time to describe a state of painful purification of the saved after life. The same word in adjectival form (purgatorius -a -um, cleansing), which appears also in non-religious writing,[12] was already used by Christians such as Augustine of Hippo and Pope Gregory I to refer to an after-death cleansing. ### The Protestant Reformation Martin Luther denounces the doctrine of particular judgment, professing instead the belief that the soul sleeps until Judgment Day. John Calvin denounces Luther's doctrine, writing instead that the souls of the elect rest in blessedness while awaiting the resurrection of the dead. ### Swedenborg and the Enlightenment During the Age of Enlightenment, theologians and philosophers presented various philosophies and beliefs. A notable example is Emanuel Swedenborg who wrote some 18 theological works which describe in detail the nature of the afterlife according to his claimed spiritual experiences, the most famous of which is Heaven and Hell. On the other hand, the enlightenment produced more rationalist philosophies such as deism. Many deist freethinkers held that belief in an afterlife with reward and punishment was a necessity of reason and good moral order. ### Afterlife in Latter-Day Saints (Mormonism) President Joseph F. Smith of The Church of Jesus Christ of Latter-day Saints presents an elaborate vision of the Afterlife. It is revealed as the scene of an extensive missionary effort by righteous spirits to redeem those still in darkness - a spirit prison or "hell" where the spirits of the dead remain until judgement. It is divided into two parts: Spirit Prison and Paradise. Together these are also known as the Spirit World (also Abraham's Bosom; see Luke 16:19-25). They believe that Christ visited spirit prison (1 Peter 3:18-20) and opened the gate for those who repent to cross over to Paradise. This is similar to the Harrowing of Hell doctrine of some mainstream Christian faiths. Both Spirit Prison and Paradise are temporary according to Latter-day Saint beliefs. After the resurrection spirits are assigned "permanently" to three degrees of heavenly glory (1 Cor 15:44-42; Doctrine and Covenants, Section 76) or are cast with Satan into Outer Darkness. (See Doctrine and Covenants, Section 76.) This continues to be the belief system of most Mormons. ### Salvation, faith, and merit from ancient to modern Christianity Most Christians deny that entry into Heaven can be properly earned, rather it is a gift that is solely God's to give through his unmerited grace. This belief follows the theology of St. Paul: For it is by grace you have been saved, through faith--and this not from yourselves, it is the gift of God, not by works, so that no one can boast. The Augustinian, Thomist, Lutheran, and Calvinist theological traditions all emphasize the necessity of God's undeserved grace for salvation, and reject so-called Pelagianism, which would make man earn salvation through good works. Not all Christian sects accept this doctrine, leading many controversies on grace and free will, and the idea of predestination. In particular, the belief that heaven is a reward for good behavior is a common folk belief in Christian societies, even among members of churches which reject that belief. Christian theologians Thomas Aquinas and Jonathan Edwards wrote that the saved in heaven will delight in the suffering of the damned. Hell, however, doesn't fit modern, humanitarian concepts of punishment because it can't deter the unbeliever nor rehabilitate the damned, this however, does not affect the Christian belief which places Biblical teaching above the ideas of society. Some Christian believers have come to downplay the punishment of hell. Universalists teach that salvation is for all. Jehovah's Witnesses and Seventh-day Adventists, though they have among the strictest rules on how to conduct their lives, teach that sinners are destroyed rather than tortured forever. ### The dead as Angels in Heaven In the informal folk beliefs of many Christians, the souls of virtuous people ascend to Heaven and are converted into angels. More formal Christian theology makes a sharp distinction between angels, who were created by God before the creation of humanity, and saints, who are people who have received immortality from the grace of God through faith in the Son of God Jesus (John 3:16). ### Universalists Some sects, such as the Universalists, believe in universalism which holds that all will eventually be rewarded regardless of what they have done or believed. ### Jehovah's Witnesses Jehovah's Witnesses understand Ecclesiastes 9:5 to preclude an afterlife: For the living are conscious that they will die; but as for the dead, they are conscious of nothing at all, neither do they any more have wages, because the remembrance of them has been forgotten. They believe that following Armageddon a resurrection in the flesh[13] to an Edenic Earth[14] will be rewarded to both righteous and unrighteous (but not wicked) dead. Acts 24:15 states, "“I have hope toward God . . . that there is going to be a resurrection of both the righteous and the unrighteous.” Eternal death (non-existence) is the punishment for sin lacking repentance after Armageddon. Although those who are not dead when Armageddon occurs will be judged and possibly slain during Armageddon because of their potential regretless sins. They believe that death is the price for sinning (that is why most dead will be resurrected - they paid the price already).[15][16] ### The Modern Catholic Church In the 1990s, the Catechism of the Catholic Church defined hell not as punishment imposed on the sinner but rather as the sinner's self-exclusion from God. ## Islam The Islamic belief in the afterlife as stated in the Qur'an is unique, its official description is more detailed. The word used to describe Paradise in Islam is referred to as jannat and to describe Hell is jahannam. Jannat and Jahannam both have different levels. Souls will not get there until after the Judgment Day, but their level of comfort while in the grave depends on their belief in The God and hereafter, as well as their deeds during this life. The levels are 7 for Jannat and 5 for Hell. Islam teaches that the purpose of Mans creation is to worship the Creator of the Heavens and Earth, Allah, the Arabic word used to refer to The One and Only God of the Abrahamic Tradition. Islam teaches that life lived on this Earth is a test for man to determine each individuals ultimate Reward or Punishment in the Afterlife, which is eternal and everlasting. According to the Qur’an, the basic criteria for salvation in afterlife is: 1. The belief in one and only God 2. To believe in the afterlife, resurrection and Last Judgment 3. Performing good deeds and abstaining from bad actions 4. To believe in ALL the seen and unseen messengers of Allah: All of the Angels (i.e. Gabriel and Michael); All of the Prophets including Adam, Noah, Abraham, Jesus (including his miraculous birth and Second Coming), as well as believing that Muhammad is the last messenger of God, Peace and Blessings upon all of them. When one holds these to be true, then they are considered to be a Muslim, or one who submits to Allah, and should formally declare their Islam at their local masjid. # Afterlife as reincarnation An afterlife concept that is found among Hindus, Rosicrucians, Spiritists, and Wicca is reincarnation, as evolving humans life after life in the physical world, that is, acquiring a superior grade of consciousness and altruism by means of successive reincarnations. This succession is conceived to lead toward an eventual liberation or spiritual rebirth as spiritual beings. Some practitioners of eastern religions follow a different concept called metempsychosis which purposes that human beings can transmigrate into animals, vegetables, or even minerals.[citation needed] One consequence of the Hindu and Spiritist beliefs is that our current lives are also an afterlife. According to those beliefs events in our current life are consequences of actions taken in previous lives, or Karma. ### Eastern Religions The Upanishads describe reincarnation, or samsara. The Bhagavad Gita, an important book for Hinduism talks extensively about the afterlife. Here, the Lord Krishna says that just as a man discards his old clothes and wears new ones; similarly the soul discards the old body and takes on a new one. In Hinduism, the belief is that the body is but a shell, the soul inside is immutable and indestructible and takes on different lives in a cycle of birth and death. The end of this cycle is Moksha or salvation. However, not all Hindus believe in reincarnation. Buddhists believe that rebirth takes place without a self (similar to soul) and that the process of rebirth is simply a continuation of the previous life. The process of being reborn as any other being is based on your karma. From a Buddhist perspective, the current life is a continuation of the past life. If one dies with a peaceful state of mind, this will cause fortunate karma to ripen and a fortunate rebirth as a human or god will follow. If one dies with a negative state of mind, this will ripen negative karma and a lower rebirth such as an animal, ghost, or hell-being will follow. In Tibetan Buddhism the Tibetan Book of the Dead explains the intermediate state of humans between death and reincarnation. The deceased will find the bright light of wisdom, which shows a straightforward path to move upward and leave the cycle of reincarnation. There are various reasons why the deceased do not follow that light. Some had no briefing about the intermediate state in the former life. Others only used to follow their basic instincts like animals. And some have fear, which results from foul deeds in the former life or from insistent haughtiness. In the intermediate state the awareness is very flexible, so it is important to be virtuous, adopt a positive attitude, and avoid negative ideas. Ideas which are rising from subconsciousness can cause extreme tempers and cowing visions. In this situation they have to understand, that these manifestations are just reflections of the inner thoughts. No one can really hurt them, because they have no more material body. The deceased get help from different Buddhas who show them the path to the bright light. The ones who do not follow the path after all will get hints for a better reincarnation. They have to release the things and beings on which or whom they still hang from the life before. It is recommended to choose a family where the parents trust in the Dharma and to reincarnate with the will to care for the welfare of all beings. Sikhs also believe in reincarnation. They believe that the soul belongs to the spiritual universe which has its origins in God. It is like a see-saw, the amount of good done in life will store up blessings, thus uniting with God. A soul may need to live many lives before it is one with God. But there is more to it than this; there are four classes that are included in this belief...Above these four classes is God "Waheguru" and you can stay with him if you like or take another step and go to your people and serve them. Below these four classes are non humans such as plants and viruses. You move up and down according to your deeds, a good life and death moves you up to a higher class and a bad life and death results in going down a class.Bolo satnam waheguru. ### Other believers in reincarnation Rosicrucians,[17] in the same way of those who have had near-death experiences, speak of a life review period occurring immediately after death and before entering the afterlife's planes of existence (before the silver cord is broken), followed by a judgment, more akin to a Final Review or End Report over one's life.[18] Some Neopagans believe in personal reincarnation, whereas some believe that the energy of one's soul reintegrates with a continuum of such energy which is recycled into other living things as they are born.[citation needed] Many Wiccans, though not all, profess a belief in an afterlife called the Summerland, a peaceful and sunny place where the souls of the newly dead are sent. Here, souls rest, recuperate from life, and reflect on the experiences they had during their lives. After a period of rest, the souls are reincarnated, and the memory of their previous lives is erased. Shi'a Muslims believe to Raj'a that can be understood as a limited reincarnation.	https://www.wikidoc.org/index.php/Afterlife
8386525c53fa11bc9dded339e515efca603fb045	wikidoc	Afterload	Afterload # Overview In cardiac physiology, afterload is used to mean the tension produced by a chamber of the heart in order to contract. If the chamber is not mentioned, it is usually assumed to be the left ventricle. However, the strict definition of the term relates to the properties of a single cardiac myocyte. It is therefore only of direct relevance in the laboratory; in the clinic, the term end-systolic pressure is usually more appropriate, although not equivalent. Afterload can also be described as the pressure that the chamber of the heart has to generate in order to eject blood out of the chamber. Everything else held equal, as afterload increases, cardiac output decreases. In the case of the left ventricle, the afterload is a consequence of the blood pressure, since the pressure in the ventricle must be greater than the peripheral blood pressure in order to open the aortic valve. # Pathology Disease processes that increase the left ventricular afterload include increased blood pressure and aortic valve disease. Hypertension (Increased blood pressure) increases the left ventricular afterload because the left ventricle has to work harder to eject blood into the aorta. This is because the aortic valve won't open until the pressure generated in the left ventricle is higher than the elevated blood pressure. Aortic stenosis increases the afterload because the left ventricle has to overcome the pressure gradient caused by the stenotic aortic valve in addition to the blood pressure in order to eject blood into the aorta. For instance, if the blood pressure is 120/80, and the aortic valve stenosis creates a trans-valvular gradient of 30 mmHg, the left ventricle has to generate a pressure of 150 mmHg in order to open the aortic valve and eject blood into the aorta. Aortic insufficiency increases afterload because a percentage of the blood that is ejected forward regurgitates back through the diseased aortic valve. This leads to elevated systolic blood pressure as well as dialostic blood pressure. Mitral regurgitation decreases the afterload. During ventricular systole, the blood can regurgitate through the diseased mitral valve as well as be ejected through the aortic valve. This means that the left ventricle has to work less to eject blood, causing a decreased afterload. Afterload is largely dependent upon aortic pressure.	Afterload Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor: Cafer Zorkun, M.D., Ph.D. [2] # Overview In cardiac physiology, afterload is used to mean the tension produced by a chamber of the heart in order to contract. If the chamber is not mentioned, it is usually assumed to be the left ventricle. However, the strict definition of the term relates to the properties of a single cardiac myocyte. It is therefore only of direct relevance in the laboratory; in the clinic, the term end-systolic pressure is usually more appropriate, although not equivalent. Afterload can also be described as the pressure that the chamber of the heart has to generate in order to eject blood out of the chamber. Everything else held equal, as afterload increases, cardiac output decreases. In the case of the left ventricle, the afterload is a consequence of the blood pressure, since the pressure in the ventricle must be greater than the peripheral blood pressure in order to open the aortic valve. # Pathology Disease processes that increase the left ventricular afterload include increased blood pressure and aortic valve disease. Hypertension (Increased blood pressure) increases the left ventricular afterload because the left ventricle has to work harder to eject blood into the aorta. This is because the aortic valve won't open until the pressure generated in the left ventricle is higher than the elevated blood pressure. Aortic stenosis increases the afterload because the left ventricle has to overcome the pressure gradient caused by the stenotic aortic valve in addition to the blood pressure in order to eject blood into the aorta. For instance, if the blood pressure is 120/80, and the aortic valve stenosis creates a trans-valvular gradient of 30 mmHg, the left ventricle has to generate a pressure of 150 mmHg in order to open the aortic valve and eject blood into the aorta. Aortic insufficiency increases afterload because a percentage of the blood that is ejected forward regurgitates back through the diseased aortic valve. This leads to elevated systolic blood pressure as well as dialostic blood pressure. Mitral regurgitation decreases the afterload. During ventricular systole, the blood can regurgitate through the diseased mitral valve as well as be ejected through the aortic valve. This means that the left ventricle has to work less to eject blood, causing a decreased afterload. Afterload is largely dependent upon aortic pressure.	https://www.wikidoc.org/index.php/Afterload
1b100eae7e62b7c7af7f97e4f683366544da90d0	wikidoc	Tirofiban	Tirofiban # 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 Tirofiban is a platelet aggregation inhibitor that is FDA approved for the treatment of reduce the rate of thrombotic cardiovascular events. Common adverse reactions include bradyarrhythmia, bleeding, pain in pelvis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Reduction the rate of thrombotic cardiovascular events - Dosing information - 25 mcg/kg IV over 3 minutes and then 0.15 mcg/kg/min (or 0.075 mcg/kg/min for patients with serum creatinine ≤60 mL/min), for up to 18 hours. This is not the regimen that was used in studies that established effectiveness of Tirofiban . - The instructions by weight and creatinine clearance are tabulated in Table 1. - Important Administration Instructions - To open the container, first tear off its foil overpouch. The plastic may be somewhat opaque because of moisture absorption during sterilization; the opacity will diminish gradually. Check for leaks by squeezing the inner bag firmly; if any leaks are found or sterility is suspect then the solution should be discarded. Do not use unless the solution is clear and the seal is intact. Suspend the container from its eyelet support, remove the plastic protector from the outlet port, and attach a conventional administration set. - You may administer Tirofiban in the same intravenous line as atropine sulfate, dobutamine, dopamine, epinephrine hydrochloride (HCl), famotidine injection, furosemide, lidocaine, midazolam HCl, morphine sulfate, nitroglycerin, potassium chloride, and propranolol HCl. :* :- Do not administer Tirofiban through the same IV line as diazepam. - Do not add other drugs or remove solution directly from the bag with a syringe. - Do not use plastic containers in series connections; such use can result in air embolism by drawing air from the first container if it is empty of solution. - Discard any unused portion left in the bag. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tirofiban sandbox in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tirofiban sandbox in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tirofiban sandbox in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tirofiban sandbox in pediatric patients. # Contraindications - Severe hypersensitivity reaction to Tirofiban (i.e., anaphylactic reactions) . - A history of thrombocytopenia following prior exposure to Tirofiban . - Active internal bleeding or a history of bleeding diathesis, major surgical procedure or severe physical trauma within the previous month # Warnings ## General Risk of Bleeding Bleeding is the most common complication encountered during therapy with Tirofiban. Most bleeding associated with Tirofiban occurs at the arterial access site for cardiac catheterization. Minimize the use of traumatic or potentially traumatic procedures such arterial and venous punctures, intramuscular injections, nasotracheal intubation, etc. Fatal bleeding events have been reported . Concomitant use offibrinolytics, oral anticoagulants and antiplatelet drugs increases the risk of bleeding. ## Thrombocytopenia Profound thrombocytopenia has been reported with Tirofiban. Monitor platelet counts beginning about 6 hours after treatment initiation and daily thereafter. If the platelet count decreases to less than 90,000/mm3, monitor platelet counts to exclude pseudothrombocytopenia. If thrombocytopenia is confirmed, discontinue Tirofiban and heparin. Previous exposure to a glycoprotein (GP) IIb/IIIa receptor antagonist may increase the risk of developing thrombocytopenia . # 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. In the PRISM (Platelet Receptor Inhibition for Ischemic Syndrome Management), PRISM-PLUS (Platelet Receptor Inhibition for Ischemic Syndrome Management — Patients Limited by Unstable Signs and Symptoms) and RESTORE (Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis) trials, 1946 patients received Tirofiban in combination with heparin and 2002 patients received Tirofiban alone for about 3 days. Forty-three percent of the population was greater than 65 years of age and approximately 30% of patients were female. In clinical studies with the recommended regimen (25 mcg/kg bolus followed by a 0.15 mcg/kg/min maintenance infusion), Tirofiban was administered in combination with aspirin, clopidogrel and heparin or bivalirudin to over 8000 patients for typically ≤24 hours. Approximately 30% of the population was >65 years of age and approximately 25% were female. ### Bleeding PRISM-PLUS Regimen The incidences of major and minor bleeding using the TIMI criteria in the PRISM-PLUS study are shown below. ## Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of Tirofiban. 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 the drug exposure. Hypersensitivity: Severe allergic reactions including anaphylactic reactions have occurred during the first day of Tirofiban infusion, during initial treatment, and during readministration of Tirofiban. Some cases have been associated with severe thrombocytopenia (platelet counts less than 10,000/mm3). No information is available on the formation of antibodies to tirofiban. # Drug Interactions Use ofthrombolytics, anticoagulants, and other antiplatelet agents. Coadministration of antiplatelet agents, thrombolytics, heparin, and aspirin increases the risk of bleeding. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B There are no adequate and well-controlled studies in pregnant women. Tirofiban has been shown to cross the placenta in pregnant rats and rabbits. Studies with tirofiban HCl at intravenous doses up to 5 mg/kg/day (about 5 and 13 times the maximum recommended daily human dose for rat and rabbit, respectively, when compared on a body surface area basis) have revealed no harm to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tirofiban in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tirofiban during labor and delivery. ### Nursing Mothers It is not known whether tirofiban is excreted in human milk. However, significant levels of tirofiban were shown to be present in rat milk. Because many drugs are excreted in human milk, and because of the potential for adverse effects on the nursing infant, discontinue nursing or discontinue Tirofiban. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use Of the total number of patients in controlled clinical studies of Tirofiban, 43% were 65 years and over, while 12% were 75 and over. With respect to efficacy, the effect of Tirofiban in the elderly (≥65 years) appeared similar to that seen in younger patients (less than 65 years). Elderly patients receiving Tirofiban with heparin or heparin alone had a higher incidence of bleeding complications than did younger patients, but the incremental risk of bleeding in patients treated with Tirofiban in combination with heparin compared to the risk in patients treated withheparin alone was similar regardless of age. No dose adjustment is recommended for the elderly population . ### Gender There is no FDA guidance on the use of Tirofiban with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tirofiban with respect to specific racial populations. ### Renal Impairment Patients with moderate to severerenal insufficiency have decreased plasma clearance of Tirofiban. Reduce the dosage of Tirofiban in patients with severe renal insufficiency . Safety and efficacy of Tirofiban has not been established in patients on hemodialysis. ### Hepatic Impairment There is no FDA guidance on the use of Tirofiban in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tirofiban in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tirofiban in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Tirofiban Administration in the drug label. ### Monitoring There is limited information regarding Tirofiban Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Tirofiban and IV administrations. # Overdosage In clinical trials, inadvertent overdosage with Tirofiban occurred in doses up to 2 times the recommended dose for initial infusion doses. Inadvertent overdosage occurred in doses up to 9.8 times the 0.15 mcg/kg/min maintenance infusion rate. The most frequently reported manifestation of overdosage was bleeding, primarily minor mucocutaneous bleeding events and minor bleeding at the sites of cardiac catheterization . Overdosage of Tirofiban should be treated by assessment of the patient’s clinical condition and cessation or adjustment of the drug infusion as appropriate. Tirofiban can be removed by hemodialysis. # Pharmacology ## Mechanism of Action Tirofiban is a reversible antagonist of fibrinogen binding to the GP IIb/IIIa receptor, the major platelet surface receptor involved in platelet aggregation. When administered intravenously, Tirofiban inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. When given according to the PRISM-PLUS regimen of 0.4 mcg/kg/min for 30 minutes followed by a 0.1 mcg/kg/min maintenance infusion, greater than 90% inhibition of platelet aggregation is attained by the end of the 30-minute infusion. When given according to the recommended regimen of 25 mcg/kg over 3 min followed by a 0.15 mcg/kg/min maintenance infusion, greater than 90% inhibition of platelet aggregation is attained within 10 minutes. Platelet aggregation inhibition is reversible following cessation of the infusion of Tirofiban. ## Structure Tirofiban contains tirofiban hydrochloride, a non-peptide antagonist of the platelet GP IIb/IIIa receptor, inhibits platelet aggregation. Tirofiban hydrochloride monohydrate is chemically described as N(butylsulfonyl)-O--L-tyrosine monohydrochloride monohydrate. Its molecular formula is C22H36N2O5SHClH2O and its structural formula is: Tirofiban hydrochloride monohydrate is a white to off-white, non-hygroscopic, free-flowing powder, with a molecular weight of 495.08. It is very slightly soluble in water. Tirofiban Injection Premixed is supplied as a sterile solution in water for injection, for intravenous use only, in plastic containers of 100 mL or 250 mL. Each 100 mL of the premixed, iso-osmotic intravenous injection contains 5.618 mg tirofiban hydrochloride monohydrate equivalent to 5 mg tirofiban (50 mcg/mL) and the following inactive ingredients: 0.9 g sodium chloride, 54 mg sodium citrate dihydrate, and 3.2 mg citric acid anhydrous. Each 250 mL of the premixed, iso-osmotic intravenous injection contains 14.045 mg tirofiban hydrochloride monohydrate equivalent to 12.5 mg tirofiban (50 mcg/mL) and the following inactive ingredients: 2.25 g sodium chloride, 135 mg sodium citrate dihydrate, and 8 mg citric acid anhydrous. The pH of the solution ranges from 5.5 to 6.5 and may have been adjusted with hydrochloric acid and/or sodium hydroxide. The flexible container is manufactured from a specially designed multilayer plastic (PL 2408). Solutions in contact with the plastic container leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials. ## Pharmacodynamics Tirofiban inhibits platelet function, as demonstrated by its ability to inhibit ex vivo adenosine phosphate (ADP)-induced platelet aggregation and prolong bleeding time in healthy subjects and patients with coronary artery disease. The time course of inhibition parallels the plasma concentration profile of the drug. Following discontinuation of an infusion of Tirofiban 0.10 mcg/kg/min, ex vivo platelet aggregation returns to near baseline in 4 to 8 hours in approximately 90% of patients with coronary artery disease. The addition of heparin to this regimen does not significantly alter the percentage of subjects with >70% inhibition of platelet aggregation (IPA), but does increase the average bleeding time, as well as the number of patients with bleeding times prolonged to >30 minutes. Similar platelet aggregation recovery rates are observed following discontinuation of a 0.15 mcg/kg/min infusion. ## Pharmacokinetics Tirofiban has a half-life of approximately 2 hours. It is cleared from the plasma largely by renal excretion, with about 65% of an administered dose appearing in urine and about 25% in feces, both largely as unchanged tirofiban. Metabolism appears to be limited. Tirofiban is not highly bound to plasma proteins and protein binding is concentration independent over the range of 0.01 to 25 mcg/mL. The unbound fraction in human plasma is 35%. The steady state volume of distribution of tirofiban ranges from 22 to 42 liters. In healthy subjects, the plasma clearance of tirofiban ranges from 213 to 314 mL/min. Renal clearance accounts for 39 to 69% of plasma clearance. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of Tirofiban has not been evaluated. Tirofiban HCI was negative in the in vitro microbial mutagenesis and V-79 mammalian cell mutagenesis assays. In addition, there was no evidence of direct genotoxicity in the in vitro alkaline elution and in vitro chromosomal aberration assays. There was no induction of chromosomal aberrations in bone marrow cells of male mice after the administration of intravenous doses up to 5 mg tirofiban/kg (about 3 times the maximum recommended daily human dose when compared on a body surface area basis). Fertility and reproductive performance were not affected in studies with male and female rats given intravenous doses of tirofiban up to 5 mg/kg/day (about 5 times the maximum recommended daily human dose when compared on a body surface area basis). # Clinical Studies Two large-scale clinical studies established the efficacy of Tirofiban in the treatment of patients with NSTE-ACS (unstable angina/]non-ST elevation MI). The two studies examined Tirofiban alone and added to heparin, prior to and after percutaneous coronary revascularization (if indicated) (PRISM-PLUS) and in comparison to heparin in a similar population (PRISM). These trials are discussed in detail below. PRISM-PLUS (Platelet Receptor Inhibition for Ischemic Syndrome Management — Patients Limited by Unstable Signs and Symptoms) In the double-blind PRISM-PLUS trial, 1570 patients with documented NSTE-ACS within 12 hours of entry into the study were randomized to Tirofiban (30 minute initial infusion of 0.4 mcg/kg/min followed by a maintenance infusion of 0.10 mcg/kg /min) in combination with heparin (bolus of 5,000 U followed by an infusion of 1,000 U/h titrated to maintain an APTT of approximately 2 times control) or to heparin alone. All patients received concomitant aspirin unless contraindicated. Patients who were medically managed or who underwent revascularization procedures were studied. Patients underwent 48 hours of medical stabilization on study drug therapy, and they were to undergo angiography before 96 hours (and, if indicated, angioplasty/atherectomy, while continuing on Tirofiban and heparin for 12-24 hours after the procedure). Tirofiban and heparin could be continued for up to 108 hours. Exclusions included contraindications to anticoagulation, decompensated heart failure, platelet count 2.5 mg/dL. The mean age of the population was 63 years; 32% of patients were female and approximately half of the population presented with non-ST elevation myocardial infarction. On average, patients received Tirofiban for 71 hours. A third group of patients was initially randomized to Tirofiban alone (no heparin). This arm was stopped when the group was found, at an interim look, to have greater mortality than the other two groups. The primary endpoint of the study was a composite of refractory ischemia, new MI and death within 7 days. There was a 32% risk reduction in the overall composite primary endpoint. The components of the composite were examined separately and the results are shown in Table 5. Note that the sum of the individual components may be greater than the composite (if a patient experiences multiple component events only one event counts towards the composite). The benefit seen at 7 days was maintained over time. The risk reduction in the composite endpoint at 30 days and 6 months is shown in the Kaplan-Meier curve below. An analysis of the results by sex suggests that women who are medically managed or who undergo subsequent PTCA/atherectomy may receive less benefit from Tirofiban (95% confidence limits for relative risk of 0.61-1.74) than do men (0.43-0.89) (p=0.11). This difference may be a true treatment difference, the effect of other differences in these subgroups, or a chance occurrence. Approximately 90% of patients in the PRISM-PLUS study underwent coronary angiography and 30% underwent angioplasty/atherectomy during the first 30 days of the study. The majority of these patients continued on study drug throughout these procedures. Tirofiban was continued for 12-24 hours (average 15 hours) after angioplasty/atherectomy. The effects of Tirofiban at Day 30 did not appear to differ among sub-populations that did or did not receive PTCA or CABG, both prior to and after the procedure. PRISM (Platelet Receptor Inhibition for Ischemic Syndrome Management) In the PRISM study, a randomized, parallel, double-blind study, 3232 patients with NSTE-ACS intended to be managed without coronary intervention were randomized to Tirofiban (initial dose of 0.6 mcg/kg/min for 30 minutes followed by 0.15 mcg/kg/min for 47.5 hours) or heparin (5000-unit intravenous bolus followed by an infusion of 1000 U/h for 48 hours). The mean age of the population was 62 years; 32% of the population was female and 25% had non-ST elevation MI on presentation. Thirty percent had no ECG evidence of cardiac ischemia. Exclusion criteria were similar to PRISM-PLUS. The primary endpoint was the composite endpoint of refractory ischemia, MI or death at the end of the 48-hour drug infusion. The results are shown in Table 6. In the PRISM study, no adverse effect of Tirofiban on mortality at either 7 or 30 days was detected. This result is different from that in the PRISM-PLUS study, where the arm that included Tirofiban without heparin (n=345) was dropped at an interim analysis by the Data Safety Monitoring Committee for increased mortality at 7 days. # How Supplied There is limited information regarding Tirofiban How Supplied in the drug label. ## Storage There is limited information regarding Tirofiban Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise patients to watch closely for any signs of bleeding or bruising and to report these to their health care provider when they occur. Advise patients to discuss with their health care provider their use of any other medications, including over-the-counter or herbal products prior to Tirofiban use. Patent: www.medicure.com/Tirofiban/patents Tirofiban is manufactured for: MEDICURE INTERNATIONAL, INC. by: BAXTER HEALTHCARE CORPORATION Deerfield, Illinois 60015 USA Distributed by: MEDICURE PHARMA, INC. Somerset, NJ 08873 USA Printed in USA - Registered trademark of Medicure International Inc. Copyright used under license. All rights reserved. Intravia is a registered trademark of Baxter International Inc. alcohol=Alcohol-Tirofiban sandbox interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Precautions with Alcohol Alcohol-Tirofiban interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names AGGRASTAT # Look-Alike Drug Names Tirofiban - argatroban # Drug Shortage Status # Price	Tirofiban Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2];Aparna Vuppala, M.B.B.S. [3] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Tirofiban is a platelet aggregation inhibitor that is FDA approved for the treatment of reduce the rate of thrombotic cardiovascular events. Common adverse reactions include bradyarrhythmia, bleeding, pain in pelvis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Reduction the rate of thrombotic cardiovascular events - Dosing information - 25 mcg/kg IV over 3 minutes and then 0.15 mcg/kg/min (or 0.075 mcg/kg/min for patients with serum creatinine ≤60 mL/min), for up to 18 hours. This is not the regimen that was used in studies that established effectiveness of Tirofiban . - The instructions by weight and creatinine clearance are tabulated in Table 1. - Important Administration Instructions - To open the container, first tear off its foil overpouch. The plastic may be somewhat opaque because of moisture absorption during sterilization; the opacity will diminish gradually. Check for leaks by squeezing the inner bag firmly; if any leaks are found or sterility is suspect then the solution should be discarded. Do not use unless the solution is clear and the seal is intact. Suspend the container from its eyelet support, remove the plastic protector from the outlet port, and attach a conventional administration set. - You may administer Tirofiban in the same intravenous line as atropine sulfate, dobutamine, dopamine, epinephrine hydrochloride (HCl), famotidine injection, furosemide, lidocaine, midazolam HCl, morphine sulfate, nitroglycerin, potassium chloride, and propranolol HCl. :* :* Do not administer Tirofiban through the same IV line as diazepam. - Do not add other drugs or remove solution directly from the bag with a syringe. - Do not use plastic containers in series connections; such use can result in air embolism by drawing air from the first container if it is empty of solution. - Discard any unused portion left in the bag. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tirofiban sandbox in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tirofiban sandbox in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tirofiban sandbox in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tirofiban sandbox in pediatric patients. # Contraindications - Severe hypersensitivity reaction to Tirofiban (i.e., anaphylactic reactions) . - A history of thrombocytopenia following prior exposure to Tirofiban . - Active internal bleeding or a history of bleeding diathesis, major surgical procedure or severe physical trauma within the previous month # Warnings ## General Risk of Bleeding Bleeding is the most common complication encountered during therapy with Tirofiban. Most bleeding associated with Tirofiban occurs at the arterial access site for cardiac catheterization. Minimize the use of traumatic or potentially traumatic procedures such arterial and venous punctures, intramuscular injections, nasotracheal intubation, etc. Fatal bleeding events have been reported . Concomitant use offibrinolytics, oral anticoagulants and antiplatelet drugs increases the risk of bleeding. ## Thrombocytopenia Profound thrombocytopenia has been reported with Tirofiban. Monitor platelet counts beginning about 6 hours after treatment initiation and daily thereafter. If the platelet count decreases to less than 90,000/mm3, monitor platelet counts to exclude pseudothrombocytopenia. If thrombocytopenia is confirmed, discontinue Tirofiban and heparin. Previous exposure to a glycoprotein (GP) IIb/IIIa receptor antagonist may increase the risk of developing thrombocytopenia . # 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. In the PRISM (Platelet Receptor Inhibition for Ischemic Syndrome Management), PRISM-PLUS (Platelet Receptor Inhibition for Ischemic Syndrome Management — Patients Limited by Unstable Signs and Symptoms) and RESTORE (Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis) trials, 1946 patients received Tirofiban in combination with heparin and 2002 patients received Tirofiban alone for about 3 days. Forty-three percent of the population was greater than 65 years of age and approximately 30% of patients were female. In clinical studies with the recommended regimen (25 mcg/kg bolus followed by a 0.15 mcg/kg/min maintenance infusion), Tirofiban was administered in combination with aspirin, clopidogrel and heparin or bivalirudin to over 8000 patients for typically ≤24 hours. Approximately 30% of the population was >65 years of age and approximately 25% were female. ### Bleeding PRISM-PLUS Regimen The incidences of major and minor bleeding using the TIMI criteria in the PRISM-PLUS study are shown below. ## Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of Tirofiban. 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 the drug exposure. Hypersensitivity: Severe allergic reactions including anaphylactic reactions have occurred during the first day of Tirofiban infusion, during initial treatment, and during readministration of Tirofiban. Some cases have been associated with severe thrombocytopenia (platelet counts less than 10,000/mm3). No information is available on the formation of antibodies to tirofiban. # Drug Interactions Use ofthrombolytics, anticoagulants, and other antiplatelet agents. Coadministration of antiplatelet agents, thrombolytics, heparin, and aspirin increases the risk of bleeding. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B There are no adequate and well-controlled studies in pregnant women. Tirofiban has been shown to cross the placenta in pregnant rats and rabbits. Studies with tirofiban HCl at intravenous doses up to 5 mg/kg/day (about 5 and 13 times the maximum recommended daily human dose for rat and rabbit, respectively, when compared on a body surface area basis) have revealed no harm to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tirofiban in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tirofiban during labor and delivery. ### Nursing Mothers It is not known whether tirofiban is excreted in human milk. However, significant levels of tirofiban were shown to be present in rat milk. Because many drugs are excreted in human milk, and because of the potential for adverse effects on the nursing infant, discontinue nursing or discontinue Tirofiban. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use Of the total number of patients in controlled clinical studies of Tirofiban, 43% were 65 years and over, while 12% were 75 and over. With respect to efficacy, the effect of Tirofiban in the elderly (≥65 years) appeared similar to that seen in younger patients (less than 65 years). Elderly patients receiving Tirofiban with heparin or heparin alone had a higher incidence of bleeding complications than did younger patients, but the incremental risk of bleeding in patients treated with Tirofiban in combination with heparin compared to the risk in patients treated withheparin alone was similar regardless of age. No dose adjustment is recommended for the elderly population . ### Gender There is no FDA guidance on the use of Tirofiban with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tirofiban with respect to specific racial populations. ### Renal Impairment Patients with moderate to severerenal insufficiency have decreased plasma clearance of Tirofiban. Reduce the dosage of Tirofiban in patients with severe renal insufficiency . Safety and efficacy of Tirofiban has not been established in patients on hemodialysis. ### Hepatic Impairment There is no FDA guidance on the use of Tirofiban in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tirofiban in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tirofiban in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Tirofiban Administration in the drug label. ### Monitoring There is limited information regarding Tirofiban Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Tirofiban and IV administrations. # Overdosage In clinical trials, inadvertent overdosage with Tirofiban occurred in doses up to 2 times the recommended dose for initial infusion doses. Inadvertent overdosage occurred in doses up to 9.8 times the 0.15 mcg/kg/min maintenance infusion rate. The most frequently reported manifestation of overdosage was bleeding, primarily minor mucocutaneous bleeding events and minor bleeding at the sites of cardiac catheterization . Overdosage of Tirofiban should be treated by assessment of the patient’s clinical condition and cessation or adjustment of the drug infusion as appropriate. Tirofiban can be removed by hemodialysis. # Pharmacology ## Mechanism of Action Tirofiban is a reversible antagonist of fibrinogen binding to the GP IIb/IIIa receptor, the major platelet surface receptor involved in platelet aggregation. When administered intravenously, Tirofiban inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. When given according to the PRISM-PLUS regimen of 0.4 mcg/kg/min for 30 minutes followed by a 0.1 mcg/kg/min maintenance infusion, greater than 90% inhibition of platelet aggregation is attained by the end of the 30-minute infusion. When given according to the recommended regimen of 25 mcg/kg over 3 min followed by a 0.15 mcg/kg/min maintenance infusion, greater than 90% inhibition of platelet aggregation is attained within 10 minutes. Platelet aggregation inhibition is reversible following cessation of the infusion of Tirofiban. ## Structure Tirofiban contains tirofiban hydrochloride, a non-peptide antagonist of the platelet GP IIb/IIIa receptor, inhibits platelet aggregation. Tirofiban hydrochloride monohydrate is chemically described as N(butylsulfonyl)-O-[4-(4-piperidinyl)butyl]-L-tyrosine monohydrochloride monohydrate. Its molecular formula is C22H36N2O5S•HCl•H2O and its structural formula is: Tirofiban hydrochloride monohydrate is a white to off-white, non-hygroscopic, free-flowing powder, with a molecular weight of 495.08. It is very slightly soluble in water. Tirofiban Injection Premixed is supplied as a sterile solution in water for injection, for intravenous use only, in plastic containers of 100 mL or 250 mL. Each 100 mL of the premixed, iso-osmotic intravenous injection contains 5.618 mg tirofiban hydrochloride monohydrate equivalent to 5 mg tirofiban (50 mcg/mL) and the following inactive ingredients: 0.9 g sodium chloride, 54 mg sodium citrate dihydrate, and 3.2 mg citric acid anhydrous. Each 250 mL of the premixed, iso-osmotic intravenous injection contains 14.045 mg tirofiban hydrochloride monohydrate equivalent to 12.5 mg tirofiban (50 mcg/mL) and the following inactive ingredients: 2.25 g sodium chloride, 135 mg sodium citrate dihydrate, and 8 mg citric acid anhydrous. The pH of the solution ranges from 5.5 to 6.5 and may have been adjusted with hydrochloric acid and/or sodium hydroxide. The flexible container is manufactured from a specially designed multilayer plastic (PL 2408). Solutions in contact with the plastic container leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials. ## Pharmacodynamics Tirofiban inhibits platelet function, as demonstrated by its ability to inhibit ex vivo adenosine phosphate (ADP)-induced platelet aggregation and prolong bleeding time in healthy subjects and patients with coronary artery disease. The time course of inhibition parallels the plasma concentration profile of the drug. Following discontinuation of an infusion of Tirofiban 0.10 mcg/kg/min, ex vivo platelet aggregation returns to near baseline in 4 to 8 hours in approximately 90% of patients with coronary artery disease. The addition of heparin to this regimen does not significantly alter the percentage of subjects with >70% inhibition of platelet aggregation (IPA), but does increase the average bleeding time, as well as the number of patients with bleeding times prolonged to >30 minutes. Similar platelet aggregation recovery rates are observed following discontinuation of a 0.15 mcg/kg/min infusion. ## Pharmacokinetics Tirofiban has a half-life of approximately 2 hours. It is cleared from the plasma largely by renal excretion, with about 65% of an administered dose appearing in urine and about 25% in feces, both largely as unchanged tirofiban. Metabolism appears to be limited. Tirofiban is not highly bound to plasma proteins and protein binding is concentration independent over the range of 0.01 to 25 mcg/mL. The unbound fraction in human plasma is 35%. The steady state volume of distribution of tirofiban ranges from 22 to 42 liters. In healthy subjects, the plasma clearance of tirofiban ranges from 213 to 314 mL/min. Renal clearance accounts for 39 to 69% of plasma clearance. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of Tirofiban has not been evaluated. Tirofiban HCI was negative in the in vitro microbial mutagenesis and V-79 mammalian cell mutagenesis assays. In addition, there was no evidence of direct genotoxicity in the in vitro alkaline elution and in vitro chromosomal aberration assays. There was no induction of chromosomal aberrations in bone marrow cells of male mice after the administration of intravenous doses up to 5 mg tirofiban/kg (about 3 times the maximum recommended daily human dose when compared on a body surface area basis). Fertility and reproductive performance were not affected in studies with male and female rats given intravenous doses of tirofiban up to 5 mg/kg/day (about 5 times the maximum recommended daily human dose when compared on a body surface area basis). # Clinical Studies Two large-scale clinical studies established the efficacy of Tirofiban in the treatment of patients with NSTE-ACS (unstable angina/]non-ST elevation MI). The two studies examined Tirofiban alone and added to heparin, prior to and after percutaneous coronary revascularization (if indicated) (PRISM-PLUS) and in comparison to heparin in a similar population (PRISM). These trials are discussed in detail below. PRISM-PLUS (Platelet Receptor Inhibition for Ischemic Syndrome Management — Patients Limited by Unstable Signs and Symptoms) In the double-blind PRISM-PLUS trial, 1570 patients with documented NSTE-ACS within 12 hours of entry into the study were randomized to Tirofiban (30 minute initial infusion of 0.4 mcg/kg/min followed by a maintenance infusion of 0.10 mcg/kg /min) in combination with heparin (bolus of 5,000 U followed by an infusion of 1,000 U/h titrated to maintain an APTT of approximately 2 times control) or to heparin alone. All patients received concomitant aspirin unless contraindicated. Patients who were medically managed or who underwent revascularization procedures were studied. Patients underwent 48 hours of medical stabilization on study drug therapy, and they were to undergo angiography before 96 hours (and, if indicated, angioplasty/atherectomy, while continuing on Tirofiban and heparin for 12-24 hours after the procedure). Tirofiban and heparin could be continued for up to 108 hours. Exclusions included contraindications to anticoagulation, decompensated heart failure, platelet count <150,000/mm3, and serum creatinine >2.5 mg/dL. The mean age of the population was 63 years; 32% of patients were female and approximately half of the population presented with non-ST elevation myocardial infarction. On average, patients received Tirofiban for 71 hours. A third group of patients was initially randomized to Tirofiban alone (no heparin). This arm was stopped when the group was found, at an interim look, to have greater mortality than the other two groups. The primary endpoint of the study was a composite of refractory ischemia, new MI and death within 7 days. There was a 32% risk reduction in the overall composite primary endpoint. The components of the composite were examined separately and the results are shown in Table 5. Note that the sum of the individual components may be greater than the composite (if a patient experiences multiple component events only one event counts towards the composite). The benefit seen at 7 days was maintained over time. The risk reduction in the composite endpoint at 30 days and 6 months is shown in the Kaplan-Meier curve below. An analysis of the results by sex suggests that women who are medically managed or who undergo subsequent PTCA/atherectomy may receive less benefit from Tirofiban (95% confidence limits for relative risk of 0.61-1.74) than do men (0.43-0.89) (p=0.11). This difference may be a true treatment difference, the effect of other differences in these subgroups, or a chance occurrence. Approximately 90% of patients in the PRISM-PLUS study underwent coronary angiography and 30% underwent angioplasty/atherectomy during the first 30 days of the study. The majority of these patients continued on study drug throughout these procedures. Tirofiban was continued for 12-24 hours (average 15 hours) after angioplasty/atherectomy. The effects of Tirofiban at Day 30 did not appear to differ among sub-populations that did or did not receive PTCA or CABG, both prior to and after the procedure. PRISM (Platelet Receptor Inhibition for Ischemic Syndrome Management) In the PRISM study, a randomized, parallel, double-blind study, 3232 patients with NSTE-ACS intended to be managed without coronary intervention were randomized to Tirofiban (initial dose of 0.6 mcg/kg/min for 30 minutes followed by 0.15 mcg/kg/min for 47.5 hours) or heparin (5000-unit intravenous bolus followed by an infusion of 1000 U/h for 48 hours). The mean age of the population was 62 years; 32% of the population was female and 25% had non-ST elevation MI on presentation. Thirty percent had no ECG evidence of cardiac ischemia. Exclusion criteria were similar to PRISM-PLUS. The primary endpoint was the composite endpoint of refractory ischemia, MI or death at the end of the 48-hour drug infusion. The results are shown in Table 6. In the PRISM study, no adverse effect of Tirofiban on mortality at either 7 or 30 days was detected. This result is different from that in the PRISM-PLUS study, where the arm that included Tirofiban without heparin (n=345) was dropped at an interim analysis by the Data Safety Monitoring Committee for increased mortality at 7 days. # How Supplied There is limited information regarding Tirofiban How Supplied in the drug label. ## Storage There is limited information regarding Tirofiban Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise patients to watch closely for any signs of bleeding or bruising and to report these to their health care provider when they occur. Advise patients to discuss with their health care provider their use of any other medications, including over-the-counter or herbal products prior to Tirofiban use. Patent: www.medicure.com/Tirofiban/patents Tirofiban is manufactured for: MEDICURE INTERNATIONAL, INC. by: BAXTER HEALTHCARE CORPORATION Deerfield, Illinois 60015 USA Distributed by: MEDICURE PHARMA, INC. Somerset, NJ 08873 USA 1-800-509-0544 Printed in USA 07-19-72-370 - Registered trademark of Medicure International Inc. © 2013 Copyright used under license. All rights reserved. Intravia is a registered trademark of Baxter International Inc. alcohol=Alcohol-Tirofiban sandbox interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Precautions with Alcohol Alcohol-Tirofiban interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names AGGRASTAT # Look-Alike Drug Names Tirofiban - argatroban [1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Aggrastat
ffbc69e2af9e7b1524df6961bda0e7106190bd61	wikidoc	Glycoside	Glycoside In chemistry, glycosides are certain molecules in which a sugar part is bound to some other part. Glycosides play numerous important roles in living organisms. Many plants store important chemicals in the form of inactive glycosides; if these chemicals are needed, the glycosides are brought in contact with water and an enzyme, and the sugar part is broken off, making the chemical available for use. Many such plant glycosides are used as medications. In animals (including humans), poisons are often bound to sugar molecules in order to remove them from the body. Formally, a glycoside is any molecule in which a sugar group is bonded through its anomeric carbon to another group via an O-glycosidic bond or an S-glycosidic bond; glycosides involving the latter are also called thioglycosides. The given definition is the one used by IUPAC. Many authors require in addition that the sugar be bonded to a non-sugar for the molecule to qualify as a glycoside, thus excluding the polysaccharides. The sugar group is then known as the glycone and the non-sugar group as the aglycone or genin part of the glycoside. The glycone can consist of a single sugar group (monosaccharide) or several sugar groups (oligosaccharide). # Related compounds Molecules containing an N-glycosidic bond are known as glycosylamines and are not discussed in this article. (Many authors in biochemistry call these compounds N-glycosides and group them with the glycosides; this is considered a misnomer and discouraged by IUPAC.) # Chemistry Much of the chemistry of glycosides is explained in the article on glycosidic bonds. For example, the glycone and aglycone portions can be chemically separated by hydrolysis in the presence of acid. There are also numerous enzymes that can form and break glycosidic bonds. The most important cleavage enzymes are the glycoside hydrolases, and the most important synthetic enzymes in nature are glycosyltransferases. Mutant enzymes termed glycosynthases have been developed that can form glycosidic bonds in excellent yield. There are a great many ways to chemically synthesize glycosidic bonds. Fischer glycosidation refers to the synthesis of glycosides by the reaction of unprotected monosaccharides with alcohols (usually as solvent) in the presence of a strong acid catalyst. The Koenigs-Knorr reaction is the condensation of glycosyl halides and alcohols in the presence of metal salts such as silver carbonate or mercuric oxide. # Classification We can classify glycosides by the glycone, by the type of glycosidic bond, and by the aglycone. ## By glycone If the glycone group of a glycoside is glucose, then the molecule is a glucoside; if it is fructose, then the molecule is a fructoside; if it is glucuronic acid, then the molecule is a glucuronide; etc. In the body, toxic substances are often bonded to glucuronic acid to increase their water solubility; the resulting glucuronides are then excreted. ## By type of glycosidic bond Depending on whether the glycosidic bond lies "above" or "below" the plane of the cyclic sugar molecule, glycosides are classified as α-glycosides or β-glycosides. Some enzymes such as α-amylase can only hydrolize α-linkages; others, such as emulsin, can only affect β-linkages. ## By aglycone Glycosides are also classified according to the chemical nature of the aglycone. For purposes of biochemistry and pharmacology, this is the most useful classification. ### Alcoholic glycosides An example of an alcoholic glycoside is salicin which is found in the genus salix. Salicin is converted in the body into salicylic acid, which is closely related to aspirin and has analgesic, antipyretic and antiinflammatory effects. ### Anthraquinone glycosides These glycosides contain an aglycone group that is a derivative of anthraquinone. They are present in senna, rhubarb and aloes; they have a laxative effect. ### Coumarin glycosides Here the aglycone is coumarin. An example is apterin which is reported to dilate the coronary arteries as well as block calcium channels.those obtained from dried leaves of Psoralia corylifolia have Main glycosides psoralin and corylifolin. ### Cyanogenic glycosides In this case, the aglycone contains a cyanide group, and the glycoside can release the poisonous hydrogen cyanide if acted upon by some enzyme. An example of these is amygdalin from almonds. Cyanogenic glycosides can be found in the fruits (and wilting leaves) of the rose family (including cherries, apples, plums, almonds, peaches, apricots, raspberries, and crabapples). Cassava, an important food plant in Africa and South America, contains cyanogenic glucosides and therefore has to be washed and ground under running water prior to consumption. ### Flavonoid glycosides Here the aglycone is a flavonoid. This is a large group of flavonoid glycosides. Examples include: - Hesperidin (aglycone: Hesperetin, glycone: Rutinose) - Naringin (aglycone: Naringenin, glycone: Rutinose) - Rutin (aglycone: Quercetin, glycone: Rutinose) - Quercitrin (aglycone: Quercetin, glycone: Rhamnose) Among the important effects of flavonoids are their antioxidant effect. They are also known to decrease capillary fragility. ### Phenolic glycosides (simple) Here the aglycone is a simple phenolic structure. An example is arbutin found in the Common Bearberry Arctostaphylos uva-ursi. It has a urinary antiseptic effect. Rutin found in rooibos tea. ### Saponins These compounds give a permanent froth when shaken with water. They also cause hemolysis of red blood cells. Saponin glycosides are found in liquorice. Their medicinal value is due to their expectorant effect. ### Steroidal glycosides or cardiac glycosides Here the aglycone part is a steroidal nucleus. These glycosides are found in the plant genera Digitalis, Scilla, and Strophanthus. They are used in the treatment of heart diseases e.g. congestive heart failure (historically as now recognised does not improve survivability; other agents are now preferred] and arrhythmia. ### Steviol glycosides These sweet glycosides found in the stevia plant Stevia rebaudiana bertoni have 40-300 times the sweetness of sucrose. The two primary glycosides, stevioside and rebaudioside A, are used as natural sweeteners in many countries. These glycosides have steviol as the aglycone part. Glucose or rhamnose-glucose combinations are bound to the ends of the aglycone to form the different compounds. ### Thioglycosides As the name implies, these compounds contain sulfur. Examples include sinigrin, found in black mustard, and sinalbin, found in white mustard.	Glycoside Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] In chemistry, glycosides are certain molecules in which a sugar part is bound to some other part. Glycosides play numerous important roles in living organisms. Many plants store important chemicals in the form of inactive glycosides; if these chemicals are needed, the glycosides are brought in contact with water and an enzyme, and the sugar part is broken off, making the chemical available for use. Many such plant glycosides are used as medications. In animals (including humans), poisons are often bound to sugar molecules in order to remove them from the body. Formally, a glycoside is any molecule in which a sugar group is bonded through its anomeric carbon to another group via an O-glycosidic bond or an S-glycosidic bond; glycosides involving the latter are also called thioglycosides. The given definition is the one used by IUPAC. Many authors require in addition that the sugar be bonded to a non-sugar for the molecule to qualify as a glycoside, thus excluding the polysaccharides. The sugar group is then known as the glycone and the non-sugar group as the aglycone or genin part of the glycoside. The glycone can consist of a single sugar group (monosaccharide) or several sugar groups (oligosaccharide). # Related compounds Molecules containing an N-glycosidic bond are known as glycosylamines and are not discussed in this article. (Many authors in biochemistry call these compounds N-glycosides and group them with the glycosides; this is considered a misnomer and discouraged by IUPAC.) # Chemistry Much of the chemistry of glycosides is explained in the article on glycosidic bonds. For example, the glycone and aglycone portions can be chemically separated by hydrolysis in the presence of acid. There are also numerous enzymes that can form and break glycosidic bonds. The most important cleavage enzymes are the glycoside hydrolases, and the most important synthetic enzymes in nature are glycosyltransferases. Mutant enzymes termed glycosynthases have been developed that can form glycosidic bonds in excellent yield. There are a great many ways to chemically synthesize glycosidic bonds. Fischer glycosidation refers to the synthesis of glycosides by the reaction of unprotected monosaccharides with alcohols (usually as solvent) in the presence of a strong acid catalyst. The Koenigs-Knorr reaction is the condensation of glycosyl halides and alcohols in the presence of metal salts such as silver carbonate or mercuric oxide. # Classification We can classify glycosides by the glycone, by the type of glycosidic bond, and by the aglycone. ## By glycone If the glycone group of a glycoside is glucose, then the molecule is a glucoside; if it is fructose, then the molecule is a fructoside; if it is glucuronic acid, then the molecule is a glucuronide; etc. In the body, toxic substances are often bonded to glucuronic acid to increase their water solubility; the resulting glucuronides are then excreted. ## By type of glycosidic bond Depending on whether the glycosidic bond lies "above" or "below" the plane of the cyclic sugar molecule, glycosides are classified as α-glycosides or β-glycosides. Some enzymes such as α-amylase can only hydrolize α-linkages; others, such as emulsin, can only affect β-linkages. ## By aglycone Glycosides are also classified according to the chemical nature of the aglycone. For purposes of biochemistry and pharmacology, this is the most useful classification. ### Alcoholic glycosides An example of an alcoholic glycoside is salicin which is found in the genus salix. Salicin is converted in the body into salicylic acid, which is closely related to aspirin and has analgesic, antipyretic and antiinflammatory effects. ### Anthraquinone glycosides These glycosides contain an aglycone group that is a derivative of anthraquinone. They are present in senna, rhubarb and aloes; they have a laxative effect. ### Coumarin glycosides Here the aglycone is coumarin. An example is apterin which is reported to dilate the coronary arteries as well as block calcium channels.those obtained from dried leaves of Psoralia corylifolia have Main glycosides psoralin and corylifolin. ### Cyanogenic glycosides In this case, the aglycone contains a cyanide group, and the glycoside can release the poisonous hydrogen cyanide if acted upon by some enzyme. An example of these is amygdalin from almonds. Cyanogenic glycosides can be found in the fruits (and wilting leaves) of the rose family (including cherries, apples, plums, almonds, peaches, apricots, raspberries, and crabapples). Cassava, an important food plant in Africa and South America, contains cyanogenic glucosides and therefore has to be washed and ground under running water prior to consumption. ### Flavonoid glycosides Here the aglycone is a flavonoid. This is a large group of flavonoid glycosides. Examples include: - Hesperidin (aglycone: Hesperetin, glycone: Rutinose) - Naringin (aglycone: Naringenin, glycone: Rutinose) - Rutin (aglycone: Quercetin, glycone: Rutinose) - Quercitrin (aglycone: Quercetin, glycone: Rhamnose) Among the important effects of flavonoids are their antioxidant effect. They are also known to decrease capillary fragility. ### Phenolic glycosides (simple) Here the aglycone is a simple phenolic structure. An example is arbutin found in the Common Bearberry Arctostaphylos uva-ursi. It has a urinary antiseptic effect. Rutin found in rooibos tea. ### Saponins These compounds give a permanent froth when shaken with water. They also cause hemolysis of red blood cells. Saponin glycosides are found in liquorice. Their medicinal value is due to their expectorant effect. ### Steroidal glycosides or cardiac glycosides Here the aglycone part is a steroidal nucleus. These glycosides are found in the plant genera Digitalis, Scilla, and Strophanthus. They are used in the treatment of heart diseases e.g. congestive heart failure (historically as now recognised does not improve survivability; other agents are now preferred] and arrhythmia. ### Steviol glycosides These sweet glycosides found in the stevia plant Stevia rebaudiana bertoni have 40-300 times the sweetness of sucrose. The two primary glycosides, stevioside and rebaudioside A, are used as natural sweeteners in many countries. These glycosides have steviol as the aglycone part. Glucose or rhamnose-glucose combinations are bound to the ends of the aglycone to form the different compounds. ### Thioglycosides As the name implies, these compounds contain sulfur. Examples include sinigrin, found in black mustard, and sinalbin, found in white mustard. # External links - Definition of glycosides, from the IUPAC Compendium of Chemical Terminology, the "Gold Book" - IUPAC naming rules for glycosides Template:Glycosides ar:غليكوزيدات bg:Гликозид cs:Glykosidy de:Glykoside et:Glükosiidid he:גליקוזיד it:Glicoside mk:Гликозид nl:Glycoside sl:Glikozid fi:Glykosidi sv:Glykosider uk:Глікозиди sr:гликозиди Template:WH Template:WS Template:Jb1	https://www.wikidoc.org/index.php/Aglycone
c9528abd34badaab5d06a7016cf1f7e9a4d62e87	wikidoc	Akathisia	Akathisia # Overview Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of "inner" restlessness that manifests itself with an inability to sit still or remain motionless, hence its origin in Ancient Greek α (a), + κάθισις (káthisis), . Its most common cause is as a side effect of medications, mainly neuroleptic antipsychotics especially the phenothiazines (such as perphenazine and chlorpromazine), dibenzoxazepines (such as Loxapine), thioxanthenes (such as flupenthixol and zuclopenthixol) and butyrophenones (such as haloperidol (Haldol)), piperazines (such as ziprasidone), and rarely, antidepressants. Akathisia can also, to a lesser extent, be caused by Parkinson disease and related syndromes. But all neuroleptic antipsychotic psychotropic drugs cause Parkinsonian like symptoms due to blockage of dopamine receptors in the nigrostriatal pathway of the brain. Akathisia may range in intensity from a mild sense of disquiet or anxiety (which may be easily overlooked) to a total inability to sit still, accompanied by overwhelming anxiety, malaise, and severe dysphoria (manifesting as an almost indescribable sense of terror and doom). The condition is difficult for the patient to describe and is often misdiagnosed. When misdiagnosis occurs in antipsychotic neuroleptic-induced akathisia, more antipsychotic neuroleptics may be prescribed, potentially worsening the symptoms. High-functioning patients have described the feeling as a sense of inner tension and torment or chemical torture. Akathisia makes some patients act out in violent fits of rage throwing and breaking things or harming others. Ironically antipsychotic drugs are many times prescribed as “mood stabilizers” but then have the opposite intended effect, which often leads to increased doses further escalating the symptoms when the intent was to ameliorate the symptoms. The presence and severity of akathisia can be measured using the Barnes Akathisia Scale. # Description Healy, et al (2006), described the following regarding akathisia: tension, insomnia, a sense of discomfort, motor restlessness, and marked anxiety and panic. Increased labile affect can result, such as weepiness. Interestingly, in some people the opposite response to SSRIs occurs, in the form of emotional blunting; but sufficient clinical research has not yet been made in this area. Jack Henry Abbot (1981) described the effects of akathisia produced by antipsychotic drugs: These drugs, in this family, do not calm or sedate the nerves. They attack. They attack from so deep inside you, you cannot locate the source of the pain ... The muscles of your jawbone go berserk, so that you bite the inside of your mouth and your jaw locks and the pain throbs. For hours every day this will occur. Your spinal column stiffens so that you can hardly move your head or your neck and sometimes your back bends like a bow and you cannot stand up. The pain grinds into your fiber ... You ache with restlessness, so you feel you have to walk, to pace. And then as soon as you start pacing, the opposite occurs to you; you must sit and rest. Back and forth, up and down you go in pain you cannot locate, in such wretched anxiety you are overwhelmed, because you cannot get relief even in breathing. In severe cases, akathisia can be so tormenting that the patient is compelled to take action, such as suicide attempts. Treatment non-compliance is a common consequence of neuroleptic-induced akathisia. At the extreme end of non-compliance, patients who have been treated with neuroleptic antipsychotics for psychotic episodes or prochlorperazine for nausea may rarely run away from hospitals or emergency rooms due to this disconcerting sensation. # Causes Akathisia is most often seen as a side effect of antipsychotic medications, but has other causes as well: - Non-sedating antipsychotics such as Asenapine maleate, Chlorpromazine, haloperidol (Haldol), droperidol, pimozide, trifluoperazine, amisulpride, risperidone, and aripiprazole, Thiothixene, (Abilify). Less common in sedating antipsychotics such as zuclopenthixol (Cisordinol) or chlorpromazine where anticholinergic and antihistaminergic effects counteract akathisia to a degree. - SSRIs, such as fluoxetine (Prozac). It has also been documented with the use of paroxetine (Paxil). Akathisia has been studied as the mechanism by which SSRI-induced suicidality occurs. - Other antidepressants, such as the tricyclics and trazodone (Desyrel). - Certain anti-emetic drugs, particularly the dopamine blockers, such as metoclopramide (Reglan) and prochlorperazine (Compazine). Nabilone. - Certain recreational drugs, such as GHB, methamphetamine and MDMA when administered in excessive doses. - Other medications- Fluphenazine, Pergolide The 2006 UK study by Healy, Herxheimer, and Menkes observed that akathisia is often miscoded in antidepressant clinical trials as "agitation, emotional lability, and hyperkinesis (overactivity)". The study further points out that misdiagnosis of akathisia as simple motor restlessness occurs, but that this is more properly classed as dyskinesia. Healy, et al., further show links between antidepressant-induced akathisia and violence, including suicide, as akathisia can "exacerbate psychopathology." The study goes on to state that there is extensive clinical evidence correlating akathisia with SSRI use, showing that approximately ten times as many patients on SSRIs as those on placebos showed symptoms severe enough to drop out of a trial (5.0% compared to 0.5%). # Treatment Treatment includes the discontinuation or reduction of dose of the causative agent. The most common treatment for antipsychotic akathisia is the anticholinergic medication benztropine (Cogentin). But since benztropine is for extrapyramidal side effects such as muscle spasms, muscle stiffness and tremors it is not effective in treating akathisia which is not a true extrapyramidal side effect. Other anticholinergic medications such as diphenhydramine may also be used in the treatment of akathisia. Akathisia can be reduced by administering other drugs, though effectiveness can vary with more severe cases resistant to most drug treatment. Benzodiazepines like clonazepam (Klonopin) are effective. Some consider the drug of choice for the treatment of akathisia to be beta-blockers such as propranolol (Inderal) or metoprolol. The antihistamine cyproheptadine is also effective, though with shorter effect than beta blockers. One study showed that vitamin B6 is effective for the treatment of neuroleptic-induced akathisia. # Related Chapters - Agitation (emotion) - Anxiety - Psychomotor agitation	Akathisia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of "inner" restlessness that manifests itself with an inability to sit still or remain motionless, hence its origin in Ancient Greek α (a), [without, not] + κάθισις (káthisis), [sitting]. Its most common cause is as a side effect of medications, mainly neuroleptic antipsychotics especially the phenothiazines (such as perphenazine and chlorpromazine), dibenzoxazepines (such as Loxapine), thioxanthenes (such as flupenthixol and zuclopenthixol) and butyrophenones (such as haloperidol (Haldol)), piperazines (such as ziprasidone), and rarely, antidepressants. Akathisia can also, to a lesser extent, be caused by Parkinson disease and related syndromes.[1] But all neuroleptic antipsychotic psychotropic drugs cause Parkinsonian like symptoms due to blockage of dopamine receptors in the nigrostriatal pathway of the brain. Akathisia may range in intensity from a mild sense of disquiet or anxiety (which may be easily overlooked) to a total inability to sit still, accompanied by overwhelming anxiety, malaise, and severe dysphoria (manifesting as an almost indescribable sense of terror and doom). The condition is difficult for the patient to describe and is often misdiagnosed. When misdiagnosis occurs in antipsychotic neuroleptic-induced akathisia, more antipsychotic neuroleptics may be prescribed, potentially worsening the symptoms.[1] High-functioning patients have described the feeling as a sense of inner tension and torment or chemical torture. Akathisia makes some patients act out in violent fits of rage throwing and breaking things or harming others. Ironically antipsychotic drugs are many times prescribed as “mood stabilizers” but then have the opposite intended effect, which often leads to increased doses further escalating the symptoms when the intent was to ameliorate the symptoms. The presence and severity of akathisia can be measured using the Barnes Akathisia Scale.[2][3][4] # Description Healy, et al (2006), described the following regarding akathisia: tension, insomnia, a sense of discomfort, motor restlessness, and marked anxiety and panic. Increased labile affect can result, such as weepiness. Interestingly, in some people the opposite response to SSRIs occurs, in the form of emotional blunting; but sufficient clinical research has not yet been made in this area.[5] Jack Henry Abbot (1981) described the effects of akathisia produced by antipsychotic drugs: These drugs, in this family, do not calm or sedate the nerves. They attack. They attack from so deep inside you, you cannot locate the source of the pain ... The muscles of your jawbone go berserk, so that you bite the inside of your mouth and your jaw locks and the pain throbs. For hours every day this will occur. Your spinal column stiffens so that you can hardly move your head or your neck and sometimes your back bends like a bow and you cannot stand up. The pain grinds into your fiber ... You ache with restlessness, so you feel you have to walk, to pace. And then as soon as you start pacing, the opposite occurs to you; you must sit and rest. Back and forth, up and down you go in pain you cannot locate, in such wretched anxiety you are overwhelmed, because you cannot get relief even in breathing. In severe cases, akathisia can be so tormenting that the patient is compelled to take action, such as suicide attempts.[1] Treatment non-compliance is a common consequence of neuroleptic-induced akathisia. At the extreme end of non-compliance, patients who have been treated with neuroleptic antipsychotics for psychotic episodes or prochlorperazine for nausea may rarely run away from hospitals or emergency rooms due to this disconcerting sensation.[6] # Causes Akathisia is most often seen as a side effect of antipsychotic medications, but has other causes as well: - Non-sedating antipsychotics[7] such as Asenapine maleate, Chlorpromazine, haloperidol (Haldol), droperidol, pimozide, trifluoperazine, amisulpride, risperidone, and aripiprazole, Thiothixene, (Abilify). Less common in sedating antipsychotics such as zuclopenthixol (Cisordinol) or chlorpromazine where anticholinergic and antihistaminergic effects counteract akathisia to a degree. - SSRIs, such as fluoxetine (Prozac).[8] It has also been documented with the use of paroxetine (Paxil).[5] Akathisia has been studied as the mechanism by which SSRI-induced suicidality occurs.[8] - Other antidepressants, such as the tricyclics and trazodone (Desyrel). - Certain anti-emetic drugs, particularly the dopamine blockers, such as metoclopramide (Reglan) and prochlorperazine (Compazine). Nabilone. - Certain recreational drugs, such as GHB, methamphetamine and MDMA when administered in excessive doses. - Other medications- Fluphenazine, Pergolide The 2006 UK study by Healy, Herxheimer, and Menkes observed that akathisia is often miscoded in antidepressant clinical trials as "agitation, emotional lability, and hyperkinesis (overactivity)".[5] The study further points out that misdiagnosis of akathisia as simple motor restlessness occurs, but that this is more properly classed as dyskinesia. Healy, et al., further show links between antidepressant-induced akathisia and violence, including suicide, as akathisia can "exacerbate psychopathology." The study goes on to state that there is extensive clinical evidence correlating akathisia with SSRI use, showing that approximately ten times as many patients on SSRIs as those on placebos showed symptoms severe enough to drop out of a trial (5.0% compared to 0.5%). # Treatment Treatment includes the discontinuation or reduction of dose of the causative agent. The most common treatment for antipsychotic akathisia is the anticholinergic medication benztropine (Cogentin). But since benztropine is for extrapyramidal side effects such as muscle spasms, muscle stiffness and tremors it is not effective in treating akathisia which is not a true extrapyramidal side effect. Other anticholinergic medications such as diphenhydramine may also be used in the treatment of akathisia. Akathisia can be reduced by administering other drugs, though effectiveness can vary with more severe cases resistant to most drug treatment. Benzodiazepines like clonazepam (Klonopin) are effective. Some consider the drug of choice for the treatment of akathisia to be beta-blockers such as propranolol (Inderal) or metoprolol. The antihistamine cyproheptadine is also effective, though with shorter effect than beta blockers. One study showed that vitamin B6 is effective for the treatment of neuroleptic-induced akathisia.[9] # Related Chapters - Agitation (emotion) - Anxiety - Psychomotor agitation	https://www.wikidoc.org/index.php/Akathisia
5a97e6de40cc67404a2f19a70b77970e5239792a	wikidoc	Biperiden	Biperiden # Overview Biperiden is an antiparkinsonian agent of the anticholinergic type. The original brand name - still existing - is Akineton®, manufactured by BASF/Knoll Pharma. Generics are available worldwide. # Pharmacokinetics The oral bioavailability is only 33 +/- 5% due to extensive first-pass metabolization. In young, healthy volunteers peak plasma concentrations following an oral single dose of 4mg in immediate release form are reached after 1.5 hours. The elimination half-life has been determined as 18.4 hours, and may be prolonged in geriatric patients. After IV dosing of 4mg the elimination half-life is approximately 24 hours. # Pharmacology Biperiden has an atropine-like blocking effect on all peripheral structures which are parasympathetic-innervated (e.g. cardiovascular and visceral organs). It also has a prominent central blocking effect on M1 receptors. # Uses Biperiden is used for the adjunctive treatment of all forms of Parkinson's disease (postencephalitic, idiopathic, and arteriosclerotic). It seems to exert better effects in the postencephalitic and idiopathic than in the arteriosclerotic type. Biperiden is also commonly used to improve parkinsonian signs and symptoms related to antipsychotic drug therapy. It relieves muscle rigidity, reduces abnormal sweating and salivation, improves abnormal gait, and to lesser extend, tremor. # Contraindications and cautions - Hypersensitivity to biperiden - Narrow angle glaucoma - Ileus - Caution : Patients with obstructive diseases of the urogenital tract, patients with a known history of seizures and those with potentially dangerous tachycardia # Special patient groups ## Pregnancy and lactation - Pregnancy : In animal studies biperiden had no embryo- or fetotoxic effects. There is no sufficient clinical data on pregnant women. The drug should therefore be used cautiously during pregnancy. - Lactation : Biperiden is found in the milk of lactating women. No sufficient clinical data exists regarding effects for the newborns. Additionally, biperiden may decrease maternal milk production. It is therefore recommended that biperiden is not used during lactation. ## Pediatric patients Children and adolescents aged 1 year and older may be treated. The clinical experience is mainly on the shortterm treatment of acute drug induced dystonic reactions. Doses should be reduced according to the weight of the patients. # Side effects Dose-dependent side effects are frequent. Particularly geriatric patients may react with confusional states or develop delirium. - CNS : Drowsiness, vertigo, headache, and dizziness are frequent. With high doses nervousness, agitation, anxiety, delirium, and confusion are noted. Biperiden may be abused due to a short acting mood-elevating and euphoriant effect. The normal sleep architecture may be altered (REM sleep depression). Biperiden may lower the seizure-threshold. Some instances of dementia have been noted to correllate with chronic administration of anticholinergic medications such as Biperiden for Parkinson's disease. - Peripheral side effects : Blurred vision, dry mouth, impaired sweating, abdominal discomfort, and obstipation are frequent. Tachycardia may be noted. Allergic skin reactions may occur. Parenteral use may cause orthostatic hypotension. - Eyes : Biperiden causes mydriasis with or without photophobia. It may precipitate narrow angle glaucoma. # Interactions - Other anticholinergic drugs (e.g. spasmolytics, antihistamines, TCAs) : Side effects of biperiden may be increased. - Quinidine : Increased anticholinergic action (particular on AV conduction). - Antipsychotics : Long term use of biperiden may mask or increase the risk of tardive dyskinesia. - Pethidine (meperidine) : Central effects and side effects of pethidine may be increased. - Metoclopramide : Action of metoclopramide is decreased. - Alcohol : Risk of serious intoxication. # Dosage Strictly individual. Oral, and in some countries, IV and IM use is possible. The usual oral daily doses are between 2 and 16mg. If possible, patients should be started with a low initial dose which is increased slowly. # Overdose Biperiden mimics an atropine intoxication with mydriasis, dryness of mucous membranes, red face, atonic states of bowels and bladder, and hyperthermia in high doses. Central consequences are agitation, confusion, and hallucinations. An untreated overdose may be fatal, particular in children. Premortal signs are respiratory depression and cardiac arrest. A specific antagonist is physostigmine which combines a peripheral and a central action. Carbachol can be used to treat atonic bowels and bladder. The vital functions should be monitored and stabilized. It may be necessary to treat hyperthermia with cooling blankets. # History Biperiden was synthesized by the German chemist W. Klavehn from Knoll AG, Germany. In March 1953 a patent was applied for in Germany and subsequently in many other countries. # Notes - ↑ Nishiyama K, Mizuno T, Sakuta M, Kurisaki H (1993). "Chronic dementia in Parkinson's disease treated by anticholinergic agents. Neuropsychological and neuroradiological examination". Adv Neurol. 60: 479–83. PMID 8420174.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}	Biperiden Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Biperiden is an antiparkinsonian agent of the anticholinergic type. The original brand name - still existing - is Akineton®, manufactured by BASF/Knoll Pharma. Generics are available worldwide. # Pharmacokinetics The oral bioavailability is only 33 +/- 5% due to extensive first-pass metabolization. In young, healthy volunteers peak plasma concentrations following an oral single dose of 4mg in immediate release form are reached after 1.5 hours. The elimination half-life has been determined as 18.4 hours, and may be prolonged in geriatric patients. After IV dosing of 4mg the elimination half-life is approximately 24 hours. # Pharmacology Biperiden has an atropine-like blocking effect on all peripheral structures which are parasympathetic-innervated (e.g. cardiovascular and visceral organs). It also has a prominent central blocking effect on M1 receptors. # Uses Biperiden is used for the adjunctive treatment of all forms of Parkinson's disease (postencephalitic, idiopathic, and arteriosclerotic). It seems to exert better effects in the postencephalitic and idiopathic than in the arteriosclerotic type. Biperiden is also commonly used to improve parkinsonian signs and symptoms related to antipsychotic drug therapy. It relieves muscle rigidity, reduces abnormal sweating and salivation, improves abnormal gait, and to lesser extend, tremor. # Contraindications and cautions - Hypersensitivity to biperiden - Narrow angle glaucoma - Ileus - Caution : Patients with obstructive diseases of the urogenital tract, patients with a known history of seizures and those with potentially dangerous tachycardia # Special patient groups ## Pregnancy and lactation - Pregnancy : In animal studies biperiden had no embryo- or fetotoxic effects. There is no sufficient clinical data on pregnant women. The drug should therefore be used cautiously during pregnancy. - Lactation : Biperiden is found in the milk of lactating women. No sufficient clinical data exists regarding effects for the newborns. Additionally, biperiden may decrease maternal milk production. It is therefore recommended that biperiden is not used during lactation. ## Pediatric patients Children and adolescents aged 1 year and older may be treated. The clinical experience is mainly on the shortterm treatment of acute drug induced dystonic reactions. Doses should be reduced according to the weight of the patients. # Side effects Dose-dependent side effects are frequent. Particularly geriatric patients may react with confusional states or develop delirium. - CNS : Drowsiness, vertigo, headache, and dizziness are frequent. With high doses nervousness, agitation, anxiety, delirium, and confusion are noted. Biperiden may be abused due to a short acting mood-elevating and euphoriant effect. The normal sleep architecture may be altered (REM sleep depression). Biperiden may lower the seizure-threshold. Some instances of dementia have been noted to correllate with chronic administration of anticholinergic medications such as Biperiden for Parkinson's disease.[1] - Peripheral side effects : Blurred vision, dry mouth, impaired sweating, abdominal discomfort, and obstipation are frequent. Tachycardia may be noted. Allergic skin reactions may occur. Parenteral use may cause orthostatic hypotension. - Eyes : Biperiden causes mydriasis with or without photophobia. It may precipitate narrow angle glaucoma. # Interactions - Other anticholinergic drugs (e.g. spasmolytics, antihistamines, TCAs) : Side effects of biperiden may be increased. - Quinidine : Increased anticholinergic action (particular on AV conduction). - Antipsychotics : Long term use of biperiden may mask or increase the risk of tardive dyskinesia. - Pethidine (meperidine) : Central effects and side effects of pethidine may be increased. - Metoclopramide : Action of metoclopramide is decreased. - Alcohol : Risk of serious intoxication. # Dosage Strictly individual. Oral, and in some countries, IV and IM use is possible. The usual oral daily doses are between 2 and 16mg. If possible, patients should be started with a low initial dose which is increased slowly. # Overdose Biperiden mimics an atropine intoxication with mydriasis, dryness of mucous membranes, red face, atonic states of bowels and bladder, and hyperthermia in high doses. Central consequences are agitation, confusion, and hallucinations. An untreated overdose may be fatal, particular in children. Premortal signs are respiratory depression and cardiac arrest. A specific antagonist is physostigmine which combines a peripheral and a central action. Carbachol can be used to treat atonic bowels and bladder. The vital functions should be monitored and stabilized. It may be necessary to treat hyperthermia with cooling blankets. # History Biperiden was synthesized by the German chemist W. Klavehn from Knoll AG, Germany. In March 1953 a patent was applied for in Germany and subsequently in many other countries. # Notes - ↑ Nishiyama K, Mizuno T, Sakuta M, Kurisaki H (1993). "Chronic dementia in Parkinson's disease treated by anticholinergic agents. Neuropsychological and neuroradiological examination". Adv Neurol. 60: 479–83. PMID 8420174.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}	https://www.wikidoc.org/index.php/Akineton_HCl
458400d7532aee176407fee57dfc3e66f0bebd42	wikidoc	Akuammine	Akuammine # Overview Akuammine, an indole alkaloid, is the most abundant active alkaloid found in the seeds from the tree Picralima nitida, commonly known as Akuamma. The dried seeds from this plant are used in traditional medicine throughout West Africa, particularly in Ghana as well as in the Ivory Coast and Nigeria. The seeds are crushed or powdered and taken orally, and are mainly used for the treatment of malaria and diarrhoea, and as a painkiller. An enterprising Ghanaian hospital started manufacturing standardised 250mg capsules of the powdered P. nitida seed, and sold them around the country where they became widely accepted as a safe and effective pain relief product. This then led researchers to try and discover the active component of the seeds. P. nitida seeds contain a mixture of alkaloids producing antipyretic and antiinflammatory effects along with analgesia. Several of these were shown to bind to opioid receptors in vitro, and two compounds, akuammidine and ψ-akuammigine, were found to be potent μ-opioid agonists, although not particularly selective. Surprisingly the main alkaloid from the seeds, akuammine, was found to be an opioid antagonist when tested in vitro and canceled out the effects of the active agonist components. Given the confirmed activity of the whole seed extract in humans, this makes it likely that akuammine is in fact being metabolised once inside the body to form an active metabolite, in a similar way to how the closely related compound mitragynine is metabolised to the more active 7-hydroxymitragynine. Akuammine is the main alkaloid found in the seeds, comprising 0.56% of the dried powder, indicating that the 250 mg "Picap Capsules" sold commercially should contain approximately 1.4 mg of akuammine, plus 0.085 mg akuammidine and 0.015 mg ψ-akuammigine. Akuammine is structurally related to both yohimbine and mitragynine, both of which are alkaloid plant products with uses in medicine.	Akuammine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Akuammine, an indole alkaloid, is the most abundant active alkaloid found in the seeds from the tree Picralima nitida, commonly known as Akuamma. The dried seeds from this plant are used in traditional medicine throughout West Africa, particularly in Ghana as well as in the Ivory Coast and Nigeria. The seeds are crushed or powdered and taken orally, and are mainly used for the treatment of malaria[1] and diarrhoea, and as a painkiller. An enterprising Ghanaian hospital started manufacturing standardised 250mg capsules of the powdered P. nitida seed, and sold them around the country where they became widely accepted as a safe and effective pain relief product. This then led researchers to try and discover the active component of the seeds. P. nitida seeds contain a mixture of alkaloids producing antipyretic and antiinflammatory effects along with analgesia.[2][3] Several of these were shown to bind to opioid receptors in vitro, and two compounds, akuammidine and ψ-akuammigine, were found to be potent μ-opioid agonists, although not particularly selective. Surprisingly the main alkaloid from the seeds, akuammine, was found to be an opioid antagonist when tested in vitro and canceled out the effects of the active agonist components.[4] Given the confirmed activity of the whole seed extract in humans, this makes it likely that akuammine is in fact being metabolised once inside the body to form an active metabolite, in a similar way to how the closely related compound mitragynine is metabolised to the more active 7-hydroxymitragynine. Akuammine is the main alkaloid found in the seeds, comprising 0.56% of the dried powder, indicating that the 250 mg "Picap Capsules" sold commercially should contain approximately 1.4 mg of akuammine, plus 0.085 mg akuammidine and 0.015 mg ψ-akuammigine. Akuammine is structurally related to both yohimbine and mitragynine, both of which are alkaloid plant products with uses in medicine.	https://www.wikidoc.org/index.php/Akuammine
a5d5b57e644bd1845331f43920ecb928120a9e55	wikidoc	Al Herpin	Al Herpin # Background Al Herpin was known as the "Man Who Never Slept." Born in 1853 in, Trenton, New Jersey, Al Herpin claimed to have developed a rare case of insomnia, whereby he could not sleep. The supposed cause is unknown, although it may be linked to his mother suffering a major injury a few days prior to his birth. In the late 1940s, Al Herpin's claim attracted the attention of several medical professionals, who marched to his door one day. They found no bed, or other sleep-related furniture, but only a rocking chair. Herpin claimed that after a long day's work, he would rest in his rocking chair reading the newspaper until dawn, then return to work. He was in good health, and had a constant level of high awareness, defying all scientific understanding of the necessity for sleep. A piece in the New York Times on February 29, 1904 reported that: Albert Herpin, born in France in 1862 and for fifteen years a hostler in the employ of Freeholder Walter Phares of this city, declares that he has not slept a wink during the past ten years. Notwithstanding this, he is in perfect health, and does not seem to suffer any discomfort from his remarkable condition. Al Herpin died on January 3, 1947 at the age of 94. His death saw another New York Times story more skeptical of his claim: Death came today for Alfred E. Herpin, a recluse who lived on the outskirts of the city and insisted that he never slept. He was 94 years old and, when questioned concerning his claim of "sleeplessness", maintained that he never actually dozed but merely "rested". No other person with total insomnia has lived for such a long period of time. It was likely that he died for other reasons, not sleep deprivation, as his insomnia did not seem to have any effect on his health.	Al Herpin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Background Al Herpin was known as the "Man Who Never Slept." Born in 1853 in, Trenton, New Jersey, Al Herpin claimed to have developed a rare case of insomnia, whereby he could not sleep. The supposed cause is unknown, although it may be linked to his mother suffering a major injury a few days prior to his birth. In the late 1940s, Al Herpin's claim attracted the attention of several medical professionals, who marched to his door one day. They found no bed, or other sleep-related furniture, but only a rocking chair. Herpin claimed that after a long day's work, he would rest in his rocking chair reading the newspaper until dawn, then return to work. He was in good health, and had a constant level of high awareness, defying all scientific understanding of the necessity for sleep. A piece in the New York Times on February 29, 1904 reported that: Albert Herpin, born in France in 1862 and for fifteen years a hostler in the employ of Freeholder Walter Phares of this city, declares that he has not slept a wink during the past ten years. Notwithstanding this, he is in perfect health, and does not seem to suffer any discomfort from his remarkable condition. Al Herpin died on January 3, 1947 at the age of 94. His death saw another New York Times story more skeptical of his claim: Death came today for Alfred E. Herpin, a recluse who lived on the outskirts of the city and insisted that he never slept. He was 94 years old and, when questioned concerning his claim of "sleeplessness", maintained that he never actually dozed but merely "rested". No other person with total insomnia has lived for such a long period of time. It was likely that he died for other reasons, not sleep deprivation, as his insomnia did not seem to have any effect on his health.	https://www.wikidoc.org/index.php/Al_Herpin
d05a14dd89071b7edfe117e2ff26bceb2a6d151c	wikidoc	Ketotifen	Ketotifen # 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 Ketotifen is an Antihistamine that is FDA approved for the prophylaxis of Allergic conjunctivitis. Common adverse reactions include {{{adverseReactions}}}. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Allergic conjuntivitis - 1 drop in the affected eye(s) twice daily, every 8 to 12 hours, no more than twice per day. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ketotifen in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ketotifen in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Allergic conjuntivitis - Children 3 years of age and older: Put 1 drop in the affected eye(s) twice daily, every 8 to 12 hours, no more than twice per day. - Children under 3 years of age: Consult a doctor. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ketotifen in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ketotifen in pediatric patients. # Contraindications There is limited information regarding Ketotifen Contraindications in the drug label. # Warnings ### Do not use - If you are sensitive to any ingredient in this product - If solution changes color or becomes cloudy - To treat contact lens related irritation ### When using this product - Remove contact lenses before use - Wait at least 10 minutes before re-inserting contact lenses after use - Do not touch tip of container to any surface to avoid contamination - Replace cap after each use ### Stop use and ask doctor if you experience any of the following: - Eye pain - Changes in vision - Medness of the eyes - Itching that worsens or lasts more than 72 hours K*eep out of reach of children. - If swallowed, get medical help or contact a Poison Control Center right away. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Ketotifen Clinical Trials Experience in the drug label. ## Postmarketing Experience There is limited information regarding Ketotifen Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Ketotifen Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There is no FDA guidance on usage of Ketotifen in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ketotifen in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Ketotifen during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Ketotifen in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Ketotifen in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Ketotifen in geriatric settings. ### Gender There is no FDA guidance on the use of Ketotifen with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ketotifen with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Ketotifen in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Ketotifen in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Ketotifen in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Ketotifen in patients who are immunocompromised. # Administration and Monitoring ### Administration - Ophthalmic ### Monitoring There is limited information regarding Ketotifen Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Ketotifen and IV administrations. # Overdosage There is limited information regarding Ketotifen overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action There is limited information regarding Ketotifen Mechanism of Action in the drug label. ## Structure There is limited information regarding Ketotifen Structure in the drug label. ## Pharmacodynamics There is limited information regarding Ketotifen Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Ketotifen Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Ketotifen Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Ketotifen Clinical Studies in the drug label. # How Supplied There is limited information regarding Ketotifen How Supplied in the drug label. ## Storage - Store at 20° to 25°C (68° to 77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Ketotifen Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Ketotifen interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Zaditor - Alaway - Claritin Eye - Zyrtec Itchy Eye # Look-Alike Drug Names There is limited information regarding Ketotifen Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Ketotifen Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [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 Ketotifen is an Antihistamine that is FDA approved for the prophylaxis of Allergic conjunctivitis. Common adverse reactions include {{{adverseReactions}}}. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Allergic conjuntivitis - 1 drop in the affected eye(s) twice daily, every 8 to 12 hours, no more than twice per day. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ketotifen in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ketotifen in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Allergic conjuntivitis - Children 3 years of age and older: Put 1 drop in the affected eye(s) twice daily, every 8 to 12 hours, no more than twice per day. - Children under 3 years of age: Consult a doctor. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ketotifen in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ketotifen in pediatric patients. # Contraindications There is limited information regarding Ketotifen Contraindications in the drug label. # Warnings ### Do not use - If you are sensitive to any ingredient in this product - If solution changes color or becomes cloudy - To treat contact lens related irritation ### When using this product - Remove contact lenses before use - Wait at least 10 minutes before re-inserting contact lenses after use - Do not touch tip of container to any surface to avoid contamination - Replace cap after each use ### Stop use and ask doctor if you experience any of the following: - Eye pain - Changes in vision - Medness of the eyes - Itching that worsens or lasts more than 72 hours K*eep out of reach of children. - If swallowed, get medical help or contact a Poison Control Center right away. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Ketotifen Clinical Trials Experience in the drug label. ## Postmarketing Experience There is limited information regarding Ketotifen Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Ketotifen Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There is no FDA guidance on usage of Ketotifen in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ketotifen in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Ketotifen during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Ketotifen in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Ketotifen in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Ketotifen in geriatric settings. ### Gender There is no FDA guidance on the use of Ketotifen with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ketotifen with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Ketotifen in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Ketotifen in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Ketotifen in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Ketotifen in patients who are immunocompromised. # Administration and Monitoring ### Administration - Ophthalmic ### Monitoring There is limited information regarding Ketotifen Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Ketotifen and IV administrations. # Overdosage There is limited information regarding Ketotifen overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action There is limited information regarding Ketotifen Mechanism of Action in the drug label. ## Structure There is limited information regarding Ketotifen Structure in the drug label. ## Pharmacodynamics There is limited information regarding Ketotifen Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Ketotifen Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Ketotifen Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Ketotifen Clinical Studies in the drug label. # How Supplied There is limited information regarding Ketotifen How Supplied in the drug label. ## Storage - Store at 20° to 25°C (68° to 77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Ketotifen Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Ketotifen interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Zaditor[2] - Alaway - Claritin Eye - Zyrtec Itchy Eye # Look-Alike Drug Names There is limited information regarding Ketotifen Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Alaway
10ca27d788d9852ae6ea4386a0150a65584177e7	wikidoc	Egg white	Egg white Egg white is the common name for the clear liquid (also called the albumen or the glair/glaire) contained within an egg. It is the cytoplasm of the egg, which until fertilization is a single cell (including the yolk). It consists mainly of about 15% proteins dissolved in water. Its primary natural purpose is to protect the egg yolk and provide additional nutrition for the growth of the embryo, as it is rich in proteins and is of high nutritional value. Unlike the egg yolk, it contains a negligible amount of fat. Egg whites have many culinary and non-culinary uses for humans. # Composition The egg white is approximately two-thirds of the total egg's weight out of its shell with 90% of that weight coming from water. The remaining weight of the egg white comes from protein, trace minerals, fatty material, vitamins, and glucose. The U.S. large egg's white weighs 38 grams with 9.6 grams of protein, 0.3 grams of carbohydrate and 62 milligrams of sodium. The U.S. large egg white contains about 20 calories. Egg white contains approximately 40 different proteins. Below is a list of the proteins found in egg whites by percentage along with their natural functions. - Ovalbumin 54% Nourishment; blocks digestive enzymes - Ovotransferrin 12% Binds iron - Ovomucoid 11% Blocks digestive enzymes - Globulins 8% Plugs defects in membranes, shell - Lysozyme 3.5% Enzyme that digests bacterial cell walls - Ovomucin 1.5% Thickens egg white; inhibits viruses - Avidin .06% Binds vitamin (biotin) - Others 10% Bind vitamins, block digestive enzymes... Egg white is also conspicuously lacking in dietary cholesterol, which is a target component for reduction in the American diet. # Uses - It is often separated and used for cooking (for glairs, meringues, soufflés, and some omelets), hence it derives its name: when egg white is beaten or cooked it turns white. - In recipes calling for egg yolk, two egg whites can often be used to replace one egg yolk. - In schools it is often used to teach pupils how to test for protein using Biuret reagent. - It is used to remove sediments from champagne and beer and to clarify broths. - It was used in the emulsion of traditional photographic paper. - It was used in medieval medicine to treat wounds and broken bones. - They are recommended for consumption by chemotherapy and renal patients as a source of 90.0g of lean protein. - It is used by athletes and bodybuilders as a health food supplement. - It can be used as a base for waterproof glues. # Nutrition Biotin deficiency can be caused by excessive consumption of raw egg whites over a long period (months to years). Egg whites contain high levels of avidin, a protein that binds the vitamin biotin strongly. # Denaturation All proteins, including those in egg white, are made of long chains of amino acids which are similar to beads on a string. In a raw egg, these chains are raveled up in a specifically arranged compact mass. Chemical bonds and interactions between the amino acids within each protein hold this mass in a specific shape and stop it from unraveling. As an egg cooks, the heat causes the bonds within the proteins to break, a process called denaturation. As these proteins chains unfold and entangle with other proteins, new bonds form between these amino acids and the amino acids of neighboring proteins, causing the texture to change. # Egg white foam ## Creating an egg foam The physical stress of beating the egg white can create a foam. There are two types of physical stress caused by the beating of the egg whites with a whisk, the first being that the whisk drags the liquid through itself creating a force that unfolds the protein molecules. This process is called denaturation. The second stress comes from the mixing of air into the whites which causes the proteins to come out of their natural state. These denatured proteins gather together where the air and water meet and create multiple bonds with the other unraveled proteins and thus becomes a foam holding the incorporated air into place. ## Stabilizing egg white foam for culinary purposes ### Copper Bowl Copper bowls have been used in France since the 18th century to stabilize egg foams. The copper in the bowl assists in creating a tighter bond in reactive sulfur items such as egg whites. The bond created is so tight that the sulfurs are prevented from reacting with any other material. A silver plated bowl will have the same result as the copper bowl or a pinch of powdered copper supplement from a health store used in a glass bowl will yield the same result as well. Drawbacks of the copper bowl include the expense of the bowl itself, as well as the fact that the bowls are difficult to keep clean. Copper contamination from the bowl is minimal as a cup of foam will contain a tenth of one's daily normal intake level. ### Adding an acid Cream of tartar (potassium bitartrate) is an acidic salt that can be used to change the pH of the egg white to an acidic range by boosting the number of free-floating hydrogen ions in the egg white. This has the effect of stabilizing the foam, and is therefore an alternative to using a copper bowl. 1/8 teaspoon/0.5g cream of tartar should be used per one egg white to create this effect. 1/2 teaspoon/2ml of lemon juice can also be used to create the same results.	Egg white Egg white is the common name for the clear liquid (also called the albumen or the glair/glaire) contained within an egg. It is the cytoplasm of the egg, which until fertilization is a single cell (including the yolk). It consists mainly of about 15% proteins dissolved in water. Its primary natural purpose is to protect the egg yolk and provide additional nutrition for the growth of the embryo, as it is rich in proteins and is of high nutritional value. Unlike the egg yolk, it contains a negligible amount of fat. Egg whites have many culinary and non-culinary uses for humans. # Composition The egg white is approximately two-thirds of the total egg's weight out of its shell with 90% of that weight coming from water. The remaining weight of the egg white comes from protein, trace minerals, fatty material, vitamins, and glucose.[1] The U.S. large egg's white weighs 38 grams with 9.6 grams of protein, 0.3 grams of carbohydrate and 62 milligrams of sodium. The U.S. large egg white contains about 20 calories.[2] Egg white contains approximately 40 different proteins.[3] Below is a list of the proteins found in egg whites by percentage along with their natural functions. - Ovalbumin 54% Nourishment; blocks digestive enzymes - Ovotransferrin 12% Binds iron - Ovomucoid 11% Blocks digestive enzymes - Globulins 8% Plugs defects in membranes, shell - Lysozyme 3.5% Enzyme that digests bacterial cell walls - Ovomucin 1.5% Thickens egg white; inhibits viruses - Avidin .06% Binds vitamin (biotin) - Others 10% Bind vitamins, block digestive enzymes... [4] Egg white is also conspicuously lacking in dietary cholesterol, which is a target component for reduction in the American diet.[5] # Uses - It is often separated and used for cooking (for glairs, meringues, soufflés, and some omelets), hence it derives its name: when egg white is beaten or cooked it turns white. - In recipes calling for egg yolk, two egg whites can often be used to replace one egg yolk.[5] - In schools it is often used to teach pupils how to test for protein using Biuret reagent. - It is used to remove sediments from champagne and beer and to clarify broths. - It was used in the emulsion of traditional photographic paper. - It was used in medieval medicine to treat wounds and broken bones.[6] - They are recommended for consumption by chemotherapy and renal patients as a source of 90.0g of lean protein.[7][8] - It is used by athletes and bodybuilders as a health food supplement.[9] - It can be used as a base for waterproof glues. [10] # Nutrition Biotin deficiency can be caused by excessive consumption of raw egg whites over a long period (months to years). Egg whites contain high levels of avidin, a protein that binds the vitamin biotin strongly. # Denaturation All proteins, including those in egg white, are made of long chains of amino acids which are similar to beads on a string. In a raw egg, these chains are raveled up in a specifically arranged compact mass. Chemical bonds and interactions between the amino acids within each protein hold this mass in a specific shape and stop it from unraveling. As an egg cooks, the heat causes the bonds within the proteins to break, a process called denaturation.[11] As these proteins chains unfold and entangle with other proteins, new bonds form between these amino acids and the amino acids of neighboring proteins, causing the texture to change. # Egg white foam ## Creating an egg foam The physical stress of beating the egg white can create a foam. There are two types of physical stress caused by the beating of the egg whites with a whisk, the first being that the whisk drags the liquid through itself creating a force that unfolds the protein molecules. This process is called denaturation. The second stress comes from the mixing of air into the whites which causes the proteins to come out of their natural state. These denatured proteins gather together where the air and water meet and create multiple bonds with the other unraveled proteins and thus becomes a foam holding the incorporated air into place.[12] ## Stabilizing egg white foam for culinary purposes ### Copper Bowl Copper bowls have been used in France since the 18th century to stabilize egg foams. The copper in the bowl assists in creating a tighter bond in reactive sulfur items such as egg whites. The bond created is so tight that the sulfurs are prevented from reacting with any other material. A silver plated bowl will have the same result as the copper bowl or a pinch of powdered copper supplement from a health store used in a glass bowl will yield the same result as well. Drawbacks of the copper bowl include the expense of the bowl itself, as well as the fact that the bowls are difficult to keep clean. Copper contamination from the bowl is minimal as a cup of foam will contain a tenth of one's daily normal intake level.[13] ### Adding an acid Cream of tartar (potassium bitartrate) is an acidic salt that can be used to change the pH of the egg white to an acidic range by boosting the number of free-floating hydrogen ions in the egg white. This has the effect of stabilizing the foam, and is therefore an alternative to using a copper bowl. 1/8 teaspoon/0.5g cream of tartar should be used per one egg white to create this effect. 1/2 teaspoon/2ml of lemon juice can also be used to create the same results.[14]	https://www.wikidoc.org/index.php/Albumen
087417c5b03054ef18502af849c548d5e4624f47	wikidoc	Alectinib	Alectinib # 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 Alectinib is a kinase inhibitor that is FDA approved for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. Common adverse reactions include fatigue, constipation, edema and myalgia (≥20%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Alectinib is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. - Dosing and Administration - The recommended dose of Alectinib is 600 mg orally twice daily with food. Administer Alectinib until disease progression or unacceptable toxicity. - Do not open or dissolve the contents of the capsule. - If a dose of Alectinib is missed or vomiting occurs after taking a dose of Alectinib, take the next dose at the scheduled time. - Dose Modifications for Adverse Reactions - The dose reduction schedule for Alectinib is provided in TABLE 1. - Table 1. Alectinib Dose Reduction Schedule - Discontinue if patients are unable to tolerate the 300 mg twice daily dose. - Recommendations for dose modifications of Alectinib in case of adverse reactions are provided in TABLE 2. - Table 2. Alectinib Dose Modifications for Adverse Reactions ALECENSA: Alectinib's Brand name ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Alectinib in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Alectinib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of Alectinib in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Alectinib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Alectinib in pediatric patients. # Contraindications None # Warnings Elevations of AST greater than 5 times the upper limit of normal (ULN) occurred in 3.6% of patients, and elevations of ALT greater than 5 times the ULN occurred in 4.8% of patients. Elevations of bilirubin greater than 3 times the ULN occurred in 2.8% of patients in Studies 1 and 2. The majority (76% of the patients with hepatic transaminase elevations and 68% of the patients with bilirubin elevations) of these events occurred during the first 3 months of treatment. Four patients discontinued Alectinib for Grade 3-4 AST and/or ALT elevations, and 3 patients discontinued Alectinib for Grade 3 bilirubin elevations. In Studies 1 and 2, two patients with Grade 3-4 AST/ALT elevations had documented drug induced liver injury by liver biopsy. Concurrent elevations in ALT or AST greater than or equal to three times the ULN and total bilirubin greater than or equal to two times the ULN, with normal alkaline phosphatase, occurred in less than 1% of patients treated with Alectinib across clinical trials. Monitor liver function tests including ALT, AST, and total bilirubin every 2 weeks during the first 3 months of treatment, then once a month and as clinically indicated, with more frequent testing in patients who develop transaminase and bilirubin elevations. Based on the severity of the adverse drug reaction, withhold Alectinib and resume at a reduced dose, or permanently discontinue Alectinib as described in Table 2. Severe ILD (Grade 3) occurred in one (0.4%) of 253 patients exposed to Alectinib in Studies 1 and 2. Promptly investigate for ILD/pneumonitis in any patient who presents with worsening of respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough and fever). Immediately withhold Alectinib treatment in patients diagnosed with ILD/pneumonitis and permanently discontinue Alectinib if no other potential causes of ILD/pneumonitis have been identified. Symptomatic bradycardia can occur with Alectinib. Cases of bradycardia (7.5%) have been reported in patients treated with Alectinib. Twenty percent of 221 patients treated with Alectinib for whom serial ECGs were available had heart rates of less than 50 beats per minute (bpm). Monitor heart rate and blood pressure regularly. Dose modification is not required in cases of asymptomatic bradycardia. In cases of symptomatic bradycardia that is not life-threatening, withhold Alectinib until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above and evaluate concomitant medications known to cause bradycardia, as well as anti-hypertensive medications. If attributable to a concomitant medication, resume Alectinib at a reduced dose (see TABLE 1) upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring as clinically indicated. Permanently discontinue Alectinib in case of recurrence. Permanently discontinue Alectinib in cases of life-threatening bradycardia if no contributing concomitant medication is identified. Myalgia or musculoskeletal pain occurred in 29% of patients in Studies 1 and 2. The incidence of Grade 3 myalgia/musculoskeletal pain was 1.2%. Dose modifications for myalgia/musculoskeletal pain were required in 0.8% of patients. Elevations of CPK occurred in 43% of 218 patients with CPK laboratory data available in Study 1 and Study 2. The incidence of Grade 3 elevations of CPK was 4.6%. Median time to Grade 3 CPK elevation was 14 days (interquartile range 13-14 days). Dose modifications for elevation of CPK occurred in 5.0% of patients. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Assess CPK levels every two weeks for the first month of treatment and as clinically indicated in patients reporting symptoms. Based on the severity of the CPK elevation, withhold Alectinib, then resume or reduce dose . Based on findings from animal studies and its mechanism of action, Alectinib can cause fetal harm when administered to pregnant women. Administration of alectinib to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal toxicity and abortion at maternally toxic doses with exposures approximately 2.7-times those observed in humans with alectinib 600 mg twice daily. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Alectinib and for 1 week following the final dose. # Adverse Reactions ## Clinical Trials Experience The following adverse reactions are discussed in greater detail in other sections of the label: - Hepatotoxicity - Interstitial Lung Disease (ILD)/Pneumonitis - Bradycardia - Severe Myalgia and Creatine Phosphokinase (CPK) Elevation - Embryo-Fetal Toxicity 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 Alectinib was evaluated in 253 patients with ALK-positive non-small cell lung cancer (NSCLC) treated with Alectinib 600 mg orally twice daily in two clinical trials, Studies 1 and 2. The median duration of exposure to Alectinib was 9.3 months. One hundred sixty-nine patients (67%) were exposed to Alectinib for more than 6 months, and 100 patients (40%) for more than one year. The population characteristics were: median age 53 years, age less than 65 (86%), female (55%), White (74%), Asian (18%), NSCLC adenocarcinoma histology (96%), never or former smoker (98%), ECOG Performance Status (PS) 0 or 1 (91%), and prior chemotherapy treatment (78%). Serious adverse reactions occurred in 19% of patients; the most frequently reported serious adverse reactions were pulmonary embolism (1.2%), dyspnea (1.2%), and hyperbilirubinemia (1.2%). Fatal adverse reactions occurred in 2.8% of patients and included hemorrhage (0.8%), intestinal perforation (0.4%), dyspnea (0.4%), pulmonary embolism (0.4%), and endocarditis (0.4%). Permanent discontinuation of Alectinib for adverse reactions occurred in 6% of patients. The most frequent adverse reactions that led to permanent discontinuation were hyperbilirubinemia (1.6%), increased ALT levels (1.6%), and increased AST levels (1.2%). Overall, 23% of patients initiating treatment at the recommended dose required at least one dose reduction. The median time to first dose reduction was 48 days. The most frequent adverse reactions that led to dose reductions or interruptions were elevations in bilirubin (6%), CPK (4.3%), ALT (4.0%), and AST (2.8%), and vomiting (2.8%). TABLE 3 summarizes adverse reactions in Studies 1 and 2. - Table 3. Adverse Reactions in ≥ 10% (All Grades) or ≥ 2% (Grade 3-4) of Patients in Studies 1 and 2 ALECENSA: Alectinib's Brand name - Additional safety information from clinical trial experience - Photosensitivity occurred in 9.9% of patients exposed to Alectinib in Studies 1 and 2. Patients were advised to avoid sun exposure and to use broad-spectrum sunscreen. The incidence of Grade 2 photosensitivity was 0.4%; the remaining events were Grade 1 in severity. - TABLE 4 summarizes laboratory abnormalities of Alectinib in Studies 1 and 2. - Table 4. Laboratory Abnormalities Occurring in >20% of Patients in Studies 1 and 2 ## Postmarketing Experience There is limited information regarding Alectinib Postmarketing Experience in the drug label. # Drug Interactions No pharmacokinetic interactions with alectinib requiring dosage adjustment have been identified. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): N - Risk Summary - Based on animal studies and its mechanism of action, Alectinib can cause fetal harm when administered to a pregnant woman. There are no available data on Alectinib use in pregnant women. - Administration of alectinib to pregnant rats and rabbits by oral gavage during the period of organogenesis resulted in embryo-fetal toxicity and abortion at maternally toxic doses with exposures approximately 2.7-times those observed in humans treated with alectinib at 600 mg twice daily. Advise pregnant women of the potential risk to a fetus. - In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively. - Data - Animal Data - In a preliminary rabbit embryo-fetal study, administration of alectinib by oral gavage during the period of organogenesis resulted in abortion or complete embryo-fetal mortality at a maternally toxic dose of 27 mg/kg/day (approximately 2.9-fold the estimated area under the curve (AUC(0-24h,ss)) in humans treated with alectinib 600 mg BID) in three of six pregnant rabbits. The remaining three pregnant rabbits in this group had few live fetuses, decreased fetal and placental weights, and retroesophageal subclavian artery. In a rat preliminary embryo-fetal development study, administration of alectinib during organogenesis resulted in complete litter loss in all pregnant rats at 27 mg/kg/day (approximately 4.5-fold the estimated AUC(0-24h,ss) in humans treated with alectinib 600 mg BID). Doses greater than or equal to 9 mg/kg/day (approximately 2.7-fold the estimated human AUC(0-24h,ss) in humans treated with alectinib 600 mg BID), resulted in maternal toxicity as well as developmental toxicities including decreased fetal weight, dilated ureter, thymic cord, small ventricle and thin ventricle wall, and reduced number of sacral and caudal vertebrae. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alectinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Alectinib during labor and delivery. ### Nursing Mothers There are no data on the presence of alectinib or its metabolites in human milk, the effects of alectinib on the breast-fed infant, or its effects on milk production. Because of the potential for serious adverse reactions in breast-fed infants from alectinib, advise a lactating woman not to breastfeed during treatment with Alectinib and for 1 week after the final dose. ### Pediatric Use The safety and effectiveness of Alectinib in pediatric patients have not been established. - Animal Data - Juvenile animal studies have not been conducted using alectinib. In general toxicology studies, treatment of rats with doses of alectinib resulting in exposures greater than or equal to approximately 4.5 times those in humans treated with alectinib at 600 mg twice daily resulted in changes in the growing teeth and bones. Findings in teeth included discoloration and changes in tooth size along with histopathological disarrangement of the ameloblast and odontoblast layers. There were also decreases in the trabecular bone and increased osteoclast activity in the femur and sternum. ### Geriatic Use Clinical studies of Alectinib did not include sufficient number of subjects aged 65 and older to determine whether they respond differently from younger subjects. ### Gender There is no FDA guidance on the use of Alectinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Alectinib with respect to specific racial populations. ### Renal Impairment No dose adjustment is recommended for patients with mild or moderate renal impairment. The safety of Alectinib in patients with severe renal impairment (creatinine clearance less than 30 mL/min) or end-stage renal disease has not been studied. ### Hepatic Impairment No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin less than or equal to upper limit of normal (ULN) and aspartate transaminase (AST) greater than ULN or total bilirubin greater than 1.0 to 1.5 times ULN and any AST). The safety of Alectinib in patients with moderate or severe hepatic impairment has not been studied. ### Females of Reproductive Potential and Males - Females - Alectinib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Alectinib and for 1 week after the final dose. - Males - Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with Alectinib and for 3 months following the final dose. ### Immunocompromised Patients There is no FDA guidance one the use of Alectinib in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Alectinib Administration in the drug label. ### Monitoring There is limited information regarding Alectinib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Alectinib and IV administrations. # Overdosage No experience with overdose is available. There is no specific antidote for overdose with Alectinib. Alectinib and its major active metabolite M4 are > 99% bound to plasma proteins; therefore, hemodialysis is likely to be ineffective in the treatment of overdose. # Pharmacology ## Mechanism of Action Alectinib is a tyrosine kinase inhibitor that targets ALK and RET. In nonclinical studies, alectinib inhibited ALK phosphorylation and ALK-mediated activation of the downstream signaling proteins STAT3 and AKT, and decreased tumor cell viability in multiple cell lines harboring ALK fusions, amplifications, or activating mutations. The major active metabolite of alectinib, M4, showed similar in vitro potency and activity. Alectinib and M4 demonstrated in vitro and in vivo activity against multiple mutant forms of the ALK enzyme, including some mutations identified in NSCLC tumors in patients who have progressed on crizotinib. In mouse models implanted with tumors carrying ALK fusions, administration of alectinib resulted in antitumor activity and prolonged survival, including in mouse models implanted intracranially with ALK-driven tumor cell lines. ## Structure Alectinib is a kinase inhibitor for oral administration. The molecular formula for alectinib is C30H34N4O2 ∙ HCl. The molecular weight is 482.62 g/mol (free base form) and 519.08 g/mol (hydrochloride salt). Alectinib is described chemically as 9-ethyl-6, 6-dimethyl-8--11-oxo-6, 11-dihydro-5H-benzocarbazole-3-carbonitrile hydrochloride. The chemical structure of alectinib is shown below: Alectinib HCl is a white to yellow white powder or powder with lumps with a pKa of 7.05 (base). Alectinib is supplied as hard capsules containing 150 mg of alectinib (equivalent to 161.33 mg alectinib HCl) and the following inactive ingredients: lactose monohydrate, hydroxypropylcellulose, sodium lauryl sulfate, magnesium stearate, and carboxymethylcellulose calcium. The capsule shell contains hypromellose, carrageenan, potassium chloride, titanium dioxide, corn starch, and carnauba wax. The printing ink contains red iron oxide (E172), yellow iron oxide (E172), FD&C Blue No. 2 aluminum lake (E132), carnauba wax, white shellac, and glyceryl monooleate. ## Pharmacodynamics - Cardiac Electrophysiology - The ability of alectinib to prolong the QT interval was assessed in 221 patients administered Alectinib 600 mg twice daily in clinical studies. Alectinib did not prolong the QTc (QT corrected for heart rate) interval to any clinically relevant extent. One patient had a maximum post-baseline QTcF value of greater than 500 msec and one patient had a maximum QTcF change from baseline of greater than 60 msec. ## Pharmacokinetics The pharmacokinetics of alectinib and its major active metabolite M4 have been characterized in patients with ALK-positive NSCLC and healthy subjects. In patients with ALK-positive NSCLC, the geometric mean (coefficient of variation %) steady-state maximal concentration (Cmax,ss) for alectinib was 665 ng/mL (44%) and for M4 was 246 ng/mL (45%) with peak to trough concentration ratio of 1.2. The geometric mean steady-state area under the curve from 0 to 12 hours (AUC(0-12h,ss)) for alectinib was 7,430 ngh/mL (46%) and for M4 was 2,810 ngh/mL (46%). Alectinib exposure is dose proportional across the dose range of 460 mg to 900 mg (i.e., 0.75 to 1.5 times the approved recommended dosage) under fed conditions. Alectinib and M4 reached steady-state concentrations by day 7. The geometric mean accumulation was approximately 6-fold for both alectinib and M4. - Absorption - Alectinib reached maximal concentrations at 4 hours following administration of Alectinib 600 mg twice daily under fed conditions in patients with ALK-positive NSCLC. - The absolute bioavailability of alectinib was 37% (90% CI: 34%, 40%) under fed conditions. - A high-fat, high-calorie meal increased the combined exposure (AUC(0-inf)) of alectinib plus M4 by 3.1-fold (90% CI: 2.7, 3.6) following oral administration of a single 600 mg dose of Alectinib. - Distribution - The apparent volume of distribution is 4,016 L for alectinib and 10,093 L for M4. - Alectinib and M4 are bound to human plasma proteins greater than 99%, independent of drug concentration. - Alectinib concentrations in the cerebrospinal fluid in patients with ALK-positive NSCLC approximate estimated alectinib free concentrations in the plasma. - In vitro studies suggest that alectinib is not a substrate of P-glycoprotein (P-gp), but M4 is a substrate of P-gp. Alectinib and M4 are not substrates of breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP) 1B1, or OATP1B3. - Elimination - The apparent clearance (CL/F) is 81.9 L/hour for alectinib and 217 L/hour for M4. The geometric mean elimination half-life is 33 hours for alectinib and 31 hours for M4 in patients with ALK-positive NSCLC. - Metabolism - Alectinib is metabolized by CYP3A4 to its major active metabolite M4. The geometric mean metabolite/parent exposure ratio at steady-state is 0.40. M4 is subsequently metabolized by CYP3A4. Alectinib and M4 were the main circulating moieties in plasma, constituting 76% of the total radioactivity. - Excretion - Ninety-eight percent of the radioactivity was excreted in feces following oral administration of a single radiolabeled dose of alectinib under fed conditions. Eighty-four percent of the dose was excreted in the feces as unchanged alectinib and 6% of the dose was excreted as M4. Excretion of radioactivity in urine was less than 0.5% of administered radiolabeled dose of alectinib. - Specific Populations - Age, body weight, mild hepatic impairment, mild to moderate renal impairment (creatinine clearance 30 to 89 mL/min), race (White, Asian, and Other), and sex had no clinically meaningful effect on the systemic exposure of alectinib and M4. The pharmacokinetics of alectinib has not been studied in patients with severe renal impairment, end-stage renal disease or moderate to severe hepatic impairment. - Drug Interactions - Effect of Other Drugs on Alectinib - No clinically meaningful effect on the combined exposure of alectinib plus M4 was observed in clinical studies following co-administration of Alectinib with a strong CYP3A inhibitor (posaconazole), a strong CYP3A inducer (rifampin), or an acid-reducing agent (esomeprazole). - Effect of Alectinib on Other Drugs - No clinically meaningful effect on the exposure of midazolam (sensitive CYP3A substrate) or repaglinide (sensitive CYP2C8 substrate) is expected following co-administration with Alectinib. - In vitro studies suggest that alectinib and M4 do not inhibit CYP1A2, 2B6, 2C9, 2C19 or 2D6. - In vitro studies suggest that alectinib and M4 inhibit P-gp and BCRP. Alectinib did not inhibit OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 transport activity in vitro. ## Nonclinical Toxicology Carcinogenicity studies with alectinib have not been conducted. Alectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay, but was positive with an increased number of micronuclei in a rat bone marrow micronucleus test. The mechanism of micronucleus induction was abnormal chromosome segregation (aneugenicity) and not a clastogenic effect on chromosomes. No studies in animals have been performed to evaluate the effect of alectinib on fertility. No adverse effects on male and female reproductive organs were observed in general toxicology studies conducted in rats and monkeys. # Clinical Studies The safety and efficacy of Alectinib were established in two single-arm, multicenter clinical trials (Studies 1 and 2). Patients with locally advanced or metastatic ALK-positive NSCLC, who have progressed on crizotinib, with documented ALK positive NSCLC based on an FDA-approved test, and ECOG PS of 0-2 were enrolled in both studies. Eligibility criteria permitted enrollment of patients with prior chemotherapy and prior CNS radiotherapy provided that CNS metastases were stable for at least two weeks. All patients received Alectinib 600 mg orally twice daily. The major efficacy outcome measure in both studies was objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1) as evaluated per Independent Review Committee (IRC). Additional outcome measures as evaluated by the IRC included duration of response (DOR), CNS ORR, and CNS DOR. Study 1 was conducted in North America and enrolled 87 patients. Baseline demographic and disease characteristics in Study 1 were median age 54 years old (range 29 to 79, 18% 65 and over), 84% White and 8% Asian, 55% female, 35% ECOG PS 0 and 55% ECOG PS 1, 100% never or former smokers, 99% Stage IV, 94% adenocarcinoma, and 74% prior chemotherapy. The most common sites of extra-thoracic metastasis included 60% CNS (of whom 65% had received CNS radiation), 43% lymph nodes, 36% bone, and 34% liver. Study 2 was conducted internationally and enrolled 138 patients. Baseline demographic and disease characteristics in Study 2 were median age 52 years old (range 22 to 79, 10% 65 and over), 67% White and 26% Asian, 56% female, 32% ECOG PS 0 and 59% ECOG PS 1, 98% never or former smokers, 99% Stage IV, 96% adenocarcinoma, and 80% prior chemotherapy. The most common sites of extra-thoracic metastasis included 61% CNS (of whom 73% had received CNS radiation), 51% bone, 38% lymph nodes, and 30% liver. Efficacy results from Studies 1 and 2 in all treated patients are summarized in TABLE 5. The median duration of follow-up on Study 1 was 4.8 months for both IRC and Investigator assessments and on Study 2, 10.9 months for IRC assessment and 7.0 months for Investigator assessment. All responses were partial responses. - Table 5: Efficacy Results in Studies 1 and 2 An assessment of ORR and duration of response for CNS metastases in the subgroup of 51 patients in Studies 1 and 2 with baseline measurable lesions in the CNS according to RECIST v1.1 are summarized in TABLE 6. Thirty-five (69%) patients with measurable CNS lesions had received prior brain radiation, including 25 (49%) who completed radiation treatment at least 6 months before starting treatment with Alectinib. Responses were observed irrespective of prior brain radiation status. - Table 6: CNS Objective Response in Patients with Measurable CNS Lesions in Studies 1 and 2 # How Supplied Hard capsules, white 150 mg capsules with "ALE" printed in black ink on the cap and "150 mg" printed in black ink on the body, available in: 240 capsules per bottle: NDC 50242-130-01 ## Storage Do not store above 30°C (86°F). Store in the original container to protect from light and moisture. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Patient Information). Inform patients of the following: - Hepatotoxicity - Inform patients of the signs and symptoms of bilirubin and hepatic transaminase elevations. Advise patients to contact their healthcare provider immediately for signs or symptoms of bilirubin and hepatic transaminase elevations. - Interstitial Lung Disease (ILD)/Pneumonitis - Inform patients of the risks of severe ILD/pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms. - Bradycardia - Inform patients that symptoms of bradycardia including dizziness, lightheadedness, and syncope can occur while taking Alectinib. Advise patients to contact their healthcare provider to report these symptoms and to inform their healthcare provider about the use of any heart or blood pressure medications. - Severe Myalgia/CPK elevation - Inform patients of signs and symptoms of myalgia, including unexplained and/or persistent muscle pain, tenderness, or weakness. Advise patients to contact their healthcare provider immediately to report new or worsening symptoms of muscle pain or weakness. - Photosensitivity Inform patients of the signs and symptoms of photosensitivity. Advise patients to avoid prolonged sun exposure while taking Alectinib and for at least 7 days after study drug discontinuation and to use proper protection from the sun. Advise patients to use a broad spectrum ultraviolet A (UVA)/ultraviolet B (UVB) sunscreen and lip balm (SPF ≥50) to help protect against potential sunburn. - Embryo-Fetal Toxicity - Alectinib can cause fetal harm if taken during pregnancy. Advise a pregnant woman of the potential risk to a fetus. - Advise females of reproductive potential to use effective contraception during treatment with Alectinib and for at least 1 week after the last dose of Alectinib. Advise patients to inform their healthcare provider of a known or suspected pregnancy. - Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Alectinib and for 3 months after the last dose. - Lactation Advise women not to breastfeed during treatment with Alectinib and for one week after the last dose. - Administration Instruct patients to take Alectinib twice a day. Advise patients to take Alectinib with food and to swallow Alectinib capsules whole. - Missed Dose Advise patients that if a dose of Alectinib is missed or if the patient vomits after taking a dose of Alectinib, patients should be advised not to take an extra dose, but to take the next dose at the regular time. # Precautions with Alcohol Alcohol-Alectinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names ALECENSA® # Look-Alike Drug Names There is limited information regarding Alectinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Alectinib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Alectinib is a kinase inhibitor that is FDA approved for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. Common adverse reactions include fatigue, constipation, edema and myalgia (≥20%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Alectinib is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. - Dosing and Administration - The recommended dose of Alectinib is 600 mg orally twice daily with food. Administer Alectinib until disease progression or unacceptable toxicity. - Do not open or dissolve the contents of the capsule. - If a dose of Alectinib is missed or vomiting occurs after taking a dose of Alectinib, take the next dose at the scheduled time. - Dose Modifications for Adverse Reactions - The dose reduction schedule for Alectinib is provided in TABLE 1. - Table 1. Alectinib Dose Reduction Schedule - Discontinue if patients are unable to tolerate the 300 mg twice daily dose. - Recommendations for dose modifications of Alectinib in case of adverse reactions are provided in TABLE 2. - Table 2. Alectinib Dose Modifications for Adverse Reactions ALECENSA: Alectinib's Brand name ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Alectinib in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Alectinib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of Alectinib in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Alectinib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Alectinib in pediatric patients. # Contraindications None # Warnings Elevations of AST greater than 5 times the upper limit of normal (ULN) occurred in 3.6% of patients, and elevations of ALT greater than 5 times the ULN occurred in 4.8% of patients. Elevations of bilirubin greater than 3 times the ULN occurred in 2.8% of patients in Studies 1 and 2. The majority (76% of the patients with hepatic transaminase elevations and 68% of the patients with bilirubin elevations) of these events occurred during the first 3 months of treatment. Four patients discontinued Alectinib for Grade 3-4 AST and/or ALT elevations, and 3 patients discontinued Alectinib for Grade 3 bilirubin elevations. In Studies 1 and 2, two patients with Grade 3-4 AST/ALT elevations had documented drug induced liver injury by liver biopsy. Concurrent elevations in ALT or AST greater than or equal to three times the ULN and total bilirubin greater than or equal to two times the ULN, with normal alkaline phosphatase, occurred in less than 1% of patients treated with Alectinib across clinical trials. Monitor liver function tests including ALT, AST, and total bilirubin every 2 weeks during the first 3 months of treatment, then once a month and as clinically indicated, with more frequent testing in patients who develop transaminase and bilirubin elevations. Based on the severity of the adverse drug reaction, withhold Alectinib and resume at a reduced dose, or permanently discontinue Alectinib as described in Table 2. Severe ILD (Grade 3) occurred in one (0.4%) of 253 patients exposed to Alectinib in Studies 1 and 2. Promptly investigate for ILD/pneumonitis in any patient who presents with worsening of respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough and fever). Immediately withhold Alectinib treatment in patients diagnosed with ILD/pneumonitis and permanently discontinue Alectinib if no other potential causes of ILD/pneumonitis have been identified. Symptomatic bradycardia can occur with Alectinib. Cases of bradycardia (7.5%) have been reported in patients treated with Alectinib. Twenty percent of 221 patients treated with Alectinib for whom serial ECGs were available had heart rates of less than 50 beats per minute (bpm). Monitor heart rate and blood pressure regularly. Dose modification is not required in cases of asymptomatic bradycardia. In cases of symptomatic bradycardia that is not life-threatening, withhold Alectinib until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above and evaluate concomitant medications known to cause bradycardia, as well as anti-hypertensive medications. If attributable to a concomitant medication, resume Alectinib at a reduced dose (see TABLE 1) upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring as clinically indicated. Permanently discontinue Alectinib in case of recurrence. Permanently discontinue Alectinib in cases of life-threatening bradycardia if no contributing concomitant medication is identified. Myalgia or musculoskeletal pain occurred in 29% of patients in Studies 1 and 2. The incidence of Grade 3 myalgia/musculoskeletal pain was 1.2%. Dose modifications for myalgia/musculoskeletal pain were required in 0.8% of patients. Elevations of CPK occurred in 43% of 218 patients with CPK laboratory data available in Study 1 and Study 2. The incidence of Grade 3 elevations of CPK was 4.6%. Median time to Grade 3 CPK elevation was 14 days (interquartile range 13-14 days). Dose modifications for elevation of CPK occurred in 5.0% of patients. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Assess CPK levels every two weeks for the first month of treatment and as clinically indicated in patients reporting symptoms. Based on the severity of the CPK elevation, withhold Alectinib, then resume or reduce dose [see DOSAGE AND ADMINISTRATION (2.2)]. Based on findings from animal studies and its mechanism of action, Alectinib can cause fetal harm when administered to pregnant women. Administration of alectinib to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal toxicity and abortion at maternally toxic doses with exposures approximately 2.7-times those observed in humans with alectinib 600 mg twice daily. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Alectinib and for 1 week following the final dose. # Adverse Reactions ## Clinical Trials Experience The following adverse reactions are discussed in greater detail in other sections of the label: - Hepatotoxicity - Interstitial Lung Disease (ILD)/Pneumonitis - Bradycardia - Severe Myalgia and Creatine Phosphokinase (CPK) Elevation - Embryo-Fetal Toxicity 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 Alectinib was evaluated in 253 patients with ALK-positive non-small cell lung cancer (NSCLC) treated with Alectinib 600 mg orally twice daily in two clinical trials, Studies 1 and 2. The median duration of exposure to Alectinib was 9.3 months. One hundred sixty-nine patients (67%) were exposed to Alectinib for more than 6 months, and 100 patients (40%) for more than one year. The population characteristics were: median age 53 years, age less than 65 (86%), female (55%), White (74%), Asian (18%), NSCLC adenocarcinoma histology (96%), never or former smoker (98%), ECOG Performance Status (PS) 0 or 1 (91%), and prior chemotherapy treatment (78%). Serious adverse reactions occurred in 19% of patients; the most frequently reported serious adverse reactions were pulmonary embolism (1.2%), dyspnea (1.2%), and hyperbilirubinemia (1.2%). Fatal adverse reactions occurred in 2.8% of patients and included hemorrhage (0.8%), intestinal perforation (0.4%), dyspnea (0.4%), pulmonary embolism (0.4%), and endocarditis (0.4%). Permanent discontinuation of Alectinib for adverse reactions occurred in 6% of patients. The most frequent adverse reactions that led to permanent discontinuation were hyperbilirubinemia (1.6%), increased ALT levels (1.6%), and increased AST levels (1.2%). Overall, 23% of patients initiating treatment at the recommended dose required at least one dose reduction. The median time to first dose reduction was 48 days. The most frequent adverse reactions that led to dose reductions or interruptions were elevations in bilirubin (6%), CPK (4.3%), ALT (4.0%), and AST (2.8%), and vomiting (2.8%). TABLE 3 summarizes adverse reactions in Studies 1 and 2. - Table 3. Adverse Reactions in ≥ 10% (All Grades) or ≥ 2% (Grade 3-4) of Patients in Studies 1 and 2 ALECENSA: Alectinib's Brand name - Additional safety information from clinical trial experience - Photosensitivity occurred in 9.9% of patients exposed to Alectinib in Studies 1 and 2. Patients were advised to avoid sun exposure and to use broad-spectrum sunscreen. The incidence of Grade 2 photosensitivity was 0.4%; the remaining events were Grade 1 in severity. - TABLE 4 summarizes laboratory abnormalities of Alectinib in Studies 1 and 2. - Table 4. Laboratory Abnormalities Occurring in >20% of Patients in Studies 1 and 2 ## Postmarketing Experience There is limited information regarding Alectinib Postmarketing Experience in the drug label. # Drug Interactions No pharmacokinetic interactions with alectinib requiring dosage adjustment have been identified. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): N - Risk Summary - Based on animal studies and its mechanism of action, Alectinib can cause fetal harm when administered to a pregnant woman. There are no available data on Alectinib use in pregnant women. - Administration of alectinib to pregnant rats and rabbits by oral gavage during the period of organogenesis resulted in embryo-fetal toxicity and abortion at maternally toxic doses with exposures approximately 2.7-times those observed in humans treated with alectinib at 600 mg twice daily. Advise pregnant women of the potential risk to a fetus. - In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively. - Data - Animal Data - In a preliminary rabbit embryo-fetal study, administration of alectinib by oral gavage during the period of organogenesis resulted in abortion or complete embryo-fetal mortality at a maternally toxic dose of 27 mg/kg/day (approximately 2.9-fold the estimated area under the curve (AUC(0-24h,ss)) in humans treated with alectinib 600 mg BID) in three of six pregnant rabbits. The remaining three pregnant rabbits in this group had few live fetuses, decreased fetal and placental weights, and retroesophageal subclavian artery. In a rat preliminary embryo-fetal development study, administration of alectinib during organogenesis resulted in complete litter loss in all pregnant rats at 27 mg/kg/day (approximately 4.5-fold the estimated AUC(0-24h,ss) in humans treated with alectinib 600 mg BID). Doses greater than or equal to 9 mg/kg/day (approximately 2.7-fold the estimated human AUC(0-24h,ss) in humans treated with alectinib 600 mg BID), resulted in maternal toxicity as well as developmental toxicities including decreased fetal weight, dilated ureter, thymic cord, small ventricle and thin ventricle wall, and reduced number of sacral and caudal vertebrae. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alectinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Alectinib during labor and delivery. ### Nursing Mothers There are no data on the presence of alectinib or its metabolites in human milk, the effects of alectinib on the breast-fed infant, or its effects on milk production. Because of the potential for serious adverse reactions in breast-fed infants from alectinib, advise a lactating woman not to breastfeed during treatment with Alectinib and for 1 week after the final dose. ### Pediatric Use The safety and effectiveness of Alectinib in pediatric patients have not been established. - Animal Data - Juvenile animal studies have not been conducted using alectinib. In general toxicology studies, treatment of rats with doses of alectinib resulting in exposures greater than or equal to approximately 4.5 times those in humans treated with alectinib at 600 mg twice daily resulted in changes in the growing teeth and bones. Findings in teeth included discoloration and changes in tooth size along with histopathological disarrangement of the ameloblast and odontoblast layers. There were also decreases in the trabecular bone and increased osteoclast activity in the femur and sternum. ### Geriatic Use Clinical studies of Alectinib did not include sufficient number of subjects aged 65 and older to determine whether they respond differently from younger subjects. ### Gender There is no FDA guidance on the use of Alectinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Alectinib with respect to specific racial populations. ### Renal Impairment No dose adjustment is recommended for patients with mild or moderate renal impairment. The safety of Alectinib in patients with severe renal impairment (creatinine clearance less than 30 mL/min) or end-stage renal disease has not been studied. ### Hepatic Impairment No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin less than or equal to upper limit of normal (ULN) and aspartate transaminase (AST) greater than ULN or total bilirubin greater than 1.0 to 1.5 times ULN and any AST). The safety of Alectinib in patients with moderate or severe hepatic impairment has not been studied. ### Females of Reproductive Potential and Males - Females - Alectinib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Alectinib and for 1 week after the final dose. - Males - Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with Alectinib and for 3 months following the final dose. ### Immunocompromised Patients There is no FDA guidance one the use of Alectinib in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Alectinib Administration in the drug label. ### Monitoring There is limited information regarding Alectinib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Alectinib and IV administrations. # Overdosage No experience with overdose is available. There is no specific antidote for overdose with Alectinib. Alectinib and its major active metabolite M4 are > 99% bound to plasma proteins; therefore, hemodialysis is likely to be ineffective in the treatment of overdose. # Pharmacology ## Mechanism of Action Alectinib is a tyrosine kinase inhibitor that targets ALK and RET. In nonclinical studies, alectinib inhibited ALK phosphorylation and ALK-mediated activation of the downstream signaling proteins STAT3 and AKT, and decreased tumor cell viability in multiple cell lines harboring ALK fusions, amplifications, or activating mutations. The major active metabolite of alectinib, M4, showed similar in vitro potency and activity. Alectinib and M4 demonstrated in vitro and in vivo activity against multiple mutant forms of the ALK enzyme, including some mutations identified in NSCLC tumors in patients who have progressed on crizotinib. In mouse models implanted with tumors carrying ALK fusions, administration of alectinib resulted in antitumor activity and prolonged survival, including in mouse models implanted intracranially with ALK-driven tumor cell lines. ## Structure Alectinib is a kinase inhibitor for oral administration. The molecular formula for alectinib is C30H34N4O2 ∙ HCl. The molecular weight is 482.62 g/mol (free base form) and 519.08 g/mol (hydrochloride salt). Alectinib is described chemically as 9-ethyl-6, 6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6, 11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride. The chemical structure of alectinib is shown below: Alectinib HCl is a white to yellow white powder or powder with lumps with a pKa of 7.05 (base). Alectinib is supplied as hard capsules containing 150 mg of alectinib (equivalent to 161.33 mg alectinib HCl) and the following inactive ingredients: lactose monohydrate, hydroxypropylcellulose, sodium lauryl sulfate, magnesium stearate, and carboxymethylcellulose calcium. The capsule shell contains hypromellose, carrageenan, potassium chloride, titanium dioxide, corn starch, and carnauba wax. The printing ink contains red iron oxide (E172), yellow iron oxide (E172), FD&C Blue No. 2 aluminum lake (E132), carnauba wax, white shellac, and glyceryl monooleate. ## Pharmacodynamics - Cardiac Electrophysiology - The ability of alectinib to prolong the QT interval was assessed in 221 patients administered Alectinib 600 mg twice daily in clinical studies. Alectinib did not prolong the QTc (QT corrected for heart rate) interval to any clinically relevant extent. One patient had a maximum post-baseline QTcF value of greater than 500 msec and one patient had a maximum QTcF change from baseline of greater than 60 msec. ## Pharmacokinetics The pharmacokinetics of alectinib and its major active metabolite M4 have been characterized in patients with ALK-positive NSCLC and healthy subjects. In patients with ALK-positive NSCLC, the geometric mean (coefficient of variation %) steady-state maximal concentration (Cmax,ss) for alectinib was 665 ng/mL (44%) and for M4 was 246 ng/mL (45%) with peak to trough concentration ratio of 1.2. The geometric mean steady-state area under the curve from 0 to 12 hours (AUC(0-12h,ss)) for alectinib was 7,430 ngh/mL (46%) and for M4 was 2,810 ngh/mL (46%). Alectinib exposure is dose proportional across the dose range of 460 mg to 900 mg (i.e., 0.75 to 1.5 times the approved recommended dosage) under fed conditions. Alectinib and M4 reached steady-state concentrations by day 7. The geometric mean accumulation was approximately 6-fold for both alectinib and M4. - Absorption - Alectinib reached maximal concentrations at 4 hours following administration of Alectinib 600 mg twice daily under fed conditions in patients with ALK-positive NSCLC. - The absolute bioavailability of alectinib was 37% (90% CI: 34%, 40%) under fed conditions. - A high-fat, high-calorie meal increased the combined exposure (AUC(0-inf)) of alectinib plus M4 by 3.1-fold (90% CI: 2.7, 3.6) following oral administration of a single 600 mg dose of Alectinib. - Distribution - The apparent volume of distribution is 4,016 L for alectinib and 10,093 L for M4. - Alectinib and M4 are bound to human plasma proteins greater than 99%, independent of drug concentration. - Alectinib concentrations in the cerebrospinal fluid in patients with ALK-positive NSCLC approximate estimated alectinib free concentrations in the plasma. - In vitro studies suggest that alectinib is not a substrate of P-glycoprotein (P-gp), but M4 is a substrate of P-gp. Alectinib and M4 are not substrates of breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP) 1B1, or OATP1B3. - Elimination - The apparent clearance (CL/F) is 81.9 L/hour for alectinib and 217 L/hour for M4. The geometric mean elimination half-life is 33 hours for alectinib and 31 hours for M4 in patients with ALK-positive NSCLC. - Metabolism - Alectinib is metabolized by CYP3A4 to its major active metabolite M4. The geometric mean metabolite/parent exposure ratio at steady-state is 0.40. M4 is subsequently metabolized by CYP3A4. Alectinib and M4 were the main circulating moieties in plasma, constituting 76% of the total radioactivity. - Excretion - Ninety-eight percent of the radioactivity was excreted in feces following oral administration of a single radiolabeled dose of alectinib under fed conditions. Eighty-four percent of the dose was excreted in the feces as unchanged alectinib and 6% of the dose was excreted as M4. Excretion of radioactivity in urine was less than 0.5% of administered radiolabeled dose of alectinib. - Specific Populations - Age, body weight, mild hepatic impairment, mild to moderate renal impairment (creatinine clearance 30 to 89 mL/min), race (White, Asian, and Other), and sex had no clinically meaningful effect on the systemic exposure of alectinib and M4. The pharmacokinetics of alectinib has not been studied in patients with severe renal impairment, end-stage renal disease or moderate to severe hepatic impairment. - Drug Interactions - Effect of Other Drugs on Alectinib - No clinically meaningful effect on the combined exposure of alectinib plus M4 was observed in clinical studies following co-administration of Alectinib with a strong CYP3A inhibitor (posaconazole), a strong CYP3A inducer (rifampin), or an acid-reducing agent (esomeprazole). - Effect of Alectinib on Other Drugs - No clinically meaningful effect on the exposure of midazolam (sensitive CYP3A substrate) or repaglinide (sensitive CYP2C8 substrate) is expected following co-administration with Alectinib. - In vitro studies suggest that alectinib and M4 do not inhibit CYP1A2, 2B6, 2C9, 2C19 or 2D6. - In vitro studies suggest that alectinib and M4 inhibit P-gp and BCRP. Alectinib did not inhibit OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 transport activity in vitro. ## Nonclinical Toxicology Carcinogenicity studies with alectinib have not been conducted. Alectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay, but was positive with an increased number of micronuclei in a rat bone marrow micronucleus test. The mechanism of micronucleus induction was abnormal chromosome segregation (aneugenicity) and not a clastogenic effect on chromosomes. No studies in animals have been performed to evaluate the effect of alectinib on fertility. No adverse effects on male and female reproductive organs were observed in general toxicology studies conducted in rats and monkeys. # Clinical Studies The safety and efficacy of Alectinib were established in two single-arm, multicenter clinical trials (Studies 1 and 2). Patients with locally advanced or metastatic ALK-positive NSCLC, who have progressed on crizotinib, with documented ALK positive NSCLC based on an FDA-approved test, and ECOG PS of 0-2 were enrolled in both studies. Eligibility criteria permitted enrollment of patients with prior chemotherapy and prior CNS radiotherapy provided that CNS metastases were stable for at least two weeks. All patients received Alectinib 600 mg orally twice daily. The major efficacy outcome measure in both studies was objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1) as evaluated per Independent Review Committee (IRC). Additional outcome measures as evaluated by the IRC included duration of response (DOR), CNS ORR, and CNS DOR. Study 1 was conducted in North America and enrolled 87 patients. Baseline demographic and disease characteristics in Study 1 were median age 54 years old (range 29 to 79, 18% 65 and over), 84% White and 8% Asian, 55% female, 35% ECOG PS 0 and 55% ECOG PS 1, 100% never or former smokers, 99% Stage IV, 94% adenocarcinoma, and 74% prior chemotherapy. The most common sites of extra-thoracic metastasis included 60% CNS (of whom 65% had received CNS radiation), 43% lymph nodes, 36% bone, and 34% liver. Study 2 was conducted internationally and enrolled 138 patients. Baseline demographic and disease characteristics in Study 2 were median age 52 years old (range 22 to 79, 10% 65 and over), 67% White and 26% Asian, 56% female, 32% ECOG PS 0 and 59% ECOG PS 1, 98% never or former smokers, 99% Stage IV, 96% adenocarcinoma, and 80% prior chemotherapy. The most common sites of extra-thoracic metastasis included 61% CNS (of whom 73% had received CNS radiation), 51% bone, 38% lymph nodes, and 30% liver. Efficacy results from Studies 1 and 2 in all treated patients are summarized in TABLE 5. The median duration of follow-up on Study 1 was 4.8 months for both IRC and Investigator assessments and on Study 2, 10.9 months for IRC assessment and 7.0 months for Investigator assessment. All responses were partial responses. - Table 5: Efficacy Results in Studies 1 and 2 An assessment of ORR and duration of response for CNS metastases in the subgroup of 51 patients in Studies 1 and 2 with baseline measurable lesions in the CNS according to RECIST v1.1 are summarized in TABLE 6. Thirty-five (69%) patients with measurable CNS lesions had received prior brain radiation, including 25 (49%) who completed radiation treatment at least 6 months before starting treatment with Alectinib. Responses were observed irrespective of prior brain radiation status. - Table 6: CNS Objective Response in Patients with Measurable CNS Lesions in Studies 1 and 2 # How Supplied Hard capsules, white 150 mg capsules with "ALE" printed in black ink on the cap and "150 mg" printed in black ink on the body, available in: 240 capsules per bottle: NDC 50242-130-01 ## Storage Do not store above 30°C (86°F). Store in the original container to protect from light and moisture. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Patient Information). Inform patients of the following: - Hepatotoxicity - Inform patients of the signs and symptoms of bilirubin and hepatic transaminase elevations. Advise patients to contact their healthcare provider immediately for signs or symptoms of bilirubin and hepatic transaminase elevations. - Interstitial Lung Disease (ILD)/Pneumonitis - Inform patients of the risks of severe ILD/pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms. - Bradycardia - Inform patients that symptoms of bradycardia including dizziness, lightheadedness, and syncope can occur while taking Alectinib. Advise patients to contact their healthcare provider to report these symptoms and to inform their healthcare provider about the use of any heart or blood pressure medications. - Severe Myalgia/CPK elevation - Inform patients of signs and symptoms of myalgia, including unexplained and/or persistent muscle pain, tenderness, or weakness. Advise patients to contact their healthcare provider immediately to report new or worsening symptoms of muscle pain or weakness. - Photosensitivity Inform patients of the signs and symptoms of photosensitivity. Advise patients to avoid prolonged sun exposure while taking Alectinib and for at least 7 days after study drug discontinuation and to use proper protection from the sun. Advise patients to use a broad spectrum ultraviolet A (UVA)/ultraviolet B (UVB) sunscreen and lip balm (SPF ≥50) to help protect against potential sunburn. - Embryo-Fetal Toxicity - Alectinib can cause fetal harm if taken during pregnancy. Advise a pregnant woman of the potential risk to a fetus. - Advise females of reproductive potential to use effective contraception during treatment with Alectinib and for at least 1 week after the last dose of Alectinib. Advise patients to inform their healthcare provider of a known or suspected pregnancy. - Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Alectinib and for 3 months after the last dose. - Lactation Advise women not to breastfeed during treatment with Alectinib and for one week after the last dose. - Administration Instruct patients to take Alectinib twice a day. Advise patients to take Alectinib with food and to swallow Alectinib capsules whole. - Missed Dose Advise patients that if a dose of Alectinib is missed or if the patient vomits after taking a dose of Alectinib, patients should be advised not to take an extra dose, but to take the next dose at the regular time. # Precautions with Alcohol Alcohol-Alectinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names ALECENSA® # Look-Alike Drug Names There is limited information regarding Alectinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Alectinib
bd4213ba921081778af22c5b79f72f16e08fa460	wikidoc	Alefacept	Alefacept # Overview Alefacept is a genetically engineered immunosuppressive drug sold under the brand name Amevive in Canada, the United States, and Australia. It is used to control inflammation in moderate to severe psoriasis with plaque formation, where it interferes with lymphocyte activation. # Mode of Action The exact mode of action is very complicated, but is has been explored that alefacept inhibits the activation of CD2+, CD4+, and CD8+ T cells which in return stimulate hyperproliferation of keratinocyts resulting in the typical psoriatic symptoms. Therefore, alefacept leads to clinical improvement of moderate to severe psoriasis by blunting these reactions. # Drawbacks Due to safety issues (immunosuppression, risk of infections, malignancies, and allergies) the European Medicines Agency (EMEA) has so far rejected to approve alefacept. # Indications Alefacept is indicated for the management of patients with moderate to severe chronic plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy. The concomitant use of low-potency topical corticosteroids was permitted during the treatment phase with alefacept and does not seem to pose any additional risks. The drug was approved based upon studies involving 1,869 patients altogether with plaques covering at least 10% of body surface. Either 7.5 mg IV or 15 mg IM once a week were applied. The long term results (reduction of at least 75% in pretreatment PASI scores) were 14% and 21%, respectively. Additional improvements ensuing after completion of the 12-week treatment phase or after completion of a second alefacept treatment were also seen. Often the remissions were maintained for 7 to 12 months after end of treatment. # Contraindications and Precautions - Alefacept reduces CD4+ T cell counts and may worsen the clinical course of HIV infections. It is therefore contraindicated in patients with HIV infections. - Pretreatment CD4+ and/or CD8+ cell counts below the accepted lower limit - History of systemic malignancy - Caution: Patients at high risk to develop a systemic malignancy - Known hypersensitivity to alefacept or to any other ingredient of the preparation - Caution: There is little experience in geriatric patients (65 years of age or older); so far no differences to the younger age group have been noted. # Pregnancy and Lactation - Alefacept has been assigned to Pregnancy Category B in the US and to C in Australia. - Lactation : It is not known if the drug is excreted into human milk. Either the drug or breastfeeding should be terminated, taking into account the importance of treatment to the mother. # Pediatric Patients No clinical experience exists in patients under 18 years of age. The drug should therefore not be used in pediatric patients. # Side effects - Lymphopenia : Most common in clinical trials was a significant and dose-related reduction of CD4+ and CD8+ counts in 10 to 59% of patients. However, only 0 to 2% of patients experienced reductions below the accepted lower limit. Consequences of lymphopenia may be infections and/or treatment related malignancies (see below). - Malignancies : In clinical studies among 1,869 patients 63 treatment-emerged malignancies in 43 patients were observed. Most of these were nonmelanoma and melanoma skin cancers, other solid tumors, and lymphomas. - Infections : In clinical studies 0.9% of patients experienced significant infections compared to 0.2% in the placebo group. Among the infections were serious ones such as sepsis, pneumonia, abscesses, wound infections and toxic shock syndrome. - Sensitivity reactions: Urticaria and angioedema were observed. If an anaphylactic reaction should occur symptomatic treatment should be initiated at once. - Forming of antibodies to alefacept : About 3% of patients developed low-titer antibodies with unknown importance for the clinical efficiency of the drug. Longterm immune effects have not been well explored. - Hepatic Toxicity : Postmarketing reports revealed asymtomatic increases in transaminases (ALT and/or AST), fatty liver degeneration, decompensation of preexisting liver cirrhosis, and acute treatment-related liver failure. It is not known if some or all of these manifestations are attributable to alefacept-therapy, but it is recommended to discontinue therapy as soon as any sign of liver toxicity develops. - Different Common Side Effects : side effects such as pharyngitis, cough, dizziness, nausea, pruritus, myalgias, chills, and reactions at injection sites were observed quite frequently. # Interactions - Patients currently undergoing immunosuppressive therapy (phototherapy, or concomitant application of other immunosuppressant agents) should not receive alefacept in order to avoid the risks of excessive immunosuppression. Studies concerning the combination with cyclosporine or methotrexate are conducted, but no results have been published so far. - Live vaccines : The efficiency of concomitant application of live vaccines has not been fully examined yet. However, the effect of tetanus toxoid was well preserved in clinical trials. # Necessary Laboratory Examinations - CD4+ cell counts should be obtained before initiation of therapy and during the 12-week course of therapy in intervals of 2 weeks. - It may be desirable to monitor liver function studies (AST and ALT) in patients at high risk to develop liver toxicity (e.g., preexisting hepatitis, or high daily consumption of alcohol). # Dosage Regimes The standard dosage regime is the weekly application of either 7.5 mg IV or 15 mg IM for a course of 12 weeks. The benefits and risks of repeated courses have not been explored in sufficient detail. Therapy should be conducted under the supervision of a physician experienced in the use of immunosuppressant agents. # Notes - ↑ "New drugs". Australian Prescriber. 27 (101): 5. 2004. Retrieved 2006-08-20..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}	Alefacept Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Alefacept is a genetically engineered immunosuppressive drug sold under the brand name Amevive in Canada, the United States, and Australia. It is used to control inflammation in moderate to severe psoriasis with plaque formation, where it interferes with lymphocyte activation.[1] # Mode of Action The exact mode of action is very complicated, but is has been explored that alefacept inhibits the activation of CD2+, CD4+, and CD8+ T cells which in return stimulate hyperproliferation of keratinocyts resulting in the typical psoriatic symptoms. Therefore, alefacept leads to clinical improvement of moderate to severe psoriasis by blunting these reactions. # Drawbacks Due to safety issues (immunosuppression, risk of infections, malignancies, and allergies) the European Medicines Agency (EMEA) has so far rejected to approve alefacept. # Indications Alefacept is indicated for the management of patients with moderate to severe chronic plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy. The concomitant use of low-potency topical corticosteroids was permitted during the treatment phase with alefacept and does not seem to pose any additional risks. The drug was approved based upon studies involving 1,869 patients altogether with plaques covering at least 10% of body surface. Either 7.5 mg IV or 15 mg IM once a week were applied. The long term results (reduction of at least 75% in pretreatment PASI scores) were 14% and 21%, respectively. Additional improvements ensuing after completion of the 12-week treatment phase or after completion of a second alefacept treatment were also seen. Often the remissions were maintained for 7 to 12 months after end of treatment. # Contraindications and Precautions - Alefacept reduces CD4+ T cell counts and may worsen the clinical course of HIV infections. It is therefore contraindicated in patients with HIV infections. - Pretreatment CD4+ and/or CD8+ cell counts below the accepted lower limit - History of systemic malignancy - Caution: Patients at high risk to develop a systemic malignancy - Known hypersensitivity to alefacept or to any other ingredient of the preparation - Caution: There is little experience in geriatric patients (65 years of age or older); so far no differences to the younger age group have been noted. # Pregnancy and Lactation - Alefacept has been assigned to Pregnancy Category B in the US and to C in Australia. - Lactation : It is not known if the drug is excreted into human milk. Either the drug or breastfeeding should be terminated, taking into account the importance of treatment to the mother. # Pediatric Patients No clinical experience exists in patients under 18 years of age. The drug should therefore not be used in pediatric patients. # Side effects - Lymphopenia : Most common in clinical trials was a significant and dose-related reduction of CD4+ and CD8+ counts in 10 to 59% of patients. However, only 0 to 2% of patients experienced reductions below the accepted lower limit. Consequences of lymphopenia may be infections and/or treatment related malignancies (see below). - Malignancies : In clinical studies among 1,869 patients 63 treatment-emerged malignancies in 43 patients were observed. Most of these were nonmelanoma and melanoma skin cancers, other solid tumors, and lymphomas. - Infections : In clinical studies 0.9% of patients experienced significant infections compared to 0.2% in the placebo group. Among the infections were serious ones such as sepsis, pneumonia, abscesses, wound infections and toxic shock syndrome. - Sensitivity reactions: Urticaria and angioedema were observed. If an anaphylactic reaction should occur symptomatic treatment should be initiated at once. - Forming of antibodies to alefacept : About 3% of patients developed low-titer antibodies with unknown importance for the clinical efficiency of the drug. Longterm immune effects have not been well explored. - Hepatic Toxicity : Postmarketing reports revealed asymtomatic increases in transaminases (ALT and/or AST), fatty liver degeneration, decompensation of preexisting liver cirrhosis, and acute treatment-related liver failure. It is not known if some or all of these manifestations are attributable to alefacept-therapy, but it is recommended to discontinue therapy as soon as any sign of liver toxicity develops. - Different Common Side Effects : side effects such as pharyngitis, cough, dizziness, nausea, pruritus, myalgias, chills, and reactions at injection sites were observed quite frequently. # Interactions - Patients currently undergoing immunosuppressive therapy (phototherapy, or concomitant application of other immunosuppressant agents) should not receive alefacept in order to avoid the risks of excessive immunosuppression. Studies concerning the combination with cyclosporine or methotrexate are conducted, but no results have been published so far. - Live vaccines : The efficiency of concomitant application of live vaccines has not been fully examined yet. However, the effect of tetanus toxoid was well preserved in clinical trials. # Necessary Laboratory Examinations - CD4+ cell counts should be obtained before initiation of therapy and during the 12-week course of therapy in intervals of 2 weeks. - It may be desirable to monitor liver function studies (AST and ALT) in patients at high risk to develop liver toxicity (e.g., preexisting hepatitis, or high daily consumption of alcohol). # Dosage Regimes The standard dosage regime is the weekly application of either 7.5 mg IV or 15 mg IM for a course of 12 weeks. The benefits and risks of repeated courses have not been explored in sufficient detail. Therapy should be conducted under the supervision of a physician experienced in the use of immunosuppressant agents. # Notes - ↑ "New drugs". Australian Prescriber. 27 (101): 5. 2004. Retrieved 2006-08-20..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} # External links - Koo J, Bagel J, Sweetser M, Ticho B. "Alefacept in combination with ultraviolet B phototherapy for the treatment of chronic plaque psoriasis: results from an open-label, multicenter study". J Drugs Dermatol. 5 (7): 623–8. PMID 16865867.CS1 maint: Multiple names: authors list (link) - Krell J (2006). "Use of alefacept and etanercept in 3 patients whose psoriasis failed to respond to etanercept". J Am Acad Dermatol. 54 (6): 1099–101. PMID 16713481. - Parrish C, Sobera J, Robbins C, Cantrell W, Desmond R, Elewski B (2006). "Alefacept in the treatment of psoriatic nail disease: a proof of concept study". J Drugs Dermatol. 5 (4): 339–40. PMID 16673801.CS1 maint: Multiple names: authors list (link) - AHFS Database online Template:Immunosuppressants	https://www.wikidoc.org/index.php/Alefacept
d9d3518fde78e5762ae61c1104921aaff895c836	wikidoc	Alesse-28	Alesse-28 Synonyms / Brand Names: # Dosing and Administration To achieve maximum contraceptive effectiveness, Alesse® (levonorgestrel and ethinyl estradiol tablets) must be taken exactly as directed and at intervals not exceeding 24 hours. The dosage of Alesse-28 is one pink tablet daily for 21 consecutive days, followed by one light-green inert tablet daily for 7 consecutive days, according to the prescribed schedule. It is recommended that Alesse-28 tablets be taken at the same time each day. The dispenser should be kept in the wallet supplied to avoid possible fading of the pills. If the pills fade, patients should continue to take them as directed. FDA Package Insert Resources Indications, Contraindications, Side Effects, Drug Interactions, etc. Calculate Creatine Clearance On line calculator of your patients Cr Cl by a variety of formulas. Convert pounds to Kilograms On line calculator of your patients weight in pounds to Kg for dosing estimates. Publication Resources Recent articles, WikiDoc State of the Art Review, Textbook Information Trial Resources Ongoing Trials, Trial Results Guidelines & Evidence Based Medicine Resources US National Guidelines, Cochrane Collaboration, etc. Media Resources Slides, Video, Images, MP3, Podcasts, etc. Patient Resources Discussion Groups, Handouts, Blogs, News, etc. International Resources en Español # FDA Package Insert Resources Indications Contraindications Side Effects Drug Interactions Precautions Overdose Instructions for Administration How Supplied Pharmacokinetics and Molecular Data FDA label FDA on Alesse-28 Return to top # Publication Resources Most Recent Articles on Alesse-28 Review Articles on Alesse-28 Articles on Alesse-28 in N Eng J Med, Lancet, BMJ WikiDoc State of the Art Review Textbook Information on Alesse-28 Return to top # Trial Resources Ongoing Trials with Alesse-28 at Clinical Trials.gov Trial Results with Alesse-28 Return to top # Guidelines & Evidence Based Medicine Resources US National Guidelines Clearinghouse on Alesse-28 Cochrane Collaboration on Alesse-28 Cost Effectiveness of Alesse-28 Return to top # Media Resources Powerpoint Slides on Alesse-28 Images of Alesse-28 Podcasts & MP3s on Alesse-28 Videos on Alesse-28 Return to top # Patient Resources Patient Information from National Library of Medicine Patient Resources on Alesse-28 Discussion Groups on Alesse-28 Patient Handouts on Alesse-28 Blogs on Alesse-28 Alesse-28 in the News Alesse-28 in the Marketplace Return to top # International Resources Alesse-28 en Español Return to top Adapted from the FDA Package Insert.	Alesse-28 Synonyms / Brand Names: Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Dosing and Administration To achieve maximum contraceptive effectiveness, Alesse® (levonorgestrel and ethinyl estradiol tablets) must be taken exactly as directed and at intervals not exceeding 24 hours. The dosage of Alesse-28 is one pink tablet daily for 21 consecutive days, followed by one light-green inert tablet daily for 7 consecutive days, according to the prescribed schedule. It is recommended that Alesse-28 tablets be taken at the same time each day. The dispenser should be kept in the wallet supplied to avoid possible fading of the pills. If the pills fade, patients should continue to take them as directed. FDA Package Insert Resources Indications, Contraindications, Side Effects, Drug Interactions, etc. Calculate Creatine Clearance On line calculator of your patients Cr Cl by a variety of formulas. Convert pounds to Kilograms On line calculator of your patients weight in pounds to Kg for dosing estimates. Publication Resources Recent articles, WikiDoc State of the Art Review, Textbook Information Trial Resources Ongoing Trials, Trial Results Guidelines & Evidence Based Medicine Resources US National Guidelines, Cochrane Collaboration, etc. Media Resources Slides, Video, Images, MP3, Podcasts, etc. Patient Resources Discussion Groups, Handouts, Blogs, News, etc. International Resources en Español # FDA Package Insert Resources Indications Contraindications Side Effects Drug Interactions Precautions Overdose Instructions for Administration How Supplied Pharmacokinetics and Molecular Data FDA label FDA on Alesse-28 Return to top # Publication Resources Most Recent Articles on Alesse-28 Review Articles on Alesse-28 Articles on Alesse-28 in N Eng J Med, Lancet, BMJ WikiDoc State of the Art Review Textbook Information on Alesse-28 Return to top # Trial Resources Ongoing Trials with Alesse-28 at Clinical Trials.gov Trial Results with Alesse-28 Return to top # Guidelines & Evidence Based Medicine Resources US National Guidelines Clearinghouse on Alesse-28 Cochrane Collaboration on Alesse-28 Cost Effectiveness of Alesse-28 Return to top # Media Resources Powerpoint Slides on Alesse-28 Images of Alesse-28 Podcasts & MP3s on Alesse-28 Videos on Alesse-28 Return to top # Patient Resources Patient Information from National Library of Medicine Patient Resources on Alesse-28 Discussion Groups on Alesse-28 Patient Handouts on Alesse-28 Blogs on Alesse-28 Alesse-28 in the News Alesse-28 in the Marketplace Return to top # International Resources Alesse-28 en Español Return to top Adapted from the FDA Package Insert.	https://www.wikidoc.org/index.php/Alesse-28
0b9d0402dfb52cfa1ab038d190eb177bfd0b818d	wikidoc	Alfuzosin	Alfuzosin # 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 Alfuzosin is an alpha adrenergic antagonist that is FDA approved for the {{{indicationType}}} of benign prostatic hyperplasia. Common adverse reactions include dizziness, upper respiratory tract infection, headache, and fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - The recommended dosage is one 10 mg alfuzosin hydrochloride extended-release tablet once daily. The extent of absorption of alfuzosin is 50% lower under fasting conditions. Therefore, alfuzosin hydrochloride should be taken with food and with the same meal each day. The tablets should not be chewed or crushed. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Alfuzosin in adult patients. ### Non–Guideline-Supported Use - Alfuzosin 10 milligrams (mg) once daily. - Alfuzosin 10 mg orally once daily for 4 weeks. - Oral alfuzosin 5 milligrams. - Alfuzosin 10 milligrams. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Alfuzosin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Alfuzosin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Alfuzosin in pediatric patients. # Contraindications - Alfuzosin hydrochloride is contraindicated for use: - in patients with moderate or severe hepatic impairment (Childs-Pugh categories B and C), since alfuzosin blood levels are increased in these patients. - with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, and ritonavir, since alfuzosin blood levels are increased. - in patients with known hypersensitivity, such as urticaria and angioedema, to alfuzosin hydrochloride or any component of alfuzosin hydrochloride tablets. # Warnings ### Precautions - Postural Hypotension - Postural hypotension with or without symptoms (e.g., dizziness) may develop within a few hours following administration of alfuzosin hydrochloride. As with other alpha adrenergic antagonists, there is a potential for syncope. Patients should be warned of the possible occurrence of such events and should avoid situations where injury could result should syncope occur. There may be an increased risk of hypotension/postural hypotension and syncope when taking alfuzosin hydrochloride concomitantly with anti-hypertensive medication and nitrates. Care should be taken when alfuzosin hydrochloride is administered to patients with symptomatic hypotension or patients who have had a hypotensive response to other medications. - Patients with Renal Impairment - Caution should be exercised when alfuzosin hydrochloride is administered in patients with severe renal impairment (creatinine clearance < 30 mL/min). - Patients with Hepatic Impairment - Alfuzosin hydrochloride is contraindicated for use in patients with moderate or severe hepatic impairment. Although the pharmacokinetics of alfuzosin hydrochloride have not been studied in patients with mild hepatic impairment, caution should be exercised when alfuzosin hydrochloride is administered to such patients. - Drug-Drug Interactions - Potent CYP3A4 Inhibitors: Alfuzosin hydrochloride is contraindicated for use with potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir) since alfuzosin blood levels are increased. - Other alpha adrenergic antagonists: Alfuzosin hydrochloride is an alpha adrenergic antagonist and should not be used in combination with other alpha adrenergic antagonist. - Phosphodiesterase-5 (PDE5) Inhibitors: PDE5-inhibitors are also vasodilators. Caution is advised for concomitant use of PDE5-inhibitors and alfuzosin hydrochloride, as this combination can potentially cause symptomatic hypotension. - Prostatic Carcinoma - Carcinoma of the prostate and benign prostatic hyperplasia (BPH) cause many of the same symptoms. These two diseases frequently coexist. Therefore, patients thought to have BPH should be examined to rule out the presence of carcinoma of the prostate prior to starting treatment with alfuzosin hydrochloride. - Intraoperative Floppy Iris Syndrome (IFIS) - IFIS has been observed during cataract surgery in some patients on or previously treated with alpha adrenergic antagonists. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s ophthalmologist should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. - There does not appear to be a benefit of stopping alpha adrenergic antagonist therapy prior to cataract surgery. - Priapism - Rarely (probably less than 1 in 50,000), alfuzosin, like other alpha adrenergic antagonists, has been associated with priapism (persistent painful penile erection unrelated to sexual activity). Because this condition can lead to permanent impotence if not properly treated, patients should be advised about the seriousness of the condition. - Coronary Insufficiency - If symptoms of angina pectoris should appear or worsen, alfuzosin hydrochloride should be discontinued. - Patients with Congenital or Acquired QT Prolongation - Use with caution in patients with acquired or congenital QT prolongation or who are taking medications that prolong the QT interval. # 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 incidence of adverse reactions has been ascertained from 3 placebo-controlled clinical trials involving 1,608 men where daily doses of 10 and 15 mg alfuzosin were evaluated. In these 3 trials, 473 men received alfuzosin hydrochloride 10 mg extended-release tablets. In these trials, 4% of patients taking alfuzosin hydrochloride 10 mg extended-release tablets withdrew from the trial due to adverse reactions, compared with 3% in the placebo group. - Table 1 summarizes adverse reactions that occurred in ≥2% of patients receiving alfuzosin hydrochloride, and at a higher incidence than that of the placebo group. In general, the adverse reactions seen in long-term use were similar in type and frequency to the events described below for the 3-month trials. - The following adverse reactions, reported by between 1% and 2% of patients receiving alfuzosin hydrochloride and occurring more frequently than with placebo, are listed alphabetically by body system and by decreasing frequency within body system: Pain Abdominal pain, dyspepsia, constipation, nausea Impotence Bronchitis, sinusitis, pharyngitis - Signs and Symptoms of Orthostasis in Clinical Trials: The adverse reactions related to orthostasis that occurred in the double-blind phase 3 trials with alfuzosin 10 mg are summarized in Table 2. Approximately 20% to 30% of patients in these trials were taking antihypertensive medication. - Testing for blood pressure changes or orthostatic hypotension was conducted in three controlled studies. Decreased systolic blood pressure (≤90 mm Hg, with a decrease ≥20 mm Hg from baseline) was observed in none of the 674 placebo patients and 1 (0.2%) of the 469 alfuzosin hydrochloride patients. Decreased diastolic blood pressure (≤50 mm Hg, with a decrease ≥15 mm Hg from baseline) was observed in 3 (0.4%) of the placebo patients and in 4 (0.9%) of the alfuzosin hydrochloride patients. A positive orthostatic test (decrease in systolic blood pressure of ≥20 mm Hg upon standing from the supine position) was seen in 52 (7.7%) of placebo patients and in 31 (6.6%) of the alfuzosin hydrochloride patients. ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of alfuzosin hydrochloride. 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. Edema Tachycardia, chest pain, angina pectoris in patients with pre-existing coronary artery disease, atrial fibrillation Diarrhea Hepatocellular and cholestatic liver injury (including cases with jaundice leading to drug discontinuation) Rhinitis Priapism Rash, pruritis, urticaria, angioedema Flushing Thrombocytopenia - During cataract surgery, a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) has been reported in some patients on or previously treated with alpha adrenergic antagonists. # Drug Interactions - CYP3A4 inhibitors - Alfuzosin hydrochloride is contraindicated for use with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, or ritonavir, since alfuzosin blood levels are increased. - Alpha adrenergic antagonists - The pharmacokinetic and pharmacodynamic interactions between alfuzosin hydrochloride and other alpha adrenergic antagonists have not been determined. However, interactions may be expected, and alfuzosin hydrochloride should not be used in combination with other alpha adrenergic antagonists. - Antihypertensive Medication and Nitrates - There may be an increased risk of hypotension/postural hypotension and syncope when taking alfuzosin hydrochloride concomitantly with anti-hypertensive medication and nitrates. - PDE5 Inhibitors - Caution is advised when alpha adrenergic antagonists, including alfuzosin hydrochloride, are coadministered with PDE5 inhibitors. Alpha adrenergic antagonists and PDE5 inhibitors are both vasodilators that can lower blood pressure. - Concomitant use of these two drug classes can potentially cause symptomatic hypotension. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - Alfuzosin hydrochloride is not indicated for use in women, and there are no studies of alfuzosin in pregnant women. - Alfuzosin was not teratogenic, embryotoxic or fetotoxic in rats at plasma exposure levels (based on AUC of unbound drug) up to 1200 times (maternal oral dose of 250 mg/kg/day) the maximum recommended human dose (MRHD) of 10 mg. In rabbits administered up to 3 times the MRHD (based on body surface area) (maternal oral dose of 100 mg/kg/day) no embryofetal toxicity or teratogenicity was observed. Gestation was slightly prolonged in rats at exposure levels (based on AUC of unbound drug) approximately 12 times (greater than 5 mg/kg/day oral maternal dose) the MRHD, but difficulties with parturition were not observed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alfuzosin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Alfuzosin during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Alfuzosin with respect to nursing mothers. ### Pediatric Use - Alfuzosin hydrochloride extended release tablets are not indicated for use in the pediatric population. Additional information regarding a clinical study in which efficacy was not demonstrated in pediatric patients ages 2 to 16 years is approved for Sanofi-Aventis U.S. LLC’s alfuzosin hydrochloride extended-release tablets. However, due to Sanofi-Aventis U.S. LLC’s marketing exclusivity rights, this drug is not labeled with that pediatric information. ### Geriatic Use - Of the total number of subjects in clinical studies of alfuzosin hydrochloride, 48% were 65 years of age and over, whereas 11% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Alfuzosin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Alfuzosin with respect to specific racial populations. ### Renal Impairment - Systemic exposure was increased by approximately 50% in pharmacokinetic studies of patients with mild, moderate, and severe renal impairment. In phase 3 studies, the safety profile of patients with mild (n=172) or moderate (n=56) renal impairment was similar to the patients with normal renal function in those studies. Safety data are available in only a limited number of patients (n=6) with creatinine clearance below 30 mL/min; therefore, caution should be exercised when alfuzosin hydrochloride is administered in patients with severe renal impairment. ### Hepatic Impairment - The pharmacokinetics of alfuzosin hydrochloride have not been studied in patients with mild hepatic impairment. Alfuzosin hydrochloride is contraindicated for use in patients with moderate or severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Alfuzosin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Alfuzosin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Alfuzosin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Alfuzosin in the drug label. # Overdosage ## Acute Overdose - Should overdose of alfuzosin hydrochloride lead to hypotension, support of the cardiovascular system is of first importance. Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position. If this measure is inadequate, then the administration of intravenous fluids should be considered. If necessary, vasopressors should then be used, and the renal function should be monitored and supported as needed. Alfuzosin is 82% to 90% protein bound; therefore, dialysis may not be of benefit. ## Chronic Overdose There is limited information regarding Chronic Overdose of Alfuzosin in the drug label. # Pharmacology ## Mechanism of Action - Alfuzosin is a selective antagonist of post-synaptic alpha1-adrenoreceptors, which are located in the prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra. ## Structure - Each alfuzosin hydrochloride extended-release tablet contains 10 mg alfuzosin hydrochloride as the active ingredient. Alfuzosin hydrochloride is a white to off-white crystalline powder that melts at approximately 240°C. It is freely soluble in water, sparingly soluble in alcohol, and practically insoluble in dichloromethane. Alfuzosin hydrochloride, USP is (R,S)-N- propyl] tetrahydro-2-furancarboxamide hydrochloride. The empirical formula of alfuzosin hydrochloride is C19H27N5O4HCl. The molecular weight of alfuzosin hydrochloride is 425.9. - The tablet also contains the following inactive ingredients: microcrystalline cellulose (NF), guar gum (NF), hydroxypropyl methyl cellulose (USP), colloidal silicon dioxide (NF) and magnesium stearate (NF). ## Pharmacodynamics - Alfuzosin exhibits selectivity for alpha adrenergic receptors in the lower urinary tract. Blockade of these adrenoreceptors can cause smooth muscle in the bladder neck and prostate to relax, resulting in an improvement in urine flow and a reduction in symptoms of BPH. - Cardiac Electrophysiology - The effect of 10 mg and 40 mg alfuzosin on QT interval was evaluated in a double-blind, randomized, placebo and active-controlled (moxifloxacin 400 mg), 4-way crossover single dose study in 45 healthy white male subjects aged 19 to 45 years. The QT interval was measured at the time of peak alfuzosin plasma concentrations. The 40 mg dose of alfuzosin was chosen because this dose achieves higher blood levels than those achieved with the co-administration of alfuzosin hydrochloride and ketoconazole 400 mg. Table 3 summarizes the effect on uncorrected QT and mean corrected QT interval (QTc) with different methods of correction (Fridericia, population specific and subject-specific correction methods) at the time of peak alfuzosin plasma concentrations. No single one of these correction methodologies is known to be more valid. The mean change of heart rate associated with a 10 mg dose of alfuzosin in this study was 5.2 beats/minute and 5.8 beats/minute with 40 mg alfuzosin. The change in heart rate with moxifloxacin was 2.8 beats/minute. - The QT effect appeared greater for 40 mg compared to 10 mg alfuzosin. The effect of the highest alfuzosin dose (four times the therapeutic dose) studied did not appear as large as that of the active control moxifloxacin at its therapeutic dose. This study, however, was not designed to make direct statistical comparisons between the drugs or the dose levels. There has been no signal of Torsade de Pointes in the extensive post-marketing experience with alfuzosin outside the United States. - A separate post-marketing QT study evaluated the effect of the co-administration of 10 mg alfuzosin with a drug of similar QT effect size. In this study, the mean placebo-subtracted QTcF increase of alfuzosin 10 mg alone was 1.9 msec (upperbound 95% Cl, 5.5 msec). The concomitant administration of the two drugs showed an increased QT effect when compared with either drug alone. This QTcF increase was not more than additive. Although this study was not designed to make direct statistical comparisons between drugs, the QT increase with both drugs given together appeared to be lower than the QTcF increase seen with the positive control moxifloxacin 400 mg . The clinical impact of these QTc changes is unknown. ## Pharmacokinetics - The pharmacokinetics of alfuzosin hydrochloride have been evaluated in adult healthy male volunteers after single and/or multiple administration with daily doses ranging from 7.5 mg to 30 mg, and in patients with BPH at doses from 7.5 mg to 15 mg. - Absorption - The absolute bioavailability of alfuzosin hydrochloride 10 mg tablets under fed conditions is 49%. Following multiple dosing of 10 mg alfuzosin hydrochloride under fed conditions, the time to maximum concentration is 8 hours. Cmax and AUC0-24 are 13.6 (SD = 5.6) ng/mL and 194 (SD = 75) ngh/mL, respectively. Alfuzosin hydrochloride exhibits linear kinetics following single and multiple dosing up to 30 mg. Steady-state plasma levels are reached with the second dose of alfuzosin hydrochloride administration. Steady-state alfuzosin plasma concentrations are 1.2- to 1.6-fold higher than those observed after a single administration. - Effect of Food - As illustrated in Figure 1, the extent of absorption is 50% lower under fasting conditions. Therefore, alfuzosin hydrochloride should be taken with food and with the same meal each day. - The volume of distribution following intravenous administration in healthy male middle-aged volunteers was 3.2 L/kg. Results of in vitro studies indicate that alfuzosin is moderately bound to human plasma proteins (82% to 90%), with linear binding over a wide concentration range (5 to 5,000 ng/mL). - Metabolism - Alfuzosin undergoes extensive metabolism by the liver, with only 11% of the administered dose excreted unchanged in the urine. Alfuzosin is metabolized by three metabolic pathways: oxidation, O-demethylation, and N-dealkylation. The metabolites are not pharmacologically active. CYP3A4 is the principal hepatic enzyme isoform involved in its metabolism. - Excretion - Following oral administration of 14C-labeled alfuzosin solution, the recovery of radioactivity after 7 days (expressed as a percentage of the administered dose) was 69% in feces and 24% in urine. Following oral administration of alfuzosin hydrochloride 10 mg tablets, the apparent elimination half-life is 10 hours. - Specific Populations - Geriatric Use - In a pharmacokinetic assessment during phase 3 clinical studies in patients with BPH, there was no relationship between peak plasma concentrations of alfuzosin and age. - However, trough levels were positively correlated with age. The concentrations in subjects ≥75 years of age were approximately 35% greater than in those below 65 years of age. - Renal Impairment - The Pharmacokinetic profiles of alfuzosin hydrochloride 10 mg tablets in subjects with normal renal function (CLCR>80 mL/min), mild impairment (CLCR 60 to 80 mL/min), moderate impairment (CLCR 30 to 59 mL/min), and severe impairment (CLCR <30 mL/min) were compared. These clearances were calculated by the Cockcroft-Gault formula. Relative to subjects with normal renal function, the mean Cmax and AUC values were increased by approximately 50% in patients with mild, moderate, or severe renal impairment. - Hepatic Impairment - The pharmacokinetics of alfuzosin hydrochloride have not been studied in patients with mild hepatic impairment. In patients with moderate or severe hepatic insufficiency (Child-Pugh categories B and C), the plasma apparent clearance (CL/F) was reduced to approximately one-third to one-fourth that observed in healthy subjects. This reduction in clearance results in three to four-fold higher plasma concentrations of alfuzosin in these patients compared to healthy subjects. Therefore, alfuzosin hydrochloride is contraindicated in patients with moderate to severe hepatic impairment. - Pediatric Use - Alfuzosin hydrochloride tablets are not indicated for use in the pediatric population. - Drug-Drug Interactions - Metabolic Interactions - CYP3A4 is the principal hepatic enzyme isoform involved in the metabolism of alfuzosin. - Potent CYP3A4 Inhibitors - Repeated oral administration of 400 mg/day of ketoconazole, a potent inhibitor of CYP3A4, increased alfuzosin Cmax by 2.3-fold and AUClast by 3.2-fold, following a single 10 mg dose of alfuzosin. - In another study, repeated oral administration of a lower (200 mg/day) dose of ketoconazole increased alfuzosin Cmax by 2.1 -fold and AUClast by 2.5-fold, following a single 10 mg dose of alfuzosin. Therefore, alfuzosin hydrochloride is contraindicated for co-administration with potent inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, or ritonavir) because of increased alfuzosin exposure. - Moderate CYP3A4 Inhibitors - Diltiazem: Repeated co-administration of 240 mg/day of diltiazem, a moderately-potent inhibitor of CYP3A4, with 7.5 mg/day (2.5 mg three times daily) alfuzosin (equivalent to the exposure with alfuzosin hydrochloride) increased the Cmax and AUC0-24 of alfuzosin 1.5- and 1.3-fold, respectively. Alfuzosin increased the Cmax and AUC0-12 of diltiazem 1.4-fold. Although no changes in blood pressure were observed in this study, diltiazem is an antihypertensive medication and the combination of alfuzosin hydrochloride and antihypertensive medications has the potential to cause hypotension in some patients. - In human liver microsomes, at concentrations that are achieved at the therapeutic dose, alfuzosin did not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6 or 3A4 isoenzymes. In primary culture of human hepatocytes, alfuzosin did not induce CYP1A, 2A6 or 3A4 isoenzymes. - Other Interactions - Warfarin: Multiple dose administration of an immediate release tablet formulation of alfuzosin 5 mg twice daily for six days to six healthy male volunteers did not affect the pharmacological response to a single 25 mg oral dose of warfarin. - Digoxin: Repeated co-administration of alfuzosin hydrochloride 10 mg tablets and digoxin 0.25 mg/day for 7 days did not influence the steady-state pharmacokinetics of either drug. - Cimetidine: Repeated administration of 1 g/day cimetidine increased both alfuzosin Cmax and AUC values by 20%. - Atenolol: Single administration of 100 mg atenolol with a single dose of 2.5 mg of an immediate release alfuzosin tablet in eight healthy young male volunteers increased alfuzosin Cmax and AUC values by 28% and 21%, respectively. Alfuzosin increased atenolol Cmax and AUC values by 26% and 14%, respectively. In this study, the combination of alfuzosin with atenolol caused significant reductions in mean blood pressure and in mean heart rate. - Hydrochlorothiazide: Single administration of 25 mg hydrochlorothiazide did not modify the pharmacokinetic parameters of alfuzosin. There was no evidence of pharmacodynamic interaction between alfuzosin and hydrochlorothiazide in the 8 patients in this study. ## Nonclinical Toxicology - There was no evidence of a drug-related increase in the incidence of tumors in mice following dietary administration of 100 mg/kg/day alfuzosin for 98 weeks (13 and 15 times the maximum recommended human dose of 10 mg based on AUC of unbound drug), in females and males, respectively. The highest dose tested in female mice may not have constituted a maximally tolerated dose. Likewise, there was no evidence of a drug-related increase in the incidence of tumors in rats following dietary administration of 100 mg/kg/day alfuzosin for 104 weeks (53 and 37 times the MRHD in females and males, respectively). - Alfuzosin showed no evidence of mutagenic effect in the Ames and mouse lymphoma assays, and was free of any clastogenic effects in the Chinese hamster ovary cell and in vivo mouse micronucleus assays. Alfuzosin treatment did not induce DNA repair in a human cell line. - There was no evidence of reproductive organ toxicity when male rats were administered oral doses of several hundred times (250 mg/kg/day for 26 weeks) the MRHD of alfuzosin. No impairment of fertility was observed following oral (gavage) administration to male rats at doses of up to 125 mg/kg/day for 70 days. Estrous cycling was inhibited in rats and dogs at approximately 12 and 18 times the MRHD respectively (doses of 25 mg/kg and 20 mg/kg, respectively), but did not result in impaired fertility in female rats. # Clinical Studies - Three randomized placebo-controlled, double-blind, parallel-arm, 12-week trials were conducted with the 10 mg daily dose of alfuzosin. In these three trials, 1,608 patients were randomized and 473 patients received alfuzosin hydrochloride 10 mg daily. Table 4 provides the results of the three trials that evaluated the 10 mg dose. - There were two primary efficacy variables in these three studies. The International Prostate Symptom Score (IPSS, or AUA Symptom Score) consists of seven questions that assess the severity of both irritative (frequency, urgency, nocturia) and obstructive (incomplete emptying, stopping and starting, weak stream, and pushing or straining) symptoms, with possible scores ranging from 0 to 35 with higher numerical scores on the IPSS total symptom score representing greater severity of symptoms. The second efficacy variable was peak urinary flow rate. The peak flow rate was measured just prior to the next dose in study 2 and on average at 16 hours post dosing in trials 1 and 3. - There was a statistically significant reduction from baseline to last assessment (Week 12) in the IPSS total symptom score versus placebo in all three studies, indicating a reduction in symptom severity (Table 5 and Figures 2, 3, and 4). # How Supplied - Alfuzosin hydrochloride Extended-Release tablets are supplied as follows: - Alfuzosin hydrochloride extended-release tablets 10 mg are available as off white, round, biconvex tablets debossed with ‘IG’ on one side and “302” on other. Alfuzosin hydrochloride is supplied as follows: - Package NDC Number - Bottles of 100 76282-302-01 - Bottles of 500 76282-302-05 - Store at 20° to 25°C (68° to 77°F). - Protect from light and moisture. - Dispense in a tight, light-resistant container as defined in the USP. - Keep alfuzosin hydrochloride out of reach of children. ## Storage There is limited information regarding Alfuzosin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Hypotension/Syncope: - Patients should be told about the possible occurrence of symptoms related to postural hypotension, such as dizziness, when beginning alfuzosin hydrochloride, and they should be cautioned about driving, operating machinery, or performing hazardous tasks during this period. This is important for those with low blood pressure or who are taking antihypertensive medications or nitrates. - Intraoperative Floppy Iris Syndrome: - Patients should be instructed to tell their ophthalmologist about their use of alfuzosin hydrochloride before cataract surgery or other procedures involving the eyes, even if the patient is no longer taking alfuzosin hydrochloride. - Priapism - Patients should be advised about the possibility of priapism resulting from treatment with alfuzosin hydrochloride and medications in the same class. Although this reaction is extremely rare, but if not brought to immediate medical attention, can lead to permanent erectile dysfunction (impotence). - Instructions of use - Alfuzosin hydrochloride should be taken with food and with the same meal each day. Patients should be advised not to crush or chew alfuzosin hydrochloride tablets. # Precautions with Alcohol - Alcohol-Alfuzosin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ALFUZOSIN HYDROCHLORIDE® # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Alfuzosin 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 Alfuzosin is an alpha adrenergic antagonist that is FDA approved for the {{{indicationType}}} of benign prostatic hyperplasia. Common adverse reactions include dizziness, upper respiratory tract infection, headache, and fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - The recommended dosage is one 10 mg alfuzosin hydrochloride extended-release tablet once daily. The extent of absorption of alfuzosin is 50% lower under fasting conditions. Therefore, alfuzosin hydrochloride should be taken with food and with the same meal each day. The tablets should not be chewed or crushed. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Alfuzosin in adult patients. ### Non–Guideline-Supported Use - Alfuzosin 10 milligrams (mg) once daily.[1] - Alfuzosin 10 mg orally once daily for 4 weeks.[2] - Oral alfuzosin 5 milligrams.[3] - Alfuzosin 10 milligrams.[4] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Alfuzosin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Alfuzosin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Alfuzosin in pediatric patients. # Contraindications - Alfuzosin hydrochloride is contraindicated for use: - in patients with moderate or severe hepatic impairment (Childs-Pugh categories B and C), since alfuzosin blood levels are increased in these patients. - with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, and ritonavir, since alfuzosin blood levels are increased. - in patients with known hypersensitivity, such as urticaria and angioedema, to alfuzosin hydrochloride or any component of alfuzosin hydrochloride tablets. # Warnings ### Precautions - Postural Hypotension - Postural hypotension with or without symptoms (e.g., dizziness) may develop within a few hours following administration of alfuzosin hydrochloride. As with other alpha adrenergic antagonists, there is a potential for syncope. Patients should be warned of the possible occurrence of such events and should avoid situations where injury could result should syncope occur. There may be an increased risk of hypotension/postural hypotension and syncope when taking alfuzosin hydrochloride concomitantly with anti-hypertensive medication and nitrates. Care should be taken when alfuzosin hydrochloride is administered to patients with symptomatic hypotension or patients who have had a hypotensive response to other medications. - Patients with Renal Impairment - Caution should be exercised when alfuzosin hydrochloride is administered in patients with severe renal impairment (creatinine clearance < 30 mL/min). - Patients with Hepatic Impairment - Alfuzosin hydrochloride is contraindicated for use in patients with moderate or severe hepatic impairment. Although the pharmacokinetics of alfuzosin hydrochloride have not been studied in patients with mild hepatic impairment, caution should be exercised when alfuzosin hydrochloride is administered to such patients. - Drug-Drug Interactions - Potent CYP3A4 Inhibitors: Alfuzosin hydrochloride is contraindicated for use with potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir) since alfuzosin blood levels are increased. - Other alpha adrenergic antagonists: Alfuzosin hydrochloride is an alpha adrenergic antagonist and should not be used in combination with other alpha adrenergic antagonist. - Phosphodiesterase-5 (PDE5) Inhibitors: PDE5-inhibitors are also vasodilators. Caution is advised for concomitant use of PDE5-inhibitors and alfuzosin hydrochloride, as this combination can potentially cause symptomatic hypotension. - Prostatic Carcinoma - Carcinoma of the prostate and benign prostatic hyperplasia (BPH) cause many of the same symptoms. These two diseases frequently coexist. Therefore, patients thought to have BPH should be examined to rule out the presence of carcinoma of the prostate prior to starting treatment with alfuzosin hydrochloride. - Intraoperative Floppy Iris Syndrome (IFIS) - IFIS has been observed during cataract surgery in some patients on or previously treated with alpha adrenergic antagonists. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s ophthalmologist should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. - There does not appear to be a benefit of stopping alpha adrenergic antagonist therapy prior to cataract surgery. - Priapism - Rarely (probably less than 1 in 50,000), alfuzosin, like other alpha adrenergic antagonists, has been associated with priapism (persistent painful penile erection unrelated to sexual activity). Because this condition can lead to permanent impotence if not properly treated, patients should be advised about the seriousness of the condition. - Coronary Insufficiency - If symptoms of angina pectoris should appear or worsen, alfuzosin hydrochloride should be discontinued. - Patients with Congenital or Acquired QT Prolongation - Use with caution in patients with acquired or congenital QT prolongation or who are taking medications that prolong the QT interval. # 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 incidence of adverse reactions has been ascertained from 3 placebo-controlled clinical trials involving 1,608 men where daily doses of 10 and 15 mg alfuzosin were evaluated. In these 3 trials, 473 men received alfuzosin hydrochloride 10 mg extended-release tablets. In these trials, 4% of patients taking alfuzosin hydrochloride 10 mg extended-release tablets withdrew from the trial due to adverse reactions, compared with 3% in the placebo group. - Table 1 summarizes adverse reactions that occurred in ≥2% of patients receiving alfuzosin hydrochloride, and at a higher incidence than that of the placebo group. In general, the adverse reactions seen in long-term use were similar in type and frequency to the events described below for the 3-month trials. - The following adverse reactions, reported by between 1% and 2% of patients receiving alfuzosin hydrochloride and occurring more frequently than with placebo, are listed alphabetically by body system and by decreasing frequency within body system: Pain Abdominal pain, dyspepsia, constipation, nausea Impotence Bronchitis, sinusitis, pharyngitis - Signs and Symptoms of Orthostasis in Clinical Trials: The adverse reactions related to orthostasis that occurred in the double-blind phase 3 trials with alfuzosin 10 mg are summarized in Table 2. Approximately 20% to 30% of patients in these trials were taking antihypertensive medication. - Testing for blood pressure changes or orthostatic hypotension was conducted in three controlled studies. Decreased systolic blood pressure (≤90 mm Hg, with a decrease ≥20 mm Hg from baseline) was observed in none of the 674 placebo patients and 1 (0.2%) of the 469 alfuzosin hydrochloride patients. Decreased diastolic blood pressure (≤50 mm Hg, with a decrease ≥15 mm Hg from baseline) was observed in 3 (0.4%) of the placebo patients and in 4 (0.9%) of the alfuzosin hydrochloride patients. A positive orthostatic test (decrease in systolic blood pressure of ≥20 mm Hg upon standing from the supine position) was seen in 52 (7.7%) of placebo patients and in 31 (6.6%) of the alfuzosin hydrochloride patients. ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of alfuzosin hydrochloride. 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. Edema Tachycardia, chest pain, angina pectoris in patients with pre-existing coronary artery disease, atrial fibrillation Diarrhea Hepatocellular and cholestatic liver injury (including cases with jaundice leading to drug discontinuation) Rhinitis Priapism Rash, pruritis, urticaria, angioedema Flushing Thrombocytopenia - During cataract surgery, a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) has been reported in some patients on or previously treated with alpha adrenergic antagonists. # Drug Interactions - CYP3A4 inhibitors - Alfuzosin hydrochloride is contraindicated for use with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, or ritonavir, since alfuzosin blood levels are increased. - Alpha adrenergic antagonists - The pharmacokinetic and pharmacodynamic interactions between alfuzosin hydrochloride and other alpha adrenergic antagonists have not been determined. However, interactions may be expected, and alfuzosin hydrochloride should not be used in combination with other alpha adrenergic antagonists. - Antihypertensive Medication and Nitrates - There may be an increased risk of hypotension/postural hypotension and syncope when taking alfuzosin hydrochloride concomitantly with anti-hypertensive medication and nitrates. - PDE5 Inhibitors - Caution is advised when alpha adrenergic antagonists, including alfuzosin hydrochloride, are coadministered with PDE5 inhibitors. Alpha adrenergic antagonists and PDE5 inhibitors are both vasodilators that can lower blood pressure. - Concomitant use of these two drug classes can potentially cause symptomatic hypotension. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - Alfuzosin hydrochloride is not indicated for use in women, and there are no studies of alfuzosin in pregnant women. - Alfuzosin was not teratogenic, embryotoxic or fetotoxic in rats at plasma exposure levels (based on AUC of unbound drug) up to 1200 times (maternal oral dose of 250 mg/kg/day) the maximum recommended human dose (MRHD) of 10 mg. In rabbits administered up to 3 times the MRHD (based on body surface area) (maternal oral dose of 100 mg/kg/day) no embryofetal toxicity or teratogenicity was observed. Gestation was slightly prolonged in rats at exposure levels (based on AUC of unbound drug) approximately 12 times (greater than 5 mg/kg/day oral maternal dose) the MRHD, but difficulties with parturition were not observed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alfuzosin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Alfuzosin during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Alfuzosin with respect to nursing mothers. ### Pediatric Use - Alfuzosin hydrochloride extended release tablets are not indicated for use in the pediatric population. Additional information regarding a clinical study in which efficacy was not demonstrated in pediatric patients ages 2 to 16 years is approved for Sanofi-Aventis U.S. LLC’s alfuzosin hydrochloride extended-release tablets. However, due to Sanofi-Aventis U.S. LLC’s marketing exclusivity rights, this drug is not labeled with that pediatric information. ### Geriatic Use - Of the total number of subjects in clinical studies of alfuzosin hydrochloride, 48% were 65 years of age and over, whereas 11% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Alfuzosin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Alfuzosin with respect to specific racial populations. ### Renal Impairment - Systemic exposure was increased by approximately 50% in pharmacokinetic studies of patients with mild, moderate, and severe renal impairment. In phase 3 studies, the safety profile of patients with mild (n=172) or moderate (n=56) renal impairment was similar to the patients with normal renal function in those studies. Safety data are available in only a limited number of patients (n=6) with creatinine clearance below 30 mL/min; therefore, caution should be exercised when alfuzosin hydrochloride is administered in patients with severe renal impairment. ### Hepatic Impairment - The pharmacokinetics of alfuzosin hydrochloride have not been studied in patients with mild hepatic impairment. Alfuzosin hydrochloride is contraindicated for use in patients with moderate or severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Alfuzosin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Alfuzosin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Alfuzosin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Alfuzosin in the drug label. # Overdosage ## Acute Overdose - Should overdose of alfuzosin hydrochloride lead to hypotension, support of the cardiovascular system is of first importance. Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position. If this measure is inadequate, then the administration of intravenous fluids should be considered. If necessary, vasopressors should then be used, and the renal function should be monitored and supported as needed. Alfuzosin is 82% to 90% protein bound; therefore, dialysis may not be of benefit. ## Chronic Overdose There is limited information regarding Chronic Overdose of Alfuzosin in the drug label. # Pharmacology ## Mechanism of Action - Alfuzosin is a selective antagonist of post-synaptic alpha1-adrenoreceptors, which are located in the prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra. ## Structure - Each alfuzosin hydrochloride extended-release tablet contains 10 mg alfuzosin hydrochloride as the active ingredient. Alfuzosin hydrochloride is a white to off-white crystalline powder that melts at approximately 240°C. It is freely soluble in water, sparingly soluble in alcohol, and practically insoluble in dichloromethane. Alfuzosin hydrochloride, USP is (R,S)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino] propyl] tetrahydro-2-furancarboxamide hydrochloride. The empirical formula of alfuzosin hydrochloride is C19H27N5O4•HCl. The molecular weight of alfuzosin hydrochloride is 425.9. - The tablet also contains the following inactive ingredients: microcrystalline cellulose (NF), guar gum (NF), hydroxypropyl methyl cellulose (USP), colloidal silicon dioxide (NF) and magnesium stearate (NF). ## Pharmacodynamics - Alfuzosin exhibits selectivity for alpha adrenergic receptors in the lower urinary tract. Blockade of these adrenoreceptors can cause smooth muscle in the bladder neck and prostate to relax, resulting in an improvement in urine flow and a reduction in symptoms of BPH. - Cardiac Electrophysiology - The effect of 10 mg and 40 mg alfuzosin on QT interval was evaluated in a double-blind, randomized, placebo and active-controlled (moxifloxacin 400 mg), 4-way crossover single dose study in 45 healthy white male subjects aged 19 to 45 years. The QT interval was measured at the time of peak alfuzosin plasma concentrations. The 40 mg dose of alfuzosin was chosen because this dose achieves higher blood levels than those achieved with the co-administration of alfuzosin hydrochloride and ketoconazole 400 mg. Table 3 summarizes the effect on uncorrected QT and mean corrected QT interval (QTc) with different methods of correction (Fridericia, population specific and subject-specific correction methods) at the time of peak alfuzosin plasma concentrations. No single one of these correction methodologies is known to be more valid. The mean change of heart rate associated with a 10 mg dose of alfuzosin in this study was 5.2 beats/minute and 5.8 beats/minute with 40 mg alfuzosin. The change in heart rate with moxifloxacin was 2.8 beats/minute. - The QT effect appeared greater for 40 mg compared to 10 mg alfuzosin. The effect of the highest alfuzosin dose (four times the therapeutic dose) studied did not appear as large as that of the active control moxifloxacin at its therapeutic dose. This study, however, was not designed to make direct statistical comparisons between the drugs or the dose levels. There has been no signal of Torsade de Pointes in the extensive post-marketing experience with alfuzosin outside the United States. - A separate post-marketing QT study evaluated the effect of the co-administration of 10 mg alfuzosin with a drug of similar QT effect size. In this study, the mean placebo-subtracted QTcF increase of alfuzosin 10 mg alone was 1.9 msec (upperbound 95% Cl, 5.5 msec). The concomitant administration of the two drugs showed an increased QT effect when compared with either drug alone. This QTcF increase [5.9 msec (UB 95% Cl, 9.4 msec)] was not more than additive. Although this study was not designed to make direct statistical comparisons between drugs, the QT increase with both drugs given together appeared to be lower than the QTcF increase seen with the positive control moxifloxacin 400 mg [10.2 msec (UB 95% Cl, 13.8 msec)]. The clinical impact of these QTc changes is unknown. ## Pharmacokinetics - The pharmacokinetics of alfuzosin hydrochloride have been evaluated in adult healthy male volunteers after single and/or multiple administration with daily doses ranging from 7.5 mg to 30 mg, and in patients with BPH at doses from 7.5 mg to 15 mg. - Absorption - The absolute bioavailability of alfuzosin hydrochloride 10 mg tablets under fed conditions is 49%. Following multiple dosing of 10 mg alfuzosin hydrochloride under fed conditions, the time to maximum concentration is 8 hours. Cmax and AUC0-24 are 13.6 (SD = 5.6) ng/mL and 194 (SD = 75) ng•h/mL, respectively. Alfuzosin hydrochloride exhibits linear kinetics following single and multiple dosing up to 30 mg. Steady-state plasma levels are reached with the second dose of alfuzosin hydrochloride administration. Steady-state alfuzosin plasma concentrations are 1.2- to 1.6-fold higher than those observed after a single administration. - Effect of Food - As illustrated in Figure 1, the extent of absorption is 50% lower under fasting conditions. Therefore, alfuzosin hydrochloride should be taken with food and with the same meal each day. - The volume of distribution following intravenous administration in healthy male middle-aged volunteers was 3.2 L/kg. Results of in vitro studies indicate that alfuzosin is moderately bound to human plasma proteins (82% to 90%), with linear binding over a wide concentration range (5 to 5,000 ng/mL). - Metabolism - Alfuzosin undergoes extensive metabolism by the liver, with only 11% of the administered dose excreted unchanged in the urine. Alfuzosin is metabolized by three metabolic pathways: oxidation, O-demethylation, and N-dealkylation. The metabolites are not pharmacologically active. CYP3A4 is the principal hepatic enzyme isoform involved in its metabolism. - Excretion - Following oral administration of 14C-labeled alfuzosin solution, the recovery of radioactivity after 7 days (expressed as a percentage of the administered dose) was 69% in feces and 24% in urine. Following oral administration of alfuzosin hydrochloride 10 mg tablets, the apparent elimination half-life is 10 hours. - Specific Populations - Geriatric Use - In a pharmacokinetic assessment during phase 3 clinical studies in patients with BPH, there was no relationship between peak plasma concentrations of alfuzosin and age. - However, trough levels were positively correlated with age. The concentrations in subjects ≥75 years of age were approximately 35% greater than in those below 65 years of age. - Renal Impairment - The Pharmacokinetic profiles of alfuzosin hydrochloride 10 mg tablets in subjects with normal renal function (CLCR>80 mL/min), mild impairment (CLCR 60 to 80 mL/min), moderate impairment (CLCR 30 to 59 mL/min), and severe impairment (CLCR <30 mL/min) were compared. These clearances were calculated by the Cockcroft-Gault formula. Relative to subjects with normal renal function, the mean Cmax and AUC values were increased by approximately 50% in patients with mild, moderate, or severe renal impairment. - Hepatic Impairment - The pharmacokinetics of alfuzosin hydrochloride have not been studied in patients with mild hepatic impairment. In patients with moderate or severe hepatic insufficiency (Child-Pugh categories B and C), the plasma apparent clearance (CL/F) was reduced to approximately one-third to one-fourth that observed in healthy subjects. This reduction in clearance results in three to four-fold higher plasma concentrations of alfuzosin in these patients compared to healthy subjects. Therefore, alfuzosin hydrochloride is contraindicated in patients with moderate to severe hepatic impairment. - Pediatric Use - Alfuzosin hydrochloride tablets are not indicated for use in the pediatric population. - Drug-Drug Interactions - Metabolic Interactions - CYP3A4 is the principal hepatic enzyme isoform involved in the metabolism of alfuzosin. - Potent CYP3A4 Inhibitors - Repeated oral administration of 400 mg/day of ketoconazole, a potent inhibitor of CYP3A4, increased alfuzosin Cmax by 2.3-fold and AUClast by 3.2-fold, following a single 10 mg dose of alfuzosin. - In another study, repeated oral administration of a lower (200 mg/day) dose of ketoconazole increased alfuzosin Cmax by 2.1 -fold and AUClast by 2.5-fold, following a single 10 mg dose of alfuzosin. Therefore, alfuzosin hydrochloride is contraindicated for co-administration with potent inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, or ritonavir) because of increased alfuzosin exposure. - Moderate CYP3A4 Inhibitors - Diltiazem: Repeated co-administration of 240 mg/day of diltiazem, a moderately-potent inhibitor of CYP3A4, with 7.5 mg/day (2.5 mg three times daily) alfuzosin (equivalent to the exposure with alfuzosin hydrochloride) increased the Cmax and AUC0-24 of alfuzosin 1.5- and 1.3-fold, respectively. Alfuzosin increased the Cmax and AUC0-12 of diltiazem 1.4-fold. Although no changes in blood pressure were observed in this study, diltiazem is an antihypertensive medication and the combination of alfuzosin hydrochloride and antihypertensive medications has the potential to cause hypotension in some patients. - In human liver microsomes, at concentrations that are achieved at the therapeutic dose, alfuzosin did not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6 or 3A4 isoenzymes. In primary culture of human hepatocytes, alfuzosin did not induce CYP1A, 2A6 or 3A4 isoenzymes. - Other Interactions - Warfarin: Multiple dose administration of an immediate release tablet formulation of alfuzosin 5 mg twice daily for six days to six healthy male volunteers did not affect the pharmacological response to a single 25 mg oral dose of warfarin. - Digoxin: Repeated co-administration of alfuzosin hydrochloride 10 mg tablets and digoxin 0.25 mg/day for 7 days did not influence the steady-state pharmacokinetics of either drug. - Cimetidine: Repeated administration of 1 g/day cimetidine increased both alfuzosin Cmax and AUC values by 20%. - Atenolol: Single administration of 100 mg atenolol with a single dose of 2.5 mg of an immediate release alfuzosin tablet in eight healthy young male volunteers increased alfuzosin Cmax and AUC values by 28% and 21%, respectively. Alfuzosin increased atenolol Cmax and AUC values by 26% and 14%, respectively. In this study, the combination of alfuzosin with atenolol caused significant reductions in mean blood pressure and in mean heart rate. - Hydrochlorothiazide: Single administration of 25 mg hydrochlorothiazide did not modify the pharmacokinetic parameters of alfuzosin. There was no evidence of pharmacodynamic interaction between alfuzosin and hydrochlorothiazide in the 8 patients in this study. ## Nonclinical Toxicology - There was no evidence of a drug-related increase in the incidence of tumors in mice following dietary administration of 100 mg/kg/day alfuzosin for 98 weeks (13 and 15 times the maximum recommended human dose [MRHD] of 10 mg based on AUC of unbound drug), in females and males, respectively. The highest dose tested in female mice may not have constituted a maximally tolerated dose. Likewise, there was no evidence of a drug-related increase in the incidence of tumors in rats following dietary administration of 100 mg/kg/day alfuzosin for 104 weeks (53 and 37 times the MRHD in females and males, respectively). - Alfuzosin showed no evidence of mutagenic effect in the Ames and mouse lymphoma assays, and was free of any clastogenic effects in the Chinese hamster ovary cell and in vivo mouse micronucleus assays. Alfuzosin treatment did not induce DNA repair in a human cell line. - There was no evidence of reproductive organ toxicity when male rats were administered oral doses of several hundred times (250 mg/kg/day for 26 weeks) the MRHD of alfuzosin. No impairment of fertility was observed following oral (gavage) administration to male rats at doses of up to 125 mg/kg/day for 70 days. Estrous cycling was inhibited in rats and dogs at approximately 12 and 18 times the MRHD respectively (doses of 25 mg/kg and 20 mg/kg, respectively), but did not result in impaired fertility in female rats. # Clinical Studies - Three randomized placebo-controlled, double-blind, parallel-arm, 12-week trials were conducted with the 10 mg daily dose of alfuzosin. In these three trials, 1,608 patients [mean age 64.2 years, range 49-92 years; Caucasian (96.1%), Black (1.6%), Asian (1.1%), other (1.2%)] were randomized and 473 patients received alfuzosin hydrochloride 10 mg daily. Table 4 provides the results of the three trials that evaluated the 10 mg dose. - There were two primary efficacy variables in these three studies. The International Prostate Symptom Score (IPSS, or AUA Symptom Score) consists of seven questions that assess the severity of both irritative (frequency, urgency, nocturia) and obstructive (incomplete emptying, stopping and starting, weak stream, and pushing or straining) symptoms, with possible scores ranging from 0 to 35 with higher numerical scores on the IPSS total symptom score representing greater severity of symptoms. The second efficacy variable was peak urinary flow rate. The peak flow rate was measured just prior to the next dose in study 2 and on average at 16 hours post dosing in trials 1 and 3. - There was a statistically significant reduction from baseline to last assessment (Week 12) in the IPSS total symptom score versus placebo in all three studies, indicating a reduction in symptom severity (Table 5 and Figures 2, 3, and 4). # How Supplied - Alfuzosin hydrochloride Extended-Release tablets are supplied as follows: - Alfuzosin hydrochloride extended-release tablets 10 mg are available as off white, round, biconvex tablets debossed with ‘IG’ on one side and “302” on other. Alfuzosin hydrochloride is supplied as follows: - Package NDC Number - Bottles of 100 76282-302-01 - Bottles of 500 76282-302-05 - Store at 20° to 25°C (68° to 77°F). - Protect from light and moisture. - Dispense in a tight, light-resistant container as defined in the USP. - Keep alfuzosin hydrochloride out of reach of children. ## Storage There is limited information regarding Alfuzosin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Hypotension/Syncope: - Patients should be told about the possible occurrence of symptoms related to postural hypotension, such as dizziness, when beginning alfuzosin hydrochloride, and they should be cautioned about driving, operating machinery, or performing hazardous tasks during this period. This is important for those with low blood pressure or who are taking antihypertensive medications or nitrates. - Intraoperative Floppy Iris Syndrome: - Patients should be instructed to tell their ophthalmologist about their use of alfuzosin hydrochloride before cataract surgery or other procedures involving the eyes, even if the patient is no longer taking alfuzosin hydrochloride. - Priapism - Patients should be advised about the possibility of priapism resulting from treatment with alfuzosin hydrochloride and medications in the same class. Although this reaction is extremely rare, but if not brought to immediate medical attention, can lead to permanent erectile dysfunction (impotence). - Instructions of use - Alfuzosin hydrochloride should be taken with food and with the same meal each day. Patients should be advised not to crush or chew alfuzosin hydrochloride tablets. # Precautions with Alcohol - Alcohol-Alfuzosin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ALFUZOSIN HYDROCHLORIDE®[5] # Look-Alike Drug Names - A® — B®[6] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Alfuzosin
75b20ed018081c2d6f025acd068583c514ca6907	wikidoc	Algorithm	Algorithm # Overview In mathematics, computing, linguistics and related subjects, an algorithm is a sequence of instructions, often used for calculation and data processing. It is formally a type of effective method in which a list of well-defined instructions for completing a task will, when given an initial state, proceed through a well-defined series of successive states, eventually terminating in an end-state. The transition from one state to the next is not necessarily deterministic; some algorithms, known as probabilistic algorithms, incorporate randomness. A partial formalization of the concept began with attempts to solve the Entscheidungsproblem (the "decision problem") posed by David Hilbert in 1928. Subsequent formalizations were framed as attempts to define "effective calculability" (Kleene 1943:274) or "effective method" (Rosser 1939:225); those formalizations included the Gödel-Herbrand-Kleene recursive functions of 1930, 1934 and 1935, Alonzo Church's lambda calculus of 1936, Emil Post's "Formulation I" of 1936, and Alan Turing's Turing machines of 1936–7 and 1939. # Etymology Al-Khwārizmī, Persian astronomer and mathematician, wrote a treatise in Arabic in 825 AD, On Calculation with Hindu Numerals. (See algorism). It was translated into Latin in the 12th century as Algoritmi de numero Indorum (al-Daffa 1977), which title was likely intended to mean "Algoritmi on the numbers of the Indians", where "Algoritmi" was the translator's rendition of the author's name; but people misunderstanding the title treated Algoritmi as a Latin plural and this led to the word "algorithm" (Latin algorismus) coming to mean "calculation method". The intrusive "th" is most likely due to a false cognate with the Greek ἀριθμός (arithmos) meaning "number". # Why algorithms are necessary: an informal definition No generally accepted formal definition of "algorithm" exists yet. An informal definition could be "an algorithm is a computer program that calculates something." For some people, a program is only an algorithm if it stops eventually. For others, a program is only an algorithm if it stops before a given number of calculation steps. A prototypical example of an "algorithm" is Euclid's algorithm to determine the maximum common divisor of two integers greater than one: "subtract the smallest number from the biggest one, repeat until you get a zero or a one". This procedure is known to stop always, and the number of subtractions needed is always smaller than the biggest of the two numbers. We can derive clues to the issues involved and an informal meaning of the word from the following quotation from Template:Harvtxt (boldface added): No human being can write fast enough, or long enough, or small enough to list all members of an enumerably infinite set by writing out their names, one after another, in some notation. But humans can do something equally useful, in the case of certain enumerably infinite sets: They can give explicit instructions for determining the nth member of the set, for arbitrary finite n. Such instructions are to be given quite explicitly, in a form in which they could be followed by a computing machine, or by a human who is capable of carrying out only very elementary operations on symbols Template:Harv The words "enumerably infinite" mean "countable using integers perhaps extending to infinity". Thus Boolos and Jeffrey are saying that an algorithm implies instructions for a process that "creates" output integers from an arbitrary "input" integer or integers that, in theory, can be chosen from 0 to infinity. Thus we might expect an algorithm to be an algebraic equation such as y = m + n — two arbitrary "input variables" m and n that produce an output y. As we see in Algorithm characterizations — the word algorithm implies much more than this, something on the order of (for our addition example): The concept of algorithm is also used to define the notion of decidability. That notion is central for explaining how formal systems come into being starting from a small set of axioms and rules. In logic, the time that an algorithm requires to complete cannot be measured, as it is not apparently related with our customary physical dimension. From such uncertainties, that characterize ongoing work, stems the unavailability of a definition of algorithm that suits both concrete (in some sense) and abstract usage of the term. # Formalization of algorithms Algorithms are essential to the way computers process information. Many computer programs contain algorithms that specify the specific instructions a computer should perform (in a specific order) to carry out a specified task, such as calculating employees’ paychecks or printing students’ report cards. Thus, an algorithm can be considered to be any sequence of operations that can be simulated by a Turing-complete system. Authors who assert this thesis include Savage (1987) and Gurevich (2000): ...Turing's informal argument in favor of his thesis justifies a stronger thesis: every algorithm can be simulated by a Turing machine (Gurevich 2000:1)...according to Savage , an algorithm is a computational process defined by a Turing machine. (Gurevich 2000:3) Typically, when an algorithm is associated with processing information, data is read from an input source, written to an output device, and/or stored for further processing. Stored data is regarded as part of the internal state of the entity performing the algorithm. In practice, the state is stored in one or more data structures. For any such computational process, the algorithm must be rigorously defined: specified in the way it applies in all possible circumstances that could arise. That is, any conditional steps must be systematically dealt with, case-by-case; the criteria for each case must be clear (and computable). Because an algorithm is a precise list of precise steps, the order of computation will always be critical to the functioning of the algorithm. Instructions are usually assumed to be listed explicitly, and are described as starting "from the top" and going "down to the bottom", an idea that is described more formally by flow of control. So far, this discussion of the formalization of an algorithm has assumed the premises of imperative programming. This is the most common conception, and it attempts to describe a task in discrete, "mechanical" means. Unique to this conception of formalized algorithms is the assignment operation, setting the value of a variable. It derives from the intuition of "memory" as a scratchpad. There is an example below of such an assignment. For some alternate conceptions of what constitutes an algorithm see functional programming and logic programming . ## Termination Some writers restrict the definition of algorithm to procedures that eventually finish. In such a category Kleene places the "decision procedure or decision method or algorithm for the question" (Kleene 1952:136). Others, including Kleene, include procedures that could run forever without stopping; such a procedure has been called a "computational method" (Knuth 1997:5) or "calculation procedure or algorithm" (Kleene 1952:137); however, Kleene notes that such a method must eventually exhibit "some object" (Kleene 1952:137). Minsky makes the pertinent observation, in regards to determining whether an algorithm will eventually terminate (from a particular starting state): But if the length of the process is not known in advance, then "trying" it may not be decisive, because if the process does go on forever — then at no time will we ever be sure of the answer (Minsky 1967:105). As it happens, no other method can do any better, as was shown by Alan Turing with his celebrated result on the undecidability of the so-called halting problem. There is no algorithmic procedure for determining of arbitrary algorithms whether or not they terminate from given starting states. The analysis of algorithms for their likelihood of termination is called termination analysis. See the examples of (im-)"proper" subtraction at partial function for more about what can happen when an algorithm fails for certain of its input numbers — e.g., (i) non-termination, (ii) production of "junk" (output in the wrong format to be considered a number) or no number(s) at all (halt ends the computation with no output), (iii) wrong number(s), or (iv) a combination of these. Kleene proposed that the production of "junk" or failure to produce a number is solved by having the algorithm detect these instances and produce e.g., an error message (he suggested "0"), or preferably, force the algorithm into an endless loop (Kleene 1952:322). Davis does this to his subtraction algorithm — he fixes his algorithm in a second example so that it is proper subtraction (Davis 1958:12-15). Along with the logical outcomes "true" and "false" Kleene also proposes the use of a third logical symbol "u" — undecided (Kleene 1952:326) — thus an algorithm will always produce something when confronted with a "proposition". The problem of wrong answers must be solved with an independent "proof" of the algorithm e.g., using induction: We normally require auxiliary evidence for this (that the algorithm correctly defines a mu recursive function), e.g., in the form of an inductive proof that, for each argument value, the computation terminates with a unique value (Minsky 1967:186). ## Expressing algorithms Algorithms can be expressed in many kinds of notation, including natural languages, pseudocode, flowcharts, and programming languages. Natural language expressions of algorithms tend to be verbose and ambiguous, and are rarely used for complex or technical algorithms. Pseudocode and flowcharts are structured ways to express algorithms that avoid many of the ambiguities common in natural language statements, while remaining independent of a particular implementation language. Programming languages are primarily intended for expressing algorithms in a form that can be executed by a computer, but are often used as a way to define or document algorithms. There is a wide variety of representations possible and one can express a given Turing machine program as a sequence of machine tables (see more at finite state machine and state transition table), as flowcharts (see more at state diagram), or as a form of rudimentary machine code or assembly code called "sets of quadruples" (see more at Turing machine). Sometimes it is helpful in the description of an algorithm to supplement small "flow charts" (state diagrams) with natural-language and/or arithmetic expressions written inside "block diagrams" to summarize what the "flow charts" are accomplishing. Representations of algorithms are generally classed into three accepted levels of Turing machine description (Sipser 2006:157): - 1 High-level description: - 2 Implementation description: - 3 Formal description: ## Implementation Most algorithms are intended to be implemented as computer programs. However, algorithms are also implemented by other means, such as in a biological neural network (for example, the human brain implementing arithmetic or an insect looking for food), in an electrical circuit, or in a mechanical device. # Example One of the simplest algorithms is to find the largest number in an (unsorted) list of numbers. The solution necessarily requires looking at every number in the list, but only once at each. From this follows a simple algorithm, which can be stated in a high-level description English prose, as: High-level description: - Assume the first item is largest. - Look at each of the remaining items in the list and if it is larger than the largest item so far, make a note of it. - The last noted item is the largest in the list when the process is complete. (Quasi-)formal description: Written in prose but much closer to the high-level language of a computer program, the following is the more formal coding of the algorithm in pseudocode or pidgin code: For a more complex example of an algorithm, see Euclid's algorithm for the greatest common divisor, one of the earliest algorithms known. ## Algorithm analysis As it happens, it is important to know how much of a particular resource (such as time or storage) is required for a given algorithm. Methods have been developed for the analysis of algorithms to obtain such quantitative answers; for example, the algorithm above has a time requirement of O(n), using the big O notation with n as the length of the list. At all times the algorithm only needs to remember two values: the largest number found so far, and its current position in the input list. Therefore it is said to have a space requirement of O(1), if the space required to store the input numbers is not counted, or O (log n) if it is counted. Different algorithms may complete the same task with a different set of instructions in less or more time, space, or effort than others. For example, given two different recipes for making potato salad, one may have peel the potato before boil the potato while the other presents the steps in the reverse order, yet they both call for these steps to be repeated for all potatoes and end when the potato salad is ready to be eaten. The analysis and study of algorithms is a discipline of computer science, and is often practiced abstractly without the use of a specific programming language or implementation. In this sense, algorithm analysis resembles other mathematical disciplines in that it focuses on the underlying properties of the algorithm and not on the specifics of any particular implementation. Usually pseudocode is used for analysis as it is the simplest and most general representation. # Classes There are various ways to classify algorithms, each with its own merits. ## Classification by implementation One way to classify algorithms is by implementation means. - Recursion or iteration: A recursive algorithm is one that invokes (makes reference to) itself repeatedly until a certain condition matches, which is a method common to functional programming. Iterative algorithms use repetitive constructs like loops and sometimes additional data structures like stacks to solve the given problems. Some problems are naturally suited for one implementation or the other. For example, towers of hanoi is well understood in recursive implementation. Every recursive version has an equivalent (but possibly more or less complex) iterative version, and vice versa. - Logical: An algorithm may be viewed as controlled logical deduction. This notion may be expressed as: Algorithm = logic + control (Kowalski 1979). The logic component expresses the axioms that may be used in the computation and the control component determines the way in which deduction is applied to the axioms. This is the basis for the logic programming paradigm. In pure logic programming languages the control component is fixed and algorithms are specified by supplying only the logic component. The appeal of this approach is the elegant semantics: a change in the axioms has a well defined change in the algorithm. - Serial or parallel or distributed: Algorithms are usually discussed with the assumption that computers execute one instruction of an algorithm at a time. Those computers are sometimes called serial computers. An algorithm designed for such an environment is called a serial algorithm, as opposed to parallel algorithms or distributed algorithms. Parallel algorithms take advantage of computer architectures where several processors can work on a problem at the same time, whereas distributed algorithms utilize multiple machines connected with a network. Parallel or distributed algorithms divide the problem into more symmetrical or asymmetrical subproblems and collect the results back together. The resource consumption in such algorithms is not only processor cycles on each processor but also the communication overhead between the processors. Sorting algorithms can be parallelized efficiently, but their communication overhead is expensive. Iterative algorithms are generally parallelizable. Some problems have no parallel algorithms, and are called inherently serial problems. - Deterministic or non-deterministic: Deterministic algorithms solve the problem with exact decision at every step of the algorithm whereas non-deterministic algorithm solve problems via guessing although typical guesses are made more accurate through the use of heuristics. - Exact or approximate: While many algorithms reach an exact solution, approximation algorithms seek an approximation that is close to the true solution. Approximation may use either a deterministic or a random strategy. Such algorithms have practical value for many hard problems. ## Classification by design paradigm Another way of classifying algorithms is by their design methodology or paradigm. There is a certain number of paradigms, each different from the other. Furthermore, each of these categories will include many different types of algorithms. Some commonly found paradigms include: - Divide and conquer. A divide and conquer algorithm repeatedly reduces an instance of a problem to one or more smaller instances of the same problem (usually recursively), until the instances are small enough to solve easily. One such example of divide and conquer is merge sorting. Sorting can be done on each segment of data after dividing data into segments and sorting of entire data can be obtained in conquer phase by merging them. A simpler variant of divide and conquer is called decrease and conquer algorithm, that solves an identical subproblem and uses the solution of this subproblem to solve the bigger problem. Divide and conquer divides the problem into multiple subproblems and so conquer stage will be more complex than decrease and conquer algorithms. An example of decrease and conquer algorithm is binary search algorithm. - Dynamic programming. When a problem shows optimal substructure, meaning the optimal solution to a problem can be constructed from optimal solutions to subproblems, and overlapping subproblems, meaning the same subproblems are used to solve many different problem instances, a quicker approach called dynamic programming avoids recomputing solutions that have already been computed. For example, the shortest path to a goal from a vertex in a weighted graph can be found by using the shortest path to the goal from all adjacent vertices. Dynamic programming and memoization go together. The main difference between dynamic programming and divide and conquer is that subproblems are more or less independent in divide and conquer, whereas subproblems overlap in dynamic programming. The difference between dynamic programming and straightforward recursion is in caching or memoization of recursive calls. When subproblems are independent and there is no repetition, memoization does not help; hence dynamic programming is not a solution for all complex problems. By using memoization or maintaining a table of subproblems already solved, dynamic programming reduces the exponential nature of many problems to polynomial complexity. - The greedy method. A greedy algorithm is similar to a dynamic programming algorithm, but the difference is that solutions to the subproblems do not have to be known at each stage; instead a "greedy" choice can be made of what looks best for the moment. The greedy method extends the solution with the best possible decision (not all feasible decisions) at an algorithmic stage based on the current local optimum and the best decision (not all possible decisions) made in previous stage. It is not exhaustive, and does not give accurate answer to many problems. But when it works, it will be the fastest method. The most popular greedy algorithm is finding the minimal spanning tree as given by Kruskal. - Linear programming. When solving a problem using linear programming, specific inequalities involving the inputs are found and then an attempt is made to maximize (or minimize) some linear function of the inputs. Many problems (such as the maximum flow for directed graphs) can be stated in a linear programming way, and then be solved by a 'generic' algorithm such as the simplex algorithm. A more complex variant of linear programming is called integer programming, where the solution space is restricted to the integers. - Reduction. This technique involves solving a difficult problem by transforming it into a better known problem for which we have (hopefully) asymptotically optimal algorithms. The goal is to find a reducing algorithm whose complexity is not dominated by the resulting reduced algorithm's. For example, one selection algorithm for finding the median in an unsorted list involves first sorting the list (the expensive portion) and then pulling out the middle element in the sorted list (the cheap portion). This technique is also known as transform and conquer. - Search and enumeration. Many problems (such as playing chess) can be modeled as problems on graphs. A graph exploration algorithm specifies rules for moving around a graph and is useful for such problems. This category also includes search algorithms, branch and bound enumeration and backtracking. - The probabilistic and heuristic paradigm. Algorithms belonging to this class fit the definition of an algorithm more loosely. - Probabilistic algorithms are those that make some choices randomly (or pseudo-randomly); for some problems, it can in fact be proven that the fastest solutions must involve some randomness. - Genetic algorithms attempt to find solutions to problems by mimicking biological evolutionary processes, with a cycle of random mutations yielding successive generations of "solutions". Thus, they emulate reproduction and "survival of the fittest". In genetic programming, this approach is extended to algorithms, by regarding the algorithm itself as a "solution" to a problem. - Heuristic algorithms, whose general purpose is not to find an optimal solution, but an approximate solution where the time or resources are limited. They are not practical to find perfect solutions. An example of this would be local search, tabu search, or simulated annealing algorithms, a class of heuristic probabilistic algorithms that vary the solution of a problem by a random amount. The name "simulated annealing" alludes to the metallurgic term meaning the heating and cooling of metal to achieve freedom from defects. The purpose of the random variance is to find close to globally optimal solutions rather than simply locally optimal ones, the idea being that the random element will be decreased as the algorithm settles down to a solution. ## Classification by field of study Every field of science has its own problems and needs efficient algorithms. Related problems in one field are often studied together. Some example classes are search algorithms, sorting algorithms, merge algorithms, numerical algorithms, graph algorithms, string algorithms, computational geometric algorithms, combinatorial algorithms, machine learning, cryptography, data compression algorithms and parsing techniques. Fields tend to overlap with each other, and algorithm advances in one field may improve those of other, sometimes completely unrelated, fields. For example, dynamic programming was originally invented for optimization of resource consumption in industry, but is now used in solving a broad range of problems in many fields. ## Classification by complexity Algorithms can be classified by the amount of time they need to complete compared to their input size. There is a wide variety: some algorithms complete in linear time relative to input size, some do so in an exponential amount of time or even worse, and some never halt. Additionally, some problems may have multiple algorithms of differing complexity, while other problems might have no algorithms or no known efficient algorithms. There are also mappings from some problems to other problems. Owing to this, it was found to be more suitable to classify the problems themselves instead of the algorithms into equivalence classes based on the complexity of the best possible algorithms for them. ## Classification by computing power Another way to classify algorithms is by computing power. This is typically done by considering some collection (class) of algorithms. A recursive class of algorithms is one that includes algorithms for all Turing computable functions. Looking at classes of algorithms allows for the possibility of restricting the available computational resources (time and memory) used in a computation. A subrecursive class of algorithms is one in which not all Turing computable functions can be obtained. For example, the algorithms that run in polynomial time suffice for many important types of computation but do not exhaust all Turing computable functions. The class algorithms implemented by primitive recursive functions is another subrecursive class. Burgin (2005, p. 24) uses a generalized definition of algorithms that relaxes the common requirement that the output of the algorithm that computes a function must be determined after a finite number of steps. He defines a super-recursive class of algorithms as "a class of algorithms in which it is possible to compute functions not computable by any Turing machine" (Burgin 2005, p. 107). This is closely related to the study of methods of hypercomputation. # Legal issues Algorithms, by themselves, are not usually patentable. In the United States, a claim consisting solely of simple manipulations of abstract concepts, numbers, or signals do not constitute "processes" (USPTO 2006) and hence algorithms are not patentable (as in Gottschalk v. Benson). However, practical applications of algorithms are sometimes patentable. For example, in Diamond v. Diehr, the application of a simple feedback algorithm to aid in the curing of synthetic rubber was deemed patentable. The patenting of software is highly controversial, and there are highly criticized patents involving algorithms, especially data compression algorithms, such as Unisys' LZW patent. Additionally, some cryptographic algorithms have export restrictions (see export of cryptography). # History: Development of the notion of "algorithm" ## Origin of the word The word algorithm comes from the name of the 9th century Persian mathematician Abu Abdullah Muhammad ibn Musa al-Khwarizmi whose works introduced Indian numerals and algebraic concepts. He worked in Baghdad at the time when it was the centre of scientific studies and trade. The word algorism originally referred only to the rules of performing arithmetic using Arabic numerals but evolved via European Latin translation of al-Khwarizmi's name into algorithm by the 18th century. The word evolved to include all definite procedures for solving problems or performing tasks. ## Discrete and distinguishable symbols Tally-marks: To keep track of their flocks, their sacks of grain and their money the ancients used tallying: accumulating stones or marks scratched on sticks, or making discrete symbols in clay. Through the Babylonian and Egyptian use of marks and symbols, eventually Roman numerals and the abacus evolved (Dilson, p.16–41). Tally marks appear prominently in unary numeral system arithmetic used in Turing machine and Post-Turing machine computations. ## Manipulation of symbols as "place holders" for numbers: algebra The work of the ancient Greek geometers, Persian mathematician Al-Khwarizmi (often considered the "father of algebra" and from whose name the terms "algorism" and "algorithm" are derived), and Western European mathematicians culminated in Leibniz's notion of the calculus ratiocinator (ca 1680): ## Mechanical contrivances with discrete states The clock: Bolter credits the invention of the weight-driven clock as “The key invention ", in particular the verge escapement< (Bolter 1984:24) that provides us with the tick and tock of a mechanical clock. “The accurate automatic machine” (Bolter 1984:26) led immediately to "mechanical automata" beginning in the thirteenth century and finally to “computational machines" – the difference engine and analytical engines of Charles Babbage and Countess Ada Lovelace (Bolter p.33–34, p.204–206). Jacquard loom, Hollerith punch cards, telegraphy and telephony — the electromechanical relay: Bell and Newell (1971) indicate that the Jacquard loom (1801), precursor to Hollerith cards (punch cards, 1887), and “telephone switching technologies” were the roots of a tree leading to the development of the first computers (Bell and Newell diagram p. 39, cf Davis 2000). By the mid-1800s the telegraph, the precursor of the telephone, was in use throughout the world, its discrete and distinguishable encoding of letters as “dots and dashes” a common sound. By the late 1800s the ticker tape (ca 1870s) was in use, as was the use of Hollerith cards in the 1890 U.S. census. Then came the Teletype (ca 1910) with its punched-paper use of Baudot code on tape. Telephone-switching networks of electromechanical relays (invented 1835) was behind the work of George Stibitz (1937), the inventor of the digital adding device. As he worked in Bell Laboratories, he observed the “burdensome’ use of mechanical calculators with gears. "He went home one evening in 1937 intending to test his idea.... When the tinkering was over, Stibitz had constructed a binary adding device". (Valley News, p. 13). Davis (2000) observes the particular importance of the electromechanical relay (with its two "binary states" open and closed): ## Mathematics during the 1800s up to the mid-1900s Symbols and rules: In rapid succession the mathematics of George Boole (1847, 1854), Gottlob Frege (1879), and Giuseppe Peano (1888–1889) reduced arithmetic to a sequence of symbols manipulated by rules. Peano's The principles of arithmetic, presented by a new method (1888) was "the first attempt at an axiomatization of mathematics in a symbolic language" (van Heijenoort:81ff). But Heijenoort gives Frege (1879) this kudos: Frege’s is "perhaps the most important single work ever written in logic. ... in which we see a " 'formula language', that is a lingua characterica, a language written with special symbols, "for pure thought", that is, free from rhetorical embellishments ... constructed from specific symbols that are manipulated according to definite rules" (van Heijenoort:1). The work of Frege was further simplified and amplified by Alfred North Whitehead and Bertrand Russell in their Principia Mathematica (1910–1913). The paradoxes: At the same time a number of disturbing paradoxes appeared in the literature, in particular the Burali-Forti paradox (1897), the Russell paradox (1902–03), and the Richard Paradox (Dixon 1906, cf Kleene 1952:36–40). The resultant considerations led to Kurt Gödel’s paper (1931) — he specifically cites the paradox of the liar — that completely reduces rules of recursion to numbers. Effective calculability: In an effort to solve the Entscheidungsproblem defined precisely by Hilbert in 1928, mathematicians first set about to define what was meant by an "effective method" or "effective calculation" or "effective calculability" (i.e., a calculation that would succeed). In rapid succession the following appeared: Alonzo Church, Stephen Kleene and J.B. Rosser's λ-calculus, (cf footnote in Alonzo Church 1936a:90, 1936b:110) a finely-honed definition of "general recursion" from the work of Gödel acting on suggestions of Jacques Herbrand (cf Gödel's Princeton lectures of 1934) and subsequent simplifications by Kleene (1935-6:237ff, 1943:255ff). Church's proof (1936:88ff) that the Entscheidungsproblem was unsolvable, Emil Post's definition of effective calculability as a worker mindlessly following a list of instructions to move left or right through a sequence of rooms and while there either mark or erase a paper or observe the paper and make a yes-no decision about the next instruction (cf "Formulation I", Post 1936:289-290). Alan Turing's proof of that the Entscheidungsproblem was unsolvable by use of his "a- machine"(Turing 1936-7:116ff) -- in effect almost identical to Post's "formulation", J. Barkley Rosser's definition of "effective method" in terms of "a machine" (Rosser 1939:226). S. C. Kleene's proposal of a precursor to "Church thesis" that he called "Thesis I" (Kleene 1943:273–274), and a few years later Kleene's renaming his Thesis "Church's Thesis" (Kleene 1952:300, 317) and proposing "Turing's Thesis" (Kleene 1952:376). ## Emil Post (1936) and Alan Turing (1936-7, 1939) Here is a remarkable coincidence of two men not knowing each other but describing a process of men-as-computers working on computations — and they yield virtually identical definitions. Emil Post (1936) described the actions of a "computer" (human being) as follows: His symbol space would be Alan Turing’s work (1936, 1939:160) preceded that of Stibitz (1937); it is unknown whether Stibitz knew of the work of Turing. Turing’s biographer believed that Turing’s use of a typewriter-like model derived from a youthful interest: “Alan had dreamt of inventing typewriters as a boy; Mrs. Turing had a typewriter; and he could well have begun by asking himself what was meant by calling a typewriter 'mechanical'" (Hodges, p. 96). Given the prevalence of Morse code and telegraphy, ticker tape machines, and Teletypes we might conjecture that all were influences. Turing — his model of computation is now called a Turing machine — begins, as did Post, with an analysis of a human computer that he whittles down to a simple set of basic motions and "states of mind". But he continues a step further and creates a machine as a model of computation of numbers (Turing 1936-7:116). Turing's reduction yields the following: "It may be that some of these change necessarily invoke a change of state of mind. The most general single operation must therefore be taken to be one of the following: A few years later, Turing expanded his analysis (thesis, definition) with this forceful expression of it: ## J. B. Rosser (1939) and S. C. Kleene (1943) J. Barkley Rosser boldly defined an ‘effective method’ in the following manner (boldface added): Rosser's footnote #5 references the work of (1) Church and Kleene and their definition of λ-definability, in particular Church's use of it in his An Unsolvable Problem of Elementary Number Theory (1936); (2) Herbrand and Gödel and their use of recursion in particular Gödel's use in his famous paper On Formally Undecidable Propositions of Principia Mathematica and Related Systems I (1931); and (3) Post (1936) and Turing (1936-7) in their mechanism-models of computation. Stephen C. Kleene defined as his now-famous "Thesis I" known as the Church-Turing thesis. But he did this in the following context (boldface in original): ## History after 1950 A number of efforts have been directed toward further refinement of the definition of "algorithm", and activity is on-going because of issues surrounding, in particular, foundations of mathematics (especially the Church-Turing Thesis) and philosophy of mind (especially arguments around artificial intelligence). For more, see Algorithm characterizations. # Algorithmic Repositories - LEDA - Stanford GraphBase - Combinatorica - Netlib - XTango	Algorithm Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview In mathematics, computing, linguistics and related subjects, an algorithm is a sequence of instructions, often used for calculation and data processing. It is formally a type of effective method in which a list of well-defined instructions for completing a task will, when given an initial state, proceed through a well-defined series of successive states, eventually terminating in an end-state. The transition from one state to the next is not necessarily deterministic; some algorithms, known as probabilistic algorithms, incorporate randomness. A partial formalization of the concept began with attempts to solve the Entscheidungsproblem (the "decision problem") posed by David Hilbert in 1928. Subsequent formalizations were framed as attempts to define "effective calculability" (Kleene 1943:274) or "effective method" (Rosser 1939:225); those formalizations included the Gödel-Herbrand-Kleene recursive functions of 1930, 1934 and 1935, Alonzo Church's lambda calculus of 1936, Emil Post's "Formulation I" of 1936, and Alan Turing's Turing machines of 1936–7 and 1939. # Etymology Al-Khwārizmī, Persian astronomer and mathematician, wrote a treatise in Arabic in 825 AD, On Calculation with Hindu Numerals. (See algorism). It was translated into Latin in the 12th century as Algoritmi de numero Indorum (al-Daffa 1977), which title was likely intended to mean "Algoritmi on the numbers of the Indians", where "Algoritmi" was the translator's rendition of the author's name; but people misunderstanding the title treated Algoritmi as a Latin plural and this led to the word "algorithm" (Latin algorismus) coming to mean "calculation method". The intrusive "th" is most likely due to a false cognate with the Greek ἀριθμός (arithmos) meaning "number". # Why algorithms are necessary: an informal definition No generally accepted formal definition of "algorithm" exists yet. An informal definition could be "an algorithm is a computer program that calculates something." For some people, a program is only an algorithm if it stops eventually. For others, a program is only an algorithm if it stops before a given number of calculation steps. A prototypical example of an "algorithm" is Euclid's algorithm to determine the maximum common divisor of two integers greater than one: "subtract the smallest number from the biggest one, repeat until you get a zero or a one". This procedure is known to stop always, and the number of subtractions needed is always smaller than the biggest of the two numbers. We can derive clues to the issues involved and an informal meaning of the word from the following quotation from Template:Harvtxt (boldface added): No human being can write fast enough, or long enough, or small enough to list all members of an enumerably infinite set by writing out their names, one after another, in some notation. But humans can do something equally useful, in the case of certain enumerably infinite sets: They can give explicit instructions for determining the nth member of the set, for arbitrary finite n. Such instructions are to be given quite explicitly, in a form in which they could be followed by a computing machine, or by a human who is capable of carrying out only very elementary operations on symbols Template:Harv The words "enumerably infinite" mean "countable using integers perhaps extending to infinity". Thus Boolos and Jeffrey are saying that an algorithm implies instructions for a process that "creates" output integers from an arbitrary "input" integer or integers that, in theory, can be chosen from 0 to infinity. Thus we might expect an algorithm to be an algebraic equation such as y = m + n — two arbitrary "input variables" m and n that produce an output y. As we see in Algorithm characterizations — the word algorithm implies much more than this, something on the order of (for our addition example): The concept of algorithm is also used to define the notion of decidability. That notion is central for explaining how formal systems come into being starting from a small set of axioms and rules. In logic, the time that an algorithm requires to complete cannot be measured, as it is not apparently related with our customary physical dimension. From such uncertainties, that characterize ongoing work, stems the unavailability of a definition of algorithm that suits both concrete (in some sense) and abstract usage of the term. # Formalization of algorithms Algorithms are essential to the way computers process information. Many computer programs contain algorithms that specify the specific instructions a computer should perform (in a specific order) to carry out a specified task, such as calculating employees’ paychecks or printing students’ report cards. Thus, an algorithm can be considered to be any sequence of operations that can be simulated by a Turing-complete system. Authors who assert this thesis include Savage (1987) and Gurevich (2000): ...Turing's informal argument in favor of his thesis justifies a stronger thesis: every algorithm can be simulated by a Turing machine (Gurevich 2000:1)...according to Savage [1987], an algorithm is a computational process defined by a Turing machine. (Gurevich 2000:3) Typically, when an algorithm is associated with processing information, data is read from an input source, written to an output device, and/or stored for further processing. Stored data is regarded as part of the internal state of the entity performing the algorithm. In practice, the state is stored in one or more data structures. For any such computational process, the algorithm must be rigorously defined: specified in the way it applies in all possible circumstances that could arise. That is, any conditional steps must be systematically dealt with, case-by-case; the criteria for each case must be clear (and computable). Because an algorithm is a precise list of precise steps, the order of computation will always be critical to the functioning of the algorithm. Instructions are usually assumed to be listed explicitly, and are described as starting "from the top" and going "down to the bottom", an idea that is described more formally by flow of control. So far, this discussion of the formalization of an algorithm has assumed the premises of imperative programming. This is the most common conception, and it attempts to describe a task in discrete, "mechanical" means. Unique to this conception of formalized algorithms is the assignment operation, setting the value of a variable. It derives from the intuition of "memory" as a scratchpad. There is an example below of such an assignment. For some alternate conceptions of what constitutes an algorithm see functional programming and logic programming . ## Termination Some writers restrict the definition of algorithm to procedures that eventually finish. In such a category Kleene places the "decision procedure or decision method or algorithm for the question" (Kleene 1952:136). Others, including Kleene, include procedures that could run forever without stopping; such a procedure has been called a "computational method" (Knuth 1997:5) or "calculation procedure or algorithm" (Kleene 1952:137); however, Kleene notes that such a method must eventually exhibit "some object" (Kleene 1952:137). Minsky makes the pertinent observation, in regards to determining whether an algorithm will eventually terminate (from a particular starting state): But if the length of the process is not known in advance, then "trying" it may not be decisive, because if the process does go on forever — then at no time will we ever be sure of the answer (Minsky 1967:105). As it happens, no other method can do any better, as was shown by Alan Turing with his celebrated result on the undecidability of the so-called halting problem. There is no algorithmic procedure for determining of arbitrary algorithms whether or not they terminate from given starting states. The analysis of algorithms for their likelihood of termination is called termination analysis. See the examples of (im-)"proper" subtraction at partial function for more about what can happen when an algorithm fails for certain of its input numbers — e.g., (i) non-termination, (ii) production of "junk" (output in the wrong format to be considered a number) or no number(s) at all (halt ends the computation with no output), (iii) wrong number(s), or (iv) a combination of these. Kleene proposed that the production of "junk" or failure to produce a number is solved by having the algorithm detect these instances and produce e.g., an error message (he suggested "0"), or preferably, force the algorithm into an endless loop (Kleene 1952:322). Davis does this to his subtraction algorithm — he fixes his algorithm in a second example so that it is proper subtraction (Davis 1958:12-15). Along with the logical outcomes "true" and "false" Kleene also proposes the use of a third logical symbol "u" — undecided (Kleene 1952:326) — thus an algorithm will always produce something when confronted with a "proposition". The problem of wrong answers must be solved with an independent "proof" of the algorithm e.g., using induction: We normally require auxiliary evidence for this (that the algorithm correctly defines a mu recursive function), e.g., in the form of an inductive proof that, for each argument value, the computation terminates with a unique value (Minsky 1967:186). ## Expressing algorithms Algorithms can be expressed in many kinds of notation, including natural languages, pseudocode, flowcharts, and programming languages. Natural language expressions of algorithms tend to be verbose and ambiguous, and are rarely used for complex or technical algorithms. Pseudocode and flowcharts are structured ways to express algorithms that avoid many of the ambiguities common in natural language statements, while remaining independent of a particular implementation language. Programming languages are primarily intended for expressing algorithms in a form that can be executed by a computer, but are often used as a way to define or document algorithms. There is a wide variety of representations possible and one can express a given Turing machine program as a sequence of machine tables (see more at finite state machine and state transition table), as flowcharts (see more at state diagram), or as a form of rudimentary machine code or assembly code called "sets of quadruples" (see more at Turing machine). Sometimes it is helpful in the description of an algorithm to supplement small "flow charts" (state diagrams) with natural-language and/or arithmetic expressions written inside "block diagrams" to summarize what the "flow charts" are accomplishing. Representations of algorithms are generally classed into three accepted levels of Turing machine description (Sipser 2006:157): - 1 High-level description: - 2 Implementation description: - 3 Formal description: ## Implementation Most algorithms are intended to be implemented as computer programs. However, algorithms are also implemented by other means, such as in a biological neural network (for example, the human brain implementing arithmetic or an insect looking for food), in an electrical circuit, or in a mechanical device. # Example One of the simplest algorithms is to find the largest number in an (unsorted) list of numbers. The solution necessarily requires looking at every number in the list, but only once at each. From this follows a simple algorithm, which can be stated in a high-level description English prose, as: High-level description: - Assume the first item is largest. - Look at each of the remaining items in the list and if it is larger than the largest item so far, make a note of it. - The last noted item is the largest in the list when the process is complete. (Quasi-)formal description: Written in prose but much closer to the high-level language of a computer program, the following is the more formal coding of the algorithm in pseudocode or pidgin code: Template:Algorithm-begin Template:Algorithm-end For a more complex example of an algorithm, see Euclid's algorithm for the greatest common divisor, one of the earliest algorithms known. ## Algorithm analysis As it happens, it is important to know how much of a particular resource (such as time or storage) is required for a given algorithm. Methods have been developed for the analysis of algorithms to obtain such quantitative answers; for example, the algorithm above has a time requirement of O(n), using the big O notation with n as the length of the list. At all times the algorithm only needs to remember two values: the largest number found so far, and its current position in the input list. Therefore it is said to have a space requirement of O(1), if the space required to store the input numbers is not counted, or O (log n) if it is counted. Different algorithms may complete the same task with a different set of instructions in less or more time, space, or effort than others. For example, given two different recipes for making potato salad, one may have peel the potato before boil the potato while the other presents the steps in the reverse order, yet they both call for these steps to be repeated for all potatoes and end when the potato salad is ready to be eaten. The analysis and study of algorithms is a discipline of computer science, and is often practiced abstractly without the use of a specific programming language or implementation. In this sense, algorithm analysis resembles other mathematical disciplines in that it focuses on the underlying properties of the algorithm and not on the specifics of any particular implementation. Usually pseudocode is used for analysis as it is the simplest and most general representation. # Classes There are various ways to classify algorithms, each with its own merits. ## Classification by implementation One way to classify algorithms is by implementation means. - Recursion or iteration: A recursive algorithm is one that invokes (makes reference to) itself repeatedly until a certain condition matches, which is a method common to functional programming. Iterative algorithms use repetitive constructs like loops and sometimes additional data structures like stacks to solve the given problems. Some problems are naturally suited for one implementation or the other. For example, towers of hanoi is well understood in recursive implementation. Every recursive version has an equivalent (but possibly more or less complex) iterative version, and vice versa. - Logical: An algorithm may be viewed as controlled logical deduction. This notion may be expressed as: Algorithm = logic + control (Kowalski 1979). The logic component expresses the axioms that may be used in the computation and the control component determines the way in which deduction is applied to the axioms. This is the basis for the logic programming paradigm. In pure logic programming languages the control component is fixed and algorithms are specified by supplying only the logic component. The appeal of this approach is the elegant semantics: a change in the axioms has a well defined change in the algorithm. - Serial or parallel or distributed: Algorithms are usually discussed with the assumption that computers execute one instruction of an algorithm at a time. Those computers are sometimes called serial computers. An algorithm designed for such an environment is called a serial algorithm, as opposed to parallel algorithms or distributed algorithms. Parallel algorithms take advantage of computer architectures where several processors can work on a problem at the same time, whereas distributed algorithms utilize multiple machines connected with a network. Parallel or distributed algorithms divide the problem into more symmetrical or asymmetrical subproblems and collect the results back together. The resource consumption in such algorithms is not only processor cycles on each processor but also the communication overhead between the processors. Sorting algorithms can be parallelized efficiently, but their communication overhead is expensive. Iterative algorithms are generally parallelizable. Some problems have no parallel algorithms, and are called inherently serial problems. - Deterministic or non-deterministic: Deterministic algorithms solve the problem with exact decision at every step of the algorithm whereas non-deterministic algorithm solve problems via guessing although typical guesses are made more accurate through the use of heuristics. - Exact or approximate: While many algorithms reach an exact solution, approximation algorithms seek an approximation that is close to the true solution. Approximation may use either a deterministic or a random strategy. Such algorithms have practical value for many hard problems. ## Classification by design paradigm Another way of classifying algorithms is by their design methodology or paradigm. There is a certain number of paradigms, each different from the other. Furthermore, each of these categories will include many different types of algorithms. Some commonly found paradigms include: - Divide and conquer. A divide and conquer algorithm repeatedly reduces an instance of a problem to one or more smaller instances of the same problem (usually recursively), until the instances are small enough to solve easily. One such example of divide and conquer is merge sorting. Sorting can be done on each segment of data after dividing data into segments and sorting of entire data can be obtained in conquer phase by merging them. A simpler variant of divide and conquer is called decrease and conquer algorithm, that solves an identical subproblem and uses the solution of this subproblem to solve the bigger problem. Divide and conquer divides the problem into multiple subproblems and so conquer stage will be more complex than decrease and conquer algorithms. An example of decrease and conquer algorithm is binary search algorithm. - Dynamic programming. When a problem shows optimal substructure, meaning the optimal solution to a problem can be constructed from optimal solutions to subproblems, and overlapping subproblems, meaning the same subproblems are used to solve many different problem instances, a quicker approach called dynamic programming avoids recomputing solutions that have already been computed. For example, the shortest path to a goal from a vertex in a weighted graph can be found by using the shortest path to the goal from all adjacent vertices. Dynamic programming and memoization go together. The main difference between dynamic programming and divide and conquer is that subproblems are more or less independent in divide and conquer, whereas subproblems overlap in dynamic programming. The difference between dynamic programming and straightforward recursion is in caching or memoization of recursive calls. When subproblems are independent and there is no repetition, memoization does not help; hence dynamic programming is not a solution for all complex problems. By using memoization or maintaining a table of subproblems already solved, dynamic programming reduces the exponential nature of many problems to polynomial complexity. - The greedy method. A greedy algorithm is similar to a dynamic programming algorithm, but the difference is that solutions to the subproblems do not have to be known at each stage; instead a "greedy" choice can be made of what looks best for the moment. The greedy method extends the solution with the best possible decision (not all feasible decisions) at an algorithmic stage based on the current local optimum and the best decision (not all possible decisions) made in previous stage. It is not exhaustive, and does not give accurate answer to many problems. But when it works, it will be the fastest method. The most popular greedy algorithm is finding the minimal spanning tree as given by Kruskal. - Linear programming. When solving a problem using linear programming, specific inequalities involving the inputs are found and then an attempt is made to maximize (or minimize) some linear function of the inputs. Many problems (such as the maximum flow for directed graphs) can be stated in a linear programming way, and then be solved by a 'generic' algorithm such as the simplex algorithm. A more complex variant of linear programming is called integer programming, where the solution space is restricted to the integers. - Reduction. This technique involves solving a difficult problem by transforming it into a better known problem for which we have (hopefully) asymptotically optimal algorithms. The goal is to find a reducing algorithm whose complexity is not dominated by the resulting reduced algorithm's. For example, one selection algorithm for finding the median in an unsorted list involves first sorting the list (the expensive portion) and then pulling out the middle element in the sorted list (the cheap portion). This technique is also known as transform and conquer. - Search and enumeration. Many problems (such as playing chess) can be modeled as problems on graphs. A graph exploration algorithm specifies rules for moving around a graph and is useful for such problems. This category also includes search algorithms, branch and bound enumeration and backtracking. - The probabilistic and heuristic paradigm. Algorithms belonging to this class fit the definition of an algorithm more loosely. - Probabilistic algorithms are those that make some choices randomly (or pseudo-randomly); for some problems, it can in fact be proven that the fastest solutions must involve some randomness. - Genetic algorithms attempt to find solutions to problems by mimicking biological evolutionary processes, with a cycle of random mutations yielding successive generations of "solutions". Thus, they emulate reproduction and "survival of the fittest". In genetic programming, this approach is extended to algorithms, by regarding the algorithm itself as a "solution" to a problem. - Heuristic algorithms, whose general purpose is not to find an optimal solution, but an approximate solution where the time or resources are limited. They are not practical to find perfect solutions. An example of this would be local search, tabu search, or simulated annealing algorithms, a class of heuristic probabilistic algorithms that vary the solution of a problem by a random amount. The name "simulated annealing" alludes to the metallurgic term meaning the heating and cooling of metal to achieve freedom from defects. The purpose of the random variance is to find close to globally optimal solutions rather than simply locally optimal ones, the idea being that the random element will be decreased as the algorithm settles down to a solution. ## Classification by field of study Template:Seealso Every field of science has its own problems and needs efficient algorithms. Related problems in one field are often studied together. Some example classes are search algorithms, sorting algorithms, merge algorithms, numerical algorithms, graph algorithms, string algorithms, computational geometric algorithms, combinatorial algorithms, machine learning, cryptography, data compression algorithms and parsing techniques. Fields tend to overlap with each other, and algorithm advances in one field may improve those of other, sometimes completely unrelated, fields. For example, dynamic programming was originally invented for optimization of resource consumption in industry, but is now used in solving a broad range of problems in many fields. ## Classification by complexity Algorithms can be classified by the amount of time they need to complete compared to their input size. There is a wide variety: some algorithms complete in linear time relative to input size, some do so in an exponential amount of time or even worse, and some never halt. Additionally, some problems may have multiple algorithms of differing complexity, while other problems might have no algorithms or no known efficient algorithms. There are also mappings from some problems to other problems. Owing to this, it was found to be more suitable to classify the problems themselves instead of the algorithms into equivalence classes based on the complexity of the best possible algorithms for them. ## Classification by computing power Another way to classify algorithms is by computing power. This is typically done by considering some collection (class) of algorithms. A recursive class of algorithms is one that includes algorithms for all Turing computable functions. Looking at classes of algorithms allows for the possibility of restricting the available computational resources (time and memory) used in a computation. A subrecursive class of algorithms is one in which not all Turing computable functions can be obtained. For example, the algorithms that run in polynomial time suffice for many important types of computation but do not exhaust all Turing computable functions. The class algorithms implemented by primitive recursive functions is another subrecursive class. Burgin (2005, p. 24) uses a generalized definition of algorithms that relaxes the common requirement that the output of the algorithm that computes a function must be determined after a finite number of steps. He defines a super-recursive class of algorithms as "a class of algorithms in which it is possible to compute functions not computable by any Turing machine" (Burgin 2005, p. 107). This is closely related to the study of methods of hypercomputation. # Legal issues Algorithms, by themselves, are not usually patentable. In the United States, a claim consisting solely of simple manipulations of abstract concepts, numbers, or signals do not constitute "processes" (USPTO 2006) and hence algorithms are not patentable (as in Gottschalk v. Benson). However, practical applications of algorithms are sometimes patentable. For example, in Diamond v. Diehr, the application of a simple feedback algorithm to aid in the curing of synthetic rubber was deemed patentable. The patenting of software is highly controversial, and there are highly criticized patents involving algorithms, especially data compression algorithms, such as Unisys' LZW patent. Additionally, some cryptographic algorithms have export restrictions (see export of cryptography). # History: Development of the notion of "algorithm" ## Origin of the word Template:Seealso The word algorithm comes from the name of the 9th century Persian mathematician Abu Abdullah Muhammad ibn Musa al-Khwarizmi whose works introduced Indian numerals and algebraic concepts. He worked in Baghdad at the time when it was the centre of scientific studies and trade. The word algorism originally referred only to the rules of performing arithmetic using Arabic numerals but evolved via European Latin translation of al-Khwarizmi's name into algorithm by the 18th century. The word evolved to include all definite procedures for solving problems or performing tasks. ## Discrete and distinguishable symbols Tally-marks: To keep track of their flocks, their sacks of grain and their money the ancients used tallying: accumulating stones or marks scratched on sticks, or making discrete symbols in clay. Through the Babylonian and Egyptian use of marks and symbols, eventually Roman numerals and the abacus evolved (Dilson, p.16–41). Tally marks appear prominently in unary numeral system arithmetic used in Turing machine and Post-Turing machine computations. ## Manipulation of symbols as "place holders" for numbers: algebra The work of the ancient Greek geometers, Persian mathematician Al-Khwarizmi (often considered the "father of algebra" and from whose name the terms "algorism" and "algorithm" are derived), and Western European mathematicians culminated in Leibniz's notion of the calculus ratiocinator (ca 1680): ## Mechanical contrivances with discrete states The clock: Bolter credits the invention of the weight-driven clock as “The key invention [of Europe in the Middle Ages]", in particular the verge escapement< (Bolter 1984:24) that provides us with the tick and tock of a mechanical clock. “The accurate automatic machine” (Bolter 1984:26) led immediately to "mechanical automata" beginning in the thirteenth century and finally to “computational machines" – the difference engine and analytical engines of Charles Babbage and Countess Ada Lovelace (Bolter p.33–34, p.204–206). Jacquard loom, Hollerith punch cards, telegraphy and telephony — the electromechanical relay: Bell and Newell (1971) indicate that the Jacquard loom (1801), precursor to Hollerith cards (punch cards, 1887), and “telephone switching technologies” were the roots of a tree leading to the development of the first computers (Bell and Newell diagram p. 39, cf Davis 2000). By the mid-1800s the telegraph, the precursor of the telephone, was in use throughout the world, its discrete and distinguishable encoding of letters as “dots and dashes” a common sound. By the late 1800s the ticker tape (ca 1870s) was in use, as was the use of Hollerith cards in the 1890 U.S. census. Then came the Teletype (ca 1910) with its punched-paper use of Baudot code on tape. Telephone-switching networks of electromechanical relays (invented 1835) was behind the work of George Stibitz (1937), the inventor of the digital adding device. As he worked in Bell Laboratories, he observed the “burdensome’ use of mechanical calculators with gears. "He went home one evening in 1937 intending to test his idea.... When the tinkering was over, Stibitz had constructed a binary adding device". (Valley News, p. 13). Davis (2000) observes the particular importance of the electromechanical relay (with its two "binary states" open and closed): ## Mathematics during the 1800s up to the mid-1900s Symbols and rules: In rapid succession the mathematics of George Boole (1847, 1854), Gottlob Frege (1879), and Giuseppe Peano (1888–1889) reduced arithmetic to a sequence of symbols manipulated by rules. Peano's The principles of arithmetic, presented by a new method (1888) was "the first attempt at an axiomatization of mathematics in a symbolic language" (van Heijenoort:81ff). But Heijenoort gives Frege (1879) this kudos: Frege’s is "perhaps the most important single work ever written in logic. ... in which we see a " 'formula language', that is a lingua characterica, a language written with special symbols, "for pure thought", that is, free from rhetorical embellishments ... constructed from specific symbols that are manipulated according to definite rules" (van Heijenoort:1). The work of Frege was further simplified and amplified by Alfred North Whitehead and Bertrand Russell in their Principia Mathematica (1910–1913). The paradoxes: At the same time a number of disturbing paradoxes appeared in the literature, in particular the Burali-Forti paradox (1897), the Russell paradox (1902–03), and the Richard Paradox (Dixon 1906, cf Kleene 1952:36–40). The resultant considerations led to Kurt Gödel’s paper (1931) — he specifically cites the paradox of the liar — that completely reduces rules of recursion to numbers. Effective calculability: In an effort to solve the Entscheidungsproblem defined precisely by Hilbert in 1928, mathematicians first set about to define what was meant by an "effective method" or "effective calculation" or "effective calculability" (i.e., a calculation that would succeed). In rapid succession the following appeared: Alonzo Church, Stephen Kleene and J.B. Rosser's λ-calculus, (cf footnote in Alonzo Church 1936a:90, 1936b:110) a finely-honed definition of "general recursion" from the work of Gödel acting on suggestions of Jacques Herbrand (cf Gödel's Princeton lectures of 1934) and subsequent simplifications by Kleene (1935-6:237ff, 1943:255ff). Church's proof (1936:88ff) that the Entscheidungsproblem was unsolvable, Emil Post's definition of effective calculability as a worker mindlessly following a list of instructions to move left or right through a sequence of rooms and while there either mark or erase a paper or observe the paper and make a yes-no decision about the next instruction (cf "Formulation I", Post 1936:289-290). Alan Turing's proof of that the Entscheidungsproblem was unsolvable by use of his "a- [automatic-] machine"(Turing 1936-7:116ff) -- in effect almost identical to Post's "formulation", J. Barkley Rosser's definition of "effective method" in terms of "a machine" (Rosser 1939:226). S. C. Kleene's proposal of a precursor to "Church thesis" that he called "Thesis I" (Kleene 1943:273–274), and a few years later Kleene's renaming his Thesis "Church's Thesis" (Kleene 1952:300, 317) and proposing "Turing's Thesis" (Kleene 1952:376). ## Emil Post (1936) and Alan Turing (1936-7, 1939) Here is a remarkable coincidence of two men not knowing each other but describing a process of men-as-computers working on computations — and they yield virtually identical definitions. Emil Post (1936) described the actions of a "computer" (human being) as follows: His symbol space would be Alan Turing’s work (1936, 1939:160) preceded that of Stibitz (1937); it is unknown whether Stibitz knew of the work of Turing. Turing’s biographer believed that Turing’s use of a typewriter-like model derived from a youthful interest: “Alan had dreamt of inventing typewriters as a boy; Mrs. Turing had a typewriter; and he could well have begun by asking himself what was meant by calling a typewriter 'mechanical'" (Hodges, p. 96). Given the prevalence of Morse code and telegraphy, ticker tape machines, and Teletypes we might conjecture that all were influences. Turing — his model of computation is now called a Turing machine — begins, as did Post, with an analysis of a human computer that he whittles down to a simple set of basic motions and "states of mind". But he continues a step further and creates a machine as a model of computation of numbers (Turing 1936-7:116). Turing's reduction yields the following: "It may be that some of these change necessarily invoke a change of state of mind. The most general single operation must therefore be taken to be one of the following: A few years later, Turing expanded his analysis (thesis, definition) with this forceful expression of it: ## J. B. Rosser (1939) and S. C. Kleene (1943) J. Barkley Rosser boldly defined an ‘effective [mathematical] method’ in the following manner (boldface added): Rosser's footnote #5 references the work of (1) Church and Kleene and their definition of λ-definability, in particular Church's use of it in his An Unsolvable Problem of Elementary Number Theory (1936); (2) Herbrand and Gödel and their use of recursion in particular Gödel's use in his famous paper On Formally Undecidable Propositions of Principia Mathematica and Related Systems I (1931); and (3) Post (1936) and Turing (1936-7) in their mechanism-models of computation. Stephen C. Kleene defined as his now-famous "Thesis I" known as the Church-Turing thesis. But he did this in the following context (boldface in original): ## History after 1950 A number of efforts have been directed toward further refinement of the definition of "algorithm", and activity is on-going because of issues surrounding, in particular, foundations of mathematics (especially the Church-Turing Thesis) and philosophy of mind (especially arguments around artificial intelligence). For more, see Algorithm characterizations. # Algorithmic Repositories - LEDA - Stanford GraphBase - Combinatorica - Netlib - XTango	https://www.wikidoc.org/index.php/Algorithm
4335b813c46c949cfb15b49305395123915283a4	wikidoc	Aliskiren	Aliskiren # 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 Aliskiren is a renin inhibitor that is FDA approved for the {{{indicationType}}} of hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, dizziness, headache, and elevated serum creatinine. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Aliskiren is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes. There are no controlled trials demonstrating risk reduction with Aliskiren. - Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High blood pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High blood pressure (JNC). - Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. - Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. - Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. - Aliskiren may be administered with some other antihypertensive agents. In diabetics, do not use in combination with angiotensin receptor blockers (ARBs) or angiotensin converting enzyme inhibitors (ACEIs). Concomitant use of aliskiren with an ARB or ACEI is not recommended in patients with GFR <60 ml/min. Most exposure to date is with diuretics, an angiotensin receptor blocker (valsartan) or a calcium channel blocker (amlodipine). Aliskiren used together with these drugs has a greater effect at their maximum recommended doses than either drug alone. - It is not known whether additive effects are present when aliskiren is used with angiotensin-converting enzyme inhibitors (ACEIs) or beta blockers (BB). - Patients should establish a routine pattern for taking Aliskiren with regard to meals. High fat meals decrease absorption substantially. - Dosing Information - The usual recommended starting dose is 150 mg once daily. - In patients whose blood pressure is not adequately controlled, the daily dose may be increased to 300 mg. - Doses above 300 mg did not give an increased blood pressure response but resulted in an increased rate of diarrhea. The antihypertensive effect of a given dose is substantially attained (85-90%) by 2 weeks. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Aliskiren in adult patients. ### Non–Guideline-Supported Use - Dosing Information - 300 mg PO qd # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness of aliskiren in pediatric patients <18 years have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Aliskiren in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Aliskiren in pediatric patients. # Contraindications - Do not use aliskiren with ARBs or ACEIs in patients with diabetes. # Warnings - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Aliskiren as soon as possible. - Aliskiren is contraindicated in patients with diabetes who are receiving ARBs or ACEIs because of the increased risk of renal impairment, hyperkalemia, and hypotension. - Avoid use of Aliskiren with ARBs or ACEIs in patients with moderate renal impairment (GFR <60 ml/min). - Hypersensitivity reactions such as anaphylactic reactions and angioedema of the face, extremities, lips, tongue, glottis and/or larynx have been reported in patients treated with Aliskiren and has necessitated hospitalization and intubation. This may occur at any time during treatment and has occurred in patients with and without a history of angioedema with ACE inhibitors or angiotensin receptor antagonists. Anaphylactic reactions have been reported from post-marketing experience with unknown frequency. If angioedema involves the throat, tongue, glottis or larynx, or if the patient has a history of upper respiratory surgery, airway obstruction may occur and be fatal. Patients who experience these effects, even without respiratory distress, require prolonged observation and appropriate monitoring measures since treatment with antihistamines and corticosteroids may not be sufficient to prevent respiratory involvement. Prompt administration of subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 ml) and measures to ensure a patent airway may be necessary. - Discontinue Aliskiren immediately in patients who develop anaphylactic reactions or angioedema, and do not readminister. - Symptomatic hypotension may occur after initiation of treatment with Aliskiren in patients with marked volume depletion, patients with salt depletion, or with combined use of aliskiren and other agents acting on the renin-angiotensin-aldosterone system. The volume or salt depletion should be corrected prior to administration of Aliskiren, or the treatment should start under close medical supervision. - A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. - Monitor renal function periodically in patients treated with Aliskiren. Changes in renal function, including acute renal failure, can be caused by drugs that affect the renin-angiotensin-aldosterone system. Patients whose renal function may depend in part on the activity of the renin-angiotensin-aldosterone system (e.g., patients with renal artery stenosis, severe heart failure, post-myocardial infarction or volume depletion) or patients receiving ARB, ACEI or non-steroidal anti-inflammatory (NSAID) therapy may be at particular risk for developing acute renal failure on Aliskiren. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function. - Monitor serum potassium periodically in patients receiving Aliskiren. Drugs that affect the renin-angiotensin-aldosterone system can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes, combination use with ARBs or ACEIs, NSAIDs, or potassium supplements or potassium sparing diuretics. - When aliskiren was given with cyclosporine or itraconazole, the blood concentrations of aliskiren were significantly increased. Avoid concomitant use of aliskiren with cyclosporine or itraconazole. # 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 clinical trials of another drug and may not reflect the rates observed in practice. - Data described below reflect the evaluation of the safety of Aliskiren in more than 6,460 patients, including over 1,740 treated for longer than 6 months, and more than 1,250 patients for longer than 1 year. In placebo controlled clinical trials, discontinuation of therapy due to a clinical adverse event, including uncontrolled hypertension occurred in 2.2% of patients treated with Aliskiren vs. 3.5% of patients given placebo. These data do not include information from the ALTITUDE study which evaluated the use of aliskiren in combination with ARBs or ACEIs. - Two cases of angioedema with respiratory symptoms were reported with Aliskiren use in the clinical studies. Two other cases of periorbital edema without respiratory symptoms were reported as possible angioedema and resulted in discontinuation. The rate of these angioedema cases in the completed studies was 0.06%. In addition, 26 other cases of edema involving the face, hands, or whole body were reported with Aliskiren use including 4 leading to discontinuation. In the placebo controlled studies, however, the incidence of edema involving the face, hands or whole body was 0.4% with Aliskiren compared with 0.5% with placebo. In a long term active control study with Aliskiren and HCTZ arms, the incidence of edema involving the face, hand or whole body was 0.4% in both treatment arms. - Aliskiren produces dose-related gastrointestinal (GI) adverse reactions. Diarrhea was reported by 2.3% of patients at 300 mg, compared to 1.2% in placebo patients. In women and the elderly (age ≥ 65) increases in diarrhea rates were evident starting at a dose of 150 mg daily, with rates for these subgroups at 150 mg comparable to those seen at 300 mg for men or younger patients (all rates about 2.0-2.3%). Other GI symptoms included abdominal pain, dyspepsia, and gastroesophageal reflux, although increased rates for abdominal pain and dyspepsia were distinguished from placebo only at 600 mg daily. Diarrhea and other GI symptoms were typically mild and rarely led to discontinuation. - Aliskiren was associated with a slight increase in cough in the placebo-controlled studies (1.1% for any Aliskiren use vs. 0.6% for placebo). In active-controlled trials with ACE inhibitor (ramipril, lisinopril) arms, the rates of cough for the Aliskiren arms were about one-third to one-half the rates in the ACE inhibitor arms. - Single episodes of tonic-clonic seizures with loss of consciousness were reported in two patients treated with Aliskiren in the clinical trials. One of these patients did have predisposing causes for seizures and had a negative electroencephalogram (EEG) and cerebral imaging following the seizures (for the other patient EEG and imaging results were not reported). Aliskiren was discontinued and there was no re-challenge. - Other adverse effects with increased rates for Aliskiren compared to placebo included rash (1% vs. 0.3%), elevated uric acid (0.4% vs. 0.1%), gout (0.2% vs. 0.1%) and renal stones (0.2% vs. 0%). - Aliskiren’s effect on ECG intervals was studied in a randomized, double-blind, placebo and active-controlled (moxifloxacin), 7-day repeat dosing study with Holter-monitoring and 12 lead ECGs throughout the interdosing interval. No effect of aliskiren on QT interval was seen. ### Clinical Laboratory Findings - In controlled clinical trials, clinically relevant changes in standard laboratory parameters were rarely associated with the administration of Aliskiren in patients with hypertension not concomitantly treated with an ARB or ACEI. In multiple-dose studies in hypertensive patients, Aliskiren had no clinically important effects on total cholesterol, HDL, fasting triglycerides, or fasting glucose. - In patients with hypertension not concomitantly treated with an ARB or ACEI, minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 7% of patients treated with Aliskiren alone vs. 6% on placebo. - Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.08 g/dL and 0.16 volume percent, respectively, for all aliskiren monotherapy) were observed. The decreases were dose-related and were 0.24 g/dL and 0.79 volume percent for 600 mg daily. This effect is also seen with other agents acting on the renin angiotensin system, such as angiotensin inhibitors and angiotensin receptor blockers and may be mediated by reduction of angiotensin II which stimulates erythropoietin production via the AT1 receptor. These decreases led to slight increases in rates of anemia with aliskiren compared to placebo were observed (0.1% for any aliskiren use, 0.3% for aliskiren 600 mg daily, vs 0% for placebo). No patients discontinued therapy due to anemia. - In patients with hypertension not concomitantly treated with an ARB or ACEI, increases in serum potassium >5.5 mEq/L were infrequent (0.9% compared to 0.6% with placebo). - Aliskiren monotherapy produced small median increases in serum uric acid levels (about 6 μmol/L) while HCTZ produced larger increases (about 30 μmol/L). The combination of aliskiren with HCTZ appears to be additive (about 40 μmol/L increase). The increases in uric acid appear to lead to slight increases in uric acid-related AEs: elevated uric acid (0.4% vs 0.1%), gout (0.2% vs. 0.1%), and renal stones (0.2% vs 0%). - Increases in creatine kinase of >300% were recorded in about 1% of aliskiren monotherapy patients vs. 0.5% of placebo patients. Five cases of creatine kinase rises, three leading to discontinuation and one diagnosed as subclinical rhabdomyolysis, and another as myositis, were reported as adverse events with aliskiren use in the clinical trials. No cases were associated with renal dysfunction. ## Postmarketing Experience - The following adverse reactions have been reported in aliskiren post-marketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. - Hypersensitivity: anaphylactic reactions and angioedema requiring airway management and hospitalization - Urticaria - Peripheral edema - Hepatic enzyme increase with clinical symptoms of hepatic dysfunction - Severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis - Pruritus - Erythema # Drug Interactions - Cyclosporine - Avoid co-administration of cyclosporine with aliskiren. - Itraconazole - Avoid co-administration of itraconazole with aliskiren. - Non-Steroidal Anti-Inflammatory Agents (NSAIDs) including selective Cyclooxygenase-2 inhibitors (COX-2 inhibitors) - In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors with agents that affect the renin-angiotensin-aldosterone system, including aliskiren, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving aliskiren and NSAID therapy. - The antihypertensive effect of aliskiren may be attenuated by NSAIDs. - Dual Blockade of the renin-angiotensin-aldosterone system - The concomitant use of aliskiren with other agents acting on the renin-angiotensin-aldosterone system such as ACEIs or ARBs is associated with an increased risk of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Monitor blood pressure, renal function, and electrolytes in patients on aliskiren and other agents that affect the renin-angiotensin-aldosterone system. - The concomitant use of aliskiren with an ARB or an ACEI in diabetic patients is contraindicated and should be avoided in patients with moderate renal impairment. - Furosemide - Oral co-administration of aliskiren and furosemide reduced exposure to furosemide. Monitor diuretic effects when furosemide is co-administered with aliskiren. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category D - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Aliskiren as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. - In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Aliskiren, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Aliskiren for hypotension, oliguria, and hyperkalemia. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Aliskiren in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Aliskiren during labor and delivery. ### Nursing Mothers - It is not known whether aliskiren is excreted in human breast milk. Aliskiren was secreted in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and effectiveness of aliskiren in pediatric patients <18 years have not been established. - Neonates with a history of in utero exposure to Aliskiren - If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. ### Geriatic Use - Of the total number of patients receiving aliskiren in clinical studies, 1,275 (19%) were 65 years or older and 231 (3.4%) were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. 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 Aliskiren with respect to specific gender populations. ### Race There is no FDA guidance on the use of Aliskiren with respect to specific racial populations. ### Renal Impairment - Safety and effectiveness of Aliskiren in patients with severe renal impairment (CrCl <30 ml/min) have not been established as patients with eGFR <30ml/min were excluded in clinical trials. ### Hepatic Impairment There is no FDA guidance on the use of Aliskiren in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Aliskiren in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Aliskiren in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Monitor renal function periodically in patients treated with Aliskiren. - Monitor serum potassium periodically in patients receiving Aliskiren. - The concomitant use of aliskiren with other agents acting on the renin-angiotensin-aldosterone system such as ACEIs or ARBs is associated with an increased risk of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Monitor blood pressure, renal function, and electrolytes in patients on aliskiren and other agents that affect the renin-angiotensin-aldosterone system. - Oral co-administration of aliskiren and furosemide reduced exposure to furosemide. Monitor diuretic effects when furosemide is co-administered with aliskiren. # IV Compatibility There is limited information regarding IV Compatibility of Aliskiren in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Limited data are available related to overdosage in humans. The most likely manifestation of overdosage would be hypotension. ### Management - If symptomatic hypotension occurs, supportive treatment should be initiated. - Aliskiren is poorly dialyzed. Therefore, hemodialysis is not adequate to treat aliskiren overexposure. ## Chronic Overdose There is limited information regarding Chronic Overdose of Aliskiren in the drug label. # Pharmacology ## Mechanism of Action - Renin is secreted by the kidney in response to decreases in blood volume and renal perfusion. Renin cleaves angiotensinogen to form the inactive decapeptide angiotensin I (Ang I). Ang I is converted to the active octapeptide angiotensin II (Ang II) by angiotensin-converting enzyme (ACE) and non-ACE pathways. Ang II is a powerful vasoconstrictor and leads to the release of catecholamines from the adrenal medulla and prejunctional nerve endings. It also promotes aldosterone secretion and sodium reabsorption. Together, these effects increase blood pressure. Ang II also inhibits renin release, thus providing a negative feedback to the system. This cycle, from renin through angiotensin to aldosterone and its associated negative feedback loop, is known as the renin-angiotensin-aldosterone system (RAAS). Aliskiren is a direct renin inhibitor, decreasing plasma renin activity (PRA) and inhibiting the conversion of angiotensinogen to Ang I. Whether aliskiren affects other RAAS components, e.g., ACE or non-ACE pathways, is not known. - All agents that inhibit the RAAS, including renin inhibitors, suppress the negative feedback loop, leading to a compensatory rise in plasma renin concentration. When this rise occurs during treatment with ACE inhibitors and ARBs, the result is increased levels of PRA. During treatment with aliskiren, however, the effect of increased renin levels is blocked so that PRA, Ang I and Ang II are all reduced, whether aliskiren is used as monotherapy or in combination with other antihypertensive agents. ## Structure - Aliskiren contains aliskiren hemifumarate, a renin inhibitor, that is provided as tablets for oral administration. Aliskiren hemifumarate is chemically described as (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8--octanamide hemifumarate and its structural formula is: - Molecular formula: C30H53N3O6 - 0.5 C4H4O4 - Aliskiren hemifumarate is a white to slightly yellowish crystalline powder with a molecular weight of 609.8 (free base- 551.8). It is soluble in phosphate buffer, n-octanol, and highly soluble in water. ## Pharmacodynamics - In placebo controlled clinical trials, plasma renin activity (PRA) was decreased in a range of 50–80%. This reduction in PRA was not dose-related and did not correlate with blood pressure reductions. The clinical implications of the differences in effect on PRA are not known. ## Pharmacokinetics - Aliskiren is poorly absorbed (bioavailability about 2.5%) with an approximate accumulation half life of 24 hours. Steady state blood levels are reached in about 7-8 days. - Following oral administration, peak plasma concentrations of aliskiren are reached within 1 – 3 hours. When taken with a high fat meal, mean AUC and Cmax of aliskiren are decreased by 71% and 85% respectively. In the clinical trials of aliskiren, it was administered without requiring a fixed relation of administration to meals. - About one fourth of the absorbed dose appears in the urine as parent drug. How much of the absorbed dose is metabolized is unknown. Based on the in vitro studies, the major enzyme responsible for aliskiren metabolism appears to be CYP3A4. Aliskiren does not inhibit the CYP450 isoenzymes (CYP 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) or induce CYP 3A4. - Transporters: Pgp (MDR1/Mdr1a/1b) was found to be the major efflux system involved in absorption and disposition of aliskiren in preclinical studies. The potential for drug interactions at the Pgp site will likely depend on the degree of inhibition of this transporter. - The effect of co-administered drugs on the pharmacokinetics of aliskiren and vice versa, were studied in several single and multiple dose studies. Pharmacokinetic measures indicating the magnitude of these interactions are presented in Figure 1 (impact of co-administered drugs on aliskiren) and Figure 2 (impact of aliskiren on co-administered drugs). - Warfarin: There was no clinically significant effect of a single dose of warfarin 25 mg on the pharmacokinetics of aliskiren. - Furosemide: In patients with heart failure, co-administration of aliskiren (300 mg/day) reduced plasma AUC and Cmax of oral furosemide (60 mg/day) by 17% and 27%, respectively, and reduced 24 hour urinary furosemide excretion by 29%. This change in exposure did not result in statistically significant difference in total urine volume and urinary sodium excretion over 24 hours. However, a transient decrease in urinary sodium excretion and urine volume effects up to 12 hours were observed when furosemide was co-administered with aliskiren 300 mg/day. - Renally Impaired Patients - Aliskiren was evaluated in patients with varying degrees of renal insufficiency. The rate and extent of exposure (AUC and Cmax) of aliskiren in subjects with renal impairment did not show a consistent correlation with the severity of renal impairment. Adjustment of the starting dose is not required in these patients. The pharmacokinetics of aliskiren following administration of a single oral dose of 300 mg was evaluated in patients with End Stage Renal Disease (ESRD) undergoing hemodialysis. When compared to matched healthy subjects, changes in the rate and extent of aliskiren exposure (Cmax and AUC) in ESRD patients undergoing hemodialysis was not clinically significant. Timing of hemodialysis did not significantly alter the pharmacokinetics of aliskiren in ESRD patients. Therefore, no dose adjustment is warranted in ESRD patients receiving hemodialysis. - Hepatically Impaired Patients - The pharmacokinetics of aliskiren were not significantly affected in patients with mild to severe liver disease. Consequently, adjustment of the starting dose is not required in these patients. - Pediatric Patients - The pharmacokinetics of aliskiren have not been investigated in patients <18 years of age. - Geriatric Patients - Exposure (measured by AUC) is increased in elderly patients ≥65 years. Adjustment of the starting dose is not required in these patients. - Race - The pharmacokinetic differences between Blacks, Caucasians, and the Japanese are minimal. ## Nonclinical Toxicology - Carcinogenic potential was assessed in a 2-year rat study and a 6-month transgenic (rasH2) mouse study with aliskiren hemifumarate at oral doses of up to 1500 mg aliskiren/kg/day. Although there were no statistically significant increases in tumor incidence associated with exposure to aliskiren, mucosal epithelial hyperplasia (with or without erosion/ulceration) was observed in the lower gastrointestinal tract at doses of ≥750 mg/kg/day in both species, with a colonic adenoma identified in one rat and a cecal adenocarcinoma identified in another, rare tumors in the strain of rat studied. On a systemic exposure (AUC0-24hr) basis, 1500 mg/kg/day in the rat is about 4 times and in the mouse about 1.5 times the maximum recommended human dose (300 mg aliskiren/day). Mucosal hyperplasia in the cecum or colon of rats was also observed at doses of 250 mg/kg/day (the lowest tested dose) as well as at higher doses in 4- and 13-week studies. - Aliskiren hemifumarate was devoid of genotoxic potential in the Ames reverse mutation assay with S. typhimurium and E. coli, the in vitro Chinese hamster ovary cell chromosomal aberration assay, the in vitro Chinese hamster V79 cell gene mutation test and the in vivo mouse bone marrow micronucleus assay. - Fertility of male and female rats was unaffected at doses of up to 250 mg aliskiren/kg/day (8 times the maximum recommended human dose of 300 mg Aliskiren/60 kg on a mg/m2 basis.) - Reproductive Toxicology Studies: Reproductive toxicity studies of aliskiren hemifumarate did not reveal any evidence of teratogenicity at oral doses up to 600 mg aliskiren/kg/day (20 times the maximum recommended human dose (MRHD) of 300 mg/day on a mg/m2 basis) in pregnant rats or up to 100 mg aliskiren/kg/day (7 times the MRHD on a mg/m2 basis) in pregnant rabbits. Fetal birth weight was adversely affected in rabbits at 50 mg/kg/day (3.2 times the MRHD on a mg/m2 basis). Aliskiren was present in placenta, amniotic fluid and fetuses of pregnant rabbits. # Clinical Studies - The antihypertensive effects of Aliskiren have been demonstrated in six randomized, double-blind, placebo-controlled 8-week clinical trials in patients with mild-to-moderate hypertension. The placebo response and placebo-subtracted changes from baseline in seated trough cuff blood pressure are shown in Table 1. - The studies included approximately 2,730 patients given doses of 75-600 mg of aliskiren and 1,231 patients given placebo. As shown in Table 1, there is some increase in response with administered dose in all studies, with reasonable effects seen at 150-300 mg, and no clear further increases at 600 mg. A substantial proportion (85%-90%) of the blood pressure lowering effect was observed within 2 weeks of treatment studies with ambulatory blood pressure monitoring showed reasonable control throughout the interdosing interval; the ratios of mean daytime to mean nighttime ambulatory BP range from 0.6 to 0.9. - Patients in the placebo-controlled trials continued open-label aliskiren for up to one year. A persistent blood pressure lowering effect was demonstrated by a randomized withdrawal study (patients randomized to continue drug or placebo), which showed a statistically significant difference between patients kept on aliskiren and those randomized to placebo. With cessation of treatment, blood pressure gradually returned toward baseline levels over a period of several weeks. There was no evidence of rebound hypertension after abrupt cessation of therapy. - Aliskiren lowered blood pressure in all demographic subgroups, although Black patients tended to have smaller reduction than Caucasians and Asians, as has been seen with ACE inhibitors and ARBs. - There are no studies of Aliskiren or members of the direct renin inhibitors demonstrating reductions in cardiovascular risk in patients with hypertension. Hydrochlorothiazide - Aliskiren 75, 150, and 300 mg and hydrochlorothiazide 6.25, 12.5, and 25 mg were studied alone and in combination in an 8-week, 2,776-patient, randomized, double-blind, placebo-controlled, parallel-group, 15-arm factorial study. Blood pressure reductions with the combinations were greater than the reductions with the monotherapies as shown in Table 2. Valsartan - Aliskiren 150 and 300 mg and valsartan 160 and 320 mg were studied alone and in combination in an 8-week, 1,797-patient, randomized, double-blind, placebo-controlled, parallel-group, 4-arm, dose-escalation study. The dosages of aliskiren and valsartan were started at 150 and 160 mg, respectively, and increased at four weeks to 300 mg and 320 mg, respectively. Seated trough cuff blood pressure was measured at baseline, 4, and 8 weeks. Blood pressure reductions with the combinations were greater than the reductions with the monotherapies as shown in Table 3. Amlodipine - Aliskiren 150 mg and 300 mg and amlodipine besylate 5 mg and 10 mg were studied alone and in combination in an 8-week, 1,685-patient, randomized, double-blind, placebo-controlled, multifactorial study. Treatment with aliskiren and amlodipine resulted overall in significantly greater reductions in diastolic and systolic blood pressure compared to the respective monotherapy components as shown in Table 4. ACE inhibitors - Aliskiren has not been studied when added to maximal doses of ACE inhibitors to determine whether aliskiren produces additional blood pressure reduction. - Patients with diabetes with renal disease (defined either by the presence of albuminuria or reduced GFR) were randomized to aliskiren 300 mg daily (n=4296) or placebo (n=4310). All patients were receiving background therapy with an ARB or ACEI. The primary efficacy outcome was the time to the first event of the primary composite endpoint consisting of cardiovascular death, resuscitated sudden death, non-fatal myocardial infarction, non-fatal stroke, unplanned hospitalization for heart failure, onset of end stage renal disease, renal death, and doubling of serum creatinine concentration from baseline sustained for at least one month. After a median follow up of about 32 months, the trial was terminated early for lack of efficacy. Higher risk of renal impairment, hypotension and hyperkalemia was observed in aliskiren compared to placebo treated patients, as shown in the table below. - The risk of stroke (3.4% aliskiren vs 2.7% placebo) and death (8.4% aliskiren vs. 8.0% placebo) were also numerically higher in aliskiren treated patients. # How Supplied - Aliskiren is supplied as a light-pink, biconvex round tablet containing 150 mg of aliskiren, and as a light-red biconvex ovaloid tablet containing 300 mg of aliskiren. Tablets are imprinted with NVR on one side and IL, IU, on the other side of the 150, and 300 mg tablets, respectively. - All strengths are packaged in bottles and unit-dose blister packages (10 strips or 10 tablets) as described below in Table 6. - Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF) . Protect from moisture. - Dispense in original container. ## Storage There is limited information regarding Aliskiren Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Pregnancy - Female patients of child bearing age should be told about the consequences of exposure to Aliskiren during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. - Anaphylactic Reactions and Angioedema - Patients should be advised and told to report immediately any signs or symptoms suggesting a severe allergic reaction (difficulty breathing or swallowing, tightness of the chest, hives, general rash, swelling, itching, dizziness, vomiting, or abdominal pain) or angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physicians. Angioedema, including laryngeal edema, may occur at any time during treatment with Aliskiren. - Symptomatic Hypotension - A patient receiving Aliskiren should be cautioned that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. The patients should be told that if syncope occurs, Aliskiren should be discontinued until the physician has been consulted. - All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope. - Potassium Supplements - A patient receiving Aliskiren should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician. - Relationship to Meals - Patients should establish a routine pattern for taking Aliskiren with regard to meals. High-fat meals decrease absorption substantially. # Precautions with Alcohol - Alcohol-Aliskiren interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Tekturna® # Look-Alike Drug Names - N/A # Drug Shortage Status # Price	Aliskiren Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi # 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 Aliskiren is a renin inhibitor that is FDA approved for the {{{indicationType}}} of hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, dizziness, headache, and elevated serum creatinine. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Aliskiren is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes. There are no controlled trials demonstrating risk reduction with Aliskiren. - Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High blood pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High blood pressure (JNC). - Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. - Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. - Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. - Aliskiren may be administered with some other antihypertensive agents. In diabetics, do not use in combination with angiotensin receptor blockers (ARBs) or angiotensin converting enzyme inhibitors (ACEIs). Concomitant use of aliskiren with an ARB or ACEI is not recommended in patients with GFR <60 ml/min. Most exposure to date is with diuretics, an angiotensin receptor blocker (valsartan) or a calcium channel blocker (amlodipine). Aliskiren used together with these drugs has a greater effect at their maximum recommended doses than either drug alone. - It is not known whether additive effects are present when aliskiren is used with angiotensin-converting enzyme inhibitors (ACEIs) or beta blockers (BB). - Patients should establish a routine pattern for taking Aliskiren with regard to meals. High fat meals decrease absorption substantially. - Dosing Information - The usual recommended starting dose is 150 mg once daily. - In patients whose blood pressure is not adequately controlled, the daily dose may be increased to 300 mg. - Doses above 300 mg did not give an increased blood pressure response but resulted in an increased rate of diarrhea. The antihypertensive effect of a given dose is substantially attained (85-90%) by 2 weeks. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Aliskiren in adult patients. ### Non–Guideline-Supported Use - Dosing Information - 300 mg PO qd[1] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness of aliskiren in pediatric patients <18 years have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Aliskiren in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Aliskiren in pediatric patients. # Contraindications - Do not use aliskiren with ARBs or ACEIs in patients with diabetes. # Warnings - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Aliskiren as soon as possible. - Aliskiren is contraindicated in patients with diabetes who are receiving ARBs or ACEIs because of the increased risk of renal impairment, hyperkalemia, and hypotension. - Avoid use of Aliskiren with ARBs or ACEIs in patients with moderate renal impairment (GFR <60 ml/min). - Hypersensitivity reactions such as anaphylactic reactions and angioedema of the face, extremities, lips, tongue, glottis and/or larynx have been reported in patients treated with Aliskiren and has necessitated hospitalization and intubation. This may occur at any time during treatment and has occurred in patients with and without a history of angioedema with ACE inhibitors or angiotensin receptor antagonists. Anaphylactic reactions have been reported from post-marketing experience with unknown frequency. If angioedema involves the throat, tongue, glottis or larynx, or if the patient has a history of upper respiratory surgery, airway obstruction may occur and be fatal. Patients who experience these effects, even without respiratory distress, require prolonged observation and appropriate monitoring measures since treatment with antihistamines and corticosteroids may not be sufficient to prevent respiratory involvement. Prompt administration of subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 ml) and measures to ensure a patent airway may be necessary. - Discontinue Aliskiren immediately in patients who develop anaphylactic reactions or angioedema, and do not readminister. - Symptomatic hypotension may occur after initiation of treatment with Aliskiren in patients with marked volume depletion, patients with salt depletion, or with combined use of aliskiren and other agents acting on the renin-angiotensin-aldosterone system. The volume or salt depletion should be corrected prior to administration of Aliskiren, or the treatment should start under close medical supervision. - A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. - Monitor renal function periodically in patients treated with Aliskiren. Changes in renal function, including acute renal failure, can be caused by drugs that affect the renin-angiotensin-aldosterone system. Patients whose renal function may depend in part on the activity of the renin-angiotensin-aldosterone system (e.g., patients with renal artery stenosis, severe heart failure, post-myocardial infarction or volume depletion) or patients receiving ARB, ACEI or non-steroidal anti-inflammatory (NSAID) therapy may be at particular risk for developing acute renal failure on Aliskiren. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function. - Monitor serum potassium periodically in patients receiving Aliskiren. Drugs that affect the renin-angiotensin-aldosterone system can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes, combination use with ARBs or ACEIs, NSAIDs, or potassium supplements or potassium sparing diuretics. - When aliskiren was given with cyclosporine or itraconazole, the blood concentrations of aliskiren were significantly increased. Avoid concomitant use of aliskiren with cyclosporine or itraconazole. # 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 clinical trials of another drug and may not reflect the rates observed in practice. - Data described below reflect the evaluation of the safety of Aliskiren in more than 6,460 patients, including over 1,740 treated for longer than 6 months, and more than 1,250 patients for longer than 1 year. In placebo controlled clinical trials, discontinuation of therapy due to a clinical adverse event, including uncontrolled hypertension occurred in 2.2% of patients treated with Aliskiren vs. 3.5% of patients given placebo. These data do not include information from the ALTITUDE study which evaluated the use of aliskiren in combination with ARBs or ACEIs. - Two cases of angioedema with respiratory symptoms were reported with Aliskiren use in the clinical studies. Two other cases of periorbital edema without respiratory symptoms were reported as possible angioedema and resulted in discontinuation. The rate of these angioedema cases in the completed studies was 0.06%. In addition, 26 other cases of edema involving the face, hands, or whole body were reported with Aliskiren use including 4 leading to discontinuation. In the placebo controlled studies, however, the incidence of edema involving the face, hands or whole body was 0.4% with Aliskiren compared with 0.5% with placebo. In a long term active control study with Aliskiren and HCTZ arms, the incidence of edema involving the face, hand or whole body was 0.4% in both treatment arms. - Aliskiren produces dose-related gastrointestinal (GI) adverse reactions. Diarrhea was reported by 2.3% of patients at 300 mg, compared to 1.2% in placebo patients. In women and the elderly (age ≥ 65) increases in diarrhea rates were evident starting at a dose of 150 mg daily, with rates for these subgroups at 150 mg comparable to those seen at 300 mg for men or younger patients (all rates about 2.0-2.3%). Other GI symptoms included abdominal pain, dyspepsia, and gastroesophageal reflux, although increased rates for abdominal pain and dyspepsia were distinguished from placebo only at 600 mg daily. Diarrhea and other GI symptoms were typically mild and rarely led to discontinuation. - Aliskiren was associated with a slight increase in cough in the placebo-controlled studies (1.1% for any Aliskiren use vs. 0.6% for placebo). In active-controlled trials with ACE inhibitor (ramipril, lisinopril) arms, the rates of cough for the Aliskiren arms were about one-third to one-half the rates in the ACE inhibitor arms. - Single episodes of tonic-clonic seizures with loss of consciousness were reported in two patients treated with Aliskiren in the clinical trials. One of these patients did have predisposing causes for seizures and had a negative electroencephalogram (EEG) and cerebral imaging following the seizures (for the other patient EEG and imaging results were not reported). Aliskiren was discontinued and there was no re-challenge. - Other adverse effects with increased rates for Aliskiren compared to placebo included rash (1% vs. 0.3%), elevated uric acid (0.4% vs. 0.1%), gout (0.2% vs. 0.1%) and renal stones (0.2% vs. 0%). - Aliskiren’s effect on ECG intervals was studied in a randomized, double-blind, placebo and active-controlled (moxifloxacin), 7-day repeat dosing study with Holter-monitoring and 12 lead ECGs throughout the interdosing interval. No effect of aliskiren on QT interval was seen. ### Clinical Laboratory Findings - In controlled clinical trials, clinically relevant changes in standard laboratory parameters were rarely associated with the administration of Aliskiren in patients with hypertension not concomitantly treated with an ARB or ACEI. In multiple-dose studies in hypertensive patients, Aliskiren had no clinically important effects on total cholesterol, HDL, fasting triglycerides, or fasting glucose. - In patients with hypertension not concomitantly treated with an ARB or ACEI, minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 7% of patients treated with Aliskiren alone vs. 6% on placebo. - Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.08 g/dL and 0.16 volume percent, respectively, for all aliskiren monotherapy) were observed. The decreases were dose-related and were 0.24 g/dL and 0.79 volume percent for 600 mg daily. This effect is also seen with other agents acting on the renin angiotensin system, such as angiotensin inhibitors and angiotensin receptor blockers and may be mediated by reduction of angiotensin II which stimulates erythropoietin production via the AT1 receptor. These decreases led to slight increases in rates of anemia with aliskiren compared to placebo were observed (0.1% for any aliskiren use, 0.3% for aliskiren 600 mg daily, vs 0% for placebo). No patients discontinued therapy due to anemia. - In patients with hypertension not concomitantly treated with an ARB or ACEI, increases in serum potassium >5.5 mEq/L were infrequent (0.9% compared to 0.6% with placebo). - Aliskiren monotherapy produced small median increases in serum uric acid levels (about 6 μmol/L) while HCTZ produced larger increases (about 30 μmol/L). The combination of aliskiren with HCTZ appears to be additive (about 40 μmol/L increase). The increases in uric acid appear to lead to slight increases in uric acid-related AEs: elevated uric acid (0.4% vs 0.1%), gout (0.2% vs. 0.1%), and renal stones (0.2% vs 0%). - Increases in creatine kinase of >300% were recorded in about 1% of aliskiren monotherapy patients vs. 0.5% of placebo patients. Five cases of creatine kinase rises, three leading to discontinuation and one diagnosed as subclinical rhabdomyolysis, and another as myositis, were reported as adverse events with aliskiren use in the clinical trials. No cases were associated with renal dysfunction. ## Postmarketing Experience - The following adverse reactions have been reported in aliskiren post-marketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. - Hypersensitivity: anaphylactic reactions and angioedema requiring airway management and hospitalization - Urticaria - Peripheral edema - Hepatic enzyme increase with clinical symptoms of hepatic dysfunction - Severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis - Pruritus - Erythema # Drug Interactions - Cyclosporine - Avoid co-administration of cyclosporine with aliskiren. - Itraconazole - Avoid co-administration of itraconazole with aliskiren. - Non-Steroidal Anti-Inflammatory Agents (NSAIDs) including selective Cyclooxygenase-2 inhibitors (COX-2 inhibitors) - In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors with agents that affect the renin-angiotensin-aldosterone system, including aliskiren, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving aliskiren and NSAID therapy. - The antihypertensive effect of aliskiren may be attenuated by NSAIDs. - Dual Blockade of the renin-angiotensin-aldosterone system - The concomitant use of aliskiren with other agents acting on the renin-angiotensin-aldosterone system such as ACEIs or ARBs is associated with an increased risk of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Monitor blood pressure, renal function, and electrolytes in patients on aliskiren and other agents that affect the renin-angiotensin-aldosterone system. - The concomitant use of aliskiren with an ARB or an ACEI in diabetic patients is contraindicated and should be avoided in patients with moderate renal impairment. - Furosemide - Oral co-administration of aliskiren and furosemide reduced exposure to furosemide. Monitor diuretic effects when furosemide is co-administered with aliskiren. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category D - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Aliskiren as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. - In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Aliskiren, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Aliskiren for hypotension, oliguria, and hyperkalemia. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Aliskiren in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Aliskiren during labor and delivery. ### Nursing Mothers - It is not known whether aliskiren is excreted in human breast milk. Aliskiren was secreted in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and effectiveness of aliskiren in pediatric patients <18 years have not been established. - Neonates with a history of in utero exposure to Aliskiren - If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. ### Geriatic Use - Of the total number of patients receiving aliskiren in clinical studies, 1,275 (19%) were 65 years or older and 231 (3.4%) were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. 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 Aliskiren with respect to specific gender populations. ### Race There is no FDA guidance on the use of Aliskiren with respect to specific racial populations. ### Renal Impairment - Safety and effectiveness of Aliskiren in patients with severe renal impairment (CrCl <30 ml/min) have not been established as patients with eGFR <30ml/min were excluded in clinical trials. ### Hepatic Impairment There is no FDA guidance on the use of Aliskiren in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Aliskiren in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Aliskiren in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Monitor renal function periodically in patients treated with Aliskiren. - Monitor serum potassium periodically in patients receiving Aliskiren. - The concomitant use of aliskiren with other agents acting on the renin-angiotensin-aldosterone system such as ACEIs or ARBs is associated with an increased risk of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Monitor blood pressure, renal function, and electrolytes in patients on aliskiren and other agents that affect the renin-angiotensin-aldosterone system. - Oral co-administration of aliskiren and furosemide reduced exposure to furosemide. Monitor diuretic effects when furosemide is co-administered with aliskiren. # IV Compatibility There is limited information regarding IV Compatibility of Aliskiren in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Limited data are available related to overdosage in humans. The most likely manifestation of overdosage would be hypotension. ### Management - If symptomatic hypotension occurs, supportive treatment should be initiated. - Aliskiren is poorly dialyzed. Therefore, hemodialysis is not adequate to treat aliskiren overexposure. ## Chronic Overdose There is limited information regarding Chronic Overdose of Aliskiren in the drug label. # Pharmacology ## Mechanism of Action - Renin is secreted by the kidney in response to decreases in blood volume and renal perfusion. Renin cleaves angiotensinogen to form the inactive decapeptide angiotensin I (Ang I). Ang I is converted to the active octapeptide angiotensin II (Ang II) by angiotensin-converting enzyme (ACE) and non-ACE pathways. Ang II is a powerful vasoconstrictor and leads to the release of catecholamines from the adrenal medulla and prejunctional nerve endings. It also promotes aldosterone secretion and sodium reabsorption. Together, these effects increase blood pressure. Ang II also inhibits renin release, thus providing a negative feedback to the system. This cycle, from renin through angiotensin to aldosterone and its associated negative feedback loop, is known as the renin-angiotensin-aldosterone system (RAAS). Aliskiren is a direct renin inhibitor, decreasing plasma renin activity (PRA) and inhibiting the conversion of angiotensinogen to Ang I. Whether aliskiren affects other RAAS components, e.g., ACE or non-ACE pathways, is not known. - All agents that inhibit the RAAS, including renin inhibitors, suppress the negative feedback loop, leading to a compensatory rise in plasma renin concentration. When this rise occurs during treatment with ACE inhibitors and ARBs, the result is increased levels of PRA. During treatment with aliskiren, however, the effect of increased renin levels is blocked so that PRA, Ang I and Ang II are all reduced, whether aliskiren is used as monotherapy or in combination with other antihypertensive agents. ## Structure - Aliskiren contains aliskiren hemifumarate, a renin inhibitor, that is provided as tablets for oral administration. Aliskiren hemifumarate is chemically described as (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifumarate and its structural formula is: - Molecular formula: C30H53N3O6 • 0.5 C4H4O4 - Aliskiren hemifumarate is a white to slightly yellowish crystalline powder with a molecular weight of 609.8 (free base- 551.8). It is soluble in phosphate buffer, n-octanol, and highly soluble in water. ## Pharmacodynamics - In placebo controlled clinical trials, plasma renin activity (PRA) was decreased in a range of 50–80%. This reduction in PRA was not dose-related and did not correlate with blood pressure reductions. The clinical implications of the differences in effect on PRA are not known. ## Pharmacokinetics - Aliskiren is poorly absorbed (bioavailability about 2.5%) with an approximate accumulation half life of 24 hours. Steady state blood levels are reached in about 7-8 days. - Following oral administration, peak plasma concentrations of aliskiren are reached within 1 – 3 hours. When taken with a high fat meal, mean AUC and Cmax of aliskiren are decreased by 71% and 85% respectively. In the clinical trials of aliskiren, it was administered without requiring a fixed relation of administration to meals. - About one fourth of the absorbed dose appears in the urine as parent drug. How much of the absorbed dose is metabolized is unknown. Based on the in vitro studies, the major enzyme responsible for aliskiren metabolism appears to be CYP3A4. Aliskiren does not inhibit the CYP450 isoenzymes (CYP 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) or induce CYP 3A4. - Transporters: Pgp (MDR1/Mdr1a/1b) was found to be the major efflux system involved in absorption and disposition of aliskiren in preclinical studies. The potential for drug interactions at the Pgp site will likely depend on the degree of inhibition of this transporter. - The effect of co-administered drugs on the pharmacokinetics of aliskiren and vice versa, were studied in several single and multiple dose studies. Pharmacokinetic measures indicating the magnitude of these interactions are presented in Figure 1 (impact of co-administered drugs on aliskiren) and Figure 2 (impact of aliskiren on co-administered drugs). - Warfarin: There was no clinically significant effect of a single dose of warfarin 25 mg on the pharmacokinetics of aliskiren. - Furosemide: In patients with heart failure, co-administration of aliskiren (300 mg/day) reduced plasma AUC and Cmax of oral furosemide (60 mg/day) by 17% and 27%, respectively, and reduced 24 hour urinary furosemide excretion by 29%. This change in exposure did not result in statistically significant difference in total urine volume and urinary sodium excretion over 24 hours. However, a transient decrease in urinary sodium excretion and urine volume effects up to 12 hours were observed when furosemide was co-administered with aliskiren 300 mg/day. - Renally Impaired Patients - Aliskiren was evaluated in patients with varying degrees of renal insufficiency. The rate and extent of exposure (AUC and Cmax) of aliskiren in subjects with renal impairment did not show a consistent correlation with the severity of renal impairment. Adjustment of the starting dose is not required in these patients. The pharmacokinetics of aliskiren following administration of a single oral dose of 300 mg was evaluated in patients with End Stage Renal Disease (ESRD) undergoing hemodialysis. When compared to matched healthy subjects, changes in the rate and extent of aliskiren exposure (Cmax and AUC) in ESRD patients undergoing hemodialysis was not clinically significant. Timing of hemodialysis did not significantly alter the pharmacokinetics of aliskiren in ESRD patients. Therefore, no dose adjustment is warranted in ESRD patients receiving hemodialysis. - Hepatically Impaired Patients - The pharmacokinetics of aliskiren were not significantly affected in patients with mild to severe liver disease. Consequently, adjustment of the starting dose is not required in these patients. - Pediatric Patients - The pharmacokinetics of aliskiren have not been investigated in patients <18 years of age. - Geriatric Patients - Exposure (measured by AUC) is increased in elderly patients ≥65 years. Adjustment of the starting dose is not required in these patients. - Race - The pharmacokinetic differences between Blacks, Caucasians, and the Japanese are minimal. ## Nonclinical Toxicology - Carcinogenic potential was assessed in a 2-year rat study and a 6-month transgenic (rasH2) mouse study with aliskiren hemifumarate at oral doses of up to 1500 mg aliskiren/kg/day. Although there were no statistically significant increases in tumor incidence associated with exposure to aliskiren, mucosal epithelial hyperplasia (with or without erosion/ulceration) was observed in the lower gastrointestinal tract at doses of ≥750 mg/kg/day in both species, with a colonic adenoma identified in one rat and a cecal adenocarcinoma identified in another, rare tumors in the strain of rat studied. On a systemic exposure (AUC0-24hr) basis, 1500 mg/kg/day in the rat is about 4 times and in the mouse about 1.5 times the maximum recommended human dose (300 mg aliskiren/day). Mucosal hyperplasia in the cecum or colon of rats was also observed at doses of 250 mg/kg/day (the lowest tested dose) as well as at higher doses in 4- and 13-week studies. - Aliskiren hemifumarate was devoid of genotoxic potential in the Ames reverse mutation assay with S. typhimurium and E. coli, the in vitro Chinese hamster ovary cell chromosomal aberration assay, the in vitro Chinese hamster V79 cell gene mutation test and the in vivo mouse bone marrow micronucleus assay. - Fertility of male and female rats was unaffected at doses of up to 250 mg aliskiren/kg/day (8 times the maximum recommended human dose of 300 mg Aliskiren/60 kg on a mg/m2 basis.) - Reproductive Toxicology Studies: Reproductive toxicity studies of aliskiren hemifumarate did not reveal any evidence of teratogenicity at oral doses up to 600 mg aliskiren/kg/day (20 times the maximum recommended human dose (MRHD) of 300 mg/day on a mg/m2 basis) in pregnant rats or up to 100 mg aliskiren/kg/day (7 times the MRHD on a mg/m2 basis) in pregnant rabbits. Fetal birth weight was adversely affected in rabbits at 50 mg/kg/day (3.2 times the MRHD on a mg/m2 basis). Aliskiren was present in placenta, amniotic fluid and fetuses of pregnant rabbits. # Clinical Studies - The antihypertensive effects of Aliskiren have been demonstrated in six randomized, double-blind, placebo-controlled 8-week clinical trials in patients with mild-to-moderate hypertension. The placebo response and placebo-subtracted changes from baseline in seated trough cuff blood pressure are shown in Table 1. - The studies included approximately 2,730 patients given doses of 75-600 mg of aliskiren and 1,231 patients given placebo. As shown in Table 1, there is some increase in response with administered dose in all studies, with reasonable effects seen at 150-300 mg, and no clear further increases at 600 mg. A substantial proportion (85%-90%) of the blood pressure lowering effect was observed within 2 weeks of treatment studies with ambulatory blood pressure monitoring showed reasonable control throughout the interdosing interval; the ratios of mean daytime to mean nighttime ambulatory BP range from 0.6 to 0.9. - Patients in the placebo-controlled trials continued open-label aliskiren for up to one year. A persistent blood pressure lowering effect was demonstrated by a randomized withdrawal study (patients randomized to continue drug or placebo), which showed a statistically significant difference between patients kept on aliskiren and those randomized to placebo. With cessation of treatment, blood pressure gradually returned toward baseline levels over a period of several weeks. There was no evidence of rebound hypertension after abrupt cessation of therapy. - Aliskiren lowered blood pressure in all demographic subgroups, although Black patients tended to have smaller reduction than Caucasians and Asians, as has been seen with ACE inhibitors and ARBs. - There are no studies of Aliskiren or members of the direct renin inhibitors demonstrating reductions in cardiovascular risk in patients with hypertension. Hydrochlorothiazide - Aliskiren 75, 150, and 300 mg and hydrochlorothiazide 6.25, 12.5, and 25 mg were studied alone and in combination in an 8-week, 2,776-patient, randomized, double-blind, placebo-controlled, parallel-group, 15-arm factorial study. Blood pressure reductions with the combinations were greater than the reductions with the monotherapies as shown in Table 2. Valsartan - Aliskiren 150 and 300 mg and valsartan 160 and 320 mg were studied alone and in combination in an 8-week, 1,797-patient, randomized, double-blind, placebo-controlled, parallel-group, 4-arm, dose-escalation study. The dosages of aliskiren and valsartan were started at 150 and 160 mg, respectively, and increased at four weeks to 300 mg and 320 mg, respectively. Seated trough cuff blood pressure was measured at baseline, 4, and 8 weeks. Blood pressure reductions with the combinations were greater than the reductions with the monotherapies as shown in Table 3. Amlodipine - Aliskiren 150 mg and 300 mg and amlodipine besylate 5 mg and 10 mg were studied alone and in combination in an 8-week, 1,685-patient, randomized, double-blind, placebo-controlled, multifactorial study. Treatment with aliskiren and amlodipine resulted overall in significantly greater reductions in diastolic and systolic blood pressure compared to the respective monotherapy components as shown in Table 4. ACE inhibitors - Aliskiren has not been studied when added to maximal doses of ACE inhibitors to determine whether aliskiren produces additional blood pressure reduction. - Patients with diabetes with renal disease (defined either by the presence of albuminuria or reduced GFR) were randomized to aliskiren 300 mg daily (n=4296) or placebo (n=4310). All patients were receiving background therapy with an ARB or ACEI. The primary efficacy outcome was the time to the first event of the primary composite endpoint consisting of cardiovascular death, resuscitated sudden death, non-fatal myocardial infarction, non-fatal stroke, unplanned hospitalization for heart failure, onset of end stage renal disease, renal death, and doubling of serum creatinine concentration from baseline sustained for at least one month. After a median follow up of about 32 months, the trial was terminated early for lack of efficacy. Higher risk of renal impairment, hypotension and hyperkalemia was observed in aliskiren compared to placebo treated patients, as shown in the table below. - The risk of stroke (3.4% aliskiren vs 2.7% placebo) and death (8.4% aliskiren vs. 8.0% placebo) were also numerically higher in aliskiren treated patients. # How Supplied - Aliskiren is supplied as a light-pink, biconvex round tablet containing 150 mg of aliskiren, and as a light-red biconvex ovaloid tablet containing 300 mg of aliskiren. Tablets are imprinted with NVR on one side and IL, IU, on the other side of the 150, and 300 mg tablets, respectively. - All strengths are packaged in bottles and unit-dose blister packages (10 strips or 10 tablets) as described below in Table 6. - Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF) [See USP Controlled Room Temperature]. Protect from moisture. - Dispense in original container. ## Storage There is limited information regarding Aliskiren Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Pregnancy - Female patients of child bearing age should be told about the consequences of exposure to Aliskiren during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. - Anaphylactic Reactions and Angioedema - Patients should be advised and told to report immediately any signs or symptoms suggesting a severe allergic reaction (difficulty breathing or swallowing, tightness of the chest, hives, general rash, swelling, itching, dizziness, vomiting, or abdominal pain) or angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physicians. Angioedema, including laryngeal edema, may occur at any time during treatment with Aliskiren. - Symptomatic Hypotension - A patient receiving Aliskiren should be cautioned that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. The patients should be told that if syncope occurs, Aliskiren should be discontinued until the physician has been consulted. - All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope. - Potassium Supplements - A patient receiving Aliskiren should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician. - Relationship to Meals - Patients should establish a routine pattern for taking Aliskiren with regard to meals. High-fat meals decrease absorption substantially. # Precautions with Alcohol - Alcohol-Aliskiren interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Tekturna®[2] # Look-Alike Drug Names - N/A[3] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Aliskiren
e899a8e485cfa69f5bbf5d7abffae247c8e290e5	wikidoc	Alkalosis	Alkalosis # Overview Alkalosis refers to a condition reducing hydrogen ion concentration of arterial blood plasma (alkalemia) through the loss of acids or retention of bicarbonate. Generally alkalosis is said to occur when pH of the blood exceeds 7.45. The opposite condition is acidosis. # Classification More specifically, alkalosis can refer to: - Respiratory alkalosis - Metabolic alkalosis # Causes ## Common Causes The main cause of respiratory alkalosis is hyperventilation, resulting in a loss of carbon dioxide. Compensatory mechanisms for this would include increased dissociation of the carbonic acid buffering intermediate into hydrogen ions, and the related consumption of bicarbonate, both of which would lower blood pH. Metabolic alkalosis can be caused by prolonged vomitting, resulting in a loss of hydrochloric acid with the stomach content. Severe dehydration, and the consumption of alkali are other causes. Compensatory mechanism for metabolic alkalosis involve slowed breathing by the lungs to increase serum carbon dioxide, a condition leaning toward respiratory acidosis. As respiratory acidosis often accompanies the compensation for metabolic alkalosis, and visa versa, a delicate balance is created between these two conditions. ## Causes in Alphabetical Order ## Metabolic Alkalosis - Administration of citrates - After respiratory acidosis - Alkali therapy for stomach problems - Bartter's Syndrome - Conn syndrome - Cushing's Syndrome - Cystic Fibrosis - Diarrhea - Gastric juice drainage - Hepatic coma - Hyperemesis gravidarum - Milk Alkali Syndrome - Mineralcorticoid therapy - Overcorrection of acidosis with bicarbonates - Renal potassium loss - Vomiting # Pathophysiology ## Metabolic Alkalosis It is thought that metabolic is the result of the shift of hydrogen ions intracellularly, reduced blood volume, loss of gastric acid, and extracellular volume expansion. ### Shift of hydrogen ions intracellularly - Electrolyte imbalance like hypokalemia causes a shift of hydrogen ions intracellular caused defect of protons and an increase in bicarbonate ion concentration. ### Reduced Blood volume - Volume depletion results in reduced glomerular filtration rate. This stimulates the production of Angiotensin II, sympathetic nervous system activation, and aldosterone secretion. - The sympathetic nervous system and angiotensin II causes increased absorption of sodium in proximal convoluted tubules via sodium hydrogen exchange. - Aldosterone acts primarily on the principal cells of the late distal convoluted tubule and collecting ducts. It causes sodium and water retention in exchange for potassium and hydrogen ions secretion. The loop and thiazide diuretics also act by similar mechanisms of action. ### Loss of Gastric acid - The hydrogen ions are primarily secreted in large amounts in the gastric juice. The hydrogen ions are secreted via active transport mediated by hydrogen potassium ATPase pump. Excessive vomiting causes loss of a large amount of gastric juice with depletion of hydrogen and chloride from the body. ### Extracellular volume expansion - Primary hyperaldosteronism (Conn’s syndrome) causes increased sodium reabsorption with the resultant increase in extracellular volume. The patient may be hypertensive or normotensive. The hypokalemia caused by the action of aldosterone causes increased reabsorption of sodium bicarbonate in the proximal convoluted tubule with a worsening of metabolic alkalosis. ## Respiratory Alkalosis - It is thought that the respiratory alkalosis is the result of hyperventilation. The causes of hyperventilation can be due to increased stimulation of the medullary respiratory center, low oxygen tension in blood, lung pathologies, and iatrogenic. The stimulation of the respiratory center occurs due to stroke, head injury, metabolic disease like hyperthyroidism, emotional stress, panic attack, and side effect of medications like aspirin. The low oxygen tension in the blood causes stimulation of the respiratory center resulting in hyperventilation and hypocapnia. The acute attack of asthma, COPD, pulmonary embolism can cause tachypnea with increase loss of carbon dioxide. # Epidemiology and Demographics - The prevalence of alkalosis ranges from 32,727 to 80,000 per 100,000 in hospitalized patients with an acid-base metabolic disorder. - The prevalence of alkalosis is approximately 44,046 per 100,000 in acute heart failure patients. # Differential Diagnosis Differential diagnosis of metabolic alkalosis is as follow: Differential diagnosis of respiratory alkalosis is as follow:	Alkalosis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Alkalosis refers to a condition reducing hydrogen ion concentration of arterial blood plasma (alkalemia) through the loss of acids or retention of bicarbonate. Generally alkalosis is said to occur when pH of the blood exceeds 7.45. The opposite condition is acidosis. # Classification More specifically, alkalosis can refer to: - Respiratory alkalosis - Metabolic alkalosis # Causes ## Common Causes The main cause of respiratory alkalosis is hyperventilation, resulting in a loss of carbon dioxide. Compensatory mechanisms for this would include increased dissociation of the carbonic acid buffering intermediate into hydrogen ions, and the related consumption of bicarbonate, both of which would lower blood pH. Metabolic alkalosis can be caused by prolonged vomitting, resulting in a loss of hydrochloric acid with the stomach content. Severe dehydration, and the consumption of alkali are other causes. Compensatory mechanism for metabolic alkalosis involve slowed breathing by the lungs to increase serum carbon dioxide, a condition leaning toward respiratory acidosis. As respiratory acidosis often accompanies the compensation for metabolic alkalosis, and visa versa, a delicate balance is created between these two conditions. ## Causes in Alphabetical Order ## Metabolic Alkalosis - Administration of citrates - After respiratory acidosis - Alkali therapy for stomach problems - Bartter's Syndrome - Conn syndrome - Cushing's Syndrome - Cystic Fibrosis - Diarrhea - Gastric juice drainage - Hepatic coma - Hyperemesis gravidarum - Milk Alkali Syndrome - Mineralcorticoid therapy - Overcorrection of acidosis with bicarbonates - Renal potassium loss - Vomiting # Pathophysiology ## Metabolic Alkalosis It is thought that metabolic [alkalosis] is the result of the shift of hydrogen ions intracellularly, reduced blood volume, loss of gastric acid, and extracellular volume expansion. ### Shift of hydrogen ions intracellularly - Electrolyte imbalance like hypokalemia causes a shift of hydrogen ions intracellular caused defect of protons and an increase in bicarbonate ion concentration. [1] ### Reduced Blood volume - Volume depletion results in reduced glomerular filtration rate. This stimulates the production of Angiotensin II, sympathetic nervous system activation, and aldosterone secretion. - The sympathetic nervous system and angiotensin II causes increased absorption of sodium in proximal convoluted tubules via sodium hydrogen exchange. - Aldosterone acts primarily on the principal cells of the late distal convoluted tubule and collecting ducts. It causes sodium and water retention in exchange for potassium and hydrogen ions secretion. The loop and thiazide diuretics also act by similar mechanisms of action.[2] ### Loss of Gastric acid - The hydrogen ions are primarily secreted in large amounts in the gastric juice. The hydrogen ions are secreted via active transport mediated by hydrogen potassium ATPase pump. Excessive vomiting causes loss of a large amount of gastric juice with depletion of hydrogen and chloride from the body. ### Extracellular volume expansion - Primary hyperaldosteronism (Conn’s syndrome) causes increased sodium reabsorption with the resultant increase in extracellular volume. The patient may be hypertensive or normotensive. The hypokalemia caused by the action of aldosterone causes increased reabsorption of sodium bicarbonate in the proximal convoluted tubule with a worsening of metabolic alkalosis. ## Respiratory Alkalosis - It is thought that the respiratory alkalosis is the result of hyperventilation. The causes of hyperventilation can be due to increased stimulation of the medullary respiratory center, low oxygen tension in blood, lung pathologies, and iatrogenic. The stimulation of the respiratory center occurs due to stroke, head injury, metabolic disease like hyperthyroidism, emotional stress, panic attack, and side effect of medications like aspirin. The low oxygen tension in the blood causes stimulation of the respiratory center resulting in hyperventilation and hypocapnia. The acute attack of asthma, COPD, pulmonary embolism can cause tachypnea with increase loss of carbon dioxide. # Epidemiology and Demographics - The prevalence of alkalosis ranges from 32,727 to 80,000 per 100,000 in hospitalized patients with an acid-base metabolic disorder. [3][4] - The prevalence of alkalosis is approximately 44,046 per 100,000 in acute heart failure patients. [5] # Differential Diagnosis Differential diagnosis of metabolic alkalosis is as follow: Differential diagnosis of respiratory alkalosis is as follow:	https://www.wikidoc.org/index.php/Alkalosis
7da6171b0b3e8c8bab23dae69117f3ac796dc5b8	wikidoc	Vaginitis	Vaginitis # Overview Vulvovaginitis, a common condition for which women seek medical care, accounts for greater than 10% of visits made to providers of women's health care. It is characterized by symptoms that cause itching, irritation, burning, and abnormal vaginal discharge. The three most common causes of vaginal discharge in women within the reproductive age group are bacterial vaginosis, candida vulvovaginitis, and trichomoniasis. All patients with vulvovaginitis present with common symptoms like vaginal discharge, itching, and dysuria. Diagnosis of vulvovaginitis requires a detailed history of the patient's symptoms, as well as her sexual history, both of which facilitate an accurate diagnosis. Physical examination of the external genitalia and speculum examination should focus on documenting the nature of the discharge, the presence of any vulvar or labial lesions, foreign body, presence of cervical inflammation, cervical lesions, and any cervical motion or adnexal tenderness with a bimanual examination. It is essential to rule out pelvic inflammatory disease and cervical lesions as the cause of vaginal discharge. Estimation of vaginal pH and vaginal smear wet mount examination constitute the initial diagnostic test, which helps differentiate among common etiologies. Treatment of vulvovaginitis includes medical therapy targeted against the causative pathogen and counseling on hygiene, voiding techniques, and sexual practices. The prognosis is good in most patients, though a minority of patients experience recurrence. # Classification Based on the etiology vaginitis is classified into the following: - Candida Vulvovaginitis - Bacterial vaginosis - Trichomoniasis - Atrophic vaginitis - Aerobic vagnitis # Differential Diagnosis The differential diagnosis for patients presenting with vaginal discharge includes the following considerations: ## Diagnosis and Treatment The following table summarizes the diagnosis and management of common vaginitis conditions:	Vaginitis For patient information click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2], Dima Nimri, M.D. [3], Aravind Kuchkuntla, M.B.B.S[4] # Overview Vulvovaginitis, a common condition for which women seek medical care, accounts for greater than 10% of visits made to providers of women's health care.[1] It is characterized by symptoms that cause itching, irritation, burning, and abnormal vaginal discharge. The three most common causes of vaginal discharge in women within the reproductive age group are bacterial vaginosis, candida vulvovaginitis, and trichomoniasis. All patients with vulvovaginitis present with common symptoms like vaginal discharge, itching, and dysuria. Diagnosis of vulvovaginitis requires a detailed history of the patient's symptoms, as well as her sexual history, both of which facilitate an accurate diagnosis. Physical examination of the external genitalia and speculum examination should focus on documenting the nature of the discharge, the presence of any vulvar or labial lesions, foreign body, presence of cervical inflammation, cervical lesions, and any cervical motion or adnexal tenderness with a bimanual examination. It is essential to rule out pelvic inflammatory disease and cervical lesions as the cause of vaginal discharge. Estimation of vaginal pH and vaginal smear wet mount examination constitute the initial diagnostic test, which helps differentiate among common etiologies. Treatment of vulvovaginitis includes medical therapy targeted against the causative pathogen and counseling on hygiene, voiding techniques, and sexual practices. The prognosis is good in most patients, though a minority of patients experience recurrence. # Classification Based on the etiology vaginitis is classified into the following: - Candida Vulvovaginitis - Bacterial vaginosis - Trichomoniasis - Atrophic vaginitis - Aerobic vagnitis # Differential Diagnosis The differential diagnosis for patients presenting with vaginal discharge includes the following considerations: ## Diagnosis and Treatment The following table summarizes the diagnosis and management of common vaginitis conditions:[4]	https://www.wikidoc.org/index.php/Allergic_vaginitis
cdf9c43c07fec306c15fd7d413b6cf4e6a78347a	wikidoc	Allergies	Allergies An allergy may be a damaging immune response by the body to a substance, especially pollen, fur, a particular food, or dust, to which it has become hypersensitive. # Theoretical allergies Def. a "disorder of the immune system causing adverse reactions to substances (allergens) not harmful to most and marked by the body's production of histamines and associated with atopy, anaphylaxis, and asthma" is called an allergy. # Pollen allergy in Europe "The allergenic content of the atmosphere varies according to climate, geography and vegetation. Data on the presence and prevalence of allergenic airborne pollens, obtained from both aerobiological studies and allergological investigations, make it possible to design pollen calendars with the approximate flowering period of the plants in the sampling area." "Aerobiological and allergological studies show that the pollen map of Europe is changing also as a result of cultural factors (for example, importation of plants such as birch and cypress for urban parklands), greater international travel (e.g. colonization by ragweed in France, northern Italy, Austria, Hungary etc.) and climate change. In this regard, the higher frequency of weather extremes, like thunderstorms, and increasing episodes of long range transport of allergenic pollen represent new challenges for researchers." "Pollen allergy has a remarkable clinical impact all over Europe, and there is a body of evidence suggesting that the prevalence of respiratory allergic reactions induced by pollens in Europe has been on the increase in the past decades (1–6)." "The prevalence of pollen allergy is presently estimated to be up 40%. Exposure to allergens represents a key factor among the environmental determinants of asthma, which include air pollution (8)." "In Europe, the main pollination period covers about half the year, from spring to autumn, and the distribution of airborne pollen taxa of allergological interest is related to five vegetational areas": - Arctic: birch - Central: deciduous forest, birch, grasses - Eastern: grasses, mugwort, ragweed - Mountains: grasses (with a pollination season delayed by three-four weeks in comparison with areas at sea level) - Mediterranean: Parietaria, olive trees, grasses and also cypress # Gramineae "The grass family (Gramineae) comprises more than 600 genera and over 10 000 species, of which more than 400 herbaceous, wind-pollinated plants are found in Europe (15). The most abundant airborne grass pollen originates from tall meadow grasses such as timothy (Phleum pratense), orchard grass (Dactylis glomerata), or meadow foxtail (Alopecurus pratensis). Cultivated rye (Secale cereale), which has remarkably high pollen production, is another potent source of allergens (16). However, with very few exceptions, all grass-pollen types show a very high degree of cross reactivity (17, 18)." "Grass allergens induce mostly nasal and conjunctival symptoms. Djukanovic et al. (21) provided evidence that natural exposure to grass pollen may exacerbate asthma, and, so, induce an inflammatory response involving T cells, mast cells and eosinophils." # Trees "The most allergenic tree pollen is produced by birch (Betula) in north, central, and eastern Europe, and by Olive (Olea europaea) as also cypress (Cupressus) in the Mediterranen regions." Fagales "comprises three families: Betulaceae, including the genera Betula (birch) and Alnus (alder); Corylaceae, including the genera Corylus (hazel), Carpinus (hornbeam), and Ostrya (hopbeam); Fagaceae, including the genera Quercus (oak), Fagus (beech), and Castanea (sweet chestnut)." A "high cross-reactivity exists within cupressacace family (Cupressus, Juniperus and Cryptomeria) and between Cupressacae and Taxacee (53–56) which have quite different pollination seasons, overlapping or preceding the cypress pollination period. This observation is of clinical importance, where cross-reacting and earlier flowering plants (C. arizonica is one of the most spread in several European areas) are well represented." # Weeds "Parietaria is the main allergenic genus of the Urticaceae (nettle) family. The major allergens of both species are small glycoproteins with molecular weights ranging between 10 and 14 kDa, with high cross-reactivity (61). Recent findings showed that P judaica pollen contains an aminopeptidase which is able to disrupt epithelium barrier, enhancing the delivery of allergenic protein to dendritic cells (62)." An "increasing body of evidence support use of sublingual specific immunotherapy for subjects with symptoms due to Parietaria pollen (74, 75)." "The Compositae (Asteraceae), is one of the largest plant families with almost 20 000 species. Ragweed (Ambrosia) and mugwort (Artemisia) are the most involved in pollenosis" # Pathogenetics "In the context of allergy, pollen grains have been simply regarded as allergen carriers, and little attention has been devoted to the nonprotein compounds of pollen. However, individuals are rarely exposed to pure allergens, but rather to particles releasing the allergen, such as pollen grains or pollen-derived granules (107–109). Notably, lipids are major components of pollen exine and exsudate (108). In addition, long chain unsaturated fatty acids in pollen, such as linolenic acid, serve as precursors for the biosynthesis of several plant hormones, such as dinor isoprostanes, recently termed phytoprostanes. These phytoprostanes are formed non-enzymatically via autooxidation in plants and structurally resemble prostaglandins and isoprostanes in humans (110–112)." "It has been demonstrated recently that pollen grain, under physiological exposure conditions, releases not only allergens but also bioactive lipids that activate human neutrophils and eosinophils in vitro (115–117). Moreover, intact grains of pollen induce activation and maturation of dendritic cells in vitro, suggesting that pollen can act not only as allergen carrier but also as an adjuvant in the induction phase of the allergic immune response (118)." # Pollen allergen carrying small particles "In the early 1970s, Busse et al. (125) were the first to demonstrate the presence of specific ragweed allergens carried by small particles. By different techniques, this observation was confirmed and extended, first to ragweed-pollen allergen (126–128). Subsequently, the same phenomenon was observed in grass-pollen allergen (129–131), red oak-pollen allergen (132), Japanese cedar-pollen allergen (133), and birch-pollen allergen (134). With cascade impactors or other instruments that fractionate the sampled airborne matter into several size classes, it was established that these small particles range from some micrometers, i.e. 2–10 μm (paucimicronic) to less than 1 μm (submicronic) sizes (127, 128, 131, 133, 134)."	Allergies Editor-In-Chief: Henry A. Hoff An allergy may be a damaging immune response by the body to a substance, especially pollen, fur, a particular food, or dust, to which it has become hypersensitive. # Theoretical allergies Def. a "disorder of the immune system causing adverse reactions to substances (allergens) not harmful to most and marked by the body's production of histamines and associated with atopy, anaphylaxis, and asthma"[1] is called an allergy. # Pollen allergy in Europe "The allergenic content of the atmosphere varies according to climate, geography and vegetation. Data on the presence and prevalence of allergenic airborne pollens, obtained from both aerobiological studies and allergological investigations, make it possible to design pollen calendars with the approximate flowering period of the plants in the sampling area."[2] "Aerobiological and allergological studies show that the pollen map of Europe is changing also as a result of cultural factors (for example, importation of plants such as birch and cypress for urban parklands), greater international travel (e.g. colonization by ragweed in France, northern Italy, Austria, Hungary etc.) and climate change. In this regard, the higher frequency of weather extremes, like thunderstorms, and increasing episodes of long range transport of allergenic pollen represent new challenges for researchers."[2] "Pollen allergy has a remarkable clinical impact all over Europe, and there is a body of evidence suggesting that the prevalence of respiratory allergic reactions induced by pollens in Europe has been on the increase in the past decades (1–6)."[2] "The prevalence of pollen allergy is presently estimated to be up 40%. Exposure to allergens represents a key factor among the environmental determinants of asthma, which include air pollution (8)."[2] "In Europe, the main pollination period covers about half the year, from spring to autumn, and the distribution of airborne pollen taxa of allergological interest is related to five vegetational areas":[2] - Arctic: birch - Central: deciduous forest, birch, grasses - Eastern: grasses, mugwort, ragweed - Mountains: grasses (with a pollination season delayed by three-four weeks in comparison with areas at sea level) - Mediterranean: Parietaria, olive trees, grasses and also cypress # Gramineae "The grass family (Gramineae) comprises more than 600 genera and over 10 000 species, of which more than 400 herbaceous, wind-pollinated plants are found in Europe (15). The most abundant airborne grass pollen originates from tall meadow grasses such as timothy (Phleum pratense), orchard grass (Dactylis glomerata), or meadow foxtail (Alopecurus pratensis). Cultivated rye (Secale cereale), which has remarkably high pollen production, is another potent source of allergens (16). However, with very few exceptions, all grass-pollen types show a very high degree of cross reactivity (17, 18)."[2] "Grass allergens induce mostly nasal and conjunctival symptoms. Djukanovic et al. (21) provided evidence that natural exposure to grass pollen may exacerbate asthma, and, so, induce an inflammatory response involving T cells, mast cells and eosinophils."[2] # Trees "The most allergenic tree pollen is produced by birch (Betula) in north, central, and eastern Europe, and by Olive (Olea europaea) as also cypress (Cupressus) in the Mediterranen regions."[2] Fagales "comprises three families: Betulaceae, including the genera Betula (birch) and Alnus (alder); Corylaceae, including the genera Corylus (hazel), Carpinus (hornbeam), and Ostrya (hopbeam); Fagaceae, including the genera Quercus (oak), Fagus (beech), and Castanea (sweet chestnut)."[2] A "high cross-reactivity exists within cupressacace family (Cupressus, Juniperus and Cryptomeria) and between Cupressacae and Taxacee (53–56) which have quite different pollination seasons, overlapping or preceding the cypress pollination period. This observation is of clinical importance, where cross-reacting and earlier flowering plants (C. arizonica is one of the most spread in several European areas) are well represented."[2] # Weeds "Parietaria is the main allergenic genus of the Urticaceae (nettle) family. [...] The major allergens of both species are small glycoproteins with molecular weights ranging between 10 and 14 kDa, with high cross-reactivity (61). Recent findings showed that P judaica pollen contains an aminopeptidase which is able to disrupt epithelium barrier, enhancing the delivery of allergenic protein to dendritic cells (62)."[2] An "increasing body of evidence support use of sublingual specific immunotherapy for subjects with symptoms due to Parietaria pollen (74, 75)."[2] "The Compositae (Asteraceae), is one of the largest plant families with almost 20 000 species. Ragweed (Ambrosia) and mugwort (Artemisia) are the most involved in pollenosis"[2] # Pathogenetics "In the context of allergy, pollen grains have been simply regarded as allergen carriers, and little attention has been devoted to the nonprotein compounds of pollen. However, individuals are rarely exposed to pure allergens, but rather to particles releasing the allergen, such as pollen grains or pollen-derived granules (107–109). Notably, lipids are major components of pollen exine and exsudate (108). In addition, long chain unsaturated fatty acids in pollen, such as linolenic acid, serve as precursors for the biosynthesis of several plant hormones, such as dinor isoprostanes, recently termed phytoprostanes. These phytoprostanes are formed non-enzymatically via autooxidation in plants and structurally resemble prostaglandins and isoprostanes in humans (110–112)."[2] "It has been demonstrated recently that pollen grain, under physiological exposure conditions, releases not only allergens but also bioactive lipids that activate human neutrophils and eosinophils in vitro (115–117). Moreover, intact grains of pollen induce activation and maturation of dendritic cells in vitro, suggesting that pollen can act not only as allergen carrier but also as an adjuvant in the induction phase of the allergic immune response (118)."[2] # Pollen allergen carrying small particles "In the early 1970s, Busse et al. (125) were the first to demonstrate the presence of specific ragweed allergens carried by small particles. By different techniques, this observation was confirmed and extended, first to ragweed-pollen allergen (126–128). Subsequently, the same phenomenon was observed in grass-pollen allergen (129–131), red oak-pollen allergen (132), Japanese cedar-pollen allergen (133), and birch-pollen allergen (134). With cascade impactors or other instruments that fractionate the sampled airborne matter into several size classes, it was established that these small particles range from some micrometers, i.e. 2–10 μm (paucimicronic) to less than 1 μm (submicronic) sizes (127, 128, 131, 133, 134)."[2]	https://www.wikidoc.org/index.php/Allergies
4f78fd5b21346569a4c1705e890e5db147510962	wikidoc	Allodynia	Allodynia Allodynia, meaning "other pain", is an exaggerated response to otherwise non-noxious stimuli and can be either static or mechanical. Allodynia is not referred pain, but can occur in other areas than the one stimulated; it is also dysesthetic. For example, a person with allodynia may perceive light pressure or the movement of clothes over the skin as painful, whereas a healthy individual will not feel pain. # Pathophysiology One explanation of the mechanism for allodynia is that the associated nerve damage results in decreased firing thresholds of nociceptive fibres. Alternatively, it has been postulated that peripheral nerve injury could induce collateral sprouting of non-nociceptive primary afferent neurones, such as A-beta low threshold mechanoreceptors, into the superficial (nociceptive) laminae in the dorsal horn of the spinal cord. These collateral branches could form functional contacts with nociceptive second order neurons, normally innervated by C-fibre nociceptive primary afferent neurones and transmit an innocous input as noxious. # Associated disturbances Allodynia is a clinical feature of pain conditions such as migraine, postherpetic neuralgia, fibromyalgia, and neuropathies. # Types There are different kinds or types of allodynia: - Mechanical allodynia (also known as tactile allodynia) - Pain from light touch/pressure applied to the skin in the area of the damaged nerve. Mechanical allodynia can be dynamic or static. Also it has been shown that lowering barometric pressure aggravates mechanical allodynia in a rat model of neuropathic pain - Thermal (heat or cold) allodynia - Pain from normally mild skin temperatures in the affected area.	Allodynia Allodynia, meaning "other pain", is an exaggerated response to otherwise non-noxious stimuli and can be either static or mechanical. Allodynia is not referred pain, but can occur in other areas than the one stimulated; it is also dysesthetic. For example, a person with allodynia may perceive light pressure or the movement of clothes over the skin as painful, whereas a healthy individual will not feel pain. # Pathophysiology One explanation of the mechanism for allodynia is that the associated nerve damage results in decreased firing thresholds of nociceptive fibres. Alternatively, it has been postulated that peripheral nerve injury could induce collateral sprouting of non-nociceptive primary afferent neurones, such as A-beta low threshold mechanoreceptors, into the superficial (nociceptive) laminae in the dorsal horn of the spinal cord. These collateral branches could form functional contacts with nociceptive second order neurons, normally innervated by C-fibre nociceptive primary afferent neurones and transmit an innocous input as noxious. # Associated disturbances Allodynia is a clinical feature of pain conditions such as migraine, postherpetic neuralgia, fibromyalgia, and neuropathies. # Types There are different kinds or types of allodynia: - Mechanical allodynia (also known as tactile allodynia) - Pain from light touch/pressure applied to the skin in the area of the damaged nerve. Mechanical allodynia can be dynamic or static. Also it has been shown that lowering barometric pressure aggravates mechanical allodynia in a rat model of neuropathic pain - Thermal (heat or cold) allodynia - Pain from normally mild skin temperatures in the affected area. Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Allodynia
e4d536a8c53aebec4d3b4c2fbe13dc4ff405b9b6	wikidoc	Allograft	Allograft # Overview An allograft or allogeneic transplant or homograft is a transplant in which transplanted cells, tissues, or organs are sourced from a genetically non-identical member of the same species. Most human tissue and organ transplants are allografts. In contrast, a transplant from another species is called a xenograft. When a transplanted organ or tissue from a genetically identical donor, i.e., an identical twin, is termed an isograft. Finally, when a tissue is transplanted from one site to another on the same patient, it is termed an autograft. Allografts and xenografts will be recognised by the recipient's immune system as foreign and will therefore be attacked in a process termed rejection. This does not occur in autografts or true isografts, although in practice, transplants between identical twins are usually covered with immunosuppressants in case they are not 100% genetically identical. # Tissue allografts A variety of tissue and organs types can be used for allografts. These include: - skin transplants - corneal transplants - heart transplants - liver transplants - kidney transplants - bone marrow transplants - bone allograft - ligament or tendon allograft	Allograft Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview An allograft or allogeneic transplant or homograft is a transplant in which transplanted cells, tissues, or organs are sourced from a genetically non-identical member of the same species. Most human tissue and organ transplants are allografts. In contrast, a transplant from another species is called a xenograft. When a transplanted organ or tissue from a genetically identical donor, i.e., an identical twin, is termed an isograft. Finally, when a tissue is transplanted from one site to another on the same patient, it is termed an autograft. Allografts and xenografts will be recognised by the recipient's immune system as foreign and will therefore be attacked in a process termed rejection. This does not occur in autografts or true isografts, although in practice, transplants between identical twins are usually covered with immunosuppressants in case they are not 100% genetically identical. # Tissue allografts A variety of tissue and organs types can be used for allografts. These include: - skin transplants - corneal transplants - heart transplants - liver transplants - kidney transplants - bone marrow transplants - bone allograft - ligament or tendon allograft	https://www.wikidoc.org/index.php/Allogeneic
e50d600eb0e71cfe80664222f646eb3041530f68	wikidoc	Allophone	Allophone In phonetics, an allophone is one of several similar phones that belong to the same phoneme. A phone is a sound that has a definite shape as a sound wave, while a phoneme is a basic group of sounds that can distinguish words (i.e. changing one phoneme in a word can produce another word); speakers of a particular language perceive a phoneme as a single distinctive sound in that language. Thus an allophone is a phone considered as a member of one phoneme. We may distinguish complementary allophones, which are distributed regularly within the idiolect of the same speaker according to phonetic environment, from free variants, which are a matter of personal habit or regional accent. In the case of complementary allophones, each allophone is used in a specific phonetic context and many times there is some sort of phonological process. Not all phonemes have significantly different allophones, but there are always minor differences in articulation from one piece of speech to the next. # Examples in English For example, Template:IPA as in pin and Template:IPA as in spin are allophones for the phoneme Template:IPA in the English language because they occur in complementary distribution. English speakers generally treat these as the same sound, but they are different; the first is aspirated and the second is unaspirated (plain). Plain Template:IPA also occurs as the p in cap Template:IPA, or the second p in paper Template:IPA. In contexts where plain p appears in English (e.g. spin, cap, paper), speakers may hear it as b since the p in these contexts lacks the burst of air found with the p in pin. Besides, there are many different allophones in English, like lack of plosion, nasal plosion, partial devoicing of sonorants, complete devoicing of sonorants, partial devoicing of obstruents, lengthening and shortening vowels, dentalisation and retruction. Certain Chinese languages treat these two phones differently, for example in Mandarin, Template:IPA is always written b in pinyin; thus, they are not allophones. English-speaking people may become aware of the difference between two allophones of the phoneme t when they consider the pronunciations of the following phrases: - Night rate: IPA Template:IPA - Nitrate: IPA Template:IPA # "Elsewhere" condition When there are two allophones for one phoneme in a given language, linguists use the "elsewhere condition" to determine which is the original allophone and which is the variation. For example, to determine when oral and nasalized vowels occur in English, the pattern is noted that all vowels are oral, except when the vowel comes before a nasal within the same syllable. Therefore, according to the "elsewhere condition", nasalized vowels are allophones of their oral counterparts.	Allophone In phonetics, an allophone is one of several similar phones that belong to the same phoneme. A phone is a sound that has a definite shape as a sound wave, while a phoneme is a basic group of sounds that can distinguish words (i.e. changing one phoneme in a word can produce another word); speakers of a particular language perceive a phoneme as a single distinctive sound in that language. Thus an allophone is a phone considered as a member of one phoneme. We may distinguish complementary allophones, which are distributed regularly within the idiolect of the same speaker according to phonetic environment, from free variants, which are a matter of personal habit or regional accent. In the case of complementary allophones, each allophone is used in a specific phonetic context and many times there is some sort of phonological process. Not all phonemes have significantly different allophones, but there are always minor differences in articulation from one piece of speech to the next. # Examples in English For example, Template:IPA as in pin and Template:IPA as in spin are allophones for the phoneme Template:IPA in the English language because they occur in complementary distribution. English speakers generally treat these as the same sound, but they are different; the first is aspirated and the second is unaspirated (plain). Plain Template:IPA also occurs as the p in cap Template:IPA, or the second p in paper Template:IPA. In contexts where plain p appears in English (e.g. spin, cap, paper), speakers may hear it as b since the p in these contexts lacks the burst of air found with the p in pin. Besides, there are many different allophones in English, like lack of plosion, nasal plosion, partial devoicing of sonorants, complete devoicing of sonorants, partial devoicing of obstruents, lengthening and shortening vowels, dentalisation and retruction. Certain Chinese languages treat these two phones differently, for example in Mandarin, Template:IPA is always written b in pinyin; thus, they are not allophones. English-speaking people may become aware of the difference between two allophones of the phoneme t when they consider the pronunciations of the following phrases: - Night rate: IPA Template:IPA - Nitrate: IPA Template:IPA # "Elsewhere" condition When there are two allophones for one phoneme in a given language, linguists use the "elsewhere condition" to determine which is the original allophone and which is the variation. For example, to determine when oral and nasalized vowels occur in English, the pattern is noted that all vowels are oral, except when the vowel comes before a nasal within the same syllable. Therefore, according to the "elsewhere condition", nasalized vowels are allophones of their oral counterparts.	https://www.wikidoc.org/index.php/Allophone
97c2e2d1960ca90b0b6e92047a4104805fd994c3	wikidoc	Alloplant	Alloplant # Overview Alloplant is an experimental, chemically processed biomaterial used for transplantation. It is made primarily from deceased human flesh. The tissue is subjected to radiating sterilization and is being studied for possible regeneration of tissues of the recipient. The concept has been rejected by the general medical community. # Use in eye transplant The primary advocate of alloplants is the Russian surgeon Ernest Muldashev. In 2000, he claimed to have successfully transplanted a human eye onto a blind woman using a harvested cornea and retina combined with an alloplant. The operation happened after he and his colleagues made a trip to Tibet. According to Muldashev, this voyage gave him an innate and unprecedented understanding of certain worldly ideas and concepts. He claims he witnessed paranormal phenomena involving "time mirrors" in search of forefather "giants". The claim was widely rejected by the scientific and medical community. Although they avoid the use of the term "quack", doctors interviewed by The Guardian maintain that such transplants are medically impossible and not supported by peer-reviewed medical evidence. Nevertheless, the patient in question claims to have developed the ability to distinguish shapes, colors, and even letters with her transplanted eye.	Alloplant # Overview Alloplant is an experimental, chemically processed biomaterial used for transplantation. It is made primarily from deceased human flesh. The tissue is subjected to radiating sterilization and is being studied for possible regeneration of tissues of the recipient. The concept has been rejected by the general medical community. # Use in eye transplant The primary advocate of alloplants is the Russian surgeon Ernest Muldashev. In 2000, he claimed to have successfully transplanted a human eye onto a blind woman using a harvested cornea and retina combined with an alloplant. The operation happened after he and his colleagues made a trip to Tibet. According to Muldashev, this voyage gave him an innate and unprecedented understanding of certain worldly ideas and concepts. He claims he witnessed paranormal phenomena involving "time mirrors" in search of forefather "giants". The claim was widely rejected by the scientific and medical community. Although they avoid the use of the term "quack", doctors interviewed by The Guardian maintain that such transplants are medically impossible and not supported by peer-reviewed medical evidence. Nevertheless, the patient in question claims to have developed the ability to distinguish shapes, colors, and even letters with her transplanted eye.[1]	https://www.wikidoc.org/index.php/Alloplant
f650f30d2de2c6bb5c5f442325ad1279626fbdf7	wikidoc	Allotropy	Allotropy Allotropy (Gr. allos, other, and tropos, manner) is a behavior exhibited by certain chemical elements: these elements can exist in two or more different forms, known as allotropes of that element. In each different allotrope, the element's atoms are bonded together in a different manner. Allotropes are different structural modifications of an element. The phenomenon of allotropy is sometimes also called allotropism. For example, the element carbon has two common allotropes: diamond, where the carbon atoms are bonded together in a tetrahedral lattice arrangement, and graphite, where the carbon atoms are bonded together in sheets of a hexagonal lattice. Note that allotropy refers only to different forms of an element within the same phase or state of matter (i.e. different solid, liquid or gas forms) - the changes of state between solid, liquid and gas in themselves are not considered allotropy. For some elements, allotropes have different molecular formulae which can persist in different phases - for example, the two allotropes of oxygen (dioxygen, O2 and ozone, O3), can both exist in the solid, liquid and gaseous states. Conversely, some elements do not maintain distinct allotropes in different phases: for example phosphorus has numerous solid allotropes, which all revert to the same P4 form when melted to the liquid state. # History The concept of allotropy was originally proposed in 1841 by the Swedish scientist Baron Jons Jakob Berzelius (1779-1848) who offered no explanation. After the acceptance of Avogadro's hypothesis in 1860 it was understood that elements could exist as polyatomic molecules, and the two allotropes of oxygen were recognized as O2 and O3. In the early 20th century it was recognized that other cases such as carbon were due to differences in crystal structure. By 1912, Ostwald noted that the allotropy of elements is just a special case of the phenomenon of polymorphism known for compounds, and proposed that the terms allotrope and allotropy be abandoned and replaced by polymorph and polymorphism. Although many other chemists have repeated this advice, IUPAC and most chemistry texts still favour the usage of allotrope and allotropy for elements only. # Differences in properties of an element's allotropes Allotropes are different structural forms of the same element and can exhibit quite different physical properties and chemical behaviours. The change between allotropic forms is triggered by the same forces that affect other structures, i.e. pressure, light, and temperature. Therefore the stability of the particular allotropes depends on particular conditions. For instance, iron changes from a body-centered cubic structure (ferrite) to a face-centered cubic structure (austenite) above 906 °C, and tin undergoes a transformation known as tin pest from a metallic phase to a semiconductor phase below 13.2 °C. # List of allotropes Typically, elements capable of variable coordination number and/or oxidation states tend to exhibit greater numbers of allotropic forms. Another contributing factor is the ability of an element to catenate. Allotropes are typically more noticeable in non-metals and metalloids. Nevertheless, metals tend to have many allotropes. Examples of allotropes include: ## Non-metals Carbon: - diamond - an extremely hard, transparent crystal, with the carbon atoms arranged in a tetrahedral lattice. A poor electrical conductor. An excellent thermal conductor. - graphite - a soft, black, flaky solid, a moderate electrical conductor. The C atoms are bonded in flat hexagonal lattices, which are then layered in sheets. - amorphous carbon - fullerenes, including "buckyballs", such as C60, and carbon nanotubes Phosphorus: - White phosphorus - crystalline solid P4 - Red phosphorus - polymeric solid - Scarlet phosphorus - Violet phosphorus - Black phosphorus - semiconductor, analogous to graphite - Diphosphorus Oxygen: - dioxygen, O2 - colorless - ozone, O3 - blue - tetraoxygen, O4 - metastable - octaoxygen, O8 - red Nitrogen: - dinitrogen - tetranitrogen - trinitrogen - two solid forms: one hexagonal close-packed and the other alpha cubic Sulfur: - Plastic (amorphous) sulfur - polymeric solid - Rhombic sulfur - large crystals composed of S8 molecules - Monoclinic sulfur - fine needle-like crystals - Other ring molecules such as S7 and S12 Selenium: - "Red selenium," cyclo-Se8 - Gray selenium, polymeric Se - Black selenium ## Metalloids Boron - amorphous boron - brown powder - crystalline boron - black, hard (9.3 on Mohs' scale), and a weak conductor at room temperature. Silicon - amorphous silicon - brown powder - nanocrystalline silicon - similar to the amorphous silicon - crystalline silicon - has a metallic luster and a grayish color. Single crystals of crystalline silicon can be grown with a process known as the Czochralski process Arsenic: - Yellow arsenic - molecular non-metallic As4 - Gray arsenic, polymeric As (metalloid) - Black arsenic (metalloid) and several similar other ones. Antimony: - blue-white antimony - the stable form (metalloid) - yellow antimony (non-metallic) - black antimony (non-metallic) - (a fourth one too) Polonium has two metallic allotropes. ## Metals Tin - grey tin (alpha-tin) - white tin (beta tin) - rhombic tin (gamma) Iron - ferrite (alpha iron) - forms below 770°C (the Curie point, Tc ); the iron becomes magnetic in its alpha form; BCC - beta - forms below 912°C (BCC) - gamma - forms below 1401°C; face centred cubic (FCC) crystal structure - delta - forms from cooling down molten iron below 1535°C; has a body-centred cubic (BCC) crystal structure Titanium has two allotropes Strontium has three allotropes ### Lantanides and actinides - Plutonium has six distinct solid allotropes under "normal" pressures. Their densities vary within a ratio of some 4:3, which vastly complicates all kinds of work with the metal (particularly casting, machining, and storage). A seventh plutonium allotrope exists at very high pressures, which adds further difficulties in exotic applications. - Ytterbium has three allotropes - Terbium has two crystalline allotropes - Promethium has two allotropic forms - Curium has 3 allotropes (also Americium, Berkelium, Californium do)	Allotropy Allotropy (Gr. allos, other, and tropos, manner) is a behavior exhibited by certain chemical elements: these elements can exist in two or more different forms, known as allotropes of that element. In each different allotrope, the element's atoms are bonded together in a different manner. Allotropes are different structural modifications of an element.[1] The phenomenon of allotropy is sometimes also called allotropism. For example, the element carbon has two common allotropes: diamond, where the carbon atoms are bonded together in a tetrahedral lattice arrangement, and graphite, where the carbon atoms are bonded together in sheets of a hexagonal lattice. Note that allotropy refers only to different forms of an element within the same phase or state of matter (i.e. different solid, liquid or gas forms) - the changes of state between solid, liquid and gas in themselves are not considered allotropy. For some elements, allotropes have different molecular formulae which can persist in different phases - for example, the two allotropes of oxygen (dioxygen, O2 and ozone, O3), can both exist in the solid, liquid and gaseous states. Conversely, some elements do not maintain distinct allotropes in different phases: for example phosphorus has numerous solid allotropes, which all revert to the same P4 form when melted to the liquid state. # History The concept of allotropy was originally proposed in 1841 by the Swedish scientist Baron Jons Jakob Berzelius (1779-1848) who offered no explanation.[2] After the acceptance of Avogadro's hypothesis in 1860 it was understood that elements could exist as polyatomic molecules, and the two allotropes of oxygen were recognized as O2 and O3. In the early 20th century it was recognized that other cases such as carbon were due to differences in crystal structure. By 1912, Ostwald noted that the allotropy of elements is just a special case of the phenomenon of polymorphism known for compounds, and proposed that the terms allotrope and allotropy be abandoned and replaced by polymorph and polymorphism. Although many other chemists have repeated this advice, IUPAC and most chemistry texts still favour the usage of allotrope and allotropy for elements only. # Differences in properties of an element's allotropes Allotropes are different structural forms of the same element and can exhibit quite different physical properties and chemical behaviours. The change between allotropic forms is triggered by the same forces that affect other structures, i.e. pressure, light, and temperature. Therefore the stability of the particular allotropes depends on particular conditions. For instance, iron changes from a body-centered cubic structure (ferrite) to a face-centered cubic structure (austenite) above 906 °C, and tin undergoes a transformation known as tin pest from a metallic phase to a semiconductor phase below 13.2 °C. # List of allotropes Typically, elements capable of variable coordination number and/or oxidation states tend to exhibit greater numbers of allotropic forms. Another contributing factor is the ability of an element to catenate. Allotropes are typically more noticeable in non-metals and metalloids. Nevertheless, metals tend to have many allotropes. Examples of allotropes include: ## Non-metals Carbon: - diamond - an extremely hard, transparent crystal, with the carbon atoms arranged in a tetrahedral lattice. A poor electrical conductor. An excellent thermal conductor. - graphite - a soft, black, flaky solid, a moderate electrical conductor. The C atoms are bonded in flat hexagonal lattices, which are then layered in sheets. - amorphous carbon - fullerenes, including "buckyballs", such as C60, and carbon nanotubes Phosphorus: - White phosphorus - crystalline solid P4 - Red phosphorus - polymeric solid - Scarlet phosphorus - Violet phosphorus - Black phosphorus - semiconductor, analogous to graphite - Diphosphorus Oxygen: - dioxygen, O2 - colorless - ozone, O3 - blue - tetraoxygen, O4 - metastable - octaoxygen, O8 - red Nitrogen: - dinitrogen - tetranitrogen - trinitrogen - two solid forms: one hexagonal close-packed and the other alpha cubic Sulfur: - Plastic (amorphous) sulfur - polymeric solid - Rhombic sulfur - large crystals composed of S8 molecules - Monoclinic sulfur - fine needle-like crystals - Other ring molecules such as S7 and S12 Selenium: - "Red selenium," cyclo-Se8 - Gray selenium, polymeric Se - Black selenium ## Metalloids Boron - amorphous boron - brown powder - crystalline boron - black, hard (9.3 on Mohs' scale), and a weak conductor at room temperature. Silicon - amorphous silicon - brown powder - nanocrystalline silicon - similar to the amorphous silicon - crystalline silicon - has a metallic luster and a grayish color. Single crystals of crystalline silicon can be grown with a process known as the Czochralski process Arsenic: - Yellow arsenic - molecular non-metallic As4 - Gray arsenic, polymeric As (metalloid) - Black arsenic (metalloid) and several similar other ones. Antimony: - blue-white antimony - the stable form (metalloid) - yellow antimony (non-metallic) - black antimony (non-metallic) - (a fourth one too) Polonium has two metallic allotropes. ## Metals Tin - grey tin (alpha-tin) - white tin (beta tin) - rhombic tin (gamma) Iron - ferrite (alpha iron) - forms below 770°C (the Curie point, Tc ); the iron becomes magnetic in its alpha form; BCC - beta - forms below 912°C (BCC) - gamma - forms below 1401°C; face centred cubic (FCC) crystal structure - delta - forms from cooling down molten iron below 1535°C; has a body-centred cubic (BCC) crystal structure Titanium has two allotropes Strontium has three allotropes ### Lantanides and actinides - Plutonium has six distinct solid allotropes under "normal" pressures. Their densities vary within a ratio of some 4:3, which vastly complicates all kinds of work with the metal (particularly casting, machining, and storage). A seventh plutonium allotrope exists at very high pressures, which adds further difficulties in exotic applications.[citation needed] - Ytterbium has three allotropes - Terbium has two crystalline allotropes - Promethium has two allotropic forms - Curium has 3 allotropes (also Americium, Berkelium, Californium do) [3]	https://www.wikidoc.org/index.php/Allotrope
bdf3ed10d1f6d77d6ff4be64efc21f20e6e92e86	wikidoc	Almitrine	Almitrine # Overview Almitrine (marketed as Duxil by Servier) is a diphenylmethylpiperazine derivative classified as a respiratory stimulant by the ATC. It enhances respiration by acting as an agonist of peripheral chemoreceptors located on the carotid bodies. The drug increases arterial oxygen tension while decreasing arterial carbon dioxide tension in patients with chronic obstructive pulmonary disease. It may also prove useful in the treatment of nocturnal oxygen desaturation without impairing the quality of sleep. A significant literature exists for this compound, including over 60 papers that Medline labels as reviews. The clinical efficacy of almitrine-raubasine combination therapy for age related cerebral disorders and functional rehabilitation after stroke has been reviewed by Allain and Bentué-Ferrer. They summarize two studies in which almitrine-raubasine improved some symptoms significantly more than placebo, especially in vascular cases. Their paper also suggests that other studies have shown a beneficial effect of this compound on neurosensory vascular disorders, specifically chorioretinal dysfunctions (visual symptomatology) and vertigo associated with electronystagmographic modifications. This paper further claims that the dosage and tolerance of the compound have been confirmed in a French multi-center study of 5,361 outpatients.	Almitrine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Almitrine (marketed as Duxil by Servier) is a diphenylmethylpiperazine derivative classified as a respiratory stimulant by the ATC. It enhances respiration by acting as an agonist of peripheral chemoreceptors located on the carotid bodies. The drug increases arterial oxygen tension while decreasing arterial carbon dioxide tension in patients with chronic obstructive pulmonary disease. It may also prove useful in the treatment of nocturnal oxygen desaturation without impairing the quality of sleep. A significant literature exists for this compound, including over 60 papers that Medline labels as reviews. The clinical efficacy of almitrine-raubasine combination therapy for age related cerebral disorders and functional rehabilitation after stroke has been reviewed by Allain and Bentué-Ferrer.[1] They summarize two studies in which almitrine-raubasine improved some symptoms significantly more than placebo, especially in vascular cases. Their paper also suggests that other studies have shown a beneficial effect of this compound on neurosensory vascular disorders, specifically chorioretinal dysfunctions (visual symptomatology) and vertigo associated with electronystagmographic modifications. This paper further claims that the dosage and tolerance of the compound have been confirmed in a French multi-center study of 5,361 outpatients.	https://www.wikidoc.org/index.php/Almitrine
76c26bc443c19660cd5ee7d019910fe286532c7b	wikidoc	Aloe vera	Aloe vera Aloe vera (syn. A. barbadensis Mill., A. vulgaris Lam.) is a species of Aloe, native to northern Africa. It is a stemless or very short-stemmed succulent plant growing to 80-100 cm tall, spreading by offsets and root sprouts. The leaves are lanceolate, thick and fleshy, green to grey-green, with a serrated margin. The flowers are produced on a spike up to 90 cm tall, each flower pendulous, with a yellow tubular corolla 2-3 cm long. # Cultivation Aloe vera is relatively easy to care for in cultivation in frost-free climates. The species requires well-drained sandy potting soil in moderate light. If planted in pot or other containers ensure sufficient drainage with drainage holes.The use of a good quality commercial potting mix to which extra perlite, granite grit, or coarse sand are added is recommended. Alternatively, pre-packaged 'cacti and succulent mixes' may also be used. Potted plants should be allowed to completely dry prior to re-watering. During winter, A. vera may become dormant, during which little moisture is required. In areas that receive frost or snow the species is best kept indoors or in heated glasshouses. A. vera has a long history of cultivation throughout the drier tropical and subtropical regions of the world, both as an ornamental plant and for herbal medicine. For its herbal and medicinal uses, many of which are shared with related species, see Aloe. ## Food preservative Researchers at the University of Miguel Hernández in Alicante, Spain, have developed a gel based on A. vera that prolongs the conservation of fresh produce, such as fresh fruit and legumes. This gel is tasteless, colorless and odorless. This natural product is a safe and environmentally friendly alternative to synthetic preservatives such as sulfur dioxide. The study showed that grapes at 1°C coated with this gel could be preserved for 35 days against 7 days for untreated grapes. According to the researchers, this gel operates through a combination of mechanics (Serrano et al., 2006), forming a protective layer against the oxygen and moisture of the air and inhibiting, through its various antibiotic and antifungal compounds, the action of micro-organisms that cause foodborne illnesses. ## Medicinal uses A. vera has been used externally to treat various skin conditions such as cuts, burns and eczema. It is alleged that sap from Aloe vera eases pain and reduces inflammation. Evidence on the effects of A. vera sap on wound healing, however, is contradictory (Vogler and Ernst, 1999). A study performed in the 1990s showed that the healing time of a moderate to severe burn was reduced when the wound was treated on a regular basis with Aloe vera gel, compared to the healing of the wound covered in a gauze bandage (Farrar, 2005). In contrast, another study suggested wounds to which Aloe vera gel was applied were significantly slower to heal (Schmidt and Greenspoon, 1991). A. vera's beneficial properties may be attributed to mucopolysaccharides present in the inner gel of the leaf, especially acemannan (acetylated mannans). An injectable form of acemannan manufactured and marketed by Carrington Laboratories as Acemannan Immunostimulant™ has been approved in the USA for treatment of fibrosarcoma (a type of cancer) in dogs and cats after clinical trials. It has not been approved for use by humans, and, although it is not a drug, its sale is controlled and it can only be obtained through a veterinary doctor. Cosmetic companies add sap or other derivatives from A. vera to products such as makeup, moisturisers, soaps, sunscreens, shampoos and lotions, though the effectiveness of Aloe vera in these products remain unknown. A. vera gel is also alleged to be useful for dry skin conditions, especially eczema around the eyes and sensitive facial skin. An article published in the British Journal of General Practice suggests that A. vera is effective at treating athlete's foot. Whether or not it promotes wound healing is unknown, and even though there are some promising results, clinical effectiveness of oral or topical A. vera remains unclear at present. Aloe vera juice may help some people with ulcerative colitis, an inflammatory bowel disease. # Parts that can be used The lower leaf of the plant is used for medicinal purpose. If the lower leaf is sliced open, the gel obtained can be applied on the affected area of the skin. Leaves and seeds are the two edible parts of Aloe Vera. ## Use in foods In Japan Aloe Vera is commonly used as an ingredient in commercially available yogurt. There are also many companies which produce Aloe Vera beverages. In Pakistan, the plant has been used for centuries as a carminative and digestive aid. The dried gel is mixed with seeds of various herbs and consumed after a meal. Pashtuns in the Hazara region of the North West Frontier Province have been using Aloe Vera for centuries to improve physical endurance, probably due to the high nutrient content of the gel. People in Rajastahn state of India prepare vegetable out of Aloe Vera along with fenugreek seeds. People in Tamil Nadu, another state of India prepare a curry using Aloe Vera which is taken along with Indian bread or rice. Some popular beverages, such as SoBe's Strawberry Daiquirí, contain Aloe Vera. In Mexico smoothies made out of Aloe Vera are fairly common. # Notes "Aloe Vera Drinks"..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}	Aloe vera Template:No citations Aloe vera (syn. A. barbadensis Mill., A. vulgaris Lam.) is a species of Aloe, native to northern Africa. It is a stemless or very short-stemmed succulent plant growing to 80-100 cm tall, spreading by offsets and root sprouts. The leaves are lanceolate, thick and fleshy, green to grey-green, with a serrated margin. The flowers are produced on a spike up to 90 cm tall, each flower pendulous, with a yellow tubular corolla 2-3 cm long. # Cultivation Aloe vera is relatively easy to care for in cultivation in frost-free climates. The species requires well-drained sandy potting soil in moderate light. If planted in pot or other containers ensure sufficient drainage with drainage holes.The use of a good quality commercial potting mix to which extra perlite, granite grit, or coarse sand are added is recommended. Alternatively, pre-packaged 'cacti and succulent mixes' may also be used. Potted plants should be allowed to completely dry prior to re-watering. During winter, A. vera may become dormant, during which little moisture is required. In areas that receive frost or snow the species is best kept indoors or in heated glasshouses[citation needed]. A. vera has a long history of cultivation throughout the drier tropical and subtropical regions of the world, both as an ornamental plant and for herbal medicine. For its herbal and medicinal uses, many of which are shared with related species, see Aloe. ## Food preservative Researchers at the University of Miguel Hernández in Alicante, Spain, have developed a gel based on A. vera that prolongs the conservation of fresh produce, such as fresh fruit and legumes. This gel is tasteless, colorless and odorless. This natural product is a safe and environmentally friendly alternative to synthetic preservatives such as sulfur dioxide. The study showed that grapes at 1°C coated with this gel could be preserved for 35 days against 7 days for untreated grapes. According to the researchers, this gel operates through a combination of mechanics (Serrano et al., 2006), forming a protective layer against the oxygen and moisture of the air and inhibiting, through its various antibiotic and antifungal compounds, the action of micro-organisms that cause foodborne illnesses. ## Medicinal uses A. vera has been used externally to treat various skin conditions such as cuts, burns and eczema. It is alleged that sap from Aloe vera eases pain and reduces inflammation. Evidence on the effects of A. vera sap on wound healing, however, is contradictory (Vogler and Ernst, 1999). A study performed in the 1990s showed that the healing time of a moderate to severe burn was reduced when the wound was treated on a regular basis with Aloe vera gel, compared to the healing of the wound covered in a gauze bandage (Farrar, 2005). In contrast, another study suggested wounds to which Aloe vera gel was applied were significantly slower to heal (Schmidt and Greenspoon, 1991). A. vera's beneficial properties may be attributed to mucopolysaccharides present in the inner gel of the leaf, especially acemannan (acetylated mannans). An injectable form of acemannan manufactured and marketed by Carrington Laboratories as Acemannan Immunostimulant™ has been approved in the USA for treatment of fibrosarcoma (a type of cancer) in dogs and cats after clinical trials. It has not been approved for use by humans, and, although it is not a drug, its sale is controlled and it can only be obtained through a veterinary doctor. Cosmetic companies add sap or other derivatives from A. vera to products such as makeup, moisturisers, soaps, sunscreens, shampoos and lotions, though the effectiveness of Aloe vera in these products remain unknown. A. vera gel is also alleged to be useful for dry skin conditions, especially eczema around the eyes and sensitive facial skin[citation needed]. An article published in the British Journal of General Practice suggests that A. vera is effective at treating athlete's foot[citation needed]. Whether or not it promotes wound healing is unknown, and even though there are some promising results, clinical effectiveness of oral or topical A. vera remains unclear at present. Aloe vera juice may help some people with ulcerative colitis, an inflammatory bowel disease. # Parts that can be used The lower leaf of the plant is used for medicinal purpose. If the lower leaf is sliced open, the gel obtained can be applied on the affected area of the skin. Leaves and seeds are the two edible parts of Aloe Vera[citation needed]. ## Use in foods In Japan Aloe Vera is commonly used as an ingredient in commercially available yogurt. There are also many companies which produce Aloe Vera beverages.[1] In Pakistan, the plant has been used for centuries as a carminative and digestive aid. The dried gel is mixed with seeds of various herbs and consumed after a meal.[citation needed] Pashtuns in the Hazara region of the North West Frontier Province have been using Aloe Vera for centuries to improve physical endurance, probably due to the high nutrient content of the gel.[citation needed] People in Rajastahn state of India prepare vegetable out of Aloe Vera along with fenugreek seeds.[citation needed] People in Tamil Nadu, another state of India prepare a curry using Aloe Vera which is taken along with Indian bread or rice.[citation needed] Some popular beverages, such as SoBe's Strawberry Daiquirí, contain Aloe Vera. In Mexico smoothies made out of Aloe Vera are fairly common.[citation needed] # Notes - ↑ "Aloe Vera Drinks"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}	https://www.wikidoc.org/index.php/Aloe_Vera
56f4fa6c8162078957c6149f77e0d00109db97e2	wikidoc	Bisacodyl	Bisacodyl # 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. NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies. # Overview Bisacodyl is a gastrointestinal agent, laxative and stimulant that is FDA approved for the treatment of constipation. Common adverse reactions include abdominal colic, abdominal discomfort, diarrhea and proctitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Tablet Forms= - For temporary relief of occasional constipation and irregularity - This product generally produces a bowel movement in 6 to 12 hours - Take with a glass of water ### Suppository Form - For the relief of occasional constipation. - Bowel movement is generally produced in 15 minutes to 1 hour. - See chart below for dose - Remove foil wrapper - Insert suppository well up into the rectum as indicated, and retain it about 15 to 20 minutes - In the presence of anal fissures or hemorrhoids, suppositories should be coated at the tip with petroleum jelly. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Bisacodyl in adult patients. ### Non–Guideline-Supported Use - Bowel care - Spinal cord injury - Neurogenic bowel # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Bisacodyl in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Bisacodyl in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Bisacodyl in pediatric patients. # Contraindications There is limited information regarding Bisacodyl Contraindications in the drug label. # Warnings ### Oral Form - If you cannot swallow without chewing. - Stomach pain, nausea, or vomiting - A sudden change in bowel habits that lasts more than 2 weeks. - Do not chew or crush tablet(s) - Do not use within 1 hour after taking an antacid or milk - It may cause stomach discomfort, faintness and cramps - You have rectal bleeding or no bowel movement after using this product. These could be signs of a serious condition. - You need to use a laxative for more than 1 week - Ask a health professional before use. - In case of overdose, get medical help or contact a Poison Control Center right away. ### Suppository Form - For rectal use only - Do not use laxative products for a period longer than one week unless directed by a doctor - Ask a doctor before use if you have - Abdominal pain, nausea or vomiting - A sudden change in bowel habits that lasts longer than 2 weeks - Stop use and ask a doctor if rectal bleeding occurs or you fail to have a bowel movement after using a laxative. These may be signs of a serious condition. - Keep out of reach of children - If swallowed, get medical help or contact a Poison Control Center right away. # Adverse Reactions ## Clinical Trials Experience - Nausea, vomiting, abdominal pain - It may cause stomach discomfort, faintness and cramps - A sudden change in bowel habits that lasts more than 2 weeks ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Bisacodyl in the drug label. # Drug Interactions There is limited information regarding Drug Interactions of Bisacodyl in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Ask a health professional before use. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bisacodyl in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Bisacodyl during labor and delivery. ### Nursing Mothers - Ask a health professional before use. ### Pediatric Use There is no FDA guidance on the use of Bisacodyl with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Bisacodyl with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Bisacodyl with respect to specific gender populations. ### Race There is no FDA guidance on the use of Bisacodyl with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Bisacodyl in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Bisacodyl in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Bisacodyl in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Bisacodyl in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Suppository ### Monitoring There is limited information regarding Monitoring of Bisacodyl in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Bisacodyl in the drug label. # Overdosage There is limited information regarding Chronic Overdose of Bisacodyl in the drug label. # Pharmacology ## Mechanism of Action - Bisacodyl works by stimulating enteric nerves to cause colonic mass movements (contractions). It is also a contact laxative; it increases fluid and NaCl secretion. Action of bisacodyl on small intestine is negligible; stimulant laxatives mainly promote evacuation of the colon ## Structure ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Bisacodyl in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Bisacodyl in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Bisacodyl in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Bisacodyl in the drug label. # How Supplied There is limited information regarding Bisacodyl How Supplied in the drug label. ## Storage - Store between 20º-25ºC (68º-77ºF) # Images ## Drug Images ## Package and Label Display Panel ## Oral Form= Compare to the active ingredient in Dulcolax®* Laxative Bisacodyl Stimulant laxative for gentle, dependable overnight relief Comfort Coated TABLETS 5 mg Each - This product is not manufactured or distributed by Boehringer Ingelheim Pharmaceuticals, Inc., distributor of Dulcolax® Laxative. PROUDLY DISTRIBUTED BY: VALU MERCHANDISERS, CO. 5000 KANSAS AVE KANSAS CITY, KS 66106 TAMPER EVIDENT: DO NOT USE IF CARTON IS OPENED OR IF BLISTER UNIT IS TORN, BROKEN OR SHOWS ANY SIGNS OF TAMPERING. KEEP OUTER CARTON FOR COMPLETE WARNINGS AND PRODUCT INFORMATION. ### Suppository Form NDC 0713-0109-08 G&W® BISAC-EVAC™ Bisacodyl USP LAXATIVE 8 SUPPOSITORIES 10 mg each # Patient Counseling Information There is limited information regarding Patient Counseling Information of Bisacodyl in the drug label. # Precautions with Alcohol - Alcohol-Bisacodyl interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Dulcolax Correctol Doxidan - Biscolax® - Bisac-Evac® - Alophen® - Fleet Bisacodyl® - Feen-A-Mint® # Look-Alike Drug Names - Dulcolax®(bisacodyl) - Dulcolax® (docusate sodium) # Drug Shortage Status # Price	Bisacodyl Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies. # Overview Bisacodyl is a gastrointestinal agent, laxative and stimulant that is FDA approved for the treatment of constipation. Common adverse reactions include abdominal colic, abdominal discomfort, diarrhea and proctitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Tablet Forms= - For temporary relief of occasional constipation and irregularity - This product generally produces a bowel movement in 6 to 12 hours - Take with a glass of water ### Suppository Form - For the relief of occasional constipation. - Bowel movement is generally produced in 15 minutes to 1 hour. - See chart below for dose - Remove foil wrapper - Insert suppository well up into the rectum as indicated, and retain it about 15 to 20 minutes - In the presence of anal fissures or hemorrhoids, suppositories should be coated at the tip with petroleum jelly. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Bisacodyl in adult patients. ### Non–Guideline-Supported Use - Bowel care - Spinal cord injury - Neurogenic bowel # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Bisacodyl in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Bisacodyl in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Bisacodyl in pediatric patients. # Contraindications There is limited information regarding Bisacodyl Contraindications in the drug label. # Warnings ### Oral Form - If you cannot swallow without chewing. - Stomach pain, nausea, or vomiting - A sudden change in bowel habits that lasts more than 2 weeks. - Do not chew or crush tablet(s) - Do not use within 1 hour after taking an antacid or milk - It may cause stomach discomfort, faintness and cramps - You have rectal bleeding or no bowel movement after using this product. These could be signs of a serious condition. - You need to use a laxative for more than 1 week - Ask a health professional before use. - In case of overdose, get medical help or contact a Poison Control Center right away. ### Suppository Form - For rectal use only - Do not use laxative products for a period longer than one week unless directed by a doctor - Ask a doctor before use if you have - Abdominal pain, nausea or vomiting - A sudden change in bowel habits that lasts longer than 2 weeks - Stop use and ask a doctor if rectal bleeding occurs or you fail to have a bowel movement after using a laxative. These may be signs of a serious condition. - Keep out of reach of children - If swallowed, get medical help or contact a Poison Control Center right away. # Adverse Reactions ## Clinical Trials Experience - Nausea, vomiting, abdominal pain - It may cause stomach discomfort, faintness and cramps - A sudden change in bowel habits that lasts more than 2 weeks ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Bisacodyl in the drug label. # Drug Interactions There is limited information regarding Drug Interactions of Bisacodyl in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Ask a health professional before use. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bisacodyl in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Bisacodyl during labor and delivery. ### Nursing Mothers - Ask a health professional before use. ### Pediatric Use There is no FDA guidance on the use of Bisacodyl with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Bisacodyl with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Bisacodyl with respect to specific gender populations. ### Race There is no FDA guidance on the use of Bisacodyl with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Bisacodyl in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Bisacodyl in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Bisacodyl in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Bisacodyl in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Suppository ### Monitoring There is limited information regarding Monitoring of Bisacodyl in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Bisacodyl in the drug label. # Overdosage There is limited information regarding Chronic Overdose of Bisacodyl in the drug label. # Pharmacology ## Mechanism of Action - Bisacodyl works by stimulating enteric nerves to cause colonic mass movements (contractions). It is also a contact laxative; it increases fluid and NaCl secretion. Action of bisacodyl on small intestine is negligible; stimulant laxatives mainly promote evacuation of the colon ## Structure ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Bisacodyl in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Bisacodyl in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Bisacodyl in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Bisacodyl in the drug label. # How Supplied There is limited information regarding Bisacodyl How Supplied in the drug label. ## Storage - Store between 20º-25ºC (68º-77ºF) # Images ## Drug Images ## Package and Label Display Panel ## Oral Form= Compare to the active ingredient in Dulcolax®* Laxative Bisacodyl Stimulant laxative for gentle, dependable overnight relief Comfort Coated TABLETS 5 mg Each - This product is not manufactured or distributed by Boehringer Ingelheim Pharmaceuticals, Inc., distributor of Dulcolax® Laxative. PROUDLY DISTRIBUTED BY: VALU MERCHANDISERS, CO. 5000 KANSAS AVE KANSAS CITY, KS 66106 TAMPER EVIDENT: DO NOT USE IF CARTON IS OPENED OR IF BLISTER UNIT IS TORN, BROKEN OR SHOWS ANY SIGNS OF TAMPERING. KEEP OUTER CARTON FOR COMPLETE WARNINGS AND PRODUCT INFORMATION. ### Suppository Form NDC 0713-0109-08 G&W® BISAC-EVAC™ Bisacodyl USP LAXATIVE 8 SUPPOSITORIES 10 mg each # Patient Counseling Information There is limited information regarding Patient Counseling Information of Bisacodyl in the drug label. # Precautions with Alcohol - Alcohol-Bisacodyl interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Dulcolax Correctol Doxidan - Biscolax® - Bisac-Evac® - Alophen® - Fleet Bisacodyl® - Feen-A-Mint® # Look-Alike Drug Names - Dulcolax®(bisacodyl) - Dulcolax® (docusate sodium) # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Alophen
3d0cfbf5cdc391a81bb982a379283560838c5838	wikidoc	Alosetron	Alosetron # 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 Alosetron is a selective serotonin 5-HT3 antagonist that is FDA approved for the {{{indicationType}}} of severe diarrhea-predominant irritable bowel syndrome (IBS). There is a Black Box Warning for this drug as shown here. Common adverse reactions include constipation, abdominal pain, nausea, and gastrointestinal discomfort and pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - LOTRONEX is indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have: - chronic IBS symptoms (generally lasting 6 months or longer), - had anatomic or biochemical abnormalities of the gastrointestinal tract excluded, and - not responded adequately to conventional therapy. - Diarrhea-predominant IBS is severe if it includes diarrhea and one or more of the following: - frequent and severe abdominal pain/discomfort, - frequent bowel urgency or fecal incontinence, - disability or restriction of daily activities due to IBS. - Because of infrequent but serious gastrointestinal adverse reactions associated with LOTRONEX, the indication is restricted to those patients for whom the benefit-to-risk balance is most favorable. - Dosing Information - To lower the risk of constipation, LOTRONEX should be started at a dosage of 0.5 mg twice a day. Patients who become constipated at this dosage should stop taking LOTRONEX until the constipation resolves. They may be restarted at 0.5 mg once a day. If constipation recurs at the lower dose, LOTRONEX should be discontinued immediately. - Patients well controlled on 0.5 mg once or twice a day may be maintained on this regimen. If after 4 weeks the dosage is well tolerated but does not adequately control IBS symptoms, then the dosage can be increased to up to 1 mg twice a day. LOTRONEX should be discontinued in patients who have not had adequate control of IBS symptoms after 4 weeks of treatment with 1 mg twice a day. - LOTRONEX can be taken with or without food. - LOTRONEX should be discontinued immediately in patients who develop constipation or signs of ischemic colitis. LOTRONEX should not be restarted in patients who develop ischemic colitis. - Clinical trial and postmarketing experience suggest that debilitated patients or patients taking additional medications that decrease gastrointestinal motility may be at greater risk of serious complications of constipation. Therefore, appropriate caution and follow-up should be exercised if LOTRONEX is prescribed for these patients. - Postmarketing experience suggests that elderly patients may be at greater risk for complications of constipation; therefore, appropriate caution and follow-up should be exercised if LOTRONEX is prescribed for these patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Alosetron in adult patients. ### Non–Guideline-Supported Use - Alosetron 0.5 mg. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Alosetron in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Alosetron in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Alosetron in pediatric patients. # Contraindications - Constipation - LOTRONEX should not be initiated in patients with constipation. - History of Severe Bowel or Hepatic Disorders - LOTRONEX is contraindicated in patients with a history of the following: chronic or severe constipation or sequelae from constipation intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation, and/or adhesions ischemic colitis, impaired intestinal circulation, thrombophlebitis, or hypercoagulable state Crohn's disease or ulcerative colitis diverticulitis severe hepatic impairment - chronic or severe constipation or sequelae from constipation - intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation, and/or adhesions - ischemic colitis, impaired intestinal circulation, thrombophlebitis, or hypercoagulable state - Crohn's disease or ulcerative colitis - diverticulitis - severe hepatic impairment - Lack of Understanding of Patient Acknowledgement Form - LOTRONEX should not be used by patients who are unable to understand or comply with the Patient Acknowledgement Form for LOTRONEX. - Concomitant Use of Fluvoxamine - Concomitant administration of LOTRONEX with fluvoxamine is contraindicated. Fluvoxamine, a known strong inhibitor of CYP1A2, has been shown to increase mean alosetron plasma concentrations (AUC) approximately 6-fold and prolong the half-life by approximately 3-fold. # Warnings ### Precautions - Serious Complications of Constipation - Some patients have experienced serious complications of constipation without warning. - Serious complications of constipation, including obstruction, ileus, impaction, toxic megacolon, and secondary bowel ischemia, have been reported with use of LOTRONEX during clinical trials. Complications of constipation have been reported with use of 1 mg twice daily and with lower doses. A dose response relationship has not been established for serious complications of constipation. The incidence of serious complications of constipation was approximately 0.1% (1 per 1,000 patients) in women receiving either LOTRONEX or placebo. In addition, rare cases of perforation and death have been reported from postmarketing clinical practice. In some cases, complications of constipation required intestinal surgery, including colectomy. Patients who are elderly, debilitated, or taking additional medications that decrease gastrointestinal motility may be at greater risk for complications of constipation. - LOTRONEX should be discontinued immediately in patients who develop constipation . - Ischemic Colitis - Some patients have experienced ischemic colitis without warning. - Ischemic colitis has been reported in patients receiving LOTRONEX in clinical trials as well as during marketed use of the drug. In IBS clinical trials, the cumulative incidence of ischemic colitis in women receiving LOTRONEX was 0.2% (2 per 1,000 patients, 95% confidence interval 1 to 3) through 3 months and was 0.3% (3 per 1,000 patients, 95% confidence interval 1 to 4) through 6 months. Ischemic colitis has been reported with use of 1 mg twice daily and with lower doses. A dose-response relationship has not been established. Ischemic colitis was reported in one patient receiving placebo. The patient experience in controlled clinical trials is insufficient to estimate the incidence of ischemic colitis in patients taking LOTRONEX for longer than 6 months. - LOTRONEX should be discontinued immediately in patients with signs of ischemic colitis such as rectal bleeding, bloody diarrhea, or new or worsening abdominal pain. Because ischemic colitis can be life-threatening, patients with signs or symptoms of ischemic colitis should be evaluated promptly and have appropriate diagnostic testing performed. Treatment with LOTRONEX should not be resumed in patients who develop ischemic colitis. - Prescribing Program for LOTRONEX - To prescribe LOTRONEX, the prescriber must be enrolled in the Prescribing Program for LOTRONEX. To enroll, prescribers must understand the benefits and risks of treatment with LOTRONEX for severe diarrhea-predominant IBS, including the information in the Prescribing Information, Medication Guide, and Patient Acknowledgement Form for LOTRONEX. - To enroll in the Prescribing Program for LOTRONEX, call 1-888-423-5227 or visit www.lotronexppl.com to complete the Prescriber Enrollment Form. # 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. - Patients With Irritable Bowel Syndrome: Table 1 summarizes adverse reactions from 22 repeat-dose studies in patients with IBS who were treated with 1 mg of LOTRONEX twice daily for 8 to 24 weeks. The adverse reactions in Table 1 were reported in 1% or more of patients who received LOTRONEX and occurred more frequently on LOTRONEX than on placebo. A statistically significant difference was observed for constipation in patients treated with LOTRONEX compared to placebo (p<0.0001). - Gastrointestinal: Constipation is a frequent and dose-related side effect of treatment with LOTRONEX. In clinical studies constipation was reported in approximately 29% of patients with IBS treated with LOTRONEX 1 mg twice daily (n = 9,316). This effect was statistically significant compared to placebo (p<;&lt0.0001). Eleven percent (11%) of patients treated with LOTRONEX 1 mg twice daily withdrew from the studies due to constipation. Although the number of patients with IBS treated with LOTRONEX 0.5 mg twice daily is relatively small (n = 243), only 11% of those patients reported constipation and 4% withdrew from clinical studies due to constipation. Among the patients treated with LOTRONEX 1 mg twice daily who reported constipation, 75% reported a single episode and most reports of constipation (70%) occurred during the first month of treatment, with the median time to first report of constipation onset of 8 days. Occurrences of constipation in clinical trials were generally mild to moderate in intensity, transient in nature, and resolved either spontaneously with continued treatment or with an interruption of treatment. However, serious complications of constipation have been reported in clinical studies and in postmarketing experience. In Studies 1 and 2, 9% of patients treated with LOTRONEX reported constipation and 4 consecutive days with no bowel movement. Following interruption of treatment, 78% of the affected patients resumed bowel movements within a 2-day period and were able to re-initiate treatment with LOTRONEX. - Hepatic: A similar incidence in elevation of ALT (>2-fold) was seen in patients receiving LOTRONEX or placebo (1.0% vs. 1.2%). A single case of hepatitis (elevated ALT, AST, alkaline phosphatase, and bilirubin) without jaundice in a patient receiving LOTRONEX was reported in a 12-week study. A causal association with LOTRONEX has not been established. - Long-Term Safety: Patient experience in controlled clinical trials is insufficient to estimate the incidence of ischemic colitis in patients taking LOTRONEX for longer than 6 months. - Women With Severe Diarrhea-Predominant Irritable Bowel Syndrome: Table 2 summarizes the gastrointestinal adverse reactions from 1 repeat-dose study in female patients with severe diarrhea-predominant IBS who were treated for 12 weeks. The adverse reactions in Table 2 were reported in 3% or more of patients who received LOTRONEX and occurred more frequently with LOTRONEX than with placebo. Other events reported in 3% or more of patients who received LOTRONEX and occurring more frequently with LOTRONEX than with placebo included upper respiratory tract infection, viral gastroenteritis, muscle spasms, headaches, and fatigue. - Adverse reactions reported in another study of 701 women with severe diarrhea-predominant IBS were similar to those shown in Table 2. Gastrointestinal adverse reactions reported in 3% or more of patients who received LOTRONEX and occurring more frequently with LOTRONEX than with placebo included constipation (14% and 10% of patients taking LOTRONEX 1 mg twice daily or 0.5 mg as needed, respectively, compared with 2% taking placebo), abdominal pain, nausea, vomiting, and flatulence. Other events reported in 3% or more of patients who received LOTRONEX and occurring more frequently with LOTRONEX than with placebo included nasopharyngitis, sinusitis, upper respiratory tract infection, urinary tract infection, viral gastroenteritis, and cough. - Constipation: Constipation was the most frequent adverse reaction among women with severe diarrhea-predominant IBS represented in Table 2. There was a dose response in the groups treated with LOTRONEX in the number of patients withdrawn due to constipation (2% on placebo, 5% on 0.5 mg once daily, 8% on 1 mg once daily, and 11% on 1 mg twice daily). Among these patients with severe diarrhea-predominant IBS treated with LOTRONEX who reported constipation most (75%) reported one episode which occurred within the first 15 days of treatment and persisted for 4 to 5 days. - Other Events Observed During Clinical Evaluation of LOTRONEX: During its assessment in clinical trials, multiple and single doses of LOTRONEX were administered, resulting in 11,874 subject exposures in 86 completed clinical studies. The conditions, dosages, and duration of exposure to LOTRONEX varied between trials, and the studies included healthy male and female volunteers as well as male and female patients with IBS and other indications. - In the listing that follows, reported adverse reactions were classified using a standardized coding dictionary. Only those events that an investigator believed were possibly related to LOTRONEX, occurred in at least 2 patients, and occurred at a greater frequency during treatment with LOTRONEX than during placebo administration are presented. Serious adverse reactions occurring in at least 1 patient for whom an investigator believed there was reasonable possibility that the event was related to treatment with LOTRONEX and occurring at a greater frequency in patients treated with LOTRONEX than placebo-treated patients are also presented. - In the following listing, events are categorized by body system. Within each body system, events are presented in descending order of frequency. The following definitions are used: infrequent adverse reactions are those occurring on one or more occasion in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring on one or more occasion in fewer than 1/1,000 patients. - Although the events reported occurred during treatment with LOTRONEX, they were not necessarily caused by it. Rare: Quantitative red cell or hemoglobin defects, and hemorrhage. Infrequent: Tachyarrhythmias. Rare: Arrhythmias, increased blood pressure, and extrasystoles. Rare: Contusions and hematomas. Rare: Ear, nose, and throat infections; viral ear, nose, and throat infections; and laryngitis. Rare: Disorders of calcium and phosphate metabolism, hyperglycemia, hypothalamus/pituitary hypofunction, hypoglycemia, and fluid disturbances. Rare: Light sensitivity of eyes. Infrequent: Hyposalivation, dyspeptic symptoms, gastrointestinal spasms, ischemic colitis, and gastrointestinal lesions. Rare: Abnormal tenderness, colitis, gastrointestinal signs and symptoms, proctitis, diverticulitis, positive fecal occult blood, hyperacidity, decreased gastrointestinal motility and ileus, gastrointestinal obstructions, oral symptoms, gastrointestinal intussusception, gastritis, gastroduodenitis, gastroenteritis, and ulcerative colitis. Rare: Abnormal bilirubin levels and cholecystitis. Infrequent: Breathing disorders. Rare: Muscle pain; muscle stiffness, tightness and rigidity; and bone and skeletal pain. Infrequent: Hypnagogic effects. Rare: Memory effects, tremors, dreams, cognitive function disorders, disturbances of sense of taste, disorders of equilibrium, confusion, sedation, and hypoesthesia. Infrequent: Malaise and fatigue, cramps, pain, temperature regulation disturbances. Rare: Burning sensations, hot and cold sensations, cold sensations, and fungal infections. Infrequent: Anxiety. Rare: Depressive moods. Rare: Sexual function disorders, female reproductive tract bleeding and hemorrhage, reproductive infections, and fungal reproductive infections. Infrequent: Sweating and urticaria. Rare: Hair loss and alopecia; acne and folliculitis; disorders of sweat and sebum; allergic skin reaction; eczema; skin infections; dermatitis and dermatosis; and nail disorders. Infrequent: Urinary frequency. Rare: Bladder inflammation; polyuria and diuresis; and urinary tract hemorrhage. ## Postmarketing Experience - In addition to events reported in clinical trials, the following events have been identified during use of LOTRONEX in clinical practice. Because they were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to LOTRONEX. Impaction, perforation, ulceration, small bowel mesenteric ischemia. Headache. Rash. # Drug Interactions - In vivo data suggest that alosetron is primarily metabolized by cytochrome P450 (CYP) 1A2, with minor contributions from CYP3A4 and CYP2C9. Therefore, inducers or inhibitors of these enzymes may change the clearance of alosetron. - CYP1A2 Inhibitors - Fluvoxamine is a known strong inhibitor of CYP1A2 and also inhibits CYP3A4, CYP2C9, and CYP2C19. In a pharmacokinetic study, 40 healthy female subjects received fluvoxamine in escalating doses from 50 to 200 mg/ day for 16 days, with coadministration of alosetron 1 mg on the last day. Fluvoxamine increased mean alosetron plasma concentrations (AUC) approximately 6-fold and prolonged the half-life by approximately 3-fold. Concomitant administration of alosetron and fluvoxamine is contraindicated . - Concomitant administration of alosetron and moderate CYP1A2 inhibitors, including quinolone antibiotics and cimetidine, has not been evaluated, but should be avoided unless clinically necessary because of similar potential drug interactions. - CYP3A4 Inhibitors - Ketoconazole is a known strong inhibitor of CYP3A4. In a pharmacokinetic study, 38 healthy female subjects received ketoconazole 200 mg twice daily for 7 days, with coadministration of alosetron 1 mg on the last day. Ketoconazole increased mean alosetron plasma concentrations (AUC) by 29%. Caution should be used when alosetron and ketoconazole are administered concomitantly. Coadministration of alosetron and strong CYP3A4 inhibitors such as clarithromycin, telithromycin, protease inhibitors, voriconazole, and itraconazole has not been evaluated but should be undertaken with caution because of similar potential drug interactions. The effect of induction or inhibition of other pathways on exposure to alosetron and its metabolites is not known. - Other CYP Enzymes - In vitro human liver microsome studies and an in vivo metabolic probe study demonstrated that alosetron did not inhibit CYP enzymes 3A4, 2C9, or 2C19. In vitro at total drug concentrations 27-fold higher than peak plasma concentrations observed with the 1 mg dose, alosetron inhibited CYP enzymes 1A2 (60%) and 2E1 (50%). In an in vivo metabolic probe study, alosetron did not inhibit CYP2E1 but did produce 30% inhibition of both CYP1A2 and N-acetyltransferase. Although not studied with alosetron, inhibition of N-acetyltransferase may have clinically relevant consequences for drugs such as isoniazid, procainamide, and hydralazine. The effect on CYP1A2 was explored further in a clinical interaction study with theophylline and no effect on metabolism was observed. Another study showed that alosetron had no clinically significant effect on plasma concentrations of the oral contraceptive agents ethinyl estradiol and levonorgestrel (CYP3A4 substrates). A clinical interaction study was also conducted with alosetron and the CYP3A4 substrate cisapride. No significant effects on cisapride metabolism or QT interval were noted. The effects of alosetron on monoamine oxidases and on intestinal first pass secondary to high intraluminal concentrations have not been examined. Based on the above data from in vitro and in vivo studies, it is unlikely that alosetron will inhibit the hepatic metabolic clearance of drugs metabolized by the CYP enzymes 2C9, 2C19, or 2E1. - Alosetron does not appear to induce the major cytochrome P450 drug-metabolizing enzyme 3A. Alosetron also does not appear to induce CYP enzymes 2E1 or 2C19. It is not known whether alosetron might induce other enzymes. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - Reproduction studies have been performed in rats at doses up to 40 mg/kg/day (about 160 times the recommended human dose based on body surface area) and rabbits at oral doses up to 30 mg/kg/day (about 240 times the recommended daily human dose based on body surface area). These studies have revealed no evidence of impaired fertility or harm to the fetus due to alosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, LOTRONEX should be used during pregnancy only if clearly needed Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alosetron in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Alosetron during labor and delivery. ### Nursing Mothers - Alosetron and/or metabolites of alosetron are excreted in the breast milk of lactating rats. It is not known whether alosetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when LOTRONEX is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. Use of LOTRONEX is not recommended in the pediatric population, based upon the risk of serious complications of constipation and ischemic colitis in adults. ### Geriatic Use - In some studies in healthy men or women, plasma concentrations were elevated by approximately 40% in individuals 65 years and older compared to young adults. However, this effect was not consistently observed in men. - Postmarketing experience suggests that elderly patients may be at greater risk for complications of constipation therefore, appropriate caution and follow-up should be exercised if LOTRONEX is prescribed for these patients. ### Gender There is no FDA guidance on the use of Alosetron with respect to specific gender populations. ### Race There is no FDA guidance on the use of Alosetron with respect to specific racial populations. ### Renal Impairment - Renal impairment (creatinine clearance 4 to 56 mL/min) has no effect on the renal elimination of alosetron due to the minor contribution of this pathway to elimination. The effect of renal impairment on metabolite pharmacokinetics and the effect of end-stage renal disease have not been assessed. ### Hepatic Impairment - Due to the extensive hepatic metabolism of alosetron, increased exposure to alosetron and/or its metabolites is likely to occur in patients with hepatic impairment. Alosetron should not be used in patients with severe hepatic impairment and should be used with caution in patients with mild or moderate hepatic impairment. - A single 1 mg oral dose of alosetron was administered to 1 female and 5 male patients with moderate hepatic impairment (Child-Pugh score of 7 to 9) and to 1 female and 2 male patients with severe hepatic impairment (Child-Pugh score of >9). In comparison with historical data from healthy subjects, patients with severe hepatic impairment displayed higher systemic exposure to alosetron. The female with severe hepatic impairment displayed approximately 14-fold higher exposure, while the female with moderate hepatic impairment displayed approximately 1.6-fold higher exposure, than healthy females. Due to the small number of subjects and high intersubject variability in the pharmacokinetic findings, no definitive quantitative conclusions can be made. However, due to the greater exposure to alosetron in the female with severe hepatic impairment, alosetron should not be used in females with severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Alosetron in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Alosetron in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Alosetron in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Alosetron in the drug label. # Overdosage ## Acute Overdose - There is no specific antidote for overdose of LOTRONEX. Patients should be managed with appropriate supportive therapy. Individual oral doses as large as 16 mg have been administered in clinical studies without significant adverse reactions. This dose is 8 times higher than the recommended total daily dose. Inhibition of the metabolic elimination and reduced first pass of other drugs might occur with overdoses of LOTRONEX. ## Chronic Overdose There is limited information regarding Chronic Overdose of Alosetron in the drug label. # Pharmacology ## Mechanism of Action - Alosetron is a potent and selective 5-HT3 receptor antagonist. 5-HT3 receptors are ligand-gated cation channels that are extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations. Activation of these channels and the resulting neuronal depolarization affect the regulation of visceral pain, colonic transit, and gastrointestinal secretions, processes that relate to the pathophysiology of IBS. 5-HT3 receptor antagonists such as alosetron inhibit activation of non-selective cation channels, which results in the modulation of the enteric nervous system. - The cause of IBS is unknown. IBS is characterized by visceral hypersensitivity and hyperactivity of the gastrointestinal tract, which lead to abnormal sensations of pain and motor activity. Following distention of the rectum, patients with IBS exhibit pain and discomfort at lower volumes than healthy volunteers. Following such distention, alosetron reduced pain and exaggerated motor responses, possibly due to blockade of 5-HT3 receptors. ## Structure - The active ingredient in LOTRONEX Tablets is alosetron hydrochloride (HCl), a potent and selective antagonist of the serotonin 5-HT3 receptor type. Chemically, alosetron is designated as 2,3,4,5-tetrahydro-5-methyl-2--1H-pyridoindol-1-one, monohydrochloride. Alosetron is achiral and has the empirical formula C17H18N4OHCl, representing a molecular weight of 330.8. Alosetron is a white to beige solid that has a solubility of 61 mg/mL in water, 42 mg/mL in 0.1M hydrochloric acid, 0.3 mg/mL in pH 6 phosphate buffer, and <;&lt0.1 mg/mL in pH 8 phosphate buffer. The chemical structure of alosetron is: - LOTRONEX Tablets are supplied for oral administration as 0.5 mg (white) and 1 mg (blue) tablets. The 0.5 mg tablet contains 0.562 mg alosetron HCl equivalent to 0.5 mg alosetron, and the 1 mg tablet contains 1.124 mg alosetron HCl equivalent to 1 mg of alosetron. Each tablet also contains the inactive ingredients lactose (anhydrous), magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The white film coat for the 0.5 mg tablet contains hypromellose, titanium dioxide, and triacetin. The blue film coat for the 1 mg tablet contains hypromellose, titanium dioxide, triacetin, and indigo carmine. ## Pharmacodynamics - In healthy volunteers and patients with IBS, alosetron (2 mg orally, twice daily for 8 days) increased colonic transit time without affecting orocecal transit time. In healthy volunteers, alosetron also increased basal jejunal water and sodium absorption after a single 4 mg dose. In patients with IBS, multiple oral dosages of alosetron (4 mg twice daily for 6.5 days) significantly increased colonic compliance. - Single oral doses of alosetron administered to healthy men produced a dose-dependent reduction in the flare response seen after intradermal injection of serotonin. Urinary 6-β-hydroxycortisol excretion decreased by 52% in elderly subjects after 27.5 days of alosetron 2 mg administered orally twice daily. This decrease was not statistically significant. In another study utilizing alosetron 1 mg administered orally twice daily for 4 days, there was a significant decrease in urinary 6-β-hydroxycortisol excretion. However, there was no change in the ratio of 6-β-hydroxycortisol to cortisol, indicating a possible decrease in cortisol production. The clinical significance of these findings is unknown. ## Pharmacokinetics - The pharmacokinetics of alosetron have been studied after single oral doses ranging from 0.05 to 16 mg in healthy men. The pharmacokinetics of alosetron have also been evaluated in healthy women and men and in patients with IBS after repeated oral dosages ranging from 1 mg twice daily to 8 mg twice daily. - Absorption: Alosetron was rapidly absorbed after oral administration with a mean absolute bioavailability of approximately 50% to 60% (approximate range, 30% to >90%). After administration of radiolabeled alosetron, only 1% of the dose was recovered in the feces as unchanged drug. Following oral administration of a 1 mg alosetron dose to young men, a peak plasma concentration of approximately 5 ng/mL occurred at 1 hour. In young women, the mean peak plasma concentration was approximately 9 ng/mL, with a similar time to peak. - Plasma concentrations were 30% to 50% lower and less variable in men compared to women given the same oral dose. Population pharmacokinetic analysis in IBS patients confirmed that alosetron concentrations were influenced by gender (27% lower in men). - Food Effects: Alosetron absorption is decreased by approximately 25% by co-administration with food, with a mean delay in time to peak concentration of 15 minutes. - Distribution: Alosetron demonstrates a volume of distribution of approximately 65 to 95 L. Plasma protein binding is 82% over a concentration range of 20 to 4,000 ng/mL. - Metabolism and Elimination: Plasma concentrations of alosetron increase proportionately with increasing single oral doses up to 8 mg and more than proportionately at a single oral dose of 16 mg. Twice-daily oral dosing of alosetron does not result in accumulation. The terminal elimination half-life of alosetron is approximately 1.5 hours (plasma clearance is approximately 600 mL/min). Population pharmacokinetic analysis in patients with IBS confirmed that alosetron clearance is minimally influenced by doses up to 8 mg. - Renal elimination of unchanged alosetron accounts for only 13% of the dose. Renal clearance is approximately 112 mL/min. - A study with 14C-labeled alosetron in Caucasian males (n = 3) and females (n = 3) and an Asian male (n = 1) showed similar serum metabolite profiles. Unchanged alosetron was the major component in serum, with other metabolites being present at low concentrations, none amounting to more than 15% of the unmetabolized alosetron concentration. The circulating metabolites were identified as 6-hydroxy glucuronide, 6-hydroxy sulphate, 7-hydroxy sulphate, hydroxymethyl imidazole, and mono- and bis-oxygenated imidazole derivatives of alosetron. The metabolites are unlikely to contribute to the biological activity of alosetron. Of the circulating Phase I metabolites, only the hydroxymethyl imidazole has weak pharmacological activity, around 10-fold less potent than alosetron. Total recovery of radioactivity in the excreta was 85 ± 6%. The majority of the radiolabeled dose is excreted in the urine (74 ± 5%). The major urinary metabolites were the 6-hydroxy glucuronide and the mono- and bis-oxygenated imidazole derivatives of alosetron. 11 ± 4% of the radiolabeled dose was excreted in the feces with less than 1% of the dose being excreted as the unchanged alosetron. - Alosetron is metabolized by human microsomal cytochrome P450 (CYP), shown in vitro to involve enzymes 2C9 (30%), 3A4 (18%), and 1A2 (10%). Non–CYP-mediated Phase I metabolic conversion also contributes to an extent of about 11%. However, in vivo data suggest that CYP1A2 plays a more prominent role in alosetron metabolism (62 to 97% of alosetron clearance) based on correlation of alosetron clearance with in vivo CYP1A2 activity measured by probe substrate, increased clearance induced by smoking, and inhibition of clearance by fluvoxamine. ## Nonclinical Toxicology - In 2-year oral studies, alosetron was not carcinogenic in mice at doses up to 30 mg/kg/day or in rats at doses up to 40 mg/kg/day. These doses are about 60 to 160 times, respectively, the recommended human dose of alosetron of 2 mg/day (1 mg twice daily) based on body surface area. Alosetron was not genotoxic in the Ames tests, the mouse lymphoma cell (L5178Y/TK±) forward gene mutation test, the human lymphocyte chromosome aberration test, the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, or the in vivo rat micronucleus test for mutagenicity. Alosetron at oral doses up to 40 mg/kg/day (about 160 times the recommended daily human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male or female rats. # Clinical Studies - Dose-Ranging Study - Data from a dose-ranging study of women (n = 85) who received LOTRONEX 0.5 mg twice daily indicated that the incidence of constipation (14%) was lower than that experienced by women receiving 1 mg twice daily (29%). Therefore, to lower the risk of constipation, LOTRONEX should be started at a dosage of 0.5 mg twice a day. The efficacy of the 0.5 mg twice-daily dosage in treating severe diarrhea-predominant IBS has not been adequately evaluated in clinical trials. - Efficacy Studies - LOTRONEX has been studied in women with IBS in five 12-week US multicenter, randomized, double-blind, placebo-controlled clinical studies. - Studies in Non-Constipated Women with Irritable Bowel Syndrome: Studies 1 and 2 were conducted in non-constipated women with IBS meeting the Rome Criteria1 for at least 6 months. Women with severe pain or a history of severe constipation were excluded. A 2-week run-in period established baseline IBS symptoms. - About two thirds of the women had diarrhea-predominant IBS. Compared with placebo, 10% to 19% more women with diarrhea-predominant IBS who received LOTRONEX had adequate relief of IBS abdominal pain and discomfort during each month of the study. - Studies in Women With Severe Diarrhea-Predominant Irritable Bowel Syndrome: LOTRONEX is indicated only for women with severe diarrhea-predominant IBS . The efficacy of LOTRONEX in this subset of the women studied in clinical trials is supported by prospective and retrospective analyses. - Prospective Analyses: Studies 3 and 4 were conducted in women with diarrhea-predominant IBS and bowel urgency on at least 50% of days at entry. Women receiving LOTRONEX had significant increases over placebo (13% to 16%) in the median percentage of days with urgency control. - The lower gastrointestinal functions of stool consistency, stool frequency, and sense of incomplete evacuation were also evaluated by patients' daily reports. Stool consistency was evaluated on a scale of 1 to 5 (1 = very hard, 2 = hard, 3 = formed, 4 = loose, and 5 = watery). At baseline, average stool consistency was approximately 4 (loose) for both treatment groups. During the 12 weeks of treatment, the average stool consistency decreased to approximately 3.0 (formed) for patients who received LOTRONEX and 3.5 for the patients who received placebo in the 2 studies. - At baseline, average stool frequency was approximately 3.2 per day for both treatment groups. During the 12 weeks of treatment, the average daily stool frequency decreased to approximately 2.1 and 2.2 for patients receiving LOTRONEX and 2.7 and 2.8 for patients receiving placebo in the 2 studies. - There was no consistent effect upon the sense of incomplete evacuation during the 12 weeks of treatment for patients receiving LOTRONEX as compared to patients receiving placebo in either study. - Study 5 was conducted in women with severe diarrhea-predominant IBS and 1 or more of the following: frequent and severe abdominal pain or discomfort, frequent bowel urgency or fecal incontinence, disability or restriction of daily activities due to IBS. To evaluate the proportion of patients who responded to treatment, patients were asked every 4 weeks to compare their IBS symptoms during the previous month of treatment with how they usually felt during the 3 months prior to the study using an ordered 7-point scale (substantially worse to substantially improved). A responder was defined as a subject who reported moderate or substantial improvement on this global improvement scale (GIS). At Week 12, all three groups receiving LOTRONEX had significantly greater percentages of GIS responders compared to the placebo group (43% to 51% vs. 31%) using a Last Observation Carried Forward (LOCF) analysis. It should be noted that approximately 4% of subjects in each LOTRONEX dose group who were classified as responders using this approach were observed only through week 4. At each of the 4 week intervals of the treatment phase, all three dosages of LOTRONEX provided improvement in the average adequate relief rate of IBS pain and discomfort, stool consistency, stool frequency, and sense of urgency compared with placebo. - Retrospective Analyses: In analyses of patients from Studies 1 and 2 who had diarrhea-predominant IBS and indicated their baseline run-in IBS symptoms were severe at the start of the trial, LOTRONEX provided greater adequate relief of IBS pain and discomfort than placebo. In further analyses of Studies 1 and 2, 57% of patients had urgency at baseline on 5 or more days per week. In this subset, 32% of patients on LOTRONEX had urgency no more than 1 day in the last week of the trial, compared with 19% of patients on placebo. - In Studies 3 and 4, 66% of patients had urgency at baseline on 5 or more days per week. In this subset, 50% of patients on LOTRONEX had urgency no more than 1 day in the last week of the trial, compared with 29% of patients on placebo. Moreover, in the same subset, 12% on LOTRONEX had urgency no more than 2 days per week in any of the 12 weeks on treatment compared with 1% of placebo patients. - In Studies 1 and 2, patient-reported subjective outcomes related to IBS were assessed by questionnaires obtained at baseline and week 12. Patients in the more severe subset who received LOTRONEX reported less difficulty sleeping, less tiredness, fewer eating problems, and less interference with social activities and work/main activities due to IBS symptoms or problems compared to those who received placebo. Change in the impact of IBS symptoms and problems on emotional and mental distress and on physical and sexual activity in women who received LOTRONEX were not statistically different from those reported by women who received placebo. - Long-Term Use - In a 48-week multinational, double-blind, placebo-controlled study, LOTRONEX 1 mg twice daily was evaluated in 714 women with non-constipated IBS. A retrospective analysis of the subset of women with severe diarrhea-predominant IBS (urgency on at least 10 days during the 2-week baseline period) was performed. Of the 417 patients with severe diarrhea-predominant IBS, 62% completed the trial. - LOTRONEX (n = 198) provided a greater average rate of adequate relief of IBS pain and discomfort (52% vs. 41%) and a greater average rate of satisfactory control of bowel urgency (60% vs. 48%) compared with placebo (n = 219). Significant improvement of these symptoms occurred for most of the 48-week treatment period with no evidence of tachyphylaxis. # How Supplied - LOTRONEX Tablets, 0.5 mg (0.562 mg alosetron HCl equivalent to 0.5 mg alosetron) are white, oval, film-coated tablets debossed with GX EX1 on one face. - Bottles of 30 (NDC 65483-894-03) with child-resistant closures. - LOTRONEX Tablets, 1 mg (1.124 mg alosetron HCl equivalent to 1 mg alosetron), are blue, oval, film-coated tablets debossed with GX CT1 on one face. - Bottles of 30 (NDC 65483-895-03) with child-resistant closures. - Store at 20-25°C (68-77°F). Protect from light and moisture. ## Storage There is limited information regarding Alosetron Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Prescriber and Patient Responsibilities - Patients should be fully counseled on and understand the risks and benefits of LOTRONEX before an initial prescription is written. The patient may be educated by the enrolled prescriber or a healthcare provider under a prescriber's direction. - Prescribers must: - counsel patients for whom LOTRONEX is appropriate about the benefits and risks of LOTRONEX and discuss the impact of IBS symptoms on the patient's life. - give the patient a copy of the Medication Guide, which outlines the benefits and risks of LOTRONEX, and instruct the patient to read it carefully. Answer all questions the patient may have about LOTRONEX. The complete text of the Medication Guide is printed at the end of this document. - review the Patient Acknowledgement Form for LOTRONEX with the patient, answer all questions, and give a copy of the signed Patient Acknowledgement Form to the patient. - provide each patient with appropriate instructions for taking LOTRONEX. - Copies of the Patient Acknowledgement Form for LOTRONEX and additional copies of the Medication Guide are available by contacting Prometheus at 1-888-423-5227 or visiting www.lotronexppl.com. - Patients who are prescribed LOTRONEX should be instructed to: - read the Medication Guide before starting LOTRONEX and each time they refill their prescription. - not start taking LOTRONEX if they are constipated. - immediately discontinue LOTRONEX and contact their prescriber if they become constipated, or have symptoms of ischemic colitis such as new or worsening abdominal pain, bloody diarrhea, or blood in the stool. Contact their prescriber again if their constipation does not resolve after discontinuation of LOTRONEX. Resume LOTRONEX only if their constipation has resolved and after discussion with and the agreement of their treating prescriber. - stop taking LOTRONEX and contact their prescriber if LOTRONEX does not adequately control IBS symptoms after 4 weeks of taking 1 mg twice a day. # Precautions with Alcohol - Alcohol-Alosetron interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - LOTRONEX® # Look-Alike Drug Names - Lotronex® — Protonix® # Drug Shortage Status # Price	Alosetron 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. # Black Box Warning # Overview Alosetron is a selective serotonin 5-HT3 antagonist that is FDA approved for the {{{indicationType}}} of severe diarrhea-predominant irritable bowel syndrome (IBS). There is a Black Box Warning for this drug as shown here. Common adverse reactions include constipation, abdominal pain, nausea, and gastrointestinal discomfort and pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - LOTRONEX is indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have: - chronic IBS symptoms (generally lasting 6 months or longer), - had anatomic or biochemical abnormalities of the gastrointestinal tract excluded, and - not responded adequately to conventional therapy. - Diarrhea-predominant IBS is severe if it includes diarrhea and one or more of the following: - frequent and severe abdominal pain/discomfort, - frequent bowel urgency or fecal incontinence, - disability or restriction of daily activities due to IBS. - Because of infrequent but serious gastrointestinal adverse reactions associated with LOTRONEX, the indication is restricted to those patients for whom the benefit-to-risk balance is most favorable. - Dosing Information - To lower the risk of constipation, LOTRONEX should be started at a dosage of 0.5 mg twice a day. Patients who become constipated at this dosage should stop taking LOTRONEX until the constipation resolves. They may be restarted at 0.5 mg once a day. If constipation recurs at the lower dose, LOTRONEX should be discontinued immediately. - Patients well controlled on 0.5 mg once or twice a day may be maintained on this regimen. If after 4 weeks the dosage is well tolerated but does not adequately control IBS symptoms, then the dosage can be increased to up to 1 mg twice a day. LOTRONEX should be discontinued in patients who have not had adequate control of IBS symptoms after 4 weeks of treatment with 1 mg twice a day. - LOTRONEX can be taken with or without food. - LOTRONEX should be discontinued immediately in patients who develop constipation or signs of ischemic colitis. LOTRONEX should not be restarted in patients who develop ischemic colitis. - Clinical trial and postmarketing experience suggest that debilitated patients or patients taking additional medications that decrease gastrointestinal motility may be at greater risk of serious complications of constipation. Therefore, appropriate caution and follow-up should be exercised if LOTRONEX is prescribed for these patients. - Postmarketing experience suggests that elderly patients may be at greater risk for complications of constipation; therefore, appropriate caution and follow-up should be exercised if LOTRONEX is prescribed for these patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Alosetron in adult patients. ### Non–Guideline-Supported Use - Alosetron 0.5 mg.[1] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Alosetron in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Alosetron in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Alosetron in pediatric patients. # Contraindications - Constipation - LOTRONEX should not be initiated in patients with constipation. - History of Severe Bowel or Hepatic Disorders - LOTRONEX is contraindicated in patients with a history of the following: chronic or severe constipation or sequelae from constipation intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation, and/or adhesions ischemic colitis, impaired intestinal circulation, thrombophlebitis, or hypercoagulable state Crohn's disease or ulcerative colitis diverticulitis severe hepatic impairment - chronic or severe constipation or sequelae from constipation - intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation, and/or adhesions - ischemic colitis, impaired intestinal circulation, thrombophlebitis, or hypercoagulable state - Crohn's disease or ulcerative colitis - diverticulitis - severe hepatic impairment - Lack of Understanding of Patient Acknowledgement Form - LOTRONEX should not be used by patients who are unable to understand or comply with the Patient Acknowledgement Form for LOTRONEX. - Concomitant Use of Fluvoxamine - Concomitant administration of LOTRONEX with fluvoxamine is contraindicated. Fluvoxamine, a known strong inhibitor of CYP1A2, has been shown to increase mean alosetron plasma concentrations (AUC) approximately 6-fold and prolong the half-life by approximately 3-fold. # Warnings ### Precautions - Serious Complications of Constipation - Some patients have experienced serious complications of constipation without warning. - Serious complications of constipation, including obstruction, ileus, impaction, toxic megacolon, and secondary bowel ischemia, have been reported with use of LOTRONEX during clinical trials. Complications of constipation have been reported with use of 1 mg twice daily and with lower doses. A dose response relationship has not been established for serious complications of constipation. The incidence of serious complications of constipation was approximately 0.1% (1 per 1,000 patients) in women receiving either LOTRONEX or placebo. In addition, rare cases of perforation and death have been reported from postmarketing clinical practice. In some cases, complications of constipation required intestinal surgery, including colectomy. Patients who are elderly, debilitated, or taking additional medications that decrease gastrointestinal motility may be at greater risk for complications of constipation. - LOTRONEX should be discontinued immediately in patients who develop constipation [see Boxed Warning]. - Ischemic Colitis - Some patients have experienced ischemic colitis without warning. - Ischemic colitis has been reported in patients receiving LOTRONEX in clinical trials as well as during marketed use of the drug. In IBS clinical trials, the cumulative incidence of ischemic colitis in women receiving LOTRONEX was 0.2% (2 per 1,000 patients, 95% confidence interval 1 to 3) through 3 months and was 0.3% (3 per 1,000 patients, 95% confidence interval 1 to 4) through 6 months. Ischemic colitis has been reported with use of 1 mg twice daily and with lower doses. A dose-response relationship has not been established. Ischemic colitis was reported in one patient receiving placebo. The patient experience in controlled clinical trials is insufficient to estimate the incidence of ischemic colitis in patients taking LOTRONEX for longer than 6 months. - LOTRONEX should be discontinued immediately in patients with signs of ischemic colitis such as rectal bleeding, bloody diarrhea, or new or worsening abdominal pain. Because ischemic colitis can be life-threatening, patients with signs or symptoms of ischemic colitis should be evaluated promptly and have appropriate diagnostic testing performed. Treatment with LOTRONEX should not be resumed in patients who develop ischemic colitis. - Prescribing Program for LOTRONEX - To prescribe LOTRONEX, the prescriber must be enrolled in the Prescribing Program for LOTRONEX. To enroll, prescribers must understand the benefits and risks of treatment with LOTRONEX for severe diarrhea-predominant IBS, including the information in the Prescribing Information, Medication Guide, and Patient Acknowledgement Form for LOTRONEX. - To enroll in the Prescribing Program for LOTRONEX, call 1-888-423-5227 or visit www.lotronexppl.com to complete the Prescriber Enrollment Form. # 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. - Patients With Irritable Bowel Syndrome: Table 1 summarizes adverse reactions from 22 repeat-dose studies in patients with IBS who were treated with 1 mg of LOTRONEX twice daily for 8 to 24 weeks. The adverse reactions in Table 1 were reported in 1% or more of patients who received LOTRONEX and occurred more frequently on LOTRONEX than on placebo. A statistically significant difference was observed for constipation in patients treated with LOTRONEX compared to placebo (p<0.0001). - Gastrointestinal: Constipation is a frequent and dose-related side effect of treatment with LOTRONEX. In clinical studies constipation was reported in approximately 29% of patients with IBS treated with LOTRONEX 1 mg twice daily (n = 9,316). This effect was statistically significant compared to placebo (p<;&lt0.0001). Eleven percent (11%) of patients treated with LOTRONEX 1 mg twice daily withdrew from the studies due to constipation. Although the number of patients with IBS treated with LOTRONEX 0.5 mg twice daily is relatively small (n = 243), only 11% of those patients reported constipation and 4% withdrew from clinical studies due to constipation. Among the patients treated with LOTRONEX 1 mg twice daily who reported constipation, 75% reported a single episode and most reports of constipation (70%) occurred during the first month of treatment, with the median time to first report of constipation onset of 8 days. Occurrences of constipation in clinical trials were generally mild to moderate in intensity, transient in nature, and resolved either spontaneously with continued treatment or with an interruption of treatment. However, serious complications of constipation have been reported in clinical studies and in postmarketing experience. In Studies 1 and 2, 9% of patients treated with LOTRONEX reported constipation and 4 consecutive days with no bowel movement. Following interruption of treatment, 78% of the affected patients resumed bowel movements within a 2-day period and were able to re-initiate treatment with LOTRONEX. - Hepatic: A similar incidence in elevation of ALT (>2-fold) was seen in patients receiving LOTRONEX or placebo (1.0% vs. 1.2%). A single case of hepatitis (elevated ALT, AST, alkaline phosphatase, and bilirubin) without jaundice in a patient receiving LOTRONEX was reported in a 12-week study. A causal association with LOTRONEX has not been established. - Long-Term Safety: Patient experience in controlled clinical trials is insufficient to estimate the incidence of ischemic colitis in patients taking LOTRONEX for longer than 6 months. - Women With Severe Diarrhea-Predominant Irritable Bowel Syndrome: Table 2 summarizes the gastrointestinal adverse reactions from 1 repeat-dose study in female patients with severe diarrhea-predominant IBS who were treated for 12 weeks. The adverse reactions in Table 2 were reported in 3% or more of patients who received LOTRONEX and occurred more frequently with LOTRONEX than with placebo. Other events reported in 3% or more of patients who received LOTRONEX and occurring more frequently with LOTRONEX than with placebo included upper respiratory tract infection, viral gastroenteritis, muscle spasms, headaches, and fatigue. - Adverse reactions reported in another study of 701 women with severe diarrhea-predominant IBS were similar to those shown in Table 2. Gastrointestinal adverse reactions reported in 3% or more of patients who received LOTRONEX and occurring more frequently with LOTRONEX than with placebo included constipation (14% and 10% of patients taking LOTRONEX 1 mg twice daily or 0.5 mg as needed, respectively, compared with 2% taking placebo), abdominal pain, nausea, vomiting, and flatulence. Other events reported in 3% or more of patients who received LOTRONEX and occurring more frequently with LOTRONEX than with placebo included nasopharyngitis, sinusitis, upper respiratory tract infection, urinary tract infection, viral gastroenteritis, and cough. - Constipation: Constipation was the most frequent adverse reaction among women with severe diarrhea-predominant IBS represented in Table 2. There was a dose response in the groups treated with LOTRONEX in the number of patients withdrawn due to constipation (2% on placebo, 5% on 0.5 mg once daily, 8% on 1 mg once daily, and 11% on 1 mg twice daily). Among these patients with severe diarrhea-predominant IBS treated with LOTRONEX who reported constipation most (75%) reported one episode which occurred within the first 15 days of treatment and persisted for 4 to 5 days. - Other Events Observed During Clinical Evaluation of LOTRONEX: During its assessment in clinical trials, multiple and single doses of LOTRONEX were administered, resulting in 11,874 subject exposures in 86 completed clinical studies. The conditions, dosages, and duration of exposure to LOTRONEX varied between trials, and the studies included healthy male and female volunteers as well as male and female patients with IBS and other indications. - In the listing that follows, reported adverse reactions were classified using a standardized coding dictionary. Only those events that an investigator believed were possibly related to LOTRONEX, occurred in at least 2 patients, and occurred at a greater frequency during treatment with LOTRONEX than during placebo administration are presented. Serious adverse reactions occurring in at least 1 patient for whom an investigator believed there was reasonable possibility that the event was related to treatment with LOTRONEX and occurring at a greater frequency in patients treated with LOTRONEX than placebo-treated patients are also presented. - In the following listing, events are categorized by body system. Within each body system, events are presented in descending order of frequency. The following definitions are used: infrequent adverse reactions are those occurring on one or more occasion in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring on one or more occasion in fewer than 1/1,000 patients. - Although the events reported occurred during treatment with LOTRONEX, they were not necessarily caused by it. Rare: Quantitative red cell or hemoglobin defects, and hemorrhage. Infrequent: Tachyarrhythmias. Rare: Arrhythmias, increased blood pressure, and extrasystoles. Rare: Contusions and hematomas. Rare: Ear, nose, and throat infections; viral ear, nose, and throat infections; and laryngitis. Rare: Disorders of calcium and phosphate metabolism, hyperglycemia, hypothalamus/pituitary hypofunction, hypoglycemia, and fluid disturbances. Rare: Light sensitivity of eyes. Infrequent: Hyposalivation, dyspeptic symptoms, gastrointestinal spasms, ischemic colitis, and gastrointestinal lesions. Rare: Abnormal tenderness, colitis, gastrointestinal signs and symptoms, proctitis, diverticulitis, positive fecal occult blood, hyperacidity, decreased gastrointestinal motility and ileus, gastrointestinal obstructions, oral symptoms, gastrointestinal intussusception, gastritis, gastroduodenitis, gastroenteritis, and ulcerative colitis. Rare: Abnormal bilirubin levels and cholecystitis. Infrequent: Breathing disorders. Rare: Muscle pain; muscle stiffness, tightness and rigidity; and bone and skeletal pain. Infrequent: Hypnagogic effects. Rare: Memory effects, tremors, dreams, cognitive function disorders, disturbances of sense of taste, disorders of equilibrium, confusion, sedation, and hypoesthesia. Infrequent: Malaise and fatigue, cramps, pain, temperature regulation disturbances. Rare: Burning sensations, hot and cold sensations, cold sensations, and fungal infections. Infrequent: Anxiety. Rare: Depressive moods. Rare: Sexual function disorders, female reproductive tract bleeding and hemorrhage, reproductive infections, and fungal reproductive infections. Infrequent: Sweating and urticaria. Rare: Hair loss and alopecia; acne and folliculitis; disorders of sweat and sebum; allergic skin reaction; eczema; skin infections; dermatitis and dermatosis; and nail disorders. Infrequent: Urinary frequency. Rare: Bladder inflammation; polyuria and diuresis; and urinary tract hemorrhage. ## Postmarketing Experience - In addition to events reported in clinical trials, the following events have been identified during use of LOTRONEX in clinical practice. Because they were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to LOTRONEX. Impaction, perforation, ulceration, small bowel mesenteric ischemia. Headache. Rash. # Drug Interactions - In vivo data suggest that alosetron is primarily metabolized by cytochrome P450 (CYP) 1A2, with minor contributions from CYP3A4 and CYP2C9. Therefore, inducers or inhibitors of these enzymes may change the clearance of alosetron. - CYP1A2 Inhibitors - Fluvoxamine is a known strong inhibitor of CYP1A2 and also inhibits CYP3A4, CYP2C9, and CYP2C19. In a pharmacokinetic study, 40 healthy female subjects received fluvoxamine in escalating doses from 50 to 200 mg/ day for 16 days, with coadministration of alosetron 1 mg on the last day. Fluvoxamine increased mean alosetron plasma concentrations (AUC) approximately 6-fold and prolonged the half-life by approximately 3-fold. Concomitant administration of alosetron and fluvoxamine is contraindicated [see Contraindications (4.3)]. - Concomitant administration of alosetron and moderate CYP1A2 inhibitors, including quinolone antibiotics and cimetidine, has not been evaluated, but should be avoided unless clinically necessary because of similar potential drug interactions. - CYP3A4 Inhibitors - Ketoconazole is a known strong inhibitor of CYP3A4. In a pharmacokinetic study, 38 healthy female subjects received ketoconazole 200 mg twice daily for 7 days, with coadministration of alosetron 1 mg on the last day. Ketoconazole increased mean alosetron plasma concentrations (AUC) by 29%. Caution should be used when alosetron and ketoconazole are administered concomitantly. Coadministration of alosetron and strong CYP3A4 inhibitors such as clarithromycin, telithromycin, protease inhibitors, voriconazole, and itraconazole has not been evaluated but should be undertaken with caution because of similar potential drug interactions. The effect of induction or inhibition of other pathways on exposure to alosetron and its metabolites is not known. - Other CYP Enzymes - In vitro human liver microsome studies and an in vivo metabolic probe study demonstrated that alosetron did not inhibit CYP enzymes 3A4, 2C9, or 2C19. In vitro at total drug concentrations 27-fold higher than peak plasma concentrations observed with the 1 mg dose, alosetron inhibited CYP enzymes 1A2 (60%) and 2E1 (50%). In an in vivo metabolic probe study, alosetron did not inhibit CYP2E1 but did produce 30% inhibition of both CYP1A2 and N-acetyltransferase. Although not studied with alosetron, inhibition of N-acetyltransferase may have clinically relevant consequences for drugs such as isoniazid, procainamide, and hydralazine. The effect on CYP1A2 was explored further in a clinical interaction study with theophylline and no effect on metabolism was observed. Another study showed that alosetron had no clinically significant effect on plasma concentrations of the oral contraceptive agents ethinyl estradiol and levonorgestrel (CYP3A4 substrates). A clinical interaction study was also conducted with alosetron and the CYP3A4 substrate cisapride. No significant effects on cisapride metabolism or QT interval were noted. The effects of alosetron on monoamine oxidases and on intestinal first pass secondary to high intraluminal concentrations have not been examined. Based on the above data from in vitro and in vivo studies, it is unlikely that alosetron will inhibit the hepatic metabolic clearance of drugs metabolized by the CYP enzymes 2C9, 2C19, or 2E1. - Alosetron does not appear to induce the major cytochrome P450 drug-metabolizing enzyme 3A. Alosetron also does not appear to induce CYP enzymes 2E1 or 2C19. It is not known whether alosetron might induce other enzymes. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - Reproduction studies have been performed in rats at doses up to 40 mg/kg/day (about 160 times the recommended human dose based on body surface area) and rabbits at oral doses up to 30 mg/kg/day (about 240 times the recommended daily human dose based on body surface area). These studies have revealed no evidence of impaired fertility or harm to the fetus due to alosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, LOTRONEX should be used during pregnancy only if clearly needed Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alosetron in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Alosetron during labor and delivery. ### Nursing Mothers - Alosetron and/or metabolites of alosetron are excreted in the breast milk of lactating rats. It is not known whether alosetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when LOTRONEX is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. Use of LOTRONEX is not recommended in the pediatric population, based upon the risk of serious complications of constipation and ischemic colitis in adults. ### Geriatic Use - In some studies in healthy men or women, plasma concentrations were elevated by approximately 40% in individuals 65 years and older compared to young adults. However, this effect was not consistently observed in men. - Postmarketing experience suggests that elderly patients may be at greater risk for complications of constipation therefore, appropriate caution and follow-up should be exercised if LOTRONEX is prescribed for these patients. ### Gender There is no FDA guidance on the use of Alosetron with respect to specific gender populations. ### Race There is no FDA guidance on the use of Alosetron with respect to specific racial populations. ### Renal Impairment - Renal impairment (creatinine clearance 4 to 56 mL/min) has no effect on the renal elimination of alosetron due to the minor contribution of this pathway to elimination. The effect of renal impairment on metabolite pharmacokinetics and the effect of end-stage renal disease have not been assessed. ### Hepatic Impairment - Due to the extensive hepatic metabolism of alosetron, increased exposure to alosetron and/or its metabolites is likely to occur in patients with hepatic impairment. Alosetron should not be used in patients with severe hepatic impairment and should be used with caution in patients with mild or moderate hepatic impairment. - A single 1 mg oral dose of alosetron was administered to 1 female and 5 male patients with moderate hepatic impairment (Child-Pugh score of 7 to 9) and to 1 female and 2 male patients with severe hepatic impairment (Child-Pugh score of >9). In comparison with historical data from healthy subjects, patients with severe hepatic impairment displayed higher systemic exposure to alosetron. The female with severe hepatic impairment displayed approximately 14-fold higher exposure, while the female with moderate hepatic impairment displayed approximately 1.6-fold higher exposure, than healthy females. Due to the small number of subjects and high intersubject variability in the pharmacokinetic findings, no definitive quantitative conclusions can be made. However, due to the greater exposure to alosetron in the female with severe hepatic impairment, alosetron should not be used in females with severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Alosetron in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Alosetron in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Alosetron in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Alosetron in the drug label. # Overdosage ## Acute Overdose - There is no specific antidote for overdose of LOTRONEX. Patients should be managed with appropriate supportive therapy. Individual oral doses as large as 16 mg have been administered in clinical studies without significant adverse reactions. This dose is 8 times higher than the recommended total daily dose. Inhibition of the metabolic elimination and reduced first pass of other drugs might occur with overdoses of LOTRONEX. ## Chronic Overdose There is limited information regarding Chronic Overdose of Alosetron in the drug label. # Pharmacology ## Mechanism of Action - Alosetron is a potent and selective 5-HT3 receptor antagonist. 5-HT3 receptors are ligand-gated cation channels that are extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations. Activation of these channels and the resulting neuronal depolarization affect the regulation of visceral pain, colonic transit, and gastrointestinal secretions, processes that relate to the pathophysiology of IBS. 5-HT3 receptor antagonists such as alosetron inhibit activation of non-selective cation channels, which results in the modulation of the enteric nervous system. - The cause of IBS is unknown. IBS is characterized by visceral hypersensitivity and hyperactivity of the gastrointestinal tract, which lead to abnormal sensations of pain and motor activity. Following distention of the rectum, patients with IBS exhibit pain and discomfort at lower volumes than healthy volunteers. Following such distention, alosetron reduced pain and exaggerated motor responses, possibly due to blockade of 5-HT3 receptors. ## Structure - The active ingredient in LOTRONEX Tablets is alosetron hydrochloride (HCl), a potent and selective antagonist of the serotonin 5-HT3 receptor type. Chemically, alosetron is designated as 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one, monohydrochloride. Alosetron is achiral and has the empirical formula C17H18N4O•HCl, representing a molecular weight of 330.8. Alosetron is a white to beige solid that has a solubility of 61 mg/mL in water, 42 mg/mL in 0.1M hydrochloric acid, 0.3 mg/mL in pH 6 phosphate buffer, and <;&lt0.1 mg/mL in pH 8 phosphate buffer. The chemical structure of alosetron is: - LOTRONEX Tablets are supplied for oral administration as 0.5 mg (white) and 1 mg (blue) tablets. The 0.5 mg tablet contains 0.562 mg alosetron HCl equivalent to 0.5 mg alosetron, and the 1 mg tablet contains 1.124 mg alosetron HCl equivalent to 1 mg of alosetron. Each tablet also contains the inactive ingredients lactose (anhydrous), magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The white film coat for the 0.5 mg tablet contains hypromellose, titanium dioxide, and triacetin. The blue film coat for the 1 mg tablet contains hypromellose, titanium dioxide, triacetin, and indigo carmine. ## Pharmacodynamics - In healthy volunteers and patients with IBS, alosetron (2 mg orally, twice daily for 8 days) increased colonic transit time without affecting orocecal transit time. In healthy volunteers, alosetron also increased basal jejunal water and sodium absorption after a single 4 mg dose. In patients with IBS, multiple oral dosages of alosetron (4 mg twice daily for 6.5 days) significantly increased colonic compliance. - Single oral doses of alosetron administered to healthy men produced a dose-dependent reduction in the flare response seen after intradermal injection of serotonin. Urinary 6-β-hydroxycortisol excretion decreased by 52% in elderly subjects after 27.5 days of alosetron 2 mg administered orally twice daily. This decrease was not statistically significant. In another study utilizing alosetron 1 mg administered orally twice daily for 4 days, there was a significant decrease in urinary 6-β-hydroxycortisol excretion. However, there was no change in the ratio of 6-β-hydroxycortisol to cortisol, indicating a possible decrease in cortisol production. The clinical significance of these findings is unknown. ## Pharmacokinetics - The pharmacokinetics of alosetron have been studied after single oral doses ranging from 0.05 to 16 mg in healthy men. The pharmacokinetics of alosetron have also been evaluated in healthy women and men and in patients with IBS after repeated oral dosages ranging from 1 mg twice daily to 8 mg twice daily. - Absorption: Alosetron was rapidly absorbed after oral administration with a mean absolute bioavailability of approximately 50% to 60% (approximate range, 30% to >90%). After administration of radiolabeled alosetron, only 1% of the dose was recovered in the feces as unchanged drug. Following oral administration of a 1 mg alosetron dose to young men, a peak plasma concentration of approximately 5 ng/mL occurred at 1 hour. In young women, the mean peak plasma concentration was approximately 9 ng/mL, with a similar time to peak. - Plasma concentrations were 30% to 50% lower and less variable in men compared to women given the same oral dose. Population pharmacokinetic analysis in IBS patients confirmed that alosetron concentrations were influenced by gender (27% lower in men). - Food Effects: Alosetron absorption is decreased by approximately 25% by co-administration with food, with a mean delay in time to peak concentration of 15 minutes. - Distribution: Alosetron demonstrates a volume of distribution of approximately 65 to 95 L. Plasma protein binding is 82% over a concentration range of 20 to 4,000 ng/mL. - Metabolism and Elimination: Plasma concentrations of alosetron increase proportionately with increasing single oral doses up to 8 mg and more than proportionately at a single oral dose of 16 mg. Twice-daily oral dosing of alosetron does not result in accumulation. The terminal elimination half-life of alosetron is approximately 1.5 hours (plasma clearance is approximately 600 mL/min). Population pharmacokinetic analysis in patients with IBS confirmed that alosetron clearance is minimally influenced by doses up to 8 mg. - Renal elimination of unchanged alosetron accounts for only 13% of the dose. Renal clearance is approximately 112 mL/min. - A study with 14C-labeled alosetron in Caucasian males (n = 3) and females (n = 3) and an Asian male (n = 1) showed similar serum metabolite profiles. Unchanged alosetron was the major component in serum, with other metabolites being present at low concentrations, none amounting to more than 15% of the unmetabolized alosetron concentration. The circulating metabolites were identified as 6-hydroxy glucuronide, 6-hydroxy sulphate, 7-hydroxy sulphate, hydroxymethyl imidazole, and mono- and bis-oxygenated imidazole derivatives of alosetron. The metabolites are unlikely to contribute to the biological activity of alosetron. Of the circulating Phase I metabolites, only the hydroxymethyl imidazole has weak pharmacological activity, around 10-fold less potent than alosetron. Total recovery of radioactivity in the excreta was 85 ± 6%. The majority of the radiolabeled dose is excreted in the urine (74 ± 5%). The major urinary metabolites were the 6-hydroxy glucuronide and the mono- and bis-oxygenated imidazole derivatives of alosetron. 11 ± 4% of the radiolabeled dose was excreted in the feces with less than 1% of the dose being excreted as the unchanged alosetron. - Alosetron is metabolized by human microsomal cytochrome P450 (CYP), shown in vitro to involve enzymes 2C9 (30%), 3A4 (18%), and 1A2 (10%). Non–CYP-mediated Phase I metabolic conversion also contributes to an extent of about 11%. However, in vivo data suggest that CYP1A2 plays a more prominent role in alosetron metabolism (62 to 97% of alosetron clearance) based on correlation of alosetron clearance with in vivo CYP1A2 activity measured by probe substrate, increased clearance induced by smoking, and inhibition of clearance by fluvoxamine. ## Nonclinical Toxicology - In 2-year oral studies, alosetron was not carcinogenic in mice at doses up to 30 mg/kg/day or in rats at doses up to 40 mg/kg/day. These doses are about 60 to 160 times, respectively, the recommended human dose of alosetron of 2 mg/day (1 mg twice daily) based on body surface area. Alosetron was not genotoxic in the Ames tests, the mouse lymphoma cell (L5178Y/TK±) forward gene mutation test, the human lymphocyte chromosome aberration test, the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, or the in vivo rat micronucleus test for mutagenicity. Alosetron at oral doses up to 40 mg/kg/day (about 160 times the recommended daily human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male or female rats. # Clinical Studies - Dose-Ranging Study - Data from a dose-ranging study of women (n = 85) who received LOTRONEX 0.5 mg twice daily indicated that the incidence of constipation (14%) was lower than that experienced by women receiving 1 mg twice daily (29%). Therefore, to lower the risk of constipation, LOTRONEX should be started at a dosage of 0.5 mg twice a day. The efficacy of the 0.5 mg twice-daily dosage in treating severe diarrhea-predominant IBS has not been adequately evaluated in clinical trials. - Efficacy Studies - LOTRONEX has been studied in women with IBS in five 12-week US multicenter, randomized, double-blind, placebo-controlled clinical studies. - Studies in Non-Constipated Women with Irritable Bowel Syndrome: Studies 1 and 2 were conducted in non-constipated women with IBS meeting the Rome Criteria1 for at least 6 months. Women with severe pain or a history of severe constipation were excluded. A 2-week run-in period established baseline IBS symptoms. - About two thirds of the women had diarrhea-predominant IBS. Compared with placebo, 10% to 19% more women with diarrhea-predominant IBS who received LOTRONEX had adequate relief of IBS abdominal pain and discomfort during each month of the study. - Studies in Women With Severe Diarrhea-Predominant Irritable Bowel Syndrome: LOTRONEX is indicated only for women with severe diarrhea-predominant IBS [see Indications and Usage (1)]. The efficacy of LOTRONEX in this subset of the women studied in clinical trials is supported by prospective and retrospective analyses. - Prospective Analyses: Studies 3 and 4 were conducted in women with diarrhea-predominant IBS and bowel urgency on at least 50% of days at entry. Women receiving LOTRONEX had significant increases over placebo (13% to 16%) in the median percentage of days with urgency control. - The lower gastrointestinal functions of stool consistency, stool frequency, and sense of incomplete evacuation were also evaluated by patients' daily reports. Stool consistency was evaluated on a scale of 1 to 5 (1 = very hard, 2 = hard, 3 = formed, 4 = loose, and 5 = watery). At baseline, average stool consistency was approximately 4 (loose) for both treatment groups. During the 12 weeks of treatment, the average stool consistency decreased to approximately 3.0 (formed) for patients who received LOTRONEX and 3.5 for the patients who received placebo in the 2 studies. - At baseline, average stool frequency was approximately 3.2 per day for both treatment groups. During the 12 weeks of treatment, the average daily stool frequency decreased to approximately 2.1 and 2.2 for patients receiving LOTRONEX and 2.7 and 2.8 for patients receiving placebo in the 2 studies. - There was no consistent effect upon the sense of incomplete evacuation during the 12 weeks of treatment for patients receiving LOTRONEX as compared to patients receiving placebo in either study. - Study 5 was conducted in women with severe diarrhea-predominant IBS and 1 or more of the following: frequent and severe abdominal pain or discomfort, frequent bowel urgency or fecal incontinence, disability or restriction of daily activities due to IBS. To evaluate the proportion of patients who responded to treatment, patients were asked every 4 weeks to compare their IBS symptoms during the previous month of treatment with how they usually felt during the 3 months prior to the study using an ordered 7-point scale (substantially worse to substantially improved). A responder was defined as a subject who reported moderate or substantial improvement on this global improvement scale (GIS). At Week 12, all three groups receiving LOTRONEX had significantly greater percentages of GIS responders compared to the placebo group (43% to 51% vs. 31%) using a Last Observation Carried Forward (LOCF) analysis. It should be noted that approximately 4% of subjects in each LOTRONEX dose group who were classified as responders using this approach were observed only through week 4. At each of the 4 week intervals of the treatment phase, all three dosages of LOTRONEX provided improvement in the average adequate relief rate of IBS pain and discomfort, stool consistency, stool frequency, and sense of urgency compared with placebo. - Retrospective Analyses: In analyses of patients from Studies 1 and 2 who had diarrhea-predominant IBS and indicated their baseline run-in IBS symptoms were severe at the start of the trial, LOTRONEX provided greater adequate relief of IBS pain and discomfort than placebo. In further analyses of Studies 1 and 2, 57% of patients had urgency at baseline on 5 or more days per week. In this subset, 32% of patients on LOTRONEX had urgency no more than 1 day in the last week of the trial, compared with 19% of patients on placebo. - In Studies 3 and 4, 66% of patients had urgency at baseline on 5 or more days per week. In this subset, 50% of patients on LOTRONEX had urgency no more than 1 day in the last week of the trial, compared with 29% of patients on placebo. Moreover, in the same subset, 12% on LOTRONEX had urgency no more than 2 days per week in any of the 12 weeks on treatment compared with 1% of placebo patients. - In Studies 1 and 2, patient-reported subjective outcomes related to IBS were assessed by questionnaires obtained at baseline and week 12. Patients in the more severe subset who received LOTRONEX reported less difficulty sleeping, less tiredness, fewer eating problems, and less interference with social activities and work/main activities due to IBS symptoms or problems compared to those who received placebo. Change in the impact of IBS symptoms and problems on emotional and mental distress and on physical and sexual activity in women who received LOTRONEX were not statistically different from those reported by women who received placebo. - Long-Term Use - In a 48-week multinational, double-blind, placebo-controlled study, LOTRONEX 1 mg twice daily was evaluated in 714 women with non-constipated IBS. A retrospective analysis of the subset of women with severe diarrhea-predominant IBS (urgency on at least 10 days during the 2-week baseline period) was performed. Of the 417 patients with severe diarrhea-predominant IBS, 62% completed the trial. - LOTRONEX (n = 198) provided a greater average rate of adequate relief of IBS pain and discomfort (52% vs. 41%) and a greater average rate of satisfactory control of bowel urgency (60% vs. 48%) compared with placebo (n = 219). Significant improvement of these symptoms occurred for most of the 48-week treatment period with no evidence of tachyphylaxis. # How Supplied - LOTRONEX Tablets, 0.5 mg (0.562 mg alosetron HCl equivalent to 0.5 mg alosetron) are white, oval, film-coated tablets debossed with GX EX1 on one face. - Bottles of 30 (NDC 65483-894-03) with child-resistant closures. - LOTRONEX Tablets, 1 mg (1.124 mg alosetron HCl equivalent to 1 mg alosetron), are blue, oval, film-coated tablets debossed with GX CT1 on one face. - Bottles of 30 (NDC 65483-895-03) with child-resistant closures. - Store at 20-25°C (68-77°F). Protect from light and moisture. ## Storage There is limited information regarding Alosetron Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Prescriber and Patient Responsibilities - Patients should be fully counseled on and understand the risks and benefits of LOTRONEX before an initial prescription is written. The patient may be educated by the enrolled prescriber or a healthcare provider under a prescriber's direction. - Prescribers must: - counsel patients for whom LOTRONEX is appropriate about the benefits and risks of LOTRONEX and discuss the impact of IBS symptoms on the patient's life. - give the patient a copy of the Medication Guide, which outlines the benefits and risks of LOTRONEX, and instruct the patient to read it carefully. Answer all questions the patient may have about LOTRONEX. The complete text of the Medication Guide is printed at the end of this document. - review the Patient Acknowledgement Form for LOTRONEX with the patient, answer all questions, and give a copy of the signed Patient Acknowledgement Form to the patient. - provide each patient with appropriate instructions for taking LOTRONEX. - Copies of the Patient Acknowledgement Form for LOTRONEX and additional copies of the Medication Guide are available by contacting Prometheus at 1-888-423-5227 or visiting www.lotronexppl.com. - Patients who are prescribed LOTRONEX should be instructed to: - read the Medication Guide before starting LOTRONEX and each time they refill their prescription. - not start taking LOTRONEX if they are constipated. - immediately discontinue LOTRONEX and contact their prescriber if they become constipated, or have symptoms of ischemic colitis such as new or worsening abdominal pain, bloody diarrhea, or blood in the stool. Contact their prescriber again if their constipation does not resolve after discontinuation of LOTRONEX. Resume LOTRONEX only if their constipation has resolved and after discussion with and the agreement of their treating prescriber. - stop taking LOTRONEX and contact their prescriber if LOTRONEX does not adequately control IBS symptoms after 4 weeks of taking 1 mg twice a day. # Precautions with Alcohol - Alcohol-Alosetron interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - LOTRONEX®[2] # Look-Alike Drug Names - Lotronex® — Protonix®[3] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Alosetron
a0d789316a6999f9b9a30c5f576d511db82800dd	wikidoc	Alpelisib	Alpelisib # 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 Alpelisib is a kinase inhibitors that is FDA approved for the treatment of . There is a Black Box Warning for this drug as shown here. Common adverse reactions include The most common adverse reactions for patients indicated for Alpelisib come in the form of laboratory abnormalities. They include increase in glucose, creatinine, GGT, ALT, or lipase, decrease in lymphocyte count, hemoglobin, appetite, weight, calcium, or glucose, the presence of diarrhea, rash, nausea, fatigue or alopecia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### ALPELISIB is indicated for: - PIQRAY is indicated for advanced metastatic breast cancer- hormone receptor positive, human epidermal growth factor receptor 2 negative, and PIK3CA mutated - The breast cancer is measured by an approved FDA test - It is a kinase inhibitor that is given concurrently with fulvestrant, a medication used to treat post menopause women with the conditions listed above ### Limitations of Use - Patients may have severe reactions to the treatment of Alpelisib (see warnings and adverse reactions for more in depth description) - Alpelisib can cause impairment of fertility and fetal health problems ### Dosing Considerations - Alpelisib appears as tablets, and comes in the dose strengths 50 mg, 150 mg, and 200 mg - Continue the recommended dose of 300 mg or the other prescribed dose by the medical administrator until the disease progresses or the toxicity becomes unacceptable - The recommended dose of fulvestrant is 500 mg along with Alpelisib. This should be administered on days 1, 15, and 29 of treatment and continue with once monthly after. ### Administration of ALPELISIB - The recommended dose for patients is 300 mg taken orally daily once along with food - The tablets appear in various strengths because adverse reactions (see adverse reactions) may cause patients to temporarily or permanently discontinue this medication ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding ALPELISIB Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding ALPELISIB 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 ALPELISIB FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding ALPELISIB Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding ALPELISIB Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - Patients may be advised to withhold this medication for a certain time period because of severe hypersensitivity to Alpelisib or any of its components (check components on the label or talk to a medical professional for more information) # Warnings ### Severe Cutaneous Reaction - Less than 2 percent of the patients have shown these possibly lethal reactions connected to the skin and mucous membranes that could be linked to eyes, ears, nose, mouth, lips etc - Diseases including Stevens-Johns Syndrome (0.4% of the patients) and Erythema Multiforme (1.1% of the patients) were linked to patients consuming or using this medication - Treatment with Piqray will not be initiated in patients with histories of this disease. Additionally patients who have had severe cutaneous reactions while undergoing treatment with this disease will not be reintroduced to Piqray - If symptoms appear in patients, temporarily discontinue the medications immediately If the signs/ symptoms are confirmed to be associated with Severe Cutaneous Reactions, patients will have to permanently discontinue the medication - If the signs/ symptoms are confirmed to be associated with Severe Cutaneous Reactions, patients will have to permanently discontinue the medication - If the reactions are not associated with Severe Cutaneous Reactions, there may be a need of dose modifications - Hyperglycemia has been reported in 65% of patients utilizing this medication. Some signs and symptoms of this disease could include excessive thirst, urinating more often than usual or higher amount of urine than usual, or increased appetite with weight loss. Ketoacidosis was reported in 0.7% of patients - Ketoacidosis was reported in 0.7% of patients - Studies have shown patients usually show signs of hyperglycemia a median time of 15 days into treatment - It is advised for patients to be tested to track FPG, HbA1c levels, and to optimize the blood glucose before initiating Piqray treatment - The FPG and blood glucose levels should be monitored for at least the first 8 weeks, once a week. Later, there should be a checkup every 2 weeks, and the time indicated by the doctor. - Patients should consider meeting with a professional with expertise in treating hyperglycemia. They may be able to help counsel the patients on lifestyle changes. - Clinical studies have not tested the effect of Piqray on patients with Type 1 diabetes and uncontrolled Type 2 diabetes. Therefore, the safety of combining these diseases with Piqray has not yet been established. Patients should check with a medical practitioner and weight the pros and cons. Patients with controlled Type 2 diabetes and Diabetes Mellitus were included, and it is advised to closely monitor these patients using Piqray. - Patients with controlled Type 2 diabetes and Diabetes Mellitus were included, and it is advised to closely monitor these patients using Piqray. - Patients may have to temporarily or permanently discontinue or reduce dose and treatment of Piqray based on the severity of the hyperglycemia present. ### Pneumonitis - Pneumonitis was discovered in 1.8% of the patients who were treated with Piqray - Common forms of pneumonitis present within these patients are acute interstitial pneumonitis and interstitial lung disease - If patients begin showing signs and symptoms of pneumonitis, immediately discontinue the drug until the presence of the disease is either confirmed or denied. Symptoms of non-infectious pneumonitis include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. There are no studies performed on patients with infectious or neoplastic pneumonitis because there are no means for an appropriate investigation. - Symptoms of non-infectious pneumonitis include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. There are no studies performed on patients with infectious or neoplastic pneumonitis because there are no means for an appropriate investigation. - If patients are diagnosed with pneumonitis, discontinue the drug immediately. If they continue to have worsening symptoms, contact a medical professional immediately. ### Diarrhea - Severe diarrhea, that resulted in dehydration and acute kidney injury, have been present in 58% of patients undergoing treatment with Piqray. - In a study, 6% of patients required dose reduction, and 2.8% of the people were required to permanently discontinue the drug. There were a total of 164 patients that experienced a case of diarrhea, and 63% of the patients needed to take anti-diarrheal medications. - Patients may have to temporarily or permanently discontinue the drug, or reduce the dose if a problem with diarrhea persists or becomes severe ### Embryo-Fetal Toxicity - Female rats and rabbits pregnant were administered doses of Piqray. These studies have shown the effect Piqray can have on the mothers, and fetuses. It caused adverse developmental outcomes including embryo-fetal mortality, loss of fetal weight, and increased cases in fetal malformation. - Pregnant females, and females with reproductive potential should be advised to use effective contraception during treatment, and 1 week after the last dose. Male patients should also use effective contraception and condoms during treatment and for 1 week after the last dose. - Patients are advised to reach out to healthcare professionals if any adverse reactions persist. - Patients should talk to their healthcare provider for more information on routine checkups after discontinuing treatment ### Infusion Reactions - There is limited information on infusion reactions pertaining to Alpelisib. Contact a doctor immediately if an adverse reactions occur (see adverse reactions) # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Alpelisib Clinical Trials Experience in the drug label. ## Postmarketing Experience There is limited information regarding Alpelisib Postmarketing Experience in the drug label. # Drug Interactions ### CYP3A4 Inducer Administering Alpelisib along with a CYP3A4 Inducer may result in a decrease in Alpelisib concentration, and a decrease in effectiveness and activity. Patients should avoid co-administering Alpelisib with strong CYP3A4 inducers. ### BCRP Inhibitors Administering Alpelisib with BCRP inhibitors increases Alpelisib concentrations that can result in the risk of toxicity in patients. Coadministering Alpelisib with BCRP inhibitors should be avoided. If it is not possible to completely avoid, patients should be closely monitored for adverse reactions. ### CYP2C9 Substrates Administering Alpelisib with CYP2C9 substrates may result in reduced plasma concentrations of the drugs it is administered with. It is advised to monitor patients closely for a decrease in plasma concentrations because that can cause reduced activity and effectiveness of the drugs. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There are no available data on ALPELISIB use in pregnant women to inform a drugassociated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alpelisib in women who are pregnant. ### Labor and Delivery The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. ### Nursing Mothers Women should not breastfeed while undergoing treatment with this medication and for 1 week after the last dose. ### Pediatric Use The safety and efficacy of ALPELISIB for the treatment of PNH in pediatric patients have not been established. ### Geriatic Use There were 117 patients in Solar-1 Clinical Trial that were of age 65 or older, and of that 75 patients were of the age 75 and up. There was a higher percentage of cases of Grade 3 or 4 hyperglycemia (44%) in patients of the age 65 and older compared to the incidence in patients less than the age of 65 (32%). Studies did not show a significant gap in effectiveness of Piqray comparing patients less than 65 years, and patients greater than 65 years of age. ### Gender There is no FDA guidance on the use of ALPELISIB with respect to specific gender populations. ### Race There is no FDA guidance on the use of ALPELISIB with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of ALPELISIB in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of ALPELISIB in patients with hepatic impairment. ### Females of Reproductive Potential and Males FDA guidance suggests healthcare providers should advise and counsel all patients with reproductive potential that ALPELISIB may impair fertility. ### Immunocompromised Patients There is no FDA guidance one the use of ALPELISIB in patients who are immunocompromised. # Administration and Monitoring ### Administration - Piqray is administered orally ### Monitoring There is limited information regarding Alpelisib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Alpelisib and IV administrations. # Overdosage In cases of overdosage with Piqray, patients showed a similar set of adverse reactions as indicated in Piqray’s profile. These include hyperglycemia, nausea, rash, and asthenia. There are no established protocol to entail to Piqray overdose. As in all cases of overdose with every drug, “Initiate general symptomatic and supportive measures in all cases” If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Phosphatidylinositol-3-kinase-a (PI3Ka) mediates cell proliferation as a result of the growth-factor tyrosine kinase pathway activation. PI3Ka’s subunit is mutated in some cancers that make it hyperactive and out of control. Alpelisib inhibits PI3Ka with the highest specificity for it. ## Structure There is limited information regarding ALPELISIB Structure in the drug label. ## Pharmacodynamics There is limited information regarding Alpelisib Pharmacodynamics in the drug label. ## Pharmacokinetics - The volume of distribution is 114 L - 36% of Alpelisib is eliminated as the unchanged drug and 32% as the primary metabolite BZG791 through feces. These are for oral doses. - 2% of the oral dose for Alpelisib is eliminated as the unchanged drug and 7.1% as the primary metabolite through urine - 81% of an oral dose is eliminated in the faces and 14% in the urine - Advise patients to not breastfeed while undergoing treatment with Alpelisib and 1 week after the administration of the last dose ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Studies of carcinogenicity and mutagenicity have not yet been performed # Clinical Studies ### Study SOLAR-1 (NCT02437318) - It was a randomized, placebo controlled trial. The trail had two groups of subjects: the patients who got Piqray and fulvestrant vs the patients who got a placebo and fulvestrant. The trial was conducted with 572 patients with “HER2-negative, advanced or metastatic breast cancer whose disease had progressed or recurred on or after an aromatase inhibitor-based treatment.” - Patients with causes of adverse reactions or adverse reactions such as inflammatory breast cancer, Type 1 diabetes, uncontrolled Type 2 diabetes, or pneumonitis were not included in the study. - 60% of the enrolled patients had tumors with 1 or more PIK3CA mutations, about 50% had had liver or lung metastases, and about 6% had been previously treated with a CDK4 or 6 inhibitor The randomized section was if the patient had liver/ lung metastases and/or been previously treated with a CDK4 or 6 inhibitor - The randomized section was if the patient had liver/ lung metastases and/or been previously treated with a CDK4 or 6 inhibitor - Division of patients: there were 341 patients in the trial cohort who had at least one PIK3CA mutation and 231 patients in the trial cohorts who did not show the presence of the mutation. Of the patients who had the mutation, about 99% of the patients also had the 1 or more mutations confirmed with a FDA test. - Patients were put into 2 different groups, so they either received Piqray and fulvestrant or they received a placebo and fulvestrant. The dose of fulvestrant (500 mg) was administered intramuscularly on Days 1 and 15 of the first Cycle, and every first day of the following cycles. The patients continue the treatment in their respective groups until the cancer is shown to progress on radiographs or the patient experiences unacceptable toxicity. The tumors were assessed once every 8 weeks for the first 18 months, and every 12 weeks following the initial period. - Demographics: the median age of the patients was 63 years, with patients ranging from 25-92 years old. The majority of the patients 999.8%) were women as breast cancer is more common among women. The racial distribution was the following: White patients were 66%, Asian patients were 22%, other/ unknown patients were 10%, Black/ African American patients were 1.4%, and American Indian/ Alaskan Natives were 0.9%. - The median duration of treatment and exposure to Piqray was about 8.2 months, with an average of 59% of patients’ treatment lasting more than 6 months. - About 98% of the patients received hormonal therapy prior to initiating the treatment with the study. About 13% of the patients showed signs of primary endocrine resistance which means patients’ diseases progress in less than 6months of endocrine therapy, or relapse within 24 months of initiating therapy. About 72% of patients were observed to have secondary resistance defined as relapse after 24 months consecutive months of hormone therapy, relapsed within 12 months with the same criteria, or disease progression within 6 months of initiating therapy. - There was no benefit of PFS (Progression-free survival) shown for patients who did not have a PIK3CA tissue mutation. The results for patients with the PIK3CA tissue or plasma mutations showed consistency. - About 27% of the patients in the 341 patients cohort had died by the evaluation of PFS # How Supplied - Alpelisib comes in 3 strengths: 50 mg, 150 mg, and 200 mg film-coated tablets - Patients may be advised to take this medication in strengths of 300 mg, 250 mg, and 200 mg - 300 mg: They come in cartons with 2 blister packs. Each of the blister packs has a 14-day supply of 28 tablets because the strengths of each tablet is 150 mg. - 250 mg: This carton contains 2 blister packs. Each of the packs contains a 14-day supply of 28 tablets which means that there are 14 tablets of 200 mg strength and 14 tablets of 50 mg strength in each packet. - 200 mg: Each carton for a 200 mg strength supply contains one blister pack with 28 tablets for 28 days ## Storage Alpelisib should be stored at 20°C to 25°C (68°F to 77°F), but is allowed to be exposed to temperatures ranging from 15°C and 30°C (59°F and 86°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### Severe Hypersensitivity - Advise patients of the risk of severe hypersensitivity to Alpelisib or any of its contents. Symptoms of severe hypersensitivity include dyspnea, flushing, rash, fever, and/or tachycardia. - If these signs or symptoms occur, advise patients to call their healthcare professional immediately. - This may result in discontinuation of the drug ### Severe Cutaneous Reaction - Advise and counsel patients on the signs and symptoms of severe cutaneous reactions: prodrome of fever, flu-like symptoms, mucosal lesions or progressive skin rash) These reactions could possibly be lethal if nothing is done about it - These reactions could possibly be lethal if nothing is done about it - Advise patients to immediately call their doctor if any of these signs/ symptoms occurs. - Inform patients that there is a possibility of developing hyperglycemia through the treatment of Alpelisib - Patients must note the importance of monitoring blood-glucose levels “periodically” throughout treatment and for a while after - Patients should be made aware of the signs and symptoms of hyperglycemia: excessive thirst, urinating more often than usual or higher amount of urine than usual, or increased appetite with weight loss. ### Pneumonitis - Patients should be asked if they have a history of pneumonitis - Advise patients to contact the healthcare provider immediately if they experience any respiratory problems including hypoxia, cough, dyspnea, or interstitial infiltrates - Depending on the severity of the disease, patients may be required to stop treatment and use of Alpelisib ### Diarrhea - Warn patients that treatment of Alpelisib may cause mild to severe diarrhea - If diarrhea is severe, patients will need to discontinue the drug - Advise and counsel patients that they may need to take antidiarrheal medication and increase fluids - Additionally, patients will need to contact their healthcare provider if this problem occurs because severe cases may require patients to permanently discontinue the medication ### Embryo-Fetal Toxicity - Counsel pregnant women and women with reproductive potential on the effects Alpelisib may have on a fetus (see warnings) A patient should notify their healthcare provider immediately if they become/ suspect they are pregnant while undergoing treatment with Alpelisib - A patient should notify their healthcare provider immediately if they become/ suspect they are pregnant while undergoing treatment with Alpelisib - Females undergoing treatment with reproductive potential are strongly advised to wear contraception during treatment and 1 week after the last dose. Males/ male patients with female partners of the same caliber are strongly advised to wear protections and contraception during treatment and 1 week after the last dose ### Discontinuation - Patients will be advised to temporarily or permanently discontinue the medication if adverse reactions become severe or persist. ### Infusion reactions - Advise patients that administration of ALPELISIB may result in infusion reactions. # Precautions with Alcohol Alcohol-Alpelisib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Piqray # Look-Alike Drug Names There is limited information regarding ALPELISIB Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	Alpelisib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Uma Maveli[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 Alpelisib is a kinase inhibitors that is FDA approved for the treatment of . There is a Black Box Warning for this drug as shown here. Common adverse reactions include The most common adverse reactions for patients indicated for Alpelisib come in the form of laboratory abnormalities. They include increase in glucose, creatinine, GGT, ALT, or lipase, decrease in lymphocyte count, hemoglobin, appetite, weight, calcium, or glucose, the presence of diarrhea, rash, nausea, fatigue or alopecia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### ALPELISIB is indicated for: - PIQRAY is indicated for advanced metastatic breast cancer- hormone receptor positive, human epidermal growth factor receptor 2 negative, and PIK3CA mutated - The breast cancer is measured by an approved FDA test - It is a kinase inhibitor that is given concurrently with fulvestrant, a medication used to treat post menopause women with the conditions listed above ### Limitations of Use - Patients may have severe reactions to the treatment of Alpelisib (see warnings and adverse reactions for more in depth description) - Alpelisib can cause impairment of fertility and fetal health problems ### Dosing Considerations - Alpelisib appears as tablets, and comes in the dose strengths 50 mg, 150 mg, and 200 mg - Continue the recommended dose of 300 mg or the other prescribed dose by the medical administrator until the disease progresses or the toxicity becomes unacceptable - The recommended dose of fulvestrant is 500 mg along with Alpelisib. This should be administered on days 1, 15, and 29 of treatment and continue with once monthly after. ### Administration of ALPELISIB - The recommended dose for patients is 300 mg taken orally daily once along with food - The tablets appear in various strengths because adverse reactions (see adverse reactions) may cause patients to temporarily or permanently discontinue this medication ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding ALPELISIB Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding ALPELISIB 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 ALPELISIB FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding ALPELISIB Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding ALPELISIB Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - Patients may be advised to withhold this medication for a certain time period because of severe hypersensitivity to Alpelisib or any of its components (check components on the label or talk to a medical professional for more information) # Warnings ### Severe Cutaneous Reaction - Less than 2 percent of the patients have shown these possibly lethal reactions connected to the skin and mucous membranes that could be linked to eyes, ears, nose, mouth, lips etc - Diseases including Stevens-Johns Syndrome (0.4% of the patients) and Erythema Multiforme (1.1% of the patients) were linked to patients consuming or using this medication - Treatment with Piqray will not be initiated in patients with histories of this disease. Additionally patients who have had severe cutaneous reactions while undergoing treatment with this disease will not be reintroduced to Piqray - If symptoms appear in patients, temporarily discontinue the medications immediately If the signs/ symptoms are confirmed to be associated with Severe Cutaneous Reactions, patients will have to permanently discontinue the medication - If the signs/ symptoms are confirmed to be associated with Severe Cutaneous Reactions, patients will have to permanently discontinue the medication - If the reactions are not associated with Severe Cutaneous Reactions, there may be a need of dose modifications - Hyperglycemia has been reported in 65% of patients utilizing this medication. Some signs and symptoms of this disease could include excessive thirst, urinating more often than usual or higher amount of urine than usual, or increased appetite with weight loss. Ketoacidosis was reported in 0.7% of patients - Ketoacidosis was reported in 0.7% of patients - Studies have shown patients usually show signs of hyperglycemia a median time of 15 days into treatment - It is advised for patients to be tested to track FPG, HbA1c levels, and to optimize the blood glucose before initiating Piqray treatment - The FPG and blood glucose levels should be monitored for at least the first 8 weeks, once a week. Later, there should be a checkup every 2 weeks, and the time indicated by the doctor. - Patients should consider meeting with a professional with expertise in treating hyperglycemia. They may be able to help counsel the patients on lifestyle changes. - Clinical studies have not tested the effect of Piqray on patients with Type 1 diabetes and uncontrolled Type 2 diabetes. Therefore, the safety of combining these diseases with Piqray has not yet been established. Patients should check with a medical practitioner and weight the pros and cons. Patients with controlled Type 2 diabetes and Diabetes Mellitus were included, and it is advised to closely monitor these patients using Piqray. - Patients with controlled Type 2 diabetes and Diabetes Mellitus were included, and it is advised to closely monitor these patients using Piqray. - Patients may have to temporarily or permanently discontinue or reduce dose and treatment of Piqray based on the severity of the hyperglycemia present. ### Pneumonitis - Pneumonitis was discovered in 1.8% of the patients who were treated with Piqray - Common forms of pneumonitis present within these patients are acute interstitial pneumonitis and interstitial lung disease - If patients begin showing signs and symptoms of pneumonitis, immediately discontinue the drug until the presence of the disease is either confirmed or denied. Symptoms of non-infectious pneumonitis include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. There are no studies performed on patients with infectious or neoplastic pneumonitis because there are no means for an appropriate investigation. - Symptoms of non-infectious pneumonitis include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. There are no studies performed on patients with infectious or neoplastic pneumonitis because there are no means for an appropriate investigation. - If patients are diagnosed with pneumonitis, discontinue the drug immediately. If they continue to have worsening symptoms, contact a medical professional immediately. ### Diarrhea - Severe diarrhea, that resulted in dehydration and acute kidney injury, have been present in 58% of patients undergoing treatment with Piqray. - In a study, 6% of patients required dose reduction, and 2.8% of the people were required to permanently discontinue the drug. There were a total of 164 patients that experienced a case of diarrhea, and 63% of the patients needed to take anti-diarrheal medications. - Patients may have to temporarily or permanently discontinue the drug, or reduce the dose if a problem with diarrhea persists or becomes severe ### Embryo-Fetal Toxicity - Female rats and rabbits pregnant were administered doses of Piqray. These studies have shown the effect Piqray can have on the mothers, and fetuses. It caused adverse developmental outcomes including embryo-fetal mortality, loss of fetal weight, and increased cases in fetal malformation. - Pregnant females, and females with reproductive potential should be advised to use effective contraception during treatment, and 1 week after the last dose. Male patients should also use effective contraception and condoms during treatment and for 1 week after the last dose. - Patients are advised to reach out to healthcare professionals if any adverse reactions persist. - Patients should talk to their healthcare provider for more information on routine checkups after discontinuing treatment ### Infusion Reactions - There is limited information on infusion reactions pertaining to Alpelisib. Contact a doctor immediately if an adverse reactions occur (see adverse reactions) # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Alpelisib Clinical Trials Experience in the drug label. ## Postmarketing Experience There is limited information regarding Alpelisib Postmarketing Experience in the drug label. # Drug Interactions ### CYP3A4 Inducer Administering Alpelisib along with a CYP3A4 Inducer may result in a decrease in Alpelisib concentration, and a decrease in effectiveness and activity. Patients should avoid co-administering Alpelisib with strong CYP3A4 inducers. ### BCRP Inhibitors Administering Alpelisib with BCRP inhibitors increases Alpelisib concentrations that can result in the risk of toxicity in patients. Coadministering Alpelisib with BCRP inhibitors should be avoided. If it is not possible to completely avoid, patients should be closely monitored for adverse reactions. ### CYP2C9 Substrates Administering Alpelisib with CYP2C9 substrates may result in reduced plasma concentrations of the drugs it is administered with. It is advised to monitor patients closely for a decrease in plasma concentrations because that can cause reduced activity and effectiveness of the drugs. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There are no available data on ALPELISIB use in pregnant women to inform a drugassociated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alpelisib in women who are pregnant. ### Labor and Delivery The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. ### Nursing Mothers Women should not breastfeed while undergoing treatment with this medication and for 1 week after the last dose. ### Pediatric Use The safety and efficacy of ALPELISIB for the treatment of PNH in pediatric patients have not been established. ### Geriatic Use There were 117 patients in Solar-1 Clinical Trial that were of age 65 or older, and of that 75 patients were of the age 75 and up. There was a higher percentage of cases of Grade 3 or 4 hyperglycemia (44%) in patients of the age 65 and older compared to the incidence in patients less than the age of 65 (32%). Studies did not show a significant gap in effectiveness of Piqray comparing patients less than 65 years, and patients greater than 65 years of age. ### Gender There is no FDA guidance on the use of ALPELISIB with respect to specific gender populations. ### Race There is no FDA guidance on the use of ALPELISIB with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of ALPELISIB in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of ALPELISIB in patients with hepatic impairment. ### Females of Reproductive Potential and Males FDA guidance suggests healthcare providers should advise and counsel all patients with reproductive potential that ALPELISIB may impair fertility. ### Immunocompromised Patients There is no FDA guidance one the use of ALPELISIB in patients who are immunocompromised. # Administration and Monitoring ### Administration - Piqray is administered orally ### Monitoring There is limited information regarding Alpelisib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Alpelisib and IV administrations. # Overdosage In cases of overdosage with Piqray, patients showed a similar set of adverse reactions as indicated in Piqray’s profile. These include hyperglycemia, nausea, rash, and asthenia. There are no established protocol to entail to Piqray overdose. As in all cases of overdose with every drug, “Initiate general symptomatic and supportive measures in all cases” If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Phosphatidylinositol-3-kinase-a (PI3Ka) mediates cell proliferation as a result of the growth-factor tyrosine kinase pathway activation. PI3Ka’s subunit is mutated in some cancers that make it hyperactive and out of control. Alpelisib inhibits PI3Ka with the highest specificity for it. ## Structure There is limited information regarding ALPELISIB Structure in the drug label. ## Pharmacodynamics There is limited information regarding Alpelisib Pharmacodynamics in the drug label. ## Pharmacokinetics - The volume of distribution is 114 L - 36% of Alpelisib is eliminated as the unchanged drug and 32% as the primary metabolite BZG791 through feces. These are for oral doses. - 2% of the oral dose for Alpelisib is eliminated as the unchanged drug and 7.1% as the primary metabolite through urine - 81% of an oral dose is eliminated in the faces and 14% in the urine - Advise patients to not breastfeed while undergoing treatment with Alpelisib and 1 week after the administration of the last dose ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Studies of carcinogenicity and mutagenicity have not yet been performed # Clinical Studies ### Study SOLAR-1 (NCT02437318) - It was a randomized, placebo controlled trial. The trail had two groups of subjects: the patients who got Piqray and fulvestrant vs the patients who got a placebo and fulvestrant. The trial was conducted with 572 patients with “HER2-negative, advanced or metastatic breast cancer whose disease had progressed or recurred on or after an aromatase inhibitor-based treatment.” - Patients with causes of adverse reactions or adverse reactions such as inflammatory breast cancer, Type 1 diabetes, uncontrolled Type 2 diabetes, or pneumonitis were not included in the study. - 60% of the enrolled patients had tumors with 1 or more PIK3CA mutations, about 50% had had liver or lung metastases, and about 6% had been previously treated with a CDK4 or 6 inhibitor The randomized section was if the patient had liver/ lung metastases and/or been previously treated with a CDK4 or 6 inhibitor - The randomized section was if the patient had liver/ lung metastases and/or been previously treated with a CDK4 or 6 inhibitor - Division of patients: there were 341 patients in the trial cohort who had at least one PIK3CA mutation and 231 patients in the trial cohorts who did not show the presence of the mutation. Of the patients who had the mutation, about 99% of the patients also had the 1 or more mutations confirmed with a FDA test. - Patients were put into 2 different groups, so they either received Piqray and fulvestrant or they received a placebo and fulvestrant. The dose of fulvestrant (500 mg) was administered intramuscularly on Days 1 and 15 of the first Cycle, and every first day of the following cycles. The patients continue the treatment in their respective groups until the cancer is shown to progress on radiographs or the patient experiences unacceptable toxicity. The tumors were assessed once every 8 weeks for the first 18 months, and every 12 weeks following the initial period. - Demographics: the median age of the patients was 63 years, with patients ranging from 25-92 years old. The majority of the patients 999.8%) were women as breast cancer is more common among women. The racial distribution was the following: White patients were 66%, Asian patients were 22%, other/ unknown patients were 10%, Black/ African American patients were 1.4%, and American Indian/ Alaskan Natives were 0.9%. - The median duration of treatment and exposure to Piqray was about 8.2 months, with an average of 59% of patients’ treatment lasting more than 6 months. - About 98% of the patients received hormonal therapy prior to initiating the treatment with the study. About 13% of the patients showed signs of primary endocrine resistance which means patients’ diseases progress in less than 6months of endocrine therapy, or relapse within 24 months of initiating therapy. About 72% of patients were observed to have secondary resistance defined as relapse after 24 months consecutive months of hormone therapy, relapsed within 12 months with the same criteria, or disease progression within 6 months of initiating therapy. - There was no benefit of PFS (Progression-free survival) shown for patients who did not have a PIK3CA tissue mutation. The results for patients with the PIK3CA tissue or plasma mutations showed consistency. - About 27% of the patients in the 341 patients cohort had died by the evaluation of PFS # How Supplied - Alpelisib comes in 3 strengths: 50 mg, 150 mg, and 200 mg film-coated tablets - Patients may be advised to take this medication in strengths of 300 mg, 250 mg, and 200 mg - 300 mg: They come in cartons with 2 blister packs. Each of the blister packs has a 14-day supply of 28 tablets because the strengths of each tablet is 150 mg. - 250 mg: This carton contains 2 blister packs. Each of the packs contains a 14-day supply of 28 tablets which means that there are 14 tablets of 200 mg strength and 14 tablets of 50 mg strength in each packet. - 200 mg: Each carton for a 200 mg strength supply contains one blister pack with 28 tablets for 28 days ## Storage Alpelisib should be stored at 20°C to 25°C (68°F to 77°F), but is allowed to be exposed to temperatures ranging from 15°C and 30°C (59°F and 86°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### Severe Hypersensitivity - Advise patients of the risk of severe hypersensitivity to Alpelisib or any of its contents. Symptoms of severe hypersensitivity include dyspnea, flushing, rash, fever, and/or tachycardia. - If these signs or symptoms occur, advise patients to call their healthcare professional immediately. - This may result in discontinuation of the drug ### Severe Cutaneous Reaction - Advise and counsel patients on the signs and symptoms of severe cutaneous reactions: prodrome of fever, flu-like symptoms, mucosal lesions or progressive skin rash) These reactions could possibly be lethal if nothing is done about it - These reactions could possibly be lethal if nothing is done about it - Advise patients to immediately call their doctor if any of these signs/ symptoms occurs. - Inform patients that there is a possibility of developing hyperglycemia through the treatment of Alpelisib - Patients must note the importance of monitoring blood-glucose levels “periodically” throughout treatment and for a while after - Patients should be made aware of the signs and symptoms of hyperglycemia: excessive thirst, urinating more often than usual or higher amount of urine than usual, or increased appetite with weight loss. ### Pneumonitis - Patients should be asked if they have a history of pneumonitis - Advise patients to contact the healthcare provider immediately if they experience any respiratory problems including hypoxia, cough, dyspnea, or interstitial infiltrates - Depending on the severity of the disease, patients may be required to stop treatment and use of Alpelisib ### Diarrhea - Warn patients that treatment of Alpelisib may cause mild to severe diarrhea - If diarrhea is severe, patients will need to discontinue the drug - Advise and counsel patients that they may need to take antidiarrheal medication and increase fluids - Additionally, patients will need to contact their healthcare provider if this problem occurs because severe cases may require patients to permanently discontinue the medication ### Embryo-Fetal Toxicity - Counsel pregnant women and women with reproductive potential on the effects Alpelisib may have on a fetus (see warnings) A patient should notify their healthcare provider immediately if they become/ suspect they are pregnant while undergoing treatment with Alpelisib - A patient should notify their healthcare provider immediately if they become/ suspect they are pregnant while undergoing treatment with Alpelisib - Females undergoing treatment with reproductive potential are strongly advised to wear contraception during treatment and 1 week after the last dose. Males/ male patients with female partners of the same caliber are strongly advised to wear protections and contraception during treatment and 1 week after the last dose ### Discontinuation - Patients will be advised to temporarily or permanently discontinue the medication if adverse reactions become severe or persist. ### Infusion reactions - Advise patients that administration of ALPELISIB may result in infusion reactions. # Precautions with Alcohol Alcohol-Alpelisib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Piqray # Look-Alike Drug Names There is limited information regarding ALPELISIB Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Alpelisib
1ee56cde5589ff24bb27621ebf0a9d95a30bf348	wikidoc	Alpha-GPC	Alpha-GPC # Overview L-Alpha Glycerylphosphorylcholine (Alpha GPC) is a naturally occurring phospholipid precursor and metabolite. Alpha GPC delivers choline to the brain across the blood-brain barrier. Studies have investigated its efficacy for cognitive disorders including stroke and Alzheimer’s Disease. An Italian multicentre clinical trial on 2,044 patients suffering from recent stroke were supplied alpha-GPC in doses of 1,000 mg/day for 28 days and 400 mg/day for five ensuing months. The trial confirmed the therapeutic role of alpha-GPC on the cognitive recovery of patients based on four measurement scales, three of which reached statistical significance.	Alpha-GPC # Overview L-Alpha Glycerylphosphorylcholine (Alpha GPC) is a naturally occurring phospholipid precursor and metabolite. Alpha GPC delivers choline to the brain across the blood-brain barrier. Studies have investigated its efficacy for cognitive disorders including stroke and Alzheimer’s Disease. An Italian multicentre clinical trial on 2,044 patients suffering from recent stroke were supplied alpha-GPC in doses of 1,000 mg/day for 28 days and 400 mg/day for five ensuing months. The trial confirmed the therapeutic role of alpha-GPC on the cognitive recovery of patients based on four measurement scales, three of which reached statistical significance.[1]	https://www.wikidoc.org/index.php/Alpha-GPC
ee2f997d876553833271cedb09d63f18e0cdb511	wikidoc	Meprodine	Meprodine Meprodine is an opioid analgesic that is an analogue of pethidine (meperidine). It is closely related to the drug prodine, the only difference being that meprodine has an ethyl group rather than a methyl at the 3-position of the piperidine ring. As with prodine, there are two isomers of meprodine, Alphameprodine and Betameprodine, with the α isomer having been more widely used. Meprodine has similar effects to other opioids, and produces analgesia, sedation and euphoria. Side effects can include itching, nausea and potentially serious respiratory depression which can be life-threatening.	Meprodine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Meprodine is an opioid analgesic that is an analogue of pethidine (meperidine). It is closely related to the drug prodine, the only difference being that meprodine has an ethyl group rather than a methyl at the 3-position of the piperidine ring. As with prodine, there are two isomers of meprodine, Alphameprodine and Betameprodine, with the α isomer having been more widely used. Meprodine has similar effects to other opioids, and produces analgesia, sedation and euphoria. Side effects can include itching, nausea and potentially serious respiratory depression which can be life-threatening.	https://www.wikidoc.org/index.php/Alphameprodine
3ed7cfd72a7a47628c36519dad9b4c03b7da9bd0	wikidoc	Aluminium	Aluminium # Overview Aluminium (Template:IPAEng, Template:IPA) or aluminum (Template:IPA, see spelling below) is a silvery white and ductile member of the poor metal group of chemical elements. It has the symbol Al; its atomic number is 13. Aluminium is the most abundant metal in the Earth's crust, and the third most abundant element overall, after oxygen and silicon. It makes up about 8% by weight of the Earth’s solid surface. Aluminium is too reactive chemically to occur in nature as the free metal. Instead, it is found combined in over 270 different minerals. The chief source of aluminium is bauxite ore. Aluminium is remarkable for its ability to resist corrosion (due to the phenomenon of passivation) and its light weight. Structural components made from aluminium and its alloys are vital to the aerospace industry and very important in other areas of transportation and building. # History Ancient Greeks and Romans used aluminium salts as dyeing mordants and as astringents for dressing wounds; alum is still used as a styptic. In 1761 Guyton de Morveau suggested calling the base alum alumine. In 1808, Humphry Davy identified the existence of a metal base of alum, which he at first termed alumium and later aluminum (see Etymology section, below). Friedrich Wöhler is generally credited with isolating aluminium (Latin alumen, alum) in 1827 by mixing anhydrous aluminium chloride with potassium. The metal was, however, produced for the first time two years earlier (in an impure form) by the Danish physicist and chemist Hans Christian Ørsted. Therefore, Ørsted can also be listed as the discoverer of the metal. Further, Pierre Berthier discovered aluminium in bauxite ore and successfully extracted it. The Frenchman Henri Etienne Sainte-Claire Deville improved Wöhler's method in 1846 and described his improvements in a book in 1859, chief among these being the substitution of sodium for the considerably more expensive potassium. (Note: The title of Deville's book is "De l'aluminium, ses propriétés, sa fabrication" (Paris, 1859). It was rather likely that Deville also conceived the idea of the electrolysis of aluminium oxide dissolved in cryolite; however, Charles Martin Hall and Paul Héroult might have developed the more practical process after Deville.) Before the Hall-Héroult process was developed, aluminium was initially found to be exceedingly difficult to extract from its various ores. This made pure aluminium more valuable than gold. Bars of aluminium were exhibited alongside the French crown jewels at the Exposition Universelle of 1855, and Napoleon III was said to have reserved a set of aluminium dinner plates for his most honored guests. Aluminium was selected as the material to be used for the apex of the Washington Monument in 1884, a time when one ounce (30 grams) cost the daily wage of a common worker on the project; aluminium was about the same value as silver. The Cowles companies supplied aluminium alloy in quantity in the United States and England using smelters like the furnace of Carl Wilhelm Siemens by 1886. Charles Martin Hall of Ohio in the U.S. and Paul Héroult of France independently developed the Hall-Héroult electrolytic process that made extracting aluminium from minerals cheaper and is now the principal method used worldwide. The Hall-Heroult process cannot produce Super Purity Aluminium directly. Hall's process, in 1888 with the financial backing of Alfred E. Hunt, started the Pittsburgh Reduction Company today known as Alcoa. Héroult's process was in production by 1889 in Switzerland at Aluminium Industrie, now Alcan, and atBritish Aluminium, now Luxfer Group and Alcoa, by 1896 in Scotland. By 1895 the metal was being used as a building material as far away as Sydney, Australia in the dome of the Chief Secretary's Building. # Etymology ## Nomenclature history The earliest citation given in the gay Oxford English Dictionary for any word used as a name for this element is alumium, which Humphry Davy employed in 1808 for the metal he was trying to isolate electrolytically from the mineral alumina. The citation is from his journal Philosophical Transactions: "Had I been so fortunate as..to have procured the metallic substances I was in search of, I should have proposed for them the names of silicium, alumium, zirconium, and glucium." By 1812, Davy had settled on aluminum, which, as other sources note, matches its Latin root. He wrote in the journal Chemical Philosophy: "As yet Aluminum has not been obtained in a perfectly free state." But the same year, an anonymous contributor to the Quarterly Review, a British political-literary journal, objected to aluminum and proposed the name aluminium, "for so we shall take the liberty of writing the word, in preference to aluminum, which has a less classical sound." The -ium suffix had the advantage of conforming to the precedent set in other newly discovered elements of the time: potassium, sodium, magnesium, calcium, and strontium (all of which Davy had isolated himself). Nevertheless, -um spellings for elements were not unknown at the time, as for example platinum, known to Europeans since the sixteenth century, molybdenum, discovered in 1778, and tantalum, discovered in 1802. Americans adopted -ium to fit the standard form of the periodic table of elements, for most of the nineteenth century, with aluminium appearing in Webster's Dictionary of 1828. In 1892, however, Charles Martin Hall used the -um spelling in an advertising handbill for his new electrolytic method of producing the metal, despite his constant use of the -ium spelling in all the patents he filed between 1886 and 1903. It has consequently been suggested that the spelling reflects an easier to pronounce word with one fewer syllable, or that the spelling on the flier was a spelling mistake. Hall's domination of production of the metal ensured that the spelling aluminum became the standard in North America; the Webster Unabridged Dictionary of 1913, though, continued to use the -ium version. In 1926, the American Chemical Society officially decided to use aluminum in its publications; American dictionaries typically label the spelling aluminium as a British variant. ## Present-day spelling In the UK and other countries using British spelling, only aluminium is used. In the United States, the spelling aluminium is largely unknown, and the spelling aluminum predominates. The Canadian Oxford Dictionary prefers aluminum, whereas the Australian Macquarie Dictionary prefers aluminium. The spelling in virtually all other languages is analogous to the -ium ending. The International Union of Pure and Applied Chemistry (IUPAC) adopted Aluminium as the standard international name for the element in 1990, but three years later recognized aluminum as an acceptable variant. Hence their periodic table includes both, but places aluminium first. IUPAC officially prefers the use of Aluminium in its internal publications, although several IUPAC publications use the spelling aluminum. # Isotopes Aluminium has nine isotopes, whose mass numbers range from 23 to 30. Only 27Al (stable isotope) and 26Al (radioactive isotope, t1/2 = 7.2 × 105 y) occur naturally, however 27Al has a natural abundance of 99.9+ %. 26Al is produced from argon in the atmosphere by spallation caused by cosmic-ray protons. Aluminium isotopes have found practical application in dating marine sediments, manganese nodules, glacial ice, quartz in rock exposures, and meteorites. The ratio of 26Al to 10Be has been used to study the role of transport, deposition, sediment storage, burial times, and erosion on 105 to 106 year time scales. Cosmogenic 26Al was first applied in studies of the Moon and meteorites. Meteorite fragments, after departure from their parent bodies, are exposed to intense cosmic-ray bombardment during their travel through space, causing substantial 26Al production. After falling to Earth, atmospheric shielding protects the meteorite fragments from further 26Al production, and its decay can then be used to determine the meteorite's terrestrial age. Meteorite research has also shown that 26Al was relatively abundant at the time of formation of our planetary system. Most meteoriticists believe that the energy released by the decay of 26Al was responsible for the melting and differentiation of some asteroids after their formation 4.55 billion years ago. # Properties Aluminium is a soft, lightweight, malleable metal with appearance ranging from silvery to dull gray, depending on the surface roughness. Aluminium is nontoxic, nonmagnetic, and nonsparking. The yield strength of pure aluminium is 7–11 MPa, while aluminium alloys have yield strengths ranging from 200 MPa to 600 MPa. Aluminium has about one-third the density and stiffness of steel. It is ductile, and easily machined, cast, and extruded. Corrosion resistance is excellent due to a thin surface layer of aluminium oxide that forms when the metal is exposed to air, effectively preventing further oxidation. The strongest aluminium alloys are less corrosion resistant due to galvanic reactions with alloyed copper. Aluminium atoms are arranged in an FCC structure. Aluminium has a high stacking-fault energy of approximately 200 mJ/m². Aluminium is one of the few metals that retain full silvery reflectance in finely powdered form, making it an important component of silver paints. Aluminium mirror finish has the highest reflectance of any metal in the 200–400 nm (UV) and the 3000–10000 nm (far IR) regions, while in the 400–700 nm visible range it is slightly outdone by silver and in the 700–3000 (near IR) by silver, gold, and copper. Aluminium is a good thermal and electrical conductor, by weight better than copper. Aluminium is capable of being a superconductor, with a superconducting critical temperature of 1.2 kelvins. # Production and refinement Although aluminium is the most abundant metallic element in the Earth's crust (believed to be 7.5 to 8.1 percent), it is rare in its free form, occurring in oxygen-deficient environments such as volcanic mud, and it was once considered a precious metal more valuable than gold. Napoleon III, emperor of the French, is reputed to have given a banquet where the most honoured guests were given aluminium utensils, while the other guests had to make do with gold ones. Aluminium has been produced in commercial quantities for just over 100 years. Aluminium is a reactive metal that is difficult to extract from ore, aluminium oxide (Al2O3). For example, direct reduction with carbon is not economically viable, since aluminium oxide has a melting point of about 2,000 °C. Therefore, it is extracted by electrolysis; that is, the aluminium oxide is dissolved in molten cryolite and then reduced to the pure metal. By this process, the operational temperature of the reduction cells is around 950 to 980 °C. Cryolite is found as a mineral in Greenland, but in industrial use it has been replaced by a synthetic substance. Cryolite is a mixture of aluminium, sodium, and calcium fluorides: (Na3AlF6). The aluminium oxide (a white powder) is obtained by refining bauxite in the Bayer process of Karl Bayer. (Previously, the Deville process was the predominant refining technology.) The electrolytic process replaced the Wöhler process, which involved the reduction of anhydrous aluminium chloride with potassium. Both of the electrodes used in the electrolysis of aluminium oxide are carbon. Once the ore is in the molten state, its ions are free to move around. The reaction at the cathode — the negative terminal — is Here the aluminium ion is being reduced (electrons are added). The aluminium metal then sinks to the bottom and is tapped off. At the positive electrode (anode), oxygen is formed: This carbon anode is then oxidized by the oxygen, releasing carbon dioxide. The anodes in a reduction cell must therefore be replaced regularly, since they are consumed in the process: Unlike the anodes, the cathodes are not oxidised because there is no oxygen present at the cathode. The carbon cathode is protected by the liquid aluminium inside the cells. Nevertheless, cathodes do erode, mainly due to electrochemical processes. After five to ten years, depending on the current used in the electrolysis, a cell has to be rebuilt because of cathode wear. Aluminium electrolysis with the Hall-Héroult process consumes a lot of energy, but alternative processes were always found to be less viable economically and/or ecologically. The world-wide average specific energy consumption is approximately 15±0.5 kilowatt-hours per kilogram of aluminium produced from alumina. (52 to 56 MJ/kg). The most modern smelters reach approximately 12.8 kW·h/kg (46.1 MJ/kg). (Compare this to the heat of reaction, 31 MJ/kg, and the Gibbs free energy of reaction, 29 MJ/kg.) Reduction line current for older technologies are typically 100 to 200 kA. State-of-the-art smelters operate with about 350 kA. Trials have been reported with 500 kA cells. Recovery of the metal via recycling has become an important facet of the aluminium industry. Recycling involves melting the scrap, a process that uses only five percent of the energy needed to produce aluminium from ore. However, a significant part (up to 15% of input material) is lost as dross (ash-like oxide). Recycling was a low-profile activity until the late 1960s, when the growing use of aluminium beverage cans brought it to the public consciousness. Electric power represents about 20% to 40% of the cost of producing aluminium, depending on the location of the smelter. Smelters tend to be situated where electric power is both plentiful and inexpensive, such as South Africa, the South Island of New Zealand, Australia, the People's Republic of China, the Middle East, Russia, Quebec and British Columbia in Canada, and Iceland. In 2005, the People's Republic of China was the top producer of aluminium with almost one-fifth world share followed by Russia, Canada and USA reports the British Geological Survey. Over the last 50 years, Australia has become a major producer of bauxite ore and a major producer and exporter of alumina. Australia produced 62 million tonnes of bauxite in 2005. The Australian deposits have some refining problems, some being high in silica but have the advantage of being shallow and relatively easy to mine. # Chemistry ## Oxidation state one - AlH is produced when aluminium is heated in an atmosphere of hydrogen. - Al2O is made by heating the normal oxide, Al2O3, with silicon at 1800 °C in a vacuum. - Al2S can be made by heating Al2S3 with aluminium shavings at 1300 °C in a vacuum. It quickly disproportionates to the starting materials. The selenide is made in a parallel manner. - AlF, AlCl and AlBr exist in the gaseous phase when the tri-halide is heated with aluminium. Aluminium halides usually exist in the form AlX3. e.g. AlF3, AlCl3, AlBr3, AlI3 etc. ## Oxidation state two - Aluminium monoxide, AlO, is present when aluminium powder burns in oxygen. ## Oxidation state three - Fajans' rules show that the simple trivalent cation Al3+ is not expected to be found in anhydrous salts or binary compounds such as Al2O3. The hydroxide is a weak base and aluminium salts of weak acids, such as carbonate, can't be prepared. The salts of strong acids, such as nitrate, are stable and soluble in water, forming hydrates with at least six molecules of water of crystallization. - Aluminium hydride, (AlH3)n, can be produced from trimethylaluminium and an excess of hydrogen. It burns explosively in air. It can also be prepared by the action of aluminium chloride on lithium hydride in ether solution, but cannot be isolated free from the solvent. - Aluminium carbide, Al4C3 is made by heating a mixture of the elements above 1000 °C. The pale yellow crystals have a complex lattice structure, and react with water or dilute acids to give methane. The acetylide, Al2(C2)3, is made by passing acetylene over heated aluminium. - Aluminium nitride, AlN, can be made from the elements at 800 °C. It is hydrolysed by water to form ammonia and aluminium hydroxide. - Aluminium phosphide, AlP, is made similarly, and hydrolyses to give phosphine. - Aluminium oxide, Al2O3, occurs naturally as corundum, and can be made by burning aluminium in oxygen or by heating the hydroxide, nitrate or sulfate. As a gemstone, its hardness is only exceeded by diamond, boron nitride, and carborundum. It is almost insoluble in water. - Aluminium hydroxide may be prepared as a gelatinous precipitate by adding ammonia to an aqueous solution of an aluminium salt. It is amphoteric, being both a very weak acid, and forming aluminates with alkalis. It exists in various crystalline forms. - Aluminium sulfide, Al2S3, may be prepared by passing hydrogen sulfide over aluminium powder. It is polymorphic. - Aluminium iodide, (AlI3)2, is a dimer with applications in organic synthesis. - Aluminium fluoride, AlF3, is made by treating the hydroxide with HF, or can be made from the elements. It consists of a giant molecule which sublimes without melting at 1291 °C. It is very inert. The other trihalides are dimeric, having a bridge-like structure. - Aluminium fluoride/water complexes: When aluminium and fluoride are together in aqueous solution, they readily form complex ions such as AlF(H2O)5+2, AlF3(H2O)30, AlF6-3. Of these, AlF6-3 is the most stable. This is explained by the fact that aluminium and fluoride, which are both very compact ions, fit together just right to form the octahedral aluminium hexafluoride complex. When aluminium and fluoride are together in water in a 1:6 molar ratio, AlF6-3 is the most common form, even in rather low concentrations. - Organo-metallic compounds of empirical formula AlR3 exist and, if not also giant molecules, are at least dimers or trimers. They have some uses in organic synthesis, for instance trimethylaluminium. - Alumino-hydrides of the most electropositive elements are known, the most useful being lithium aluminium hydride, Li. It decomposes into lithium hydride, aluminium and hydrogen when heated, and is hydrolysed by water. It has many uses in organic chemistry, particularly as a reducing agent. The aluminohalides have a similar structure. ## Clusters In the journal Science of 14 January 2005 it was reported that clusters of 13 aluminium atoms (Al13) had been made to behave like an iodine atom; and, 14 aluminium atoms (Al14) behaved like an alkaline earth atom. The researchers also bound 12 iodine atoms to an Al13 cluster to form a new class of polyiodide. This discovery is reported to give rise to the possibility of a new characterisation of the periodic table: superatoms. The research teams were led by Shiv N. Khanna (Virginia Commonwealth University) and A. Welford Castleman Jr (Penn State University). # Applications ## General use Aluminium is the most widely used non-ferrous metal. Global production of aluminium in 2005 was 31.9 million tonnes. It exceeded that of any other metal except iron (837.5 million tonnes). Relatively pure aluminium is encountered only when corrosion resistance and/or workability is more important than strength or hardness. A thin layer of aluminium can be deposited onto a flat surface by physical vapor deposition or (very infrequently) chemical vapor deposition or other chemical means to form optical coatings and mirrors. When so deposited, a fresh, pure aluminium film serves as a good reflector (approximately 92%) of visible light and an excellent reflector (as much as 98%) of medium and far infrared. Pure aluminium has a low tensile strength, but when combined with thermo-mechanical processing, aluminium alloys display a marked improvement in mechanical properties, especially when tempered. Aluminium alloys form vital components of aircraft and rockets as a result of their high strength-to-weight ratio. Aluminium readily forms alloys with many elements such as copper, zinc, magnesium, manganese and silicon (e.g., duralumin). Today, almost all bulk metal materials that are referred to loosely as "aluminium," are actually alloys. For example, the common aluminium foils are alloys of 92% to 99% aluminium. Some of the many uses for aluminium metal are in: - Transportation (automobiles, aircraft, trucks, railway cars, marine vessels, bicycles etc.) - Packaging (cans, foil, etc.) - Water treatment - Treatment against fish parasites such as Gyrodactylus salaris. - Construction (windows, doors, siding, building wire, etc.) - Cooking utensils - Electrical transmission lines for power distribution - MKM steel and Alnico magnets - Super purity aluminium (SPA, 99.980% to 99.999% Al), used in electronics and CDs. - Heat sinks for electronic appliances such as transistors and CPUs. - Powdered aluminium is used in paint, and in pyrotechnics such as solid rocket fuels and thermite. - In the blades of prop swords and knives used in stage combat. ## Aluminium compounds - Aluminium ammonium sulfate (2), ammonium alum is used as a mordant, in water purification and sewage treatment, in paper production, as a food additive, and in leather tanning. - Aluminium acetate is a salt used in solution as an astringent. - Aluminium borate (Al2O3 B2O3) is used in the production of glass and ceramic. - Aluminium borohydride (Al(BH4)3) is used as an additive to jet fuel. - Aluminium chloride (AlCl3) is used: in paint manufacturing, in antiperspirants, in petroleum refining and in the production of synthetic rubber. - Aluminium chlorohydride is used as an antiperspirant and in the treatment of hyperhidrosis. - Aluminium fluorosilicate (Al2(SiF6)3) is used in the production of synthetic gemstones, glass and ceramic. - Aluminium hydroxide (Al(OH)3) is used: as an antacid, as a mordant, in water purification, in the manufacture of glass and ceramic and in the waterproofing of fabrics. - Aluminium oxide (Al2O3), alumina, is found naturally as corundum (rubies and sapphires), emery, and is used in glass making. Synthetic ruby and sapphire are used in lasers for the production of coherent light. - Aluminium phosphate (AlPO4) is used in the manufacture: of glass and ceramic, pulp and paper products, cosmetics, paints and varnishes and in making dental cement. - Aluminium sulfate (Al2(SO4)3) is used: in the manufacture of paper, as a mordant, in a fire extinguisher, in water purification and sewage treatment, as a food additive, in fireproofing, and in leather tanning. - In many vaccines, certain aluminium salts serve as an immune adjuvant (immune response booster) to allow the protein in the vaccine to achieve sufficient potency as an immune stimulant. ## Aluminium alloys in structural applications Aluminium alloys with a wide range of properties are used in engineering structures. Alloy systems are classified by a number system (ANSI) or by names indicating their main alloying constituents (DIN and ISO). The strength and durability of aluminium alloys vary widely, not only as a result of the components of the specific alloy, but also as a result of heat treatments and manufacturing processes. A lack of knowledge of these aspects has from time to time led to improperly designed structures and gained aluminium a bad reputation. (See main article) One important structural limitation of aluminium alloys is their fatigue strength. Unlike steels, aluminium alloys have no well-defined fatigue limit, meaning that fatigue failure will eventually occur under even very small cyclic loadings. This implies that engineers must assess these loads and design for a fixed life rather than an infinite life. Another important property of aluminium alloys is their sensitivity to heat. Workshop procedures involving heating are complicated by the fact that aluminium, unlike steel, will melt without first glowing red. Forming operations where a blow torch is used therefore requires some expertise, since no visual signs reveal how close the material is to melting. Aluminium alloys, like all structural alloys, also are subject to internal stresses following heating operations such as welding and casting. The problem with aluminium alloys in this regard is their low melting point, which make them more susceptible to distortions from thermally induced stress relief. Controlled stress relief can be done during manufacturing by heat-treating the parts in an oven, followed by gradual cooling -- in effect annealing the stresses. The low melting point of aluminium alloys has not precluded their use in rocketry; even for use in constructing combustion chambers where gases can reach 3500 K. The Agena upper stage engine used a regeneratively cooled aluminium design for some parts of the nozzle, including the thermally critical throat region. ## Household wiring Aluminium has about 65% of the conductivity of copper, the traditional household wiring material. In the 1960s aluminium was considerably cheaper than copper, and so was introduced for household electrical wiring in the United States, even though many fixtures had not been designed to accept aluminium wire. However, in some cases the greater coefficient of thermal expansion of aluminium causes the wire to expand and contract relative to the dissimilar metal screw connection, eventually loosening the connection. Also, pure aluminium has a tendency to creep under steady sustained pressure (to a greater degree as the temperature rises), again loosening the connection. Finally, Galvanic corrosion from the dissimilar metals increased the electrical resistance of the connection. All of this resulted in overheated and loose connections, and this in turn resulted in fires. Builders then became wary of using the wire, and many jurisdictions outlawed its use in very small sizes in new construction. Eventually, newer fixtures were introduced with connections designed to avoid loosening and overheating. At first they were marked "Al/Cu", but they now bear a "CO/ALR" coding. In older assemblies, workers forestall the heating problem using a properly-done crimp of the aluminium wire to a short "pigtail" of copper wire. Today, new alloys, designs, and methods are used for aluminium wiring in combination with aluminium terminations. # Precautions Aluminium is a neurotoxin that alters the function of the blood-brain barrier. It is one of the few abundant elements that appear to have no beneficial function to living cells. A small percent of people are allergic to it — they experience contact dermatitis from any form of it: an itchy rash from using styptic or antiperspirant products, digestive disorders and inability to absorb nutrients from eating food cooked in aluminium pans, and vomiting and other symptoms of poisoning from ingesting such products as Amphojel, and Maalox (antacids). In other people, aluminium is not considered as toxic as heavy metals, but there is evidence of some toxicity if it is consumed in excessive amounts. The use of aluminium cookware, popular because of its corrosion resistance and good heat conduction, has not been shown to lead to aluminium toxicity in general. Excessive consumption of antacids containing aluminium compounds and excessive use of aluminium-containing antiperspirants are more likely causes of toxicity. In research published in the Journal of Applied Toxicology, Dr. Philippa D. Darby of the University of Reading has shown that aluminium salts increase estrogen-related gene expression in human breast cancer cells grown in the laboratory. These salts' estrogen-like effects have led to their classification as a metalloestrogen. It has been suggested that aluminium is a cause of Alzheimer's disease, as some brain plaques have been found to contain the metal. Research in this area has been inconclusive; aluminium accumulation may be a consequence of the Alzheimer's damage, not the cause. In any event, if there is any toxicity of aluminium it must be via a very specific mechanism, since total human exposure to the element in the form of naturally occurring clay in soil and dust is enormously large over a lifetime. Mercury applied to the surface of an aluminium alloy can damage the protective oxide surface film by forming amalgam. This may cause further corrosion and weakening of the structure. For this reason, mercury thermometers are not allowed on many airliners, as aluminium is used in many aircraft structures. Powdered aluminium can react with Fe2O3 to form Fe and Al2O3. This mixture is known as thermite, which burns with a high energy output. Thermite can be produced inadvertently during grinding operations, but the high ignition temperature makes incidents unlikely in most workshop environments. ## Aluminium and plants (phytoremediation) Aluminium is primary among the factors that contribute to the loss of plant production on acid soils. Although it is generally harmless to plant growth in pH-neutral soils, the concentration in acid soils of toxic Al3+ cations increases and disturbs root growth and function. Wheat's adaptation to allow aluminium tolerance is such that the aluminium induces a release of organic compounds that bind to the harmful aluminium cations. Sorghum is believed to have the same tolerance mechanism. The first gene for aluminium tolerance has been identified in wheat. A group in the U.S. Department of Agriculture showed that sorghum's aluminium tolerance is controlled by a single gene, as for wheat. This is not the case in all plants.	Aluminium Template:Infobox aluminium # Overview Aluminium (Template:IPAEng, Template:IPA) or aluminum (Template:IPA, see spelling below) is a silvery white and ductile member of the poor metal group of chemical elements. It has the symbol Al; its atomic number is 13. Aluminium is the most abundant metal in the Earth's crust, and the third most abundant element overall, after oxygen and silicon. It makes up about 8% by weight of the Earth’s solid surface. Aluminium is too reactive chemically to occur in nature as the free metal. Instead, it is found combined in over 270 different minerals.[1] The chief source of aluminium is bauxite ore. Aluminium is remarkable for its ability to resist corrosion (due to the phenomenon of passivation) and its light weight. Structural components made from aluminium and its alloys are vital to the aerospace industry and very important in other areas of transportation and building. # History Ancient Greeks and Romans used aluminium salts as dyeing mordants and as astringents for dressing wounds; alum is still used as a styptic. In 1761 Guyton de Morveau suggested calling the base alum alumine. In 1808, Humphry Davy identified the existence of a metal base of alum, which he at first termed alumium and later aluminum (see Etymology section, below). Friedrich Wöhler is generally credited with isolating aluminium (Latin alumen, alum) in 1827 by mixing anhydrous aluminium chloride with potassium. The metal was, however, produced for the first time two years earlier (in an impure form) by the Danish physicist and chemist Hans Christian Ørsted. Therefore, Ørsted can also be listed as the discoverer of the metal.[2] Further, Pierre Berthier discovered aluminium in bauxite ore and successfully extracted it.[3] The Frenchman Henri Etienne Sainte-Claire Deville improved Wöhler's method in 1846 and described his improvements in a book in 1859, chief among these being the substitution of sodium for the considerably more expensive potassium. (Note: The title of Deville's book is "De l'aluminium, ses propriétés, sa fabrication" (Paris, 1859). It was rather likely that Deville also conceived the idea of the electrolysis of aluminium oxide dissolved in cryolite; however, Charles Martin Hall and Paul Héroult might have developed the more practical process after Deville.) Before the Hall-Héroult process was developed, aluminium was initially found to be exceedingly difficult to extract from its various ores. This made pure aluminium more valuable than gold. Bars of aluminium were exhibited alongside the French crown jewels at the Exposition Universelle of 1855, and Napoleon III was said to have reserved a set of aluminium dinner plates for his most honored guests. Aluminium was selected as the material to be used for the apex of the Washington Monument in 1884, a time when one ounce (30 grams) cost the daily wage of a common worker on the project;[4] aluminium was about the same value as silver. The Cowles companies supplied aluminium alloy in quantity in the United States and England using smelters like the furnace of Carl Wilhelm Siemens by 1886.[5] Charles Martin Hall of Ohio in the U.S. and Paul Héroult of France independently developed the Hall-Héroult electrolytic process that made extracting aluminium from minerals cheaper and is now the principal method used worldwide. The Hall-Heroult process cannot produce Super Purity Aluminium directly. Hall's process,[6] in 1888 with the financial backing of Alfred E. Hunt, started the Pittsburgh Reduction Company today known as Alcoa. Héroult's process was in production by 1889 in Switzerland at Aluminium Industrie, now Alcan, and atBritish Aluminium, now Luxfer Group and Alcoa, by 1896 in Scotland.[7] By 1895 the metal was being used as a building material as far away as Sydney, Australia in the dome of the Chief Secretary's Building. # Etymology ## Nomenclature history The earliest citation given in the gay Oxford English Dictionary for any word used as a name for this element is alumium, which Humphry Davy employed in 1808 for the metal he was trying to isolate electrolytically from the mineral alumina. The citation is from his journal Philosophical Transactions: "Had I been so fortunate as..to have procured the metallic substances I was in search of, I should have proposed for them the names of silicium, alumium, zirconium, and glucium."[8] By 1812, Davy had settled on aluminum, which, as other sources note, matches its Latin root. He wrote in the journal Chemical Philosophy: "As yet Aluminum has not been obtained in a perfectly free state."[9] But the same year, an anonymous contributor to the Quarterly Review, a British political-literary journal, objected to aluminum and proposed the name aluminium, "for so we shall take the liberty of writing the word, in preference to aluminum, which has a less classical sound."[10] The -ium suffix had the advantage of conforming to the precedent set in other newly discovered elements of the time: potassium, sodium, magnesium, calcium, and strontium (all of which Davy had isolated himself). Nevertheless, -um spellings for elements were not unknown at the time, as for example platinum, known to Europeans since the sixteenth century, molybdenum, discovered in 1778, and tantalum, discovered in 1802. Americans adopted -ium to fit the standard form of the periodic table of elements, for most of the nineteenth century, with aluminium appearing in Webster's Dictionary of 1828. In 1892, however, Charles Martin Hall used the -um spelling in an advertising handbill for his new electrolytic method of producing the metal, despite his constant use of the -ium spelling in all the patents[6] he filed between 1886 and 1903.[11] It has consequently been suggested that the spelling reflects an easier to pronounce word with one fewer syllable, or that the spelling on the flier was a spelling mistake. Hall's domination of production of the metal ensured that the spelling aluminum became the standard in North America; the Webster Unabridged Dictionary of 1913, though, continued to use the -ium version. In 1926, the American Chemical Society officially decided to use aluminum in its publications; American dictionaries typically label the spelling aluminium as a British variant. ## Present-day spelling In the UK and other countries using British spelling, only aluminium is used. In the United States, the spelling aluminium is largely unknown, and the spelling aluminum predominates.[12][13] The Canadian Oxford Dictionary prefers aluminum, whereas the Australian Macquarie Dictionary prefers aluminium. The spelling in virtually all other languages is analogous to the -ium ending. The International Union of Pure and Applied Chemistry (IUPAC) adopted Aluminium as the standard international name for the element in 1990, but three years later recognized aluminum as an acceptable variant. Hence their periodic table includes both, but places aluminium first.[14] IUPAC officially prefers the use of Aluminium in its internal publications, although several IUPAC publications use the spelling aluminum.[15] # Isotopes Aluminium has nine isotopes, whose mass numbers range from 23 to 30. Only 27Al (stable isotope) and 26Al (radioactive isotope, t1/2 = 7.2 × 105 y) occur naturally, however 27Al has a natural abundance of 99.9+ %. 26Al is produced from argon in the atmosphere by spallation caused by cosmic-ray protons. Aluminium isotopes have found practical application in dating marine sediments, manganese nodules, glacial ice, quartz in rock exposures, and meteorites. The ratio of 26Al to 10Be has been used to study the role of transport, deposition, sediment storage, burial times, and erosion on 105 to 106 year time scales. Cosmogenic 26Al was first applied in studies of the Moon and meteorites. Meteorite fragments, after departure from their parent bodies, are exposed to intense cosmic-ray bombardment during their travel through space, causing substantial 26Al production. After falling to Earth, atmospheric shielding protects the meteorite fragments from further 26Al production, and its decay can then be used to determine the meteorite's terrestrial age. Meteorite research has also shown that 26Al was relatively abundant at the time of formation of our planetary system. Most meteoriticists believe that the energy released by the decay of 26Al was responsible for the melting and differentiation of some asteroids after their formation 4.55 billion years ago.[16] # Properties Aluminium is a soft, lightweight, malleable metal with appearance ranging from silvery to dull gray, depending on the surface roughness. Aluminium is nontoxic, nonmagnetic, and nonsparking. The yield strength of pure aluminium is 7–11 MPa, while aluminium alloys have yield strengths ranging from 200 MPa to 600 MPa.[17] Aluminium has about one-third the density and stiffness of steel. It is ductile, and easily machined, cast, and extruded. Corrosion resistance is excellent due to a thin surface layer of aluminium oxide that forms when the metal is exposed to air, effectively preventing further oxidation. The strongest aluminium alloys are less corrosion resistant due to galvanic reactions with alloyed copper.[17] Aluminium atoms are arranged in an FCC structure. Aluminium has a high stacking-fault energy of approximately 200 mJ/m².[18] Aluminium is one of the few metals that retain full silvery reflectance in finely powdered form, making it an important component of silver paints. Aluminium mirror finish has the highest reflectance of any metal in the 200–400 nm (UV) and the 3000–10000 nm (far IR) regions, while in the 400–700 nm visible range it is slightly outdone by silver and in the 700–3000 (near IR) by silver, gold, and copper. Aluminium is a good thermal and electrical conductor, by weight better than copper. Aluminium is capable of being a superconductor, with a superconducting critical temperature of 1.2 kelvins.[19] # Production and refinement Although aluminium is the most abundant metallic element in the Earth's crust (believed to be 7.5 to 8.1 percent), it is rare in its free form, occurring in oxygen-deficient environments such as volcanic mud, and it was once considered a precious metal more valuable than gold. Napoleon III, emperor of the French, is reputed to have given a banquet where the most honoured guests were given aluminium utensils, while the other guests had to make do with gold ones.[20][21] Aluminium has been produced in commercial quantities for just over 100 years. Aluminium is a reactive metal that is difficult to extract from ore, aluminium oxide (Al2O3). For example, direct reduction with carbon is not economically viable, since aluminium oxide has a melting point of about 2,000 °C. Therefore, it is extracted by electrolysis; that is, the aluminium oxide is dissolved in molten cryolite and then reduced to the pure metal. By this process, the operational temperature of the reduction cells is around 950 to 980 °C. Cryolite is found as a mineral in Greenland, but in industrial use it has been replaced by a synthetic substance. Cryolite is a mixture of aluminium, sodium, and calcium fluorides: (Na3AlF6). The aluminium oxide (a white powder) is obtained by refining bauxite in the Bayer process of Karl Bayer. (Previously, the Deville process was the predominant refining technology.) The electrolytic process replaced the Wöhler process, which involved the reduction of anhydrous aluminium chloride with potassium. Both of the electrodes used in the electrolysis of aluminium oxide are carbon. Once the ore is in the molten state, its ions are free to move around. The reaction at the cathode — the negative terminal — is Here the aluminium ion is being reduced (electrons are added). The aluminium metal then sinks to the bottom and is tapped off. At the positive electrode (anode), oxygen is formed: This carbon anode is then oxidized by the oxygen, releasing carbon dioxide. The anodes in a reduction cell must therefore be replaced regularly, since they are consumed in the process: Unlike the anodes, the cathodes are not oxidised because there is no oxygen present at the cathode. The carbon cathode is protected by the liquid aluminium inside the cells. Nevertheless, cathodes do erode, mainly due to electrochemical processes. After five to ten years, depending on the current used in the electrolysis, a cell has to be rebuilt because of cathode wear. Aluminium electrolysis with the Hall-Héroult process consumes a lot of energy, but alternative processes were always found to be less viable economically and/or ecologically. The world-wide average specific energy consumption is approximately 15±0.5 kilowatt-hours per kilogram of aluminium produced from alumina. (52 to 56 MJ/kg). The most modern smelters reach approximately 12.8 kW·h/kg (46.1 MJ/kg). (Compare this to the heat of reaction, 31 MJ/kg, and the Gibbs free energy of reaction, 29 MJ/kg.) Reduction line current for older technologies are typically 100 to 200 kA. State-of-the-art smelters operate with about 350 kA. Trials have been reported with 500 kA cells. Recovery of the metal via recycling has become an important facet of the aluminium industry. Recycling involves melting the scrap, a process that uses only five percent of the energy needed to produce aluminium from ore. However, a significant part (up to 15% of input material) is lost as dross (ash-like oxide).[22] Recycling was a low-profile activity until the late 1960s, when the growing use of aluminium beverage cans brought it to the public consciousness. Electric power represents about 20% to 40% of the cost of producing aluminium, depending on the location of the smelter. Smelters tend to be situated where electric power is both plentiful and inexpensive, such as South Africa, the South Island of New Zealand, Australia, the People's Republic of China, the Middle East, Russia, Quebec and British Columbia in Canada, and Iceland. In 2005, the People's Republic of China was the top producer of aluminium with almost one-fifth world share followed by Russia, Canada and USA reports the British Geological Survey. Over the last 50 years, Australia has become a major producer of bauxite ore and a major producer and exporter of alumina.[23] Australia produced 62 million tonnes of bauxite in 2005. The Australian deposits have some refining problems, some being high in silica but have the advantage of being shallow and relatively easy to mine.[24] # Chemistry ## Oxidation state one - AlH is produced when aluminium is heated in an atmosphere of hydrogen. - Al2O is made by heating the normal oxide, Al2O3, with silicon at 1800 °C in a vacuum. - Al2S can be made by heating Al2S3 with aluminium shavings at 1300 °C in a vacuum. It quickly disproportionates to the starting materials. The selenide is made in a parallel manner. - AlF, AlCl and AlBr exist in the gaseous phase when the tri-halide is heated with aluminium. Aluminium halides usually exist in the form AlX3. e.g. AlF3, AlCl3, AlBr3, AlI3 etc. ## Oxidation state two - Aluminium monoxide, AlO, is present when aluminium powder burns in oxygen. ## Oxidation state three - Fajans' rules show that the simple trivalent cation Al3+ is not expected to be found in anhydrous salts or binary compounds such as Al2O3. The hydroxide is a weak base and aluminium salts of weak acids, such as carbonate, can't be prepared. The salts of strong acids, such as nitrate, are stable and soluble in water, forming hydrates with at least six molecules of water of crystallization. - Aluminium hydride, (AlH3)n, can be produced from trimethylaluminium and an excess of hydrogen. It burns explosively in air. It can also be prepared by the action of aluminium chloride on lithium hydride in ether solution, but cannot be isolated free from the solvent. - Aluminium carbide, Al4C3 is made by heating a mixture of the elements above 1000 °C. The pale yellow crystals have a complex lattice structure, and react with water or dilute acids to give methane. The acetylide, Al2(C2)3, is made by passing acetylene over heated aluminium. - Aluminium nitride, AlN, can be made from the elements at 800 °C. It is hydrolysed by water to form ammonia and aluminium hydroxide. - Aluminium phosphide, AlP, is made similarly, and hydrolyses to give phosphine. - Aluminium oxide, Al2O3, occurs naturally as corundum, and can be made by burning aluminium in oxygen or by heating the hydroxide, nitrate or sulfate. As a gemstone, its hardness is only exceeded by diamond, boron nitride, and carborundum. It is almost insoluble in water. - Aluminium hydroxide may be prepared as a gelatinous precipitate by adding ammonia to an aqueous solution of an aluminium salt. It is amphoteric, being both a very weak acid, and forming aluminates with alkalis. It exists in various crystalline forms. - Aluminium sulfide, Al2S3, may be prepared by passing hydrogen sulfide over aluminium powder. It is polymorphic. - Aluminium iodide, (AlI3)2, is a dimer with applications in organic synthesis. - Aluminium fluoride, AlF3, is made by treating the hydroxide with HF, or can be made from the elements. It consists of a giant molecule which sublimes without melting at 1291 °C. It is very inert. The other trihalides are dimeric, having a bridge-like structure. - Aluminium fluoride/water complexes: When aluminium and fluoride are together in aqueous solution, they readily form complex ions such as AlF(H2O)5+2, AlF3(H2O)30, AlF6-3. Of these, AlF6-3 is the most stable. This is explained by the fact that aluminium and fluoride, which are both very compact ions, fit together just right to form the octahedral aluminium hexafluoride complex. When aluminium and fluoride are together in water in a 1:6 molar ratio, AlF6-3 is the most common form, even in rather low concentrations. - Organo-metallic compounds of empirical formula AlR3 exist and, if not also giant molecules, are at least dimers or trimers. They have some uses in organic synthesis, for instance trimethylaluminium. - Alumino-hydrides of the most electropositive elements are known, the most useful being lithium aluminium hydride, Li[AlH4]. It decomposes into lithium hydride, aluminium and hydrogen when heated, and is hydrolysed by water. It has many uses in organic chemistry, particularly as a reducing agent. The aluminohalides have a similar structure. ## Clusters In the journal Science of 14 January 2005 it was reported that clusters of 13 aluminium atoms (Al13) had been made to behave like an iodine atom; and, 14 aluminium atoms (Al14) behaved like an alkaline earth atom. The researchers also bound 12 iodine atoms to an Al13 cluster to form a new class of polyiodide. This discovery is reported to give rise to the possibility of a new characterisation of the periodic table: superatoms. The research teams were led by Shiv N. Khanna (Virginia Commonwealth University) and A. Welford Castleman Jr (Penn State University).[25] # Applications ## General use Aluminium is the most widely used non-ferrous metal.[26] Global production of aluminium in 2005 was 31.9 million tonnes. It exceeded that of any other metal except iron (837.5 million tonnes).[27] Relatively pure aluminium is encountered only when corrosion resistance and/or workability is more important than strength or hardness. A thin layer of aluminium can be deposited onto a flat surface by physical vapor deposition or (very infrequently) chemical vapor deposition or other chemical means to form optical coatings and mirrors. When so deposited, a fresh, pure aluminium film serves as a good reflector (approximately 92%) of visible light and an excellent reflector (as much as 98%) of medium and far infrared. Pure aluminium has a low tensile strength, but when combined with thermo-mechanical processing, aluminium alloys display a marked improvement in mechanical properties, especially when tempered. Aluminium alloys form vital components of aircraft and rockets as a result of their high strength-to-weight ratio. Aluminium readily forms alloys with many elements such as copper, zinc, magnesium, manganese and silicon (e.g., duralumin). Today, almost all bulk metal materials that are referred to loosely as "aluminium," are actually alloys. For example, the common aluminium foils are alloys of 92% to 99% aluminium.[28] Some of the many uses for aluminium metal are in: - Transportation (automobiles, aircraft, trucks, railway cars, marine vessels, bicycles etc.) - Packaging (cans, foil, etc.) - Water treatment - Treatment against fish parasites such as Gyrodactylus salaris. - Construction (windows, doors, siding, building wire, etc.) - Cooking utensils - Electrical transmission lines for power distribution - MKM steel and Alnico magnets - Super purity aluminium (SPA, 99.980% to 99.999% Al), used in electronics and CDs. - Heat sinks for electronic appliances such as transistors and CPUs. - Powdered aluminium is used in paint, and in pyrotechnics such as solid rocket fuels and thermite. - In the blades of prop swords and knives used in stage combat. ## Aluminium compounds - Aluminium ammonium sulfate ([Al(NH4)](SO4)2), ammonium alum is used as a mordant, in water purification and sewage treatment, in paper production, as a food additive, and in leather tanning. - Aluminium acetate is a salt used in solution as an astringent. - Aluminium borate (Al2O3 B2O3) is used in the production of glass and ceramic. - Aluminium borohydride (Al(BH4)3) is used as an additive to jet fuel. - Aluminium chloride (AlCl3) is used: in paint manufacturing, in antiperspirants, in petroleum refining and in the production of synthetic rubber. - Aluminium chlorohydride is used as an antiperspirant and in the treatment of hyperhidrosis. - Aluminium fluorosilicate (Al2(SiF6)3) is used in the production of synthetic gemstones, glass and ceramic. - Aluminium hydroxide (Al(OH)3) is used: as an antacid, as a mordant, in water purification, in the manufacture of glass and ceramic and in the waterproofing of fabrics. - Aluminium oxide (Al2O3), alumina, is found naturally as corundum (rubies and sapphires), emery, and is used in glass making. Synthetic ruby and sapphire are used in lasers for the production of coherent light. - Aluminium phosphate (AlPO4) is used in the manufacture: of glass and ceramic, pulp and paper products, cosmetics, paints and varnishes and in making dental cement. - Aluminium sulfate (Al2(SO4)3) is used: in the manufacture of paper, as a mordant, in a fire extinguisher, in water purification and sewage treatment, as a food additive, in fireproofing, and in leather tanning. - In many vaccines, certain aluminium salts serve as an immune adjuvant (immune response booster) to allow the protein in the vaccine to achieve sufficient potency as an immune stimulant. ## Aluminium alloys in structural applications Aluminium alloys with a wide range of properties are used in engineering structures. Alloy systems are classified by a number system (ANSI) or by names indicating their main alloying constituents (DIN and ISO). The strength and durability of aluminium alloys vary widely, not only as a result of the components of the specific alloy, but also as a result of heat treatments and manufacturing processes. A lack of knowledge of these aspects has from time to time led to improperly designed structures and gained aluminium a bad reputation. (See main article) One important structural limitation of aluminium alloys is their fatigue strength. Unlike steels, aluminium alloys have no well-defined fatigue limit, meaning that fatigue failure will eventually occur under even very small cyclic loadings. This implies that engineers must assess these loads and design for a fixed life rather than an infinite life. Another important property of aluminium alloys is their sensitivity to heat. Workshop procedures involving heating are complicated by the fact that aluminium, unlike steel, will melt without first glowing red. Forming operations where a blow torch is used therefore requires some expertise, since no visual signs reveal how close the material is to melting. Aluminium alloys, like all structural alloys, also are subject to internal stresses following heating operations such as welding and casting. The problem with aluminium alloys in this regard is their low melting point, which make them more susceptible to distortions from thermally induced stress relief. Controlled stress relief can be done during manufacturing by heat-treating the parts in an oven, followed by gradual cooling -- in effect annealing the stresses. The low melting point of aluminium alloys has not precluded their use in rocketry; even for use in constructing combustion chambers where gases can reach 3500 K. The Agena upper stage engine used a regeneratively cooled aluminium design for some parts of the nozzle, including the thermally critical throat region. ## Household wiring Aluminium has about 65% of the conductivity of copper, the traditional household wiring material. In the 1960s aluminium was considerably cheaper than copper, and so was introduced for household electrical wiring in the United States, even though many fixtures had not been designed to accept aluminium wire. However, in some cases the greater coefficient of thermal expansion of aluminium causes the wire to expand and contract relative to the dissimilar metal screw connection, eventually loosening the connection. Also, pure aluminium has a tendency to creep under steady sustained pressure (to a greater degree as the temperature rises), again loosening the connection. Finally, Galvanic corrosion from the dissimilar metals increased the electrical resistance of the connection. All of this resulted in overheated and loose connections, and this in turn resulted in fires. Builders then became wary of using the wire, and many jurisdictions outlawed its use in very small sizes in new construction. Eventually, newer fixtures were introduced with connections designed to avoid loosening and overheating. At first they were marked "Al/Cu", but they now bear a "CO/ALR" coding. In older assemblies, workers forestall the heating problem using a properly-done crimp of the aluminium wire to a short "pigtail" of copper wire. Today, new alloys, designs, and methods are used for aluminium wiring in combination with aluminium terminations. # Precautions Aluminium is a neurotoxin that alters the function of the blood-brain barrier.[29] It is one of the few abundant elements that appear to have no beneficial function to living cells. A small percent of people are allergic to it — they experience contact dermatitis from any form of it: an itchy rash from using styptic or antiperspirant products, digestive disorders and inability to absorb nutrients from eating food cooked in aluminium pans, and vomiting and other symptoms of poisoning from ingesting such products as Amphojel, and Maalox (antacids). In other people, aluminium is not considered as toxic as heavy metals, but there is evidence of some toxicity if it is consumed in excessive amounts. The use of aluminium cookware, popular because of its corrosion resistance and good heat conduction, has not been shown to lead to aluminium toxicity in general. Excessive consumption of antacids containing aluminium compounds and excessive use of aluminium-containing antiperspirants are more likely causes of toxicity. In research published in the Journal of Applied Toxicology, Dr. Philippa D. Darby of the University of Reading has shown that aluminium salts increase estrogen-related gene expression in human breast cancer cells grown in the laboratory. These salts' estrogen-like effects have led to their classification as a metalloestrogen. It has been suggested that aluminium is a cause of Alzheimer's disease, as some brain plaques have been found to contain the metal. Research in this area has been inconclusive; aluminium accumulation may be a consequence of the Alzheimer's damage, not the cause. In any event, if there is any toxicity of aluminium it must be via a very specific mechanism, since total human exposure to the element in the form of naturally occurring clay in soil and dust is enormously large over a lifetime.[30][31] Mercury applied to the surface of an aluminium alloy can damage the protective oxide surface film by forming amalgam. This may cause further corrosion and weakening of the structure. For this reason, mercury thermometers are not allowed on many airliners, as aluminium is used in many aircraft structures. Powdered aluminium can react with Fe2O3 to form Fe and Al2O3. This mixture is known as thermite, which burns with a high energy output. Thermite can be produced inadvertently during grinding operations, but the high ignition temperature makes incidents unlikely in most workshop environments. ## Aluminium and plants (phytoremediation) Aluminium is primary among the factors that contribute to the loss of plant production on acid soils. Although it is generally harmless to plant growth in pH-neutral soils, the concentration in acid soils of toxic Al3+ cations increases and disturbs root growth and function. Wheat's adaptation to allow aluminium tolerance is such that the aluminium induces a release of organic compounds that bind to the harmful aluminium cations. Sorghum is believed to have the same tolerance mechanism. The first gene for aluminium tolerance has been identified in wheat. A group in the U.S. Department of Agriculture showed that sorghum's aluminium tolerance is controlled by a single gene, as for wheat. This is not the case in all plants.	https://www.wikidoc.org/index.php/Aluminium
07eb6430ae0f9fa511a0103412eb6bcd9d18df0b	wikidoc	Alveolate	Alveolate The alveolates are a major line of protists. There are three phyla, which are very divergent in form, but are now known to be close relatives based on various ultrastructural and genetic similarities: The most notable shared characteristic is the presence of cortical alveoli, flattened vesicles packed into a continuous layer supporting the membrane, typically forming a flexible pellicle. In dinoflagellates they often form armor plates. Alveolates have mitochondria with tubular cristae, and their flagella or cilia have a distinct structure. The Apicomplexa and dinoflagellates may be more closely related to each other than to the ciliates. Both have plastids, and most share a bundle or cone of microtubules at the top of the cell. In apicomplexans this forms part of a complex used to enter host cells, while in some colorless dinoflagellates it forms a peduncle used to ingest prey. Various other genera are closely related to these two groups, mostly flagellates with a similar apical structure. These include free-living members in Oxyrrhis and Colponema, and parasites in Perkinsus, Parvilucifera, Rastrimonas, and the ellobiopsids. In 2001, direct amplification of the rRNA gene in marine picoplankton samples revealed the presence of two novel alveolate linages, called group I and II. Group I has no cultivated relatives, while group II is related to the dinoflagellate parasite Amoebophrya, which was classified until now in the Syndiniales dinoflagellate order. Relationships between some of these the major groups were suggested during the 1980s, and between all three by Cavalier-Smith, who introduced the formal name Alveolata in 1991. They were confirmed by a genetic study by Gajadhar et al. Some studies suggested the haplosporids, mostly parasites of marine invertebrates, might belong here but they lack alveoli and are now placed among the Cercozoa. The development of plastids among the alveolates is uncertain. Cavalier-Smith proposed the alveolates developed from a chloroplast-containing ancestor, which also gave rise to the Chromista (the chromalveolate hypothesis). However, as plastids only appear in relatively advanced groups, others argue the alveolates originally lacked them and possibly the dinoflagellates and Apicomplexa acquired them separately.	Alveolate Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The alveolates are a major line of protists. There are three phyla, which are very divergent in form, but are now known to be close relatives based on various ultrastructural and genetic similarities: The most notable shared characteristic is the presence of cortical alveoli, flattened vesicles packed into a continuous layer supporting the membrane, typically forming a flexible pellicle. In dinoflagellates they often form armor plates. Alveolates have mitochondria with tubular cristae, and their flagella or cilia have a distinct structure. The Apicomplexa and dinoflagellates may be more closely related to each other than to the ciliates. Both have plastids, and most share a bundle or cone of microtubules at the top of the cell. In apicomplexans this forms part of a complex used to enter host cells, while in some colorless dinoflagellates it forms a peduncle used to ingest prey. Various other genera are closely related to these two groups, mostly flagellates with a similar apical structure. These include free-living members in Oxyrrhis and Colponema, and parasites in Perkinsus, Parvilucifera, Rastrimonas, and the ellobiopsids. In 2001, direct amplification of the rRNA gene in marine picoplankton samples revealed the presence of two novel alveolate linages, called group I and II[1][2]. Group I has no cultivated relatives, while group II is related to the dinoflagellate parasite Amoebophrya, which was classified until now in the Syndiniales dinoflagellate order. Relationships between some of these the major groups were suggested during the 1980s, and between all three by Cavalier-Smith, who introduced the formal name Alveolata in 1991[3]. They were confirmed by a genetic study by Gajadhar et al.[4] Some studies suggested the haplosporids, mostly parasites of marine invertebrates, might belong here but they lack alveoli and are now placed among the Cercozoa. The development of plastids among the alveolates is uncertain. Cavalier-Smith proposed the alveolates developed from a chloroplast-containing ancestor, which also gave rise to the Chromista (the chromalveolate hypothesis). However, as plastids only appear in relatively advanced groups, others argue the alveolates originally lacked them and possibly the dinoflagellates and Apicomplexa acquired them separately.	https://www.wikidoc.org/index.php/Alveolata
85c0df3a88616979262e63e5c01ca03b51594c31	wikidoc	Alvimopan	Alvimopan # 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 Alvimopan is an opioid antagonist that is FDA approved for the {{{indicationType}}} of postoperative ileus following upper and lower gastrointestinal surgeries that include partial bowel resection with primary anastomosis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include dyspepsia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - ENTEREG is indicated to accelerate the time to upper and lower gastrointestinal recovery following surgeries that include partial bowel resection with primary anastomosis. - For hospital use only. The recommended adult dosage of ENTEREG is 12 mg administered 30 minutes to 5 hours prior to surgery followed by 12 mg twice daily beginning the day after surgery until discharge for a maximum of 7 days. Patients should not receive more than 15 doses of ENTEREG. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Alvimopan in adult patients. ### Non–Guideline-Supported Use - Alvimopan 0.5 mg orally twice daily for 12 weeks. - Alvimopan 6 mg, or alvimopan 12 mg, given a minimum of 2 hours prior to surgery, then continued twice daily until hospital discharge or a maximum of 7 to 10 days postoperatively. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Alvimopan in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Alvimopan in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Alvimopan in pediatric patients. # Contraindications - ENTEREG is contraindicated in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking ENTEREG. # Warnings ### Precautions - Potential Risk of Myocardial Infarction with Long-term Use - There were more reports of myocardial infarctions in patients treated with alvimopan 0.5 mg twice daily compared with placebo-treated patients in a 12-month study of patients treated with opioids for chronic non-cancer pain (alvimopan 0.5 mg, n = 538; placebo, n = 267). In this study, the majority of myocardial infarctions occurred between 1 and 4 months after initiation of treatment. This imbalance has not been observed in other studies of ENTEREG in patients treated with opioids for chronic pain, nor in patients treated within the surgical setting, including patients undergoing surgeries that included bowel resection who received ENTEREG 12 mg twice daily for up to 7 days (the indicated dose and patient population; ENTEREG 12 mg, n = 1,142; placebo, n = 1,120). A causal relationship with alvimopan with long-term use has not been established. - ENTEREG is available only through a program under a REMS that restricts use to enrolled hospitals. - E.A.S.E. ENTEREG REMS Program - ENTEREG is available only through a program called the ENTEREG Access Support and Education (E.A.S.E.) ENTEREG REMS Program that restricts use to enrolled hospitals because of the potential risk of myocardial infarction with long-term use of ENTEREG. - Notable requirements of the E.A.S.E. Program include the following: ENTEREG is available only for short-term (15 doses) use in hospitalized patients. Only hospitals that have enrolled in and met all of the requirements for the E.A.S.E. program may use ENTEREG. - ENTEREG is available only for short-term (15 doses) use in hospitalized patients. Only hospitals that have enrolled in and met all of the requirements for the E.A.S.E. program may use ENTEREG. - To enroll in the E.A.S.E. Program, an authorized hospital representative must acknowledge that: hospital staff who prescribe, dispense, or administer ENTEREG have been provided the educational materials on the need to limit use of ENTEREG to short-term, inpatient use; patients will not receive more than 15 doses of ENTEREG; and ENTEREG will not be dispensed to patients after they have been discharged from the hospital. - hospital staff who prescribe, dispense, or administer ENTEREG have been provided the educational materials on the need to limit use of ENTEREG to short-term, inpatient use; - patients will not receive more than 15 doses of ENTEREG; and - ENTEREG will not be dispensed to patients after they have been discharged from the hospital. - Further information is available at www.ENTEREGREMS.com or 1-877-282-4786. - Gastrointestinal-Related Adverse Reactions in Opioid-Tolerant Patients - Patients recently exposed to opioids are expected to be more sensitive to the effects of μ-opioid receptor antagonists, such as ENTEREG. Since ENTEREG acts peripherally, clinical signs and symptoms of increased sensitivity would be related to the gastrointestinal tract (e.g., abdominal pain, nausea and vomiting, diarrhea). Patients receiving more than 3 doses of an opioid within the week prior to surgery were not studied in the postoperative ileus clinical trials. Therefore, if ENTEREG is administered to these patients, they should be monitored for gastrointestinal adverse reactions. ENTEREG is contraindicated in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking ENTEREG. - Risk of Serious Adverse Reactions in Patients with Severe Hepatic Impairment - Patients with severe hepatic impairment may be at higher risk of serious adverse reactions (including dose-related serious adverse reactions) because up to 10-fold higher plasma levels of drug have been observed in such patients compared with patients with normal hepatic function. Therefore, the use of ENTEREG is not recommended in this population. - End-Stage Renal Disease - No studies have been conducted in patients with end-stage renal disease. ENTEREG is not recommended for use in these patients. - Risk of Serious Adverse Reactions in Patients with Complete Gastrointestinal Obstruction - No studies have been conducted in patients with complete gastrointestinal obstruction or in patients who have surgery for correction of complete bowel obstruction. ENTEREG is not recommended for use in these patients. - Risk of Serious Adverse Reactions in Pancreatic and Gastric Anastomoses - ENTEREG has not been studied in patients having pancreatic or gastric anastomosis. Therefore, ENTEREG is not recommended for use in these patients. # 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 compared directly with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The adverse event information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. - The data described below reflect exposure to ENTEREG 12 mg in 1,793 patients in 10 placebo-controlled studies. The population was 19 to 97 years old, 64% were female, and 84% were Caucasian; 64% were undergoing a surgery that included bowel resection. The first dose of ENTEREG was administered 30 minutes to 5 hours before the scheduled start of surgery and then twice daily until hospital discharge (or for a maximum of 7 days of postoperative treatment). - Among ENTEREG-treated patients undergoing surgeries that included a bowel resection, the most common adverse reaction (incidence ≥1.5%) occurring with a higher frequency than placebo was dyspepsia (ENTEREG, 1.5%; placebo, 0.8%). Adverse reactions are events that occurred after the first dose of study medication treatment and within 7 days of the last dose of study medication or events present at baseline that increased in severity after the start of study medication treatment. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Alvimopan in the drug label. # Drug Interactions - Potential for Drugs to Affect Alvimopan Pharmacokinetics - An in vitro study indicates that alvimopan is not a substrate of CYP enzymes. Therefore, concomitant administration of ENTEREG with inducers or inhibitors of CYP enzymes is unlikely to alter the metabolism of alvimopan. - Potential for Alvimopan to Affect the Pharmacokinetics of Other Drugs - Based on in vitro data, ENTEREG is unlikely to alter the pharmacokinetics of coadministered drugs through inhibition of CYP isoforms such as 1A2, 2C9, 2C19, 3A4, 2D6, and 2E1 or induction of CYP isoforms such as 1A2, 2B6, 2C9, 2C19, and 3A4. - In vitro, ENTEREG did not inhibit p-glycoprotein. - Effects of Alvimopan on Intravenous Morphine - Coadministration of alvimopan does not appear to alter the pharmacokinetics of morphine and its metabolite, morphine-6-glucuronide, to a clinically significant degree when morphine is administered intravenously. Dosage adjustment for intravenously administered morphine is not necessary when it is coadministered with alvimopan. - Effects of Concomitant Acid Blockers or Antibiotics - A population pharmacokinetic analysis suggests that the pharmacokinetics of alvimopan were not affected by concomitant administration of acid blockers or antibiotics. No dosage adjustments are necessary in patients taking acid blockers or antibiotics. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - Risk Summary: There are no adequate and/or well-controlled studies with ENTEREG in pregnant women. No fetal harm was observed in animal reproduction studies with oral administration of alvimopan to rats at doses 68 to 136 times the recommended human oral dose, or with intravenous administration to rats and rabbits at doses 3.4 to 6.8 times, and 5 to 10 times, respectively, the recommended human oral dose. Because animal reproduction studies are not always predictive of human response, ENTEREG should be used during pregnancy only if clearly needed. - Animal Data: Reproduction studies were performed in pregnant rats at oral doses up to 200 mg/kg/day (about 68 to 136 times the recommended human oral dose based on body surface area) and at intravenous doses up to 10 mg/kg/day (about 3.4 to 6.8 times the recommended human oral dose based on body surface area) and in pregnant rabbits at intravenous doses up to 15 mg/kg/day (about 5 to 10 times the recommended human oral dose based on body surface area), and revealed no evidence of impaired fertility or harm to the fetus due to alvimopa Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alvimopan in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Alvimopan during labor and delivery. ### Nursing Mothers - It is not known whether ENTEREG is present in human milk. Alvimopan and its 'metabolite' are detected in the milk of lactating rats. Exercise caution when administering ENTEREG to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Of the total number of patients in 6 clinical efficacy studies treated with ENTEREG 12 mg or placebo, 46% were 65 years of age and over, while 18% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, 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. No dosage adjustment based on increased age is required. ### Gender There is no FDA guidance on the use of Alvimopan with respect to specific gender populations. ### Race - No dosage adjustment is necessary in Black, Hispanic, and Japanese patients. However, the exposure to ENTEREG in Japanese healthy male volunteers was approximately 2-fold greater than in Caucasian subjects. Japanese patients should be closely monitored for possible adverse effects (e.g., diarrhea, gastrointestinal pain, cramping) that could indicate high drug or 'metabolite' levels, and ENTEREG should be discontinued if adverse events occur. ### Renal Impairment - ENTEREG is not recommended for use in patients with end-stage renal disease. Dosage adjustment is not required for patients with mild-to-severe renal impairment, but they should be monitored for adverse effects. Patients with severe renal impairment should be closely monitored for possible adverse effects (e.g., diarrhea, gastrointestinal pain, cramping) that could indicate high drug or 'metabolite' levels, and ENTEREG should be discontinued if adverse events occur. ### Hepatic Impairment - ENTEREG is not recommended for use in patients with severe hepatic impairment. - Dosage adjustment is not required for patients with mild-to-moderate hepatic impairment. Patients with mild-to-moderate hepatic impairment should be closely monitored for possible adverse effects (e.g., diarrhea, gastrointestinal pain, cramping) that could indicate high drug or 'metabolite' levels, and ENTEREG should be discontinued if adverse events occur. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Alvimopan in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Alvimopan in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Alvimopan in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Alvimopan in the drug label. # Overdosage ## Chronic Overdose There is limited information regarding Chronic Overdose of Alvimopan in the drug label. # Pharmacology ## Mechanism of Action - Alvimopan is a selective antagonist of the cloned human μ-opioid receptor with a Ki of 0.4 nM (0.2 ng/mL) and no measurable opioid-agonist effects in standard pharmacologic assays. The dissociation of -alvimopan from the human μ-opioid receptor is slower than that of other opioid ligands, consistent with its higher affinity for the receptor. At concentrations of 1 to 10 µM, alvimopan demonstrated no activity at any of over 70 non-opioid receptors, enzymes, and ion channels. - Postoperative ileus is the impairment of gastrointestinal motility after intra-abdominal surgery or other, non-abdominal surgeries. Postoperative ileus affects all segments of the gastrointestinal tract and may last from 5 to 6 days, or even longer. This may potentially delay gastrointestinal recovery and hospital discharge until its resolution. It is characterized by abdominal distention and bloating, nausea, vomiting, pain, accumulation of gas and fluids in the bowel, and delayed passage of flatus and defecation. Postoperative ileus is the result of a multifactorial process that includes inhibitory sympathetic input and release of hormones, neurotransmitters, and other mediators (e.g., endogenous opioids). A component of postoperative ileus also results from an inflammatory reaction and the effects of opioid analgesics. Morphine and other μ-opioid receptor agonists are universally used for the treatment of acute postsurgical pain; however, they are known to have an inhibitory effect on gastrointestinal motility and may prolong the duration of postoperative ileus. - Following oral administration, alvimopan antagonizes the peripheral effects of opioids on gastrointestinal motility and secretion by competitively binding to gastrointestinal tract μ-opioid receptors. The antagonism produced by alvimopan at opioid receptors is evident in isolated guinea pig ileum preparations in which alvimopan competitively antagonizes the effects of morphine on contractility. Alvimopan achieves this selective gastrointestinal opioid antagonism without reversing the central analgesic effects of μ-opioid agonists. ## Structure - ENTEREG capsules contain alvimopan, an opioid antagonist. Chemically, alvimopan is the single stereoisomer methyl]-1-oxo-3-phenylpropyl]amino]acetic acid dihydrate. It has the following structural formula: - Alvimopan is a white to light beige powder with a molecular weight of 460.6, and the empirical formula is C25H32N2O42H2O. It has a solubility of <0.1 mg/mL in water or buffered solutions between pH 3.0 and 9.0, 1 to 5 mg/mL in buffered solutions at pH 1.2, and 10 to 25 mg/mL in aqueous 0.1 N sodium hydroxide. At physiological pH, alvimopan is zwitterionic, a property that contributes to its low solubility. - ENTEREG capsules for oral administration contain 12 mg of alvimopan on an anhydrous basis suspended in the inactive ingredient polyethylene glycol. ## Pharmacodynamics - In an exploratory study in healthy volunteers, alvimopan 12 mg administered twice a day reduced the delay in small and large bowel transit induced by codeine 30 mg administered 4 times a day, as measured by gastrointestinal scintigraphy. In the same study, concomitant alvimopan did not reduce the delay in gastric emptying induced by codeine. - In a study designed to evaluate potential effects on cardiac conduction, alvimopan did not cause clinically significant QTc prolongation at doses up to 24 mg twice daily (twice the approved dosage regimen) for 7 days. The potential for QTc effects at higher doses has not been studied. ## Pharmacokinetics - Following oral administration of alvimopan, an amide hydrolysis compound is present in the systemic circulation, which is considered a product exclusively of intestinal flora metabolism. This compound is referred to as the 'metabolite'. It is also a μ-opioid receptor antagonist with a Ki of 0.8 nM (0.3 ng/mL). - Absorption: Following oral administration of ENTEREG capsules in healthy volunteers, plasma alvimopan concentration peaked at approximately 2 hours postdose. No significant accumulation in alvimopan concentration was observed following twice daily (BID) dosing. The mean peak plasma concentration was 10.98 (±6.43) ng/mL and mean AUC0–12h was 40.2 (±22.5) ngh/mL after dosing of alvimopan at 12 mg BID for 5 days. The absolute bioavailability was estimated to be 6% (range, 1% to 19%). There was a delay in the appearance of the 'metabolite', which had a median Tmax of 36 hours following administration of a single dose of alvimopan. Concentrations of the 'metabolite' were highly variable between subjects and within a subject. The 'metabolite' accumulated after multiple doses of ENTEREG. The mean Cmax for the 'metabolite' after alvimopan 12 mg twice daily for 5 days was 35.73 ± 35.29 ng/mL. - Concentrations of alvimopan and its 'metabolite' are higher (~1.9-fold and ~1.4-fold, respectively) in postoperative ileus patients than in healthy volunteers. - Food Effects: A high-fat meal decreased the extent and rate of alvimopan absorption. The Cmax and AUC were decreased by approximately 38% and 21%, respectively, and the Tmax was prolonged by approximately 1 hour. The clinical significance of this decreased bioavailability is unknown. In postoperative ileus clinical trials, the preoperative dose of ENTEREG was administered in a fasting state. Subsequent doses were given without regard to meals. - Distribution: The steady-state volume of distribution of alvimopan was estimated to be 30±10 L. Plasma protein binding of alvimopan and its 'metabolite' was independent of concentration over ranges observed clinically and averaged 80% and 94%, respectively. Both alvimopan and the 'metabolite' were bound to albumin and not to alpha-1 acid glycoprotein. - Metabolism and Elimination: In vitro data suggest that alvimopan is not a substrate of CYP enzymes. The average plasma clearance for alvimopan was 402 (±89) mL/min. Renal excretion accounted for approximately 35% of total clearance. There was no evidence that hepatic metabolism was a significant route for alvimopan elimination. Biliary secretion was considered the primary pathway for alvimopan elimination. Unabsorbed drug and unchanged alvimopan resulting from biliary excretion were then hydrolyzed to its 'metabolite' by gut microflora. The 'metabolite' was eliminated in the feces and in the urine as unchanged 'metabolite', the glucuronide conjugate of the 'metabolite', and other minor metabolites. The mean terminal phase half-life of alvimopan after multiple oral doses of ENTEREG ranged from 10 to 17 hours. The terminal half-life of the 'metabolite' ranged from 10 to 18 hours. - Specific Populations: - Age: The pharmacokinetics of alvimopan, but not its 'metabolite', were related to age, but this effect was not clinically significant and does not warrant dosage adjustment based on increased age. - Race: The pharmacokinetic characteristics of alvimopan were not affected by Hispanic or Black race. Plasma 'metabolite' concentrations were lower in Black and Hispanic patients (by 43% and 82%, respectively) than in Caucasian patients following alvimopan administration. These changes are not considered to be clinically significant in surgical patients. Japanese healthy male volunteers had an approximately 2-fold increase in plasma alvimopan concentrations, but no change in 'metabolite' pharmacokinetics. The pharmacokinetics of alvimopan have not been studied in subjects of other East Asian ancestry. Dosage adjustment in Japanese patients is not required. - Gender: There was no effect of gender on the pharmacokinetics of alvimopan or the 'metabolite'. - Hepatic Impairment: Exposure to alvimopan following a single 12 mg dose tended to be higher (1.5- to 2-fold, on average) in patients with mild or moderate hepatic impairment (as defined by Child-Pugh Class A and B, n = 8 each) compared with healthy controls (n = 4). There were no consistent effects on the Cmax or half-life of alvimopan in patients with hepatic impairment. However, 2 of 16 patients with mild-to-moderate hepatic impairment had longer than expected half-lives of alvimopan, indicating that some accumulation may occur upon multiple dosing. The Cmax of the 'metabolite' tended to be more variable in patients with mild or moderate hepatic impairment than in matched normal subjects. A study of 3 patients with severe hepatic impairment (Child-Pugh Class C), indicated similar alvimopan exposure in 2 patients and an approximately 10-fold increase in Cmax and exposure in 1 patient with severe hepatic impairment when compared with healthy control volunteers . - Renal Impairment: There was no relationship between renal function (i.e., creatinine clearance ) and plasma alvimopan pharmacokinetics (Cmax, AUC, or half-life) in patients with mild (CrCl 51–80 mL/min), moderate (CrCl 31–50 mL/min), or severe (CrCl <30 mL/min) renal impairment (n = 6 each). Renal clearance of alvimopan was related to renal function; however, because renal clearance was only a small fraction (35%) of the total clearance, renal impairment had a small effect on the apparent oral clearance of alvimopan. The half-lives of alvimopan were comparable in the mild, moderate, and control renal impairment groups but longer in the severe renal impairment group. Exposure to the 'metabolite' tended to be 2- to 5-fold higher in patients with moderate or severe renal impairment compared with patients with mild renal impairment or control subjects. Thus, there may be accumulation of alvimopan and 'metabolite' in patients with severe renal impairment receiving multiple doses of ENTEREG. Patients with end-stage renal disease were not studied. - Crohn's Disease: There was no relationship between disease activity in patients with Crohn's disease (measured as Crohn's Disease Activity Index or bowel movement frequency) and alvimopan pharmacokinetics (AUC or Cmax). Patients with active or quiescent Crohn's disease had increased variability in alvimopan pharmacokinetics, and exposure tended to be 2-fold higher in patients with quiescent disease than in those with active disease or in normal subjects. Concentrations of the 'metabolite' were lower in patients with Crohn's disease. - Drug Interactions: - Potential for Drugs to Affect Alvimopan Pharmacokinetics: Concomitant administration of ENTEREG with inducers or inhibitors of CYP enzymes is unlikely to alter the metabolism of alvimopan because ENTEREG is metabolized mainly by non-CYP enzyme pathway. No clinical studies have been performed to assess the effect of concomitant administration of inducers or inhibitors of cytochrome P450 enzymes on alvimopan pharmacokinetics. - In vitro studies suggest that alvimopan and its 'metabolite' are substrates for p-glycoprotein. A population pharmacokinetic analysis did not reveal any evidence that alvimopan or 'metabolite' pharmacokinetics were influenced by concomitant medications that are mild-to-moderate p-glycoprotein inhibitors. No clinical studies of concomitant administration of alvimopan and strong inhibitors of p-glycoprotein (e.g., verapamil, cyclosporine, amiodarone, itraconazole, quinine, spironolactone, quinidine, diltiazem, bepridil) have been conducted. - A population pharmacokinetic analysis suggests that the pharmacokinetics of alvimopan were not affected by concomitant administration of acid blockers or antibiotics. However, plasma concentrations of the 'metabolite' were lower in patients receiving acid blockers or preoperative oral antibiotics (49% and 81%, respectively). No dosage adjustments are necessary in these patients. - Potential for Alvimopan to Affect the Pharmacokinetics of Other Drugs: Alvimopan and its 'metabolite' are not inhibitors of CYP 1A2, 2C9, 2C19, 3A4, 2D6, and 2E1 in vitro at concentrations far in excess of those observed clinically. - Alvimopan and its 'metabolite' are not inducers of CYP 1A2, 2B6, 2C9, 2C19, and 3A4. - In vitro studies also suggest that alvimopan and its 'metabolite' are not inhibitors of p-glycoprotein. - These in vitro findings suggest that ENTEREG is unlikely to alter the pharmacokinetics of coadministered drugs through inhibition or induction of CYP enzymes or inhibition of p-glycoprotein. ## Nonclinical Toxicology - Carcinogenesis: Two-year carcinogenicity studies were conducted with alvimopan in CD-1 mice at oral doses up to 4000 mg/kg/day and in Sprague-Dawley rats at oral doses up to 500 mg/kg/day. Oral administration of alvimopan for 104 weeks produced significant increases in the incidences of fibroma, fibrosarcoma, and sarcoma in the skin/subcutis, and of osteoma/osteosarcoma in bones of female mice at 4000 mg/kg/day (about 674 times the recommended human dose based on body surface area). In rats, oral administration of alvimopan for 104 weeks did not produce any tumor up to 500 mg/kg/day (about 166 times the recommended human dose based on body surface area). - Mutagenesis: Alvimopan was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK+/−) forward mutation test, the Chinese Hamster Ovary (CHO) cell chromosome aberration test, or the mouse micronucleus test. The pharmacologically active 'metabolite' ADL 08-0011 was negative in the Ames test, chromosome aberration test in CHO cells, and mouse micronucleus test. - Impairment of Fertility: Alvimopan at intravenous doses up to 10 mg/kg/day (about 3.4 to 6.8 times the recommended human oral dose based on body surface area) was found to have no adverse effect on fertility and reproductive performance of male or female rats. # Clinical Studies - The efficacy of ENTEREG in the management of postoperative ileus was evaluated in 6 multicenter, randomized, double-blind, parallel-group, placebo-controlled studies: 5 US studies (Studies 1-4 and 6) and 1 non–US study (Study 5). Patients 18 years of age or older undergoing partial large or small bowel resection surgery with primary anastomosis for colorectal or small bowel disease, total abdominal hysterectomy, or radical cystectomy for bladder cancer (in this procedure, resected segments of bowel are used for reconstruction of the urinary tract) under general anesthesia were randomly assigned to receive oral doses of ENTEREG 12 mg or matching placebo. The initial dose was administered at least 30 minutes and up to 5 hours prior to the scheduled start of surgery for most patients, and subsequent doses were administered twice daily beginning on the first postoperative day and continued until hospital discharge or a maximum of 7 days. There were no limitations on the type of general anesthesia used, but intrathecal or epidural opioids or anesthetics were prohibited. - All patients in the US studies were scheduled to receive intravenous patient-controlled opioid analgesia. In the non–US study, patients were scheduled to receive opioids either by intravenous patient-controlled opioid analgesia or bolus parenteral administration (intravenous or intramuscular). In all studies, there was no restriction on the type of opioid used or the duration of intravenous patient-controlled opioid analgesia. A standardized accelerated postoperative care pathway was implemented: early nasogastric tube removal (before the first postoperative dose); early ambulation (day following surgery); early diet advancement (liquids offered the day following surgery for patients undergoing bowel resection and by the third day following surgery for patients undergoing radical cystectomy; solids by the second day following surgery for patients undergoing bowel resection and by the fourth day following surgery for patients undergoing radical cystectomy), as tolerated. - Patients who received more than 3 doses of an opioid (regardless of route) during the 7 days prior to surgery and patients with complete bowel obstruction or who were scheduled for a total colectomy, colostomy, or ileostomy were excluded. - The primary endpoint for all studies was time to achieve resolution of postoperative ileus, a clinically defined composite measure of both upper and lower gastrointestinal recovery. Although both 2-component (GI2: toleration of solid food and first bowel movement) and 3-component (GI3: toleration of solid food and either first flatus or bowel movement) endpoints were used in all studies, GI2 is presented as it represents the most objective and clinically relevant measure of treatment response in patients undergoing surgeries that include a bowel resection. The time from the end of surgery to when the discharge order was written represented the length of hospital stay. In the 6 studies, 1,058 patients who underwent a surgery that included a bowel resection received placebo (not including 157 for total abdominal hysterectomy) and 1,096 patients received ENTEREG 12 mg (not including 143 for total abdominal hysterectomy). - The efficacy of ENTEREG following total abdominal hysterectomy has not been established. Therefore, the following data are presented only for surgeries that included a bowel resection (i.e., bowel resection or radical cystectomy). - Bowel Resection or Radical Cystectomy: A total of 2,154 patients underwent a surgery that included a bowel resection. The average age was 62 years, 54% were males, and 89% were Caucasian. The most common indications for surgery were colon or rectal cancer/malignancy, bladder cancer, and diverticular disease. In the non–US bowel resection study (Study 5), average daily postoperative opioid consumption was approximately 50% lower and the use of non-opioid analgesics substantially higher, as compared with the US bowel resection studies (Studies 1-4) for both treatment groups. During the first 48 hours postoperatively, the use of non-opioid analgesics was 69% compared with 4% for the non–US and US bowel resection studies, respectively. In each of the 6 studies, ENTEREG accelerated the time to recovery of gastrointestinal function, as measured by the composite endpoint GI2, and time to discharge order written as compared with placebo. Hazard ratios greater than 1 indicate a higher probability of achieving the event during the study period with treatment with ENTEREG than with placebo. Table 1 provides the Hazard Ratios, Kaplan Meier means, medians, and mean and median treatment differences (hours) in gastrointestinal recovery between ENTEREG and placebo. - The Kaplan Meier estimate probabilities of patients receiving ENTEREG who achieved GI2 were numerically higher at all times throughout the study observation period compared with those of patients receiving placebo (see Figures 1 and 2). - In Studies 1–4, the differences between ENTEREG and placebo patient groups in median time to 'discharge order written' ranged from 6 to 22 hours, in favor of ENTEREG patients. The group differences in mean time to 'discharge order written' ranged from 13 to 21 hours. In Study 6, the median time difference was 19 hours in favor of ENTEREG patients (mean time difference 22 hours). - ENTEREG did not reverse opioid analgesia as measured by visual analog scale pain intensity scores and/or amount of postoperative opioids administered across all 6 studies. - There were no gender-, age-, or race-related differences in treatment effect. - The incidence of anastomotic leak was low and comparable in patients receiving either ENTEREG or placebo (0.7% and 1.0%, respectively). # How Supplied - ENTEREG capsules, 12 mg, are blue, hard-gelatin capsules printed with "ADL2698" on both the body and the cap of the capsule. ENTEREG capsules are available in unit-dose packs of 30 capsules (30 doses) (NDC 67919-020-10) for hospital use only. - Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). ## Storage There is limited information regarding Alvimopan Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Recent Use of Opioids - Patients should be informed that they must disclose long-term or intermittent opioid pain therapy, including any use of opioids in the week prior to receiving ENTEREG. They should understand that recent use of opioids may make them more susceptible to adverse reactions to ENTEREG, primarily those limited to the gastrointestinal tract (e.g., abdominal pain, nausea and vomiting, diarrhea). - Hospital Use Only - ENTEREG is available only through a program called the ENTEREG Access Support and Education (E.A.S.E.) Program under a REMS that restricts use to enrolled hospitals because of the potential risk of myocardial infarction with long-term use of ENTEREG. Patients should be informed that ENTEREG is for hospital use only for no more than 7 days after their bowel resection surgery. - Most Common Side Effect - Patients should be informed that the most common side effect with ENTEREG in patients undergoing surgeries that include bowel resection is dyspepsia. # Precautions with Alcohol - Alcohol-Alvimopan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ENTEREG® # Look-Alike Drug Names There is limited information regarding Alvimopan Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Alvimopan 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. # Black Box Warning # Overview Alvimopan is an opioid antagonist that is FDA approved for the {{{indicationType}}} of postoperative ileus following upper and lower gastrointestinal surgeries that include partial bowel resection with primary anastomosis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include dyspepsia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - ENTEREG is indicated to accelerate the time to upper and lower gastrointestinal recovery following surgeries that include partial bowel resection with primary anastomosis. - For hospital use only. The recommended adult dosage of ENTEREG is 12 mg administered 30 minutes to 5 hours prior to surgery followed by 12 mg twice daily beginning the day after surgery until discharge for a maximum of 7 days. Patients should not receive more than 15 doses of ENTEREG. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Alvimopan in adult patients. ### Non–Guideline-Supported Use - Alvimopan 0.5 mg orally twice daily for 12 weeks.[1] - Alvimopan 6 mg, or alvimopan 12 mg, given a minimum of 2 hours prior to surgery, then continued twice daily until hospital discharge or a maximum of 7 to 10 days postoperatively.[2] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Alvimopan in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Alvimopan in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Alvimopan in pediatric patients. # Contraindications - ENTEREG is contraindicated in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking ENTEREG. # Warnings ### Precautions - Potential Risk of Myocardial Infarction with Long-term Use - There were more reports of myocardial infarctions in patients treated with alvimopan 0.5 mg twice daily compared with placebo-treated patients in a 12-month study of patients treated with opioids for chronic non-cancer pain (alvimopan 0.5 mg, n = 538; placebo, n = 267). In this study, the majority of myocardial infarctions occurred between 1 and 4 months after initiation of treatment. This imbalance has not been observed in other studies of ENTEREG in patients treated with opioids for chronic pain, nor in patients treated within the surgical setting, including patients undergoing surgeries that included bowel resection who received ENTEREG 12 mg twice daily for up to 7 days (the indicated dose and patient population; ENTEREG 12 mg, n = 1,142; placebo, n = 1,120). A causal relationship with alvimopan with long-term use has not been established. - ENTEREG is available only through a program under a REMS that restricts use to enrolled hospitals. - E.A.S.E. ENTEREG REMS Program - ENTEREG is available only through a program called the ENTEREG Access Support and Education (E.A.S.E.) ENTEREG REMS Program that restricts use to enrolled hospitals because of the potential risk of myocardial infarction with long-term use of ENTEREG. - Notable requirements of the E.A.S.E. Program include the following: ENTEREG is available only for short-term (15 doses) use in hospitalized patients. Only hospitals that have enrolled in and met all of the requirements for the E.A.S.E. program may use ENTEREG. - ENTEREG is available only for short-term (15 doses) use in hospitalized patients. Only hospitals that have enrolled in and met all of the requirements for the E.A.S.E. program may use ENTEREG. - To enroll in the E.A.S.E. Program, an authorized hospital representative must acknowledge that: hospital staff who prescribe, dispense, or administer ENTEREG have been provided the educational materials on the need to limit use of ENTEREG to short-term, inpatient use; patients will not receive more than 15 doses of ENTEREG; and ENTEREG will not be dispensed to patients after they have been discharged from the hospital. - hospital staff who prescribe, dispense, or administer ENTEREG have been provided the educational materials on the need to limit use of ENTEREG to short-term, inpatient use; - patients will not receive more than 15 doses of ENTEREG; and - ENTEREG will not be dispensed to patients after they have been discharged from the hospital. - Further information is available at www.ENTEREGREMS.com or 1-877-282-4786. - Gastrointestinal-Related Adverse Reactions in Opioid-Tolerant Patients - Patients recently exposed to opioids are expected to be more sensitive to the effects of μ-opioid receptor antagonists, such as ENTEREG. Since ENTEREG acts peripherally, clinical signs and symptoms of increased sensitivity would be related to the gastrointestinal tract (e.g., abdominal pain, nausea and vomiting, diarrhea). Patients receiving more than 3 doses of an opioid within the week prior to surgery were not studied in the postoperative ileus clinical trials. Therefore, if ENTEREG is administered to these patients, they should be monitored for gastrointestinal adverse reactions. ENTEREG is contraindicated in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking ENTEREG. - Risk of Serious Adverse Reactions in Patients with Severe Hepatic Impairment - Patients with severe hepatic impairment may be at higher risk of serious adverse reactions (including dose-related serious adverse reactions) because up to 10-fold higher plasma levels of drug have been observed in such patients compared with patients with normal hepatic function. Therefore, the use of ENTEREG is not recommended in this population. - End-Stage Renal Disease - No studies have been conducted in patients with end-stage renal disease. ENTEREG is not recommended for use in these patients. - Risk of Serious Adverse Reactions in Patients with Complete Gastrointestinal Obstruction - No studies have been conducted in patients with complete gastrointestinal obstruction or in patients who have surgery for correction of complete bowel obstruction. ENTEREG is not recommended for use in these patients. - Risk of Serious Adverse Reactions in Pancreatic and Gastric Anastomoses - ENTEREG has not been studied in patients having pancreatic or gastric anastomosis. Therefore, ENTEREG is not recommended for use in these patients. # 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 compared directly with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The adverse event information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. - The data described below reflect exposure to ENTEREG 12 mg in 1,793 patients in 10 placebo-controlled studies. The population was 19 to 97 years old, 64% were female, and 84% were Caucasian; 64% were undergoing a surgery that included bowel resection. The first dose of ENTEREG was administered 30 minutes to 5 hours before the scheduled start of surgery and then twice daily until hospital discharge (or for a maximum of 7 days of postoperative treatment). - Among ENTEREG-treated patients undergoing surgeries that included a bowel resection, the most common adverse reaction (incidence ≥1.5%) occurring with a higher frequency than placebo was dyspepsia (ENTEREG, 1.5%; placebo, 0.8%). Adverse reactions are events that occurred after the first dose of study medication treatment and within 7 days of the last dose of study medication or events present at baseline that increased in severity after the start of study medication treatment. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Alvimopan in the drug label. # Drug Interactions - Potential for Drugs to Affect Alvimopan Pharmacokinetics - An in vitro study indicates that alvimopan is not a substrate of CYP enzymes. Therefore, concomitant administration of ENTEREG with inducers or inhibitors of CYP enzymes is unlikely to alter the metabolism of alvimopan. - Potential for Alvimopan to Affect the Pharmacokinetics of Other Drugs - Based on in vitro data, ENTEREG is unlikely to alter the pharmacokinetics of coadministered drugs through inhibition of CYP isoforms such as 1A2, 2C9, 2C19, 3A4, 2D6, and 2E1 or induction of CYP isoforms such as 1A2, 2B6, 2C9, 2C19, and 3A4. - In vitro, ENTEREG did not inhibit p-glycoprotein. - Effects of Alvimopan on Intravenous Morphine - Coadministration of alvimopan does not appear to alter the pharmacokinetics of morphine and its metabolite, morphine-6-glucuronide, to a clinically significant degree when morphine is administered intravenously. Dosage adjustment for intravenously administered morphine is not necessary when it is coadministered with alvimopan. - Effects of Concomitant Acid Blockers or Antibiotics - A population pharmacokinetic analysis suggests that the pharmacokinetics of alvimopan were not affected by concomitant administration of acid blockers or antibiotics. No dosage adjustments are necessary in patients taking acid blockers or antibiotics. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - Risk Summary: There are no adequate and/or well-controlled studies with ENTEREG in pregnant women. No fetal harm was observed in animal reproduction studies with oral administration of alvimopan to rats at doses 68 to 136 times the recommended human oral dose, or with intravenous administration to rats and rabbits at doses 3.4 to 6.8 times, and 5 to 10 times, respectively, the recommended human oral dose. Because animal reproduction studies are not always predictive of human response, ENTEREG should be used during pregnancy only if clearly needed. - Animal Data: Reproduction studies were performed in pregnant rats at oral doses up to 200 mg/kg/day (about 68 to 136 times the recommended human oral dose based on body surface area) and at intravenous doses up to 10 mg/kg/day (about 3.4 to 6.8 times the recommended human oral dose based on body surface area) and in pregnant rabbits at intravenous doses up to 15 mg/kg/day (about 5 to 10 times the recommended human oral dose based on body surface area), and revealed no evidence of impaired fertility or harm to the fetus due to alvimopa Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alvimopan in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Alvimopan during labor and delivery. ### Nursing Mothers - It is not known whether ENTEREG is present in human milk. Alvimopan and its 'metabolite' are detected in the milk of lactating rats. Exercise caution when administering ENTEREG to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Of the total number of patients in 6 clinical efficacy studies treated with ENTEREG 12 mg or placebo, 46% were 65 years of age and over, while 18% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, 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. No dosage adjustment based on increased age is required. ### Gender There is no FDA guidance on the use of Alvimopan with respect to specific gender populations. ### Race - No dosage adjustment is necessary in Black, Hispanic, and Japanese patients. However, the exposure to ENTEREG in Japanese healthy male volunteers was approximately 2-fold greater than in Caucasian subjects. Japanese patients should be closely monitored for possible adverse effects (e.g., diarrhea, gastrointestinal pain, cramping) that could indicate high drug or 'metabolite' levels, and ENTEREG should be discontinued if adverse events occur. ### Renal Impairment - ENTEREG is not recommended for use in patients with end-stage renal disease. Dosage adjustment is not required for patients with mild-to-severe renal impairment, but they should be monitored for adverse effects. Patients with severe renal impairment should be closely monitored for possible adverse effects (e.g., diarrhea, gastrointestinal pain, cramping) that could indicate high drug or 'metabolite' levels, and ENTEREG should be discontinued if adverse events occur. ### Hepatic Impairment - ENTEREG is not recommended for use in patients with severe hepatic impairment. - Dosage adjustment is not required for patients with mild-to-moderate hepatic impairment. Patients with mild-to-moderate hepatic impairment should be closely monitored for possible adverse effects (e.g., diarrhea, gastrointestinal pain, cramping) that could indicate high drug or 'metabolite' levels, and ENTEREG should be discontinued if adverse events occur. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Alvimopan in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Alvimopan in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Alvimopan in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Alvimopan in the drug label. # Overdosage ## Chronic Overdose There is limited information regarding Chronic Overdose of Alvimopan in the drug label. # Pharmacology ## Mechanism of Action - Alvimopan is a selective antagonist of the cloned human μ-opioid receptor with a Ki of 0.4 nM (0.2 ng/mL) and no measurable opioid-agonist effects in standard pharmacologic assays. The dissociation of [3H]-alvimopan from the human μ-opioid receptor is slower than that of other opioid ligands, consistent with its higher affinity for the receptor. At concentrations of 1 to 10 µM, alvimopan demonstrated no activity at any of over 70 non-opioid receptors, enzymes, and ion channels. - Postoperative ileus is the impairment of gastrointestinal motility after intra-abdominal surgery or other, non-abdominal surgeries. Postoperative ileus affects all segments of the gastrointestinal tract and may last from 5 to 6 days, or even longer. This may potentially delay gastrointestinal recovery and hospital discharge until its resolution. It is characterized by abdominal distention and bloating, nausea, vomiting, pain, accumulation of gas and fluids in the bowel, and delayed passage of flatus and defecation. Postoperative ileus is the result of a multifactorial process that includes inhibitory sympathetic input and release of hormones, neurotransmitters, and other mediators (e.g., endogenous opioids). A component of postoperative ileus also results from an inflammatory reaction and the effects of opioid analgesics. Morphine and other μ-opioid receptor agonists are universally used for the treatment of acute postsurgical pain; however, they are known to have an inhibitory effect on gastrointestinal motility and may prolong the duration of postoperative ileus. - Following oral administration, alvimopan antagonizes the peripheral effects of opioids on gastrointestinal motility and secretion by competitively binding to gastrointestinal tract μ-opioid receptors. The antagonism produced by alvimopan at opioid receptors is evident in isolated guinea pig ileum preparations in which alvimopan competitively antagonizes the effects of morphine on contractility. Alvimopan achieves this selective gastrointestinal opioid antagonism without reversing the central analgesic effects of μ-opioid agonists. ## Structure - ENTEREG capsules contain alvimopan, an opioid antagonist. Chemically, alvimopan is the single stereoisomer [2(S)-[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid dihydrate. It has the following structural formula: - Alvimopan is a white to light beige powder with a molecular weight of 460.6, and the empirical formula is C25H32N2O4•2H2O. It has a solubility of <0.1 mg/mL in water or buffered solutions between pH 3.0 and 9.0, 1 to 5 mg/mL in buffered solutions at pH 1.2, and 10 to 25 mg/mL in aqueous 0.1 N sodium hydroxide. At physiological pH, alvimopan is zwitterionic, a property that contributes to its low solubility. - ENTEREG capsules for oral administration contain 12 mg of alvimopan on an anhydrous basis suspended in the inactive ingredient polyethylene glycol. ## Pharmacodynamics - In an exploratory study in healthy volunteers, alvimopan 12 mg administered twice a day reduced the delay in small and large bowel transit induced by codeine 30 mg administered 4 times a day, as measured by gastrointestinal scintigraphy. In the same study, concomitant alvimopan did not reduce the delay in gastric emptying induced by codeine. - In a study designed to evaluate potential effects on cardiac conduction, alvimopan did not cause clinically significant QTc prolongation at doses up to 24 mg twice daily (twice the approved dosage regimen) for 7 days. The potential for QTc effects at higher doses has not been studied. ## Pharmacokinetics - Following oral administration of alvimopan, an amide hydrolysis compound is present in the systemic circulation, which is considered a product exclusively of intestinal flora metabolism. This compound is referred to as the 'metabolite'. It is also a μ-opioid receptor antagonist with a Ki of 0.8 nM (0.3 ng/mL). - Absorption: Following oral administration of ENTEREG capsules in healthy volunteers, plasma alvimopan concentration peaked at approximately 2 hours postdose. No significant accumulation in alvimopan concentration was observed following twice daily (BID) dosing. The mean peak plasma concentration was 10.98 (±6.43) ng/mL and mean AUC0–12h was 40.2 (±22.5) ng•h/mL after dosing of alvimopan at 12 mg BID for 5 days. The absolute bioavailability was estimated to be 6% (range, 1% to 19%). There was a delay in the appearance of the 'metabolite', which had a median Tmax of 36 hours following administration of a single dose of alvimopan. Concentrations of the 'metabolite' were highly variable between subjects and within a subject. The 'metabolite' accumulated after multiple doses of ENTEREG. The mean Cmax for the 'metabolite' after alvimopan 12 mg twice daily for 5 days was 35.73 ± 35.29 ng/mL. - Concentrations of alvimopan and its 'metabolite' are higher (~1.9-fold and ~1.4-fold, respectively) in postoperative ileus patients than in healthy volunteers. - Food Effects: A high-fat meal decreased the extent and rate of alvimopan absorption. The Cmax and AUC were decreased by approximately 38% and 21%, respectively, and the Tmax was prolonged by approximately 1 hour. The clinical significance of this decreased bioavailability is unknown. In postoperative ileus clinical trials, the preoperative dose of ENTEREG was administered in a fasting state. Subsequent doses were given without regard to meals. - Distribution: The steady-state volume of distribution of alvimopan was estimated to be 30±10 L. Plasma protein binding of alvimopan and its 'metabolite' was independent of concentration over ranges observed clinically and averaged 80% and 94%, respectively. Both alvimopan and the 'metabolite' were bound to albumin and not to alpha-1 acid glycoprotein. - Metabolism and Elimination: In vitro data suggest that alvimopan is not a substrate of CYP enzymes. The average plasma clearance for alvimopan was 402 (±89) mL/min. Renal excretion accounted for approximately 35% of total clearance. There was no evidence that hepatic metabolism was a significant route for alvimopan elimination. Biliary secretion was considered the primary pathway for alvimopan elimination. Unabsorbed drug and unchanged alvimopan resulting from biliary excretion were then hydrolyzed to its 'metabolite' by gut microflora. The 'metabolite' was eliminated in the feces and in the urine as unchanged 'metabolite', the glucuronide conjugate of the 'metabolite', and other minor metabolites. The mean terminal phase half-life of alvimopan after multiple oral doses of ENTEREG ranged from 10 to 17 hours. The terminal half-life of the 'metabolite' ranged from 10 to 18 hours. - Specific Populations: - Age: The pharmacokinetics of alvimopan, but not its 'metabolite', were related to age, but this effect was not clinically significant and does not warrant dosage adjustment based on increased age. - Race: The pharmacokinetic characteristics of alvimopan were not affected by Hispanic or Black race. Plasma 'metabolite' concentrations were lower in Black and Hispanic patients (by 43% and 82%, respectively) than in Caucasian patients following alvimopan administration. These changes are not considered to be clinically significant in surgical patients. Japanese healthy male volunteers had an approximately 2-fold increase in plasma alvimopan concentrations, but no change in 'metabolite' pharmacokinetics. The pharmacokinetics of alvimopan have not been studied in subjects of other East Asian ancestry. Dosage adjustment in Japanese patients is not required. - Gender: There was no effect of gender on the pharmacokinetics of alvimopan or the 'metabolite'. - Hepatic Impairment: Exposure to alvimopan following a single 12 mg dose tended to be higher (1.5- to 2-fold, on average) in patients with mild or moderate hepatic impairment (as defined by Child-Pugh Class A and B, n = 8 each) compared with healthy controls (n = 4). There were no consistent effects on the Cmax or half-life of alvimopan in patients with hepatic impairment. However, 2 of 16 patients with mild-to-moderate hepatic impairment had longer than expected half-lives of alvimopan, indicating that some accumulation may occur upon multiple dosing. The Cmax of the 'metabolite' tended to be more variable in patients with mild or moderate hepatic impairment than in matched normal subjects. A study of 3 patients with severe hepatic impairment (Child-Pugh Class C), indicated similar alvimopan exposure in 2 patients and an approximately 10-fold increase in Cmax and exposure in 1 patient with severe hepatic impairment when compared with healthy control volunteers [see Warnings and Precautions (5.4) and Use in Specific Populations (8.6)]. - Renal Impairment: There was no relationship between renal function (i.e., creatinine clearance [CrCl]) and plasma alvimopan pharmacokinetics (Cmax, AUC, or half-life) in patients with mild (CrCl 51–80 mL/min), moderate (CrCl 31–50 mL/min), or severe (CrCl <30 mL/min) renal impairment (n = 6 each). Renal clearance of alvimopan was related to renal function; however, because renal clearance was only a small fraction (35%) of the total clearance, renal impairment had a small effect on the apparent oral clearance of alvimopan. The half-lives of alvimopan were comparable in the mild, moderate, and control renal impairment groups but longer in the severe renal impairment group. Exposure to the 'metabolite' tended to be 2- to 5-fold higher in patients with moderate or severe renal impairment compared with patients with mild renal impairment or control subjects. Thus, there may be accumulation of alvimopan and 'metabolite' in patients with severe renal impairment receiving multiple doses of ENTEREG. Patients with end-stage renal disease were not studied. - Crohn's Disease: There was no relationship between disease activity in patients with Crohn's disease (measured as Crohn's Disease Activity Index or bowel movement frequency) and alvimopan pharmacokinetics (AUC or Cmax). Patients with active or quiescent Crohn's disease had increased variability in alvimopan pharmacokinetics, and exposure tended to be 2-fold higher in patients with quiescent disease than in those with active disease or in normal subjects. Concentrations of the 'metabolite' were lower in patients with Crohn's disease. - Drug Interactions: - Potential for Drugs to Affect Alvimopan Pharmacokinetics: Concomitant administration of ENTEREG with inducers or inhibitors of CYP enzymes is unlikely to alter the metabolism of alvimopan because ENTEREG is metabolized mainly by non-CYP enzyme pathway. No clinical studies have been performed to assess the effect of concomitant administration of inducers or inhibitors of cytochrome P450 enzymes on alvimopan pharmacokinetics. - In vitro studies suggest that alvimopan and its 'metabolite' are substrates for p-glycoprotein. A population pharmacokinetic analysis did not reveal any evidence that alvimopan or 'metabolite' pharmacokinetics were influenced by concomitant medications that are mild-to-moderate p-glycoprotein inhibitors. No clinical studies of concomitant administration of alvimopan and strong inhibitors of p-glycoprotein (e.g., verapamil, cyclosporine, amiodarone, itraconazole, quinine, spironolactone, quinidine, diltiazem, bepridil) have been conducted. - A population pharmacokinetic analysis suggests that the pharmacokinetics of alvimopan were not affected by concomitant administration of acid blockers or antibiotics. However, plasma concentrations of the 'metabolite' were lower in patients receiving acid blockers or preoperative oral antibiotics (49% and 81%, respectively). No dosage adjustments are necessary in these patients. - Potential for Alvimopan to Affect the Pharmacokinetics of Other Drugs: Alvimopan and its 'metabolite' are not inhibitors of CYP 1A2, 2C9, 2C19, 3A4, 2D6, and 2E1 in vitro at concentrations far in excess of those observed clinically. - Alvimopan and its 'metabolite' are not inducers of CYP 1A2, 2B6, 2C9, 2C19, and 3A4. - In vitro studies also suggest that alvimopan and its 'metabolite' are not inhibitors of p-glycoprotein. - These in vitro findings suggest that ENTEREG is unlikely to alter the pharmacokinetics of coadministered drugs through inhibition or induction of CYP enzymes or inhibition of p-glycoprotein. ## Nonclinical Toxicology - Carcinogenesis: Two-year carcinogenicity studies were conducted with alvimopan in CD-1 mice at oral doses up to 4000 mg/kg/day and in Sprague-Dawley rats at oral doses up to 500 mg/kg/day. Oral administration of alvimopan for 104 weeks produced significant increases in the incidences of fibroma, fibrosarcoma, and sarcoma in the skin/subcutis, and of osteoma/osteosarcoma in bones of female mice at 4000 mg/kg/day (about 674 times the recommended human dose based on body surface area). In rats, oral administration of alvimopan for 104 weeks did not produce any tumor up to 500 mg/kg/day (about 166 times the recommended human dose based on body surface area). - Mutagenesis: Alvimopan was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK+/−) forward mutation test, the Chinese Hamster Ovary (CHO) cell chromosome aberration test, or the mouse micronucleus test. The pharmacologically active 'metabolite' ADL 08-0011 was negative in the Ames test, chromosome aberration test in CHO cells, and mouse micronucleus test. - Impairment of Fertility: Alvimopan at intravenous doses up to 10 mg/kg/day (about 3.4 to 6.8 times the recommended human oral dose based on body surface area) was found to have no adverse effect on fertility and reproductive performance of male or female rats. # Clinical Studies - The efficacy of ENTEREG in the management of postoperative ileus was evaluated in 6 multicenter, randomized, double-blind, parallel-group, placebo-controlled studies: 5 US studies (Studies 1-4 and 6) and 1 non–US study (Study 5). Patients 18 years of age or older undergoing partial large or small bowel resection surgery with primary anastomosis for colorectal or small bowel disease, total abdominal hysterectomy, or radical cystectomy for bladder cancer (in this procedure, resected segments of bowel are used for reconstruction of the urinary tract) under general anesthesia were randomly assigned to receive oral doses of ENTEREG 12 mg or matching placebo. The initial dose was administered at least 30 minutes and up to 5 hours prior to the scheduled start of surgery for most patients, and subsequent doses were administered twice daily beginning on the first postoperative day and continued until hospital discharge or a maximum of 7 days. There were no limitations on the type of general anesthesia used, but intrathecal or epidural opioids or anesthetics were prohibited. - All patients in the US studies were scheduled to receive intravenous patient-controlled opioid analgesia. In the non–US study, patients were scheduled to receive opioids either by intravenous patient-controlled opioid analgesia or bolus parenteral administration (intravenous or intramuscular). In all studies, there was no restriction on the type of opioid used or the duration of intravenous patient-controlled opioid analgesia. A standardized accelerated postoperative care pathway was implemented: early nasogastric tube removal (before the first postoperative dose); early ambulation (day following surgery); early diet advancement (liquids offered the day following surgery for patients undergoing bowel resection and by the third day following surgery for patients undergoing radical cystectomy; solids by the second day following surgery for patients undergoing bowel resection and by the fourth day following surgery for patients undergoing radical cystectomy), as tolerated. - Patients who received more than 3 doses of an opioid (regardless of route) during the 7 days prior to surgery and patients with complete bowel obstruction or who were scheduled for a total colectomy, colostomy, or ileostomy were excluded. - The primary endpoint for all studies was time to achieve resolution of postoperative ileus, a clinically defined composite measure of both upper and lower gastrointestinal recovery. Although both 2-component (GI2: toleration of solid food and first bowel movement) and 3-component (GI3: toleration of solid food and either first flatus or bowel movement) endpoints were used in all studies, GI2 is presented as it represents the most objective and clinically relevant measure of treatment response in patients undergoing surgeries that include a bowel resection. The time from the end of surgery to when the discharge order was written represented the length of hospital stay. In the 6 studies, 1,058 patients who underwent a surgery that included a bowel resection received placebo (not including 157 for total abdominal hysterectomy) and 1,096 patients received ENTEREG 12 mg (not including 143 for total abdominal hysterectomy). - The efficacy of ENTEREG following total abdominal hysterectomy has not been established. Therefore, the following data are presented only for surgeries that included a bowel resection (i.e., bowel resection or radical cystectomy). - Bowel Resection or Radical Cystectomy: A total of 2,154 patients underwent a surgery that included a bowel resection. The average age was 62 years, 54% were males, and 89% were Caucasian. The most common indications for surgery were colon or rectal cancer/malignancy, bladder cancer, and diverticular disease. In the non–US bowel resection study (Study 5), average daily postoperative opioid consumption was approximately 50% lower and the use of non-opioid analgesics substantially higher, as compared with the US bowel resection studies (Studies 1-4) for both treatment groups. During the first 48 hours postoperatively, the use of non-opioid analgesics was 69% compared with 4% for the non–US and US bowel resection studies, respectively. In each of the 6 studies, ENTEREG accelerated the time to recovery of gastrointestinal function, as measured by the composite endpoint GI2, and time to discharge order written as compared with placebo. Hazard ratios greater than 1 indicate a higher probability of achieving the event during the study period with treatment with ENTEREG than with placebo. Table 1 provides the Hazard Ratios, Kaplan Meier means, medians, and mean and median treatment differences (hours) in gastrointestinal recovery between ENTEREG and placebo. - The Kaplan Meier estimate probabilities of patients receiving ENTEREG who achieved GI2 were numerically higher at all times throughout the study observation period compared with those of patients receiving placebo (see Figures 1 and 2). - In Studies 1–4, the differences between ENTEREG and placebo patient groups in median time to 'discharge order written' ranged from 6 to 22 hours, in favor of ENTEREG patients. The group differences in mean time to 'discharge order written' ranged from 13 to 21 hours. In Study 6, the median time difference was 19 hours in favor of ENTEREG patients (mean time difference 22 hours). - ENTEREG did not reverse opioid analgesia as measured by visual analog scale pain intensity scores and/or amount of postoperative opioids administered across all 6 studies. - There were no gender-, age-, or race-related differences in treatment effect. - The incidence of anastomotic leak was low and comparable in patients receiving either ENTEREG or placebo (0.7% and 1.0%, respectively). # How Supplied - ENTEREG capsules, 12 mg, are blue, hard-gelatin capsules printed with "ADL2698" on both the body and the cap of the capsule. ENTEREG capsules are available in unit-dose packs of 30 capsules (30 doses) (NDC 67919-020-10) for hospital use only. - Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). ## Storage There is limited information regarding Alvimopan Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Recent Use of Opioids - Patients should be informed that they must disclose long-term or intermittent opioid pain therapy, including any use of opioids in the week prior to receiving ENTEREG. They should understand that recent use of opioids may make them more susceptible to adverse reactions to ENTEREG, primarily those limited to the gastrointestinal tract (e.g., abdominal pain, nausea and vomiting, diarrhea). - Hospital Use Only - ENTEREG is available only through a program called the ENTEREG Access Support and Education (E.A.S.E.) Program under a REMS that restricts use to enrolled hospitals because of the potential risk of myocardial infarction with long-term use of ENTEREG. Patients should be informed that ENTEREG is for hospital use only for no more than 7 days after their bowel resection surgery. - Most Common Side Effect - Patients should be informed that the most common side effect with ENTEREG in patients undergoing surgeries that include bowel resection is dyspepsia. # Precautions with Alcohol - Alcohol-Alvimopan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ENTEREG®[3] # Look-Alike Drug Names There is limited information regarding Alvimopan Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Alvimopan
a6d3db494e82c7690a8f7304df48fe314829b618	wikidoc	Amatoxins	Amatoxins Amatoxins are a subgroup of at least eight toxic compounds found in several genera of poisonous mushrooms, most notably Amanita phalloides and several other members of the genus Amanita, as well as some Conocybe, Galerina and Lepiota mushroom species. # Structure The compounds have a similar structure, that of eight amino-acid rings; they were isolated in 1941 by Heinrich O. Wieland and Rudolf Hallermayer of the University of Munich. All amatoxins are oligopeptides synthesized as proproteins 34 or 35 amino acids long and then cleaved by a prolyl oligopeptidase There are currently ten known amatoxins: δ-Amanitin has been reported, but its chemical structure has not been determined. # Function Their major toxic mechanism is the inhibition of RNA polymerase II, a vital enzyme in the synthesis of messenger RNA (mRNA), microRNA, and small nuclear RNA (snRNA). Without mRNA, essential protein synthesis, and hence cell metabolism, grind to a halt and the cell dies. The liver is the principal organ affected, as it is the organ which is first encountered after absorption in the gastrointestinal tract, though other organs, especially the kidneys, are susceptible. The RNA polymerase of Amanita phalloides is insensitive to the effects of amatoxins; as such, the mushroom does not poison itself. Their swift intestinal absorption coupled with their thermostability explains why their toxic effects occur in a relatively short period of time. The most severe effects are toxic hepatitis with centrolobular necrosis and hepatic steatosis, as well as acute tubulointerstitial nephropathy, which altogether induce a severe hepatorenal syndrome (with a potentially fatal outcome). The estimated minimum lethal dose is 0.1 mg/kg or 7 mg of toxin in adults. # Detection Presence of amatoxins in mushroom samples may be detected by the Meixner Test (also known as the Wieland Test).	Amatoxins Amatoxins are a subgroup of at least eight toxic compounds found in several genera of poisonous mushrooms, most notably Amanita phalloides and several other members of the genus Amanita, as well as some Conocybe, Galerina and Lepiota mushroom species. # Structure The compounds have a similar structure, that of eight amino-acid rings; they were isolated in 1941 by Heinrich O. Wieland and Rudolf Hallermayer of the University of Munich.[1] All amatoxins are oligopeptides synthesized as proproteins 34 or 35 amino acids long and then cleaved by a prolyl oligopeptidase[2] There are currently ten known amatoxins:[3] δ-Amanitin has been reported, but its chemical structure has not been determined. # Function Their major toxic mechanism is the inhibition of RNA polymerase II, a vital enzyme in the synthesis of messenger RNA (mRNA), microRNA, and small nuclear RNA (snRNA). Without mRNA, essential protein synthesis, and hence cell metabolism, grind to a halt and the cell dies.[4] The liver is the principal organ affected, as it is the organ which is first encountered after absorption in the gastrointestinal tract, though other organs, especially the kidneys, are susceptible.[5] The RNA polymerase of Amanita phalloides is insensitive to the effects of amatoxins; as such, the mushroom does not poison itself.[6] Their swift intestinal absorption coupled with their thermostability explains why their toxic effects occur in a relatively short period of time. The most severe effects are toxic hepatitis with centrolobular necrosis and hepatic steatosis, as well as acute tubulointerstitial nephropathy, which altogether induce a severe hepatorenal syndrome (with a potentially fatal outcome). The estimated minimum lethal dose is 0.1 mg/kg or 7 mg of toxin in adults. # Detection Presence of amatoxins in mushroom samples may be detected by the Meixner Test (also known as the Wieland Test).	https://www.wikidoc.org/index.php/Amatoxins
70db7d0ae3549975692888b23f9b81214fe5bd58	wikidoc	Ambien CR	Ambien CR Ambien CR (zolpidem tartrate extended release) is different from Ambien (zolpidem tartrate) in that the medication is formulated in a 2 layer tablet. The first layer of the Ambien CR tablet dissolves quickly to help people fall asleep, while the 2nd layer dissolves slowly over the night to help people stay asleep (something Ambien has not demonstrated in trials). The action of both immediate and continuous release with Ambien CR allows for increased effectiveness over the night (since blood levels are more stable 3 to 6 hours after taking medication) and is proven to be more effective than traditional Ambien in quality of sleep. Ambien CR and Ambien have the same active ingredient so the safety and tolerability profiles are similar. Even though Ambien CR helps maintain sleep throughout the middle of the night it does not increase the risk of "hangover" effects (same as regular Ambien). A recent long term study found effectiveness over 6-months, improved morning concentration and daytime function, and no risk of abuse with Ambien CR (Krystal 2007). # Uses Ambien CR is FDA-approved for both short and long-term treatment of insomnia. # Pharmacodynamics Subunit modulation of the GABA receptor chloride channel macromolecular complex is hypothesized to be responsible for sedative, anticonvulsant, anxiolytic, and myorelaxant drug properties. The major modulatory site of the GABA receptor complex is located on its alpha-(a) subunit and is referred to as the benzodiazepine (BZ) receptor. Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, pyrrolopyrazines, pyrazolopyrimidines, or other drugs with known hypnotic properties. In contrast to the benzodiazepines, which nonselectively bind to and activate all BZ receptor subtypes, zolpidem in vitro binds the BZ1 receptor preferentially with a high affinity ratio of the alpha1/alpha5 subunits. The BZ1 receptor is found primarily on the Lamina IV of the sensorimotor cortical regions, substantia nigra (pars reticulata), cerebellum's molecular layer, olfactory bulb, ventral thalamic complex, pons, inferior colliculus, and globus pallidus. This selective binding of zolpidem on the BZ1 receptor is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem at hypnotic doses. # Pharmacokinetics Ambien CR exhibits biphasic absorption characteristics, which results in rapid initial absorption from the gastrointestinal tract similar to zolpidem tartrate immediate-release, then provides extended plasma concentrations beyond three hours after administration. A study in 24 healthy male subjects was conducted to compare mean zolpidem plasma concentration-time profiles obtained after single oral administration of Ambien CR (12.5 mg) and of an immediate-release formulation of zolpidem tartrate (10 mg). The terminal elimination half-life observed with Ambien CR (12.5 mg) was similar to that obtained with immediate-release zolpidem tartrate (10 mg). The mean plasma concentration time profiles for Ambien CR (12.5 mg) and for zolpidem tartrate (10 mg) are shown below: File:Ambien cr2.gif # Absorption Following administration of Ambien CR, administered as a single 12.5-mg dose in healthy male adult subjects, the mean peak concentration (cmax) of zolpidem was 134 ng/mL (range: 68.9 to 197 ng/ml) occurring at a median time (tmax) of 1.5 hours. The mean AUC of zolpidem was 740 ng·hr/mL (range: 295 to 1359 ng·hr/mL). A food-effect study in 45 healthy volunteers compared the pharmacokinetics of Ambien CR 12.5 mg when administered while fasting or within 30 minutes after a meal. Results demonstrated that with food, mean AUC and cmax were decreased by 23% and 30%, respectively, while median tmax was increased from 2 hours to 4 hours. The half-life was not changed. These results suggest that, for faster sleep onset, Ambien CR should not be administered with or immediately after a meal. Total protein binding was found to be 92.5 ± 0.1% and remained constant, independent of concentration between 40 and 790 ng/mL. Ambien CR administered as a single 12.5 mg dose in healthy male adult subjects, the mean zolpidem elimination half-life was 2.8 hours (range: 1.62 to 4.05 hr). # Controlled Trials Ambien CR was evaluated in two placebo-controlled studies for the treatment of patients with chronic primary insomnia (as defined in the APA Diagnostic and Statistical Manual of Mental Disorders, DSM IV). Adult outpatients (18-64 years) with primary insomnia (N=212) were evaluated in a double-blind, randomized, parallel-group, 3-week trial comparing Ambien CR 12.5 mg and placebo. Ambien CR 12.5 mg decreased wake time after sleep onset (WASO) for the first 7 hours during the first 2 nights and for the first 5 hours after 2 weeks of treatment. Ambien CR 12.5 mg was superior to placebo on objective measures (polysomnography recordings) of sleep induction (by decreasing latency to persistent sleep ) during the first 2 nights of treatment and after 2 weeks of treatment. Ambien CR 12.5 mg was also superior to placebo on the patient reported global impression regarding the aid to sleep after the first 2 nights and after 3 weeks of treatment. Elderly outpatients (³ 65 years) with primary insomnia (N=205) were evaluated in a double-blind, randomized, parallel-group, 3-week trial comparing Ambien CR 6.25 mg and placebo. Ambien CR 6.25 mg decreased wake time after sleep onset (WASO) for the first 6 hours during the first 2 nights and the first 4 hours after 2 weeks of treatment. Ambien CR 6.25 mg was superior to placebo on objective measures (polysomnography recordings) of sleep induction (by decreasing latency to persistent sleep ) during the first 2 nights of treatment and after 2 weeks on treatment. Ambien CR 6.25 mg was superior to placebo on the patient reported global impression regarding the aid to sleep after the first 2 nights and after 3 weeks of treatment. In both studies, in patients treated with Ambien CR, polysomnography showed increased wakefulness at the end of the night compared to placebo-treated patients. # Side-Effects Next-day residual effects: In five clinical studies; three controlled studies in adults (18-64 years of age) administered Ambien CR 12.5 mg and two controlled studies in the elderly (³ 65 years of age) administered Ambien CR 6.25 mg or 12.5 mg, the effect of Ambien CR on vigilance, memory, or motor function were assessed using neurocognitive tests. In these studies, no significant decrease in performance was observed eight hours after a nighttime dose. In addition, no evidence of next-day residual effects were detected with Ambien CR 12.5 mg and 6.25 mg using self-ratings of sedation. Next day somnolence was reported by 15% of the adult patients who received 12.5 mg Ambien CR versus 2% of the placebo group. Next day somnolence was reported by 6% of the elderly patients who received 6.25 mg Ambien CR versus 5% of the placebo group. (See Adverse Reactions.) Rebound effects: Rebound insomnia, defined as a dose-dependent worsening in sleep parameters (latency, sleep efficiency, and number of awakenings) compared with baseline following discontinuation of treatment, is observed with short- and intermediate-acting hypnotics. In the two placebo-controlled studies in patients with primary insomnia, a rebound effect was only observed on the first night after abrupt discontinuation of Ambien CR. On the second night, there was no worsening compared to baseline in the Ambien CR group.	Ambien CR Ambien CR (zolpidem tartrate extended release) is different from Ambien (zolpidem tartrate) in that the medication is formulated in a 2 layer tablet. The first layer of the Ambien CR tablet dissolves quickly to help people fall asleep, while the 2nd layer dissolves slowly over the night to help people stay asleep (something Ambien has not demonstrated in trials). The action of both immediate and continuous release with Ambien CR allows for increased effectiveness over the night (since blood levels are more stable 3 to 6 hours after taking medication) and is proven to be more effective than traditional Ambien in quality of sleep. Ambien CR and Ambien have the same active ingredient so the safety and tolerability profiles are similar. Even though Ambien CR helps maintain sleep throughout the middle of the night it does not increase the risk of "hangover" effects (same as regular Ambien). A recent long term study found effectiveness over 6-months, improved morning concentration and daytime function, and no risk of abuse with Ambien CR (Krystal 2007). # Uses Ambien CR is FDA-approved for both short and long-term treatment of insomnia. # Pharmacodynamics Subunit modulation of the GABA receptor chloride channel macromolecular complex is hypothesized to be responsible for sedative, anticonvulsant, anxiolytic, and myorelaxant drug properties. The major modulatory site of the GABA receptor complex is located on its alpha-(a) subunit and is referred to as the benzodiazepine (BZ) receptor. Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, pyrrolopyrazines, pyrazolopyrimidines, or other drugs with known hypnotic properties. In contrast to the benzodiazepines, which nonselectively bind to and activate all BZ receptor subtypes, zolpidem in vitro binds the BZ1 receptor preferentially with a high affinity ratio of the alpha1/alpha5 subunits. The BZ1 receptor is found primarily on the Lamina IV of the sensorimotor cortical regions, substantia nigra (pars reticulata), cerebellum's molecular layer, olfactory bulb, ventral thalamic complex, pons, inferior colliculus, and globus pallidus. This selective binding of zolpidem on the BZ1 receptor is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem at hypnotic doses. # Pharmacokinetics Ambien CR exhibits biphasic absorption characteristics, which results in rapid initial absorption from the gastrointestinal tract similar to zolpidem tartrate immediate-release, then provides extended plasma concentrations beyond three hours after administration. A study in 24 healthy male subjects was conducted to compare mean zolpidem plasma concentration-time profiles obtained after single oral administration of Ambien CR (12.5 mg) and of an immediate-release formulation of zolpidem tartrate (10 mg). The terminal elimination half-life observed with Ambien CR (12.5 mg) was similar to that obtained with immediate-release zolpidem tartrate (10 mg). The mean plasma concentration time profiles for Ambien CR (12.5 mg) and for zolpidem tartrate (10 mg) are shown below: File:Ambien cr2.gif # Absorption Following administration of Ambien CR, administered as a single 12.5-mg dose in healthy male adult subjects, the mean peak concentration (cmax) of zolpidem was 134 ng/mL (range: 68.9 to 197 ng/ml) occurring at a median time (tmax) of 1.5 hours. The mean AUC of zolpidem was 740 ng·hr/mL (range: 295 to 1359 ng·hr/mL). A food-effect study in 45 healthy volunteers compared the pharmacokinetics of Ambien CR 12.5 mg when administered while fasting or within 30 minutes after a meal. Results demonstrated that with food, mean AUC and cmax were decreased by 23% and 30%, respectively, while median tmax was increased from 2 hours to 4 hours. The half-life was not changed. These results suggest that, for faster sleep onset, Ambien CR should not be administered with or immediately after a meal. Total protein binding was found to be 92.5 ± 0.1% and remained constant, independent of concentration between 40 and 790 ng/mL. Ambien CR administered as a single 12.5 mg dose in healthy male adult subjects, the mean zolpidem elimination half-life was 2.8 hours (range: 1.62 to 4.05 hr). # Controlled Trials Ambien CR was evaluated in two placebo-controlled studies for the treatment of patients with chronic primary insomnia (as defined in the APA Diagnostic and Statistical Manual of Mental Disorders, DSM IV). Adult outpatients (18-64 years) with primary insomnia (N=212) were evaluated in a double-blind, randomized, parallel-group, 3-week trial comparing Ambien CR 12.5 mg and placebo. Ambien CR 12.5 mg decreased wake time after sleep onset (WASO) for the first 7 hours during the first 2 nights and for the first 5 hours after 2 weeks of treatment. Ambien CR 12.5 mg was superior to placebo on objective measures (polysomnography recordings) of sleep induction (by decreasing latency to persistent sleep [LPS]) during the first 2 nights of treatment and after 2 weeks of treatment. Ambien CR 12.5 mg was also superior to placebo on the patient reported global impression regarding the aid to sleep after the first 2 nights and after 3 weeks of treatment. Elderly outpatients (³ 65 years) with primary insomnia (N=205) were evaluated in a double-blind, randomized, parallel-group, 3-week trial comparing Ambien CR 6.25 mg and placebo. Ambien CR 6.25 mg decreased wake time after sleep onset (WASO) for the first 6 hours during the first 2 nights and the first 4 hours after 2 weeks of treatment. Ambien CR 6.25 mg was superior to placebo on objective measures (polysomnography recordings) of sleep induction (by decreasing latency to persistent sleep [LPS]) during the first 2 nights of treatment and after 2 weeks on treatment. Ambien CR 6.25 mg was superior to placebo on the patient reported global impression regarding the aid to sleep after the first 2 nights and after 3 weeks of treatment. In both studies, in patients treated with Ambien CR, polysomnography showed increased wakefulness at the end of the night compared to placebo-treated patients. # Side-Effects Next-day residual effects: In five clinical studies; three controlled studies in adults (18-64 years of age) administered Ambien CR 12.5 mg and two controlled studies in the elderly (³ 65 years of age) administered Ambien CR 6.25 mg or 12.5 mg, the effect of Ambien CR on vigilance, memory, or motor function were assessed using neurocognitive tests. In these studies, no significant decrease in performance was observed eight hours after a nighttime dose. In addition, no evidence of next-day residual effects were detected with Ambien CR 12.5 mg and 6.25 mg using self-ratings of sedation. Next day somnolence was reported by 15% of the adult patients who received 12.5 mg Ambien CR versus 2% of the placebo group. Next day somnolence was reported by 6% of the elderly patients who received 6.25 mg Ambien CR versus 5% of the placebo group. (See Adverse Reactions.) Rebound effects: Rebound insomnia, defined as a dose-dependent worsening in sleep parameters (latency, sleep efficiency, and number of awakenings) compared with baseline following discontinuation of treatment, is observed with short- and intermediate-acting hypnotics. In the two placebo-controlled studies in patients with primary insomnia, a rebound effect was only observed on the first night after abrupt discontinuation of Ambien CR. On the second night, there was no worsening compared to baseline in the Ambien CR group.	https://www.wikidoc.org/index.php/Ambien_CR
1c9bcdbe1676f9ed6cf215ad492cbdb37decd792	wikidoc	Amblyopia	Amblyopia # Overview Amblyopia, or lazy eye, is a disorder of the eye that is characterized by poor or indistinct vision in an eye that is otherwise physically normal, or out of proportion to associated structural abnormalities. It has been estimated to affect 1–5% of the population. The problem is caused by either no transmission or poor transmission of the visual image to the brain for a sustained period of dysfunction or during early childhood. Amblyopia normally only affects one eye, but it is possible to be amblyopic in both eyes if both are similarly deprived of a good, clear visual image. Detecting the condition in early childhood increases the chance of successful treatment. # Physiology Amblyopia is a developmental problem in the brain, not an organic problem in the eye (although organic problems can induce amblyopic symptoms which persist after the organic problem has resolved). The part of the brain corresponding to the visual system from the affected eye is not stimulated properly, and develops abnormally. This has been confirmed via direct brain examination. David H. Hubel and Torsten Wiesel won the Nobel Prize in Physiology or Medicine in 1981 for their work demonstrating the irreversible damage to ocular dominance columns produced in kittens by sufficient visual deprivation during the so-called "critical period". The maximum critical period in humans is from birth to two years old. # Symptoms Many amblyopes, especially those who are only mildly so, are not even aware they have the condition until tested at older ages, since the vision in their stronger eye is normal. However, people who have severe amblyopia may experience associated visual disorders, most notably poor depth perception. Amblyopes suffer from poor spatial acuity, low sensitivity to contrast and some "higher-level" deficits to vision such as reduced sensitivity to motion. These deficits are usually specific to the amblyopic eye, not the unaffected "fellow" eye. Amblyopes also suffer from problems of binocular vision such as limited stereoscopic depth perception and usually have difficulty seeing the three-dimensional images in hidden stereoscopic displays such as autostereograms. However perception of depth from monocular cues such as size, perspective, and motion parallax is normal. # Types Amblyopia can be caused by deprivation of vision early in life, by strabismus (misaligned eyes), by vision-obstructing disorders, or by anisometropia (different degrees of myopia or hyperopia in each eye). ## Strabismic amblyopia Strabismus, sometimes erroneously also called lazy eye, is a condition in which the eyes are misaligned in a variety of different ways. Strabismus usually results in normal vision in the preferred sighting eye, but may cause abnormal vision in the deviating or strabismic eye due to the discrepancy between the images projecting to the brain from the two eyes. Adult-onset strabismus usually causes double vision (diplopia), since the two eyes are not fixated on the same object. Children's brains, however, are more plastic, and therefore can more easily adapt by ignoring images from one of the eyes, eliminating the double vision (suppression (eye)). This plastic response of the brain, however, interrupts the brain's normal development, resulting in the amblyopia. Strabismic amblyopia is treated by clarifying the visual image with glasses, and/or encouraging use of the amblyopic eye with patching or pharmacologic penalization (usually by applying atropine drops to the dominant eye to temporarily paralyze the muscles and weaken vision in the good eye—this helps to prevent the bullying and teasing associated with wearing a patch). The ocular alignment itself may be treated with surgical or non-surgical methods, depending on the type and severity of the strabismus. ## Refractive or anisometropic amblyopia Refractive amblyopia may result from anisometropia (unequal refractive errors between the two eyes). Anisometropia exists when there is a difference in the refraction between the two eyes. The eye with less far-sighted (hyperopic) refractive error provides the brain with a clearer image, and is favored by the brain. Refractive amblyopia is usually less severe than strabismic amblyopia and is commonly missed by primary care physicians because of its less dramatic appearance and lack of obvious physical manifestation, such as with strabismus. Frequently, amblyopia is associated with a combination of anisometropia and strabismus. Pure refractive amblyopia is treated by correcting the refractive error early with prescription lenses. Vision therapy and/or eye patching can also be used to develop and/or improve visual abilities, binocular vision, depth perception, etc. Meridional amblyopia is a mild condition in which lines are seen less clearly at some orientations than others after full refractive correction. An individual who had an astigmatism at a young age that was not corrected by glasses will later have astigmatism that cannot be optically corrected. ## Form-deprivation and occlusion amblyopia Form-deprivation amblyopia (Amblyopia ex anopsia) results when the ocular media become opaque, such as is the case with cataracts or corneal scarring from forceps injuries during birth. These opacities prevent adequate sensory input from reaching the eye, and therefore disrupt visual development. If not treated in a timely fashion, amblyopia may persist even after the cause of the opacity is removed. Sometimes, drooping of the eyelid (ptosis) or some other problem causes the upper eyelid to physically occlude a child's vision, which may cause amblyopia quickly. Occlusion amblyopia may be a complication of a hemangioma that blocks some or all of the eye. # Treatment and prognosis Treatment of strabismic or anisometropic amblyopia consists of correcting the optical deficit and forcing use of the amblyopic eye, either by patching the good eye, or by instilling topical atropine in the eye with better vision. One should also be wary of over-patching or over-penalizing the good eye when treating for amblyopia, as this can create so-called "reverse amblyopia" in the other eye. Form deprivation amblyopia is treated by removing the opacity as soon as possible followed by patching or penalizing the good eye to encourage use of the amblyopic eye. Although the best outcome is achieved if treatment is started before age 5, research has shown that children older than age 10 and some adults can show improvement in the affected eye. Children from 7 to 12 who wore an eye patch and performed near point activities (vision therapy) were four times as likely to show a two line improvement on a standard 11 line eye chart than amblyopic children who did not receive treatment. Children 13 to 17 showed improvement as well, albeit in smaller amounts than younger children. (NEI-funded Pediatric Eye Disease Investigator Group, 2005) Some claim the controversial Bates Method can reverse amblyopia, however, this assertion is unfounded.	Amblyopia For patient information click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Amblyopia, or lazy eye, is a disorder of the eye that is characterized by poor or indistinct vision in an eye that is otherwise physically normal, or out of proportion to associated structural abnormalities. It has been estimated to affect 1–5% of the population.[1] The problem is caused by either no transmission or poor transmission of the visual image to the brain for a sustained period of dysfunction or during early childhood. Amblyopia normally only affects one eye, but it is possible to be amblyopic in both eyes if both are similarly deprived of a good, clear visual image. Detecting the condition in early childhood increases the chance of successful treatment. # Physiology Amblyopia is a developmental problem in the brain, not an organic problem in the eye (although organic problems can induce amblyopic symptoms which persist after the organic problem has resolved).[2] The part of the brain corresponding to the visual system from the affected eye is not stimulated properly, and develops abnormally. This has been confirmed via direct brain examination. David H. Hubel and Torsten Wiesel won the Nobel Prize in Physiology or Medicine in 1981 for their work demonstrating the irreversible damage to ocular dominance columns produced in kittens by sufficient visual deprivation during the so-called "critical period". The maximum critical period in humans is from birth to two years old.[2] # Symptoms Many amblyopes, especially those who are only mildly so, are not even aware they have the condition until tested at older ages, since the vision in their stronger eye is normal. However, people who have severe amblyopia may experience associated visual disorders, most notably poor depth perception. Amblyopes suffer from poor spatial acuity, low sensitivity to contrast and some "higher-level" deficits to vision such as reduced sensitivity to motion.[3] These deficits are usually specific to the amblyopic eye, not the unaffected "fellow" eye. Amblyopes also suffer from problems of binocular vision such as limited stereoscopic depth perception and usually have difficulty seeing the three-dimensional images in hidden stereoscopic displays such as autostereograms.[4] However perception of depth from monocular cues such as size, perspective, and motion parallax is normal. # Types Amblyopia can be caused by deprivation of vision early in life, by strabismus (misaligned eyes), by vision-obstructing disorders, or by anisometropia (different degrees of myopia or hyperopia in each eye). ## Strabismic amblyopia Strabismus, sometimes erroneously also called lazy eye, is a condition in which the eyes are misaligned in a variety of different ways. Strabismus usually results in normal vision in the preferred sighting eye, but may cause abnormal vision in the deviating or strabismic eye due to the discrepancy between the images projecting to the brain from the two eyes.[5] Adult-onset strabismus usually causes double vision (diplopia), since the two eyes are not fixated on the same object. Children's brains, however, are more plastic, and therefore can more easily adapt by ignoring images from one of the eyes, eliminating the double vision (suppression (eye)). This plastic response of the brain, however, interrupts the brain's normal development, resulting in the amblyopia. Strabismic amblyopia is treated by clarifying the visual image with glasses, and/or encouraging use of the amblyopic eye with patching or pharmacologic penalization (usually by applying atropine drops to the dominant eye to temporarily paralyze the muscles and weaken vision in the good eye—this helps to prevent the bullying and teasing associated with wearing a patch). The ocular alignment itself may be treated with surgical or non-surgical methods, depending on the type and severity of the strabismus.[6] ## Refractive or anisometropic amblyopia Refractive amblyopia may result from anisometropia (unequal refractive errors between the two eyes). Anisometropia exists when there is a difference in the refraction between the two eyes. The eye with less far-sighted (hyperopic) refractive error provides the brain with a clearer image, and is favored by the brain. Refractive amblyopia is usually less severe than strabismic amblyopia and is commonly missed by primary care physicians because of its less dramatic appearance and lack of obvious physical manifestation, such as with strabismus.[7] Frequently, amblyopia is associated with a combination of anisometropia and strabismus. Pure refractive amblyopia is treated by correcting the refractive error early with prescription lenses. Vision therapy and/or eye patching can also be used to develop and/or improve visual abilities, binocular vision, depth perception, etc. Meridional amblyopia is a mild condition in which lines are seen less clearly at some orientations than others after full refractive correction. An individual who had an astigmatism at a young age that was not corrected by glasses will later have astigmatism that cannot be optically corrected. ## Form-deprivation and occlusion amblyopia Form-deprivation amblyopia (Amblyopia ex anopsia) results when the ocular media become opaque, such as is the case with cataracts or corneal scarring from forceps injuries during birth.[8] These opacities prevent adequate sensory input from reaching the eye, and therefore disrupt visual development. If not treated in a timely fashion, amblyopia may persist even after the cause of the opacity is removed. Sometimes, drooping of the eyelid (ptosis) or some other problem causes the upper eyelid to physically occlude a child's vision, which may cause amblyopia quickly. Occlusion amblyopia may be a complication of a hemangioma that blocks some or all of the eye. # Treatment and prognosis Treatment of strabismic or anisometropic amblyopia consists of correcting the optical deficit and forcing use of the amblyopic eye, either by patching the good eye, or by instilling topical atropine in the eye with better vision. One should also be wary of over-patching or over-penalizing the good eye when treating for amblyopia, as this can create so-called "reverse amblyopia" in the other eye.[6][9] Form deprivation amblyopia is treated by removing the opacity as soon as possible followed by patching or penalizing the good eye to encourage use of the amblyopic eye.[6] Although the best outcome is achieved if treatment is started before age 5, research has shown that children older than age 10 and some adults can show improvement in the affected eye. Children from 7 to 12 who wore an eye patch and performed near point activities (vision therapy) were four times as likely to show a two line improvement on a standard 11 line eye chart than amblyopic children who did not receive treatment. Children 13 to 17 showed improvement as well, albeit in smaller amounts than younger children. (NEI-funded Pediatric Eye Disease Investigator Group, 2005)[6][10] Some claim the controversial[11] Bates Method can reverse amblyopia, however, this assertion is unfounded. [12]	https://www.wikidoc.org/index.php/Amblyopia
60d0d35565ee97f9db9e7ca5b51ee3e879f61e99	wikidoc	Ames Test	Ames Test The Ames test is a biological assay to assess the mutagenic potential of chemical compounds. As cancer is often linked to DNA damage, the test also serves as a quick assay to estimate the carcinogenic potential of a compound since the standard tests for carcinogenicity done on rodents take years to complete and are expensive to do. The procedure is described in a series of papers from the early 1970s by Bruce Ames and his group at the University of California, Berkeley. # General procedure The test uses several strains of the bacterium Salmonella typhimurium that carry mutations in genes involved in histidine synthesis, so that they require histidine for growth. The variable being tested is the mutagen's ability to cause a reversion to growth on a histidine-free medium. The tester strains are specially constructed to have both frameshift and point mutations in the genes required to synthesize histidine, which allows for the detection of mutagens acting via different mechanisms. Some compounds are quite specific, causing reversions in just one or two strains. The tester strains also carry mutations in the genes responsible for lipopolysaccharide synthesis, making the cell wall of the bacteria more permeable, and in the excision repair system to make the test more sensitive. Rat liver extract is added to simulate the effect of metabolism, as some compounds, like benzopyrene, are not mutagenic themselves but their metabolic products are. The bacteria are spread on an agar plate with a small amount of histidine. This small amount of histidine in the growth medium allows the bacteria to grow for an initial time and have the opportunity to mutate. When the histidine is depleted only bacteria that have mutated to gain the ability to produce its own histidine will survive. The plate is incubated for 48 hours. The mutagenicity of a substance is proportional to the number of colonies observed. # Problems As Salmonella is a prokaryote, it is not a perfect model for humans. An adapted in vitro model has been made for eukaryotic cells, for example yeast structure.	Ames Test The Ames test is a biological assay to assess the mutagenic potential of chemical compounds. As cancer is often linked to DNA damage, the test also serves as a quick assay to estimate the carcinogenic potential of a compound since the standard tests for carcinogenicity done on rodents take years to complete and are expensive to do. The procedure is described in a series of papers from the early 1970s by Bruce Ames and his group at the University of California, Berkeley. # General procedure The test uses several strains of the bacterium Salmonella typhimurium that carry mutations in genes involved in histidine synthesis, so that they require histidine for growth. The variable being tested is the mutagen's ability to cause a reversion to growth on a histidine-free medium. The tester strains are specially constructed to have both frameshift and point mutations in the genes required to synthesize histidine, which allows for the detection of mutagens acting via different mechanisms. Some compounds are quite specific, causing reversions in just one or two strains. [1] The tester strains also carry mutations in the genes responsible for lipopolysaccharide synthesis, making the cell wall of the bacteria more permeable, [2] and in the excision repair system to make the test more sensitive. [3] Rat liver extract is added to simulate the effect of metabolism, as some compounds, like benzopyrene, are not mutagenic themselves but their metabolic products are.[4] The bacteria are spread on an agar plate with a small amount of histidine. This small amount of histidine in the growth medium allows the bacteria to grow for an initial time and have the opportunity to mutate. When the histidine is depleted only bacteria that have mutated to gain the ability to produce its own histidine will survive. The plate is incubated for 48 hours. The mutagenicity of a substance is proportional to the number of colonies observed. # Problems As Salmonella is a prokaryote, it is not a perfect model for humans. An adapted in vitro model has been made for eukaryotic cells, for example yeast structure.	https://www.wikidoc.org/index.php/Ames_Test
7afbc46142cd515165e1b0f5e78ed12d31c97d4a	wikidoc	Etomidate	Etomidate # 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 Etomidate is a general anesthetic that is FDA approved for the {{{indicationType}}} of induction of general anesthesia, maintenance of general anesthesia; adjunct.. Common adverse reactions include - dermatologic: injection site pain (20%), gastrointestinal: nausea, vomiting. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Induction of general anesthesia: induction, usual dose 0.3 mg/kg IV (range 0.2 to 0.6 mg/kg) over 30 to 60 sec. - Maintenance of general anesthesia; adjunct: maintenance, 0.01 to 0.02 mg/kg/min IV infusion; dosage must be individualized. - Procedural sedation: 0.1 to 0.2 mg/kg IV over 30 to 60 seconds, followed by 0.05 mg/kg every 3 to 5 minutes as needed for sedation. - Rapid sequence intubation, Induction: 0.15 to 0.3 mg/kg IV. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Etomidate in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Etomidate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Not recommended in children under 10 y of age - Induction of general anesthesia: (children 10 y and older) induction, usual dose 0.3 mg/kg IV (range 0.2 to 0.6 mg/kg) over 30 to 60 sec - Rapid sequence intubation, Induction: 0.2 to 0.3 mg/kg IV ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Etomidate in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Etomidate in pediatric patients. # Contraindications Etomidate is contraindicated in patients who have shown hypersensitivity to it. # Warnings - Intravenous etomidate should be administered only by persons trained in the administration of general anesthetics and in the management of complications encountered during the conduct of general anesthesia. - Because of the hazards of prolonged suppression of endogenous cortisol and aldosterone production, this formulation is not intended for administration by prolonged infusion. # Adverse Reactions ## Clinical Trials Experience - The most frequent adverse reactions associated with use of intravenous etomidate are transient venous pain on injection and transient skeletal muscle movements, including myoclonus - Transient venous pain was observed immediately following intravenous injection of etomidate in about 20% of the patients, with considerable difference in the reported incidence (1.2% to 42%). This pain is usually described as mild to moderate in severity but it is occasionally judged disturbing. The observation of venous pain is not associated with a more than usual incidence of thrombosis or thrombophlebitis at the injection site. Pain also appears to be less frequently noted when larger, more proximal arm veins are employed and it appears to be more frequently noted when smaller, more distal, hand or wrist veins are employed. - Transient skeletal muscle movements were noted following use of intravenous etomidate in about 32% of the patients, with considerable difference in the reported incidence (22.7% to 63%). Most of these observations were judged mild to moderate in severity but some were judged disturbing. The incidence of disturbing movements was less when 0.1 mg of fentanyl was given immediately before induction. These movements have been classified as myoclonic in the majority of cases (74%), but averting movements (7%), tonic movements (10%), and eye movements (9%) have also been reported. No exact classification is available, but these movements may also be placed into three groups by location: - Most movements are bilateral. The arms, legs, shoulders, neck, chest wall, trunk and all four extremities have been described in some cases, with one or more of these muscle groups predominating in each individual case. Results of electroencephalographic studies suggest that these muscle movements are a manifestation of disinhibition of cortical activity; cortical electroencephalograms, taken during periods when these muscle movements were observed, have failed to reveal seizure activity. - Other movements are described as either unilateral or having a predominance of activity of one side over the other. These movements sometimes resemble a localized response to some stimuli, such as venous pain on injection, in the lightly anesthetized patient (averting movements). Any muscle group or groups may be involved, but a predominance of movement of the arm in which the intravenous infusion is started is frequently noted. - Still other movements probably represent a mixture of the first two types. - Skeletal muscle movements appear to be more frequent in patients who also manifest venous pain on injection. ### Other Adverse Observations - Hyperventilation, hypoventilation, apnea of short duration (5 to 90 seconds with spontaneous recovery); laryngospasm, hiccup and snoring suggestive of partial upper airway obstruction have been observed in some patients. These conditions were managed by conventional countermeasures. - Hypertension, hypotension, tachycardia, bradycardia and other arrhythmias have occasionally been observed during induction and maintenance of anesthesia. One case of severe hypotension and tachycardia, judged to be anaphylactoid in character, has been reported. - Geriatric patients, particularly those with hypertension, may be at increased risk for the development of cardiac depression following etomidate administration (see Clinical pharmacology). - Postoperative nausea and/or vomiting following induction of anesthesia with etomidate is probably no more frequent than the general incidence. When etomidate was used for both induction and maintenance of anesthesia in short procedures such as dilation and curettage, or when insufficient analgesia was provided, the incidence of postoperative nausea and/or vomiting was higher than that noted in control patients who received thiopental. ## Postmarketing Experience There is limited information regarding Etomidate Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Etomidate Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Etomidate has been shown to have an embryocidal effect in rats when given in doses 1 and 4 times the human dose. There are no adequate and well-controlled studies in pregnant women. Etomidate should be used during pregnancy only if the potential benefit justifies the potential risks to the fetus. Etomidate has not been shown to be teratogenic in animals. Reproduction studies with etomidate have been shown to: - Decrease pup survival at 0.3 and 5 mg/kg in rats (approximately 1X and 16X human dosage) and at 1.5 and 4.5 mg/kg in rabbits (approximately 5X and 15X human dosage). No clear dose-related pattern was observed. - Increase slightly the number of stillborn fetuses in rats at 0.3 and 1.25 mg/kg (approximately 1X and 4X human dosage). - Cause maternal toxicity with deaths of 6/20 rats at 5 mg/kg (approximately 16X human dosage) and 6/20 rabbits at 4.5 mg/kg (approximately 15X human dosage). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Etomidate in women who are pregnant. ### Labor and Delivery - There are insufficient data to support use of intravenous etomidate in obstetrics, including Caesarean section deliveries. Therefore, such use is not recommended. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when etomidate is administered to a nursing mother. ### Pediatric Use - There are inadequate data to make dosage recommendations for induction of anesthesia in patients below the age of ten (10) years; therefore, such use is not recommended (see also Dosage And Administration). ### Geriatic Use - Clinical data indicates that etomidate may induce cardiac depression in elderly patients, particularly those with hypertension (see Clinical Pharmacology And Other Adverse ObservationS, Circulatory System). - Elderly patients may require lower doses of etomidate than younger patients. Age-related differences in phamacokinetic parameters have been observed in clinical studies (see Clinical Pharmacology And Dosage And Administration). - This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function. ### Gender There is no FDA guidance on the use of Etomidate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Etomidate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Etomidate in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Etomidate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Etomidate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Etomidate in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Etomidate Administration in the drug label. ### Monitoring There is limited information regarding Etomidate Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Etomidate and IV administrations. # Overdosage - Overdosage may occur from too rapid or repeated injections. Too rapid injection may be followed by a fall in blood pressure. No adverse cardiovascular or respiratory effects attributable to etomidate overdose have been reported. - In the event of suspected or apparent overdosage, the drug should be discontinued, a patent airway established (intubate, if necessary) or maintained and oxygen administered with assisted ventilation, if necessary. The LD50 of etomidate administered intravenously to rats is 20.4 mg/kg. # Pharmacology ## Mechanism of Action There is limited information regarding Etomidate Mechanism of Action in the drug label. ## Structure - Amidate (etomidate injection) is a sterile, nonpyrogenic solution. Each milliliter contains etomidate, 2 mg, propylene glycol 35% v/v. The pH is 6.0 (4.0 to 7.0). - It is intended for the induction of general anesthesia by intravenous injection. - The drug etomidate is chemically identified as (R)-(+)-ethyl-1-(1-phenylethyl)-1H-imidazole -5-carboxylate and has the following structural formula: ## Pharmacodynamics There is limited information regarding Etomidate Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Etomidate Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Etomidate Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Etomidate Clinical Studies in the drug label. # How Supplied - Amidate™ (etomidate injection) is supplied in single-dose containers as follows: ## Storage - Store at 20 to 25°C (68 to 77°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Etomidate Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Etomidate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Etomidate Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Etomidate Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Etomidate Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, 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 Etomidate is a general anesthetic that is FDA approved for the {{{indicationType}}} of induction of general anesthesia, maintenance of general anesthesia; adjunct.. Common adverse reactions include * dermatologic: injection site pain (20%), gastrointestinal: nausea, vomiting. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Induction of general anesthesia: induction, usual dose 0.3 mg/kg IV (range 0.2 to 0.6 mg/kg) over 30 to 60 sec. - Maintenance of general anesthesia; adjunct: maintenance, 0.01 to 0.02 mg/kg/min IV infusion; dosage must be individualized. - Procedural sedation: 0.1 to 0.2 mg/kg IV over 30 to 60 seconds, followed by 0.05 mg/kg every 3 to 5 minutes as needed for sedation. - Rapid sequence intubation, Induction: 0.15 to 0.3 mg/kg IV. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Etomidate in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Etomidate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Not recommended in children under 10 y of age - Induction of general anesthesia: (children 10 y and older) induction, usual dose 0.3 mg/kg IV (range 0.2 to 0.6 mg/kg) over 30 to 60 sec - Rapid sequence intubation, Induction: 0.2 to 0.3 mg/kg IV ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Etomidate in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Etomidate in pediatric patients. # Contraindications Etomidate is contraindicated in patients who have shown hypersensitivity to it. # Warnings - Intravenous etomidate should be administered only by persons trained in the administration of general anesthetics and in the management of complications encountered during the conduct of general anesthesia. - Because of the hazards of prolonged suppression of endogenous cortisol and aldosterone production, this formulation is not intended for administration by prolonged infusion. # Adverse Reactions ## Clinical Trials Experience - The most frequent adverse reactions associated with use of intravenous etomidate are transient venous pain on injection and transient skeletal muscle movements, including myoclonus - Transient venous pain was observed immediately following intravenous injection of etomidate in about 20% of the patients, with considerable difference in the reported incidence (1.2% to 42%). This pain is usually described as mild to moderate in severity but it is occasionally judged disturbing. The observation of venous pain is not associated with a more than usual incidence of thrombosis or thrombophlebitis at the injection site. Pain also appears to be less frequently noted when larger, more proximal arm veins are employed and it appears to be more frequently noted when smaller, more distal, hand or wrist veins are employed. - Transient skeletal muscle movements were noted following use of intravenous etomidate in about 32% of the patients, with considerable difference in the reported incidence (22.7% to 63%). Most of these observations were judged mild to moderate in severity but some were judged disturbing. The incidence of disturbing movements was less when 0.1 mg of fentanyl was given immediately before induction. These movements have been classified as myoclonic in the majority of cases (74%), but averting movements (7%), tonic movements (10%), and eye movements (9%) have also been reported. No exact classification is available, but these movements may also be placed into three groups by location: - Most movements are bilateral. The arms, legs, shoulders, neck, chest wall, trunk and all four extremities have been described in some cases, with one or more of these muscle groups predominating in each individual case. Results of electroencephalographic studies suggest that these muscle movements are a manifestation of disinhibition of cortical activity; cortical electroencephalograms, taken during periods when these muscle movements were observed, have failed to reveal seizure activity. - Other movements are described as either unilateral or having a predominance of activity of one side over the other. These movements sometimes resemble a localized response to some stimuli, such as venous pain on injection, in the lightly anesthetized patient (averting movements). Any muscle group or groups may be involved, but a predominance of movement of the arm in which the intravenous infusion is started is frequently noted. - Still other movements probably represent a mixture of the first two types. - Skeletal muscle movements appear to be more frequent in patients who also manifest venous pain on injection. ### Other Adverse Observations - Hyperventilation, hypoventilation, apnea of short duration (5 to 90 seconds with spontaneous recovery); laryngospasm, hiccup and snoring suggestive of partial upper airway obstruction have been observed in some patients. These conditions were managed by conventional countermeasures. - Hypertension, hypotension, tachycardia, bradycardia and other arrhythmias have occasionally been observed during induction and maintenance of anesthesia. One case of severe hypotension and tachycardia, judged to be anaphylactoid in character, has been reported. - Geriatric patients, particularly those with hypertension, may be at increased risk for the development of cardiac depression following etomidate administration (see Clinical pharmacology). - Postoperative nausea and/or vomiting following induction of anesthesia with etomidate is probably no more frequent than the general incidence. When etomidate was used for both induction and maintenance of anesthesia in short procedures such as dilation and curettage, or when insufficient analgesia was provided, the incidence of postoperative nausea and/or vomiting was higher than that noted in control patients who received thiopental. ## Postmarketing Experience There is limited information regarding Etomidate Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Etomidate Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Etomidate has been shown to have an embryocidal effect in rats when given in doses 1 and 4 times the human dose. There are no adequate and well-controlled studies in pregnant women. Etomidate should be used during pregnancy only if the potential benefit justifies the potential risks to the fetus. Etomidate has not been shown to be teratogenic in animals. Reproduction studies with etomidate have been shown to: - Decrease pup survival at 0.3 and 5 mg/kg in rats (approximately 1X and 16X human dosage) and at 1.5 and 4.5 mg/kg in rabbits (approximately 5X and 15X human dosage). No clear dose-related pattern was observed. - Increase slightly the number of stillborn fetuses in rats at 0.3 and 1.25 mg/kg (approximately 1X and 4X human dosage). - Cause maternal toxicity with deaths of 6/20 rats at 5 mg/kg (approximately 16X human dosage) and 6/20 rabbits at 4.5 mg/kg (approximately 15X human dosage). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Etomidate in women who are pregnant. ### Labor and Delivery - There are insufficient data to support use of intravenous etomidate in obstetrics, including Caesarean section deliveries. Therefore, such use is not recommended. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when etomidate is administered to a nursing mother. ### Pediatric Use - There are inadequate data to make dosage recommendations for induction of anesthesia in patients below the age of ten (10) years; therefore, such use is not recommended (see also Dosage And Administration). ### Geriatic Use - Clinical data indicates that etomidate may induce cardiac depression in elderly patients, particularly those with hypertension (see Clinical Pharmacology And Other Adverse ObservationS, Circulatory System). - Elderly patients may require lower doses of etomidate than younger patients. Age-related differences in phamacokinetic parameters have been observed in clinical studies (see Clinical Pharmacology And Dosage And Administration). - This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function. ### Gender There is no FDA guidance on the use of Etomidate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Etomidate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Etomidate in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Etomidate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Etomidate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Etomidate in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Etomidate Administration in the drug label. ### Monitoring There is limited information regarding Etomidate Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Etomidate and IV administrations. # Overdosage - Overdosage may occur from too rapid or repeated injections. Too rapid injection may be followed by a fall in blood pressure. No adverse cardiovascular or respiratory effects attributable to etomidate overdose have been reported. - In the event of suspected or apparent overdosage, the drug should be discontinued, a patent airway established (intubate, if necessary) or maintained and oxygen administered with assisted ventilation, if necessary. The LD50 of etomidate administered intravenously to rats is 20.4 mg/kg. # Pharmacology ## Mechanism of Action There is limited information regarding Etomidate Mechanism of Action in the drug label. ## Structure - Amidate (etomidate injection) is a sterile, nonpyrogenic solution. Each milliliter contains etomidate, 2 mg, propylene glycol 35% v/v. The pH is 6.0 (4.0 to 7.0). - It is intended for the induction of general anesthesia by intravenous injection. - The drug etomidate is chemically identified as (R)-(+)-ethyl-1-(1-phenylethyl)-1H-imidazole -5-carboxylate and has the following structural formula: ## Pharmacodynamics There is limited information regarding Etomidate Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Etomidate Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Etomidate Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Etomidate Clinical Studies in the drug label. # How Supplied - Amidate™ (etomidate injection) is supplied in single-dose containers as follows: ## Storage - Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Etomidate Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Etomidate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Etomidate Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Etomidate Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Amidate
7d11fad73a0afe361a745d8d14e34bde8ccc810a	wikidoc	Amiloride	Amiloride # 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 Amiloride is a potassium-sparing diuretic that is FDA approved for the {{{indicationType}}} of congestive heart failure or hypertension adjunctive with thiazide diuretics or other kaliuretic-diuretic agents. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash, diarrhea, loss of appetite, nausea, vomiting, asthenia, cramp, dizziness, headache, cough, and dyspnea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - 5 mg tablet daily, should be added to the usual antihypertensive or diuretic dosage of a kaliuretic diuretic. - The dosage may be increased to 10 mg per day, if necessary. - More than two 5 mg tablets of amiloride daily usually are not needed, and there is little controlled experience with such doses. - If persistent hypokalemia is documented with 10 mg, the dose can be increased to 15 mg, then 20 mg, with careful monitoring of electrolytes. - In treating patients with congestive heart failure after an initial diuresis has been achieved, potassium loss may also decrease and the need for amiloride should be re-evaluated. - Dosage adjustment may be necessary. Maintenance therapy may be on an intermittent basis. - If it is necessary to use amiloride alone, the starting dosage should be one 5 mg tablet daily. This dosage may be increased to 10 mg per day, if necessary. - More than two 5 mg tablets usually are not needed, and there is little controlled experience with such doses. If persistent hypokalemia is documented with 10 mg, the dose can be increased to 15 mg, then 20 mg, with careful monitoring of electrolytes. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Amiloride in adult patients. ### Non–Guideline-Supported Use - Dosing Information - 10 mg once daily # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Amiloride in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Amiloride in pediatric patients. # Contraindications - Hyperkalemia - Amiloride should not be used in the presence of elevated serum potassium levels (greater than 5.5 mEq per liter). - Antikaliuretic Therapy or Potassium Supplementation - Amiloride should not be given to patients receiving other potassium-conserving agents, such as spironolactone or triamterene. Potassium supplementation in the form of medication, potassium-containing salt substitutes or a potassium-rich diet should not be used with amiloride except in severe and/or refractory cases of hypokalemia. Such concomitant therapy can be associated with rapid increases in serum potassium levels. If potassium supplementation is used, careful monitoring of the serum potassium level is necessary. - Impaired Renal Function - Anuria, acute or chronic renal insufficiency, and evidence of diabetic nephropathy are contraindications to the use of amiloride. - Patients with evidence of renal functional impairment (blood urea nitrogen levels over 30 mg per 100 mL or serum creatinine levels over 1.5 mg per 100 mL) or diabetes mellitus should not receive the drug without careful, frequent and continuing monitoring of serum electrolytes, creatinine, and BUN levels. Potassium retention associated with the use of an antikaliuretic agent is accentuated in the presence of renal impairment and may result in the rapid development of hyperkalemia. - Hypersensitivity - Amiloride is contraindicated in patients who are hypersensitive to this product. # Warnings ### Hyperkalemia - The risk of hyperkalemia may be increased when potassium-conserving agents, including amiloride, are administered concomitantly with an angiotensin-converting enzyme inhibitor, an angiotensin II receptor antagonist, cyclosporine or tacrolimus. Warning signs or symptoms of hyperkalemia include paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, shock, and ECG abnormalities. Monitoring of the serum potassium level is essential because mild hyperkalemia is not usually associated with an abnormal ECG. - When abnormal, the ECG in hyperkalemia is characterized primarily by tall, peaked T waves or elevations from previous tracings. There may also be lowering of the R wave and increased depth of the S wave, widening and even disappearance of the P wave, progressive widening of the QRS complex, prolongation of the PR interval, and ST depression. - If hyperkalemia occurs in patients taking amilordie, the drug should be discontinued immediately. - If the serum potassium level exceeds 6.5 mEq per liter, active measures should be taken to reduce it. Such measures include the intravenous administration of sodium bicarbonate solution or oral or parenteral glucose with a rapid-acting insulin preparation. - If needed, a cation exchange resin such as sodium polystyrene sulfonate may be given orally or by enema. - Patients with persistent hyperkalemia may require dialysis. ### Diabetes Mellitus - In diabetic patients, hyperkalemia has been reported with the use of all potassium-conserving diuretics, including amiloride, even in patients without evidence of diabetic nephropathy. Therefore, amiloride should be avoided, if possible, in diabetic patients and, if it is used, serum electrolytes and renal function must be monitored frequently. - Amiloride should be discontinued at least three days before glucose tolerance testing. ### Metabolic or Respiratory Acidosis - Antikaliuretic therapy should be instituted only with caution in severely ill patients in whom respiratory acidosis or metabolic acidosis may occur, such as patients with cardiopulmonary disease or poorly controlled diabetes. - If amiloride is given to these patients, frequent monitoring of acid-base balance is necessary. Shifts in acid-base balance alter the ratio of extracellular/intracellular potassium, and the development of acidosis may be associated with rapid increases in serum potassium levels. ## Precautions ### Electrolyte Imbalance and BUN Increases - Hyponatremia and hypochloremia may occur when amiloride is used with other diuretics and increases in BUN levels have been reported. - These increases usually have accompanied vigorous fluid elimination, especially when diuretic therapy was used in seriously ill patients, such as those who had hepatic cirrhosis with ascites and metabolic alkalosis, or those with resistant edema. Therefore, when amiloride is given with other diuretics to such patients, careful monitoring of serum electrolytes and BUN levels is important. - In patients with pre-existing severe liver disease, hepatic encephalopathy, manifested by tremors, confusion, and coma, and increased jaundice, have been reported in association with diuretics, including amiloride HCl. ### Carcinogenicity, Mutagenicity, Impairment of Fertility - There was no evidence of a tumorigenic effect when amiloride HCl was administered for 92 weeks to mice at doses up to 10 mg/kg/day (25 times the maximum daily human dose). Amiloride HCl has also been administered for 104 weeks to male and female rats at doses up to 6 and 8 mg/kg/day (15 and 20 times the maximum daily dose for humans, respectively) and showed no evidence of carcinogenicity. - Amiloride HCl was devoid of mutagenic activity in various strains of Salmonella typhimurium with or without a mammalian liver microsomal activation system (Ames test). # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Amiloride in the drug label. ## Postmarketing Experience - Amiloride is usually well tolerated and, except for hyperkalemia (serum potassium levels greater than 5.5 mEq per liter), significant adverse effects have been reported infrequently. Minor adverse reactions were reported relatively frequently (about 20%) but the relationship of many of the reports to amiloride HCl is uncertain and the overall frequency was similar in hydrochlorothiazide treated groups. - Nausea/anorexia, abdominal pain, flatulence, and mild skin rash have been reported and probably are related to amiloride. - Other adverse experiences that have been reported with amiloride are generally those known to be associated with diuresis, or with the underlying disease being treated. - The adverse reactions for amiloride listed in the following table have been arranged into two groups: - Group 1: Incidence greater than one percent - Group 2: Incidence one percent or less - The incidence for group 1 was determined from clinical studies conducted in the United States (837 patients treated with amiloride). The adverse effects listed in group 2 include reports from the same clinical studies and voluntary reports since marketing. The probability of a causal relationship exists between amiloride and these adverse reactions, some of which have been reported only rarely. - Causal Relationship Unknown - Other reactions have been reported but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, that possibility cannot be excluded. Therefore, these observations are listed to serve as alerting information to physicians. - Activation of probable pre-existing peptic ulcer - Aplastic anemia - Neutropenia - Abnormal liver function # Drug Interactions - Angiotensin-converting enzyme inhibitor, angiotensin II receptor antagonist, Cyclosporine, or Tacrolimus - When amiloride HCl is administered concomitantly with an angiotensin-converting enzyme inhibitor, an angiotensin II receptor antagonist, cyclosporine, or tacrolimus, the risk of hyperkalemia may be increased. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium. - Lithium - Lithium generally should not be given with diuretics because they reduce its renal clearance and add a high risk of lithium toxicity. Read circulars for lithium preparations before use of such concomitant therapy. - Non-steroidal anti-inflammatory agent - In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when amiloride and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Since indomethacin and potassium-sparing diuretics, including amiloride, may each be associated with increased serum potassium levels, the potential effects on potassium kinetics and renal function should be considered when these agents are administered concurrently. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - Teratogenicity studies with amiloride HCl in rabbits and mice given 20 and 25 times the maximum human dose, respectively, revealed no evidence of harm to the fetus, although studies showed that the drug crossed the placenta in modest amounts. Reproduction studies in rats at 20 times the expected maximum daily dose for humans showed no evidence of impaired fertility. At approximately 5 or more times the expected maximum daily dose for humans, some toxicity was seen in adult rats and rabbits and a decrease in rat pup growth and survival occurred. - There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category C There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Amiloride in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Amiloride during labor and delivery. ### Nursing Mothers - Studies in rats have shown that amiloride is excreted in milk in concentrations higher than those found in blood, but it is not known whether amiloride 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 amiloride, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Clinical studies of amiloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. - This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ### Gender There is no FDA guidance on the use of Amiloride with respect to specific gender populations. ### Race There is no FDA guidance on the use of Amiloride with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Amiloride in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Amiloride in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Amiloride in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Amiloride in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Amiloride should be administered with food. ### Monitoring - It is essential to monitor serum potassium levels carefully in any patient receiving amiloride, particularly when it is first introduced, at the time of diuretic dosage adjustments, and during any illness that could affect ]. # IV Compatibility There is limited information regarding IV Compatibility of Amiloride in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - The most likely signs and symptoms to be expected with overdosage are dehydration and electrolyte imbalance. - No data are available in regard to overdosage in humans. The oral LD50 of amiloride hydrochloride (calculated as the base) is 56 mg/kg in mice and 36 to 85 mg/kg in rats, depending on the strain. ### Management - It is not known whether the drug is dialyzable. - These can be treated by established procedures. Therapy with amiloride should be discontinued and the patient observed closely. - There is no specific antidote. Emesis should be induced or gastric lavage performed. Treatment is symptomatic and supportive. - If hyperkalemia occurs, active measures should be taken to reduce the serum potassium levels. ## Chronic Overdose There is limited information regarding Chronic Overdose of Amiloride in the drug label. # Pharmacology ## Mechanism of Action - Amiloride is a potassium-conserving (antikaliuretic) drug that possesses weak (compared with thiazide diuretics) natriuretic, diuretic, and antihypertensive activity. These effects have been partially additive to the effects of thiazide diuretics in some clinical studies. When administered with a thiazide or loop diuretic, amiloride has been shown to decrease the enhanced urinary excretion of magnesium which occurs when a thiazide or loop diuretic is used alone. Amiloride has potassium-conserving activity in patients receiving kaliuretic-diuretic agents. - Amiloride is not an aldosterone antagonist and its effects are seen even in the absence of aldosterone. ## Structure - Amiloride HCl, an antikaliuretic-diuretic agent, is a pyrazine-carbonyl-guanidine that is unrelated chemically to other known antikaliuretic or diuretic agents. It is the salt of a moderately strong base (pKa 8.7). It is designated chemically as 3,5-diamino-6-chloro-N-(diaminomethylene) pyrazinecarboxamide monohydrochloride, dihydrate and has a molecular weight of 302.12. Its empirical formula is C6H8ClN7OHCl2H2O and its structural formula is: - MIDAMOR1 (Amiloride HCl) is available for oral use as tablets containing 5 mg of anhydrous amiloride HCl. Each tablet contains the following inactive ingredients: calcium phosphate, D&C Yellow 10, iron oxide, lactose, magnesium stearate and starch. ## Pharmacodynamics - Amiloride exerts its potassium sparing effect through the inhibition of sodium reabsorption at the distal convoluted tubule, cortical collecting tubule and collecting duct; this decreases the net negative potential of the tubular lumen and reduces both potassium and hydrogen secretion and their subsequent excretion. This mechanism accounts in large part for the potassium sparing action of amiloride. - Amiloride usually begins to act within 2 hours after an oral dose. Its effect on electrolyte excretion reaches a peak between 6 and 10 hours and lasts about 24 hours. Peak plasma levels are obtained in 3 to 4 hours and the plasma half-life varies from 6 to 9 hours. Effects on electrolytes increase with single doses of amiloride HCl up to approximately 15 mg. ## Pharmacokinetics - Amiloride HCl is not metabolized by the liver but is excreted unchanged by the kidneys. About 50 percent of a 20 mg dose of Amiloride is excreted in the urine and 40 percent in the stool within 72 hours. Amiloride has little effect on glomerular filtration rate or renal blood flow. Because amiloride HCl is not metabolized by the liver, drug accumulation is not anticipated in patients with hepatic dysfunction, but accumulation can occur if the hepatorenal syndrome develops. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Amiloride in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Amiloride in the drug label. # How Supplied - Tablets MIDAMOR, 5 mg, are yellow, diamond-shaped, compressed tablets, coded MSD 92 on one side and MIDAMOR on the other. They are supplied as follows: - Protect from moisture, freezing and excessive heat. ## Storage There is limited information regarding Amiloride Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Amiloride in the drug label. # Precautions with Alcohol Alcohol-Amiloride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Midamor® # Look-Alike Drug Names - aMILoride — amLODIPine # Drug Shortage Status # Price	Amiloride Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi # 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 Amiloride is a potassium-sparing diuretic that is FDA approved for the {{{indicationType}}} of congestive heart failure or hypertension adjunctive with thiazide diuretics or other kaliuretic-diuretic agents. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash, diarrhea, loss of appetite, nausea, vomiting, asthenia, cramp, dizziness, headache, cough, and dyspnea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - 5 mg tablet daily, should be added to the usual antihypertensive or diuretic dosage of a kaliuretic diuretic. - The dosage may be increased to 10 mg per day, if necessary. - More than two 5 mg tablets of amiloride daily usually are not needed, and there is little controlled experience with such doses. - If persistent hypokalemia is documented with 10 mg, the dose can be increased to 15 mg, then 20 mg, with careful monitoring of electrolytes. - In treating patients with congestive heart failure after an initial diuresis has been achieved, potassium loss may also decrease and the need for amiloride should be re-evaluated. - Dosage adjustment may be necessary. Maintenance therapy may be on an intermittent basis. - If it is necessary to use amiloride alone, the starting dosage should be one 5 mg tablet daily. This dosage may be increased to 10 mg per day, if necessary. - More than two 5 mg tablets usually are not needed, and there is little controlled experience with such doses. If persistent hypokalemia is documented with 10 mg, the dose can be increased to 15 mg, then 20 mg, with careful monitoring of electrolytes. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Amiloride in adult patients. ### Non–Guideline-Supported Use - Dosing Information - 10 mg once daily[1] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Amiloride in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Amiloride in pediatric patients. # Contraindications - Hyperkalemia - Amiloride should not be used in the presence of elevated serum potassium levels (greater than 5.5 mEq per liter). - Antikaliuretic Therapy or Potassium Supplementation - Amiloride should not be given to patients receiving other potassium-conserving agents, such as spironolactone or triamterene. Potassium supplementation in the form of medication, potassium-containing salt substitutes or a potassium-rich diet should not be used with amiloride except in severe and/or refractory cases of hypokalemia. Such concomitant therapy can be associated with rapid increases in serum potassium levels. If potassium supplementation is used, careful monitoring of the serum potassium level is necessary. - Impaired Renal Function - Anuria, acute or chronic renal insufficiency, and evidence of diabetic nephropathy are contraindications to the use of amiloride. - Patients with evidence of renal functional impairment (blood urea nitrogen levels over 30 mg per 100 mL or serum creatinine levels over 1.5 mg per 100 mL) or diabetes mellitus should not receive the drug without careful, frequent and continuing monitoring of serum electrolytes, creatinine, and BUN levels. Potassium retention associated with the use of an antikaliuretic agent is accentuated in the presence of renal impairment and may result in the rapid development of hyperkalemia. - Hypersensitivity - Amiloride is contraindicated in patients who are hypersensitive to this product. # Warnings ### Hyperkalemia - The risk of hyperkalemia may be increased when potassium-conserving agents, including amiloride, are administered concomitantly with an angiotensin-converting enzyme inhibitor, an angiotensin II receptor antagonist, cyclosporine or tacrolimus. Warning signs or symptoms of hyperkalemia include paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, shock, and ECG abnormalities. Monitoring of the serum potassium level is essential because mild hyperkalemia is not usually associated with an abnormal ECG. - When abnormal, the ECG in hyperkalemia is characterized primarily by tall, peaked T waves or elevations from previous tracings. There may also be lowering of the R wave and increased depth of the S wave, widening and even disappearance of the P wave, progressive widening of the QRS complex, prolongation of the PR interval, and ST depression. - If hyperkalemia occurs in patients taking amilordie, the drug should be discontinued immediately. - If the serum potassium level exceeds 6.5 mEq per liter, active measures should be taken to reduce it. Such measures include the intravenous administration of sodium bicarbonate solution or oral or parenteral glucose with a rapid-acting insulin preparation. - If needed, a cation exchange resin such as sodium polystyrene sulfonate may be given orally or by enema. - Patients with persistent hyperkalemia may require dialysis. ### Diabetes Mellitus - In diabetic patients, hyperkalemia has been reported with the use of all potassium-conserving diuretics, including amiloride, even in patients without evidence of diabetic nephropathy. Therefore, amiloride should be avoided, if possible, in diabetic patients and, if it is used, serum electrolytes and renal function must be monitored frequently. - Amiloride should be discontinued at least three days before glucose tolerance testing. ### Metabolic or Respiratory Acidosis - Antikaliuretic therapy should be instituted only with caution in severely ill patients in whom respiratory acidosis or metabolic acidosis may occur, such as patients with cardiopulmonary disease or poorly controlled diabetes. - If amiloride is given to these patients, frequent monitoring of acid-base balance is necessary. Shifts in acid-base balance alter the ratio of extracellular/intracellular potassium, and the development of acidosis may be associated with rapid increases in serum potassium levels. ## Precautions ### Electrolyte Imbalance and BUN Increases - Hyponatremia and hypochloremia may occur when amiloride is used with other diuretics and increases in BUN levels have been reported. - These increases usually have accompanied vigorous fluid elimination, especially when diuretic therapy was used in seriously ill patients, such as those who had hepatic cirrhosis with ascites and metabolic alkalosis, or those with resistant edema. Therefore, when amiloride is given with other diuretics to such patients, careful monitoring of serum electrolytes and BUN levels is important. - In patients with pre-existing severe liver disease, hepatic encephalopathy, manifested by tremors, confusion, and coma, and increased jaundice, have been reported in association with diuretics, including amiloride HCl. ### Carcinogenicity, Mutagenicity, Impairment of Fertility - There was no evidence of a tumorigenic effect when amiloride HCl was administered for 92 weeks to mice at doses up to 10 mg/kg/day (25 times the maximum daily human dose). Amiloride HCl has also been administered for 104 weeks to male and female rats at doses up to 6 and 8 mg/kg/day (15 and 20 times the maximum daily dose for humans, respectively) and showed no evidence of carcinogenicity. - Amiloride HCl was devoid of mutagenic activity in various strains of Salmonella typhimurium with or without a mammalian liver microsomal activation system (Ames test). # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Amiloride in the drug label. ## Postmarketing Experience - Amiloride is usually well tolerated and, except for hyperkalemia (serum potassium levels greater than 5.5 mEq per liter), significant adverse effects have been reported infrequently. Minor adverse reactions were reported relatively frequently (about 20%) but the relationship of many of the reports to amiloride HCl is uncertain and the overall frequency was similar in hydrochlorothiazide treated groups. - Nausea/anorexia, abdominal pain, flatulence, and mild skin rash have been reported and probably are related to amiloride. - Other adverse experiences that have been reported with amiloride are generally those known to be associated with diuresis, or with the underlying disease being treated. - The adverse reactions for amiloride listed in the following table have been arranged into two groups: - Group 1: Incidence greater than one percent - Group 2: Incidence one percent or less - The incidence for group 1 was determined from clinical studies conducted in the United States (837 patients treated with amiloride). The adverse effects listed in group 2 include reports from the same clinical studies and voluntary reports since marketing. The probability of a causal relationship exists between amiloride and these adverse reactions, some of which have been reported only rarely. - Causal Relationship Unknown - Other reactions have been reported but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, that possibility cannot be excluded. Therefore, these observations are listed to serve as alerting information to physicians. - Activation of probable pre-existing peptic ulcer - Aplastic anemia - Neutropenia - Abnormal liver function # Drug Interactions - Angiotensin-converting enzyme inhibitor, angiotensin II receptor antagonist, Cyclosporine, or Tacrolimus - When amiloride HCl is administered concomitantly with an angiotensin-converting enzyme inhibitor, an angiotensin II receptor antagonist, cyclosporine, or tacrolimus, the risk of hyperkalemia may be increased. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium. - Lithium - Lithium generally should not be given with diuretics because they reduce its renal clearance and add a high risk of lithium toxicity. Read circulars for lithium preparations before use of such concomitant therapy. - Non-steroidal anti-inflammatory agent - In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when amiloride and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Since indomethacin and potassium-sparing diuretics, including amiloride, may each be associated with increased serum potassium levels, the potential effects on potassium kinetics and renal function should be considered when these agents are administered concurrently. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - Teratogenicity studies with amiloride HCl in rabbits and mice given 20 and 25 times the maximum human dose, respectively, revealed no evidence of harm to the fetus, although studies showed that the drug crossed the placenta in modest amounts. Reproduction studies in rats at 20 times the expected maximum daily dose for humans showed no evidence of impaired fertility. At approximately 5 or more times the expected maximum daily dose for humans, some toxicity was seen in adult rats and rabbits and a decrease in rat pup growth and survival occurred. - There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category C There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Amiloride in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Amiloride during labor and delivery. ### Nursing Mothers - Studies in rats have shown that amiloride is excreted in milk in concentrations higher than those found in blood, but it is not known whether amiloride 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 amiloride, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Clinical studies of amiloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. - This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ### Gender There is no FDA guidance on the use of Amiloride with respect to specific gender populations. ### Race There is no FDA guidance on the use of Amiloride with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Amiloride in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Amiloride in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Amiloride in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Amiloride in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Amiloride should be administered with food. ### Monitoring - It is essential to monitor serum potassium levels carefully in any patient receiving amiloride, particularly when it is first introduced, at the time of diuretic dosage adjustments, and during any illness that could affect [renal function]]. # IV Compatibility There is limited information regarding IV Compatibility of Amiloride in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - The most likely signs and symptoms to be expected with overdosage are dehydration and electrolyte imbalance. - No data are available in regard to overdosage in humans. The oral LD50 of amiloride hydrochloride (calculated as the base) is 56 mg/kg in mice and 36 to 85 mg/kg in rats, depending on the strain. ### Management - It is not known whether the drug is dialyzable. - These can be treated by established procedures. Therapy with amiloride should be discontinued and the patient observed closely. - There is no specific antidote. Emesis should be induced or gastric lavage performed. Treatment is symptomatic and supportive. - If hyperkalemia occurs, active measures should be taken to reduce the serum potassium levels. ## Chronic Overdose There is limited information regarding Chronic Overdose of Amiloride in the drug label. # Pharmacology ## Mechanism of Action - Amiloride is a potassium-conserving (antikaliuretic) drug that possesses weak (compared with thiazide diuretics) natriuretic, diuretic, and antihypertensive activity. These effects have been partially additive to the effects of thiazide diuretics in some clinical studies. When administered with a thiazide or loop diuretic, amiloride has been shown to decrease the enhanced urinary excretion of magnesium which occurs when a thiazide or loop diuretic is used alone. Amiloride has potassium-conserving activity in patients receiving kaliuretic-diuretic agents. - Amiloride is not an aldosterone antagonist and its effects are seen even in the absence of aldosterone. ## Structure - Amiloride HCl, an antikaliuretic-diuretic agent, is a pyrazine-carbonyl-guanidine that is unrelated chemically to other known antikaliuretic or diuretic agents. It is the salt of a moderately strong base (pKa 8.7). It is designated chemically as 3,5-diamino-6-chloro-N-(diaminomethylene) pyrazinecarboxamide monohydrochloride, dihydrate and has a molecular weight of 302.12. Its empirical formula is C6H8ClN7O•HCl•2H2O and its structural formula is: - MIDAMOR1 (Amiloride HCl) is available for oral use as tablets containing 5 mg of anhydrous amiloride HCl. Each tablet contains the following inactive ingredients: calcium phosphate, D&C Yellow 10, iron oxide, lactose, magnesium stearate and starch. ## Pharmacodynamics - Amiloride exerts its potassium sparing effect through the inhibition of sodium reabsorption at the distal convoluted tubule, cortical collecting tubule and collecting duct; this decreases the net negative potential of the tubular lumen and reduces both potassium and hydrogen secretion and their subsequent excretion. This mechanism accounts in large part for the potassium sparing action of amiloride. - Amiloride usually begins to act within 2 hours after an oral dose. Its effect on electrolyte excretion reaches a peak between 6 and 10 hours and lasts about 24 hours. Peak plasma levels are obtained in 3 to 4 hours and the plasma half-life varies from 6 to 9 hours. Effects on electrolytes increase with single doses of amiloride HCl up to approximately 15 mg. ## Pharmacokinetics - Amiloride HCl is not metabolized by the liver but is excreted unchanged by the kidneys. About 50 percent of a 20 mg dose of Amiloride is excreted in the urine and 40 percent in the stool within 72 hours. Amiloride has little effect on glomerular filtration rate or renal blood flow. Because amiloride HCl is not metabolized by the liver, drug accumulation is not anticipated in patients with hepatic dysfunction, but accumulation can occur if the hepatorenal syndrome develops. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Amiloride in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Amiloride in the drug label. # How Supplied - Tablets MIDAMOR, 5 mg, are yellow, diamond-shaped, compressed tablets, coded MSD 92 on one side and MIDAMOR on the other. They are supplied as follows: - Protect from moisture, freezing and excessive heat. ## Storage There is limited information regarding Amiloride Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Amiloride in the drug label.[2] # Precautions with Alcohol Alcohol-Amiloride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Midamor® # Look-Alike Drug Names - aMILoride — amLODIPine[3] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Amiloride
e09c543fd728d593e228bca1ef972b1e54ee41ba	wikidoc	Amlexanox	Amlexanox # Overview Amlexanox (trade name Aphthasol) is an anti-inflammatory antiallergic immunomodulator used to treat recurrent aphthous ulcers (canker sores), and (in Japan) several inflammatory conditions. This drug has been discontinued in the U.S. # Medical uses Amlexanox is the active ingredient in a common topical treatment for recurrent aphthous ulcers of the mouth (canker sores), reducing both healing time and pain. Amlexanox 5% paste is well-tolerated, and is typically applied four times per day directly on the ulcers. A 2011 review found it to be the most effective treatment of the eight treatments investigated for recurrent canker sores. It is also used to treat ulcers associated with Behçet disease. In Japan, it is used to treat bronchial asthma, allergic rhinitis and conjunctivitis. # Contraindications The drug is contraindicated in those with known allergies to it. # Adverse effects Amlexanox may cause a slightly painful stinging or burning sensation, nausea or diarrhea. # Mechanism of action The drug is an anti-inflammatory, antiallergic immunomodulator. Its mechanism of action is not well-determined, but it might inhibit inflammation by inhibiting the release of histamine and leukotrienes. It has been shown to selectively inhibt TBK1 and IKK-ε, producing reversible weight loss and improved insulin sensitivity, reduced inflammation and attenuated hepatic steatosis without affecting food intake in obese mice. # Physical and chemical properties The chemical itself is an odorless, white to yellowish-white powder. The 5% preparation for patient use is an adherent beige paste, and it is also available in some countries as a tablet that adheres to the ulcer in the mouth. # Pharmacokinetics Amlexanox applied to an aphthous ulcer is largely absorbed through the gastrointestinal tract; an insignificant amount enters the bloodstream through the ulcer itself. After a single 100 mg dose, mean maximum serum concentration occurs 2.4 +/- 0.9 hours after application, with a half-life of elimination (through urine) of 3.5 +/- 1.1 hours. With multiple daily applications (four doses per day), steady state serum levels occur after one week, with no accumulation occurring after four weeks. # History The patent for its use as a treatment for aphthous ulcers was issued in November 1994 to inventors Kakubhai R. Vora, Atul Khandwala and Charles G. Smith, and assigned to Chemex Pharmaceuticals, Inc. # Society and culture ## Legal status A prescription is required to obtain the medication. ## Economics A 2011 review found a one week supply of amlexanox 5% paste to cost $30. # Research A review found that, as of July 2011, robust studies investigating its effectiveness alongside other canker sore treatments were still needed. Because it is an inhibitor of the protein kinases TBK1 and IKK-ε, which are implicated in the etiology of type II diabetes and obesity, amlexanox may be a candidate for human clinical trials testing in relation to these diseases. # Synthesis	Amlexanox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Amlexanox (trade name Aphthasol) is an anti-inflammatory antiallergic immunomodulator used to treat recurrent aphthous ulcers (canker sores), and (in Japan) several inflammatory conditions. This drug has been discontinued in the U.S.[1] # Medical uses Amlexanox is the active ingredient in a common topical treatment for recurrent aphthous ulcers of the mouth (canker sores),[2] reducing both healing time[3] and pain.[4] Amlexanox 5% paste is well-tolerated,[5] and is typically applied four times per day directly on the ulcers.[3] A 2011 review found it to be the most effective treatment of the eight treatments investigated for recurrent canker sores.[6] It is also used to treat ulcers associated with Behçet disease.[7] In Japan, it is used to treat bronchial asthma, allergic rhinitis and conjunctivitis.[8] # Contraindications The drug is contraindicated in those with known allergies to it.[3] # Adverse effects Amlexanox may cause a slightly painful stinging or burning sensation, nausea or diarrhea.[3] # Mechanism of action The drug is an anti-inflammatory,[8] antiallergic[9] immunomodulator.[10] Its mechanism of action is not well-determined, but it might inhibit inflammation by inhibiting the release of histamine and leukotrienes.[8] It has been shown to selectively inhibt TBK1 and IKK-ε, producing reversible weight loss and improved insulin sensitivity, reduced inflammation and attenuated hepatic steatosis without affecting food intake in obese mice.[11] # Physical and chemical properties The chemical itself is an odorless, white to yellowish-white powder.[8] The 5% preparation for patient use is an adherent beige paste,[3][8] and it is also available in some countries as a tablet that adheres to the ulcer in the mouth.[4] # Pharmacokinetics Amlexanox applied to an aphthous ulcer is largely absorbed through the gastrointestinal tract; an insignificant amount enters the bloodstream through the ulcer itself. After a single 100 mg dose, mean maximum serum concentration occurs 2.4 +/- 0.9 hours after application, with a half-life of elimination (through urine) of 3.5 +/- 1.1 hours. With multiple daily applications (four doses per day), steady state serum levels occur after one week, with no accumulation occurring after four weeks.[8] # History The patent for its use as a treatment for aphthous ulcers was issued in November 1994 to inventors Kakubhai R. Vora, Atul Khandwala and Charles G. Smith, and assigned to Chemex Pharmaceuticals, Inc.[12] # Society and culture ## Legal status A prescription is required to obtain the medication.[13] ## Economics A 2011 review found a one week supply of amlexanox 5% paste to cost $30.[6] # Research A review found that, as of July 2011[update], robust studies investigating its effectiveness alongside other canker sore treatments were still needed.[14] Because it is an inhibitor of the protein kinases TBK1 and IKK-ε,[11] which are implicated in the etiology of type II diabetes and obesity,[15] amlexanox may be a candidate for human clinical trials testing in relation to these diseases.[11] # Synthesis	https://www.wikidoc.org/index.php/Amlexanox
b705cecec1714d93b6f3ec9f0b9d16e02bcf8c28	wikidoc	Ammonoids	Ammonoids An ammonoid is an extinct cephalopod mollusk with a flat-coiled spiral shell. An ammonite may be an ammonoid that belongs to the order Ammonitida, typically having elaborately frilled suture lines. An ammonitic ammonoid in the images on the right shows the septal surface (especially at right) with its undulating lobes and saddles. # Mollusks Def. a "soft-bodied invertebrate , " is called a mollusc. Def. a "body wall of a mollusc, from which the shell is secreted" is called a mantle. Def. a "rasping tongue of snails and most other mollusks" is called a radula. As a mollusk an ammonite may be expected to have - a mantle with a cavity for breathing and excretion, - a radula, and - a structured nervous system. # Cephalopods Def. any "mollusc, , which includes squid, cuttlefish, octopus, etc" is called a cephalopod. An ammonite is expected to have cephalopod characteristics - bilateral body symmetry, - a prominent head, and - a set of arms or tentacles (muscular hydrostats). # Theoretical ammonites Def. "the scientific study of squid (often extended to all cephalopods)" is called teuthology. "Teuthology, a branch of malacology, is the study of cephalopods." Def. "any of numerous flat spiral fossil shells of cephalopods" is called an ammonite. We "describe the overall mode of growth of ammonoids with reference to Nautilus, the only externally shelled cephalopod that is still extant. Ammonoids are, in fact, phylogenetically more closely related to coleoids than they are to Nautilus (Engeser, 1990; Jacobs and Landman, 1993; Chapter 1, this volume). However, the retention of an external shell in ammonoids implies that these extinct forms shared with Nautilus basic similarities in their processes of growth, although not necessarily a similarity in their rate of growth or age at maturity." On the right are schematic drawings of four growth stages of Hoploscaphites nicolletii in lateral and transverse cross-sections: - A is an embryonic shell called the ammonitella, scale bar 500 µm, - B is the first postembryonic stage called the neanic and the animal or shell is called the neanoconch, scale bar 1 mm, - C is a juvenile, scale bar 5 mm, and - D is an adult, scale bar is 1 cm. # Agoniatites Agoniatites are also known as Anarcestes. Agoniatites vanuxemi, on the lower right, is the only species of Ammonoid found in the Hamilton Group, Mahantango Formation. # Ammonites These are ammonites of the suborder Ammonitida. # Ceratites A ceratite may be an ammonoid of an intermediate type, typically with partly frilled and partly lobed suture lines. "The Ceratitida, which is the dominant ammonoid order of the early Mesozoic and one of the major orders of Ammonoidea, ranged from early Permian to the end of Triassic times, and has an almost worldwide distribution (Hewitt et al., 1993; Page, 1996)." # Clymeniids Any clymeniid may be an ammonoid with a dorsal siphuncle; i.e., a siphuncle on the inside of the coil rather than the outside. # Goniatites An ammonoid like the one on the right typically with simple angular suture lines is referred to as a goniatite. # Lytocerates Characteristics: - loosely coiled, - evolute, - gyroconic, - exposed whorls, - whorls touching, - subcircular to narrowly compressed whorls, - broadly arched, or keeled venter, - smooth or ribbed sides, - aptychi are single valved and concentrically striated, - suture saddle endings tend to be rounded but usually not phylloid, - lobes tend to be more jagged with thorn-like endings, and - complex moss-like suture endings with adventious and secondary subdivisions. # Nostoceratids Nipponites mirabilis on the right may be from the Upper Cretaceous. # Phyllocerates # Prolecanites "Type species by original designation of Librovitch 1957, Protocanites supradevonicus Schindewolf (1926)." In the diagrams above are the suture patterns for various species holotypes: - A - Protocanites gurleyi (Smith), - B - Eocanites supradevonicus supradevonicus (Schindewolf), - C - Eocanites semageominus (House), - D - Eocanites wangyounensis(Ruan & He), - E - Michiganites algarbiensis (Pruvost), - F - Michiganites marshallensis (Winchell), - G - Michiganites scalibrinii (Antelo), - H - Michiganites greenei (Miller). # Coleoids The subclass Coleoidea has the cohort Belemnoidea which may contain shelled cephalopods. The image second down on the right shows "the piglet squid , floating along with its tentacles waving above its head in the central Pacific Ocean near Palmyra Atoll." The "squid about 4,544 feet (1,385 meters) below the ocean surface the exploration vehicle (E/V) Nautilus." "Is that a squid? I think it's a squid. It's like a bloated squid with tiny tentacles and a little hat that's waving around. And it looks like it's got a massive, inflated mantle cavity. I've never seen anything quite like this before." The "mantle is filled with ammonia, which the squid uses to control its buoyancy." "This Nautilus expedition is an effort to explore the deep ocean waters of the Marine National Monument, near Kingman Reef, Palmyra Atoll and Jarvis Island, which are among the most remote U.S.-controlled territories." Helicocranchia is of the order Teuthida. # Belemnoids The cohort Belemnoidea has five extinct orders. Any one of these may contain cephalopods with an external shell. "Belemnites (Belemnitida) were squid-like animals belonging to the cephalopod class of the mollusc phylum, and therefore related to the ammonites of old as well as to the modern squids, octopuses and nautiluses." "Now extinct, their fossils are found in rocks of Jurassic and Cretaceous ages, with a few species hanging on into the early part of the Tertiary. The animal’s soft parts very rarely fossilise, leaving us with only the hard parts; the guard and the phragmacone." ## Aulacocerids "Pendleian age rocks in the Chainman Shale include the upper beds of the Camp Canyon Member and the Willow Gap Limestone Member. The fossil cephalopods are from these rocks in the Confusion Range and Burbank Hills of western Millard County." For the study of the "shell morphology and ultrastructure in Hematites than 30 specimens of this genus were collected by the second author from the Upper Mississippian in Arkansas. The data obtained confirm the detailed description of the external shell morphology in the genus published by FLOWER & GORDON (1959) and GORDON (1964), and it also includes new information on the conotheca structure, conotheca rostrum/mantle attachment, “living” chamber length, and morphology of the adoral portion of the rostrum." "Schematic diagram of the medial shell section in Hematites the truncation of the initial portion of the phragmocone which is plugged by the central rod structure (crs) and by the additional septum (as). Scale bar: 1 mm. as = additional septum; c = conotheca; r = rostrum; s = septum; sn = septal neck; t = place of truncation." ## Phragmoteuthids The image on the right suggests that Phragmoteuthis conocauda does not have an external shell. ## Belemnitids "Belemnites have a worldwide distribution." Shells or shell-like structures are the phragmacone in the image on the left and the rostrum, the second image on the left, which have been found apparently internal to the soft body. The second image down on the left shows rostrums from Passatoteuthis auricipitis Lang, Jurassic, Lower Lias, found in Gloucestershire. The image second down on the right shows a rostrum from the genus Peratobelus, found in the Cairn mine, South Australia. ## Diplobelids ## Belemnoteuthins # Nautiloids Def. a cephalopod mollusk with a light external spiral shell that is white with brownish bands on the outside and lined with mother-of-pearl on the inside is called a nautiloid. Nautiloidea is another subclass of cephalopods. "Nautilus is one of the few surviving animals resembling the primitive or original cephalopods. The fossilized shells of these extinct forms, called ammonites (A), are quite common. (B) is a deep-sea species Nautilus pompilius that lives in tropical waters. To the right is a section through Nautilus showing the shell (1) and siphuncle (2) wound in a spiral. Immediately behind the tentacles lies the mouth (4) leading to the intestine (7). Nautilus has an advanced nervous system with a brain (3) and respires by means of gills (6) that are located in the mantle cavity. It swims by forcing a jet of water out of its mantle cavity and through the siphon (5)." "Nautiluses first evolved in the Cambrian period and became significant marine predators during the Ordovician period." ## Actinocerids ## Ascocerids ## Bactrites ## Barrandeocerids ## Discosorids ## Ellesmerocerids ## Endocerids ## Nautilids An individual example of the genus Nautilus is on the right. A couple of Nautilus macromphalus are on the left, photographed during a night dive, at 15 meters, near Lifou, Sandal wood bay, New Caledonia. "The six living species of nautiluses are: - No common name (Allonautilus perforates), - Crusty Nautilus (Allonautilus scrobiculatus), - Palau Nautilus (Nautilus belauensis), - Bellybutton Nautilus (Nautilus macromphalus), - Chambered Nautilus (Nautilus pompilius), and - White-patch Nautilus (Nautilus stenomphalus)". ## Oncocerids ## Orthocerids Centered at the top is an artist's impression of an Orthoceras species from the middle Ordovician. On the left is a fossil of Orthoceras currens. ## Plectronocerids ## Pseudorthocerids ## Tarphycerids # Anatomy Cut in the plane of the spiral (medial or median cut), the shell reveals the chambers inside. On the left is an internal mold from a Baculites individual. The original aragonite of the outer conch and inner septa has dissolved away, leaving this articulated internal mold. Baculites is an ammonite from the Late Cretaceous of Wyoming. The tissue used to close the chamber to the outside is called an aptychus. Perisphictes on the lower left has aptychi. Agoniatites have a central siphuncle as shown in the illustration on the right with septal necks pointing to the rear (retrochoanitic). The diagrams on the lower left show median sections where the siphuncle is in a ventral position. Measurements to characterize an ammonite are indicated in the right-hand diagram. The abbreviations are for ammonitella (am), caecum (c), initial chamber (ic), primary constriction (pc), prosiphon (ps), siphunclar tube (s), proseptum (first septum, s1), primary septum (second septum, s2), third septum (s3), maximum initial chamber size (A), minimum initial chamber size (B), ammonitella size (D), and ammonitella angle (E). # Predation The fossil shell of ammonite Placenticeras whitfieldi on the right shows punctures caused by the bite of a mosasaur. "In the late Cretaceous, it is the mosasaurs that have been identified as ammonite predators, beginning with the study of Kauffman and Kesling (1960), who described a 300 mm diameter Placenticeras (first illustrated by Fenton and Fenton in 1958) from the Late Campanian Pierre Shale of South Dakota that had been bitten, in their interpretation no less than 16 times, by what they concluded to be a platycarpine mosasaur (we suggest that the mosasaur was playing with its prey, as do contemporary cetaceans)." "A juvenile specimen of the ammonite Pseudaspidoceras from the Early Turonian of the Goulmima area in the Province of Er-Rachida in south-eastern Morocco shows clear evidence of predation by a tooth-bearing vertebrate." "These are interpreted as the product of a single bite by a mosasauroid, probably a Tethysaurus." "All of the convincing well-documented examples of mosasaur-bitten ammonite shells are thus from North America, the overwhelming majority from the Late Campanian of the northern part of the Western Interior of the United States and Alberta in Canada." "The Goulmima occurrence is the only convincing record of mosasauroid attack on an ammonite outside North America, and of the latter, the overwhelming majority are restricted to the Late Campanian of the northern interior. The only adequately documented putative occurrence outside of the interior, in the Early Maastrichtian Rosario Formation of Baja California, Mexico, may not in fact be by a mosasaur, although there is evidence of mosasauroid attack on two Campanian nautiloids from San Diego County in California." "Given the above, we see no evidence to support the view that there was coevolution between ammonites and mosasaurs, nor that mosasaurs were "The ecologically dominant predators of Cretaceous marine seas" as proposed by Kauffman (1990)." # Sizes On the right is an image of the world's largest known ammonite, Parapuzosia seppenradensis (originally Pachydiscus seppenradensis) discovered in Seppenrade, Germany. The partial fossil specimen has a shell diameter of 1.95 metres (6.4 ft). But, the living chamber was incomplete. The shell diameter may have been about 2.55 metres (8.4 ft) when it was alive. # Paleocene The Paleocene dates from 65.5 ± 0.3 x 106 to 55.8 ± 0.2 x 106 b2k. # Danian The beginning of the Danian age (and the end of the preceding Maastrichtian age) is at the Cretaceous–Paleogene extinction event at 66.0 Ma. The age ended 61.6 Ma, being followed by the Selandian age. Post-"Cretaceous ammonites of the genus Hoploscaphites have been found at Stevns Klint in Denmark (Machalski & Heinberg, 2005; Machalski et al., 2009)." "The maximum age for Danian scaphitid survivors from the Cerithium Limestone at Stevns Klint, Denmark, has recently been estimated to be around 0.2 Ma following the K–Pg boundary event (Machalski and Heinberg in press). Assuming the Cretaceous– Paleogene boundary at 65.4 ± 0.1 Ma (Jagt and Kennedy 1994), the present study covers more than 4 Ma of the final stages in scaphitid evolution." "Scaphitid material from subunit IVf−7 at the very top of the Meerssen Member traditionally regarded to be uppermost Maastrichtian, has recently been reassigned to the lowermost Danian, based on microfossil and strontium isotope evidence (Smit and Brinkhuis 1996). According to Jagt et al. (2003), the scaphitid and baculitid ammonites preserved in subunit IVf−7 are early Danian survivors." Above center are Hoploscaphites constrictus johnjagti subsp. nov., adult macroconchs, ammonites from the Danian: A. MGUH 27366, lowermost Danian, Stevns Klint, Denmark, in apertural (A1), lateral (A2, A3), and ventral (A4) views. # Cretaceous "The Cretaceous period is the third and final period in the Mesozoic Era. It began 145.5 million years ago after the Jurassic Period and ended 65.5 million years ago, before the Paleogene Period of the Cenozoic Era." Scaphites hippocrepis is an index fossil for the Cretaceous. # Late Cretaceous In the top center is a 2.7 cm section of a polished shell with 6 sutures. It is from the extinct cephalopod Baculites compressus; Cretaceous, 100 million years old, Bearpaw Formation, Montana, USA. The lower center is a fossil cast of a Baculites grandis shell taken at the North American Museum of Ancient Life. On the right is an example of Plesiacanthoceras wyomingense from the late Cretaceous in Wyoming, USA. It is exhibited in Smithsonian National Museum of Natural History: Hall of Fossils. # Maastrichtian Extends from 70.6 ± 0.6 to 65.5 ± 0.3 Mya. The specimen on the left is Jeletzkytes spedeni from the Maastrichtian (Upper-Cretaceous) Fox Hills Formation, locality - South Dakota, USA. Matrix free specimen is 7.5 cm (3") in diameter, displaying pearly aragonite preservation of the shell. The center photo is of Baculites ovatus, at the Naturalis Museum, Leiden. Baculites ovatus apparently occurs in the Ripley Formation. Discoscaphites iris on the right is an ammonite from the Owl Creek Formation (Upper Cretaceous), Owl Creek, Ripley, Mississippi USA. The McNairy Formation found in Illinois is also from the Upper Cretaceous Maastrichtian. # Edmontonian Extends from 80.8 to 70.7 Mya. # Judithian Extends from 82.2 to 80.8 Mya. # Campanian The Bearpaw Formation is famous for its well-preserved ammonite fossils. These include Placenticeras meeki and Placenticeras intercalare, and the baculite Baculites compressus. Extends from 83.5 ± 0.7 to 70.6 ± 0.6 Mya. The Baylis Formation, Post Creek Formation and the Tuscaloosa Formation are Upper Cretaceous from the Campanian. # Haumurian Extends from 84 to 65.5 Mya. # Aquilan Extends from 85.2 to 82.2 Mya. # Santonian Extends from 85.8 ± 0.7 to 83.5 ± 0.7 Mya. # Piripauan Extends from 86.5 to 84 Mya. # Teratan Extends from 89.1 to 86.5 Mya. # Coniacian Extends from 89.3 ± 1.0 to 85.8 ± 0.7 Mya. # Senonian Extends from 89.3 to 65.5 Mya. # Emscherian Extends from 89.5 to 83.5 Mya. # Mangaotanean Extends from 92.1 to 89.1 Mya. # Turonian Extends from 93.5 ± 0.8 to 89.3 ± 1.0 Mya. Benueites is a Turonian ammonite genera from Nigeria. # Cenomanian These fast-moving nektonic carnivores lived during the Cenomanian stage of the Late Cretaceous (from 94.3 to 89.3 Ma). Shells of Acanthoceras rhotomagensis may reach a diameter of about 36 (Expression error: Unexpected round operator. ). Their shells have ornate ribs. Acanthoceras rhotomagensis fossils may be found in Western Europe and western North America. Hibolites is a genus of belemnite, an extinct group of cephalopods of the Cenomanian. # Arowhanan Extends from 95.2 to 92.1 Mya. # Lower Cretaceous # Albian Puzosia is a genus of Desmoceratidae (desmoceratid) ammonites, and the type genus for the Puzosiinae, which lived during the middle part of the Cretaceous, from early Aptian to Maastrichtian (125.5 to 70.6 Ma). Or, the range is from Albian to Santonian. Otohoplites is a genus of ammonite that lived in the Early Albian whose fossils were found in Svalbard, Denmark, England, France, Austria, Poland, Russia and Kazakhstan, evolved from Hemisonneratia and gave rise to genus Hoplites. Shells belonging to this genera are rather inflated to compressed and have zigzaging, or looped ribs that ends in oblique ventrolateral clavi; usually, ribs are zigzaging through venter; macroconchs have smooth body chamber and rounded venter. Kossmatella is an extinct genus of ammonoid cephalopods belonging to the family Lytoceratidae, were fast-moving nektonic carnivores that lived from Albian to Cenomanian age. Cleoniceras included in the subfamily Cleoniceratinae is a rather involute, high-whorled hoplitid from the Lower to basal Middle Albian of Europe, Madagascar, and Transcaspian region, where the shell has a generally small umbilicus, arched to acute venter, and typically at some growth stage, falcoid ribs that spring in pairs from umbilical tubercles, usually disappearing on the outer whorls. Brancoceras is a rather small, strongly ribbed, acanthoceratacean ammonite from the Albian stage of the Lower Cretaceous: - the shell is evolute with a subquadrate whorl section and rounded venter - the suture forms a finely squiggly line with well-defined lobes and saddles - Brancoceras (Eubrancoceras) aegoceratoides reached a diameter of at least 4.2 centimetres (1.6535433054 in) - Brancoceras is representative of the subfamily Brancoceratinae, which makes up part of the Acanthoceratoidea (acanthoceratacean) family Brancoceratidae - stratigraphic range is rather narrow, extending only from the upper Lower to the Middle Albian. Arcthoplites is an extinct genus of cephalopod belonging to the Ammonite subclass from the lower Albian. Anadesmoceras is an hoplitid ammonite from the lower Albian (upper Lower Cretaceous) of England, included in the subfamily Cleoniceratinae: - a shell shaped more or less like a compressed Cleoniceras but with faint ornament only on the inner whorls - the shell has bundled growth striae. The aperture is preceded by several wide sinuous constrictions. Anacleoniceras is an extinct genus of cephalopod belonging to the Ammonite subclass lower Albian. Aioloceras is an ammonite, order Ammonitida, from near the end of the Early Cretaceous: - the shell is compressed with the outer whorl covering much of the previous - sides are slightly convex, converge toward a narrowly ached venter - inner whorls have sharp falcoid ribs, outer are smooth - umbilical tubercles are lacking - similar related forms include Neosaynella and Cleoniceras - has been found in Albian (uL Cret) sediments in Madagascar, Patagonia, and possibly Queensland. # Lower Albian "Amber—ancient resins from trees—commonly traps only some terrestrial insects, plants, or animals. It’s very rare to find some sea animals in amber." "This extraordinary assemblage, a true and beautiful snapshot of a beach in the Cretaceous, is just mind-blowing." "The idea that there’s a whole community of organisms in association—that may prove more important in the long run." "If you were scuba-diving in a shallow marine setting, you absolutely would have seen ammonites. They would be as common as seeing some snails crawling around." "Based on its internal shell structure, the amber-encased ammonite is a juvenile that belongs to the subgenus Puzosia (Bhimaites), which makes a lot of sense in 99-million-year-old amber." # Aptian # Barremian # Hauterivian # Valanginian # Berriasian # Early Cretaceous # Jurassic The Jurassic/Cretaceous boundary occurs at 144.2 ± 2.6 Ma (million years ago). On the left is a photograph of Asteroceras obtusum from the Jurassic Lower Lias Formation, Obtusum Zone. Locality is Lyme Regis, Dorset, England. Complete calcified specimen measures 11.5 cm (4.5") in diameter, in a limestone matrix. Perisphinctes tiziani is an index fossil for the Jurassic. # Late Jurassic On the right is an example of Kosmoceras cromptoni from the Late Jurassic, Chippenham, England. # Upper Jurassic # Tithonian # Kimmeridgian Lithacosphinctes achilles is from the Kimmeridgian. # Oxfordian # Middle Jurassic # Callovian On the right is an image of Peltoceras solidum, an ammonite from the Matmor Formation (Jurassic, Callovian), Makhtesh Gadol, Israel. On the left is an example of Kosmoceras medea. Another species of Kosmoceras is on the lower right, specifically Kosmoceras proniae. # Bathonian # Bajocian # Aalenian Leioceras opalinum is an ammonite from the Aalenian. # Lower Jurassic Uptonia jamesoni from the lower Jurassic is in the family Polymorphitidae, superfamily Eoderocerataceae, order Ammonitida, subclass Ammonoidea, class Cephalopoda. # Toarcian # Pliensbachian Pleuroceras spinatum (Bruguière 1789) is of the family Amaltheidae. It is a pyritic specimen. The biozone index is to the end of Pliensbachian. # Sinemurian # Hettangian Psiloceras psilonotum, Psiloceras spelae tirolicum and Psiloceras planorbis are from the Hettangian. The Triassic/Jurassic boundary occurs at 205.7 ± 4.0 Ma (million years ago). # Triassic Although the example of Psiloceras tilmanni is from the Jurassic. Its lowest occurrence is in the New York Canyon section of Nevada USA which may be Triassic. Trophites subbuliatus is an index fossil for the Triassic. # Upper Triassic # Rhaetian # Norian # Carnian # Middle Triassic # Ladinian # Anisian An example of Ussuriphyllites amurensis (Kiparisova) is on the right. It is from the Lower-most Anisian, Atlasov Cape area. # Lower Triassic # Olenekian # Spathian The Spathian is sometimes referred to as the Late Olenekian. Olenekoceras meridianum is a "typical Late Olenekian differs in its lithology from the same zone of Russian Island, where the Zhitkov Suite has been recognized (Zakharov, 1997; Zakharov et al., 2004)." # Smithian The Smithian is sometimes referred to as the Early Olenekian. # Induan # Paleozoic The Paleozoic era spanned 542.0 ± 1.0 to 251.0 ± 0.7 Mb2k. # Permian The Permian lasted from 299.0 ± 0.8 to 251.0 ± 0.4 Mb2k. The Permian/Triassic boundary occurs at 248.2 ± 4.8 Ma (million years ago). # Carboniferous The Carboniferous began 359.2 ± 2.5 Mb2k and ended 299.0 ± 0.8 Mb2k. # Pennsylvanian The Pennsylvanian lasted from 318.1 ± 1.3 to 299.0 ± 0.8 Mb2k. # Mississippian The Mississippian lasted from 359.2 ± 2.5 to 318.1 ± 1.3 Mb2k. Prolecanites gurleyi is an index fossil of the Mississippian. # Middle Mississippian "This species has been consistently identified with the considerably younger, late Viséan (late Holkerian to Asbian ) genus Beyrichoceras Foord, 1903 (type species, Goniatites obtusus Phillips, 1836) (eg, Gordon, 1965, p. 284." # Devonian The Devonian spanned 416.0 ± 2.8 to 359.2 ± 2.5 Mb2k. # Upper Devonian # Famennian A specimen of Clymenia laevigata from the Upper Devonian Famennian of Poland is on the right. On the left is a fossil of Platyclymenia intracrostata also from the Famennian of Poland. # Frasnian # Middle Devonian # Givetian # Eifelian # Lower Devonian # Emsian # Pragian # Lochkovian # Early Devonian Mimagoniatites is a genus of ammonites from the early Devonian. "Shell small to large size, evolute, thinly discoidal to discoidal. Whorl cross section of the first two whorls approximately circular, in later whorls subtrapezoidal. Umbilicus narrow to moderately wide, moderately large umbilical window ( 2.5, later up to 3.9). Growth line course biconvex with prominent ventrolateral projection and deep ventral sinus." The lower boundary of the genus is "LD3C--LD3D: Anetoceras Range Zone top, 405.5 million years" and the upper boundary is "CZB maureri--sulc.antiqua Zone , 398.5 million years". Geographic distribution: "Devonian of Algeria (2 collections), Canada (1: Nunavut), China (7), the Czech Republic (5), Germany (3), Morocco (13), the Russian Federation (1), Spain (4), Turkey (3), United States (1: Pennsylvania)". # Silurian The Silurian spanned 443.7 ± 1.5 to 416.0 ± 2.8 Mb2k. Hexamoceras hertzeri is an index fossil for the Silurian. Hexamoceras is a genus of the Nautiloidea. "Rolfe made the important observation that 'Other genera are pre-Devonian and hence cannot be ammonoid aptychi, but Ruedemann's suggestion that aptychi "would naturally also have existed in the Ordovician and Silurian cephalopods" has been largely overlooked'." # Ordovician The Ordovician lasted from 488.3 ± 1.7 to 443.7 ± 1.5 Mb2k. # Upper Ordovician The image on the right is an over-encrusted, internal mold of a nautiloid from the Upper Ordovician of northern Kentucky. # Cambrian The Cambrian lasted from 542.0 ± 1.0 to 488.3 ± 1.7 Mb2k. # Middle Cambrian "We recently redescribed the Middle Cambrian organism Nectocaris pteryx known from 92 specimens from the Burgess Shale (Smith & Caron 2010). new material allowed us to identify new features consistent with a cephalopod affinity." # Hypotheses Hypotheses: - Each of the ammonoids has a set of genes producing a distinct suture mark. - Ammonoids are alive today. - Morphological descriptions should be sufficient to identify unknown ammonites at the species level. # Sciences Classification of Baculites ovatus: - Domain: Eukaryota - Regnum: Animalia - Subregnum: Eumetazoa - Cladus: Bilateria - Superphylum: Protostomia - Phylum: Mollusca - Classis: Cephalopoda - Subclassis: Ammonoidea - Ordo: Ammonitida - Subordo: Ancyloceratina - Superfamilia: Turrilitoidea - Familia: Baculitidae - Genus: Baculites - Species: Baculites ovatus (Say, 1820) The subclassis: Ammonoidea contains the ordines: Ammonitida, Ceratitida, Clymeniida, Goniatitida, and Prolecanitida. # Acknowledgements The content on this page was first contributed by: Henry A. Hoff. Initial content for this page in some instances came from Wikiversity.	Ammonoids Editor-In-Chief: Henry A. Hoff An ammonoid is an extinct cephalopod mollusk with a flat-coiled spiral shell. An ammonite may be an ammonoid that belongs to the order Ammonitida, typically having elaborately frilled suture lines. An ammonitic ammonoid in the images on the right shows the septal surface (especially at right) with its undulating lobes and saddles. # Mollusks Def. a "soft-bodied invertebrate[1] [of the phylum Mollusca][2], [typically with a hard shell of one or more pieces]"[3] is called a mollusc. Def. a "body wall of a mollusc,[4] from which the shell is secreted"[5] is called a mantle. Def. a "rasping tongue of snails and most other mollusks"[6] is called a radula. As a mollusk an ammonite may be expected to have - a mantle with a cavity for breathing and excretion, - a radula, and - a structured nervous system. # Cephalopods Def. any "mollusc, [of the class Cephalopoda][7], which includes squid, cuttlefish, octopus, [nautiloids][8] etc"[9] is called a cephalopod. An ammonite is expected to have cephalopod characteristics - bilateral body symmetry, - a prominent head, and - a set of arms or tentacles (muscular hydrostats). # Theoretical ammonites Def. "the scientific study of squid (often extended to all cephalopods)"[10] is called teuthology. "Teuthology, a branch of malacology, is the study of cephalopods."[11] Def. "any of numerous flat spiral fossil shells of cephalopods"[12] is called an ammonite. We "describe the overall mode of growth of ammonoids with reference to Nautilus, the only externally shelled cephalopod that is still extant. Ammonoids are, in fact, phylogenetically more closely related to coleoids than they are to Nautilus (Engeser, 1990; Jacobs and Landman, 1993; Chapter 1, this volume). However, the retention of an external shell in ammonoids implies that these extinct forms shared with Nautilus basic similarities in their processes of growth, although not necessarily a similarity in their rate of growth or age at maturity."[13] On the right are schematic drawings of four growth stages of Hoploscaphites nicolletii in lateral and transverse cross-sections: - A is an embryonic shell called the ammonitella, scale bar 500 µm, - B is the first postembryonic stage called the neanic and the animal or shell is called the neanoconch, scale bar 1 mm, - C is a juvenile, scale bar 5 mm, and - D is an adult, scale bar is 1 cm.[13] # Agoniatites Agoniatites are also known as Anarcestes. Agoniatites vanuxemi, on the lower right, is the only species of Ammonoid found in the Hamilton Group, Mahantango Formation. # Ammonites These are ammonites of the suborder Ammonitida. # Ceratites A ceratite may be an ammonoid of an intermediate type, typically with partly frilled and partly lobed suture lines. "The Ceratitida, which is the dominant ammonoid order of the early Mesozoic and one of the major orders of Ammonoidea, ranged from early Permian to the end of Triassic times, and has an almost worldwide distribution (Hewitt et al., 1993; Page, 1996)."[14] # Clymeniids Any clymeniid may be an ammonoid with a dorsal siphuncle; i.e., a siphuncle on the inside of the coil rather than the outside. # Goniatites An ammonoid like the one on the right typically with simple angular suture lines is referred to as a goniatite. # Lytocerates Characteristics: - loosely coiled, - evolute, - gyroconic, - exposed whorls, - whorls touching, - subcircular to narrowly compressed whorls, - broadly arched, or keeled venter, - smooth or ribbed sides, - aptychi are single valved and concentrically striated, - suture saddle endings tend to be rounded but usually not phylloid, - lobes tend to be more jagged with thorn-like endings, and - complex moss-like suture endings with adventious and secondary subdivisions. # Nostoceratids Nipponites mirabilis on the right may be from the Upper Cretaceous. # Phyllocerates # Prolecanites "Type species by original designation of Librovitch 1957, Protocanites supradevonicus Schindewolf (1926)."[15] In the diagrams above are the suture patterns for various species holotypes: - A - Protocanites gurleyi (Smith), - B - Eocanites supradevonicus supradevonicus (Schindewolf), - C - Eocanites semageominus (House), - D - Eocanites wangyounensis(Ruan & He), - E - Michiganites algarbiensis (Pruvost), - F - Michiganites marshallensis (Winchell), - G - Michiganites scalibrinii (Antelo), - H - Michiganites greenei (Miller).[15] # Coleoids The subclass Coleoidea has the cohort Belemnoidea which may contain shelled cephalopods. The image second down on the right shows "the piglet squid [Helicocranchia pfefferi], floating along with its tentacles waving above its head in the central Pacific Ocean near Palmyra Atoll."[16] The "squid [was spotted] about 4,544 feet (1,385 meters) below the ocean surface [from] the exploration vehicle (E/V) Nautilus."[16] "Is that a squid? I think it's a squid. It's like a bloated squid with tiny tentacles and a little hat that's waving around. And it looks like it's got a massive, inflated mantle cavity. I've never seen anything quite like this before."[17] The "mantle is filled with ammonia, which the squid uses to control its buoyancy."[16] "This Nautilus expedition is an effort to explore the deep ocean waters of the Marine National Monument, near Kingman Reef, Palmyra Atoll and Jarvis Island, which are among the most remote U.S.-controlled territories."[16] Helicocranchia is of the order Teuthida. # Belemnoids The cohort Belemnoidea has five extinct orders. Any one of these may contain cephalopods with an external shell. "Belemnites (Belemnitida) were squid-like animals belonging to the cephalopod class of the mollusc phylum, and therefore related to the ammonites of old as well as to the modern squids, octopuses and nautiluses."[18] "Now extinct, their fossils are found in rocks of Jurassic and Cretaceous ages, with a few species hanging on into the early part of the Tertiary. The animal’s soft parts very rarely fossilise, leaving us with only the hard parts; the guard and the phragmacone."[18] ## Aulacocerids "Pendleian age rocks in the Chainman Shale include the upper beds of the Camp Canyon Member and the Willow Gap Limestone Member. The fossil cephalopods [an example of Hematites barbarae is shown above] are from these rocks in the Confusion Range and Burbank Hills of western Millard County."[19] For the study of the "shell morphology and ultrastructure in Hematites [more] than 30 specimens of this genus were collected by the second author from the Upper Mississippian in Arkansas. The data obtained confirm the detailed description of the external shell morphology [diagrammed on the right] in the genus published by FLOWER & GORDON (1959) and GORDON (1964), and it also includes new information on the conotheca structure, conotheca rostrum/mantle attachment, “living” chamber length, and morphology of the adoral portion of the rostrum."[20] "Schematic diagram of the medial shell section in Hematites [on the right shows] the truncation of the initial portion of the phragmocone which is plugged by the central rod structure (crs) and by the additional septum (as). Scale bar: 1 mm. as = additional septum; c = conotheca; r = rostrum; s = septum; sn = septal neck; t = place of truncation."[20] ## Phragmoteuthids The image on the right suggests that Phragmoteuthis conocauda does not have an external shell. ## Belemnitids "Belemnites [...] have a worldwide distribution."[21] Shells or shell-like structures are the phragmacone in the image on the left and the rostrum, the second image on the left, which have been found apparently internal to the soft body. The second image down on the left shows rostrums from Passatoteuthis auricipitis Lang, Jurassic, Lower Lias, found in Gloucestershire. The image second down on the right shows a rostrum from the genus Peratobelus, found in the Cairn mine, South Australia. ## Diplobelids ## Belemnoteuthins # Nautiloids Def. a cephalopod mollusk with a light external spiral shell that is white with brownish bands on the outside and lined with mother-of-pearl on the inside is called a nautiloid. Nautiloidea is another subclass of cephalopods. "Nautilus [included in the diagram on the left] is one of the few surviving animals resembling the primitive or original cephalopods. The fossilized shells of these extinct forms, called ammonites (A), are quite common. (B) is a deep-sea species Nautilus pompilius that lives in tropical waters. To the right is a section through Nautilus showing the shell (1) and siphuncle (2) wound in a spiral. Immediately behind the tentacles lies the mouth (4) leading to the intestine (7). Nautilus has an advanced nervous system with a brain (3) and respires by means of gills (6) that are located in the mantle cavity. It swims by forcing a jet of water out of its mantle cavity and through the siphon (5)."[22] "Nautiluses first evolved in the Cambrian period and became significant marine predators during the Ordovician period."[22] ## Actinocerids ## Ascocerids ## Bactrites ## Barrandeocerids ## Discosorids ## Ellesmerocerids ## Endocerids ## Nautilids An individual example of the genus Nautilus is on the right. A couple of Nautilus macromphalus are on the left, photographed during a night dive, at 15 meters, near Lifou, Sandal wood bay, New Caledonia. "The six living species of nautiluses are: - No common name (Allonautilus perforates), - Crusty Nautilus (Allonautilus scrobiculatus), - Palau Nautilus (Nautilus belauensis), - Bellybutton Nautilus (Nautilus macromphalus), - Chambered Nautilus (Nautilus pompilius), and - White-patch Nautilus (Nautilus stenomphalus)".[22] ## Oncocerids ## Orthocerids Centered at the top is an artist's impression of an Orthoceras species from the middle Ordovician. On the left is a fossil of Orthoceras currens. ## Plectronocerids ## Pseudorthocerids ## Tarphycerids # Anatomy Cut in the plane of the spiral (medial or median cut), the shell reveals the chambers inside. On the left is an internal mold from a Baculites individual. The original aragonite of the outer conch and inner septa has dissolved away, leaving this articulated internal mold. Baculites is an ammonite from the Late Cretaceous of Wyoming. The tissue used to close the chamber to the outside is called an aptychus. Perisphictes on the lower left has aptychi. Agoniatites have a central siphuncle as shown in the illustration on the right with septal necks pointing to the rear (retrochoanitic). The diagrams on the lower left show median sections where the siphuncle is in a ventral position. Measurements to characterize an ammonite are indicated in the right-hand diagram. The abbreviations are for ammonitella (am), caecum (c), initial chamber (ic), primary constriction (pc), prosiphon (ps), siphunclar tube (s), proseptum (first septum, s1), primary septum (second septum, s2), third septum (s3), maximum initial chamber size (A), minimum initial chamber size (B), ammonitella size (D), and ammonitella angle (E).[14] # Predation The fossil shell of ammonite Placenticeras whitfieldi on the right shows punctures caused by the bite of a mosasaur. "In the late Cretaceous, it is the mosasaurs that have been identified as ammonite predators, beginning with the study of Kauffman and Kesling (1960), who described a 300 mm diameter Placenticeras (first illustrated by Fenton and Fenton in 1958) from the Late Campanian Pierre Shale of South Dakota that had been bitten, in their interpretation no less than 16 times, by what they concluded to be a platycarpine mosasaur (we suggest that the mosasaur was playing with its prey, as do contemporary cetaceans)."[23] "A juvenile specimen of the ammonite Pseudaspidoceras [in the image on the left] from the Early Turonian [Late Cretaceous] of the Goulmima area in the Province of Er-Rachida in south-eastern Morocco shows clear evidence of predation by a tooth-bearing vertebrate."[23] "These [teeth punctures] are interpreted as the product of a single bite by a mosasauroid, probably a Tethysaurus." "All of the convincing well-documented examples of mosasaur-bitten ammonite shells are thus from North America, the overwhelming majority from the Late Campanian of the northern part of the Western Interior of the United States and Alberta in Canada."[23] "The Goulmima occurrence is the only convincing record of mosasauroid attack on an ammonite outside North America, and of the latter, the overwhelming majority are restricted to the Late Campanian of the northern interior. The only adequately documented putative occurrence outside of the interior, in the Early Maastrichtian Rosario Formation of Baja California, Mexico, may not in fact be by a mosasaur, although there is evidence of mosasauroid attack on two Campanian nautiloids from San Diego County in California."[23] "Given the above, we see no evidence to support the view that there was coevolution between ammonites and mosasaurs, nor that mosasaurs were "The ecologically dominant predators of Cretaceous marine seas" as proposed by Kauffman (1990)."[23] # Sizes On the right is an image of the world's largest known ammonite, Parapuzosia seppenradensis (originally Pachydiscus seppenradensis) discovered in Seppenrade, Germany. The partial fossil specimen has a shell diameter of 1.95 metres (6.4 ft). But, the living chamber was incomplete. The shell diameter may have been about 2.55 metres (8.4 ft) when it was alive. # Paleocene The Paleocene dates from 65.5 ± 0.3 x 106 to 55.8 ± 0.2 x 106 b2k. # Danian The beginning of the Danian age (and the end of the preceding Maastrichtian age) is at the Cretaceous–Paleogene extinction event at 66.0 Ma. The age ended 61.6 Ma, being followed by the Selandian age.[24] Post-"Cretaceous ammonites of the genus Hoploscaphites have been found at Stevns Klint in Denmark (Machalski & Heinberg, 2005; Machalski et al., 2009)."[25] "The maximum age for Danian scaphitid survivors from the Cerithium Limestone at Stevns Klint, Denmark, has recently been estimated to be around 0.2 Ma following the K–Pg boundary event (Machalski and Heinberg in press). Assuming the Cretaceous– Paleogene boundary at 65.4 ± 0.1 Ma (Jagt and Kennedy 1994), the present study covers more than 4 Ma of the final stages in scaphitid evolution."[26] "Scaphitid material from subunit IVf−7 at the very top of the Meerssen Member [...] traditionally regarded to be uppermost Maastrichtian, has recently been reassigned to the lowermost Danian, based on microfossil and strontium isotope evidence (Smit and Brinkhuis 1996). According to Jagt et al. (2003), the scaphitid and baculitid ammonites preserved in subunit IVf−7 are early Danian survivors."[26] Above center are Hoploscaphites constrictus johnjagti subsp. nov., adult macroconchs, ammonites from the Danian: A. MGUH 27366, lowermost Danian, Stevns Klint, Denmark, in apertural (A1), lateral (A2, A3), and ventral (A4) views. # Cretaceous "The Cretaceous period is the third and final period in the Mesozoic Era. It began 145.5 million years ago after the Jurassic Period and ended 65.5 million years ago, before the Paleogene Period of the Cenozoic Era."[27] Scaphites hippocrepis is an index fossil for the Cretaceous.[28] # Late Cretaceous In the top center is a 2.7 cm section of a polished shell with 6 sutures. It is from the extinct cephalopod Baculites compressus; Cretaceous, 100 million years old, Bearpaw Formation, Montana, USA. The lower center is a fossil cast of a Baculites grandis shell taken at the North American Museum of Ancient Life. On the right is an example of Plesiacanthoceras wyomingense from the late Cretaceous in Wyoming, USA. It is exhibited in Smithsonian National Museum of Natural History: Hall of Fossils. # Maastrichtian Extends from 70.6 ± 0.6 to 65.5 ± 0.3 Mya. The specimen on the left is Jeletzkytes spedeni from the Maastrichtian (Upper-Cretaceous) Fox Hills Formation, locality - South Dakota, USA. Matrix free specimen is 7.5 cm (3") in diameter, displaying pearly aragonite preservation of the shell. The center photo is of Baculites ovatus, at the Naturalis Museum, Leiden. Baculites ovatus apparently occurs in the Ripley Formation.[29] Discoscaphites iris on the right is an ammonite from the Owl Creek Formation (Upper Cretaceous), Owl Creek, Ripley, Mississippi USA. The McNairy Formation found in Illinois is also from the Upper Cretaceous Maastrichtian. # Edmontonian Extends from 80.8 to 70.7 Mya. # Judithian Extends from 82.2 to 80.8 Mya. # Campanian The Bearpaw Formation is famous for its well-preserved ammonite fossils. These include Placenticeras meeki and Placenticeras intercalare, and the baculite Baculites compressus.[30] Extends from 83.5 ± 0.7 to 70.6 ± 0.6 Mya. The Baylis Formation, Post Creek Formation and the Tuscaloosa Formation are Upper Cretaceous from the Campanian. # Haumurian Extends from 84 to 65.5 Mya. # Aquilan Extends from 85.2 to 82.2 Mya. # Santonian Extends from 85.8 ± 0.7 to 83.5 ± 0.7 Mya. # Piripauan Extends from 86.5 to 84 Mya. # Teratan Extends from 89.1 to 86.5 Mya. # Coniacian Extends from 89.3 ± 1.0 to 85.8 ± 0.7 Mya. # Senonian Extends from 89.3 to 65.5 Mya. # Emscherian Extends from 89.5 to 83.5 Mya. # Mangaotanean Extends from 92.1 to 89.1 Mya. # Turonian Extends from 93.5 ± 0.8 to 89.3 ± 1.0 Mya. Benueites is a Turonian ammonite genera from Nigeria.[31] # Cenomanian These fast-moving nektonic carnivores lived during the Cenomanian stage of the Late Cretaceous (from 94.3 to 89.3 Ma).[32][33] Shells of Acanthoceras rhotomagensis may reach a diameter of about 36 (Expression error: Unexpected round operator. ). Their shells have ornate ribs.[34][35] Acanthoceras rhotomagensis fossils may be found in Western Europe and western North America.[36] Hibolites is a genus of belemnite, an extinct group of cephalopods of the Cenomanian.[37] # Arowhanan Extends from 95.2 to 92.1 Mya. # Lower Cretaceous # Albian Puzosia is a genus of Desmoceratidae (desmoceratid) ammonites, and the type genus for the Puzosiinae, which lived during the middle part of the Cretaceous, from early Aptian to Maastrichtian (125.5 to 70.6 Ma).[38] Or, the range is from Albian to Santonian.[39] Otohoplites is a genus of ammonite that lived in the Early Albian whose fossils were found in Svalbard, Denmark, England, France, Austria, Poland, Russia and Kazakhstan, evolved from Hemisonneratia and gave rise to genus Hoplites.[40] Shells belonging to this genera are rather inflated to compressed and have zigzaging, or looped ribs that ends in oblique ventrolateral clavi; usually, ribs are zigzaging through venter; macroconchs have smooth body chamber and rounded venter.[41] Kossmatella is an extinct genus of ammonoid cephalopods belonging to the family Lytoceratidae, were fast-moving nektonic carnivores[42] that lived from Albian to Cenomanian age.[39] Cleoniceras included in the subfamily Cleoniceratinae is a rather involute, high-whorled hoplitid from the Lower to basal Middle Albian of Europe, Madagascar, and Transcaspian region, where the shell has a generally small umbilicus, arched to acute venter, and typically at some growth stage, falcoid ribs that spring in pairs from umbilical tubercles, usually disappearing on the outer whorls.[43] Brancoceras is a rather small, strongly ribbed, acanthoceratacean ammonite from the Albian stage of the Lower Cretaceous:[44][45] - the shell is evolute with a subquadrate whorl section and rounded venter - the suture forms a finely squiggly line with well-defined lobes and saddles - Brancoceras (Eubrancoceras) aegoceratoides reached a diameter of at least 4.2 centimetres (1.6535433054 in) - Brancoceras is representative of the subfamily Brancoceratinae, which makes up part of the Acanthoceratoidea (acanthoceratacean) family Brancoceratidae - stratigraphic range is rather narrow, extending only from the upper Lower to the Middle Albian. Arcthoplites is an extinct genus of cephalopod belonging to the Ammonite subclass from the lower Albian.[39] Anadesmoceras is an hoplitid ammonite from the lower Albian (upper Lower Cretaceous) of England, included in the subfamily Cleoniceratinae: - a shell shaped more or less like a compressed Cleoniceras but with faint ornament only on the inner whorls - the shell has bundled growth striae. The aperture is preceded by several wide sinuous constrictions.[39][44] Anacleoniceras is an extinct genus of cephalopod belonging to the Ammonite subclass lower Albian.[39] Aioloceras is an ammonite, order Ammonitida, from near the end of the Early Cretaceous:[39][44] - the shell is compressed with the outer whorl covering much of the previous - sides are slightly convex, converge toward a narrowly ached venter - inner whorls have sharp falcoid ribs, outer are smooth - umbilical tubercles are lacking - similar related forms include Neosaynella and Cleoniceras - has been found in Albian (uL Cret) sediments in Madagascar, Patagonia, and possibly Queensland. # Lower Albian "Amber—ancient resins from trees—commonly traps only some terrestrial insects, plants, or animals. It’s very rare to find some sea animals in amber."[46] "This extraordinary assemblage, a true and beautiful snapshot of a beach in the Cretaceous, is just mind-blowing."[47] "The idea that there’s a whole community of organisms in association—that may prove more important in the long run."[48] "If you were scuba-diving in a shallow marine setting, you absolutely would have seen ammonites. They would be as common as seeing some snails crawling around."[49] "Based on its internal shell structure, the amber-encased ammonite is a juvenile that belongs to the subgenus Puzosia (Bhimaites), which makes a lot of sense in 99-million-year-old amber."[46] # Aptian # Barremian # Hauterivian # Valanginian # Berriasian # Early Cretaceous # Jurassic The Jurassic/Cretaceous boundary occurs at 144.2 ± 2.6 Ma (million years ago).[50] On the left is a photograph of Asteroceras obtusum from the Jurassic Lower Lias Formation, Obtusum Zone. Locality is Lyme Regis, Dorset, England. Complete calcified specimen measures 11.5 cm (4.5") in diameter, in a limestone matrix. Perisphinctes tiziani is an index fossil for the Jurassic.[28] # Late Jurassic On the right is an example of Kosmoceras cromptoni from the Late Jurassic, Chippenham, England. # Upper Jurassic # Tithonian # Kimmeridgian Lithacosphinctes achilles is from the Kimmeridgian. # Oxfordian # Middle Jurassic # Callovian On the right is an image of Peltoceras solidum, an ammonite from the Matmor Formation (Jurassic, Callovian), Makhtesh Gadol, Israel. On the left is an example of Kosmoceras medea. Another species of Kosmoceras is on the lower right, specifically Kosmoceras proniae. # Bathonian # Bajocian # Aalenian Leioceras opalinum is an ammonite from the Aalenian. # Lower Jurassic Uptonia jamesoni from the lower Jurassic is in the family Polymorphitidae, superfamily Eoderocerataceae, order Ammonitida, subclass Ammonoidea, class Cephalopoda. # Toarcian # Pliensbachian Pleuroceras spinatum (Bruguière 1789) is of the family Amaltheidae. It is a pyritic specimen. The biozone index is to the end of Pliensbachian. # Sinemurian # Hettangian Psiloceras psilonotum, Psiloceras spelae tirolicum and Psiloceras planorbis are from the Hettangian. The Triassic/Jurassic boundary occurs at 205.7 ± 4.0 Ma (million years ago).[50] # Triassic Although the example of Psiloceras tilmanni is from the Jurassic. Its lowest occurrence is in the New York Canyon section of Nevada USA which may be Triassic. Trophites subbuliatus is an index fossil for the Triassic.[28] # Upper Triassic # Rhaetian # Norian # Carnian # Middle Triassic # Ladinian # Anisian An example of Ussuriphyllites amurensis (Kiparisova) is on the right. It is from the Lower-most Anisian, Atlasov Cape area.[51] # Lower Triassic # Olenekian # Spathian The Spathian is sometimes referred to as the Late Olenekian.[52] Olenekoceras meridianum is a "typical Late Olenekian [fossil which] differs in its lithology from the same zone of Russian Island, where the Zhitkov Suite has been recognized (Zakharov, 1997; Zakharov et al., 2004)."[51] # Smithian The Smithian is sometimes referred to as the Early Olenekian.[52] # Induan # Paleozoic The Paleozoic era spanned 542.0 ± 1.0 to 251.0 ± 0.7 Mb2k. # Permian The Permian lasted from 299.0 ± 0.8 to 251.0 ± 0.4 Mb2k. The Permian/Triassic boundary occurs at 248.2 ± 4.8 Ma (million years ago).[50] # Carboniferous The Carboniferous began 359.2 ± 2.5 Mb2k and ended 299.0 ± 0.8 Mb2k. # Pennsylvanian The Pennsylvanian lasted from 318.1 ± 1.3 to 299.0 ± 0.8 Mb2k. # Mississippian The Mississippian lasted from 359.2 ± 2.5 to 318.1 ± 1.3 Mb2k. Prolecanites gurleyi is an index fossil of the Mississippian.[28] # Middle Mississippian "This species has been consistently identified with the considerably younger, late Viséan (late Holkerian to Asbian [late Meramecian to early Chesterian]) genus Beyrichoceras Foord, 1903 (type species, Goniatites obtusus Phillips, 1836) (eg, Gordon, 1965, p. 284."[53] # Devonian The Devonian spanned 416.0 ± 2.8 to 359.2 ± 2.5 Mb2k. # Upper Devonian # Famennian A specimen of Clymenia laevigata from the Upper Devonian Famennian of Poland is on the right. On the left is a fossil of Platyclymenia intracrostata also from the Famennian of Poland. # Frasnian # Middle Devonian # Givetian # Eifelian # Lower Devonian # Emsian # Pragian # Lochkovian # Early Devonian Mimagoniatites is a genus of ammonites from the early Devonian. "Shell [is] small to large size, evolute, thinly discoidal to discoidal. Whorl cross section of the first two whorls [is] approximately circular, in later whorls subtrapezoidal. Umbilicus [is] narrow to moderately wide, moderately large umbilical window (< 1 mm). Whorl expansion rate increases remarkably from the second whorl on (> 2.5, later up to 3.9). Growth line course [is] biconvex with prominent ventrolateral projection and deep ventral sinus."[54] The lower boundary of the genus is "LD3C--LD3D: Anetoceras Range Zone top, 405.5 million years" and the upper boundary is "CZB maureri--sulc.antiqua Zone [19,30], 398.5 million years".[54] Geographic distribution: "Devonian of Algeria (2 collections), Canada (1: Nunavut), China (7), the Czech Republic (5), Germany (3), Morocco (13), the Russian Federation (1), Spain (4), Turkey (3), United States (1: Pennsylvania)".[55] # Silurian The Silurian spanned 443.7 ± 1.5 to 416.0 ± 2.8 Mb2k. Hexamoceras hertzeri is an index fossil for the Silurian.[28] Hexamoceras is a genus of the Nautiloidea.[56] "Rolfe made the important observation that 'Other genera are pre-Devonian and hence cannot be ammonoid aptychi, but Ruedemann's suggestion that aptychi "would naturally also have existed in the Ordovician and Silurian cephalopods" has been largely overlooked'."[57] # Ordovician The Ordovician lasted from 488.3 ± 1.7 to 443.7 ± 1.5 Mb2k. # Upper Ordovician The image on the right is an over-encrusted, internal mold of a nautiloid from the Upper Ordovician of northern Kentucky. # Cambrian The Cambrian lasted from 542.0 ± 1.0 to 488.3 ± 1.7 Mb2k. # Middle Cambrian "We recently redescribed the Middle Cambrian organism Nectocaris pteryx known from 92 specimens from the Burgess Shale (Smith & Caron 2010). [This] new material allowed us to identify new features consistent with a cephalopod affinity."[58] # Hypotheses Hypotheses: - Each of the ammonoids has a set of genes producing a distinct suture mark. - Ammonoids are alive today. - Morphological descriptions should be sufficient to identify unknown ammonites at the species level. # Sciences Classification of Baculites ovatus: - Domain: Eukaryota - Regnum: Animalia - Subregnum: Eumetazoa - Cladus: Bilateria - Superphylum: Protostomia - Phylum: Mollusca - Classis: Cephalopoda - Subclassis: Ammonoidea - Ordo: Ammonitida - Subordo: Ancyloceratina - Superfamilia: Turrilitoidea - Familia: Baculitidae - Genus: Baculites - Species: Baculites ovatus (Say, 1820) The subclassis: Ammonoidea contains the ordines: Ammonitida, Ceratitida, Clymeniida, Goniatitida, and Prolecanitida. # 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/Ammonoids
c3e7cb67a7eb36a8c2eb4d9071ee24260c1bbe52	wikidoc	Amoebozoa	Amoebozoa # Overview The Amoebozoa are a major group of amoeboid protozoa, including the majority that move by means of internal cytoplasmic flow. Their pseudopodia are characteristically blunt and finger-like, called lobopodia. Most are unicellular, and are common in soils and aquatic habitats, with some found as symbiotes -f other organisms, including several pathogens. The Amoebozoa also include the slime moulds, multinucleate or multicellular forms that produce spores and are usually visible to the unaided eye. Amoebozoa vary greatly in size. Many are only 10-20 μm in size, but they also include many of the larger protozoa. The famous species Amoeba proteus may reach 800 μm in length, and partly on account of its size is often studied as a representative cell. Multinucleate amoebae like Chaos and Pelomyxa may be several millimetres in length, and some slime moulds cover several square feet. # Morphology The cell is typically divided into a granular central mass, called endoplasm, and a clear outer layer, called ectoplasm. During locomotion the endoplasm flows forwards and the ectoplasm runs backwards along the outside of the cell. Many amoeba move with a definite anterior and posterior; in essence the cell functions as a single pseudopod. They usually produce numerous clear projections called subpseudopodia (or determinate pseudopodia), which have a defined length and are not directly involved in locomotion. Other amoebozoans may form multiple indeterminate pseudopodia, which are more or less tubular and are mostly filled with granular endoplasm. The cell mass flows into a leading pseudopod, and the others ultimately retract unless it changes direction. Subpseudopodia are usually absent. In addition to a few naked forms like Amoeba and Chaos, this includes most amoebae that produce shells. These may be composed of organic materials, as in Arcella, or of collected particles cemented together, as in Difflugia, with a single opening through which the pseudopodia emerge. The primary mode of nutrition is by phagocytosis: the cell surrounds potential food particles, sealing them into vacuoles where the may be digested and absorbed. Some amoebae have a posterior bulb called a uroid, which may serve to accumulate waste, periodically detaching from the rest of the cell. When food is scarce, most species can form cysts, which may be carried aerially and introduce them to new environments. In slime moulds, these structures are called spores, and form on stalked structures called fruiting bodies or sporangia. Most Amoebozoa lack flagella and more generally do not form microtubule-supported structures except during mitosis. However, flagella occur among some archamoebae, and many slime moulds produce biflagellate gametes. The flagella is generally anchored by a cone of microtubules, suggesting a close relationship to the opisthokonts. The mitochondria characteristically have branching tubular cristae, but have been lost among archamoebae. # Classification Traditionally all amoebae with lobose pseudopods were treated together as the Lobosea, placed with other amoeboids in the phylum Sarcodina or Rhizopoda, but these were considered to be unnatural groups. Structural and genetic studies identified the percolozoans and several archamoebae as independent groups. In phylogenies based on rRNA their representatives were separate from other amoebae, and appeared to diverge near the base of eukaryotic evolution, as did most slime molds. However, revised trees by Cavalier-Smith and Chao in 1996 suggested that the remaining lobosans do form a monophyletic group, and that the archamoebae and Mycetozoa are closely related to it, although the percolozoans are not. Subsequently they emended the older phylum Amoebozoa to refer to this supergroup. Studies based on other genes have provided strong support for the unity of this group. Patterson treated most with the testate filose amoebae as the ramicristates, based on mitochondrial similarities, but the latter are now removed to the Cercozoa. Amoebae are difficult to classify, and relationships within the phylum remain confused. Originally the archamoebae and Mycetozoa were placed in a subphylum Conosa, which receives some support from molecular phylogenies, and the others were placed in a subphylum Lobosa, which is paraphyletic. Two major classes of Lobosa have been identified, the Tubulinea and Flabellinea, but various others remain of uncertain placement. Strong similarities between Amoebozoa and Opisthokonts lead to the proposal that they form a clade called Unikonts.	Amoebozoa # Overview The Amoebozoa are a major group of amoeboid protozoa, including the majority that move by means of internal cytoplasmic flow. Their pseudopodia are characteristically blunt and finger-like, called lobopodia. Most are unicellular, and are common in soils and aquatic habitats, with some found as symbiotes of other organisms, including several pathogens. The Amoebozoa also include the slime moulds, multinucleate or multicellular forms that produce spores and are usually visible to the unaided eye. Amoebozoa vary greatly in size. Many are only 10-20 μm in size, but they also include many of the larger protozoa. The famous species Amoeba proteus may reach 800 μm in length, and partly on account of its size is often studied as a representative cell. Multinucleate amoebae like Chaos and Pelomyxa may be several millimetres in length, and some slime moulds cover several square feet. # Morphology The cell is typically divided into a granular central mass, called endoplasm, and a clear outer layer, called ectoplasm. During locomotion the endoplasm flows forwards and the ectoplasm runs backwards along the outside of the cell. Many amoeba move with a definite anterior and posterior; in essence the cell functions as a single pseudopod. They usually produce numerous clear projections called subpseudopodia (or determinate pseudopodia), which have a defined length and are not directly involved in locomotion. Other amoebozoans may form multiple indeterminate pseudopodia, which are more or less tubular and are mostly filled with granular endoplasm. The cell mass flows into a leading pseudopod, and the others ultimately retract unless it changes direction. Subpseudopodia are usually absent. In addition to a few naked forms like Amoeba and Chaos, this includes most amoebae that produce shells. These may be composed of organic materials, as in Arcella, or of collected particles cemented together, as in Difflugia, with a single opening through which the pseudopodia emerge. The primary mode of nutrition is by phagocytosis: the cell surrounds potential food particles, sealing them into vacuoles where the may be digested and absorbed. Some amoebae have a posterior bulb called a uroid, which may serve to accumulate waste, periodically detaching from the rest of the cell. When food is scarce, most species can form cysts, which may be carried aerially and introduce them to new environments. In slime moulds, these structures are called spores, and form on stalked structures called fruiting bodies or sporangia. Most Amoebozoa lack flagella and more generally do not form microtubule-supported structures except during mitosis. However, flagella occur among some archamoebae, and many slime moulds produce biflagellate gametes. The flagella is generally anchored by a cone of microtubules, suggesting a close relationship to the opisthokonts. The mitochondria characteristically have branching tubular cristae, but have been lost among archamoebae. # Classification Traditionally all amoebae with lobose pseudopods were treated together as the Lobosea, placed with other amoeboids in the phylum Sarcodina or Rhizopoda, but these were considered to be unnatural groups. Structural and genetic studies identified the percolozoans and several archamoebae as independent groups. In phylogenies based on rRNA their representatives were separate from other amoebae, and appeared to diverge near the base of eukaryotic evolution, as did most slime molds. However, revised trees by Cavalier-Smith and Chao in 1996[1] suggested that the remaining lobosans do form a monophyletic group, and that the archamoebae and Mycetozoa are closely related to it, although the percolozoans are not. Subsequently they emended the older phylum Amoebozoa to refer to this supergroup.[2] Studies based on other genes have provided strong support for the unity of this group.[3] Patterson treated most with the testate filose amoebae as the ramicristates[4], based on mitochondrial similarities, but the latter are now removed to the Cercozoa. Amoebae are difficult to classify, and relationships within the phylum remain confused. Originally the archamoebae and Mycetozoa were placed in a subphylum Conosa, which receives some support from molecular phylogenies, and the others were placed in a subphylum Lobosa, which is paraphyletic. Two major classes of Lobosa have been identified, the Tubulinea and Flabellinea, but various others remain of uncertain placement. Strong similarities between Amoebozoa and Opisthokonts lead to the proposal that they form a clade called Unikonts.	https://www.wikidoc.org/index.php/Amoebozoa
13d8178cb96e4177fb81864744beaa9cb9346e43	wikidoc	Amoxapine	Amoxapine # 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 Amoxapine is a Tricyclic antidepressant that is FDA approved for the {{{indicationType}}} of - depression, endogenous depression, severe major depression with psychotic features.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include constipation, xerostomia, somnolence, blurred vision, fatigue.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Depression - Indicated for the relief of symptoms of depression in patients with neurotic or reactive depressive disorders as well as endogenous and psychotic depressions; indicated for depression accompanied by anxiety or agitation. - Maintenance, usual effective dose is 120-300 mg/day PO; may increase dosage to 400 mg/day after 3 weeks if there is inadequate response and hospitalized patients with no history of convulsive seizures may have the dose raised cautiously up to 600 mg/day in divided doses. Endogenous depression - Initial, 50 mg PO 2-3 times a day; may increase dosage up to 100 mg 2-3 times a day by end of the first week OR may start with 300 mg/day, but notable sedation may occur during the first few days of therapy. - Maintenance, usual effective dose is 120-300 mg/day PO; may increase dosage to 400 mg/day after 3 weeks if there is inadequate response and hospitalized patients with no history of convulsive seizures may have the dose raised cautiously up to 600 mg/day in divided doses. Severe major depression with psychotic features - Initial, 50 mg PO 2-3 times a day; may increase dosage up to 100 mg 2-3 times a day by end of the first week OR may start with 300 mg/day, but notable sedation may occur during the first few days of therapy. - Maintenance, usual effective dose is 120-300 mg/day PO; may increase dosage to 400 mg/day after 3 weeks if there is inadequate response and hospitalized patients with no history of convulsive seizures may have the dose raised cautiously up to 600 mg/day in divided doses. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Amoxapine in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Amoxapine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Depression - Safety and efficacy have not been established in patients younger than 16 years of age. Endogenous depression - Safety and efficacy have not been established in patients younger than 16 years of age. Severe major depression with psychotic features - Safety and efficacy have not been established in patients younger than 16 years of age. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Amoxapine in pediatric patients. ### Non–Guideline-Supported Use - There is limited information about Off-Label Non–Guideline-Supported Use of Amoxapine in pediatric patients. # Contraindications - Prior hypersensitivity to dibenzoxazepine compounds. - It should not be given concomitantly with monoamine oxidase inhibitors. - Hyperpyretic crises, severe convulsions, and deaths have occurred in patients receiving tricyclic antidepressants and monoamine oxidase inhibitors. - When it is desired to replace a monoamine oxidase inhibitor with amoxapine, a minimum of 14 days should be allowed to elapse after the former is discontinued. - Initiated cautiously with gradual increase in dosage. - Not recommended during the acute recovery phase following myocardial infarction. # Warnings ### Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for amoxapine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. ### Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that amoxapine is not approved for use in treating bipolar depression. ### Tardive Dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with neuroleptic (i.e., antipsychotic) drugs. (Amoxapine is not an antipsychotic, but it has substantive neuroleptic activity.) Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of neuroleptic treatment, which patients are likely to develop the syndrome. Whether neuroleptic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of neuroleptic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if neuroleptic treatment is withdrawn. Neuroleptic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, neuroleptics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic neuroleptic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to neuroleptic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on neuroleptics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. ### Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs and with amoxapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include - Immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, - Intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored since recurrences of NMS have been reported. Amoxapine should be used with caution in patients with a history of urinary retention, angle-closure glaucoma, or increased intraocular pressure. Patients with cardiovascular disorders should be watched closely. Tricyclic antidepressant drugs, particularly when given in high doses, can induce sinus tachycardia, changes in conduction time, and arrhythmias. Myocardial infarction and stroke have been reported with drugs of this class. Extreme caution should be used in treating patients with a history of convulsive disorder or those with overt or latent seizure disorders. # Adverse Reactions ## Clinical Trials Experience Central nervous system Cardiovascular Hematologic Gastrointestinal Hypersensitive Reactions Anticholinergic Endocrine Miscellaneous ## Postmarketing Experience There is limited information regarding Amoxapine Postmarketing Experience in the drug label. # Drug Interactions - Drugs Metabolized by P450 2D6 - The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7 to 10% of caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). - In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine, cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). - Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Studies performed in mice, rats, and rabbiats have demonstrated no evidence of teratogenic effect due to amoxapine. Embryotoxicity was seen in rats and rabbits given oral doses approximating the human dose. Fetotoxic effects (intrauterine death, stillbirth, decreased birth weight) were seen in animals studied at oral doses 3-10 times the human dose. Decreased postnatal survival (between days 0-4) was demonstrated in the offspring of rats at 5-10 times the human dose. There are no adequate and well-controlled studies in pregnant women. Amoxapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Amoxapine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Amoxapine during labor and delivery. ### Nursing Mothers Amoxapine, like many other systemic drugs, is excreted in human milk. Because effects of the drug on infants are unknown, caution should be exercised when amoxapine is administered to nursing women. ### Pediatric Use Anyone considering the use of amoxapine in a child or adolescent must balance the potential risks with the clinical need. ### Geriatic Use Clinical studies of amoxapine were not adequate to determine whether subjects aged 65 and over respond differently from younger subjects. Amoxapine is known to be substantially excreted by the kidney.Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered. Greater sensitivity (e.g., tardive dyskinesia, sedation) of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at a lower dose . ### Gender There is no FDA guidance on the use of Amoxapine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Amoxapine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Amoxapine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Amoxapine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Amoxapine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Amoxapine in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Amoxapine Administration in the drug label. ### Monitoring There is limited information regarding Amoxapine Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Amoxapine and IV administrations. # Overdosage There is limited information regarding Amoxapine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action Amoxapine is an antidepressant with mild sedative property and an unknown mechanism of action. It reduces norepinephrine and serotonin uptake and inhibits the response of dopamine receptors to dopamine. It is not an inhibitor of monoamine oxidase ## Structure Amoxapine is an antidepressant of the dibenzoxazepine class, chemically distinct from the dibenzazepines, dibenzocycloheptenes, and dibenzoxepines. It is designated chemically as 2-Chloro-11-(1-piperazinyl)dibenzoxazepine. The structural formula is represented below ## Pharmacodynamics Amoxapine is an antidepressant with a mild sedative component to its action. The mechanism of its clinical action in man is not well understood. In animals, amoxapine reduced the uptake of norepinephrine and serotonin and blocked the response of dopamine receptors to dopamine. Amoxapine is not a monoamine oxidase inhibitor. Amoxapine is absorbed rapidly and reaches peak blood levels approximately 90 minutes after ingestion. It is almost completely metabolized. The main route of excretion is the kidney. In vitro tests show that amoxapine binding to human serum is approximately 90%. In man, amoxapine serum concentration declines with a half-life of eight hours. However, the major metabolite, 8-hydroxyamoxapine, has a biologic half-life of 30 hours. Metabolites are excreted in the urine in conjugated form as glucuronides. Clinical studies have demonstrated that amoxapine has a more rapid onset of action than either amitriptyline or imipramine. The initial clinical effect may occur within four to seven days and occurs within two weeks in over 80% of responders. ## Pharmacokinetics There is limited information regarding Amoxapine Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Amoxapine Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Amoxapine Clinical Studies in the drug label. # How Supplied There is limited information regarding Amoxapine How Supplied in the drug label. ## Storage There is limited information regarding Amoxapine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Amoxapine Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Amoxapine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Amoxapine Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Amoxapine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Amoxapine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Pratik Bahekar, MBBS [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Amoxapine is a Tricyclic antidepressant that is FDA approved for the {{{indicationType}}} of * depression, endogenous depression, severe major depression with psychotic features.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include constipation, xerostomia, somnolence, blurred vision, fatigue.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Depression - Indicated for the relief of symptoms of depression in patients with neurotic or reactive depressive disorders as well as endogenous and psychotic depressions; indicated for depression accompanied by anxiety or agitation. - Maintenance, usual effective dose is 120-300 mg/day PO; may increase dosage to 400 mg/day after 3 weeks if there is inadequate response and hospitalized patients with no history of convulsive seizures may have the dose raised cautiously up to 600 mg/day in divided doses. Endogenous depression - Initial, 50 mg PO 2-3 times a day; may increase dosage up to 100 mg 2-3 times a day by end of the first week OR may start with 300 mg/day, but notable sedation may occur during the first few days of therapy. - Maintenance, usual effective dose is 120-300 mg/day PO; may increase dosage to 400 mg/day after 3 weeks if there is inadequate response and hospitalized patients with no history of convulsive seizures may have the dose raised cautiously up to 600 mg/day in divided doses. Severe major depression with psychotic features - Initial, 50 mg PO 2-3 times a day; may increase dosage up to 100 mg 2-3 times a day by end of the first week OR may start with 300 mg/day, but notable sedation may occur during the first few days of therapy. - Maintenance, usual effective dose is 120-300 mg/day PO; may increase dosage to 400 mg/day after 3 weeks if there is inadequate response and hospitalized patients with no history of convulsive seizures may have the dose raised cautiously up to 600 mg/day in divided doses. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Amoxapine in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Amoxapine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Depression - Safety and efficacy have not been established in patients younger than 16 years of age. Endogenous depression - Safety and efficacy have not been established in patients younger than 16 years of age. Severe major depression with psychotic features - Safety and efficacy have not been established in patients younger than 16 years of age. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Amoxapine in pediatric patients. ### Non–Guideline-Supported Use - There is limited information about Off-Label Non–Guideline-Supported Use of Amoxapine in pediatric patients. # Contraindications - Prior hypersensitivity to dibenzoxazepine compounds. - It should not be given concomitantly with monoamine oxidase inhibitors. - Hyperpyretic crises, severe convulsions, and deaths have occurred in patients receiving tricyclic antidepressants and monoamine oxidase inhibitors. - When it is desired to replace a monoamine oxidase inhibitor with amoxapine, a minimum of 14 days should be allowed to elapse after the former is discontinued. - Initiated cautiously with gradual increase in dosage. - Not recommended during the acute recovery phase following myocardial infarction. # Warnings ### Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for amoxapine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. ### Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that amoxapine is not approved for use in treating bipolar depression. ### Tardive Dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with neuroleptic (i.e., antipsychotic) drugs. (Amoxapine is not an antipsychotic, but it has substantive neuroleptic activity.) Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of neuroleptic treatment, which patients are likely to develop the syndrome. Whether neuroleptic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of neuroleptic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if neuroleptic treatment is withdrawn. Neuroleptic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, neuroleptics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic neuroleptic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to neuroleptic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on neuroleptics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. ### Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs and with amoxapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include - Immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, - Intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored since recurrences of NMS have been reported. Amoxapine should be used with caution in patients with a history of urinary retention, angle-closure glaucoma, or increased intraocular pressure. Patients with cardiovascular disorders should be watched closely. Tricyclic antidepressant drugs, particularly when given in high doses, can induce sinus tachycardia, changes in conduction time, and arrhythmias. Myocardial infarction and stroke have been reported with drugs of this class. Extreme caution should be used in treating patients with a history of convulsive disorder or those with overt or latent seizure disorders. # Adverse Reactions ## Clinical Trials Experience Central nervous system Cardiovascular Hematologic Gastrointestinal Hypersensitive Reactions Anticholinergic Endocrine Miscellaneous ## Postmarketing Experience There is limited information regarding Amoxapine Postmarketing Experience in the drug label. # Drug Interactions - Drugs Metabolized by P450 2D6 - The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7 to 10% of caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). - In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine, cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). - Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Studies performed in mice, rats, and rabbiats have demonstrated no evidence of teratogenic effect due to amoxapine. Embryotoxicity was seen in rats and rabbits given oral doses approximating the human dose. Fetotoxic effects (intrauterine death, stillbirth, decreased birth weight) were seen in animals studied at oral doses 3-10 times the human dose. Decreased postnatal survival (between days 0-4) was demonstrated in the offspring of rats at 5-10 times the human dose. There are no adequate and well-controlled studies in pregnant women. Amoxapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Amoxapine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Amoxapine during labor and delivery. ### Nursing Mothers Amoxapine, like many other systemic drugs, is excreted in human milk. Because effects of the drug on infants are unknown, caution should be exercised when amoxapine is administered to nursing women. ### Pediatric Use Anyone considering the use of amoxapine in a child or adolescent must balance the potential risks with the clinical need. ### Geriatic Use Clinical studies of amoxapine were not adequate to determine whether subjects aged 65 and over respond differently from younger subjects. Amoxapine is known to be substantially excreted by the kidney.Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered. Greater sensitivity (e.g., tardive dyskinesia, sedation) of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at a lower dose . ### Gender There is no FDA guidance on the use of Amoxapine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Amoxapine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Amoxapine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Amoxapine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Amoxapine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Amoxapine in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Amoxapine Administration in the drug label. ### Monitoring There is limited information regarding Amoxapine Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Amoxapine and IV administrations. # Overdosage There is limited information regarding Amoxapine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action Amoxapine is an antidepressant with mild sedative property and an unknown mechanism of action. It reduces norepinephrine and serotonin uptake and inhibits the response of dopamine receptors to dopamine. It is not an inhibitor of monoamine oxidase ## Structure Amoxapine is an antidepressant of the dibenzoxazepine class, chemically distinct from the dibenzazepines, dibenzocycloheptenes, and dibenzoxepines. It is designated chemically as 2-Chloro-11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine. The structural formula is represented below ## Pharmacodynamics Amoxapine is an antidepressant with a mild sedative component to its action. The mechanism of its clinical action in man is not well understood. In animals, amoxapine reduced the uptake of norepinephrine and serotonin and blocked the response of dopamine receptors to dopamine. Amoxapine is not a monoamine oxidase inhibitor. Amoxapine is absorbed rapidly and reaches peak blood levels approximately 90 minutes after ingestion. It is almost completely metabolized. The main route of excretion is the kidney. In vitro tests show that amoxapine binding to human serum is approximately 90%. In man, amoxapine serum concentration declines with a half-life of eight hours. However, the major metabolite, 8-hydroxyamoxapine, has a biologic half-life of 30 hours. Metabolites are excreted in the urine in conjugated form as glucuronides. Clinical studies have demonstrated that amoxapine has a more rapid onset of action than either amitriptyline or imipramine. The initial clinical effect may occur within four to seven days and occurs within two weeks in over 80% of responders. ## Pharmacokinetics There is limited information regarding Amoxapine Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Amoxapine Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Amoxapine Clinical Studies in the drug label. # How Supplied There is limited information regarding Amoxapine How Supplied in the drug label. ## Storage There is limited information regarding Amoxapine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Amoxapine Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Amoxapine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Amoxapine Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Amoxapine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Amoxapine
2f460c1e49f9a10026aca04c98d28b404b885b9a	wikidoc	Penectomy	Penectomy Penectomy is the surgical removal of the penis for medical reasons. Cancer, for example, sometimes necessitates removal of all or part of the penis. In very rare instances, botched circumcisions have also resulted in full or partial penectomies. Genital surgical procedures for transsexual women undergoing sex reassignment surgery do not usually involve the complete removal of the penis. Instead, part or all of the glans is usually kept and reshaped as a clitoris, while the skin of the penile shaft may also be inverted to form the vagina. When procedures such as this are not possible, other procedures such as colovaginoplasty are used which may involve the removal of the penis. Issues related to the removal of the penis appear in psychology, for example in the condition known as castration anxiety. Others, who associate the organ with rape, male dominance and aggression, may consciously or unconsciously see the organ (their own or those of others) as a weapon and express a hatred for it, potentially desiring to see it violently removed. Some men have undergone penectomies as a voluntary body modification, but professional opinion is divided as to whether or not the desire for penile amputation is a pathology, thus including it as part of a body dysmorphic disorder. Voluntary subincision, removal of the glans penis, and bifurcation of the penis are related topics.	Penectomy Penectomy is the surgical removal of the penis for medical reasons. Cancer, for example, sometimes necessitates removal of all or part of the penis.[1] In very rare instances, botched circumcisions have also resulted in full or partial penectomies. Genital surgical procedures for transsexual women undergoing sex reassignment surgery do not usually involve the complete removal of the penis. Instead, part or all of the glans is usually kept and reshaped as a clitoris, while the skin of the penile shaft may also be inverted to form the vagina. When procedures such as this are not possible, other procedures such as colovaginoplasty are used which may involve the removal of the penis. Issues related to the removal of the penis appear in psychology, for example in the condition known as castration anxiety. Others, who associate the organ with rape, male dominance and aggression, may consciously or unconsciously see the organ (their own or those of others) as a weapon and express a hatred for it, potentially desiring to see it violently removed.[citation needed] Some men have undergone penectomies as a voluntary body modification, but professional opinion is divided as to whether or not the desire for penile amputation is a pathology, thus including it as part of a body dysmorphic disorder. Voluntary subincision, removal of the glans penis, and bifurcation of the penis are related topics.	https://www.wikidoc.org/index.php/Amputation_of_penis
fc19c1780cc84979c61ebe8eb95c34a6632125df	wikidoc	Amrubicin	Amrubicin # Overview Amrubicin (INN; previously known as SM-5887) is an anthracycline used in the treatment of lung cancer. It is marketed in Japan since 2002 by Sumitomo Pharmaceuticals under the brand name Calsed. Amrubicin acts by inhibiting topoisomerase II, and has been compared in clinical trials with topotecan, a Topoisomerase I inhibitor. It has also been studied for the treatment of bladder carcinoma and gastric cancer.	Amrubicin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Amrubicin (INN; previously known as SM-5887) is an anthracycline used in the treatment of lung cancer.[1] It is marketed in Japan since 2002 by Sumitomo Pharmaceuticals under the brand name Calsed.[2] Amrubicin acts by inhibiting topoisomerase II, and has been compared in clinical trials with topotecan, a Topoisomerase I inhibitor.[3] [4] It has also been studied for the treatment of bladder carcinoma[5] and gastric cancer.[6]	https://www.wikidoc.org/index.php/Amrubicin
8782c29c130ff1660245e02f907e8d62f84f6bae	wikidoc	Amy Bloom	Amy Bloom Amy Bloom (b. 1953) is an American writer. She has been nominated for the National Book Award and the National Book Critics Circle Award. In addition to novels, Bloom has written articles in periodicals including The New Yorker, The New York Times Magazine, The Atlantic Monthly, Vogue, Slate, and Salon.com.. Her short fiction has appeared in The Best American Short Stories, The O. Henry Prize Stories and several other anthologies and has won a National Magazine Award.. Trained as a social worker, Bloom has practiced psychotherapy and is currently a part-time lecturer of Creative Writing at the department of English at Yale University.. Although not a psychologist, her involvement with psychotherapy played a role in writing the Lifetime Television network TV show, State of Mind, which takes a look at the professional lives of psychiatrists. Bloom is listed as one of the writers for the series and a co-executive producer . Bloom received her B.A. from Wesleyan University, and a M.S.W. (Masters of Social Work) from Smith College. Bloom is divorced and has two daughters and a son. She resides in Connecticut. # Bibliography ## Fiction - Come to Me: Stories (1993) (short stories) - Love Invents Us (1997) (novel) - A Blind Man Can See How Much I Love You: Stories (2000) (short stories) - Away (2007) (novel) ## Non-fiction - Normal: Transsexual CEOs, Cross-dressing Cops, and Hermaphrodites with Attitude (2002) (Psychology) ## Screenplays, teleplays and television shows - State of Mind (2007)	Amy Bloom Amy Bloom (b. 1953) is an American writer. She has been nominated for the National Book Award and the National Book Critics Circle Award. In addition to novels, Bloom has written articles in periodicals including The New Yorker, The New York Times Magazine, The Atlantic Monthly, Vogue, Slate, and Salon.com.[1]. Her short fiction has appeared in The Best American Short Stories, The O. Henry Prize Stories and several other anthologies and has won a National Magazine Award.[2]. Trained as a social worker, Bloom has practiced psychotherapy and is currently a part-time lecturer of Creative Writing at the department of English at Yale University.[3]. Although not a psychologist, her involvement with psychotherapy played a role in writing the Lifetime Television network TV show, State of Mind, which takes a look at the professional lives of psychiatrists. Bloom is listed as one of the writers for the series and a co-executive producer [4]. Bloom received her B.A. from Wesleyan University, and a M.S.W. (Masters of Social Work) from Smith College.[5] Bloom is divorced and has two daughters and a son. She resides in Connecticut. # Bibliography ## Fiction - Come to Me: Stories (1993) (short stories) - Love Invents Us (1997) (novel) - A Blind Man Can See How Much I Love You: Stories (2000) (short stories) - Away (2007) (novel) ## Non-fiction - Normal: Transsexual CEOs, Cross-dressing Cops, and Hermaphrodites with Attitude (2002) (Psychology) ## Screenplays, teleplays and television shows - State of Mind (2007)	https://www.wikidoc.org/index.php/Amy_Bloom
2da7e0d76e2ca9bdc0c103e600d7be292f8e6a16	wikidoc	Hypotonia	Hypotonia Synonyms and keywords: Muscle flaccidity; decreased muscle tone; flaccid muscle tone; floppy muscles; low muscle tone; benign congenital hypotonia; congenital hypotonia ; congenital muscle hypotonia ; congenital muscle weakness ; amyotonia congenita ; floppy baby syndrome; infantile hypotonia # Overview Hypotonia is a condition of abnormally low muscle tone (the amount of tension or resistance to movement in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength. Recognizing hypotonia, even in early infancy, is usually relatively straightforward, but diagnosing the underlying cause can be difficult and often unsuccessful. The long-term effects of hypotonia on a child's development and later life depend primarily on the severity of the muscle weakness and the nature of the cause. Some disorders have a specific treatment but the principal treatment for most hypotonia of idiopathic or neurologic cause is physical therapy to help the person compensate for the neuromuscular disability. # Causes Some conditions known to cause hypotonia include: Congenital - i.e. present from birth (including genetic disorders presenting within 6 months) - Genetic disorders are the most common cause Down's syndrome - most common 3-Methylcrotonyl-CoA carboxylase deficiency Achondroplasia Aicardi syndrome Canavan disease Centronuclear myopathy (including myotubular myopathy) Familial dysautonomia (Riley-Day syndrome) Infantile spinal muscular atrophy such as Werdnig-Hoffman disease Krabbe disease Leigh's disease Marfan's syndrome Menkes syndrome Methylmalonic acidemia Nonketotic hyperglycinemia (NKH) or Glycine encephalopathy (GCE) Prader-Willi syndrome Tay-Sachs disease Trisomy 13 22q13 deletion syndrome FG syndrome - Down's syndrome - most common - 3-Methylcrotonyl-CoA carboxylase deficiency - Achondroplasia - Aicardi syndrome - Canavan disease - Centronuclear myopathy (including myotubular myopathy) - Familial dysautonomia (Riley-Day syndrome) - Infantile spinal muscular atrophy such as Werdnig-Hoffman disease - Krabbe disease - Leigh's disease - Marfan's syndrome - Menkes syndrome - Methylmalonic acidemia - Nonketotic hyperglycinemia (NKH) or Glycine encephalopathy (GCE) - Prader-Willi syndrome - Tay-Sachs disease - Trisomy 13 - 22q13 deletion syndrome - FG syndrome - Developmental disability Cerebellar ataxia (congenital) Dysfunction in Sensory Integration (DSI) Developmental Dyspraxia Hypothyroidism (congenital) Hypotonic Cerebral palsy Teratogenesis from in utero exposure to Benzodiazepines - Cerebellar ataxia (congenital) - Dysfunction in Sensory Integration (DSI) - Developmental Dyspraxia - Hypothyroidism (congenital) - Hypotonic Cerebral palsy - Teratogenesis from in utero exposure to Benzodiazepines Acquired - i.e. onset occurs after birth - Genetic Muscular dystrophy (including Myotonic dystrophy) - most common Metachromatic leukodystrophy - Muscular dystrophy (including Myotonic dystrophy) - most common - Metachromatic leukodystrophy - Infections Encephalitis Guillian-Barre syndrome Infant botulism Meningitis Poliomyelitis Sepsis - Encephalitis - Guillian-Barre syndrome - Infant botulism - Meningitis - Poliomyelitis - Sepsis - Autoimmunity disorders Myasthenia gravis - most common Abnormal vaccine reaction - Myasthenia gravis - most common - Abnormal vaccine reaction - Metabolic disorder Hypervitaminosis Kernicterus Rickets - Hypervitaminosis - Kernicterus - Rickets - Neurological Traumatic brain injury, such as the damage that is caused by Shaken Baby Syndrome Lower motor neuron lesions Upper motor neuron lesions - Traumatic brain injury, such as the damage that is caused by Shaken Baby Syndrome - Lower motor neuron lesions - Upper motor neuron lesions - Miscellaneous Central nervous system dysfunction, including Cerebellar lesions Hypothyroidism - Central nervous system dysfunction, including Cerebellar lesions - Hypothyroidism ## Common Causes ## Causes by Organ System ## Causes in Alphabetical Order # Signs and objective manifestations Hypotonic patients may display a variety of objective manifestations that indicate decreased muscle tone. Motor skills delay is often observed, along with hypermobile or hyperflexible joints, drooling and speech difficulties, poor reflexes, decreased strength, decreased activity tolerance, rounded shoulder posture, with leaning onto supports, and poor attention and motivation. The extent and occurrence of specific objective manifestations depends upon the age of the patient, the severity of the hypotonia, the specific muscles affected, and sometimes the underlying cause. For instance, some hypotonics may experience constipation, while others have no bowel problems. Since hypotonia is most often diagnosed during infancy, it is also known as "floppy infant syndrome" or "infantile hypotonia." Infants who suffer from hypotonia are often described as feeling and appearing as though they are "rag dolls" or a "sack of jello," easily slipping through one's hands. This image demonstrates the floppiness of a hypotonic infant. They are unable to maintain flexed ligaments, and are able to extend them beyond normal lengths. Often, the movement of the head is uncontrollable, not in the sense of spasmatic movement, but chronic ataxia. Hypotonic infants often have difficulty feeding, as their mouth muscles cannot maintain a proper suck-swallow pattern, or a good breastfeeding latch. ## Developmental delay Children with normal muscle tone are expected to achieve certain physical abilities within an average timeframe after birth. Most low-tone infants have delayed developmental milestones, but the length of delay can vary widely. Motor skills are particularly susceptible to the low-tone disability. They can be divided into two areas, gross motor skills, and fine motor skills, both of which are affected. Hypotonic infants are late in lifting their heads while lying on their stomachs, rolling over, lifting themselves into a sitting position, remaining seated without falling over, balancing, crawling, and walking. Fine motor skills delays occur in grasping a toy or finger, transferring a small object from hand to hand, pointing out objects, following movement with the eyes, and self feeding. Speech difficulties can result from hypotonia. Low-tone children learn to speak later than their peers, even if they appear to understand a large vocabulary, or can obey simple commands. Difficulties with muscles in the mouth and jaw can inhibit proper pronunciation, and discourage experimentation with word combination and sentence-forming. Since the hypotonic condition is actually an objective manifestation of some underlying disorder, it can be difficult to determine whether speech delays are a result of poor muscle tone, or some other neurological condition, such as mental retardation, that may be associated with the cause of hypotonia. ## Muscle tone vs. muscle strength The low muscle tone associated with hypotonia must not be confused with low muscle strength. In body building, good muscle tone is equated with good physical condition, with taut muscles, and a lean appearance, whereas an out-of-shape, overweight individual with fleshy muscles is said to have "poor tone." Neurologically, however, muscle tone cannot be changed under voluntary control, regardless of exercise and diet. In an article by Diane E Gagnon, M.Ed., PT, she explains # Diagnosis "A diagnosis of hypotonia is sometimes considered a form of muscular dystrophy or cerebral palsy, depending on the symptoms and the doctor. If the cause of the hypotonia is thought to lie in the brain, then it might be classified as a cerebral palsy. If the cause seems to be in the muscles, it might be classified as a muscular dystrophy, even though most forms of hypotonia are not seriously dystrophic. If the cause is thought to be in the nerves, it could be classified as either or neither. In any case, hypotonia is rarely an actual muscular dystrophy or cerebral palsy, and is often not classified as either one, or anything at all for that matter." Diagnosing a patient includes obtaining family medical history and a physical examination, and may include such additional tests as computerized tomography (CT) scans, magnetic resonance imaging (MRI) scans, electroencephalogram (EEG), blood tests, genetic testing (such as chromosome karyotyping and tests for specific gene abnormalities), spinal taps, electromyography muscle tests, or muscle and nerve biopsy. Mild or benign hypotonia is often diagnosed by physical and occupational therapists through a series of exercises designed to assess developmental progress, or observation of physical interactions. Since a hypotonic child has difficulty deciphering his spatial location, he may have some recognizable coping mechanisms, such as locking the knees while attempting to walk. A common sign of low-tone infants is a tendency to observe the physical activity of those around them for a long time before attempting to imitate, due to frustration over early failures. Developmental delay can indicate hypotonia. # Differential diagnosis # Prognosis and treatment There is currently no known treatment or cure for most (or perhaps all) causes of hypotonia, and objective manifestations can be life long. The outcome in any particular case of hypotonia depends largely on the nature of the underlying disease. In some cases, muscle tone improves over time, or the patient may learn or devise coping mechanisms that enable him to overcome the most disabling aspects of the disorder. However, hypotonia caused by cerebellar dysfunction or motor neuron diseases can be progressive and life-threatening. Along with normal pediatric care, specialists who may be involved in the care of a child with hypotonia include developmental pediatricians (specialize in child development), neurologists, neonatologists (specialize in the care of newborns), geneticists, occupational therapists, physical therapists, speech therapists, orthopedists, pathologists (conduct and interpret biochemical tests and tissue analysis), and specialized nursing care. If the underlying cause is known, treatment is tailored to the specific disease, followed by symptomatic and supportive therapy for the hypotonia. In very severe cases, treatment may be primarily supportive, such as mechanical assistance with basic life functions like breathing and feeding, physical therapy to prevent muscle atrophy and maintain joint mobility, and measures to try and prevent opportunistic infections such as pneumonia. Treatments to improve neurological status might involve such things as medication for a seizure disorder, medicines or supplements to stabilize a metabolic disorder, or surgery to help relieve the pressure from hydrocephalus (increased fluid in the brain). For most hypotonics, the National Institute of Health recommends "physical therapy improve motor control and overall body strength. Occupational therapy to assist with fine motor skill development and hand control, and speech-language therapy can help breathing, speech, and swallowing difficulties. Therapy for infants and young children may also include sensory stimulation programs." Ankle/foot orthoses are sometimes used for weak ankle muscles. Toddlers and children with speech difficulties may benefit greatly by using sign language. ## Breastfeeding Low-tone infants often have difficulty feeding, especially coordinating the suck-swallow reflex required for proper breastfeeding. Early diagnosis of hypotonic newborns can help mothers find the support and information they need to establish a successful breastfeeding relationship. Hypotonic babies may take longer to breastfeed because of the poor timing of sucking bursts and the need for long rests. If feeding is inefficient, they will also require greater feeding frequency. A baby with low muscle tone may suck better when the head and bottom are level, indicating pillow support in the lap. If the infant tends to arch his back, it may be helpful to swaddle the child loosely with arms drawn across the chest and legs drawn up toward the belly with a rounded spine during feedings. It may be necessary to support the infant's chin with one's hand if jaw, ear, and temple movement are not observed. If the baby tolerates touch to the mouth and face, the mother might gently rub the baby's lips and the outer surface of the gums to stimulate muscle sensitivity before beginning feeding. "If the tongue does not have the tone, strength, or range of motion to lift and press the breast against the palate (roof of the mouth), the baby might compensate by pressing more with his jaws. This excessive compression is painful for the mother. Getting a deeper latch, making sure the baby is not tongue-tied, and using an asymmetrical latch to increase the amount of tongue in contact with the breast can all be helpful to reduce compression." Finally, if nursing is too frustrating and stressful for mother and child, breast milk can be expressed by use of a breast pump and fed through a bottle. Positions which allow for better drainage of the breast through the help of gravity or manual expressing/massage while the baby is nursing may improve milk intake at the breast. Proper latch can be taught/encouraged by reinforcing appropriate mouth/tongue movements with massage of the breast to increase flow. Taking extra time with feeds is helpful. Many low-tone babies have a hard time with the coordination of sucking, swallowing and breathing and taking frequent short breaks may be helpful. Exclusive feeding of breastmilk, especially for infants who have frequent bouts of gagging due to poor coordination, can be helpful in avoiding some of the sequelae of aspiration of formula. Breastmilk is less irritating to the lungs and less likely to cause infection if aspirated. When weighing the benefits vs. risks of formula supplementation to encourage weight gain, the possibility of aspiration should be considered. It may be better to have a little slower gain and avoid the risk of non-breastmilk fluids being aspirated. # Related Chapters - Hypertonia - Atonia	Hypotonia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Synonyms and keywords: Muscle flaccidity; decreased muscle tone; flaccid muscle tone; floppy muscles; low muscle tone; benign congenital hypotonia; congenital hypotonia ; congenital muscle hypotonia ; congenital muscle weakness ; amyotonia congenita ; floppy baby syndrome; infantile hypotonia # Overview Hypotonia is a condition of abnormally low muscle tone (the amount of tension or resistance to movement in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength. Recognizing hypotonia, even in early infancy, is usually relatively straightforward, but diagnosing the underlying cause can be difficult and often unsuccessful. The long-term effects of hypotonia on a child's development and later life depend primarily on the severity of the muscle weakness and the nature of the cause. Some disorders have a specific treatment but the principal treatment for most hypotonia of idiopathic or neurologic cause is physical therapy to help the person compensate for the neuromuscular disability. # Causes Some conditions known to cause hypotonia include: Congenital - i.e. present from birth (including genetic disorders presenting within 6 months) - Genetic disorders are the most common cause Down's syndrome - most common 3-Methylcrotonyl-CoA carboxylase deficiency [1] Achondroplasia Aicardi syndrome Canavan disease Centronuclear myopathy (including myotubular myopathy) Familial dysautonomia (Riley-Day syndrome) Infantile spinal muscular atrophy such as Werdnig-Hoffman disease Krabbe disease Leigh's disease Marfan's syndrome Menkes syndrome Methylmalonic acidemia Nonketotic hyperglycinemia (NKH) or Glycine encephalopathy (GCE) Prader-Willi syndrome Tay-Sachs disease Trisomy 13 22q13 deletion syndrome FG syndrome - Down's syndrome - most common - 3-Methylcrotonyl-CoA carboxylase deficiency [1] - Achondroplasia - Aicardi syndrome - Canavan disease - Centronuclear myopathy (including myotubular myopathy) - Familial dysautonomia (Riley-Day syndrome) - Infantile spinal muscular atrophy such as Werdnig-Hoffman disease - Krabbe disease - Leigh's disease - Marfan's syndrome - Menkes syndrome - Methylmalonic acidemia - Nonketotic hyperglycinemia (NKH) or Glycine encephalopathy (GCE) - Prader-Willi syndrome - Tay-Sachs disease - Trisomy 13 - 22q13 deletion syndrome - FG syndrome - Developmental disability Cerebellar ataxia (congenital) Dysfunction in Sensory Integration (DSI) Developmental Dyspraxia Hypothyroidism (congenital) Hypotonic Cerebral palsy Teratogenesis from in utero exposure to Benzodiazepines - Cerebellar ataxia (congenital) - Dysfunction in Sensory Integration (DSI) - Developmental Dyspraxia - Hypothyroidism (congenital) - Hypotonic Cerebral palsy - Teratogenesis from in utero exposure to Benzodiazepines Acquired - i.e. onset occurs after birth - Genetic Muscular dystrophy (including Myotonic dystrophy) - most common Metachromatic leukodystrophy - Muscular dystrophy (including Myotonic dystrophy) - most common - Metachromatic leukodystrophy - Infections Encephalitis Guillian-Barre syndrome Infant botulism Meningitis Poliomyelitis Sepsis - Encephalitis - Guillian-Barre syndrome - Infant botulism - Meningitis - Poliomyelitis - Sepsis - Autoimmunity disorders Myasthenia gravis - most common Abnormal vaccine reaction - Myasthenia gravis - most common - Abnormal vaccine reaction - Metabolic disorder Hypervitaminosis Kernicterus Rickets - Hypervitaminosis - Kernicterus - Rickets - Neurological Traumatic brain injury, such as the damage that is caused by Shaken Baby Syndrome Lower motor neuron lesions Upper motor neuron lesions - Traumatic brain injury, such as the damage that is caused by Shaken Baby Syndrome - Lower motor neuron lesions - Upper motor neuron lesions - Miscellaneous Central nervous system dysfunction, including Cerebellar lesions Hypothyroidism - Central nervous system dysfunction, including Cerebellar lesions - Hypothyroidism ## Common Causes ## Causes by Organ System ## Causes in Alphabetical Order # Signs and objective manifestations Hypotonic patients may display a variety of objective manifestations that indicate decreased muscle tone. Motor skills delay is often observed, along with hypermobile or hyperflexible joints, drooling and speech difficulties, poor reflexes, decreased strength, decreased activity tolerance, rounded shoulder posture, with leaning onto supports, and poor attention and motivation. The extent and occurrence of specific objective manifestations depends upon the age of the patient, the severity of the hypotonia, the specific muscles affected, and sometimes the underlying cause. For instance, some hypotonics may experience constipation, while others have no bowel problems. Since hypotonia is most often diagnosed during infancy, it is also known as "floppy infant syndrome" or "infantile hypotonia." Infants who suffer from hypotonia are often described as feeling and appearing as though they are "rag dolls" or a "sack of jello," easily slipping through one's hands. This image demonstrates the floppiness of a hypotonic infant. They are unable to maintain flexed ligaments, and are able to extend them beyond normal lengths. Often, the movement of the head is uncontrollable, not in the sense of spasmatic movement, but chronic ataxia. Hypotonic infants often have difficulty feeding, as their mouth muscles cannot maintain a proper suck-swallow pattern, or a good breastfeeding latch. ## Developmental delay Children with normal muscle tone are expected to achieve certain physical abilities within an average timeframe after birth. Most low-tone infants have delayed developmental milestones, but the length of delay can vary widely. Motor skills are particularly susceptible to the low-tone disability. They can be divided into two areas, gross motor skills, and fine motor skills, both of which are affected. Hypotonic infants are late in lifting their heads while lying on their stomachs, rolling over, lifting themselves into a sitting position, remaining seated without falling over, balancing, crawling, and walking. Fine motor skills delays occur in grasping a toy or finger, transferring a small object from hand to hand, pointing out objects, following movement with the eyes, and self feeding. Speech difficulties can result from hypotonia. Low-tone children learn to speak later than their peers, even if they appear to understand a large vocabulary, or can obey simple commands. Difficulties with muscles in the mouth and jaw can inhibit proper pronunciation, and discourage experimentation with word combination and sentence-forming. Since the hypotonic condition is actually an objective manifestation of some underlying disorder, it can be difficult to determine whether speech delays are a result of poor muscle tone, or some other neurological condition, such as mental retardation, that may be associated with the cause of hypotonia. ## Muscle tone vs. muscle strength The low muscle tone associated with hypotonia must not be confused with low muscle strength. In body building, good muscle tone is equated with good physical condition, with taut muscles, and a lean appearance, whereas an out-of-shape, overweight individual with fleshy muscles is said to have "poor tone." Neurologically, however, muscle tone cannot be changed under voluntary control, regardless of exercise and diet. In an article by Diane E Gagnon, M.Ed., PT,[2] she explains # Diagnosis "A diagnosis of hypotonia is sometimes considered a form of muscular dystrophy or cerebral palsy, depending on the symptoms and the doctor. If the cause of the hypotonia is thought to lie in the brain, then it might be classified as a cerebral palsy. If the cause seems to be in the muscles, it might be classified as a muscular dystrophy, even though most forms of hypotonia are not seriously dystrophic. If the cause is thought to be in the nerves, it could be classified as either or neither. In any case, hypotonia is rarely an actual muscular dystrophy or cerebral palsy, and is often not classified as either one, or anything at all for that matter."[3] Diagnosing a patient includes obtaining family medical history and a physical examination, and may include such additional tests as computerized tomography (CT) scans, magnetic resonance imaging (MRI) scans, electroencephalogram (EEG), blood tests, genetic testing (such as chromosome karyotyping and tests for specific gene abnormalities), spinal taps, electromyography muscle tests, or muscle and nerve biopsy. Mild or benign hypotonia is often diagnosed by physical and occupational therapists through a series of exercises designed to assess developmental progress, or observation of physical interactions. Since a hypotonic child has difficulty deciphering his spatial location, he may have some recognizable coping mechanisms, such as locking the knees while attempting to walk. A common sign of low-tone infants is a tendency to observe the physical activity of those around them for a long time before attempting to imitate, due to frustration over early failures. Developmental delay can indicate hypotonia. # Differential diagnosis # Prognosis and treatment There is currently no known treatment or cure for most (or perhaps all) causes of hypotonia, and objective manifestations can be life long. The outcome in any particular case of hypotonia depends largely on the nature of the underlying disease. In some cases, muscle tone improves over time, or the patient may learn or devise coping mechanisms that enable him to overcome the most disabling aspects of the disorder. However, hypotonia caused by cerebellar dysfunction or motor neuron diseases can be progressive and life-threatening. Along with normal pediatric care, specialists who may be involved in the care of a child with hypotonia include developmental pediatricians (specialize in child development), neurologists, neonatologists (specialize in the care of newborns), geneticists, occupational therapists, physical therapists, speech therapists, orthopedists, pathologists (conduct and interpret biochemical tests and tissue analysis), and specialized nursing care. If the underlying cause is known, treatment is tailored to the specific disease, followed by symptomatic and supportive therapy for the hypotonia. In very severe cases, treatment may be primarily supportive, such as mechanical assistance with basic life functions like breathing and feeding, physical therapy to prevent muscle atrophy and maintain joint mobility, and measures to try and prevent opportunistic infections such as pneumonia. Treatments to improve neurological status might involve such things as medication for a seizure disorder, medicines or supplements to stabilize a metabolic disorder, or surgery to help relieve the pressure from hydrocephalus (increased fluid in the brain). For most hypotonics, the National Institute of Health recommends "physical therapy [to] improve motor control and overall body strength. Occupational therapy to assist with fine motor skill development and hand control, and speech-language therapy can help breathing, speech, and swallowing difficulties. Therapy for infants and young children may also include sensory stimulation programs." Ankle/foot orthoses are sometimes used for weak ankle muscles. Toddlers and children with speech difficulties may benefit greatly by using sign language. ## Breastfeeding Low-tone infants often have difficulty feeding, especially coordinating the suck-swallow reflex required for proper breastfeeding.[22] Early diagnosis of hypotonic newborns can help mothers find the support and information they need to establish a successful breastfeeding relationship. Hypotonic babies may take longer to breastfeed because of the poor timing of sucking bursts and the need for long rests. If feeding is inefficient, they will also require greater feeding frequency. A baby with low muscle tone may suck better when the head and bottom are level, indicating pillow support in the lap. If the infant tends to arch his back, it may be helpful to swaddle the child loosely with arms drawn across the chest and legs drawn up toward the belly with a rounded spine during feedings. It may be necessary to support the infant's chin with one's hand if jaw, ear, and temple movement are not observed. If the baby tolerates touch to the mouth and face, the mother might gently rub the baby's lips and the outer surface of the gums to stimulate muscle sensitivity before beginning feeding. "If the tongue does not have the tone, strength, or range of motion to lift and press the breast against the palate (roof of the mouth), the baby might compensate by pressing more with his jaws. This excessive compression is painful for the mother. Getting a deeper latch, making sure the baby is not tongue-tied, and using an asymmetrical latch to increase the amount of tongue in contact with the breast can all be helpful to reduce compression." [23] Finally, if nursing is too frustrating and stressful for mother and child, breast milk can be expressed by use of a breast pump and fed through a bottle. Positions which allow for better drainage of the breast through the help of gravity or manual expressing/massage while the baby is nursing may improve milk intake at the breast. Proper latch can be taught/encouraged by reinforcing appropriate mouth/tongue movements with massage of the breast to increase flow. Taking extra time with feeds is helpful. Many low-tone babies have a hard time with the coordination of sucking, swallowing and breathing and taking frequent short breaks may be helpful. Exclusive feeding of breastmilk, especially for infants who have frequent bouts of gagging due to poor coordination, can be helpful in avoiding some of the sequelae of aspiration of formula. Breastmilk is less irritating to the lungs and less likely to cause infection if aspirated. When weighing the benefits vs. risks of formula supplementation to encourage weight gain, the possibility of aspiration should be considered. It may be better to have a little slower gain and avoid the risk of non-breastmilk fluids being aspirated. # Related Chapters - Hypertonia - Atonia	https://www.wikidoc.org/index.php/Amyotonia_congenita
9bf7e3e4a753e36e2a62a154dbcbeb8d428f8525	wikidoc	Anabasine	Anabasine Anabasine is a pyridine alkaloid found in the stem of the (Nicotiana glauca) plant, a close relative of (Nicotiana tabacum) the common tobacco plant. # Effects Anabasine is present in trace amounts in tobacco smoke. In larger amounts it is thought to be teratogenic in swine. # Pharmacology Pharmacodynamics: Anabasine is a nicotinic receptor agonist toxin and cholinesterase inhibitor which acts upon the nicotinic acetylcholine receptors. Anabasine is a minor tobacco alkaloid which can be used as an indicator of a person's exposure to tobacco smoke. In high doses, anabasine will cause a depolarizing block of the nicotinic acetylcholine receptor, which can cause death by asystolia and toxicity. As such, its principal industrial use is as an insecticide. Anabasine was also extensively investigated by the US Navy as part of Project CHATTER as a potential truth drug. # Toxicology As anabasine lacks the imine double bond of anabaseine, which significantly more toxic in mouse bioassay than S-anabasine (27-fold) and R-anabasine (18-fold). The relative agonistic potencies of the three alkaloids on human fetal nicotinic neuromuscular receptors were of the same rank order: anabaseine >> S-anabasine > R-anabasine. A mouse bioassay was used to determine the relative lethalities of S- and R-enriched anabasine enantiomers. The intravenous LD50 of the (+)-R-anabasine rich fraction was 11±1.0 mg/kg and that of the (-)-S-anabasine-rich fraction was 16±1.0 mg/kg. The LD50 of anabaseine was 0.58±0.05 mg/kg. Anabaseine was significantly more toxic in the mouse bioassay than S-anabasine (27-fold) and R-anabasine (18-fold). The relative agonistic potencies of the three alkaloids on human fetal nicotinic neuromuscular receptors were of the same rank order: anabaseine >> S-anabasine > R-anabasine.	Anabasine Template:Chembox new Anabasine is a pyridine alkaloid found in the stem of the (Nicotiana glauca) plant, a close relative of (Nicotiana tabacum) the common tobacco plant. # Effects Anabasine is present in trace amounts in tobacco smoke. In larger amounts it is thought to be teratogenic in swine. [1] Template:Cleanup-remainder # Pharmacology Pharmacodynamics: Anabasine is a nicotinic receptor agonist toxin and cholinesterase inhibitor which acts upon the nicotinic acetylcholine receptors. [2] Anabasine is a minor tobacco alkaloid which can be used as an indicator of a person's exposure to tobacco smoke.[1] In high doses, anabasine will cause a depolarizing block of the nicotinic acetylcholine receptor, which can cause death by asystolia and toxicity.[2] As such, its principal industrial use is as an insecticide. Anabasine was also extensively investigated by the US Navy as part of Project CHATTER as a potential truth drug. [3] # Toxicology As anabasine lacks the imine double bond of anabaseine, which significantly more toxic in mouse bioassay than S-anabasine (27-fold) and R-anabasine (18-fold). The relative agonistic potencies of the three alkaloids on human fetal nicotinic neuromuscular receptors were of the same rank order: anabaseine >> S-anabasine > R-anabasine. [4] A mouse bioassay was used to determine the relative lethalities of S- and R-enriched anabasine enantiomers. The intravenous LD50 of the (+)-R-anabasine rich fraction was 11±1.0 mg/kg and that of the (-)-S-anabasine-rich fraction was 16±1.0 mg/kg. The LD50 of anabaseine was 0.58±0.05 mg/kg. Anabaseine was significantly more toxic in the mouse bioassay than S-anabasine (27-fold) and R-anabasine (18-fold). The relative agonistic potencies of the three alkaloids on human fetal nicotinic neuromuscular receptors were of the same rank order: anabaseine >> S-anabasine > R-anabasine. [5]	https://www.wikidoc.org/index.php/Anabasine
8b76fac063b332249cc099bf43328c3865a82394	wikidoc	Anabolism	Anabolism Anabolism is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy. One way of categorizing metabolic processes, whether at the cellular, organ or organism level is as 'anabolic' or 'catabolic', which is the opposite. Anabolism is powered by catabolism, where large molecules are broken down into smaller parts and then used up in respiration. Many anabolic processes are powered by adenosine triphosphate (ATP). Anabolic processes tend toward "building up" organs and tissues. These processes produce growth and differentiation of cells and increase in body size, a process that involves synthesis of complex molecules. Examples of anabolic processes include growth and mineralization of bone and increase of muscle mass. Endocrinologists have traditionally classified hormones as anabolic or catabolic, depending on which part of metabolism they stimulate. The classic anabolic hormones are the anabolic steroids, which stimulate protein synthesis and muscle growth. # Classic anabolic hormones - Growth hormone - IGF1 and other insulin-like growth factors - Insulin - Testosterone - Oestrogen Newer hormones associated with the balance of the catabolic and anabolic states include - Orexin and Hypocretin (a hormone pair) - Melatonin	Anabolism Template:Otheruses4 Anabolism is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy. One way of categorizing metabolic processes, whether at the cellular, organ or organism level is as 'anabolic' or 'catabolic', which is the opposite. Anabolism is powered by catabolism, where large molecules are broken down into smaller parts and then used up in respiration. Many anabolic processes are powered by adenosine triphosphate (ATP). Anabolic processes tend toward "building up" organs and tissues. These processes produce growth and differentiation of cells and increase in body size, a process that involves synthesis of complex molecules. Examples of anabolic processes include growth and mineralization of bone and increase of muscle mass. Endocrinologists have traditionally classified hormones as anabolic or catabolic, depending on which part of metabolism they stimulate. The classic anabolic hormones are the anabolic steroids, which stimulate protein synthesis and muscle growth. # Classic anabolic hormones - Growth hormone - IGF1 and other insulin-like growth factors - Insulin - Testosterone - Oestrogen Newer hormones associated with the balance of the catabolic and anabolic states include - Orexin and Hypocretin (a hormone pair) - Melatonin	https://www.wikidoc.org/index.php/Anabolic
cb7bde147e8f81a3e3a1a02cbce786cb02a0ac79	wikidoc	Analgesic	Analgesic # Overview An analgesic (colloquially known as a painkiller) is any member of the diverse group of drugs used to relieve pain (achieve analgesia). The word analgesic derives from Greek an- ("without") and -algia ("pain"). Analgesic drugs act in various ways on the peripheral and central nervous systems; they include paracetamol (acetaminophen), the non-steroidal anti-inflammatory drugs (NSAIDs) such as the salicylates, narcotic drugs such as morphine, synthetic drugs with narcotic properties such as tramadol, and various others. Some other classes of drugs not normally considered analgesics are used to treat neuropathic pain syndromes; these include tricyclic antidepressants and anticonvulsants. # The major classes ## Paracetamol and NSAIDs The exact mechanism of action of paracetamol/acetaminophen is uncertain, but it appears to be acting centrally. Aspirin and the other NSAIDs inhibit cyclooxygenase, leading to a decrease in prostaglandin production; this reduces pain and also inflammation (in contrast to paracetamol and the opioids). Paracetamol has few side effects, but dosing is limited by possible hepatotoxicity (potential for liver damage). NSAIDs may predispose to peptic ulcers, renal failure, allergic reactions, and hearing loss. They may also increase the risk of hemorrhage by affecting platelet function. The use of certain NSAIDs in children under 16 suffering from viral illness may contribute to Reye's syndrome. ## COX-2 inhibitors These drugs have been derived from NSAIDs. The cyclooxygenase enzyme inhibited by NSAIDs was discovered to have at least 2 different versions: COX1 and COX2. Research suggested that most of the adverse effects of NSAIDs were mediated by blocking the COX1 (constitutive) enzyme, with the analgesic effects being mediated by the COX2 (inducible) enzyme. The COX2 inhibitors were thus developed to inhibit only the COX2 enzyme (traditional NSAIDs block both versions in general). These drugs (such as rofecoxib and celecoxib) are equally effective analgesics when compared with NSAIDs, but cause less gastrointestinal hemorrhage in particular. However, post-launch data indicated increased risk of cardiac and cerebrovascular events with these drugs due to an increased liklyhood of clotting in the blood due to a decrease in the production of protoglandin around the platelets causing less clotting factor to be released, and rofecoxib was subsequently withdrawn from the market. The role for this class of drug is currently hotly debated. ## Opiates and morphinomimetics Morphine, the archetypal opioid, and various other substances (e.g. codeine, oxycodone, hydrocodone, diamorphine, pethidine) all exert a similar influence on the cerebral opioid receptor system. Tramadol and buprenorphine are thought to be partial agonists of the opioid receptors. Dosing of all opioids may be limited by opioid toxicity (confusion, respiratory depression, myoclonic jerks and pinpoint pupils), but there is no dose ceiling in patients who tolerate this. Opioids, while very effective analgesics, may have some unpleasant side-effects. Up to 1 in 3 patients starting morphine may experience nausea and vomiting (generally relieved by a short course of antiemetics). Pruritus (itching) may require switching to a different opioid. Constipation occurs in almost all patients on opioids, and laxatives (lactulose, macrogol-containing or co-danthramer) are typically co-prescribed. When used appropriately, opioids and similar narcotic analgesics are otherwise safe and effective, however risks such as addiction and the body becoming used to the drug can occur. Due to the body getting used to the drug often the dose must be increased if it is for a chronic disease this is where the no ceiling limit of the drug comes into play. However what must be remembered is although there is no upper limit there is a still a toxic dose even if the body has become used to lower doses. ## Specific agents In patients with chronic or neuropathic pain, various other substances may have analgesic properties. Tricyclic antidepressants, especially amitriptyline, have been shown to improve pain in what appears to be a central manner. The exact mechanism of carbamazepine, gabapentin and pregabalin is similarly unclear, but these anticonvulsants are used to treat neuropathic pain with modest success. # Specific forms and uses ## Combinations Analgesics are frequently used in combination, such as the paracetamol and codeine preparations found in many non-prescription pain relievers. They can also be found in combination with vasoconstrictor drugs such as pseudoephedrine for sinus-related preparations, or with antihistamine drugs for allergy sufferers. The use of paracetamol, as well as aspirin, ibuprofen, naproxen, and other NSAIDS concurrently with weak to mid-range opiates (up to about the hydrocodone level) has been shown to have beneficial synergistic effects by combating pain at multiple sites of action—NSAIDs reduce inflammation which, in some cases, is the cause of the pain itself while opiates dull the perception of pain—thus, in cases of mild to moderate pain caused in part by inflammation, it is generally recommended that the two be prescribed together. ## Topical or systemic Topical analgesia is generally recommended to avoid systemic side-effects. Painful joints, for example, may be treated with an ibuprofen- or diclofenac-containing gel; capsaicin also is used topically. Lidocaine, an anesthetic, and steroids may be injected into painful joints for longer-term pain relief. Lidocaine is also used for painful mouth sores and to numb areas for dental work and minor medical procedures. ## Psychotropic agents Tetrahydrocannabinol (THC) and some other cannabinoids, either from the Cannabis sativa plant or synthetic, have analgesic properties, although the use of cannabis derivatives is illegal in many countries. Other psychotropic analgesic agents include ketamine (an NMDA receptor antagonist), clonidine and other α2-adrenoreceptor agonists, and mexiletine and other local anaesthetic analogues. ## Atypical and/or adjuvant analgesics Orphenadrine, cyclobenzaprine, scopolamine, atropine, gabapentin, first-generation antidepressants and other drugs possessing anticholinergic and/or antispasmodic properties are used in many cases along with analgesics to potentiate centrally acting analgesics such as opioids when used against pain especially of neuropathic origin and to modulate the effects of many other types of analgesics by action in the parasympathetic nervous system. Dextromethorphan has been noted to slow the development of tolerance to opioids and exert additional analgesia by acting upon the NMDA receptors; some analgesics such as methadone and ketobemidone and perhaps piritramide have intrinsic NMDA action. The use of adjuvant analgesics is an important and growing part of the pain-control field and new discoveries are made practically every year. Many of these drugs combat the side effects of opioid analgesics, an added bonus. For example, antihistamines including orphenadrine combat the release of histamine caused by many opioids, methylphenidate, caffeine, ephedrine, dextroamphetamine, and cocaine work against heavy sedation and may elevate mood in distressed patients as do the antidepressants. A well-accepted benefit of THC to chronic pain patients on opioids is its superior anti-nauseant action. However, it would make more sense to use the Marinol capsule, or oral, rectal, or vapour administration of hash oil, rather than smoking cannabis, for the same reasons most doctors advise against smoking tobacco. # Addiction In the United States in recent years, there has been a wave of new addictions to prescription narcotics such as oxycodone (such as OxyContin, or with acetaminophen, as Percocet) and hydrocodone (commonly prescribed with acetaminophen, as in Vicodin, Lortab etc.) when available in pure formulations as opposed to combined with other medications (as in Percocet which contains both oxycodone and acetaminophen/paracetamol). Hydrocodone is only available in pure form in some European countries as the original hydrocodone pharmaceutical, Dicodid tablets. Far from reducing addiction liability, the paracetamol content of many codeine, dihydrocodeine, hydrocodone, and oxycodone pharmaceuticals in the United States only saddles users with the high risk of severe liver damage, and extraction of the opioids with cold water or solvents reduces this problem for the sophisticated abuser, self-medicator, and legitimate prescription holder alike .	Analgesic Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview An analgesic (colloquially known as a painkiller) is any member of the diverse group of drugs used to relieve pain (achieve analgesia). The word analgesic derives from Greek an- ("without") and -algia ("pain"). Analgesic drugs act in various ways on the peripheral and central nervous systems; they include paracetamol (acetaminophen), the non-steroidal anti-inflammatory drugs (NSAIDs) such as the salicylates, narcotic drugs such as morphine, synthetic drugs with narcotic properties such as tramadol, and various others. Some other classes of drugs not normally considered analgesics are used to treat neuropathic pain syndromes; these include tricyclic antidepressants and anticonvulsants. # The major classes ## Paracetamol and NSAIDs The exact mechanism of action of paracetamol/acetaminophen is uncertain, but it appears to be acting centrally. Aspirin and the other NSAIDs inhibit cyclooxygenase, leading to a decrease in prostaglandin production; this reduces pain and also inflammation (in contrast to paracetamol and the opioids). Paracetamol has few side effects, but dosing is limited by possible hepatotoxicity (potential for liver damage). NSAIDs may predispose to peptic ulcers, renal failure, allergic reactions, and hearing loss. They may also increase the risk of hemorrhage by affecting platelet function. The use of certain NSAIDs in children under 16 suffering from viral illness may contribute to Reye's syndrome. ## COX-2 inhibitors These drugs have been derived from NSAIDs. The cyclooxygenase enzyme inhibited by NSAIDs was discovered to have at least 2 different versions: COX1 and COX2. Research suggested that most of the adverse effects of NSAIDs were mediated by blocking the COX1 (constitutive) enzyme, with the analgesic effects being mediated by the COX2 (inducible) enzyme. The COX2 inhibitors were thus developed to inhibit only the COX2 enzyme (traditional NSAIDs block both versions in general). These drugs (such as rofecoxib and celecoxib) are equally effective analgesics when compared with NSAIDs, but cause less gastrointestinal hemorrhage in particular. However, post-launch data indicated increased risk of cardiac and cerebrovascular events with these drugs due to an increased liklyhood of clotting in the blood due to a decrease in the production of protoglandin around the platelets causing less clotting factor to be released, and rofecoxib was subsequently withdrawn from the market. The role for this class of drug is currently hotly debated. ## Opiates and morphinomimetics Morphine, the archetypal opioid, and various other substances (e.g. codeine, oxycodone, hydrocodone, diamorphine, pethidine) all exert a similar influence on the cerebral opioid receptor system. Tramadol and buprenorphine are thought to be partial agonists of the opioid receptors. Dosing of all opioids may be limited by opioid toxicity (confusion, respiratory depression, myoclonic jerks and pinpoint pupils), but there is no dose ceiling in patients who tolerate this. Opioids, while very effective analgesics, may have some unpleasant side-effects. Up to 1 in 3 patients starting morphine may experience nausea and vomiting (generally relieved by a short course of antiemetics). Pruritus (itching) may require switching to a different opioid. Constipation occurs in almost all patients on opioids, and laxatives (lactulose, macrogol-containing or co-danthramer) are typically co-prescribed. When used appropriately, opioids and similar narcotic analgesics are otherwise safe and effective, however risks such as addiction and the body becoming used to the drug can occur. Due to the body getting used to the drug often the dose must be increased if it is for a chronic disease this is where the no ceiling limit of the drug comes into play. However what must be remembered is although there is no upper limit there is a still a toxic dose even if the body has become used to lower doses. ## Specific agents In patients with chronic or neuropathic pain, various other substances may have analgesic properties. Tricyclic antidepressants, especially amitriptyline, have been shown to improve pain in what appears to be a central manner. The exact mechanism of carbamazepine, gabapentin and pregabalin is similarly unclear, but these anticonvulsants are used to treat neuropathic pain with modest success. # Specific forms and uses ## Combinations Analgesics are frequently used in combination, such as the paracetamol and codeine preparations found in many non-prescription pain relievers. They can also be found in combination with vasoconstrictor drugs such as pseudoephedrine for sinus-related preparations, or with antihistamine drugs for allergy sufferers. The use of paracetamol, as well as aspirin, ibuprofen, naproxen, and other NSAIDS concurrently with weak to mid-range opiates (up to about the hydrocodone level) has been shown to have beneficial synergistic effects by combating pain at multiple sites of action—NSAIDs reduce inflammation which, in some cases, is the cause of the pain itself while opiates dull the perception of pain—thus, in cases of mild to moderate pain caused in part by inflammation, it is generally recommended that the two be prescribed together.[2] ## Topical or systemic Topical analgesia is generally recommended to avoid systemic side-effects. Painful joints, for example, may be treated with an ibuprofen- or diclofenac-containing gel; capsaicin also is used topically. Lidocaine, an anesthetic, and steroids may be injected into painful joints for longer-term pain relief. Lidocaine is also used for painful mouth sores and to numb areas for dental work and minor medical procedures. ## Psychotropic agents Tetrahydrocannabinol (THC) and some other cannabinoids, either from the Cannabis sativa plant or synthetic, have analgesic properties, although the use of cannabis derivatives is illegal in many countries. Other psychotropic analgesic agents include ketamine (an NMDA receptor antagonist), clonidine and other α2-adrenoreceptor agonists, and mexiletine and other local anaesthetic analogues. ## Atypical and/or adjuvant analgesics Orphenadrine, cyclobenzaprine, scopolamine, atropine, gabapentin, first-generation antidepressants and other drugs possessing anticholinergic and/or antispasmodic properties are used in many cases along with analgesics to potentiate centrally acting analgesics such as opioids when used against pain especially of neuropathic origin and to modulate the effects of many other types of analgesics by action in the parasympathetic nervous system. Dextromethorphan has been noted to slow the development of tolerance to opioids and exert additional analgesia by acting upon the NMDA receptors; some analgesics such as methadone and ketobemidone and perhaps piritramide have intrinsic NMDA action. The use of adjuvant analgesics is an important and growing part of the pain-control field and new discoveries are made practically every year. Many of these drugs combat the side effects of opioid analgesics, an added bonus. For example, antihistamines including orphenadrine combat the release of histamine caused by many opioids, methylphenidate, caffeine, ephedrine, dextroamphetamine, and cocaine work against heavy sedation and may elevate mood in distressed patients as do the antidepressants. A well-accepted benefit of THC to chronic pain patients on opioids is its superior anti-nauseant action. However, it would make more sense to use the Marinol capsule, or oral, rectal, or vapour administration of hash oil, rather than smoking cannabis, for the same reasons most doctors advise against smoking tobacco. # Addiction In the United States in recent years, there has been a wave of new addictions to prescription narcotics such as oxycodone (such as OxyContin, or with acetaminophen, as Percocet) and hydrocodone (commonly prescribed with acetaminophen, as in Vicodin, Lortab etc.) when available in pure formulations as opposed to combined with other medications (as in Percocet which contains both oxycodone and acetaminophen/paracetamol). Hydrocodone is only available in pure form in some European countries as the original hydrocodone pharmaceutical, Dicodid tablets. Far from reducing addiction liability, the paracetamol content of many codeine, dihydrocodeine, hydrocodone, and oxycodone pharmaceuticals in the United States only saddles users with the high risk of severe liver damage, and extraction of the opioids with cold water or solvents reduces this problem for the sophisticated abuser, self-medicator, and legitimate prescription holder alike [3].	https://www.wikidoc.org/index.php/Analgesia
816bda217bf1549dc13e901a212633a4e4b087df	wikidoc	Capsaicin	Capsaicin # 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. NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies. # Overview Capsaicin is a topical analgesic that is FDA approved for the treatment of for the temporary relief of minor aches and pains of muscles and joints associated with arthritis, simple backache, strains and sprains. Common adverse reactions include erythema, rash, pruritus, nausea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications - For the temporary relief of minor aches and pains of muscles and joints associated with arthritis, simple backache, strains and sprains - For use in treating neuralgias, consult a physician ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use # Indications and Dosage - Arthritis - Pain: topical, apply thin film to the affected area 3 to 4 times per day. - Musculoskeletal pain: topical, apply thin film to the affected area 3 to 4 times per day. - Neuropathic pain, associated with postherpetic neuralgia: (patch) a single 60-minute application of up to 4 patches every 3 months as needed; do not apply more frequently than every 3 months - Psoriasis: apply cream 6 times/day for 3 days, then 4 times/day ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Capsaicin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Capsaicin FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - Safety and effectiveness of capsaicin 8% patch (Qutenza(R)) not established in pediatric patients; consult a physician before using capsaicin cream on patients under 18 years of age ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Capsaicin in pediatric patients. # Contraindications There is limited information regarding Capsaicin Contraindications in the drug label. # Warnings For external use only. Do not apply to wounds or to damaged or irritated skin. When using this product - You may experience a burning sensation which is normal and related to the way the product works. With regular use, this sensation generally disappears within several days. - Do not get it on mucous membranes, into eyes, or on contract lenses. If this occurs, rinse the affected area thoroughly with water. - Do not apply immediately before or after activities such as bathing, swimming, sun bathing, or strenuous exercise. - Do not apply heat to the treated areas immediately before or after use. - Do not tightly wrap or bandage the treated area. - Avoid inhaling airborne material from dried residue. This can result in coughing, sneezing, tearing, throat or respiratory irritation. Stop use and ask a doctor if - Condition worsens or does not improve after regular use. - Blistering occurs. - Difficulty breathing or swallowing occurs. - Severe burning persists. Keep out of reach of children. - If swallowed, get medical help or contact a Poison Control Center immediately. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Capsaicin Clinical Trials Experience in the drug label. ## Postmarketing Experience Common - Dermatologic: Application site erythema (63% ), application site pain (42% ), application site rash (6% ), pruritus,application Site (6% ) - Gastrointestinal: Nausea (5% ) - Respiratory: Nasopharyngitis (4% ) Serious - Cardiovascular: Hypertension (2% ) # Drug Interactions There is limited information regarding Capsaicin Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Capsaicin in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Capsaicin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Capsaicin during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Capsaicin in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Capsaicin in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Capsaicin in geriatric settings. ### Gender There is no FDA guidance on the use of Capsaicin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Capsaicin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Capsaicin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Capsaicin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Capsaicin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Capsaicin in patients who are immunocompromised. # Administration and Monitoring ### Administration Topical ### Monitoring There is limited information regarding Capsaicin Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Capsaicin and IV administrations. # Overdosage There is limited information regarding Capsaicin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action There is limited information regarding Capsaicin Mechanism of Action in the drug label. ## Structure There is limited information regarding Capsaicin Structure in the drug label. ## Pharmacodynamics There is limited information regarding Capsaicin Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Capsaicin Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Capsaicin Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Capsaicin Clinical Studies in the drug label. # How Supplied There is limited information regarding Capsaicin How Supplied in the drug label. ## Storage Store at 15° - 30°C (59° - 86°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - For persons under 18 years of age, ask a doctor before using. - To avoid getting cream on hands use applicator pad to apply a thin film of cream to the affected area and gently rub in until fully absorbed. Discard applicator pad after use. - For optimum relief, apply 3 to 4 times daily. - Best results typically occur after 2 to 4 weeks of continuous use. - Unless treating hands, wash hands thoroughly with soap and water immediately after use. - See package insert for more information. # Precautions with Alcohol Alcohol-Capsaicin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names ZOSTRIX # Look-Alike Drug Names There is limited information regarding Capsaicin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Capsaicin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies. # Overview Capsaicin is a topical analgesic that is FDA approved for the treatment of for the temporary relief of minor aches and pains of muscles and joints associated with arthritis, simple backache, strains and sprains. Common adverse reactions include erythema, rash, pruritus, nausea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications - For the temporary relief of minor aches and pains of muscles and joints associated with arthritis, simple backache, strains and sprains - For use in treating neuralgias, consult a physician ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use # Indications and Dosage - Arthritis - Pain: topical, apply thin film to the affected area 3 to 4 times per day. - Musculoskeletal pain: topical, apply thin film to the affected area 3 to 4 times per day. - Neuropathic pain, associated with postherpetic neuralgia: (patch) a single 60-minute application of up to 4 patches every 3 months as needed; do not apply more frequently than every 3 months - Psoriasis: apply cream 6 times/day for 3 days, then 4 times/day ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Capsaicin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Capsaicin FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - Safety and effectiveness of capsaicin 8% patch (Qutenza(R)) not established in pediatric patients; consult a physician before using capsaicin cream on patients under 18 years of age ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Capsaicin in pediatric patients. # Contraindications There is limited information regarding Capsaicin Contraindications in the drug label. # Warnings For external use only. Do not apply to wounds or to damaged or irritated skin. When using this product - You may experience a burning sensation which is normal and related to the way the product works. With regular use, this sensation generally disappears within several days. - Do not get it on mucous membranes, into eyes, or on contract lenses. If this occurs, rinse the affected area thoroughly with water. - Do not apply immediately before or after activities such as bathing, swimming, sun bathing, or strenuous exercise. - Do not apply heat to the treated areas immediately before or after use. - Do not tightly wrap or bandage the treated area. - Avoid inhaling airborne material from dried residue. This can result in coughing, sneezing, tearing, throat or respiratory irritation. Stop use and ask a doctor if - Condition worsens or does not improve after regular use. - Blistering occurs. - Difficulty breathing or swallowing occurs. - Severe burning persists. Keep out of reach of children. - If swallowed, get medical help or contact a Poison Control Center immediately. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Capsaicin Clinical Trials Experience in the drug label. ## Postmarketing Experience Common - Dermatologic: Application site erythema (63% ), application site pain (42% ), application site rash (6% ), pruritus,application Site (6% ) - Gastrointestinal: Nausea (5% ) - Respiratory: Nasopharyngitis (4% ) Serious - Cardiovascular: Hypertension (2% ) # Drug Interactions There is limited information regarding Capsaicin Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Capsaicin in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Capsaicin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Capsaicin during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Capsaicin in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Capsaicin in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Capsaicin in geriatric settings. ### Gender There is no FDA guidance on the use of Capsaicin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Capsaicin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Capsaicin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Capsaicin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Capsaicin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Capsaicin in patients who are immunocompromised. # Administration and Monitoring ### Administration Topical ### Monitoring There is limited information regarding Capsaicin Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Capsaicin and IV administrations. # Overdosage There is limited information regarding Capsaicin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology Template:Pepper ## Mechanism of Action There is limited information regarding Capsaicin Mechanism of Action in the drug label. ## Structure There is limited information regarding Capsaicin Structure in the drug label. ## Pharmacodynamics There is limited information regarding Capsaicin Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Capsaicin Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Capsaicin Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Capsaicin Clinical Studies in the drug label. # How Supplied There is limited information regarding Capsaicin How Supplied in the drug label. ## Storage Store at 15° - 30°C (59° - 86°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - For persons under 18 years of age, ask a doctor before using. - To avoid getting cream on hands use applicator pad to apply a thin film of cream to the affected area and gently rub in until fully absorbed. Discard applicator pad after use. - For optimum relief, apply 3 to 4 times daily. - Best results typically occur after 2 to 4 weeks of continuous use. - Unless treating hands, wash hands thoroughly with soap and water immediately after use. - See package insert for more information. # Precautions with Alcohol Alcohol-Capsaicin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names ZOSTRIX # Look-Alike Drug Names There is limited information regarding Capsaicin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Analgesic_Balm_with_Capsaicin
4eae2945b6d68fea57c7dd88d580dc64d1e95f3f	wikidoc	Anaplasia	Anaplasia # Overview Anaplasia (from ancient Greek: ἀνά ana, "on" + πλάσις plasis, "formation") is a noun referring to a condition whereby cells lose the morphological characteristics of mature cells and their orientation with respect to each other and to endothelial cells. The term also refers to a group of morphological changes in a cell (nuclear pleomorphism, altered nuclear:cytoplasmic ratio, presence of nucleoli, high proliferation index) that point to a possible malignant transformation. Loss of structural differentiation, especially as seen in most, but not all, malignant neoplasms. Sometimes, the term also includes an increased capacity for multiplication. Lack of differentiation is considered a hallmark of aggressive malignancies (ie. differentiates leiomyosarcomas from leiomyomas). The term anaplasia literally means "to form backward". It implies dedifferentiation, or loss of structural and functional differentiation of normal cells. It is now known, however, that at least some cancers arise from stem cells in tissues; in these tumors failure of differentiation, rather than dedifferentiation of specialized cells, account for undifferentiated tumors. Anaplastic cells display marked pleomorphism. The nuclei are characteristically extremely hyperchromatic (darkly stained) and large. The nuclear-cytoplasmic ratio may approach 1:1 instead of the normal 1:4 or 1:6. Giant cells that are considerably larger than their neighbors may be formed and possess either one enormous nucleus or several nuclei (syncytia). Anaplastic nuclei are variable and bizarre in size and shape. The chromatin is coarse and clumped, and nucleoli may be of astounding size. More important, mitoses are often numerous and distinctly atypical; anarchic multiple spindles may be seen and sometimes appear as tripolar or quadripolar forms. Also, anaplastic cells usually fail to develop recognizable patterns of orientation to one another (i.e. they lose normal polarity). They may grow in sheets, with total loss of communal structures, such as gland formation or stratified squamous architecture. Anaplasia is the most extreme disturbance in cell growth encountered in the spectrum of cellular proliferations.	Anaplasia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Anaplasia (from ancient Greek: ἀνά ana, "on" + πλάσις plasis, "formation") is a noun referring to a condition whereby cells lose the morphological characteristics of mature cells and their orientation with respect to each other and to endothelial cells. The term also refers to a group of morphological changes in a cell (nuclear pleomorphism, altered nuclear:cytoplasmic ratio, presence of nucleoli, high proliferation index) that point to a possible malignant transformation. [1] Loss of structural differentiation, especially as seen in most, but not all, malignant neoplasms.[2] Sometimes, the term also includes an increased capacity for multiplication.[3] Lack of differentiation is considered a hallmark of aggressive malignancies (ie. differentiates leiomyosarcomas from leiomyomas). The term anaplasia literally means "to form backward". It implies dedifferentiation, or loss of structural and functional differentiation of normal cells. It is now known, however, that at least some cancers arise from stem cells in tissues; in these tumors failure of differentiation, rather than dedifferentiation of specialized cells, account for undifferentiated tumors. Anaplastic cells display marked pleomorphism. The nuclei are characteristically extremely hyperchromatic (darkly stained) and large. The nuclear-cytoplasmic ratio may approach 1:1 instead of the normal 1:4 or 1:6. Giant cells that are considerably larger than their neighbors may be formed and possess either one enormous nucleus or several nuclei (syncytia). Anaplastic nuclei are variable and bizarre in size and shape. The chromatin is coarse and clumped, and nucleoli may be of astounding size. More important, mitoses are often numerous and distinctly atypical; anarchic multiple spindles may be seen and sometimes appear as tripolar or quadripolar forms. Also, anaplastic cells usually fail to develop recognizable patterns of orientation to one another (i.e. they lose normal polarity). They may grow in sheets, with total loss of communal structures, such as gland formation or stratified squamous architecture. Anaplasia is the most extreme disturbance in cell growth encountered in the spectrum of cellular proliferations.[4]	https://www.wikidoc.org/index.php/Anaplasia
fdc89da041346e268ba9fe376dfcd28db613724a	wikidoc	Andrology	Andrology Andrology (from Greek: ἀνδρο, andro, "man"; and λόγος, logos, "knowledge") is the medical specialty that deals with male health, particularly relating to the problems of the male reproductive system and urological problems that are unique to men. It is the counterpart to gynaecology, which deals with medical issues which are specific to women. Andrology has only been studied as a distinct specialty since the late 1960s: the first specialist journal on the subject was the German periodical Andrologie (now called Andrologia), published from 1969 onwards . Men are more susceptible to heart disease than women, and tend to have a slightly shorter natural average life span. However, men are more resistant to many conditions that adversely affect women, such as osteoporosis. Male-specific medical and surgical procedures include vasectomy and vasovasostomy (one of the vasectomy reversal procedures) as well as intervention to deal with male genitourinary disorders such as: - balanitis - cryptorchidism - ectopia testis - epispadias - epididymitis - frenulum breve - hydrocele - hypospadias - impotence (also known more correctly as erectile dysfunction) - infertility - micropenis - orchitis - paraphimosis - penile cancer - penile fracture - Peyronie's disease - phimosis - prostatitis - prostate cancer - spermatocele - testicular cancer - testicular torsion - varicocele # Notes - ↑ Social Studies of Science (1990) 20, p. 32	Andrology Andrology (from Greek: ἀνδρο, andro, "man"; and λόγος, logos, "knowledge") is the medical specialty that deals with male health, particularly relating to the problems of the male reproductive system and urological problems that are unique to men. It is the counterpart to gynaecology, which deals with medical issues which are specific to women. Andrology has only been studied as a distinct specialty since the late 1960s: the first specialist journal on the subject was the German periodical Andrologie (now called Andrologia), published from 1969 onwards [1]. Men are more susceptible to heart disease than women, and tend to have a slightly shorter natural average life span. However, men are more resistant to many conditions that adversely affect women, such as osteoporosis. Male-specific medical and surgical procedures include vasectomy and vasovasostomy (one of the vasectomy reversal procedures) as well as intervention to deal with male genitourinary disorders such as: - balanitis - cryptorchidism - ectopia testis - epispadias - epididymitis - frenulum breve - hydrocele - hypospadias - impotence (also known more correctly as erectile dysfunction) - infertility - micropenis - orchitis - paraphimosis - penile cancer - penile fracture - Peyronie's disease - phimosis - prostatitis - prostate cancer - spermatocele - testicular cancer - testicular torsion - varicocele # Notes - ↑ Social Studies of Science (1990) 20, p. 32 # External links - International Society of Andrology - The World of Andrology ast:Androloxía bg:Андрология cs:Andrologie de:Andrologie et:Androloogia id:Andrologi it:Andrologia nl:Andrologie simple:Andrology fi:Andrologia sv:Andrologi Template:WS	https://www.wikidoc.org/index.php/Andrology
02b5ac86c5ad2f68bf9c4cabac156fe2c8e98206	wikidoc	Androtomy	Androtomy Androtomy is the dissection of the human body. The first recorded dissection of the human body in the Western world took place in ancient Alexandria by Herophilus and Erasistratus. Though none of their writings have come down to us, other medical writers recorded what they had discovered. One such writer was Celsus who wrote in On Medicine I Proem 23, "Herophilus and Erasistratus proceeded in by far the best way: they cut open living men - criminals they obtained out of prison from the kings and they observed, while their subjects still breathed, parts that nature had previously hidden, their position, color, shape , size, arrangement, hardness, softness, smoothness, points of contact, and finally the processes and recesses of each and whether any part is inserted into another or receives the part of another into itself." Galen was another such writer who was familiar with the studies of the famous Alexandrians, Herophilus and Erasistratus.	Androtomy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Androtomy is the dissection of the human body. The first recorded dissection of the human body in the Western world took place in ancient Alexandria by Herophilus and Erasistratus. Though none of their writings have come down to us, other medical writers recorded what they had discovered. One such writer was Celsus who wrote in On Medicine I Proem 23, "Herophilus and Erasistratus proceeded in by far the best way: they cut open living men - criminals they obtained out of prison from the kings and they observed, while their subjects still breathed, parts that nature had previously hidden, their position, color, shape , size, arrangement, hardness, softness, smoothness, points of contact, and finally the processes and recesses of each and whether any part is inserted into another or receives the part of another into itself." Galen was another such writer who was familiar with the studies of the famous Alexandrians, Herophilus and Erasistratus.	https://www.wikidoc.org/index.php/Androtomy
70e8d3e5cd3fc3387ec9d289fd0840c030bcb869	wikidoc	Angiogram	Angiogram # Overview Angiography or arteriography is a medical imaging technique in which an X-ray picture is taken to visualize the inner opening (lumen) of blood filled structures, including arteries, veins and the heart chambers. Its name comes from the Greek words angeion, "vessel", and graphien, "to write or record". The X-ray film or image of the blood vessels is called an angiograph, or more commonly, an angiogram. # Historical Aspect The term angiography, or angeiography, was originally used of a description of the weights, measures, vessels, etc, used by several nations. The Portuguese physician and neurologist Egas Moniz, Nobel Prize winner in 1949, developed in 1927 the technique of contrasted x-ray cerebral angiography to diagnose several kinds of nervous diseases, such as tumors and arteriovenous malformations. He is usually recognized as one of the pioneers in this field. With the introduction of the Seldinger technique in 1953, the procedure became markedly safer as no sharp introductory devices needed to remain inside the vascular lumen. # Methods Angiograms require the insertion of a catheter into a peripheral artery, e.g. the femoral artery. As blood has the same radiodensity as the surrounding tissues, a radiocontrast agent (which absorbs X-rays) is added to the blood to make angiography visualization possible. The angiographic X-ray image shows shadows of the openings within the cardiovascular structures carrying blood (actually the radiocontrast agent within). The blood vessels or heart chambers themselves remain largely to totally invisible on the X-ray image. The X-ray images may be taken as either still images, displayed on a fluoroscope or film, useful for mapping an area. Alternatively, they may be motion images, usually taken at 30 frames per second, which also show the speed of blood (actually the speed of radiocontrast within the blood) traveling within the blood vessel. The most common angiogram performed is to visualize the blood in the coronary arteries. A long, thin, flexible tube called a catheter is used so as to administer the radiocontrast agent at the desired area to be visualized. The catheter is threaded into an artery in the groin or forearm, and the tip is advanced through the arterial system into one of the two major coronary arteries. X-ray images of the transient radiocontrast distribution within the blood flowing within the coronary arteries allows visualization of the size of the artery openings. Presence or absence of atherosclerosis or atheroma within the walls of the arteries cannot be clearly determined. See coronary catheterization for more detail. Angiography is also commonly performed to identify vessel narrowing in patients with retinal vascular disorders, such as diabetic retinopathy and macular degeneration. # Clinical Applications ## Coronary Angiography One of most common angiograms performed is to visualize the blood in the coronary arteries. A long, thin, flexible tube called a catheter is used to administer the x-ray contrast agent at the desired area to be visualized. The catheter is threaded into an artery in the groin or forearm, and the tip is advanced through the arterial system into one of the two major coronary arteries. X-ray images of the transient radiocontrast distribution within the blood flowing within the coronary arteries allows visualization of the size of the artery openings. Presence or absence of atherosclerosis or atheroma within the walls of the arteries cannot be clearly determined. See coronary catheterization for more detail.. ## Neuro-vascular angiography Another increasingly common angiographic procedure is neuro-vascular digital subtraction angiography in order to visualise the arterial and venous supply to the brain. Intervention work such as coil-embolisation of aneurysms and AVM gluing can also be performed ## Peripheral Angiography Angiography is also commonly performed to identify vessel narrowing in patients with leg claudication or cramps, caused by reduced blood flow down the legs and to the feet; in patients with renal stenosis (which commonly causes high blood pressure) and can be used in the head to find and repair stroke. These are all done routinely through the femoral artery, but can also be performed through the brachial or axillary (arm) artery. Any stenoses found may be treated by the use of angioplasty. ## Other Other angiographic uses include the diagnosis of retinal vascular disorders, such as diabetic retinopathy and macular degeneration. # Types of angiographs - Cerebral angiography - Coronary angiography - Peripheral angiography (arm or leg) - Visceral angiography (the abdominal organs, or viscera) - Pulmonary angiography (lungs) - Lymphangiography (lymph vessels) - Right heart ventriculography (looking at the right side of the heart) - Left heart ventriculography (looking at the left side of the heart) - Aortography (looking at the aorta, the major artery from the heart) - Retinal angiography - Magnetic Resonance Angiography # Postmortem Angiograms: Coronary Arteries Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology - Myocardial Infarction: Postmortem angiogram of coronary arteries - Angiogram: X-ray, horizontal sections of ventricle showing penetrating artery distribution (a quite good example) - Angiogram: X-ray, postmortem coronary arteries with multiple lesions - Angiogram: X-ray postmortem normal coronaries - Angiogram: Postmortem angiogram with apparent lesions in proximal right coronary artery - Angiogram: X-ray, postmortem injection horizontal slice of left ventricle showing very well penetrating arteries - Angiogram Saphenous Vein Bypass Graft: X-ray shows rather close-up large vein anastomosing to much smaller artery - Angiogram Saphenous Vein Bypass Graft: X-ray postmortem injection showing vein anastomosis very well and the vasculature of the right and left ventricles - Coronary artery: Atherosclerosis: X-ray postmortem extensive lesions in this x-ray of whole heart - X-Ray Intramyocardial Arteries: X-ray three horizontal slices of ventricles showing quite well the penetrating arteries - X-Ray Intramyocardial Arteries: X-ray three horizontal slices of ventricles showing quite well the penetrating arteries - Coronary Artery Anomalous Origin; Left From Pulmonary Artery: Angiogram, postmortem, after switch of left coronary artery to aorta - Coronary artery: Atherosclerosis: X-ray, postmortem, dissected arteries and extensive lesions - Coronary artery: Atherosclerosis: X-ray, postmortem, close-up view of artery with extensive lesions (very good example) - Coronary artery: Atherosclerosis: X-ray, postmortem, dissected artery, lesions in small branches	Angiogram Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Template:Editor help # Overview Angiography or arteriography is a medical imaging technique in which an X-ray picture is taken to visualize the inner opening (lumen) of blood filled structures, including arteries, veins and the heart chambers. Its name comes from the Greek words angeion, "vessel", and graphien, "to write or record". The X-ray film or image of the blood vessels is called an angiograph, or more commonly, an angiogram. # Historical Aspect The term angiography, or angeiography, was originally used of a description of the weights, measures, vessels, etc, used by several nations. The Portuguese physician and neurologist Egas Moniz, Nobel Prize winner in 1949, developed in 1927 the technique of contrasted x-ray cerebral angiography to diagnose several kinds of nervous diseases, such as tumors and arteriovenous malformations. He is usually recognized as one of the pioneers in this field. With the introduction of the Seldinger technique in 1953, the procedure became markedly safer as no sharp introductory devices needed to remain inside the vascular lumen. # Methods Angiograms require the insertion of a catheter into a peripheral artery, e.g. the femoral artery. As blood has the same radiodensity as the surrounding tissues, a radiocontrast agent (which absorbs X-rays) is added to the blood to make angiography visualization possible. The angiographic X-ray image shows shadows of the openings within the cardiovascular structures carrying blood (actually the radiocontrast agent within). The blood vessels or heart chambers themselves remain largely to totally invisible on the X-ray image. The X-ray images may be taken as either still images, displayed on a fluoroscope or film, useful for mapping an area. Alternatively, they may be motion images, usually taken at 30 frames per second, which also show the speed of blood (actually the speed of radiocontrast within the blood) traveling within the blood vessel. The most common angiogram performed is to visualize the blood in the coronary arteries. A long, thin, flexible tube called a catheter is used so as to administer the radiocontrast agent at the desired area to be visualized. The catheter is threaded into an artery in the groin or forearm, and the tip is advanced through the arterial system into one of the two major coronary arteries. X-ray images of the transient radiocontrast distribution within the blood flowing within the coronary arteries allows visualization of the size of the artery openings. Presence or absence of atherosclerosis or atheroma within the walls of the arteries cannot be clearly determined. See coronary catheterization for more detail. Angiography is also commonly performed to identify vessel narrowing in patients with retinal vascular disorders, such as diabetic retinopathy and macular degeneration. # Clinical Applications ## Coronary Angiography One of most common angiograms performed is to visualize the blood in the coronary arteries. A long, thin, flexible tube called a catheter is used to administer the x-ray contrast agent at the desired area to be visualized. The catheter is threaded into an artery in the groin or forearm, and the tip is advanced through the arterial system into one of the two major coronary arteries. X-ray images of the transient radiocontrast distribution within the blood flowing within the coronary arteries allows visualization of the size of the artery openings. Presence or absence of atherosclerosis or atheroma within the walls of the arteries cannot be clearly determined. See coronary catheterization for more detail.. ## Neuro-vascular angiography Another increasingly common angiographic procedure is neuro-vascular digital subtraction angiography in order to visualise the arterial and venous supply to the brain. Intervention work such as coil-embolisation of aneurysms and AVM gluing can also be performed ## Peripheral Angiography Angiography is also commonly performed to identify vessel narrowing in patients with leg claudication or cramps, caused by reduced blood flow down the legs and to the feet; in patients with renal stenosis (which commonly causes high blood pressure) and can be used in the head to find and repair stroke. These are all done routinely through the femoral artery, but can also be performed through the brachial or axillary (arm) artery. Any stenoses found may be treated by the use of angioplasty. ## Other Other angiographic uses include the diagnosis of retinal vascular disorders, such as diabetic retinopathy and macular degeneration. # Types of angiographs - Cerebral angiography - Coronary angiography - Peripheral angiography (arm or leg) - Visceral angiography (the abdominal organs, or viscera) - Pulmonary angiography (lungs) - Lymphangiography (lymph vessels) - Right heart ventriculography (looking at the right side of the heart) - Left heart ventriculography (looking at the left side of the heart) - Aortography (looking at the aorta, the major artery from the heart) - Retinal angiography - Magnetic Resonance Angiography # Postmortem Angiograms: Coronary Arteries Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology - Myocardial Infarction: Postmortem angiogram of coronary arteries - Angiogram: X-ray, horizontal sections of ventricle showing penetrating artery distribution (a quite good example) - Angiogram: X-ray, postmortem coronary arteries with multiple lesions - Angiogram: X-ray postmortem normal coronaries - Angiogram: Postmortem angiogram with apparent lesions in proximal right coronary artery - Angiogram: X-ray, postmortem injection horizontal slice of left ventricle showing very well penetrating arteries - Angiogram Saphenous Vein Bypass Graft: X-ray shows rather close-up large vein anastomosing to much smaller artery - Angiogram Saphenous Vein Bypass Graft: X-ray postmortem injection showing vein anastomosis very well and the vasculature of the right and left ventricles - Coronary artery: Atherosclerosis: X-ray postmortem extensive lesions in this x-ray of whole heart - X-Ray Intramyocardial Arteries: X-ray three horizontal slices of ventricles showing quite well the penetrating arteries - X-Ray Intramyocardial Arteries: X-ray three horizontal slices of ventricles showing quite well the penetrating arteries - Coronary Artery Anomalous Origin; Left From Pulmonary Artery: Angiogram, postmortem, after switch of left coronary artery to aorta - Coronary artery: Atherosclerosis: X-ray, postmortem, dissected arteries and extensive lesions - Coronary artery: Atherosclerosis: X-ray, postmortem, close-up view of artery with extensive lesions (very good example) - Coronary artery: Atherosclerosis: X-ray, postmortem, dissected artery, lesions in small branches # External links - RadiologyInfo - The radiology information resource for patients: Angiography procedures - Cardiac Catheterization from Angioplasty.Org - Angiography Equipment from Siemens Medical - Cardiovascular and Interventional Radiological Society of Europe - Worldwide Angiography Manufacturer cs:Angiografie de:Angiografie it:Angiografia nl:Angiografie no:Angiografi fi:Angiografia Template:WikiDoc Sources CME Category::Cardiology	https://www.wikidoc.org/index.php/Angiogram
dc845f6212de90648b665851bcc07bff97598800	wikidoc	Angiology	Angiology Angiology (from Greek: ἀγγειο, angio, "vessel"; and λόγος, logos, "knowledge") is the medical specialty which studies the diseases of circulatory system and of the lymphatic system, i.e., arteries, veins and lymphatic vases, and its diseases. Arterial diseases include the aorta (aneurysms/dissection) and arteries supplying the legs hands, kidneys, brain, intestines. It also covers arterial thrombosis and embolism; vasculitides; and vasospastic disorders. Venous diseases include venous thrombosis, chronic venous insufficiency, and varicose veins. Lymphatic diseases include primary and secondary forms of lymphedema. It also involves modification of risk factors for vascular disease like high cholesterol, high blood pressure. High blood pressure, high cholesterol, heart attack, stroke and venous blood clots all fall under the specialty of vascular medicine. Hence a vascular medicine specialist should be able to address most of the major diseases in our age in a comprehensive manner, using a unique perspective. Currently there is a shortage of practitioners in this field, mainly due to lack of training programs and lack of awareness in patients and physicians of this as a distinct medical specialty. With an increasing burden of vascular diseases in our aging population, the establishment of a critical mass of physicians with interest in vascular diseases is paramount. In 2005, the first vascular medicine boards were administered by the American Board of Vascular Medicine.	Angiology Template:WikiDoc Cardiology News Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Angiology (from Greek: ἀγγειο, angio, "vessel"; and λόγος, logos, "knowledge") is the medical specialty which studies the diseases of circulatory system and of the lymphatic system, i.e., arteries, veins and lymphatic vases, and its diseases. Arterial diseases include the aorta (aneurysms/dissection) and arteries supplying the legs hands, kidneys, brain, intestines. It also covers arterial thrombosis and embolism; vasculitides; and vasospastic disorders. Venous diseases include venous thrombosis, chronic venous insufficiency, and varicose veins. Lymphatic diseases include primary and secondary forms of lymphedema. It also involves modification of risk factors for vascular disease like high cholesterol, high blood pressure. High blood pressure, high cholesterol, heart attack, stroke and venous blood clots all fall under the specialty of vascular medicine. Hence a vascular medicine specialist should be able to address most of the major diseases in our age in a comprehensive manner, using a unique perspective. Currently there is a shortage of practitioners in this field, mainly due to lack of training programs and lack of awareness in patients and physicians of this as a distinct medical specialty.[citation needed] With an increasing burden of vascular diseases in our aging population, the establishment of a critical mass of physicians with interest in vascular diseases is paramount. In 2005, the first vascular medicine boards were administered by the American Board of Vascular Medicine.	https://www.wikidoc.org/index.php/Angiology
ef700ca1a9af23489958d22c6b5473eeaed312fa	wikidoc	Guidewire	Guidewire Key Words and Synonyms: PCI guidewire; angioplasty guidewire; coronary guidewire; steerable wire; steerable guidewire. # Overview Angioplasty guidewires are small, soft, flexible, lubricated, wires that act as a rail over which equipment such as an angioplasty balloon, a stent, or an intravascular ultrasound device can be delivered over into the coronary artery. Angioplasty guide wires were introduced in 1982 by doctors Simpson and Roberts. The introduction of coronary guidewires was a major advance as it allowed the angioplasty balloon to be a traumatically steered to the proper location. # Guidewire Techniques # Guidewire Complications # Desirable Performance Characteristics of Coronary Guidewires # Guidewire Design Features A guidewrie has three main components - a core, a tip and a lubricous Coating. Figure : Components of a guide wire (courtesy : Abbott vascular inc) Guidewire Core \| Guidewire Coatings \| Guidewire Tip Guidewire Core Diameters \| Guidewire Wisdom \| Guidewire Tip Diameters \| Guidewire Lengths # Guidewires Classified Based Upon Support (Steerability and Trackability) ## Soft Guidewires Asahi Soft Guidewire \| Hi-torque Balance ## Moderate Support Guidewires Wisper Wire \| High Torque Balance Middle Weight ## Extra Support Guidewires Choice PT Extra Support \| PT Graphix Intermediate \| Stabilizer \| Hi-Torque Balance Heavy Weight ## Super Extra Support Guidewires Iron Man \| Asahi Grand Slam # Guidewires Classified By Crossing Profile ## Complex lesions and lesions in very tortuous vessels Prowater \| Choice PT \| PT Graphix Intermediate ## Guidewires Used to Cross Chronic Total Occlusions Wires to be used in escalating order of aggressiveness: ### First Choice Non-hydrophilic or hydrophobic wires with an intermediate stiffness are a good first choice as they have a better tactile response, are less likely to lead to a subintimal position than a hydrophilic wire, and may have an additional advantage in their ability to cross the proximal cap of the occlusion. Choices in this class include the Miracle Bros 3 and the Asahi intermediate wires. ### Second Choice Hydrophilic wires may track better after the proximal cap of the occlusion has been crossed. Hydrophilic/coated wires have better maneuverability in tortuous or calcified vessels. Intermediate stiffness hydrophilic wire choices include the Choice PT XS (Extra Support), the Pilot 50, the Pilot 100 or the PT Graphix intermediate wire. ### Third Choice Stiff non-hydrophilic wires: The Miracle Bros 6, 9 and 12, Cross-IT, Confienza, Persuader ### Fourth Choice Stiff and hydrophilic (most aggressive): Pilot 200 and Shinobi # Device Delivery Guidewires Guidewire wiggle wire- The wiggle wire has a niche role in delivering stents and balloons into areas with poor transmission of proximal push. The wiggle wire works by shifting the direction of the pushing forces thus "stepping over" the obstacle. # Peripheral Arterial Guidewires - Spartacore - The Spartacore is a peripheral arterial guidewire. - Guidewire V 18 # Guidewire Tourquing Device A torquing device is a tool interventional cardiologists use to torque a coronary guidewire and to maintain the tension on the guidewire to preserve the torque and the direction the guidewire. There is a gradual inadvertent “unwinding” of torque when the human fingers are used to steer a coronary guidewire, and this unwinding can be effectively prevented by this tool. # List of Guidewires by Manufacturer	Guidewire Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Priyantha Ranaweera [2]; Key Words and Synonyms: PCI guidewire; angioplasty guidewire; coronary guidewire; steerable wire; steerable guidewire. # Overview Angioplasty guidewires are small, soft, flexible, lubricated, wires that act as a rail over which equipment such as an angioplasty balloon, a stent, or an intravascular ultrasound device can be delivered over into the coronary artery. Angioplasty guide wires were introduced in 1982 by doctors Simpson and Roberts. The introduction of coronary guidewires was a major advance as it allowed the angioplasty balloon to be a traumatically steered to the proper location. # Guidewire Techniques # Guidewire Complications # Desirable Performance Characteristics of Coronary Guidewires # Guidewire Design Features A guidewrie has three main components - a core, a tip and a lubricous Coating. Figure : Components of a guide wire (courtesy : Abbott vascular inc) Guidewire Core \| Guidewire Coatings \| Guidewire Tip Guidewire Core Diameters \| Guidewire Wisdom \| Guidewire Tip Diameters \| Guidewire Lengths # Guidewires Classified Based Upon Support (Steerability and Trackability) ## Soft Guidewires Asahi Soft Guidewire \| Hi-torque Balance ## Moderate Support Guidewires Wisper Wire \| High Torque Balance Middle Weight ## Extra Support Guidewires Choice PT Extra Support \| PT Graphix Intermediate \| Stabilizer \| Hi-Torque Balance Heavy Weight ## Super Extra Support Guidewires Iron Man \| Asahi Grand Slam # Guidewires Classified By Crossing Profile ## Complex lesions and lesions in very tortuous vessels Prowater \| Choice PT \| PT Graphix Intermediate ## Guidewires Used to Cross Chronic Total Occlusions Wires to be used in escalating order of aggressiveness: ### First Choice Non-hydrophilic or hydrophobic wires with an intermediate stiffness are a good first choice as they have a better tactile response, are less likely to lead to a subintimal position than a hydrophilic wire, and may have an additional advantage in their ability to cross the proximal cap of the occlusion. Choices in this class include the Miracle Bros 3 and the Asahi intermediate wires. ### Second Choice Hydrophilic wires may track better after the proximal cap of the occlusion has been crossed. Hydrophilic/coated wires have better maneuverability in tortuous or calcified vessels. Intermediate stiffness hydrophilic wire choices include the Choice PT XS (Extra Support), the Pilot 50, the Pilot 100 or the PT Graphix intermediate wire. ### Third Choice Stiff non-hydrophilic wires: The Miracle Bros 6, 9 and 12, Cross-IT, Confienza, Persuader ### Fourth Choice Stiff and hydrophilic (most aggressive): Pilot 200 and Shinobi # Device Delivery Guidewires Guidewire wiggle wire- The wiggle wire has a niche role in delivering stents and balloons into areas with poor transmission of proximal push. The wiggle wire works by shifting the direction of the pushing forces thus "stepping over" the obstacle. # Peripheral Arterial Guidewires - Spartacore - The Spartacore is a peripheral arterial guidewire. - Guidewire V 18 # Guidewire Tourquing Device A torquing device is a tool interventional cardiologists use to torque a coronary guidewire and to maintain the tension on the guidewire to preserve the torque and the direction the guidewire. There is a gradual inadvertent “unwinding” of torque when the human fingers are used to steer a coronary guidewire, and this unwinding can be effectively prevented by this tool. # List of Guidewires by Manufacturer Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Angioplasty_guidewire
db9f0fec716f12df4b2196809d9230096dd7b84c	wikidoc	Eukaryote	Eukaryote # Overview Animals, plants, fungi, and protists are eukaryotes (Template:IPAEng or Template:IPAEng), organisms whose cells are organized into complex structures enclosed within membranes. The defining membrane-bound structure which differentiates eukaryotic cells from prokaryotic cells is the nucleus. The presence of a nucleus gives these organisms their name, which comes from the Greek ευ, meaning "good/true", and κάρυον, "nut". Many eukaryotic cells contain other membrane-bound organelles such as mitochondria, chloroplasts and Golgi bodies. Eukaryotes often have unique flagella made of microtubules in a 9+2 arrangement. Cell division in eukaryotes is different from organisms without a nucleus (prokaryotes). It involves separating the duplicated chromosomes, through movements directed by microtubules. There are two types of division processes. In mitosis, one cell divides to produce two genetically-identical cells. In meiosis, which is required in sexual reproduction, one diploid cell (having two instances of each chromosome, one from each parent) undergoes recombination of each pair of parental chromosomes, and then two stages of cell division, resulting in four haploid cells (gametes). Each gamete has just one complement of chromosomes, each a unique mix of the corresponding pair of parental chromosomes. Eukaryotes appear to be monophyletic, and so make up one of the three domains of life. The two other domains, bacteria and archaea, are prokaryotes, and have none of the above features. But eukaryotes do share some aspects of their biochemistry with archaea, and so are grouped with archaea in the clade Neomura. # Cell features Eukaryotic cells are typically much larger than prokaryotes. They have a variety of internal membranes and structures, called organelles, and a cytoskeleton composed of microtubules, microfilaments, and intermediate filaments, which play an important role in defining the cell's organization and shape. Eukaryotic DNA is divided into several linear bundles called chromosomes, which are separated by a microtubular spindle during nuclear division. ## Internal membrane Eukaryotic cells include a variety of membrane-bound structures, collectively referred to as the endomembrane system. Simple compartments, called vesicles or vacuoles, can form by budding off other membranes. Many cells ingest food and other materials through a process of endocytosis, where the outer membrane invaginates and then pinches off to form a vesicle. It is probable that most other membrane-bound organelles are ultimately derived from such vesicles. The nucleus is surrounded by a double membrane (commonly referred to as a nuclear envelope), with pores that allow material to move in and out. Various tube- and sheet-like extensions of the nuclear membrane form what is called the endoplasmic reticulum or ER, which is involved in protein transport and maturation. It includes the Rough ER where ribosomes are attached, and the proteins they synthesize enter the interior space or lumen. Subsequently, they generally enter vesicles, which bud off from the Smooth ER. In most eukaryotes, this protein-carrying vesicles are released and further modified in stacks of flattened vesicles, called Golgi bodies or dictyosomes. Vesicles may be specialized for various purposes.For instance, lysosomes contain enzymes that break down the contents of food vacuoles, and peroxisomes are used to break down peroxide, which is toxic otherwise. Many protozoa have contractile vacuoles, which collect and expel excess water, and extrusomes, which expel material used to deflect predators or capture prey. In multicellular organisms, hormones are often produced in vesicles. In higher plants, most of a cell's volume is taken up by a central vacuole, which primarily maintains its osmotic pressure. ## Mitochondria and plastids Mitochondria are organelles found in nearly all eukaryotes. They are surrounded by double membranes (known as the phospholipid bi-layer), the inner of which is folded into invaginations called cristae, where aerobic respiration takes place. They contain their own DNA and are only formed by the fission of other mitochondria. They are now generally held to have developed from endosymbiotic prokaryotes, probably proteobacteria. The few protozoa that lack mitochondria have been found to contain mitochondrion-derived organelles, such as hydrogenosomes and mitosomes. Plants and various groups of algae also have plastids. Again, these have their own DNA and developed from endosymbiotes, in this case cyanobacteria. They usually take the form of chloroplasts, which like cyanobacteria contain chlorophyll and produce energy through photosynthesis. Others are involved in storing food. Although plastids likely had a single origin, not all plastid-containing groups are closely related. Instead, some eukaryotes have obtained them from others through secondary endosymbiosis or ingestion. Endosymbiotic origins have also been proposed for the nucleus, for which see below, and for eukaryotic flagella, supposed to have developed from spirochaetes. This is not generally accepted, both from a lack of cytological evidence and difficulty in reconciling this with cellular reproduction. ## Cytoskeletal structures Many eukaryotes have long slender motile cytoplasmic projections, called flagella. These are composed mainly of tubulin and shorter cilia, both of which are variously involved in movement, feeding, and sensation. These are entirely distinct from prokaryotic flagella. They are supported by a bundle of microtubules arising from a basal body, also called a kinetosome or centriole, characteristically arranged as nine doublets surrounding two singlets. Flagella also may have hairs, or mastigonemes, and scales connecting membranes and internal rods. Their interior is continuous with the cell's cytoplasm. Microfilamental structures composed by actin and actin binding proteins, e.g., α-actinin, fimbrin, filamin are present in submembraneous cortical layers and bundles, as well. Motor proteins of microtubules, e.g., dynein or kinesin and actin, e.g., myosins provide dynamic character of the network. Centrioles are often present even in cells and groups that do not have flagella. They generally occur in groups of one or two, called kinetids, that give rise to various microtubular roots. These form a primary component of the cytoskeletal structure, and are often assembled over the course of several cell divisions, with one flagellum retained from the parent and the other derived from it. Centrioles may also be associated in the formation of a spindle during nuclear division. Significance of cytoskeletal structures is underlined in determination of shape of the cells, as well as their being essential components of migratory responses like chemotaxis and chemokinesis. Some protists have various other microtubule-supported organelles. These include the radiolaria and heliozoa, which produce axopodia used in flotation or to capture prey, and the haptophytes, which have a peculiar flagellum-like organelle called the haptonema. ## Plant cell wall Plant cells have a cell wall, a fairly rigid layer outside the cell membrane, providing the cell with structural support, protection, and a filtering mechanism. The cell wall also prevents over-expansion when water enters the cell. The major carbohydrates making up the primary cell wall are cellulose, hemicellulose, and pectin. The cellulose microfibrils are linked via hemicellulosic tethers to form the cellulose-hemicellulose network, which is embedded in the pectin matrix. The most common hemicellulose in the primary cell wall is xyloglucan. # Differences between eukaryotic cells There are many different types of eukaryotic cells, though animals and plants are the most familiar eukaryotes, and thus provide an excellent starting point for understanding eukaryotic structure. Fungi and many protists have some substantial differences, however. ## Animal cell An animal cell is a form of eukaryotic cell that makes up many tissues in animals. The animal cell is distinct from other eukaryotes, most notably plant cells, as they lack cell walls and chloroplasts, and they have smaller vacuoles. Due to the lack of a rigid cell wall, animal cells can adopt a variety of shapes, and a phagocytic cell can even engulf other structures. There are many different cell types. For instance, there are approximately 210 distinct cell types in the adult human body. ## Plant cell Plant cells are quite different from the cells of the other eukaryotic organisms. Their distinctive features are: - A large central vacuole (enclosed by a membrane, the tonoplast), which maintains the cell's turgor and controls movement of molecules between the cytosol and sap - A primary cell wall containing cellulose, hemicellulose and pectin, deposited by the protoplast on the outside of the cell membrane; this contrasts with the cell walls of fungi, which contain chitin, and the cell envelopes of prokaryotes, in which peptidoglycans are the main structural molecules - The plasmodesmata, linking pores in the cell wall that allow each plant cell to communicate with other adjacent cells; this is different from the functionally analogous system of gap junctions between animal cells. - Plastids, especially chloroplasts that contain chlorophyll, the pigment that gives plants their green color and allows them to perform photosynthesis - Higher plants, including conifers and flowering plants (Angiospermae) lack the flagellae and centrioles that are present in animal cells. ## Fungal cell Fungal cells are most similar to animal cells, with the following exceptions: - A cell wall containing chitin - Less definition between cells; the hyphae of higher fungi have porous partitions called septa, which allow the passage of cytoplasm, organelles, and, sometimes, nuclei. Primitive fungi have few or no septa, so each organism is essentially a giant multinucleate supercell; these fungi are described as coenocytic. - Only the most primitive fungi, chytrids, have flagella. ## Other eukaryotic cells Eukaryotes are a very diverse group, and their cell structures are equally diverse. Many have cell walls; many do not. Many have chloroplasts, derived from primary, secondary, or even tertiary endosymbiosis; and many do not. Some groups have unique structures, such as the cyanelles of the glaucophytes, the haptonema of the haptophytes, or the ejectisomes of the cryptomonads. Other structures, such as pseudopods, are found in various eukaryote groups in different forms, such as the lobose amoebozoans or the reticulose foraminiferans. # Reproduction Nuclear division is often coordinated with cell division. This generally takes place by mitosis, a process that allows each daughter nucleus to receive one copy of each chromosome. In most eukaryotes, there is also a process of sexual reproduction, typically involving an alternation between haploid generations, wherein only one copy of each chromosome is present, and diploid generations, wherein two are present, occurring through nuclear fusion (syngamy) and meiosis. There is considerable variation in this pattern, however. Eukaryotes have a smaller surface to volume area ratio than prokaryotes, and thus have lower metabolic rates and longer generation times. In some multicellular organisms, cells specialized for metabolism will have enlarged surface areas, such as intestinal vili. # Origin and evolution The origin of the eukaryotic cell was a milestone in the evolution of life, since they include all complex cells and almost all multi-cellular organisms. The timing of this series of events is hard to determine; Knoll (1992) suggests they developed approximately 1.6 - 2.1 billion years ago. Fossils that are clearly related to modern groups start appearing around 1.2 billion years ago, in the form of a red alga. However, the presence of steranes in Australian shales indicates that eukaryotes were present 2.7 billion years ago. rRNA trees constructed during the 1980s and 1990s left most eukaryotes in an unresolved "crown" group (not technically a true crown), which was usually divided by the form of the mitochondrial cristae. The few groups that lack mitochondria branched separately, and so the absence was believed to be primitive; but this is now considered an artifact of long-branch attraction, and they are known to have lost them secondarily. Trees based on actin and other molecules have painted a different and more complete picture. Most eukaryotes are now included in one of the following supergroups, although the relationship between these groups, and the monophyly of each group, is not yet clear: Several authorities recognize two larger clades, the unikonts and the bikonts, that derive from an ancestral uniflagellar organism and a biflagellate respectively. In this system, the opisthokonts and amoebozoans are considered unikonts, and the rest bikonts. The chromalveolates were originally thought to be two separate groups, the chromists and the alveolates, but the former was proved to be paraphyletic to the latter, and the two groups combined. Some small protist groups have not been related to any of these supergroups, in particular the centrohelids. Eukaryotes are closely related to Archaea, at least in terms of nuclear DNA and genetic machinery, and some place them with Archaea in the clade Neomura. In other respects, such as membrane composition, they are similar to eubacteria. Three main explanations for this have been proposed: - Eukaryotes resulted from the complete fusion of two or more cells, where the cytoplasm formed from a eubacterium, and the nucleus from an archaeon or from a virus. - Eukaryotes developed from Archaea, and acquired their eubacterial characteristics from the proto-mitochondrion. - Eukaryotes and Archaea developed separately from a modified eubacterium. The origin of the endomembrane system and mitochondria are also disputed. The phagotrophic hypothesis states the membranes originated with the development of endocytosis and later specialized; mitochondria were acquired by ingestion, like plastids. The syntrophic hypothesis states that the proto-eukaryote relied on the proto-mitochondrion for food, and so ultimately grew to surround it; the membranes originate later, in part thanks to mitochondrial genes (the hydrogen hypothesis is one particular version). In a study using genomes to construct supertrees, Pisani et al (2007) suggest that, along with evidence that there was never a mitochondrion-less eukaryote, eukaryotes evolved from a syntrophy between an archaea closely related to Thermoplasmatales and an α-proteobacterium, likely a symbiosis driven by sulfur or hydrogen. The mitochondrion and its genome is a remnant of the α-proteobacterial endosymbiont.	Eukaryote Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Animals, plants, fungi, and protists are eukaryotes (Template:IPAEng or Template:IPAEng), organisms whose cells are organized into complex structures enclosed within membranes. The defining membrane-bound structure which differentiates eukaryotic cells from prokaryotic cells is the nucleus. The presence of a nucleus gives these organisms their name, which comes from the Greek ευ, meaning "good/true", and κάρυον, "nut". Many eukaryotic cells contain other membrane-bound organelles such as mitochondria, chloroplasts and Golgi bodies. Eukaryotes often have unique flagella made of microtubules in a 9+2 arrangement. Cell division in eukaryotes is different from organisms without a nucleus (prokaryotes). It involves separating the duplicated chromosomes, through movements directed by microtubules. There are two types of division processes. In mitosis, one cell divides to produce two genetically-identical cells. In meiosis, which is required in sexual reproduction, one diploid cell (having two instances of each chromosome, one from each parent) undergoes recombination of each pair of parental chromosomes, and then two stages of cell division, resulting in four haploid cells (gametes). Each gamete has just one complement of chromosomes, each a unique mix of the corresponding pair of parental chromosomes. Eukaryotes appear to be monophyletic, and so make up one of the three domains of life. The two other domains, bacteria and archaea, are prokaryotes, and have none of the above features. But eukaryotes do share some aspects of their biochemistry with archaea, and so are grouped with archaea in the clade Neomura. # Cell features Eukaryotic cells are typically much larger than prokaryotes. They have a variety of internal membranes and structures, called organelles, and a cytoskeleton composed of microtubules, microfilaments, and intermediate filaments, which play an important role in defining the cell's organization and shape. Eukaryotic DNA is divided into several linear bundles called chromosomes, which are separated by a microtubular spindle during nuclear division. Template:Endomembrane system diagram ## Internal membrane Eukaryotic cells include a variety of membrane-bound structures, collectively referred to as the endomembrane system. Simple compartments, called vesicles or vacuoles, can form by budding off other membranes. Many cells ingest food and other materials through a process of endocytosis, where the outer membrane invaginates and then pinches off to form a vesicle. It is probable that most other membrane-bound organelles are ultimately derived from such vesicles. The nucleus is surrounded by a double membrane (commonly referred to as a nuclear envelope), with pores that allow material to move in and out. Various tube- and sheet-like extensions of the nuclear membrane form what is called the endoplasmic reticulum or ER, which is involved in protein transport and maturation. It includes the Rough ER where ribosomes are attached, and the proteins they synthesize enter the interior space or lumen. Subsequently, they generally enter vesicles, which bud off from the Smooth ER. In most eukaryotes, this protein-carrying vesicles are released and further modified in stacks of flattened vesicles, called Golgi bodies or dictyosomes. Vesicles may be specialized for various purposes.For instance, lysosomes contain enzymes that break down the contents of food vacuoles, and peroxisomes are used to break down peroxide, which is toxic otherwise. Many protozoa have contractile vacuoles, which collect and expel excess water, and extrusomes, which expel material used to deflect predators or capture prey. In multicellular organisms, hormones are often produced in vesicles. In higher plants, most of a cell's volume is taken up by a central vacuole, which primarily maintains its osmotic pressure. ## Mitochondria and plastids Mitochondria are organelles found in nearly all eukaryotes. They are surrounded by double membranes (known as the phospholipid bi-layer), the inner of which is folded into invaginations called cristae, where aerobic respiration takes place. They contain their own DNA and are only formed by the fission of other mitochondria. They are now generally held to have developed from endosymbiotic prokaryotes, probably proteobacteria. The few protozoa that lack mitochondria have been found to contain mitochondrion-derived organelles, such as hydrogenosomes and mitosomes. Plants and various groups of algae also have plastids. Again, these have their own DNA and developed from endosymbiotes, in this case cyanobacteria. They usually take the form of chloroplasts, which like cyanobacteria contain chlorophyll and produce energy through photosynthesis. Others are involved in storing food. Although plastids likely had a single origin, not all plastid-containing groups are closely related. Instead, some eukaryotes have obtained them from others through secondary endosymbiosis or ingestion. Endosymbiotic origins have also been proposed for the nucleus, for which see below, and for eukaryotic flagella, supposed to have developed from spirochaetes. This is not generally accepted, both from a lack of cytological evidence and difficulty in reconciling this with cellular reproduction. ## Cytoskeletal structures Many eukaryotes have long slender motile cytoplasmic projections, called flagella. These are composed mainly of tubulin and shorter cilia, both of which are variously involved in movement, feeding, and sensation. These are entirely distinct from prokaryotic flagella. They are supported by a bundle of microtubules arising from a basal body, also called a kinetosome or centriole, characteristically arranged as nine doublets surrounding two singlets. Flagella also may have hairs, or mastigonemes, and scales connecting membranes and internal rods. Their interior is continuous with the cell's cytoplasm. Microfilamental structures composed by actin and actin binding proteins, e.g., α-actinin, fimbrin, filamin are present in submembraneous cortical layers and bundles, as well. Motor proteins of microtubules, e.g., dynein or kinesin and actin, e.g., myosins provide dynamic character of the network. Centrioles are often present even in cells and groups that do not have flagella. They generally occur in groups of one or two, called kinetids, that give rise to various microtubular roots. These form a primary component of the cytoskeletal structure, and are often assembled over the course of several cell divisions, with one flagellum retained from the parent and the other derived from it. Centrioles may also be associated in the formation of a spindle during nuclear division. Significance of cytoskeletal structures is underlined in determination of shape of the cells, as well as their being essential components of migratory responses like chemotaxis and chemokinesis. Some protists have various other microtubule-supported organelles. These include the radiolaria and heliozoa, which produce axopodia used in flotation or to capture prey, and the haptophytes, which have a peculiar flagellum-like organelle called the haptonema. ## Plant cell wall Plant cells have a cell wall, a fairly rigid layer outside the cell membrane, providing the cell with structural support, protection, and a filtering mechanism. The cell wall also prevents over-expansion when water enters the cell. The major carbohydrates making up the primary cell wall are cellulose, hemicellulose, and pectin. The cellulose microfibrils are linked via hemicellulosic tethers to form the cellulose-hemicellulose network, which is embedded in the pectin matrix. The most common hemicellulose in the primary cell wall is xyloglucan. # Differences between eukaryotic cells There are many different types of eukaryotic cells, though animals and plants are the most familiar eukaryotes, and thus provide an excellent starting point for understanding eukaryotic structure. Fungi and many protists have some substantial differences, however. ## Animal cell An animal cell is a form of eukaryotic cell that makes up many tissues in animals. The animal cell is distinct from other eukaryotes, most notably plant cells, as they lack cell walls and chloroplasts, and they have smaller vacuoles. Due to the lack of a rigid cell wall, animal cells can adopt a variety of shapes, and a phagocytic cell can even engulf other structures. There are many different cell types. For instance, there are approximately 210 distinct cell types in the adult human body. ## Plant cell Plant cells are quite different from the cells of the other eukaryotic organisms. Their distinctive features are: - A large central vacuole (enclosed by a membrane, the tonoplast), which maintains the cell's turgor and controls movement of molecules between the cytosol and sap - A primary cell wall containing cellulose, hemicellulose and pectin, deposited by the protoplast on the outside of the cell membrane; this contrasts with the cell walls of fungi, which contain chitin, and the cell envelopes of prokaryotes, in which peptidoglycans are the main structural molecules - The plasmodesmata, linking pores in the cell wall that allow each plant cell to communicate with other adjacent cells; this is different from the functionally analogous system of gap junctions between animal cells. - Plastids, especially chloroplasts that contain chlorophyll, the pigment that gives plants their green color and allows them to perform photosynthesis - Higher plants, including conifers and flowering plants (Angiospermae) lack the flagellae and centrioles that are present in animal cells. ## Fungal cell Fungal cells are most similar to animal cells, with the following exceptions: - A cell wall containing chitin - Less definition between cells; the hyphae of higher fungi have porous partitions called septa, which allow the passage of cytoplasm, organelles, and, sometimes, nuclei. Primitive fungi have few or no septa, so each organism is essentially a giant multinucleate supercell; these fungi are described as coenocytic. - Only the most primitive fungi, chytrids, have flagella. ## Other eukaryotic cells Eukaryotes are a very diverse group, and their cell structures are equally diverse. Many have cell walls; many do not. Many have chloroplasts, derived from primary, secondary, or even tertiary endosymbiosis; and many do not. Some groups have unique structures, such as the cyanelles of the glaucophytes, the haptonema of the haptophytes, or the ejectisomes of the cryptomonads. Other structures, such as pseudopods, are found in various eukaryote groups in different forms, such as the lobose amoebozoans or the reticulose foraminiferans. # Reproduction Nuclear division is often coordinated with cell division. This generally takes place by mitosis, a process that allows each daughter nucleus to receive one copy of each chromosome. In most eukaryotes, there is also a process of sexual reproduction, typically involving an alternation between haploid generations, wherein only one copy of each chromosome is present, and diploid generations, wherein two are present, occurring through nuclear fusion (syngamy) and meiosis. There is considerable variation in this pattern, however. Eukaryotes have a smaller surface to volume area ratio than prokaryotes, and thus have lower metabolic rates and longer generation times. In some multicellular organisms, cells specialized for metabolism will have enlarged surface areas, such as intestinal vili. # Origin and evolution The origin of the eukaryotic cell was a milestone in the evolution of life, since they include all complex cells and almost all multi-cellular organisms. The timing of this series of events is hard to determine; Knoll (1992) suggests they developed approximately 1.6 - 2.1 billion years ago. Fossils that are clearly related to modern groups start appearing around 1.2 billion years ago, in the form of a red alga. However, the presence of steranes in Australian shales indicates that eukaryotes were present 2.7 billion years ago.[2] [3] rRNA trees constructed during the 1980s and 1990s left most eukaryotes in an unresolved "crown" group (not technically a true crown), which was usually divided by the form of the mitochondrial cristae. The few groups that lack mitochondria branched separately, and so the absence was believed to be primitive; but this is now considered an artifact of long-branch attraction, and they are known to have lost them secondarily.[4][5] Trees based on actin and other molecules have painted a different and more complete picture. Most eukaryotes are now included in one of the following supergroups, although the relationship between these groups, and the monophyly of each group, is not yet clear:[6][7] Template:Userboxtop Template:Clade Template:Userboxbottom Several authorities recognize two larger clades, the unikonts and the bikonts, that derive from an ancestral uniflagellar organism and a biflagellate respectively. In this system, the opisthokonts and amoebozoans are considered unikonts, and the rest bikonts. The chromalveolates were originally thought to be two separate groups, the chromists and the alveolates, but the former was proved to be paraphyletic to the latter, and the two groups combined. Some small protist groups have not been related to any of these supergroups, in particular the centrohelids. Eukaryotes are closely related to Archaea, at least in terms of nuclear DNA and genetic machinery, and some place them with Archaea in the clade Neomura. In other respects, such as membrane composition, they are similar to eubacteria. Three main explanations for this have been proposed: - Eukaryotes resulted from the complete fusion of two or more cells, where the cytoplasm formed from a eubacterium, and the nucleus from an archaeon or from a virus. - Eukaryotes developed from Archaea, and acquired their eubacterial characteristics from the proto-mitochondrion. - Eukaryotes and Archaea developed separately from a modified eubacterium. The origin of the endomembrane system and mitochondria are also disputed. The phagotrophic hypothesis states the membranes originated with the development of endocytosis and later specialized; mitochondria were acquired by ingestion, like plastids. The syntrophic hypothesis states that the proto-eukaryote relied on the proto-mitochondrion for food, and so ultimately grew to surround it; the membranes originate later, in part thanks to mitochondrial genes (the hydrogen hypothesis is one particular version). In a study using genomes to construct supertrees, Pisani et al (2007) suggest that, along with evidence that there was never a mitochondrion-less eukaryote, eukaryotes evolved from a syntrophy between an archaea closely related to Thermoplasmatales and an α-proteobacterium, likely a symbiosis driven by sulfur or hydrogen. The mitochondrion and its genome is a remnant of the α-proteobacterial endosymbiont.[8]	https://www.wikidoc.org/index.php/Animal_cell
c71dcbafed755961bf83f51bb61637e8268eb586	wikidoc	Anion gap	Anion gap # Overview The anion gap is a representative of the unmeasured anions in the plasma, and is made of negatively charged phosphates, sulfates, organic acids and plasma proteins (including albumin). Rather than measuring all these anions in a patient, an indirect way is to measure the difference of the dominant cation i.e. sodium to the dominant anion i.e. chloride and bicarbonate, with the understanding that the difference in anions is caused due to the unmeasured anions i.e. phosphate, sulfate, and albumin. Chloride and bicarbonate comprise 85% of the anions in the serum. The differential diagnosis of a patient with a metabolic acidosis is broad and can be narrowed and further evaluated by calculating the anion gap. Normal reference range AG is between 3 and 11 meq/L (average 6 meq/L). # Uses The primary function of the anion gap measurement is to allow a clinician to narrow down the possible causes of a patient's metabolic acidosis. For example, if a patient presents with metabolic acidosis, but a normal anion gap, then conditions that cause a high anion gap can be ruled out as being the cause of the acidosis. # Calculation It is calculated by subtracting the serum concentrations of chloride and bicarbonate (anions) from the concentrations of sodium plus potassium (cations): However, for daily practice, the potassium is frequently ignored, leaving the following equation: # Interpretation Anion gap can be classified as either high, normal or, in rare cases, low. A high anion gap indicates that there is loss of HCO3- without a subsequent increase in Cl-. Electroneutrality is maintained by the increased production of anions like ketones, lactate, PO4-, and SO4-; these anions are not part of the anion-gap calculation and therefore a high anion gap results. In patients with a normal anion gap the drop in HCO3- is compensated for by an increase in Cl- and hence is also known as hyperchloremic acidosis. # Complete Differential Diagnosis of the Causes of Anion gap ## Low anion gap A low anion gap is relatively rare but may occur from the presence of abnormal positively charged proteins, as in multiple myeloma, or in the setting of a low serum albumin level. The mnemonic for low anion gap is BAM - B - Bromism - A - (Low) Albumin (Hypoalbuminemia) - M - Multiple myeloma ## Normal anion gap (hyperchloremic acidosis) Usually the HCO3- lost is replaced by a chloride anion, and thus there is a normal anion gap. In normal anion gap acidosis, the increased anion is chloride, which is measured, so the anion gap does not increase. Thus, normal anion gap acidosis is also known as hyperchloremic acidosis. Urine anion gap is useful in evaluating a patient with a normal anion gap. The mnemonic for the most common causes of a normal-anion gap metabolic acidosis is "DURHAM." - D- Diarrhea - U- Ureteral diversion - R- Renal tubular acidosis - H- Hyperailmentation - A- Addison's disease, acetazolamide, ammonium chloride - M- Miscellaneous (chloridorrhea, amphotericin B, toluene - toluene causes high anion gap metabolic acidosis followed by normal anion gap metabolic acidosis. ## High anion gap The bicarbonate lost is replaced by an unmeasured anion and thus you will see a high anion gap. The mnemonic "MUDPILES" is used to remember the causes of a high anion gap. M - methanol/Metformin U - Uremia D - Diabetic ketoacidosis P - Paraldehyde/Propylene glycol I - Infection/Ischemia/Isoniazid L - Lactate E - Ethylene glycol/Ethanol S - Salicylates/Starvation Some people, especially those not in the emergency room, find the mnemonic KIL-U easier to remember and also more useful clinically: K - Ketones I - Ingestion L - lactic acid U - uremia All of the components of "mudpiles" are also covered with the "KIL-U" device, with the bonus that these are things that can kill you. Ketones: more straightforward than remembering diabetic ketosis and starvation ketosis, etc. Ingestion: methanol, metformin, paraldehyde, propylene glycol, isoniazid, ethylene glycol, ethanol, and salicilates are covered by ingestion. These can be thought of as a single group: "ingestions" during the initial consideration, especially when not triaging a patient in the emergency room. Lactate: including that caused by infection and shock ## Coexistent elevated anion gap and normal anion gap metabolic acidosis - An elevated anion gap can coexist with a normal anion gap metabolic acidosis. - In a single acid-base disorder of elevated anion gap metabolic acidosis, serum bicarbonate (HCO3) will decrease by the same amount that the anion gap increases. - However, a situation in which the anion gap increases less and serum bicarbonate decreases significantly indicates that there is another metabolic acidosis present, which is decreasing the the serum bicarbonate, but not affecting the anion gap i.e. normal anion gap metabolic acidosis is also present. - Thus, it is advised to compare the changes in the anion gap with the changes in the serum bicarbonate. - This is often referred as the delta-delta equation, or the corrected bicarbonate equation. - Delta-Delta equation: Change in anion gap = Change in bicarbonate	Anion gap Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.D. [2] # Overview The anion gap is a representative of the unmeasured anions in the plasma, and is made of negatively charged phosphates, sulfates, organic acids and plasma proteins (including albumin). Rather than measuring all these anions in a patient, an indirect way is to measure the difference of the dominant cation i.e. sodium to the dominant anion i.e. chloride and bicarbonate, with the understanding that the difference in anions is caused due to the unmeasured anions i.e. phosphate, sulfate, and albumin. Chloride and bicarbonate comprise 85% of the anions in the serum. The differential diagnosis of a patient with a metabolic acidosis is broad and can be narrowed and further evaluated by calculating the anion gap. Normal reference range AG is between 3 and 11 meq/L (average 6 meq/L). # Uses The primary function of the anion gap measurement is to allow a clinician to narrow down the possible causes of a patient's metabolic acidosis. For example, if a patient presents with metabolic acidosis, but a normal anion gap, then conditions that cause a high anion gap can be ruled out as being the cause of the acidosis. # Calculation It is calculated by subtracting the serum concentrations of chloride and bicarbonate (anions) from the concentrations of sodium plus potassium (cations): However, for daily practice, the potassium is frequently ignored, leaving the following equation: # Interpretation Anion gap can be classified as either high, normal or, in rare cases, low. A high anion gap indicates that there is loss of HCO3- without a subsequent increase in Cl-. Electroneutrality is maintained by the increased production of anions like ketones, lactate, PO4-, and SO4-; these anions are not part of the anion-gap calculation and therefore a high anion gap results. In patients with a normal anion gap the drop in HCO3- is compensated for by an increase in Cl- and hence is also known as hyperchloremic acidosis. # Complete Differential Diagnosis of the Causes of Anion gap ## Low anion gap A low anion gap is relatively rare but may occur from the presence of abnormal positively charged proteins, as in multiple myeloma, or in the setting of a low serum albumin level. The mnemonic for low anion gap is BAM - B - Bromism - A - (Low) Albumin (Hypoalbuminemia) - M - Multiple myeloma ## Normal anion gap (hyperchloremic acidosis) Usually the HCO3- lost is replaced by a chloride anion, and thus there is a normal anion gap. In normal anion gap acidosis, the increased anion is chloride, which is measured, so the anion gap does not increase. Thus, normal anion gap acidosis is also known as hyperchloremic acidosis. Urine anion gap is useful in evaluating a patient with a normal anion gap. The mnemonic for the most common causes of a normal-anion gap metabolic acidosis is "DURHAM." - D- Diarrhea - U- Ureteral diversion - R- Renal tubular acidosis - H- Hyperailmentation - A- Addison's disease, acetazolamide, ammonium chloride - M- Miscellaneous (chloridorrhea, amphotericin B, toluene - toluene causes high anion gap metabolic acidosis followed by normal anion gap metabolic acidosis. ## High anion gap The bicarbonate lost is replaced by an unmeasured anion and thus you will see a high anion gap. The mnemonic "MUDPILES" is used to remember the causes of a high anion gap. M - methanol/Metformin U - Uremia D - Diabetic ketoacidosis P - Paraldehyde/Propylene glycol I - Infection/Ischemia/Isoniazid L - Lactate E - Ethylene glycol/Ethanol S - Salicylates/Starvation Some people, especially those not in the emergency room, find the mnemonic KIL-U easier to remember and also more useful clinically: K - Ketones I - Ingestion L - lactic acid U - uremia All of the components of "mudpiles" are also covered with the "KIL-U" device, with the bonus that these are things that can kill you. Ketones: more straightforward than remembering diabetic ketosis and starvation ketosis, etc. Ingestion: methanol, metformin, paraldehyde, propylene glycol, isoniazid, ethylene glycol, ethanol, and salicilates are covered by ingestion. These can be thought of as a single group: "ingestions" during the initial consideration, especially when not triaging a patient in the emergency room. Lactate: including that caused by infection and shock ## Coexistent elevated anion gap and normal anion gap metabolic acidosis - An elevated anion gap can coexist with a normal anion gap metabolic acidosis. - In a single acid-base disorder of elevated anion gap metabolic acidosis, serum bicarbonate (HCO3) will decrease by the same amount that the anion gap increases. - However, a situation in which the anion gap increases less and serum bicarbonate decreases significantly indicates that there is another metabolic acidosis present, which is decreasing the the serum bicarbonate, but not affecting the anion gap i.e. normal anion gap metabolic acidosis is also present. - Thus, it is advised to compare the changes in the anion gap with the changes in the serum bicarbonate. - This is often referred as the delta-delta equation, or the corrected bicarbonate equation. - Delta-Delta equation: Change in anion gap = Change in bicarbonate	https://www.wikidoc.org/index.php/Anion_Gap
35a9c24a13b431e219479d4c7560a6c5a0650a74	wikidoc	Annoyance	Annoyance # Overview Annoyance is an unpleasant mental state that is characterized by such effects as irritation and distraction from one's conscious thinking. It can lead to emotions such as frustration and anger. # Etymology "Annoy" (like the French ennui, a word traced by etymologists to a Latin phrase, in odio esse, to be "in hatred" or hateful of someone), to vex or affect with irritation. In the sense of "nuisance," the noun "annoyance" is found in the English "Jury of Annoyance" appointed by an act of 1754 to report upon obstructions in the highways. # Psychology Various reasons exist for why one finds particular stimuli annoying. Measurement of annoyance is highly subjective. As an attempt at measurement, psychological studies on annoyance often rely on their subjects' own ratings of levels of annoyance on a scale. Many stimuli that one is at first neutral to, or even finds pleasant, can turn into annoyances from repeated continued exposure. One can often encounter this phenomenon with such media as popular music, commercials, and advertising jingles, which by their very nature are continually repeated over a period of weeks or months. A study published in the International Journal of Conflict Management found that one's response to an annoyance, at least when the perceived cause is another person, escalate to more extreme levels as they go unresolved. It also found that one was more likely to blame the party who was causing the annoyance in the study, rather than one's self, for the annoyance as it escalated. Psychological warfare can involve creating annoyances to distract and wear down the resistance of the target. For example, in 1993 the FBI played music "specifically selected for its irritation ability" on loudspeakers outside the Branch Davidian church in Waco, Texas in an attempt to bring about the surrender of David Koresh and his followers. # Effects Annoyance can cause stress, leading to high blood pressure. # Annoyance in United States law The Communications Decency Act (CDA) of 1996 made the communication of anything "indecent with the intent to annoy" a felony punishable by a fine and up to two-year imprisonment. President Bill Clinton signed the CDA into law after it was passed by Congress in February 1996. # Software Annoyances are used to measure how well a software program conforms to (or competes against) user expectations about how a particular feature or package should work. Individual annoyances are routinely archived and catalogued by users and reviewers. Such archives often include "annoyance busters" or "workarounds" that can be used to resolve or ameliorate the irritating effects. For top-selling software titles, archives of annoyances and workarounds are often published.	Annoyance Template:Emotion Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Annoyance is an unpleasant mental state that is characterized by such effects as irritation and distraction from one's conscious thinking. It can lead to emotions such as frustration and anger. # Etymology "Annoy" (like the French ennui, a word traced by etymologists to a Latin phrase, in odio esse, to be "in hatred" or hateful of someone), to vex or affect with irritation. In the sense of "nuisance," the noun "annoyance" is found in the English "Jury of Annoyance" appointed by an act of 1754 to report upon obstructions in the highways. # Psychology Various reasons exist for why one finds particular stimuli annoying. Measurement of annoyance is highly subjective. As an attempt at measurement, psychological studies on annoyance often rely on their subjects' own ratings of levels of annoyance on a scale. Many stimuli that one is at first neutral to, or even finds pleasant, can turn into annoyances from repeated continued exposure. One can often encounter this phenomenon with such media as popular music, commercials, and advertising jingles, which by their very nature are continually repeated over a period of weeks or months. A study published in the International Journal of Conflict Management found that one's response to an annoyance, at least when the perceived cause is another person, escalate to more extreme levels as they go unresolved.[1] It also found that one was more likely to blame the party who was causing the annoyance in the study, rather than one's self, for the annoyance as it escalated. Psychological warfare can involve creating annoyances to distract and wear down the resistance of the target. For example, in 1993 the FBI played music "specifically selected for its irritation ability" on loudspeakers outside the Branch Davidian church in Waco, Texas in an attempt to bring about the surrender of David Koresh and his followers.[2] # Effects Annoyance can cause stress, leading to high blood pressure. # Annoyance in United States law The Communications Decency Act (CDA) of 1996 made the communication of anything "indecent with the intent to annoy" a felony punishable by a fine and up to two-year imprisonment. President Bill Clinton signed the CDA into law after it was passed by Congress in February 1996. # Software Annoyances are used to measure how well a software program conforms to (or competes against) user expectations about how a particular feature or package should work. Individual annoyances are routinely archived and catalogued by users and reviewers. Such archives often include "annoyance busters" or "workarounds" that can be used to resolve or ameliorate the irritating effects. For top-selling software titles, archives of annoyances and workarounds are often published.	https://www.wikidoc.org/index.php/Annoyance
b5f58f7ba0237b63d3d0a6e582ccaf7eaaf47ca9	wikidoc	Anorectic	Anorectic # Overview Anorectics, anorexigenics or appetite suppressants are drugs that reduce the appetite ("anorectic", from the Greek an- = "not" and oreg- = "extend, reach"). # History and initial uses Used on a short term basis clinically to treat obesity, some appetite suppressants are also available over the counter. Drugs of this class are frequently stimulants of the phenethylamine family, related to amphetamine (speed). The German military experimented with issuing amphetamines to soldiers in 1945, when food supplies were very short in Germany. Following the Second World War, amphetamines were re-directed for use on the civilian market. Indeed, amphetamine itself was sold commercially as an appetite suppressant until it was outlawed in most parts of the world in the late 1950s due to increased recreational use. Many amphetamines produce side effects including addiction, tachycardia and hypertension, making prolonged unsupervised use dangerous. Many people who obtain these drugs are more interested in the amphetamine-like stimulant effects than weight loss. In those cases, it is important to make sure to keep forcing oneself to eat even when it is undesirable. # Public health concerns Epidemics of fatal pulmonary hypertension and heart valve damage associated with anorectic agents have led to the withdrawal of products from the market. This was the case with aminorex in the 1960s, and again in the 1990s with fenfluramine (see: Fen-phen). Likewise, association of the related appetite suppressant phenylpropanolamine with hemorrhagic stroke led the Food and Drug Administration (FDA) to request its withdrawal from the market in the United States in 2000, and similar concerns regarding ephedrine resulted in an FDA ban on its inclusion in dietary supplements, in 2004 (a Federal judge later overturned this ban in 2005 during a challenge by supplement maker Nutraceuticals.) # Currently marketed appetite suppressants In spite of these precedents, numerous compounds are marketed today as appetite suppressants. The following are listed as "centrally acting antiobesity preparations" by ATC: - Phentermine (Fastin®, Adipex®, Ionamin® and others) - Diethylpropion (Tenuate®) - Sibutramine (Meridia®, Reductil®) - Rimonabant (Acomplia®) The following are listed as appetite depressants by MeSH. - benfluorex - butenolide - diethylpropion - FG 7142 - norpseudoephedrine - phenmetrazine - phentermine - phenylpropanolamine - pyroglutamyl-histidyl-glycine - sibutramine Other compounds marked as appetite suppressants include: - Phendimetrazine (Prelu-2®, Bontril®) - Benzphetamine (Didrex®) - Oxyntomodulin - Methylphenidate (Concerta) (Ritalin®) - Phenylethylamine (Trimspa®)	Anorectic # Overview Anorectics, anorexigenics or appetite suppressants are drugs that reduce the appetite ("anorectic", from the Greek an- = "not" and oreg- = "extend, reach"). # History and initial uses Used on a short term basis clinically to treat obesity, some appetite suppressants are also available over the counter. Drugs of this class are frequently stimulants of the phenethylamine family, related to amphetamine (speed). The German military experimented with issuing amphetamines to soldiers in 1945, when food supplies were very short in Germany. Following the Second World War, amphetamines were re-directed for use on the civilian market. Indeed, amphetamine itself was sold commercially as an appetite suppressant until it was outlawed in most parts of the world in the late 1950s due to increased recreational use. Many amphetamines produce side effects including addiction, tachycardia and hypertension, [1]making prolonged unsupervised use dangerous. Many people who obtain these drugs are more interested in the amphetamine-like stimulant effects than weight loss. In those cases, it is important to make sure to keep forcing oneself to eat even when it is undesirable. # Public health concerns Epidemics of fatal pulmonary hypertension and heart valve damage associated with anorectic agents have led to the withdrawal of products from the market. This was the case with aminorex in the 1960s, and again in the 1990s with fenfluramine (see: Fen-phen).[2] Likewise, association of the related appetite suppressant phenylpropanolamine with hemorrhagic stroke led the Food and Drug Administration (FDA) to request its withdrawal from the market in the United States in 2000, and similar concerns regarding ephedrine resulted in an FDA ban on its inclusion in dietary supplements, in 2004 (a Federal judge later overturned this ban in 2005 during a challenge by supplement maker Nutraceuticals.) # Currently marketed appetite suppressants In spite of these precedents, numerous compounds are marketed today as appetite suppressants. The following are listed as "centrally acting antiobesity preparations" by ATC:[3] - Phentermine (Fastin®, Adipex®, Ionamin® and others) - Diethylpropion (Tenuate®) - Sibutramine (Meridia®, Reductil®) - Rimonabant (Acomplia®) The following are listed as appetite depressants by MeSH.[4] - benfluorex - butenolide - diethylpropion - FG 7142 - norpseudoephedrine - phenmetrazine - phentermine - phenylpropanolamine - pyroglutamyl-histidyl-glycine - sibutramine Other compounds marked as appetite suppressants include: - Phendimetrazine (Prelu-2®, Bontril®) - Benzphetamine (Didrex®) - Oxyntomodulin - Methylphenidate (Concerta) (Ritalin®) - Phenylethylamine (Trimspa®)	https://www.wikidoc.org/index.php/Anorectic
f6730d7cde10737aae0fdc571719c25f94b83b6e	wikidoc	Anosmin-1	Anosmin-1 Anosmin-1 is a secreted, EM associated glycoprotein found in humans and other organisms responsible for normal development, which is expressed in the brain, spinal cord and kidney. Absence or damage to the protein results in Kallmann syndrome in humans, which is characterized by loss of olfactory bulbs and GnRH secretion leading to anosmia and hypothalamic hypogonadotropic hypogonadism. Anosmin-1 is coded by the KAL-1 gene, which is found on the X chromosome. Anosmin-1 is 100 kilodaltons and is expressed on the outside of cells. Because of this and because of its contribution to normal migration of nerve cells, a role in the extracellular matrix has been postulated. During neural crest cell development, anosmin-1 plays a role in cranial neural cell formation by spatiotemporal regulation. Secreated anosmin-1 enhances FGF activity by promoting FGF8-FGFR1 complex formation, whereas inhibits both BMP5 and WNT3A activities. As a results, orchestrated regulation of FGF, BMP, and WNT by anosmin-1 control EMT and MET during neural crest cell development. In human retinal pigment epithelial cell(RPE), the expression of anosmin-1 is regulated by TGF-β which remain to be investigated. Anosmin-1 is encoded by a gene ANOS1 (earlier called ADMLX, KAL, KAL1, KALIG1). In human it is located on the X chromosome at Xp22.3 and is affected in some male individuals with Kallmann syndrome. This gene codes for a protein of the extracellular matrix named anosmin-1, which is involved in the migration of certain nerve cell precursors (neuroendocrine GnRH cells) during embryogenesis. Deletion or mutation of this gene results in loss of the functional protein and affects the proper development of the olfactory nerves and olfactory bulbs. In addition, neural cells that produce GnRH fail to migrate to the hypothalamus. Clinically, mutation results in the X-linked form of Kallmann syndrome. Individuals with Kallmann syndrome experience anosmia (lack of smell) and do not go through puberty (hypothalamic hypogonadotropic hypogonadism). ANOS1 is made of 14 exons and spans 120-200 kilobases. Mutations of ANOS1 may account for 14% of the cases of familial Kallmann syndrome and 11% of male sporadic cases.	Anosmin-1 Anosmin-1 is a secreted, EM associated glycoprotein found in humans and other organisms responsible for normal development, which is expressed in the brain, spinal cord and kidney. Absence or damage to the protein results in Kallmann syndrome in humans, which is characterized by loss of olfactory bulbs and GnRH secretion leading to anosmia and hypothalamic hypogonadotropic hypogonadism. Anosmin-1 is coded by the KAL-1 gene, which is found on the X chromosome. Anosmin-1 is 100 kilodaltons and is expressed on the outside of cells. Because of this and because of its contribution to normal migration of nerve cells, a role in the extracellular matrix has been postulated.[1] During neural crest cell development, anosmin-1 plays a role in cranial neural cell formation by spatiotemporal regulation. Secreated anosmin-1 enhances FGF activity by promoting FGF8-FGFR1 complex formation, whereas inhibits both BMP5 and WNT3A activities. As a results, orchestrated regulation of FGF, BMP, and WNT by anosmin-1 control EMT and MET during neural crest cell development. In human retinal pigment epithelial cell(RPE), the expression of anosmin-1 is regulated by TGF-β which remain to be investigated. Anosmin-1 is encoded by a gene ANOS1 (earlier called ADMLX, KAL, KAL1, KALIG1). In human it is located on the X chromosome at Xp22.3 and is affected in some male individuals with Kallmann syndrome.[2] This gene codes for a protein of the extracellular matrix named anosmin-1, which is involved in the migration of certain nerve cell precursors (neuroendocrine GnRH cells) during embryogenesis. Deletion or mutation of this gene results in loss of the functional protein and affects the proper development of the olfactory nerves and olfactory bulbs. In addition, neural cells that produce GnRH fail to migrate to the hypothalamus. Clinically, mutation results in the X-linked form of Kallmann syndrome. Individuals with Kallmann syndrome experience anosmia (lack of smell) and do not go through puberty (hypothalamic hypogonadotropic hypogonadism). ANOS1 is made of 14 exons and spans 120-200 kilobases. Mutations of ANOS1 may account for 14% of the cases of familial Kallmann syndrome and 11% of male sporadic cases.	https://www.wikidoc.org/index.php/Anosmin-1
c4f3398221f768627ddc8279da800f4b4765c216	wikidoc	Ant chalk	Ant chalk Ant chalk, also known as Chinese chalk or 'Miraculous Insecticide Chalk', is an insecticide in the form of normal looking chalk. It contains the pesticides deltamethrin and cypermethrin. While these pesticides are legal in the United States, the chalk is no longer legal due to a number of reasons including the large number of child poisionings reported while the chalk was legal, the poisonous lead packaging in which the product is sold and the improper labeling on the packaging. The product is referred to as Chinese chalk because, despite its illegal status, is still imported from China and sold in Chinatowns in the United States. # Notes - ↑ Fagerlund, Richard (2004). ""Ant chalk could harm people more than ants"". Sfgate.com. San Francisco Chronicle. Retrieved 2006-12-09..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} - ↑ ""Building Maintenance - Structural Integrated Pest Management"". Dgs.ca.gov. California Department of General Services. Retrieved 2006-12-09.	Ant chalk Ant chalk, also known as Chinese chalk or 'Miraculous Insecticide Chalk', is an insecticide in the form of normal looking chalk. It contains the pesticides deltamethrin and cypermethrin[1]. While these pesticides are legal in the United States[2], the chalk is no longer legal due to a number of reasons including the large number of child poisionings reported while the chalk was legal, the poisonous lead packaging in which the product is sold and the improper labeling on the packaging. The product is referred to as Chinese chalk because, despite its illegal status, is still imported from China and sold in Chinatowns in the United States. # Notes - ↑ Fagerlund, Richard (2004). ""Ant chalk could harm people more than ants"". Sfgate.com. San Francisco Chronicle. Retrieved 2006-12-09..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} - ↑ ""Building Maintenance - Structural Integrated Pest Management"". Dgs.ca.gov. California Department of General Services. Retrieved 2006-12-09. # External links - Chinese exporter selling Miraculous Insecticide Chalk. Includes photo.	https://www.wikidoc.org/index.php/Ant_chalk
7210eed0fdc13e944fae4ff938957b9fc0f23cb5	wikidoc	Midwifery	Midwifery Midwifery is the term traditionally used to describe the art of assisting a woman through childbirth. In the modern context, this term is used to describe the activities of those health care providers who are experts in women's health care including giving prenatal care to expecting mothers. They attend the birth of the infant and provide postpartum care to the mother and her infant. Practitioners of midwifery are known as midwives, a term used in reference to both women and men (the term means "with woman"). Midwives are autonomous practitioners who are specialists in normal pregnancy, childbirth and the postpartum. They generally strive to help women have a healthy pregnancy and natural birth experience. Midwives are also primary care givers providing general women's health care. Midwives are trained to recognize and deal with deviations from the norm. Obstetricians, in contrast, are specialists in illness related to childbearing and in surgery. The two professions can be complementary, but often are at odds because obstetricians are taught to "actively manage" labor, while midwives are taught not to intervene unless necessary. Midwives refer to obstetricians when a woman requires care beyond her or his areas of expertise. In many jurisdictions, these professions work together to provide care to childbearing women. In others, only the midwife is available to provide care. Midwives are trained to handle certain situations that are considered abnormal, including breech birth and posterior position, using non-invasive techniques. In many areas of the world, traditional midwives, renamed "traditional birth attendants" by the World Health Organization (WHO) and other groups, are the only available providers for childbearing women. Midwives once treated patients for female hysteria. # Defining midwifery According to the WHO definition, a midwife is a person who, having been regularly admitted to a midwifery educational program that is duly recognised in the country in which it is located, has successfully completed the prescribed course of studies in midwifery and has acquired the requisite qualifications to be registered and/or legally licensed to practice midwifery. The educational program may be an apprenticeship, a formal university program, or a combination. The midwife is recognised as a responsible and accountable professional who works in partnership with women to give the necessary support, care and advice during pregnancy, labour and the postpartum period, to conduct births on the midwife's own responsibility and to provide care for the infant. This care includes preventive measures, the promotion of normal birth, the detection of complications in mother and child, accessing of medical or other appropriate assistance and the carrying out of emergency measures. The midwife has an important task in health counselling and education, not only for the woman, but also within the family and community. This work should involve antenatal education and preparation for parenthood and may extend to women's health, sexual or reproductive health and childcare. A midwife may practice in any setting including in the home, the community, hospitals, clinics or health units. Adopted by the International Confederation of Midwives, 19 July 2005 This definition is controversial and not everyone agrees with the exclusion of traditional midwives who in developing countries often are the only people available to assist women in birth. # Historical perspective Historically, midwifery has been one of the few medical practices dominated by female practitioners. From Agnodice in ancient Greece to the 18th century in Europe, the care of mothers and delivery of infants has been regarded, both by patients and by the medical profession, as appropriately carried out by women. In the 18th century, a division between surgeons and midwives arose, as medical men began to assert that their modern scientific processes were better for mothers and infants than the folk-medical midwives. Whether this was a valid claim or not can be seen in the entry for Justine Siegemund, a renowned seventeenth century German midwife, whose Court Midwife (1690) was the first female-authored German medical text. At the outset of the 18th century in England, most babies were caught by a midwife, but by the onset of the 19th century, the majority of those babies born to persons of means had a surgeon involved. A number of excellent full length studies of this historical shift have been written. German social scientists Gunnar Heinsohn and Otto Steiger have put forward the theory that midwifery became a target of persecution and repression by public authorities because midwives not only possessed highly specialized knowledge and skills regarding assisting birth, but also regarding contraception and abortion . According to Heinsohn and Steiger's theory, the modern state persecuted the midwives as witches in an effort to repopulate the European continent which had suffered severe loss of manpower as a result of the bubonic plague (also known as the black death) which had swept over the continent in waves, starting in 1348. They thus interpret the witch hunts as attacking midwifery and knowledge about birth control with a demographic goal in mind. Indeed, after the witch hunts, the number of children per mother rose sharply, giving rise to what has been called the "European population explosion" of modern times, producing an enormous youth bulge that enabled Europe to colonize large parts of the rest of the world. While historians specializing in the history of the witch hunts have generally remained critical of this macroeconomic approach and continue to favor micro level perspectives and explanations, prominent historian of birth control John M. Riddle has expressed agreement. # Midwifery in the United States There are two main divisions of modern midwifery in the US: nurse-midwives and direct-entry midwives. ## Nurse-midwives Nurse-midwives were introduced in the United States in 1925 by Mary Breckinridge for use in the Frontier Nursing Service (FNS). Mrs. Breckinridge chose the nurse-midwifery model used in England and Scotland because she expected these nurse-midwives on horse back to serve the health care needs of the families living in the remote hills of eastern Kentucky. This combination of nurse and midwife was very successful. The Metropolitan Life Insurance Company studied the first seven years of the FNS, and reported a substantially lower maternal and infant mortality rate than for the rest of the country. The report concluded that if this type of care was available to other women in the USA thousands of lives would be saved, and suggested nurse-midwife training should be done in the USA. Mrs. Breckinridge opened the Frontier Graduate School of Midwifery in 1939 the first nurse-midwifery education program in the USA that is still educating nurse-midwives today /. In the United States, nurse-midwives are advanced practice nurses who have specialized in the practice of obstetrical and gynecological care of relatively healthy women. In addition to a registered nursing license, many nurse-midwives have a master's degree in nursing, public health, or midwifery. Nurse-midwives practice in hospitals, medical clinics and private offices and may deliver babies in hospitals, birth centers and at home. They are able to prescribe medications in all 50 states. Nurse-midwives provide care to women from puberty through menopause. Nurse-midwives may work closely with obstetricians, who provide consultation and assistance to patients who develop complications. Often, women with high risk pregnancies can receive the benefits of midwifery care from a nurse-midwife in collaboration with a physician. Currently, 2% of nurse-midwives are men. The American College of Nurse-Midwives accredits nurse-midwifery education programs and serves as the national professional society for the nation's certified nurse-midwives. At present approximately 5500 Certified Nurse-Midwives are practicing in the U.S. ## Direct-entry midwives A direct-entry midwife is educated in the discipline of midwifery in a program or path that does not also require her to become educated as a nurse. Direct-entry midwives learn midwifery through self-study, apprenticeship, a midwifery school, or a college- or university-based program distinct from the discipline of nursing. A direct-entry midwife is trained to provide the Midwives Model of Care to healthy women and newborns throughout the childbearing cycle primarily in out-of-hospital settings. Under the umbrella of "direct-entry midwife" are several types of midwives: A Certified Professional Midwife (CPM) is a knowledgeable, skilled and professional independent midwifery practitioner who has met the standards for certification set by the North American Registry of Midwives (NARM) and is qualified to provide the midwives model of care. The CPM is the only US credential that requires knowledge about and experience in out-of-hospital settings. At present, there are approximately 900 CPMs practicing in the US. A Licensed Midwife is a midwife who is licensed to practice in a particular state. Currently, licensure for direct-entry midwives is available in 24 states. The term "Lay Midwife" has been used to designate an uncertified or unlicensed midwife who was educated through informal routes such as self-study or apprenticeship rather than through a formal program. This term does not necessarily mean a low level of education, just that the midwife either chose not to become certified or licensed, or there was no certification available for her type of education (as was the fact before the Certified Professional Midwife credential was available). Other similar terms to describe uncertified or unlicensed midwives are traditional midwife, traditional birth attendant, granny midwife and independent midwife. The American College of Nurse-Midwives (ACNM) also provides accreditation to non-nurse midwife programs, as well as colleges that graduate nurse-midwives. This credential, called the Certified Midwife, is currently recognized in only three states (New York, New Jersey, and Rhode Island). All CMs must pass the same certifying exam administered by the American Midwifery Certification Board for CNMs. At present, there are approximately 50 CMs practicing in the US. The North American Registry of Midwives (NARM) is a certification agency whose mission is to establish and administer certification for the credential "Certified Professional Midwife" (CPM). CPM certification validates entry-level knowledge, skills, and experience vital to responsible midwifery practice. This certification process encompasses multiple educational routes of entry including apprenticeship, self-study, private midwifery schools, college- and university-based midwifery programs, and nurse-midwifery. Created in 1987 by the Midwives' Alliance of North America (MANA), NARM is committed to identifying standards and practices that reflect the excellence and diversity of the independent midwifery community in order to set the standard for North American midwifery. ## Practice in the United States Midwives work with women and their families in any number of settings. While the majority of nurse-midwives work in hospitals, some nurse-midwives and many non-nurse-midwives work within the community or home. In many states, midwives form birthing centers where a group of midwives work together. Midwives generally support and encourage natural childbirth in all practice settings. Laws regarding who can practice midwifery and in what circumstances vary from state to state, and some midwives practice outside of the law. ## Missouri Controversy Direct entry midwifery is unlawful in Missouri and practicing without a CNM license is a felony. However, on 26 May 2007 the Missouri Legislature passed a bill which provides tax incentives for those who purchase their own insurance in order to increase private health coverage for the uninsured. Attached to this legislation was a one sentence provision added by Sen. John Loudon which effectively legalizes certain direct entry midwifery. Although such measures had been previously been rejected by the legislature, Loudon was able to attach the provision undetected by use of the word tocology (word of Greek origin that means the practice of obstetrics and childbirth) rather than any reference to midwifery. Despite protests from some members of the legislature, Gov. Matt Blunt signed the bill into law. A circuit judge issued a temporary restraining order on 03 July 2007 barring the implementation of the law, which was to take effect on 28 August 2007. Following a 02 August 2007 hearing, the judge ruled the midwifery law illegal. A Columbia, Missouri-based midwives association plans to appeal the decision to the Missouri Supreme Court. # Midwifery in the United Kingdom Midwives are practitioners in their own right in the United Kingdom, and take responsibility for the antenatal, intrapartum and postnatal care of women, up until 28 days after the birth, or as required thereafter. Midwives are the lead health care professional attending the majority of births, mostly in a hospital setting, although home birth is a perfectly safe option for many births. There are a variety of routes to qualifying as a midwife. Most midwives now qualify via a direct entry course, which refers to a three- or four-year course undertaken at university that leads to either a degree or a diploma of higher education in midwifery and entitles them to apply for admission to the register. Following completion of nurse training, a nurse may become a registered midwife by completing an eighteen-month post-registration course (leading to a degree qualification), however this route is only available to adult branch nurses, and any child, mental health, or learning disability branch nurse must complete the full three-year course to qualify as a midwife. Midwifery students do not pay tuition fees and are eligible for financial support for living costs while training. Funding varies slightly depending on which country within the UK the student is in and whether the course they are on is a degree or diploma course. For direct entry students funding is in the form of either a non-means-tested bursary or a combination of student loan and means-tested bursary, while post-registration students are normally seconded by their employer and are paid a salary and have their fees paid for them. All practicing midwives must be registered with the Nursing and Midwifery Council and also must have a Supervisor of Midwives through their local supervising authority. Most midwives work within the National Health Service, providing both hospital and community care, but a significant proportion work independently, providing total care for their clients within a community setting. However, recent government proposals to require insurance for all health professionals is threatening independent midwifery in England. To be a midwife is to be responsible, at all times, for the woman for whom you are caring, to know when to refer complications to medical staff, to act as the woman's advocate, and to ensure the mother retains choice and control over her childbirth experience. Many midwives are opposed to the so-called "medicalisation" of childbirth, preferring a more normal and natural option, to ensure a more satisfactory outcome for mother and baby. ## Midwife training Midwifery training is considered one of the most challenging and competitive courses amongst other healthcare subjects. Most midwives undergo a 32 month vocational training program, or a 18 month nurse conversion course (on top of the 32 month nurse training course). Thus midwives potentially could have had up to 5 years of total training. Midwives may train to be community Health Visitors (as may Nurses). ## Community midwives Many midwives also work in the community. The roles of community midwives include the initial appointments of pregnant women, running clinics, postnatal checks in the home, and attending home births. ## Midwife phraseology In the UK there is a common guideline from the Nursing and Midwifery Council outlining a standard set of phrases to encourage and help the woman through labour. These phrases are designed and standardised to make clear the instructions for maximal clarity and effect. From the Midwifery Handbook 2005 published by the Nursing and Midwifery Council, here are a few of the most commonly used phrases: - "Give me a long push, long push, long push" - "Big breath, chin down, push out down below" - "Imagine you are constipated, give me a big push" - "You can do it, you will do it, I want to see you push" - "It is almost over (+ name), I can see the baby's head, the hardest part is over" - "You've done it, congratulations!" Many midwives rote learn these phrases as they are designed by psychologists to be most effective for promoting labour and enhancing patient birthing experience. # Midwifery in Canada Midwifery was reborn as a profession in Canada in the 1960s, along with other aspects of health care reform that trace their roots to that decade of societal ferment and change. After several decades of intensive political lobbying by midwives and consumers, regulated midwifery has become part of the health system in the provinces of British Columbia, Alberta, Manitoba, Ontario, and Quebec, and in the Northwest Territories and Nunavut. Alberta does not publicly fund midwifery. Saskatchewan has legislation but has not integrated midwifery yet. Midwifery is not yet legally recognised in the Atlantic provinces of New Brunswick, Prince Edward Island, Newfoundland and Labrador, or Nova Scotia. The governments of Nova Scotia and New Brunswick have introduced midwifery legislation but have yet to commit to funding midwifery services if and when the bills pass. Midwives in Canada have come from a variety of backgrounds, including nurse-midwifery, lay midwifery and direct-entry midwifery. However, they are all simply known as 'midwives', regardless of their original training. From the original 'alternative' style of midwifery in the 1960s and 1970s, midwifery practice has become somewhat standardized in all of the regulated provinces: midwives offer continuity of care within small group practices, choice of birthplace, and a focus on the woman as the primary decision-maker in her maternity care. When women experience deviations from normal in their pregnancies, midwives consult with other health care professionals. The women's care may continue with the midwife, in collaboration with an obstetrician or other health care specialist; her care may be transferred to an obstetrician or other health care specialist, temporarily or for the remainder of her pregnancy and birth. Woman as primary decision maker, informed choice, and choice of birth place are primary tenets of midwifery care in Canada. Three provinces now offer midwifery education, which consists of a four year university baccalaureate degree in midwifery. In British Columbia, the program is offered at the University of British Columbia. In Ontario, the Midwifery Education Program is offered by a consortium of McMaster University, Ryerson University and Laurentian University. In Quebec, the programme is offered at the Université du Québec à Trois-Rivières. In northern Quebec, Inuit women are being educated to be midwives in their own communities. A program for First Nations midwifery students will open soon in Manitoba. The legislation of midwifery has brought midwives into the mainstream of health care with universal funding for services (except in Alberta), hospital privileges, rights to prescribe medications commonly needed during pregnancy and birth, and rights to order blood work and ultrasounds for their own clients. To protect the tenets of midwifery and keep midwives providing woman-centered care, the regulatory bodies and professional associations have legislation and standards in place to provide protection, particularly for choice of birth place (see home birth), informed choice about care, and continuity of care. Midwives in Ontario have had malpractice insurance since prior to legislation, and all other legislated midwives also have malpractice insurance. Prior to legislative changes, very few Canadian women had access to midwifery care (in part because it was not funded by the health care system). Legislating midwifery has made midwifery services available to a wide and diverse population of women. # Midwifery in New Zealand Midwifery regained its status as an autonomous profession in New Zealand in 1990. The Nurses Amendment Act restored the professional and legal separation of midwifery from nursing, and established midwifery and nursing as separate and distinct professions. Nearly all midwives gaining registration now are direct entry midwives who have not undertaken any nursing training. Registration requires a Bachelor of Midwifery degree. this is currently a three year full time programme but is in the process of being reviewed by the New Zealand midwifery regulatory authority.. Women must choose one of a midwife, a General Practitioner or an Obstetrician to provide their maternity care. About 78 percent choose a midwife (8 percent GP, 8 percent Obstetrician, 6 percent unknown. ). Midwives provide maternity care from early pregnancy to 6 weeks postpartum. The midwifery scope of practise covers normal pregnancy and birth. The midwife will either consult or transfer care where there is a departure from normal. Antenatal and postnatal care is normally provided in the woman’s home. Birth can be in the home, a primary birthing unit, or a hospital. Midwifery care is fully funded by the Government. (GP care is fully funded. Obstetric care will incur a fee in addition to the government funding.)	Midwifery Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Template:TOCright Midwifery is the term traditionally used to describe the art of assisting a woman through childbirth. In the modern context, this term is used to describe the activities of those health care providers who are experts in women's health care including giving prenatal care to expecting mothers. They attend the birth of the infant and provide postpartum care to the mother and her infant. Practitioners of midwifery are known as midwives, a term used in reference to both women and men (the term means "with woman"). Midwives are autonomous practitioners who are specialists in normal pregnancy, childbirth and the postpartum. They generally strive to help women have a healthy pregnancy and natural birth experience. Midwives are also primary care givers providing general women's health care. Midwives are trained to recognize and deal with deviations from the norm. Obstetricians, in contrast, are specialists in illness related to childbearing and in surgery. The two professions can be complementary, but often are at odds because obstetricians are taught to "actively manage" labor, while midwives are taught not to intervene unless necessary. [1] Midwives refer to obstetricians when a woman requires care beyond her or his areas of expertise. In many jurisdictions, these professions work together to provide care to childbearing women. In others, only the midwife is available to provide care. Midwives are trained to handle certain situations that are considered abnormal, including breech birth and posterior position, using non-invasive techniques. In many areas of the world, traditional midwives, renamed "traditional birth attendants" by the World Health Organization (WHO) and other groups, are the only available providers for childbearing women.[citation needed] Midwives once treated patients for female hysteria. # Defining midwifery According to the WHO definition, a midwife is a person who, having been regularly admitted to a midwifery educational program that is duly recognised in the country in which it is located, has successfully completed the prescribed course of studies in midwifery and has acquired the requisite qualifications to be registered and/or legally licensed to practice midwifery. The educational program may be an apprenticeship, a formal university program, or a combination. The midwife is recognised as a responsible and accountable professional who works in partnership with women to give the necessary support, care and advice during pregnancy, labour and the postpartum period, to conduct births on the midwife's own responsibility and to provide care for the infant. This care includes preventive measures, the promotion of normal birth, the detection of complications in mother and child, accessing of medical or other appropriate assistance and the carrying out of emergency measures. The midwife has an important task in health counselling and education, not only for the woman, but also within the family and community. This work should involve antenatal education and preparation for parenthood and may extend to women's health, sexual or reproductive health and childcare. A midwife may practice in any setting including in the home, the community, hospitals, clinics or health units. Adopted by the International Confederation of Midwives, 19 July 2005 This definition is controversial and not everyone agrees with the exclusion of traditional midwives who in developing countries often are the only people available to assist women in birth. # Historical perspective Historically, midwifery has been one of the few medical practices dominated by female practitioners. From Agnodice in ancient Greece to the 18th century in Europe, the care of mothers and delivery of infants has been regarded, both by patients and by the medical profession, as appropriately carried out by women. In the 18th century, a division between surgeons and midwives arose, as medical men began to assert that their modern scientific processes were better for mothers and infants than the folk-medical midwives. Whether this was a valid claim or not can be seen in the entry for Justine Siegemund, a renowned seventeenth century German midwife, whose Court Midwife (1690) was the first female-authored German medical text.[citation needed] At the outset of the 18th century in England, most babies were caught by a midwife, but by the onset of the 19th century, the majority of those babies born to persons of means had a surgeon involved. A number of excellent full length studies of this historical shift have been written. German social scientists Gunnar Heinsohn and Otto Steiger have put forward the theory that midwifery became a target of persecution and repression by public authorities because midwives not only possessed highly specialized knowledge and skills regarding assisting birth, but also regarding contraception and abortion [2]. According to Heinsohn and Steiger's theory, the modern state persecuted the midwives as witches in an effort to repopulate the European continent which had suffered severe loss of manpower as a result of the bubonic plague (also known as the black death) which had swept over the continent in waves, starting in 1348. They thus interpret the witch hunts as attacking midwifery and knowledge about birth control with a demographic goal in mind. Indeed, after the witch hunts, the number of children per mother rose sharply, giving rise to what has been called the "European population explosion" of modern times, producing an enormous youth bulge that enabled Europe to colonize large parts of the rest of the world. While historians specializing in the history of the witch hunts have generally remained critical of this macroeconomic approach and continue to favor micro level perspectives and explanations, prominent historian of birth control John M. Riddle has expressed agreement.[3] # Midwifery in the United States There are two main divisions of modern midwifery in the US: nurse-midwives and direct-entry midwives. ## Nurse-midwives Nurse-midwives were introduced in the United States in 1925 by Mary Breckinridge for use in the Frontier Nursing Service (FNS). Mrs. Breckinridge chose the nurse-midwifery model used in England and Scotland because she expected these nurse-midwives on horse back to serve the health care needs of the families living in the remote hills of eastern Kentucky. This combination of nurse and midwife was very successful. The Metropolitan Life Insurance Company studied the first seven years of the FNS, and reported a substantially lower maternal and infant mortality rate than for the rest of the country. The report concluded that if this type of care was available to other women in the USA thousands of lives would be saved, and suggested nurse-midwife training should be done in the USA. Mrs. Breckinridge opened the Frontier Graduate School of Midwifery in 1939 the first nurse-midwifery education program in the USA that is still educating nurse-midwives today http://www.frontierschool.edu/. In the United States, nurse-midwives are advanced practice nurses who have specialized in the practice of obstetrical and gynecological care of relatively healthy women. In addition to a registered nursing license, many nurse-midwives have a master's degree in nursing, public health, or midwifery. Nurse-midwives practice in hospitals, medical clinics and private offices and may deliver babies in hospitals, birth centers and at home. They are able to prescribe medications in all 50 states. Nurse-midwives provide care to women from puberty through menopause. Nurse-midwives may work closely with obstetricians, who provide consultation and assistance to patients who develop complications. Often, women with high risk pregnancies can receive the benefits of midwifery care from a nurse-midwife in collaboration with a physician. Currently, 2% of nurse-midwives are men. The American College of Nurse-Midwives accredits nurse-midwifery education programs and serves as the national professional society for the nation's certified nurse-midwives. At present approximately 5500 Certified Nurse-Midwives are practicing in the U.S.[citation needed] ## Direct-entry midwives A direct-entry midwife is educated in the discipline of midwifery in a program or path that does not also require her to become educated as a nurse. Direct-entry midwives learn midwifery through self-study, apprenticeship, a midwifery school, or a college- or university-based program distinct from the discipline of nursing. A direct-entry midwife is trained to provide the Midwives Model of Care to healthy women and newborns throughout the childbearing cycle primarily in out-of-hospital settings. Under the umbrella of "direct-entry midwife" are several types of midwives: A Certified Professional Midwife (CPM) is a knowledgeable, skilled and professional independent midwifery practitioner who has met the standards for certification set by the North American Registry of Midwives (NARM) and is qualified to provide the midwives model of care. The CPM is the only US credential that requires knowledge about and experience in out-of-hospital settings. At present, there are approximately 900 CPMs practicing in the US. A Licensed Midwife is a midwife who is licensed to practice in a particular state. Currently, licensure for direct-entry midwives is available in 24 states. The term "Lay Midwife" has been used to designate an uncertified or unlicensed midwife who was educated through informal routes such as self-study or apprenticeship rather than through a formal program. This term does not necessarily mean a low level of education, just that the midwife either chose not to become certified or licensed, or there was no certification available for her type of education (as was the fact before the Certified Professional Midwife credential was available). Other similar terms to describe uncertified or unlicensed midwives are traditional midwife, traditional birth attendant, granny midwife and independent midwife.[citation needed] The American College of Nurse-Midwives (ACNM) also provides accreditation to non-nurse midwife programs, as well as colleges that graduate nurse-midwives. This credential, called the Certified Midwife, is currently recognized in only three states (New York, New Jersey, and Rhode Island). All CMs must pass the same certifying exam administered by the American Midwifery Certification Board for CNMs. At present, there are approximately 50 CMs practicing in the US.[citation needed] The North American Registry of Midwives (NARM) is a certification agency whose mission is to establish and administer certification for the credential "Certified Professional Midwife" (CPM). CPM certification validates entry-level knowledge, skills, and experience vital to responsible midwifery practice. This certification process encompasses multiple educational routes of entry including apprenticeship, self-study, private midwifery schools, college- and university-based midwifery programs, and nurse-midwifery. Created in 1987 by the Midwives' Alliance of North America (MANA), NARM is committed to identifying standards and practices that reflect the excellence and diversity of the independent midwifery community in order to set the standard for North American midwifery. ## Practice in the United States Midwives work with women and their families in any number of settings. While the majority of nurse-midwives work in hospitals, some nurse-midwives and many non-nurse-midwives work within the community or home. In many states, midwives form birthing centers where a group of midwives work together. Midwives generally support and encourage natural childbirth in all practice settings. Laws regarding who can practice midwifery and in what circumstances vary from state to state, and some midwives practice outside of the law. ## Missouri Controversy Direct entry midwifery is unlawful in Missouri and practicing without a CNM license is a felony. However, on 26 May 2007 the Missouri Legislature passed a bill which provides tax incentives for those who purchase their own insurance in order to increase private health coverage for the uninsured. Attached to this legislation was a one sentence provision added by Sen. John Loudon which effectively legalizes certain direct entry midwifery. Although such measures had been previously been rejected by the legislature, Loudon was able to attach the provision undetected by use of the word tocology (word of Greek origin that means the practice of obstetrics and childbirth) rather than any reference to midwifery. Despite protests from some members of the legislature, Gov. Matt Blunt signed the bill into law. [4] A circuit judge issued a temporary restraining order on 03 July 2007 barring the implementation of the law, which was to take effect on 28 August 2007. [5] Following a 02 August 2007 hearing, the judge ruled the midwifery law illegal. A Columbia, Missouri-based midwives association plans to appeal the decision to the Missouri Supreme Court. [6] # Midwifery in the United Kingdom Midwives are practitioners in their own right in the United Kingdom, and take responsibility for the antenatal, intrapartum and postnatal care of women, up until 28 days after the birth, or as required thereafter. Midwives are the lead health care professional attending the majority of births, mostly in a hospital setting, although home birth is a perfectly safe option for many births. There are a variety of routes to qualifying as a midwife. Most midwives now qualify via a direct entry course, which refers to a three- or four-year course undertaken at university that leads to either a degree or a diploma of higher education in midwifery and entitles them to apply for admission to the register. Following completion of nurse training, a nurse may become a registered midwife by completing an eighteen-month post-registration course (leading to a degree qualification), however this route is only available to adult branch nurses, and any child, mental health, or learning disability branch nurse must complete the full three-year course to qualify as a midwife. Midwifery students do not pay tuition fees and are eligible for financial support for living costs while training. Funding varies slightly depending on which country within the UK the student is in and whether the course they are on is a degree or diploma course. For direct entry students funding is in the form of either a non-means-tested bursary or a combination of student loan and means-tested bursary, while post-registration students are normally seconded by their employer and are paid a salary and have their fees paid for them.[citation needed] All practicing midwives must be registered with the Nursing and Midwifery Council and also must have a Supervisor of Midwives through their local supervising authority. Most midwives work within the National Health Service, providing both hospital and community care, but a significant proportion work independently, providing total care for their clients within a community setting. However, recent government proposals to require insurance for all health professionals is threatening independent midwifery in England. [7] To be a midwife is to be responsible, at all times, for the woman for whom you are caring, to know when to refer complications to medical staff, to act as the woman's advocate, and to ensure the mother retains choice and control over her childbirth experience. Many midwives are opposed to the so-called "medicalisation" of childbirth, preferring a more normal and natural option, to ensure a more satisfactory outcome for mother and baby.[citation needed] ## Midwife training Midwifery training is considered one of the most challenging and competitive courses amongst other healthcare subjects. Most midwives undergo a 32 month vocational training program, or a 18 month nurse conversion course (on top of the 32 month nurse training course). Thus midwives potentially could have had up to 5 years of total training. Midwives may train to be community Health Visitors (as may Nurses). ## Community midwives Many midwives also work in the community. The roles of community midwives include the initial appointments of pregnant women, running clinics, postnatal checks in the home, and attending home births. ## Midwife phraseology In the UK there is a common guideline from the Nursing and Midwifery Council outlining a standard set of phrases to encourage and help the woman through labour. These phrases are designed and standardised to make clear the instructions for maximal clarity and effect. From the Midwifery Handbook 2005 published by the Nursing and Midwifery Council, here are a few of the most commonly used phrases: - "Give me a long push, long push, long push" - "Big breath, chin down, push out down below" - "Imagine you are constipated, give me a big push" - "You can do it, you will do it, I want to see you push" - "It is almost over (+ name), I can see the baby's head, the hardest part is over" - "You've done it, congratulations!" Many midwives rote learn these phrases as they are designed by psychologists to be most effective for promoting labour and enhancing patient birthing experience. # Midwifery in Canada Midwifery was reborn as a profession in Canada in the 1960s, along with other aspects of health care reform that trace their roots to that decade of societal ferment and change. After several decades of intensive political lobbying by midwives and consumers, regulated midwifery has become part of the health system in the provinces of British Columbia, Alberta, Manitoba, Ontario, and Quebec, and in the Northwest Territories and Nunavut. Alberta does not publicly fund midwifery. Saskatchewan has legislation but has not integrated midwifery yet. Midwifery is not yet legally recognised in the Atlantic provinces of New Brunswick, Prince Edward Island, Newfoundland and Labrador, or Nova Scotia. The governments of Nova Scotia and New Brunswick have introduced midwifery legislation but have yet to commit to funding midwifery services if and when the bills pass. Midwives in Canada have come from a variety of backgrounds, including nurse-midwifery, lay midwifery and direct-entry midwifery. However, they are all simply known as 'midwives', regardless of their original training. From the original 'alternative' style of midwifery in the 1960s and 1970s, midwifery practice has become somewhat standardized in all of the regulated provinces: midwives offer continuity of care within small group practices, choice of birthplace, and a focus on the woman as the primary decision-maker in her maternity care. When women experience deviations from normal in their pregnancies, midwives consult with other health care professionals. The women's care may continue with the midwife, in collaboration with an obstetrician or other health care specialist; her care may be transferred to an obstetrician or other health care specialist, temporarily or for the remainder of her pregnancy and birth. Woman as primary decision maker, informed choice, and choice of birth place are primary tenets of midwifery care in Canada. Three provinces now offer midwifery education, which consists of a four year university baccalaureate degree in midwifery. In British Columbia, the program is offered at the University of British Columbia. In Ontario, the Midwifery Education Program is offered by a consortium of McMaster University, Ryerson University and Laurentian University. In Quebec, the programme is offered at the Université du Québec à Trois-Rivières. In northern Quebec, Inuit women are being educated to be midwives in their own communities. A program for First Nations midwifery students will open soon in Manitoba. The legislation of midwifery has brought midwives into the mainstream of health care with universal funding for services (except in Alberta), hospital privileges, rights to prescribe medications commonly needed during pregnancy and birth, and rights to order blood work and ultrasounds for their own clients. To protect the tenets of midwifery and keep midwives providing woman-centered care, the regulatory bodies and professional associations have legislation and standards in place to provide protection, particularly for choice of birth place (see home birth), informed choice about care, and continuity of care. Midwives in Ontario have had malpractice insurance since prior to legislation, and all other legislated midwives also have malpractice insurance. Prior to legislative changes, very few Canadian women had access to midwifery care (in part because it was not funded by the health care system). Legislating midwifery has made midwifery services available to a wide and diverse population of women. # Midwifery in New Zealand Midwifery regained its status as an autonomous profession in New Zealand in 1990. The Nurses Amendment Act restored the professional and legal separation of midwifery from nursing, and established midwifery and nursing as separate and distinct professions. Nearly all midwives gaining registration now are direct entry midwives who have not undertaken any nursing training. Registration requires a Bachelor of Midwifery degree. this is currently a three year full time programme but is in the process of being reviewed by the New Zealand midwifery regulatory authority.. Women must choose one of a midwife, a General Practitioner or an Obstetrician to provide their maternity care. About 78 percent choose a midwife (8 percent GP, 8 percent Obstetrician, 6 percent unknown. [8]). Midwives provide maternity care from early pregnancy to 6 weeks postpartum. The midwifery scope of practise covers normal pregnancy and birth. The midwife will either consult or transfer care where there is a departure from normal. Antenatal and postnatal care is normally provided in the woman’s home. Birth can be in the home, a primary birthing unit, or a hospital. Midwifery care is fully funded by the Government. (GP care is fully funded. Obstetric care will incur a fee in addition to the government funding.)	https://www.wikidoc.org/index.php/Antenatal
fd9ecc627757945859a2e9ee7f5ab080fa9d12f6	wikidoc	Anthralin	Anthralin # 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 Anthralin is an antipsoriatic that is FDA approved for the treatment of chronic psoriasis. Common adverse reactions include hypersensitivity. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Topical treatment of chronic psoriasis ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Anthralin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Anthralin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Anthralin 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 Anthralin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Anthralin in pediatric patients. # Contraindications There is limited information regarding Anthralin Contraindications in the drug label. # Warnings - For external use only. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Anthralin Clinical Trials Experience in the drug label. ## Postmarketing Experience - Hypersensitivity # Drug Interactions There is limited information regarding Anthralin Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Anthralin in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Anthralin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Anthralin during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Anthralin in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Anthralin in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Anthralin in geriatric settings. ### Gender There is no FDA guidance on the use of Anthralin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Anthralin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Anthralin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Anthralin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Anthralin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Anthralin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Anthralin Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Anthralin and IV administrations. # Overdosage There is limited information regarding Anthralin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action There is limited information regarding Anthralin Mechanism of Action in the drug label. ## Structure There is limited information regarding Anthralin Structure in the drug label. ## Pharmacodynamics There is limited information regarding Anthralin Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Anthralin Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Anthralin Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Anthralin Clinical Studies in the drug label. # How Supplied There is limited information regarding Anthralin How Supplied in the drug label. ## Storage There is limited information regarding Anthralin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Anthralin Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Anthralin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - DRITHO-CREME HP® # Look-Alike Drug Names There is limited information regarding Anthralin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Anthralin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Anthralin is an antipsoriatic that is FDA approved for the treatment of chronic psoriasis. Common adverse reactions include hypersensitivity. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Topical treatment of chronic psoriasis ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Anthralin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Anthralin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Anthralin 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 Anthralin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Anthralin in pediatric patients. # Contraindications There is limited information regarding Anthralin Contraindications in the drug label. # Warnings - For external use only. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Anthralin Clinical Trials Experience in the drug label. ## Postmarketing Experience - Hypersensitivity # Drug Interactions There is limited information regarding Anthralin Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Anthralin in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Anthralin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Anthralin during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Anthralin in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Anthralin in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Anthralin in geriatric settings. ### Gender There is no FDA guidance on the use of Anthralin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Anthralin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Anthralin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Anthralin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Anthralin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Anthralin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Anthralin Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Anthralin and IV administrations. # Overdosage There is limited information regarding Anthralin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action There is limited information regarding Anthralin Mechanism of Action in the drug label. ## Structure There is limited information regarding Anthralin Structure in the drug label. ## Pharmacodynamics There is limited information regarding Anthralin Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Anthralin Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Anthralin Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Anthralin Clinical Studies in the drug label. # How Supplied There is limited information regarding Anthralin How Supplied in the drug label. ## Storage There is limited information regarding Anthralin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Anthralin Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Anthralin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - DRITHO-CREME HP®[1] # Look-Alike Drug Names There is limited information regarding Anthralin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Anthralin
2e0b8f67465eb92949d1a6db4c69ce39fe4f819d	wikidoc	Logarithm	Logarithm In mathematics, the logarithm of a given number to a given base is the power or exponent to which the base must be raised in order to produce the given number. For example, the logarithm of 1000 to the common base 10 is 3, because 10 raised to the power of 3 is 1000; the base 2 logarithm of 32 is 5 because 2 to the power 5 is 32. The logarithm of x to the base b is written logb(x) or, if the base is implicit, as log(x). So, for a number x, a base b and an exponent y, An important feature of logarithms is that they reduce multiplication to addition, by the formula: That is, the logarithm of the product of two numbers is the sum of the logarithms of those numbers. The use of logarithms to facilitate complex calculations was a significant motivation in their original development. # Properties of the logarithm When x and b are restricted to positive real numbers, logb(x) is a unique real number. The magnitude of the base b must be neither 0 nor 1; the base used is typically 10, e, or 2. Logarithms are defined for real numbers and for complex numbers. The major property of logarithms is that they map multiplication to addition. This ability stems from the following identity: which by taking logarithms becomes A related property is reduction of exponentiation to multiplication. Using the identity: it follows that c to the power p (exponentiation) is: -r, taking logarithms: In words, to raise a number to a power p, find the logarithm of the number and multiply it by p. The exponentiated value is then the inverse logarithm of this product; that is, number to power = bproduct. Besides reducing multiplication operations to addition, and exponentiation to multiplication, logarithms reduce division to subtraction, and roots to division. Logarithms make lengthy numerical operations easier to perform. The whole process is made easy by using tables of logarithms, or a slide rule, antiquated now that calculators are available. Although the above practical advantages are not important for numerical work today, they are used in graphical analysis (see Bode plot). # The logarithm as a function Though logarithms have been traditionally thought of as arithmetic sequences of numbers corresponding to geometric sequences of other (positive real) numbers, as in the 1797 Britannica definition, they are also the result of applying an analytic function. The function can therefore be meaningfully extended to complex numbers. The function logb(x) depends on both b and x, but the term logarithm function (or logarithmic function) in standard usage refers to a function of the form logb(x) in which the base b is fixed and so the only argument is x. Thus there is one logarithm function for each value of the base b (which must be positive and must differ from 1). Viewed in this way, the base-b logarithm function is the inverse function of the exponential function bx. The word "logarithm" is often used to refer to a logarithm function itself as well as to particular values of this function. The base can also be a complex number; the evaluation of the log is just slightly more complicated in this case. See imaginary base. # Logarithm of a complex number When the base b is real and z is a complex number, say z = x + i y, the logarithm of z is found easily by putting z in polar form that is, z = (x2 + y2)1/2 exp (i tan−1 (y / x) ). If the base of the logarithm is chosen as e , that is, using loge (denoted by ln and called the natural logarithm), the logarithm becomes: This evaluation uses the properties of all logarithms (see above), regardless of choice of base: logb (c d ) = logb (c ) + logb (d ) and its generalization to arbitrary products logb bz = z. Because the inverse tangent is a multiple valued function of its argument, the logarithm of a complex number is not unique either. See article on complex logarithm. # Group theory From the pure mathematical perspective, the identity is fundamental in two senses. First, the remaining three arithmetic properties can be derived from it. Furthermore, it expresses an isomorphism between the multiplicative group of the positive real numbers and the additive group of all the reals. Logarithmic functions are the only continuous isomorphisms from the multiplicative group of positive real numbers to the additive group of real numbers. # Bases The most widely used bases for logarithms are 10, the mathematical constant e ≈ 2.71828... and 2. When "log" is written without a base (b missing from logb), the intent can usually be determined from context: - natural logarithm (loge, ln, log, or Ln) in mathematical analysis, statistics, economics and some engineering fields. The reasons to consider e the natural base for logarithms, though perhaps not obvious, are numerous and compelling. - common logarithm (log10 or simply log; sometimes lg) in various engineering fields, especially for power levels and power ratios, such as acoustical sound pressure, and in logarithm tables to be used to simplify hand calculations - binary logarithm (log2; sometimes lg, lb, or ld) in information theory and computer-related fields - indefinite logarithm when the base is irrelevant, e.g. in complexity theory when describing the asymptotic behavior of algorithms in big O notation. To avoid confusion, it is best to specify the base if there is any chance of misinterpretation. ## Other notations The notation "ln(x)" invariably means loge(x), i.e., the natural logarithm of x, but the implied base for "log(x)" varies by discipline: - Mathematicians generally understand both "ln(x)" and "log(x)" to mean loge(x) and write "log10(x)" when the base-10 logarithm of x is intended. Calculus textbooks will occasionally write "lg(x)" to represent "log10(x)". - Many engineers, biologists, astronomers, and some others write only "ln(x)" or "loge(x)" when they mean the natural logarithm of x, and take "log(x)" to mean log10(x) or, sometimes in the context of computing, log2(x). - On most calculators, the LOG button is log10(x) and LN is loge(x). - In most commonly used computer programming languages, including C, C++, Java, Fortran, Ruby, and BASIC, the "log" function returns the natural logarithm. The base-10 function, if it is available, is generally "log10." - Some people use Log(x) (capital L) to mean log10(x), and use log(x) with a lowercase l to mean loge(x). - The notation Log(x) is also used by mathematicians to denote the principal branch of the (natural) logarithm function. - A notation frequently used in some European countries is the notation blog(x) instead of logb(x). This chaos, historically, originates from the fact that the natural logarithm has nice mathematical properties (such as its derivative being 1/x, and having a simple definition), while the base 10 logarithms, or decimal logarithms, were more convenient for speeding calculations (back when they were used for that purpose). Thus natural logarithms were only extensively used in fields like calculus while decimal logarithms were widely used elsewhere. As recently as 1984, Paul Halmos in his "automathography" I Want to Be a Mathematician heaped contempt on what he considered the childish "ln" notation, which he said no mathematician had ever used. The notation was in fact invented in 1893 by Irving Stringham, professor of mathematics at Berkeley. As of 2005, many mathematicians have adopted the "ln" notation, but most use "log". In computer science, the base 2 logarithm is sometimes written as lg(x), as suggested by Edward Reingold and popularized by Donald Knuth. However, lg(x) is also sometimes used for the common log, and lb(x) for the binary log. In Russian literature, the notation lg(x) is also generally used for the base 10 logarithm. In German, lg(x) also denotes the base 10 logarithm, while sometimes ld(x) or lb(x) is used for the base 2 logarithm. The clear advice of the United States Department of Commerce National Institute of Standards and Technology is to follow the ISO standard Mathematical signs and symbols for use in physical sciences and technology, ISO 31-11:1992, which suggests these notations: - The notation "ln(x)" means loge(x); - The notation "lg(x)" means log10(x); - The notation "lb(x)" means log2(x). As the difference between logarithms to different bases is one of scale, it is possible to consider all logarithm functions to be the same, merely giving the answer in different units, such as dB, neper, bits, decades, etc.; see the section Science and engineering below. Logarithms to a base less than 1 have a negative scale, or a flip about the x axis, relative to logarithms of base greater than 1. ## Change of base While there are several useful identities, the most important for calculator use lets one find logarithms with bases other than those built into the calculator (usually loge and log10). To find a logarithm with base b, using any other base k: Moreover, this result implies that all logarithm functions (whatever the base) are similar to each other. So to calculate the log with base 2 of the number 16 with a calculator: # Uses of logarithms Logarithms are useful in solving equations in which exponents are unknown. They have simple derivatives, so they are often used in the solution of integrals. The logarithm is one of three closely related functions. In the equation bn = x, b can be determined with radicals, n with logarithms, and x with exponentials. See logarithmic identities for several rules governing the logarithm functions. ## Science Various quantities in science are expressed as logarithms of other quantities; see logarithmic scale for an explanation and a more complete list. - In chemistry, the negative of the base-10 logarithm of the activity of hydronium ions (H3O+, the form H+ takes in water) is the measure known as pH. The activity of hydronium ions in neutral water is 10−7 mol/L at 25 °C, hence a pH of 7. - The bel (symbol B) is a unit of measure which is the base-10 logarithm of ratios, such as power levels and voltage levels. It is mostly used in telecommunication, electronics, and acoustics. The Bel is named after telecommunications pioneer Alexander Graham Bell. The decibel (dB), equal to 0.1 bel, is more commonly used. The neper is a similar unit which uses the natural logarithm of a ratio. - The Richter scale measures earthquake intensity on a base-10 logarithmic scale. - In spectrometry and optics, the absorbance unit used to measure optical density is equivalent to −1 B. - In astronomy, the apparent magnitude measures the brightness of stars logarithmically, since the eye also responds logarithmically to brightness. - In psychophysics, the Weber–Fechner law proposes a logarithmic relationship between stimulus and sensation. - In computer science, logarithms often appear in bounds for computational complexity. For example, to sort N items using comparison can require time proportional to the product N × log N. Similarly, base-2 logarithms are used to express the amount of storage space or memory required for a binary representation of a number—with k bits (each a 0 or a 1) one can represent 2k distinct values, so any natural number N can be represented in no more than (log2 N) + 1 bits. - Similarly, in information theory logarithms are used as a measure of quantity of information. If a message recipient may expect any one of N possible messages with equal likelihood, then the amount of information conveyed by any one such message is quantified as log2 N bits. - In geometry the logarithm is used to form the metric for the half-plane model of hyperbolic geometry. - Many types of engineering and scientific data are typically graphed on log-log or semilog axes, in order to most clearly show the form of the data. - In inferential statistics, the logarithm of the data in a dataset can be used for parametric statistical testing if the original data does not meet the assumption of normality. - Musical intervals are measured logarithmically as semitones. The interval between two notes in semitones is the base-21/12 logarithm of the frequency ratio (or equivalently, 12 times the base-2 logarithm). Fractional semitones are used for non-equal temperaments. Especially to measure deviations from the equal tempered scale, intervals are also expressed in cents (hundredths of an equally-tempered semitone). The interval between two notes in cents is the base-21/1200 logarithm of the frequency ratio (or 1200 times the base-2 logarithm). In MIDI, notes are numbered on the semitone scale (logarithmic absolute nominal pitch with middle C at 60). For microtuning to other tuning systems, a logarithmic scale is defined filling in the ranges between the semitones of the equal tempered scale in a compatible way. This scale corresponds to the note numbers for whole semitones. (see microtuning in MIDI). ## Exponential functions One way of defining the exponential function ex, also written as exp(x), is as the inverse of the natural logarithm. It is positive for every real argument x. The operation of "raising b to a power p" for positive arguments b and all real exponents p is defined by The antilogarithm function is another name for the inverse of the logarithmic function. It is written antilogb(n) and means the same as bn. ## Easier computations Logarithms can be used to replace difficult operations on numbers by easier operations on their logs (in any base), as the following table summarizes. In the table, upper-case variables represent logs of corresponding lower-case variables: These arithmetic properties of logarithms make such calculations much faster. The use of logarithms was an essential skill until electronic computers and calculators became available. Indeed the discovery of logarithms, just before Newton's era, had an impact in the scientific world that can be compared with that of the advent of computers in the 20th century because it made feasible many calculations that had previously been too laborious. As an example, to approximate the product of two numbers one can look up their logarithms in a table, add them, and, using the table again, proceed from that sum to its antilogarithm, which is the desired product. The precision of the approximation can be increased by interpolating between table entries. For manual calculations that demand any appreciable precision, this process, requiring three lookups and a sum, is much faster than performing the multiplication. To achieve seven decimal places of accuracy requires a table that fills a single large volume; a table for nine-decimal accuracy occupies a few shelves. Similarly, to approximate a power cd one can look up log c in the table, look up the log of that, and add to it the log of d; roots can be approximated in much the same way. One key application of these techniques was celestial navigation. Once the invention of the chronometer made possible the accurate measurement of longitude at sea, mariners had everything necessary to reduce their navigational computations to mere additions. A five-digit table of logarithms and a table of the logarithms of trigonometric functions sufficed for most purposes, and those tables could fit in a small book. Another critical application with even broader impact was the slide rule, an essential calculating tool for engineers. Many of the powerful capabilities of the slide rule derive from a clever but simple design that relies on the arithmetic properties of logarithms. The slide rule allows computation much faster still than the techniques based on tables, but provides much less precision, although slide rule operations can be chained to calculate answers to any arbitrary precision. # Related operations ## Cologarithms The cologarithm of a number is the logarithm of the inverse of said number, meaning cologb(x)=logb(1/x)= - logb(x). ## Antilogarithms The antilogarithm is the logarithmic inverse of the logarithm, meaning that the antilogb(logb(x))=x. Thus, setting by=x implies that logb(x)=y. By taking the antilogb of both sides, antilogb(logb(x))=antilogby, thus x=antilogby. Therefore, by=antilogby. # Calculus The natural logarithm of a positive number x can be defined as The derivative of the natural logarithm function is By applying the change-of-base rule, the derivative for other bases is The antiderivative of the natural logarithm ln(x) is and so the antiderivative of the logarithm for other bases is See also: Table of limits, list of integrals of logarithmic functions. # Series for calculating the natural logarithm There are several series for calculating natural logarithms. The simplest, though inefficient, is: To derive this series, start with (\|x\|) Integrate both sides to obtain Letting z = 1-x \! and thus x = -(z-1) \!, we get A more efficient series is for z with positive real part. To derive this series, we begin by substituting −x for x and get Subtracting, we get Letting z = \frac{1+x}{1-x} \! and thus x = \frac{z-1}{z+1} \!, we get For example, applying this series to we get and thus \frac{1}{7 \cdot 1000000} + \cdots \right ) where we factored 1/10 out of the sum in the first line. For any other base b, we use # Computers Most computer languages use log(x) for the natural logarithm, while the common log is typically denoted log10(x). The argument and return values are typically a floating point (or double precision) data type. As the argument is floating point, it can be useful to consider the following: A floating point value x is represented by a mantissa m and exponent n to form Therefore Thus, instead of computing \ln(x) we compute \ln(m) for some m such that 1 ≤ m u = \frac{m - 1}{m+1} is always in the range 0 \le u . Some machines use the mantissa in the range 0.5 \le m and in that case the value for u will be in the range -\frac13 In either case, the series is even easier to compute. To compute a base 2 logarithm on a number between 1 and 2 in an alternate way, square it repeatedly. Every time it goes over 2, divide it by 2 and write a "1" bit, else just write a "0" bit. This is because squaring doubles the logarithm of a number. The integer part of the logarithm to base 2 of an unsigned integer is given by the position of the left-most bit, and can be computed in O(n) steps using the following algorithm: int log2(int x){ However, it can also be computed in O(log n) steps by trying to shift by powers of 2 and checking that the result stays nonzero: for example, first >>16, then >>8, ... (Each step reveals one bit of the result) # Generalizations The ordinary logarithm of positive reals generalizes to negative and complex arguments, though it is a multivalued function that needs a branch cut terminating at the branch point at 0 to make an ordinary function or principal branch. The logarithm (to base e) of a complex number z is the complex number ln(\|z\|) + i arg(z), where \|z\| is the modulus of z, arg(z) is the argument, and i is the imaginary unit; see complex logarithm for details. The discrete logarithm is a related notion in the theory of finite groups. It involves solving the equation bn = x, where b and x are elements of the group, and n is an integer specifying a power in the group operation. For some finite groups, it is believed that the discrete logarithm is very hard to calculate, whereas discrete exponentials are quite easy. This asymmetry has applications in public key cryptography. The logarithm of a matrix is the inverse of the matrix exponential. It is possible to take the logarithm of a quaternions and octonions. A double logarithm, \ln(\ln(x)), is the inverse function of the double exponential function. A super-logarithm or hyper-4-logarithm is the inverse function of tetration. The super-logarithm of x grows even more slowly than the double logarithm for large x. For each positive b not equal to 1, the function logb (x) is an isomorphism from the group of positive real numbers under multiplication to the group of (all) real numbers under addition. They are the only such isomorphisms that are continuous. The logarithm function can be extended to a Haar measure in the topological group of positive real numbers under multiplication. # History The method of logarithms was first publicly propounded in 1614, in a book entitled Mirifici Logarithmorum Canonis Descriptio, by John Napier, Baron of Merchiston, in Scotland. (Joost Bürgi independently discovered logarithms; however, he did not publish his discovery until four years after Napier.) Early resistance to the use of logarithms was muted by Kepler's enthusiastic support and his publication of a clear and impeccable explanation of how they worked. Their use contributed to the advance of science, and especially of astronomy, by making some difficult calculations possible. Prior to the advent of calculators and computers, they were used constantly in surveying, navigation, and other branches of practical mathematics. It supplanted the more involved method of prosthaphaeresis, which relied on trigonometric identities as a quick method of computing products. Besides the utility of the logarithm concept in computation, the natural logarithm presented a solution to the problem of quadrature of a hyperbolic sector at the hand of Gregoire de Saint-Vincent in 1647. At first, Napier called logarithms "artificial numbers" and antilogarithms "natural numbers". Later, Napier formed the word logarithm to mean a number that indicates a ratio: Template:Polytonic (logos) meaning proportion, and Template:Polytonic (arithmos) meaning number. Napier chose that because the difference of two logarithms determines the ratio of the numbers they represent, so that an arithmetic series of logarithms corresponds to a geometric series of numbers. The term antilogarithm was introduced in the late 17th century and, while never used extensively in mathematics, persisted in collections of tables until they fell into disuse. Napier did not use a base as we now understand it, but his logarithms were, up to a scaling factor, effectively to base 1/e. For interpolation purposes and ease of calculation, it is useful to make the ratio r in the geometric series close to 1. Napier chose r = 1 - 10−7 = 0.999999 (Bürgi chose r = 1 + 10−4 = 1.0001). Napier's original logarithms did not have log 1 = 0 but rather log 107 = 0. Thus if N is a number and L is its logarithm as calculated by Napier, N = 107(1 − 10−7)L. Since (1 − 10−7)107 is approximately 1/e, this makes L/107 approximately equal to log1/e N/107. # Tables of logarithms Prior to the advent of computers and calculators, using logarithms meant using tables of logarithms, which had to be created manually. Base-10 logarithms are useful in computations when electronic means are not available. See common logarithm for details, including the use of characteristics and mantissas of common (i.e., base-10) logarithms. In 1617, Henry Briggs published the first installment of his own table of common logarithms, containing the logarithms of all integers below 1000 to eight decimal places. This he followed, in 1624, by his Arithmetica Logarithmica, containing the logarithms of all integers from 1 to 20,000 and from 90,000 to 100,000 to fourteen places of decimals, together with a learned introduction, in which the theory and use of logarithms are fully developed. The interval from 20,000 to 90,000 was filled up by Adriaan Vlacq, a Dutch mathematician; but in his table, which appeared in 1628, the logarithms were given to only ten places of decimals. Vlacq's table was later found to contain 603 errors, but "this cannot be regarded as a great number, when it is considered that the table was the result of an original calculation, and that more than 2,100,000 printed figures are liable to error." An edition of Vlacq's work, containing many corrections, was issued at Leipzig in 1794 under the title Thesaurus Logarithmorum Completus by Jurij Vega. François Callet's seven-place table (Paris, 1795), instead of stopping at 100,000, gave the eight-place logarithms of the numbers between 100,000 and 108,000, in order to diminish the errors of interpolation, which were greatest in the early part of the table; and this addition was generally included in seven-place tables. The only important published extension of Vlacq's table was made by Mr. Sang in 1871, whose table contained the seven-place logarithms of all numbers below 200,000. Briggs and Vlacq also published original tables of the logarithms of the trigonometric functions. Besides the tables mentioned above, a great collection, called Tables du Cadastre, was constructed under the direction of Gaspard de Prony, by an original computation, under the auspices of the French republican government of the 1700s. This work, which contained the logarithms of all numbers up to 100,000 to nineteen places, and of the numbers between 100,000 and 200,000 to twenty-four places, exists only in manuscript, "in seventeen enormous folios," at the Observatory of Paris. It was begun in 1792; and "the whole of the calculations, which to secure greater accuracy were performed in duplicate, and the two manuscripts subsequently collated with care, were completed in the short space of two years." Cubic interpolation could be used to find the logarithm of any number to a similar accuracy.	Logarithm In mathematics, the logarithm of a given number to a given base is the power or exponent to which the base must be raised in order to produce the given number. For example, the logarithm of 1000 to the common base 10 is 3, because 10 raised to the power of 3 is 1000; the base 2 logarithm of 32 is 5 because 2 to the power 5 is 32. The logarithm of x to the base b is written logb(x) or, if the base is implicit, as log(x). So, for a number x, a base b and an exponent y, An important feature of logarithms is that they reduce multiplication to addition, by the formula: That is, the logarithm of the product of two numbers is the sum of the logarithms of those numbers. The use of logarithms to facilitate complex calculations was a significant motivation in their original development. # Properties of the logarithm When x and b are restricted to positive real numbers, logb(x) is a unique real number. The magnitude of the base b must be neither 0 nor 1; the base used is typically 10, e, or 2. Logarithms are defined for real numbers and for complex numbers. [1][2] The major property of logarithms is that they map multiplication to addition. This ability stems from the following identity: which by taking logarithms becomes A related property is reduction of exponentiation to multiplication. Using the identity: it follows that c to the power p (exponentiation) is: or, taking logarithms: In words, to raise a number to a power p, find the logarithm of the number and multiply it by p. The exponentiated value is then the inverse logarithm of this product; that is, number to power = bproduct. Besides reducing multiplication operations to addition, and exponentiation to multiplication, logarithms reduce division to subtraction, and roots to division. Logarithms make lengthy numerical operations easier to perform. The whole process is made easy by using tables of logarithms, or a slide rule, antiquated now that calculators are available. Although the above practical advantages are not important for numerical work today, they are used in graphical analysis (see Bode plot). # The logarithm as a function Though logarithms have been traditionally thought of as arithmetic sequences of numbers corresponding to geometric sequences of other (positive real) numbers, as in the 1797 Britannica definition, they are also the result of applying an analytic function. The function can therefore be meaningfully extended to complex numbers. The function logb(x) depends on both b and x, but the term logarithm function (or logarithmic function) in standard usage refers to a function of the form logb(x) in which the base b is fixed and so the only argument is x. Thus there is one logarithm function for each value of the base b (which must be positive and must differ from 1). Viewed in this way, the base-b logarithm function is the inverse function of the exponential function bx. The word "logarithm" is often used to refer to a logarithm function itself as well as to particular values of this function. The base can also be a complex number; the evaluation of the log is just slightly more complicated in this case. See imaginary base. # Logarithm of a complex number When the base b is real and z is a complex number, say z = x + i y, the logarithm of z is found easily by putting z in polar form that is, z = (x2 + y2)1/2 exp (i tan−1 (y / x) ). If the base of the logarithm is chosen as e [3], that is, using loge (denoted by ln and called the natural logarithm), the logarithm becomes: This evaluation uses the properties of all logarithms (see above), regardless of choice of base: logb (c d ) = logb (c ) + logb (d ) and its generalization to arbitrary products logb bz = z. Because the inverse tangent is a multiple valued function of its argument, the logarithm of a complex number is not unique either. See article on complex logarithm. # Group theory From the pure mathematical perspective, the identity is fundamental in two senses. First, the remaining three arithmetic properties can be derived from it. Furthermore, it expresses an isomorphism between the multiplicative group of the positive real numbers and the additive group of all the reals. Logarithmic functions are the only continuous isomorphisms from the multiplicative group of positive real numbers to the additive group of real numbers. # Bases The most widely used bases for logarithms are 10, the mathematical constant e ≈ 2.71828... and 2. When "log" is written without a base (b missing from logb), the intent can usually be determined from context: - natural logarithm (loge, ln, log, or Ln) in mathematical analysis, statistics, economics and some engineering fields. The reasons to consider e the natural base for logarithms, though perhaps not obvious, are numerous and compelling. - common logarithm (log10 or simply log; sometimes lg) in various engineering fields, especially for power levels and power ratios, such as acoustical sound pressure, and in logarithm tables to be used to simplify hand calculations - binary logarithm (log2; sometimes lg, lb, or ld) in information theory and computer-related fields - indefinite logarithm when the base is irrelevant, e.g. in complexity theory when describing the asymptotic behavior of algorithms in big O notation. To avoid confusion, it is best to specify the base if there is any chance of misinterpretation. ## Other notations The notation "ln(x)" invariably means loge(x), i.e., the natural logarithm of x, but the implied base for "log(x)" varies by discipline: - Mathematicians generally understand both "ln(x)" and "log(x)" to mean loge(x) and write "log10(x)" when the base-10 logarithm of x is intended. Calculus textbooks will occasionally write "lg(x)" to represent "log10(x)". - Many engineers, biologists, astronomers, and some others write only "ln(x)" or "loge(x)" when they mean the natural logarithm of x, and take "log(x)" to mean log10(x) or, sometimes in the context of computing, log2(x). - On most calculators, the LOG button is log10(x) and LN is loge(x). - In most commonly used computer programming languages, including C, C++, Java, Fortran, Ruby, and BASIC, the "log" function returns the natural logarithm. The base-10 function, if it is available, is generally "log10." - Some people use Log(x) (capital L) to mean log10(x), and use log(x) with a lowercase l to mean loge(x). - The notation Log(x) is also used by mathematicians to denote the principal branch of the (natural) logarithm function. - A notation frequently used in some European countries is the notation blog(x) instead of logb(x).[4] This chaos, historically, originates from the fact that the natural logarithm has nice mathematical properties (such as its derivative being 1/x, and having a simple definition), while the base 10 logarithms, or decimal logarithms, were more convenient for speeding calculations (back when they were used for that purpose). Thus natural logarithms were only extensively used in fields like calculus while decimal logarithms were widely used elsewhere. As recently as 1984, Paul Halmos in his "automathography" I Want to Be a Mathematician heaped contempt on what he considered the childish "ln" notation, which he said no mathematician had ever used. The notation was in fact invented in 1893 by Irving Stringham, professor of mathematics at Berkeley. As of 2005, many mathematicians have adopted the "ln" notation, but most use "log". In computer science, the base 2 logarithm is sometimes written as lg(x), as suggested by Edward Reingold and popularized by Donald Knuth. However, lg(x) is also sometimes used for the common log, and lb(x) for the binary log.[5] In Russian literature, the notation lg(x) is also generally used for the base 10 logarithm.[6] In German, lg(x) also denotes the base 10 logarithm, while sometimes ld(x) or lb(x) is used for the base 2 logarithm. The clear advice of the United States Department of Commerce National Institute of Standards and Technology is to follow the ISO standard Mathematical signs and symbols for use in physical sciences and technology, ISO 31-11:1992, which suggests these notations:[7] - The notation "ln(x)" means loge(x); - The notation "lg(x)" means log10(x); - The notation "lb(x)" means log2(x). As the difference between logarithms to different bases is one of scale, it is possible to consider all logarithm functions to be the same, merely giving the answer in different units, such as dB, neper, bits, decades, etc.; see the section Science and engineering below. Logarithms to a base less than 1 have a negative scale, or a flip about the x axis, relative to logarithms of base greater than 1. ## Change of base While there are several useful identities, the most important for calculator use lets one find logarithms with bases other than those built into the calculator (usually loge and log10). To find a logarithm with base b, using any other base k: Moreover, this result implies that all logarithm functions (whatever the base) are similar to each other. So to calculate the log with base 2 of the number 16 with a calculator: # Uses of logarithms Logarithms are useful in solving equations in which exponents are unknown. They have simple derivatives, so they are often used in the solution of integrals. The logarithm is one of three closely related functions. In the equation bn = x, b can be determined with radicals, n with logarithms, and x with exponentials. See logarithmic identities for several rules governing the logarithm functions. ## Science Various quantities in science are expressed as logarithms of other quantities; see logarithmic scale for an explanation and a more complete list. - In chemistry, the negative of the base-10 logarithm of the activity of hydronium ions (H3O+, the form H+ takes in water) is the measure known as pH. The activity of hydronium ions in neutral water is 10−7 mol/L at 25 °C, hence a pH of 7. - The bel (symbol B) is a unit of measure which is the base-10 logarithm of ratios, such as power levels and voltage levels. It is mostly used in telecommunication, electronics, and acoustics. The Bel is named after telecommunications pioneer Alexander Graham Bell. The decibel (dB), equal to 0.1 bel, is more commonly used. The neper is a similar unit which uses the natural logarithm of a ratio. - The Richter scale measures earthquake intensity on a base-10 logarithmic scale. - In spectrometry and optics, the absorbance unit used to measure optical density is equivalent to −1 B. - In astronomy, the apparent magnitude measures the brightness of stars logarithmically, since the eye also responds logarithmically to brightness. - In psychophysics, the Weber–Fechner law proposes a logarithmic relationship between stimulus and sensation. - In computer science, logarithms often appear in bounds for computational complexity. For example, to sort N items using comparison can require time proportional to the product N × log N. Similarly, base-2 logarithms are used to express the amount of storage space or memory required for a binary representation of a number—with k bits (each a 0 or a 1) one can represent 2k distinct values, so any natural number N can be represented in no more than (log2 N) + 1 bits. - Similarly, in information theory logarithms are used as a measure of quantity of information. If a message recipient may expect any one of N possible messages with equal likelihood, then the amount of information conveyed by any one such message is quantified as log2 N bits. - In geometry the logarithm is used to form the metric for the half-plane model of hyperbolic geometry. - Many types of engineering and scientific data are typically graphed on log-log or semilog axes, in order to most clearly show the form of the data. - In inferential statistics, the logarithm of the data in a dataset can be used for parametric statistical testing if the original data does not meet the assumption of normality. - Musical intervals are measured logarithmically as semitones. The interval between two notes in semitones is the base-21/12 logarithm of the frequency ratio (or equivalently, 12 times the base-2 logarithm). Fractional semitones are used for non-equal temperaments. Especially to measure deviations from the equal tempered scale, intervals are also expressed in cents (hundredths of an equally-tempered semitone). The interval between two notes in cents is the base-21/1200 logarithm of the frequency ratio (or 1200 times the base-2 logarithm). In MIDI, notes are numbered on the semitone scale (logarithmic absolute nominal pitch with middle C at 60). For microtuning to other tuning systems, a logarithmic scale is defined filling in the ranges between the semitones of the equal tempered scale in a compatible way. This scale corresponds to the note numbers for whole semitones. (see microtuning in MIDI). ## Exponential functions One way of defining the exponential function ex, also written as exp(x), is as the inverse of the natural logarithm. It is positive for every real argument x. The operation of "raising b to a power p" for positive arguments b and all real exponents p is defined by The antilogarithm function is another name for the inverse of the logarithmic function. It is written antilogb(n) and means the same as bn. ## Easier computations Logarithms can be used to replace difficult operations on numbers by easier operations on their logs (in any base), as the following table summarizes. In the table, upper-case variables represent logs of corresponding lower-case variables: These arithmetic properties of logarithms make such calculations much faster. The use of logarithms was an essential skill until electronic computers and calculators became available. Indeed the discovery of logarithms, just before Newton's era, had an impact in the scientific world that can be compared with that of the advent of computers in the 20th century because it made feasible many calculations that had previously been too laborious. As an example, to approximate the product of two numbers one can look up their logarithms in a table, add them, and, using the table again, proceed from that sum to its antilogarithm, which is the desired product. The precision of the approximation can be increased by interpolating between table entries. For manual calculations that demand any appreciable precision, this process, requiring three lookups and a sum, is much faster than performing the multiplication. To achieve seven decimal places of accuracy requires a table that fills a single large volume; a table for nine-decimal accuracy occupies a few shelves. Similarly, to approximate a power cd one can look up log c in the table, look up the log of that, and add to it the log of d; roots can be approximated in much the same way. One key application of these techniques was celestial navigation. Once the invention of the chronometer made possible the accurate measurement of longitude at sea, mariners had everything necessary to reduce their navigational computations to mere additions. A five-digit table of logarithms and a table of the logarithms of trigonometric functions sufficed for most purposes, and those tables could fit in a small book. Another critical application with even broader impact was the slide rule, an essential calculating tool for engineers. Many of the powerful capabilities of the slide rule derive from a clever but simple design that relies on the arithmetic properties of logarithms. The slide rule allows computation much faster still than the techniques based on tables, but provides much less precision, although slide rule operations can be chained to calculate answers to any arbitrary precision. # Related operations ## Cologarithms The cologarithm of a number is the logarithm of the inverse of said number, meaning cologb(x)=logb(1/x)= - logb(x).[8] ## Antilogarithms The antilogarithm is the logarithmic inverse of the logarithm, meaning that the antilogb(logb(x))=x. Thus, setting by=x implies that logb(x)=y. By taking the antilogb of both sides, antilogb(logb(x))=antilogby, thus x=antilogby. Therefore, by=antilogby. # Calculus The natural logarithm of a positive number x can be defined as The derivative of the natural logarithm function is By applying the change-of-base rule, the derivative for other bases is The antiderivative of the natural logarithm ln(x) is and so the antiderivative of the logarithm for other bases is See also: Table of limits, list of integrals of logarithmic functions. # Series for calculating the natural logarithm There are several series for calculating natural logarithms.[9] The simplest, though inefficient, is: To derive this series, start with (<math>\|x\|<1 \!.</math>) Integrate both sides to obtain Letting <math>z = 1-x \!</math> and thus <math>x = -(z-1) \!</math>, we get A more efficient series is for z with positive real part. To derive this series, we begin by substituting −x for x and get Subtracting, we get Letting <math>z = \frac{1+x}{1-x} \!</math> and thus <math>x = \frac{z-1}{z+1} \!</math>, we get For example, applying this series to we get and thus \frac{1}{7 \cdot 1000000} + \cdots \right ) </math> where we factored 1/10 out of the sum in the first line. For any other base b, we use # Computers Most computer languages use log(x) for the natural logarithm, while the common log is typically denoted log10(x). The argument and return values are typically a floating point (or double precision) data type. As the argument is floating point, it can be useful to consider the following: A floating point value x is represented by a mantissa m and exponent n to form Therefore Thus, instead of computing <math>\ln(x)</math> we compute <math>\ln(m)</math> for some m such that 1 ≤ m < 2. Having m in this range means that the value <math>u = \frac{m - 1}{m+1}</math> is always in the range <math>0 \le u < \frac13</math>. Some machines use the mantissa in the range <math>0.5 \le m < 1</math> and in that case the value for u will be in the range <math>-\frac13 < u \le 0</math> In either case, the series is even easier to compute. To compute a base 2 logarithm on a number between 1 and 2 in an alternate way, square it repeatedly. Every time it goes over 2, divide it by 2 and write a "1" bit, else just write a "0" bit. This is because squaring doubles the logarithm of a number. The integer part of the logarithm to base 2 of an unsigned integer is given by the position of the left-most bit, and can be computed in O(n) steps using the following algorithm: <source lang="cpp"> int log2(int x){ } </source> However, it can also be computed in O(log n) steps by trying to shift by powers of 2 and checking that the result stays nonzero: for example, first >>16, then >>8, ... (Each step reveals one bit of the result) # Generalizations The ordinary logarithm of positive reals generalizes to negative and complex arguments, though it is a multivalued function that needs a branch cut terminating at the branch point at 0 to make an ordinary function or principal branch. The logarithm (to base e) of a complex number z is the complex number ln(\|z\|) + i arg(z), where \|z\| is the modulus of z, arg(z) is the argument, and i is the imaginary unit; see complex logarithm for details. The discrete logarithm is a related notion in the theory of finite groups. It involves solving the equation bn = x, where b and x are elements of the group, and n is an integer specifying a power in the group operation. For some finite groups, it is believed that the discrete logarithm is very hard to calculate, whereas discrete exponentials are quite easy. This asymmetry has applications in public key cryptography. The logarithm of a matrix is the inverse of the matrix exponential. It is possible to take the logarithm of a quaternions and octonions. A double logarithm, <math>\ln(\ln(x))</math>, is the inverse function of the double exponential function. A super-logarithm or hyper-4-logarithm is the inverse function of tetration. The super-logarithm of x grows even more slowly than the double logarithm for large x. For each positive b not equal to 1, the function logb (x) is an isomorphism from the group of positive real numbers under multiplication to the group of (all) real numbers under addition. They are the only such isomorphisms that are continuous. The logarithm function can be extended to a Haar measure in the topological group of positive real numbers under multiplication. # History The method of logarithms was first publicly propounded in 1614, in a book entitled Mirifici Logarithmorum Canonis Descriptio, by John Napier, Baron of Merchiston, in Scotland.[10] (Joost Bürgi independently discovered logarithms; however, he did not publish his discovery until four years after Napier.) Early resistance to the use of logarithms was muted by Kepler's enthusiastic support and his publication of a clear and impeccable explanation of how they worked.[11] Their use contributed to the advance of science, and especially of astronomy, by making some difficult calculations possible. Prior to the advent of calculators and computers, they were used constantly in surveying, navigation, and other branches of practical mathematics. It supplanted the more involved method of prosthaphaeresis, which relied on trigonometric identities as a quick method of computing products. Besides the utility of the logarithm concept in computation, the natural logarithm presented a solution to the problem of quadrature of a hyperbolic sector at the hand of Gregoire de Saint-Vincent in 1647. At first, Napier called logarithms "artificial numbers" and antilogarithms "natural numbers". Later, Napier formed the word logarithm to mean a number that indicates a ratio: Template:Polytonic (logos) meaning proportion, and Template:Polytonic (arithmos) meaning number. Napier chose that because the difference of two logarithms determines the ratio of the numbers they represent, so that an arithmetic series of logarithms corresponds to a geometric series of numbers. The term antilogarithm was introduced in the late 17th century and, while never used extensively in mathematics, persisted in collections of tables until they fell into disuse. Napier did not use a base as we now understand it, but his logarithms were, up to a scaling factor, effectively to base 1/e. For interpolation purposes and ease of calculation, it is useful to make the ratio r in the geometric series close to 1. Napier chose r = 1 - 10−7 = 0.999999 (Bürgi chose r = 1 + 10−4 = 1.0001). Napier's original logarithms did not have log 1 = 0 but rather log 107 = 0. Thus if N is a number and L is its logarithm as calculated by Napier, N = 107(1 − 10−7)L. Since (1 − 10−7)107 is approximately 1/e, this makes L/107 approximately equal to log1/e N/107.[5] # Tables of logarithms Prior to the advent of computers and calculators, using logarithms meant using tables of logarithms, which had to be created manually. Base-10 logarithms are useful in computations when electronic means are not available. See common logarithm for details, including the use of characteristics and mantissas of common (i.e., base-10) logarithms. In 1617, Henry Briggs published the first installment of his own table of common logarithms, containing the logarithms of all integers below 1000 to eight decimal places. This he followed, in 1624, by his Arithmetica Logarithmica, containing the logarithms of all integers from 1 to 20,000 and from 90,000 to 100,000 to fourteen places of decimals, together with a learned introduction, in which the theory and use of logarithms are fully developed. The interval from 20,000 to 90,000 was filled up by Adriaan Vlacq, a Dutch mathematician; but in his table, which appeared in 1628, the logarithms were given to only ten places of decimals. Vlacq's table was later found to contain 603 errors, but "this cannot be regarded as a great number, when it is considered that the table was the result of an original calculation, and that more than 2,100,000 printed figures are liable to error."[12] An edition of Vlacq's work, containing many corrections, was issued at Leipzig in 1794 under the title Thesaurus Logarithmorum Completus by Jurij Vega. François Callet's seven-place table (Paris, 1795), instead of stopping at 100,000, gave the eight-place logarithms of the numbers between 100,000 and 108,000, in order to diminish the errors of interpolation, which were greatest in the early part of the table; and this addition was generally included in seven-place tables. The only important published extension of Vlacq's table was made by Mr. Sang in 1871, whose table contained the seven-place logarithms of all numbers below 200,000. Briggs and Vlacq also published original tables of the logarithms of the trigonometric functions. Besides the tables mentioned above, a great collection, called Tables du Cadastre, was constructed under the direction of Gaspard de Prony, by an original computation, under the auspices of the French republican government of the 1700s. This work, which contained the logarithms of all numbers up to 100,000 to nineteen places, and of the numbers between 100,000 and 200,000 to twenty-four places, exists only in manuscript, "in seventeen enormous folios," at the Observatory of Paris. It was begun in 1792; and "the whole of the calculations, which to secure greater accuracy were performed in duplicate, and the two manuscripts subsequently collated with care, were completed in the short space of two years." [13] Cubic interpolation could be used to find the logarithm of any number to a similar accuracy.	https://www.wikidoc.org/index.php/Antilog
61bdbb635aeaaeaf7dda315b94bdd716cbf581da	wikidoc	Deodorant	Deodorant Deodorants (Deodourants) are substances applied to the body, most frequently the underarms, to reduce the body odor caused by the bacterial breakdown of perspiration. A subgroup of deodorants are "antiperspirants", which prevent odor and reduce sweat produced by parts of the body. Antiperspirants are typically applied to the underarms, while deodorants can also be used on feet and other areas in the form of body sprays. # Overview Human sweat itself is largely odorless until it is fermented by bacteria that thrive in hot, humid environments such as the human underarm. The armpits are among the consistently warmest areas on the surface of the human body, and sweat glands provide moisture. Underarm hair adds to the odor by providing increased surface area on which this bacteria thrive. Body odor is controlled by reducing moisture, killing bacteria or over powering the bacteria's smell with perfume. Deodorants — classified and regulated as over-the-counter (OTC) cosmetics by the U.S. Food and Drug Administration (FDA) — work to inhibit the growth of bacteria which cause odors. The first commercial deodorant, Mum, was introduced in the late nineteenth century. Deodorants are usually alcohol-based, which kills bacteria effectively. Deodorants can be formulated with other, more persistent antimicrobials such as triclosan, or with metal chelant compounds that slow bacterial growth. Deodorants also often contain perfume fragrances intended to mask the odor of perspiration. Deodorants may be combined with antiperspirants — classified as drugs by the FDA — which attempt to stop or significantly reduce perspiration and thus reduce the moist climate in which bacteria thrive. Aluminum chloride, aluminum chlorohydrate, and aluminum-zirconium compounds, most notably Aluminum zirconium tetrachlorohydrex gly and Aluminum zirconium trichlorohydrex gly, are the most widely used antiperspirants. Aluminum-based complexes react with the electrolytes in the sweat to form a gel plug in the duct of the sweat gland. The plugs prevent the gland from excreting liquid and are removed over time by the natural sloughing of the skin. The blockage of a large number of sweat glands reduces the amount of sweat produced in the underarms, though this may vary from person to person. A popular alternative to modern commercial deodorants is Ammonium alum, which is a common type of Alum sold in crystal form. It has been used as a deodorant throughout history in Thailand, the Far East, Mexico and other countries. Deodorants and antiperspirants come in many forms. What is commonly used varies in different countries. In Europe, aerosol sprays are popular, as are cream and roll-on forms which are prevalent in less affluent parts of the world. In the United States, solid or gel forms are dominant. # Health effects Email rumors surfaced on the Internet in the early 1990s that antiperspirants have a link in causing breast cancer; these are now widely considered to be an urban myth. According to the National Cancer Institute (NCI) and the American Cancer Society (ACS), these rumors are largely unsubstantiated by scientific research. The rumors suggested that antiperspirants keep a person from sweating out toxins and that this would help the spread of cancer-causing toxins via the lymph nodes. While lymph nodes do help to clear toxins, they are not connected to the sweat glands. Furthermore, sweat is not a significant route for eliminating toxins from the body. NCI discusses two studies that address the breast cancer rumor: A 2002 study of over 800 patients at Fred Hutchinson Cancer Research Institute that found no link between breast cancer and the use of antiperspirant/deodorant; and a study of 437 cancer patients, published in 2003 by the European Journal of Cancer Prevention, which found a correlation between earlier diagnosis of breast cancer and antiperspirant/deodorant use. The NCI's analysis of the second study said that it "does not demonstrate a conclusive link between these underarm hygiene habits and breast cancer. Additional research is needed to investigate this relationship and other factors that may be involved." One school of thought, advanced by the studies of researcher Phillipa Darbre, PhD, hypothesizes that particular substances in deodorants, such as preservatives called parabens, or aluminum salts such as aluminum chloride used in antiperspirants, get into the bloodstream or accumulate in breast tissue, where they enhance or emulate the effects of estrogen, which stimulates the growth of cancerous breast cells. The ACS and other scientists consider these studies to be early and inconclusive, but merit further research; Darbre also stated that her findings did not show causality. The main reservations have to do with the source and significance of the parabens or other toxic substances. Michael Thun, MD, of the ACS argued that even if some of the substances in antiperspirants do promote tumor growth, the risk from cosmetic use appears minuscule compared with other known tumor promoters — from 500 to 10,000 times less potent than taking oral estrogen or being obese. ## Aluminum neurotoxicity Aluminum has been established as a neurotoxin. Aluminum chloride, an aluminum salt that is commonly used in antiperspirants, is also commonly used in studies on aluminum-induced neurotoxicity. Aluminum itself adversely affects the blood-brain barrier, is capable of causing DNA damage, and has adverse epigenetic effects. Research has shown that the aluminum salts used in antiperspirants have detrimental effects to a number of species such as non-human primates, mice, dogs and others. An increased amount of aluminum is also present in the brains of many Alzheimer's patients, although this link does not currently seem to be causal.Template:Disputed-inline An experiment with mice found that applying an aqueous solution of aluminum chloride to the skin resulted in "a significant increase in urine, serum, and whole brain aluminum." Other experiments on pregnant mice showed transplacental passage of aluminum chloride. # Culture Cultures and individuals differ in their beliefs about the need for deodorant, and on whether bodily odors are offensive. Various foods such as garlic may also affect body odor. Commercially-manufactured deodorants may also target areas of the body other than the armpits, such as the genitals, and particularly the female genitals. Such products are sometimes the target of sexually graphic humor. Tom Robbins' novel Even Cowgirls Get the Blues involves a humorous plot line that takes a position in favor of natural body odors, and presents the positions of those on both sides of the issue. An episode of Foster's Home For Imaginary Friends features the lead character, Bloo, as the mascot for an ineffective deodorant called "Deo". "Ode To Deodorant" was the first song recorded by British band Coldplay as an ensemble. # Clothing Aluminum zirconium tetrachlorohydrex gly, a common antiperspirant, is a cause of "armpit stains" on clothing, reacting with our bodies to create yellow stains.	Deodorant Deodorants (Deodourants) are substances applied to the body, most frequently the underarms, to reduce the body odor caused by the bacterial breakdown of perspiration. A subgroup of deodorants are "antiperspirants", which prevent odor and reduce sweat produced by parts of the body. Antiperspirants are typically applied to the underarms, while deodorants can also be used on feet and other areas in the form of body sprays. # Overview Human sweat itself is largely odorless until it is fermented by bacteria that thrive in hot, humid environments such as the human underarm. The armpits are among the consistently warmest areas on the surface of the human body, and sweat glands provide moisture. Underarm hair adds to the odor by providing increased surface area on which this bacteria thrive. Body odor is controlled by reducing moisture, killing bacteria or over powering the bacteria's smell with perfume. Deodorants — classified and regulated as over-the-counter (OTC) cosmetics by the U.S. Food and Drug Administration (FDA)[citation needed] — work to inhibit the growth of bacteria which cause odors. The first commercial deodorant, Mum, was introduced in the late nineteenth century. Deodorants are usually alcohol-based, which kills bacteria effectively.[1] Deodorants can be formulated with other, more persistent antimicrobials such as triclosan, or with metal chelant compounds that slow bacterial growth. Deodorants also often contain perfume fragrances intended to mask the odor of perspiration. Deodorants may be combined with antiperspirants — classified as drugs by the FDA — which attempt to stop or significantly reduce perspiration and thus reduce the moist climate in which bacteria thrive. Aluminum chloride, aluminum chlorohydrate, and aluminum-zirconium compounds, most notably Aluminum zirconium tetrachlorohydrex gly and Aluminum zirconium trichlorohydrex gly, are the most widely used antiperspirants. Aluminum-based complexes react with the electrolytes in the sweat to form a gel plug in the duct of the sweat gland. The plugs prevent the gland from excreting liquid and are removed over time by the natural sloughing of the skin. The blockage of a large number of sweat glands reduces the amount of sweat produced in the underarms, though this may vary from person to person. A popular alternative to modern commercial deodorants is Ammonium alum, which is a common type of Alum sold in crystal form. It has been used as a deodorant throughout history in Thailand, the Far East, Mexico and other countries. Deodorants and antiperspirants come in many forms. What is commonly used varies in different countries. In Europe, aerosol sprays are popular, as are cream and roll-on forms which are prevalent in less affluent parts of the world. In the United States, solid or gel forms are dominant. # Health effects Template:POV-section Email rumors[2][3] surfaced on the Internet in the early 1990s that antiperspirants have a link in causing breast cancer; these are now widely considered to be an urban myth. According to the National Cancer Institute (NCI) and the American Cancer Society (ACS), these rumors are largely unsubstantiated by scientific research.[4][5] The rumors suggested that antiperspirants keep a person from sweating out toxins and that this would help the spread of cancer-causing toxins via the lymph nodes. While lymph nodes do help to clear toxins, they are not connected to the sweat glands. Furthermore, sweat is not a significant route for eliminating toxins from the body.[6] NCI discusses two studies that address the breast cancer rumor: A 2002 study of over 800 patients at Fred Hutchinson Cancer Research Institute that found no link between breast cancer and the use of antiperspirant/deodorant;[7] and a study of 437 cancer patients, published in 2003 by the European Journal of Cancer Prevention, which found a correlation between earlier diagnosis of breast cancer and antiperspirant/deodorant use.[8] The NCI's analysis of the second study said that it "does not demonstrate a conclusive link between these underarm hygiene habits and breast cancer. Additional research is needed to investigate this relationship and other factors that may be involved."[9] One school of thought, advanced by the studies of researcher Phillipa Darbre, PhD, hypothesizes that particular substances in deodorants, such as preservatives called parabens, or aluminum salts such as aluminum chloride used in antiperspirants, get into the bloodstream or accumulate in breast tissue, where they enhance or emulate the effects of estrogen, which stimulates the growth of cancerous breast cells.[10][11] The ACS and other scientists consider these studies to be early and inconclusive, but merit further research; Darbre also stated that her findings did not show causality. The main reservations have to do with the source and significance of the parabens or other toxic substances.[12] Michael Thun, MD, of the ACS argued that even if some of the substances in antiperspirants do promote tumor growth, the risk from cosmetic use appears minuscule compared with other known tumor promoters — from 500 to 10,000 times less potent than taking oral estrogen or being obese.[13] ## Aluminum neurotoxicity Aluminum has been established as a neurotoxin.[14] Aluminum chloride, an aluminum salt that is commonly used in antiperspirants, is also commonly used in studies on aluminum-induced neurotoxicity.[15][16][17][18][19] Aluminum itself adversely affects the blood-brain barrier, is capable of causing DNA damage, and has adverse epigenetic effects.[20][21] Research has shown that the aluminum salts used in antiperspirants have detrimental effects to a number of species such as non-human primates,[22] mice,[23] dogs[24] and others. An increased amount of aluminum is also present in the brains of many Alzheimer's patients, although this link does not currently seem to be causal.Template:Disputed-inline[25][26][27] An experiment with mice found that applying an aqueous solution of aluminum chloride to the skin resulted in "a significant increase in urine, serum, and whole brain aluminum."[28] Other experiments on pregnant mice showed transplacental passage of aluminum chloride.[23] # Culture Cultures and individuals differ in their beliefs about the need for deodorant, and on whether bodily odors are offensive. Various foods such as garlic may also affect body odor. Commercially-manufactured deodorants may also target areas of the body other than the armpits, such as the genitals, and particularly the female genitals. Such products are sometimes the target of sexually graphic humor. Tom Robbins' novel Even Cowgirls Get the Blues involves a humorous plot line that takes a position in favor of natural body odors, and presents the positions of those on both sides of the issue. An episode of Foster's Home For Imaginary Friends features the lead character, Bloo, as the mascot for an ineffective deodorant called "Deo". "Ode To Deodorant" was the first song recorded by British band Coldplay as an ensemble. # Clothing Aluminum zirconium tetrachlorohydrex gly, a common antiperspirant, is a cause of "armpit stains" on clothing, reacting with our bodies to create yellow stains. [1]	https://www.wikidoc.org/index.php/Antiperspirant
d5b16d9305c6171c1d031b406a2f0bf647d5e990	wikidoc	Phenazone	Phenazone Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. # Overview Phenazone, or phenazon, is an analgesic. It is formed by reducing diortho-dinitrodiphenyl with sodium amalgam and methyl alcohol, or by heating diphenylene-ortho-dihydrazine with hydrochloric acid to 150 C. It crystallizes in needles which melt at 156 C. Potassium permanganate oxidizes it to pyridazine tetracarboxylic acid. # Synonyms Analgesine, Antipyrine, Diméthyloxyquinazine, Oxydiméthylquinazine, Oxydiméthylquinizine, Pyrazoline	Phenazone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. # Overview Phenazone, or phenazon, is an analgesic. It is formed by reducing diortho-dinitrodiphenyl with sodium amalgam and methyl alcohol, or by heating diphenylene-ortho-dihydrazine with hydrochloric acid to 150 C. It crystallizes in needles which melt at 156 C. Potassium permanganate oxidizes it to pyridazine tetracarboxylic acid. # Synonyms Analgesine, Antipyrine, Diméthyloxyquinazine, Oxydiméthylquinazine, Oxydiméthylquinizine, Pyrazoline	https://www.wikidoc.org/index.php/Antipyrine
d44f29a8649244efed4200a6257659129ed0bd71	wikidoc	Antisense	Antisense Antisense molecules interact with complementary strands of nucleic acids, modifying expression of genes. Some regions within a double strand of DNA code for genes, which are usually instructions specifying the order of amino acids in a protein along with regulatory sequences, splicing sites, noncoding introns and other complicating details. For a cell to use this information, one strand of the DNA serves as a template for the synthesis of a complementary strand of RNA. The template DNA strand is called the transcribed strand with antisense sequence and the mRNA transcript is said to be sense sequence (the complement of antisense). Because the DNA is double-stranded, the strand complementary to the antisense sequence is called non-transcribed strand and has the same sense sequence as the mRNA transcript (though T bases in DNA are substituted with U bases in RNA). DNA strand 1: sense strand DNA strand 2: antisense strand (copied to)→ RNA strand (sense) Many forms of antisense have been developed and can be broadly categorized into enzyme-dependent antisense or steric blocking antisense. Enzyme-dependent antisense includes forms dependent on RNase H activity to degrade target mRNA, including single-stranded DNA, RNA, and phosphorothioate antisense. The R1 plasmid hok/sok system is an example of mRNA antisense regulation process, through enzymatic degradation of the resulting RNA duplex. Double stranded RNA acts as enzyme-dependent antisense through the RNAi/siRNA pathway, involving target mRNA recognition through sense-antisense strand pairing followed by target mRNA degradation by the RNA-induced silencing complex (RISC). Steric blocking antisense (RNase-H independent antisense) interferes with gene expression or other mRNA-dependent cellular processes by binding to a target sequence of mRNA and getting in the way of other processes. Steric blocking antisense includes 2'-O alkyl (usually in chimeras with RNase-H dependent antisense), peptide nucleic acid (PNA), locked nucleic acid (LNA) and Morpholino antisense. Antisense nucleic acid molecules have been used experimentally to bind to mRNA and prevent expression of specific genes. Antisense therapies are also in development; in the USA, the Food and Drug Administration (FDA) has approved a phosphorothioate antisense oligo, fomivirsen (Vitravene), for human therapeutic use. Cells can produce antisense RNA molecules naturally, which interact with complementary mRNA molecules and inhibit their expression.	Antisense Antisense molecules interact with complementary strands of nucleic acids, modifying expression of genes. Some regions within a double strand of DNA code for genes, which are usually instructions specifying the order of amino acids in a protein along with regulatory sequences, splicing sites, noncoding introns and other complicating details. For a cell to use this information, one strand of the DNA serves as a template for the synthesis of a complementary strand of RNA. The template DNA strand is called the transcribed strand with antisense sequence and the mRNA transcript is said to be sense sequence (the complement of antisense). Because the DNA is double-stranded, the strand complementary to the antisense sequence is called non-transcribed strand and has the same sense sequence as the mRNA transcript (though T bases in DNA are substituted with U bases in RNA). DNA strand 1: sense strand DNA strand 2: antisense strand (copied to)→ RNA strand (sense) Many forms of antisense have been developed and can be broadly categorized into enzyme-dependent antisense or steric blocking antisense. Enzyme-dependent antisense includes forms dependent on RNase H activity to degrade target mRNA, including single-stranded DNA, RNA, and phosphorothioate antisense. The R1 plasmid hok/sok system is an example of mRNA antisense regulation process, through enzymatic degradation of the resulting RNA duplex. Double stranded RNA acts as enzyme-dependent antisense through the RNAi/siRNA pathway, involving target mRNA recognition through sense-antisense strand pairing followed by target mRNA degradation by the RNA-induced silencing complex (RISC). Steric blocking antisense (RNase-H independent antisense)[1] interferes with gene expression or other mRNA-dependent cellular processes by binding to a target sequence of mRNA and getting in the way of other processes. Steric blocking antisense includes 2'-O alkyl (usually in chimeras with RNase-H dependent antisense), peptide nucleic acid (PNA), locked nucleic acid (LNA) and Morpholino antisense. Antisense nucleic acid molecules have been used experimentally to bind to mRNA and prevent expression of specific genes. Antisense therapies are also in development; in the USA, the Food and Drug Administration (FDA) has approved a phosphorothioate antisense oligo, fomivirsen (Vitravene), for human therapeutic use. Cells can produce antisense RNA molecules naturally, which interact with complementary mRNA molecules and inhibit their expression.	https://www.wikidoc.org/index.php/Antisense
94b4d06db082d991d475535eb5bc19e68bb2c039	wikidoc	Trematoda	Trematoda # Overview The Trematoda is a class within the phylum Platyhelminthes that contains two groups of parasitic worms, commonly referred to as flukes. # Taxonomy and biodiversity The Trematoda are estimated to include 18 000 to 24 000 species, and are divided into two subclasses. Nearly all trematodes are parasites of molluscs and vertebrates. The smaller Aspidogastrea, comprising about 100 species, are obligate parasites of molluscs and may also infect turtles and fishes, including cartilaginous fishes. The Digenea, which constitute the majority of trematode diversity, are obligate parasites of both molluscs and vertebrates, but do not occur in cartilaginous fishes. Crepidostomum sp. do occur in Lake Sturgeon. Formerly the Monogenea were included in the Trematoda on the basis that these worms are also vermiform parasites, but modern phylogenetic studies have raised this group to the status of a sister class within the Platyhelminthes, along with the Cestoda. # Etymology Trematodes are commonly referred to as flukes. This term can be traced back to the Saxon name for flounder, and refers to the flattened, rhomboidal shape of the worms. The flukes can be classified into two groups, on the basis of the system which they infect in the vertebrate host. Tissue flukes infect the bile ducts, lungs, or other biological tissues. This group includes the lung fluke, Paragonimus westermani, and the liver flukes, Clonorchis sinensis and Fasciola hepatica. Blood flukes inhabit the blood in some stages of their life cycle. Blood flukes include species of the genus Schistosoma. # Life cycles All trematodes infect molluscs and most have a complex life cycle involving other hosts. Most trematodes are monoecious and alternately reproduce sexually and asexually. The two main exceptions to this are the Aspidogastrea, which have no asexual reproduction, and the schistosomes, which are dioecious. In the definitive host, in which sexual reproduction occurs, eggs are commonly shed along with host feces. Eggs shed in water release free-swimming larval forms that are infective to the intermediate host, in which asexual reproduction occurs.	Trematoda Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The Trematoda is a class within the phylum Platyhelminthes that contains two groups of parasitic worms, commonly referred to as flukes. # Taxonomy and biodiversity The Trematoda are estimated to include 18 000[1] to 24 000[2] species, and are divided into two subclasses. Nearly all trematodes are parasites of molluscs and vertebrates. The smaller Aspidogastrea, comprising about 100 species, are obligate parasites of molluscs and may also infect turtles and fishes, including cartilaginous fishes. The Digenea, which constitute the majority of trematode diversity, are obligate parasites of both molluscs and vertebrates, but do not occur in cartilaginous fishes. Crepidostomum sp. do occur in Lake Sturgeon. Formerly the Monogenea were included in the Trematoda on the basis that these worms are also vermiform parasites, but modern phylogenetic studies have raised this group to the status of a sister class within the Platyhelminthes, along with the Cestoda. # Etymology Trematodes are commonly referred to as flukes. This term can be traced back to the Saxon name for flounder, and refers to the flattened, rhomboidal shape of the worms. The flukes can be classified into two groups, on the basis of the system which they infect in the vertebrate host. Tissue flukes infect the bile ducts, lungs, or other biological tissues. This group includes the lung fluke, Paragonimus westermani, and the liver flukes, Clonorchis sinensis and Fasciola hepatica. Blood flukes inhabit the blood in some stages of their life cycle. Blood flukes include species of the genus Schistosoma. # Life cycles All trematodes infect molluscs and most have a complex life cycle involving other hosts. Most trematodes are monoecious and alternately reproduce sexually and asexually. The two main exceptions to this are the Aspidogastrea, which have no asexual reproduction, and the schistosomes, which are dioecious. In the definitive host, in which sexual reproduction occurs, eggs are commonly shed along with host feces. Eggs shed in water release free-swimming larval forms that are infective to the intermediate host, in which asexual reproduction occurs.	https://www.wikidoc.org/index.php/Antitrematodals
cfba53febbead5ac8735790d7d2dc2a03175dec9	wikidoc	Antivenin	Antivenin Antivenin (or antivenene or antivenom) is a biological product used in the treatment of venomous bites or stings. It is created by injecting a small amount of the targeted venom into an animal such as a horse, sheep, goat, or rabbit; the subject animal will suffer an immune response to the venom, producing antibodies against the venom's active molecule which can then be harvested from the animal's blood and used to treat envenomation in others. Internationally, Snake Venom Antitoxin must carefully meet the standards of Pharmacopoeia and the World Health Organization (WHO). # Therapeutic use The principle of antivenin is based on that of vaccines, developed by Louis Pasteur, however instead of inducing immunity in the patient directly, it is induced in a host animal and the hyperimmunized serum is transfused into the patient. The first antivenin for snakes (called an anti-ophidic serum) was developed by Albert Calmette, a French scientist of the Pasteur Institute working at its Indochine branch in 1895, against the Indian Cobra (Naja naja). Vital Brazil, a Brazilian scientist developed in 1901 the first monovalent and polyvalent antivenins for Central and South American Crotalus, Bothrops and Elaps genera, as well as for certain species of venomous spiders, scorpions, and frogs. They were all developed in a Brazilian institution, the Instituto Butantan, located in São Paulo, Brazil. Antivenins can be classified into monovalent (when they are effective against a given species' venom) or polyvalent (when they are effective against a range of species, or several different species at the same time). Antivenins for therapeutic use are often preserved as freeze-dried ampoules, but some are available only in liquid form and must be kept refrigerated. (They are not immediately inactivated by heat, so a minor gap in the cold chain is not disastrous.) The majority of antivenins (including all snake antivenins) are administered intravenously, however stonefish and red-back spider antivenins are given intramuscularly. The intramuscular route has been questioned in some situations as not uniformly effective. Antivenins bind to and neutralize the venom, halting further damage, but do not reverse damage already done. Thus, they should be administered as soon as possible after the venom has been injected, but are of some benefit as long as venom is present in the body. Since the advent of antivenins, some bites which were previously inevitably fatal have become only rarely fatal provided that the antivenin is administered soon enough. Antivenins are purified by several processes but will still contain other serum proteins that can act as antigens. Some individuals may react to the antivenin with an immediate hypersensitivity reaction (anaphylaxis) or a delayed hypersensitivity (serum sickness) reaction and antivenin should, therefore, be used with caution. Despite this caution, antivenin is typically the sole effective treatment for a life-threatening condition, and once the precautions for managing these reactions are in place, an anaphylactoid reaction is not grounds to refuse to give antivenin if otherwise indicated. Although it is a popular myth that a person allergic to horses "cannot" be given antivenin, the side effects are manageable, and antivenin should be given as rapidly as the side effects can be managed. Sheep are generally used in preference over horses now, however, as the potential for adverse immunological responses in humans from sheep-derived antibodies is generally somewhat less than that from horse-derived antibodies. The use of horses to raise antibodies, in Australia at least, where much antivenin research has been undertaken (by Sutherland and others for example), has been attributed to the research base originally having been comprised of a large number of veterinary officers. These vets had, in many cases, returned from taking part in the Boer and First World Wars and were generally experienced with horses (eg: cavalry). The large animal vets were similarly oriented given the use of horses as a prime source of motive power and transport, especially in the rural setting. The overall experience with horses naturally made them the preferred subject in which to raise antibodies. It was not until later that the immuno-reactivity of certain horse serum proteins was assessed to be sufficiently problematic that alternatives in which to raise antibodies were investigated. # Natural and acquired immunity Although individuals can vary in their physiopathological response and sensitivity to animal venoms, there is no natural immunity to them in humans. Some ophiophagic animals are immune to the venoms produced by some species of venomous snakes, by the presence of antihemorrhagic and antineurotoxic factors in their blood. These animals include King snakes, opossums and hedgehogs. It is quite possible to immunize a person directly with small and graded doses of venom rather than an animal. According to Greek history, King Mithridates did this in order to protect himself against attempts of poisoning, therefore this procedure is often called mithridatization. However, unlike a vaccination against disease which must only produce a latent immunity that can be roused in case of infection, to neutralize a sudden and large dose of venom requires maintaining a high level of circulating antibody (a hyperimmunized state), through repeated venom injections (typically every 21 days). The long-term health effects of this process have not been studied. For some large snakes, the total amount of antibody it is possible to maintain in one human being is not enough to neutralize one envenomation. Further, cytotoxic venom components can cause pain and minor scarring at the immunization site. Finally, the resistance is specific to the particular venom used; maintaining resistance to a variety of venoms requires multiple monthly venom injections. Thus, there is no practical purpose or favorable cost/benefit ratio for this, except for people like zoo handlers, researchers, and circus artists who deal closely with venomous animals. Mithridatization has been tried with success in Australia and Brazil and total immunity has been achieved even to multiple bites of extremely venomous cobras and pit vipers. Starting in 1950, Bill Haast successfully immunized himself to the venoms of Cape, Indian and King cobras. Because neurotoxic venoms must travel farther in the body to do harm and are produced in smaller quantities, it is easier to develop resistance to them than directly cytotoxic venoms (such as those of most vipers) that are injected in large quantity and do damage immediately upon injection. # Availability of antivenins Antivenins have been developed for the venoms associated with the following animals: ## Spiders - Funnel web spider antivenom: Sydney funnel-web spider, Australia - Soro antiaracnidico: Brazilian wandering spider, Brazil - Soro antiloxoscelico: Recluse spider, Brazil - Suero antiloxoscelico: Chilean recluse, Peru - Aracmyn: All species of Loxosceles and Latrodectus, Mexico - Redback spider antivenom: Red-back spider, Australia - Black widow antivenin: Black widow spider, USA - SAIMR Spider antivenom: Button spider, South Africa - Anti Latrodectus antivenom: Black widow spider, Argentina ## Acarids - Tick antivenom: Paralysis tick, Australia ## Insects - Soro antilonomico: Lonomia oblique caterpillar, Brazil ## Scorpions - Alacramyn: Centruroides limpidus, C. noxius, C. suffusus, Mexico - Suero Antialacran: Centruroides limpidus, C. noxius, C. suffusus, Mexico - Tunisian polyvalent antivenom: All Iranian scorpions, Tunisia - Anti-Scorpion Venom Serum I.P.(AScVS): Indian red scorpion, India - Anti-scorpionique: Androctonus spp., Buthus spp., Algeria - Scorpion antivenom: Black scorpion, Buthus occitanus, Morocco - Soro antiescorpionico: Tityus spp., Brazil - SAIMR scorpion antivenom: Parabuthus spp., South Africa - Purified polyvalent Anti-Scorpion Serum(equine): Leiurus spp.& Androctons scorpions, Egypt ## Marine animals - CSL box jellyfish antivenom: Box jellyfish, Australia - CSL stonefish antivenom Stonefish, Australia ## Snakes - Polyvalent snake antivenom: Saw-scaled Viper Echis carinatus, Russell's Viper Daboia russelli, Spectacled Cobra Naja naja, Common Krait Bungarus caeruleus. India. - Death adder antivenom: Death adder, Australia - Taipan antivenom: Taipan, Australia - Black snake antivenom: Pseudechis spp. Australia. - Tiger snake antivenom: Australian copperheads, Tiger snakes, Pseudechis spp., Rough scaled snake. Australia - Brown snake antivenom: Brown snakes. Australia - Polyvalent snake antivenom: Many Australian snakes. Australia - Sea snake antivenom: Sea snakes, Australia - Vipera tab: Vipera spp. USA - Polyvalent crotalid antivenin (CroFab - Crotalidae Polyvalent Immune Fab (Ovine)): North American pit vipers (all Rattlesnakes, Copperheads, and cottonmouths), USA - Soro antibotropicocrotalico: Pit vipers and Rattlesnakes, Brazil - Antielapidico: Coral snakes, Brazil - Soro anti-elapidico: Coral snakes, Brazil - SAIMR polyvalent antivenom: Mambas, Cobras, Rinkhalses, Puff adders (Unsuitable small adders: B. worthingtoni, B. atropos, B. caudalis, B. cornuta, B. heraldica, B. inornata, B. peringueyi, B. schneideri, B. xeropaga), South Africa - SAIMR echis antivenom: Saw-scaled vipers, South Africa - SAIMR Boomslang antivenom: Boomslang, South Africa - Panamerican serum: anticoral polyvalent serum: Coral snakes, Costa Rica - Anticoral: Coral snakes, Costa Rica - Anti-mipartitus antivenom: Coral snakes, Costa Rica - Anticoral monovalent: Coral snakes, Costa Rica - Antimicrurus: Coral snakes, Argentina - Coralmyn: Coral snakes, Mexico - Anti micruricoscorales: Coral snakes, Colombia # Antivenin sources The following groups assist in locating antivenins: - USA, Miami, Florida: The Miami-Dade Fire Rescue Antivenom Bank: Emergency: 1-786-336-6600 available 24 hours. A list of available antivenins is available at . More information about the bank is available at - USA, The Antivenom Index is a joint project of the Association of Zoos and Aquariums and the American Association of Poison Control Centers: They maintain a website to help locate rare antivenins. - USA, Colorado: Poisindex central office in Denver, Colorado, USA (1-800-332-3073). - Australia: CSL Limited, Parkville, Victoria. - Asia: Haffkine Biopharmaceutical Corporation, Parel, Mumbai, India. - Africa: South African Institute for Medical Research, Johannesburg, Republic of South Africa. - Brazil: Instituto Butantan, São Paulo # Cited references - ↑ Isbister GK. (2002). "Failure of intramuscular antivenom in Red-back spider envenoming". Emerg Med (Fremantle). 14 (4): 436–9. PMID 12534488..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} - ↑ See, for example, the Antivenin Precautions paragraph of the Medication section of James Forster, MD, MS (2006-03-14). "Snake Envenomations, Sea". eMedicine Emergency Medicine (environmental). Retrieved 2006-06-25.CS1 maint: Multiple names: authors list (link) - ↑ "Appendix: Antivenom Tables". Clinical Toxicology. 41 (3): 317–27. 2003. doi:10.1081/CLT-120021117. - ↑ Spawls S, Branch B. 1995. The Dangerous Snakes of Africa. Ralph Curtis Books. Dubai: Oriental Press. 192 pp. ISBN 0-88359-029-8.	Antivenin Antivenin (or antivenene or antivenom) is a biological product used in the treatment of venomous bites or stings. It is created by injecting a small amount of the targeted venom into an animal such as a horse, sheep, goat, or rabbit; the subject animal will suffer an immune response to the venom, producing antibodies against the venom's active molecule which can then be harvested from the animal's blood and used to treat envenomation in others. Internationally, Snake Venom Antitoxin must carefully meet the standards of Pharmacopoeia and the World Health Organization (WHO). [1] # Therapeutic use The principle of antivenin is based on that of vaccines, developed by Louis Pasteur, however instead of inducing immunity in the patient directly, it is induced in a host animal and the hyperimmunized serum is transfused into the patient. The first antivenin for snakes (called an anti-ophidic serum) was developed by Albert Calmette, a French scientist of the Pasteur Institute working at its Indochine branch in 1895, against the Indian Cobra (Naja naja). Vital Brazil, a Brazilian scientist developed in 1901 the first monovalent and polyvalent antivenins for Central and South American Crotalus, Bothrops and Elaps genera, as well as for certain species of venomous spiders, scorpions, and frogs. They were all developed in a Brazilian institution, the Instituto Butantan, located in São Paulo, Brazil. Antivenins can be classified into monovalent (when they are effective against a given species' venom) or polyvalent (when they are effective against a range of species, or several different species at the same time). Antivenins for therapeutic use are often preserved as freeze-dried ampoules, but some are available only in liquid form and must be kept refrigerated. (They are not immediately inactivated by heat, so a minor gap in the cold chain is not disastrous.) The majority of antivenins (including all snake antivenins) are administered intravenously, however stonefish and red-back spider antivenins are given intramuscularly. The intramuscular route has been questioned in some situations as not uniformly effective.[1] Antivenins bind to and neutralize the venom, halting further damage, but do not reverse damage already done. Thus, they should be administered as soon as possible after the venom has been injected, but are of some benefit as long as venom is present in the body. Since the advent of antivenins, some bites which were previously inevitably fatal have become only rarely fatal provided that the antivenin is administered soon enough. Antivenins are purified by several processes but will still contain other serum proteins that can act as antigens. Some individuals may react to the antivenin with an immediate hypersensitivity reaction (anaphylaxis) or a delayed hypersensitivity (serum sickness) reaction and antivenin should, therefore, be used with caution. Despite this caution, antivenin is typically the sole effective treatment for a life-threatening condition, and once the precautions for managing these reactions are in place, an anaphylactoid reaction is not grounds to refuse to give antivenin if otherwise indicated. Although it is a popular myth that a person allergic to horses "cannot" be given antivenin, the side effects are manageable, and antivenin should be given as rapidly as the side effects can be managed.[2] Sheep are generally used in preference over horses now, however, as the potential for adverse immunological responses in humans from sheep-derived antibodies is generally somewhat less than that from horse-derived antibodies. The use of horses to raise antibodies, in Australia at least, where much antivenin research has been undertaken (by Sutherland and others for example), has been attributed to the research base originally having been comprised of a large number of veterinary officers. These vets had, in many cases, returned from taking part in the Boer and First World Wars and were generally experienced with horses (eg: cavalry). The large animal vets were similarly oriented given the use of horses as a prime source of motive power and transport, especially in the rural setting. The overall experience with horses naturally made them the preferred subject in which to raise antibodies. It was not until later that the immuno-reactivity of certain horse serum proteins was assessed to be sufficiently problematic that alternatives in which to raise antibodies were investigated.[citation needed] # Natural and acquired immunity Although individuals can vary in their physiopathological response and sensitivity to animal venoms, there is no natural immunity to them in humans. Some ophiophagic animals are immune to the venoms produced by some species of venomous snakes, by the presence of antihemorrhagic and antineurotoxic factors in their blood. These animals include King snakes, opossums and hedgehogs. It is quite possible to immunize a person directly with small and graded doses of venom rather than an animal. According to Greek history, King Mithridates did this in order to protect himself against attempts of poisoning, therefore this procedure is often called mithridatization. However, unlike a vaccination against disease which must only produce a latent immunity that can be roused in case of infection, to neutralize a sudden and large dose of venom requires maintaining a high level of circulating antibody (a hyperimmunized state), through repeated venom injections (typically every 21 days). The long-term health effects of this process have not been studied. For some large snakes, the total amount of antibody it is possible to maintain in one human being is not enough to neutralize one envenomation. Further, cytotoxic venom components can cause pain and minor scarring at the immunization site. Finally, the resistance is specific to the particular venom used; maintaining resistance to a variety of venoms requires multiple monthly venom injections. Thus, there is no practical purpose or favorable cost/benefit ratio for this, except for people like zoo handlers, researchers, and circus artists who deal closely with venomous animals. Mithridatization has been tried with success in Australia and Brazil and total immunity has been achieved even to multiple bites of extremely venomous cobras and pit vipers. Starting in 1950, Bill Haast successfully immunized himself to the venoms of Cape, Indian and King cobras. Because neurotoxic venoms must travel farther in the body to do harm and are produced in smaller quantities, it is easier to develop resistance to them than directly cytotoxic venoms (such as those of most vipers) that are injected in large quantity and do damage immediately upon injection. # Availability of antivenins Antivenins have been developed for the venoms associated with the following animals:[3] ## Spiders - Funnel web spider antivenom: Sydney funnel-web spider, Australia - Soro antiaracnidico: Brazilian wandering spider, Brazil - Soro antiloxoscelico: Recluse spider, Brazil - Suero antiloxoscelico: Chilean recluse, Peru - Aracmyn: All species of Loxosceles and Latrodectus, Mexico - Redback spider antivenom: Red-back spider, Australia - Black widow antivenin: Black widow spider, USA - SAIMR Spider antivenom: Button spider, South Africa - Anti Latrodectus antivenom: Black widow spider, Argentina ## Acarids - Tick antivenom: Paralysis tick, Australia ## Insects - Soro antilonomico: Lonomia oblique caterpillar, Brazil ## Scorpions - Alacramyn: Centruroides limpidus, C. noxius, C. suffusus, Mexico - Suero Antialacran: Centruroides limpidus, C. noxius, C. suffusus, Mexico - Tunisian polyvalent antivenom: All Iranian scorpions, Tunisia - Anti-Scorpion Venom Serum I.P.(AScVS): Indian red scorpion, India - Anti-scorpionique: Androctonus spp., Buthus spp., Algeria - Scorpion antivenom: Black scorpion, Buthus occitanus, Morocco - Soro antiescorpionico: Tityus spp., Brazil - SAIMR scorpion antivenom: Parabuthus spp., South Africa - Purified polyvalent Anti-Scorpion Serum(equine): Leiurus spp.& Androctons scorpions, Egypt ## Marine animals - CSL box jellyfish antivenom: Box jellyfish, Australia - CSL stonefish antivenom Stonefish, Australia ## Snakes - Polyvalent snake antivenom: Saw-scaled Viper Echis carinatus, Russell's Viper Daboia russelli, Spectacled Cobra Naja naja, Common Krait Bungarus caeruleus. India. - Death adder antivenom: Death adder, Australia - Taipan antivenom: Taipan, Australia - Black snake antivenom: Pseudechis spp. Australia. - Tiger snake antivenom: Australian copperheads, Tiger snakes, Pseudechis spp., Rough scaled snake. Australia - Brown snake antivenom: Brown snakes. Australia - Polyvalent snake antivenom: Many Australian snakes. Australia - Sea snake antivenom: Sea snakes, Australia - Vipera tab: Vipera spp. USA - Polyvalent crotalid antivenin (CroFab - Crotalidae Polyvalent Immune Fab (Ovine)): North American pit vipers (all Rattlesnakes, Copperheads, and cottonmouths), USA - Soro antibotropicocrotalico: Pit vipers and Rattlesnakes, Brazil - Antielapidico: Coral snakes, Brazil - Soro anti-elapidico: Coral snakes, Brazil - SAIMR polyvalent antivenom: Mambas, Cobras, Rinkhalses, Puff adders (Unsuitable small adders: B. worthingtoni, B. atropos, B. caudalis, B. cornuta, B. heraldica, B. inornata, B. peringueyi, B. schneideri, B. xeropaga), South Africa[4] - SAIMR echis antivenom: Saw-scaled vipers, South Africa - SAIMR Boomslang antivenom: Boomslang, South Africa - Panamerican serum: anticoral polyvalent serum: Coral snakes, Costa Rica - Anticoral: Coral snakes, Costa Rica - Anti-mipartitus antivenom: Coral snakes, Costa Rica - Anticoral monovalent: Coral snakes, Costa Rica - Antimicrurus: Coral snakes, Argentina - Coralmyn: Coral snakes, Mexico - Anti micruricoscorales: Coral snakes, Colombia # Antivenin sources The following groups assist in locating antivenins: - USA, Miami, Florida: The Miami-Dade Fire Rescue Antivenom Bank: Emergency: 1-786-336-6600 available 24 hours. A list of available antivenins is available at [2]. More information about the bank is available at [3] - USA, The Antivenom Index is a joint project of the Association of Zoos and Aquariums and the American Association of Poison Control Centers: They maintain a website to help locate rare antivenins.[4] - USA, Colorado: Poisindex central office in Denver, Colorado, USA (1-800-332-3073). - Australia: CSL Limited, Parkville, Victoria. - Asia: Haffkine Biopharmaceutical Corporation, Parel, Mumbai, India. - Africa: South African Institute for Medical Research, Johannesburg, Republic of South Africa. - Brazil: Instituto Butantan, São Paulo # Cited references - ↑ Isbister GK. (2002). "Failure of intramuscular antivenom in Red-back spider envenoming". Emerg Med (Fremantle). 14 (4): 436–9. PMID 12534488..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} - ↑ See, for example, the Antivenin Precautions paragraph of the Medication section of James Forster, MD, MS (2006-03-14). "Snake Envenomations, Sea". eMedicine Emergency Medicine (environmental). Retrieved 2006-06-25.CS1 maint: Multiple names: authors list (link) - ↑ "Appendix: Antivenom Tables". Clinical Toxicology. 41 (3): 317–27. 2003. doi:10.1081/CLT-120021117. - ↑ Spawls S, Branch B. 1995. The Dangerous Snakes of Africa. Ralph Curtis Books. Dubai: Oriental Press. 192 pp. ISBN 0-88359-029-8. # External links - Snakebite. eMedicine. - New antivenin could save more snakebite victims de:Antivenin he:נסיוב uk:Антитоксини	https://www.wikidoc.org/index.php/Antivenin
7065153b81ae20b17a9569c24604aff2284cf923	wikidoc	Antivenom	Antivenom # Overview Antivenin (or antivenene or antivenom) is a biological product used in the treatment of venomous bites or stings. It is created by injecting a small amount of the targeted venom into an animal such as a horse, sheep, goat, or rabbit; the subject animal will suffer an immune response to the venom, producing antibodies against the venom's active molecule which can then be harvested from the animal's blood and used to treat envenomation in others. Internationally, Snake Venom Antitoxin must carefully meet the standards of Pharmacopoeia and the World Health Organization (WHO). # Therapeutic use The principle of antivenin is based on that of vaccines, developed by Louis Pasteur, however instead of inducing immunity in the patient directly, it is induced in a host animal and the hyperimmunized serum is transfused into the patient. The first antivenin for snakes (called an anti-ophidic serum) was developed by Albert Calmette, a French scientist of the Pasteur Institute working at its Indochine branch in 1895, against the Indian Cobra (Naja naja). Vital Brazil, a Brazilian scientist developed in 1901 the first monovalent and polyvalent antivenins for Central and South American Crotalus, Bothrops and Elaps genera, as well as for certain species of venomous spiders, scorpions, and frogs. They were all developed in a Brazilian institution, the Instituto Butantan, located in São Paulo], Brazil. Antivenins can be classified into monovalent (when they are effective against a given species' venom) or polyvalent (when they are effective against a range of species, or several different species at the same time). Antivenins for therapeutic use are often preserved as freeze-dried ampoules, but some are available only in liquid form and must be kept refrigerated. (They are not immediately inactivated by heat, so a minor gap in the cold chain is not disastrous.) The majority of antivenins (including all snake antivenins) are administered intravenously, however stonefish and red-back spider antivenins are given intramuscularly. The intramuscular route has been questioned in some situations as not uniformly effective. Antivenins bind to and neutralize the venom, halting further damage, but do not reverse damage already done. Thus, they should be administered as soon as possible after the venom has been injected, but are of some benefit as long as venom is present in the body. Since the advent of antivenins, some bites which were previously inevitably fatal have become only rarely fatal provided that the antivenin is administered soon enough. Antivenins are purified by several processes but will still contain other serum proteins that can act as antigens. Some individuals may react to the antivenin with an immediate hypersensitivity reaction (anaphylaxis) or a delayed hypersensitivity (serum sickness) reaction and antivenin should, therefore, be used with caution. Despite this caution, antivenin is typically the sole effective treatment for a life-threatening condition, and once the precautions for managing these reactions are in place, an anaphylactoid reaction is not grounds to refuse to give antivenin if otherwise indicated. Although it is a popular myth that a person allergic to horses "cannot" be given antivenin, the side effects are manageable, and antivenin should be given as rapidly as the side effects can be managed. Sheep are generally used in preference over horses now, however, as the potential for adverse immunological responses in humans from sheep-derived antibodies is generally somewhat less than that from horse-derived antibodies. The use of horses to raise antibodies, in Australia at least, where much antivenin research has been undertaken (by Sutherland and others for example), has been attributed to the research base originally having been comprised of a large number of veterinary officers. These vets had, in many cases, returned from taking part in the Boer and First World Wars and were generally experienced with horses (eg: cavalry). The large animal vets were similarly oriented given the use of horses as a prime source of motive power and transport, especially in the rural setting. The overall experience with horses naturally made them the preferred subject in which to raise antibodies. It was not until later that the immuno-reactivity of certain horse serum proteins was assessed to be sufficiently problematic that alternatives in which to raise antibodies were investigated. # Natural and acquired immunity Although individuals can vary in their physiopathological response and sensitivity to animal venoms, there is no natural immunity to them in humans. Some ophiophagic animals are immune to the venoms produced by some species of venomous snakes, by the presence of antihemorrhagic and antineurotoxic factors in their blood. These animals include king snakes, opossums and hedgehogs. It is quite possible to immunize a person directly with small and graded doses of venom rather than an animal. According to Greek mythology, King Mithridates did this in order to protect himself against attempts of poisoning, therefore this procedure is often called mithridatization. However, unlike a vaccination against disease which must only produce a latent immunity that can be roused in case of infection, to neutralize a sudden and large dose of venom requires maintaining a high level of circulating antibody (a hyperimmunized state), through repeated venom injections (typically every 21 days). The long-term health effects of this process have not been studied. For some large snakes, the total amount of antibody it is possible to maintain in one human being is not enough to neutralize one envenomation. Further, cytotoxic venom components can cause pain and minor scarring at the immunization site. Finally, the resistance is specific to the particular venom used; maintaining resistance to a variety of venoms requires multiple monthly venom injections. Thus, there is no practical purpose or favorable cost/benefit ratio for this, except for people like zoo handlers, researchers, and circus artists who deal closely with venomous animals. Mithridatization has been tried with success in Australia and Brazil and total immunity has been achieved even to multiple bites of extremely venomous cobras and pit vipers. Starting in 1950, Bill Haast successfully immunized himself to the venoms of Cape Cobra, Indian Cobra and King Cobras. Because neurotoxic venoms must travel farther in the body to do harm and are produced in smaller quantities, it is easier to develop resistance to them than directly cytotoxic venoms (such as those of most vipers) that are injected in large quantity and do damage immediately upon injection. # Availability of antivenins Antivenins have been developed for the venoms associated with the following animals: ## Spiders - Funnel web spider antivenom: Sydney funnel-web spider, Australia - Soro antiaracnidico: Brazilian wandering spider, Brazil - Soro antiloxoscelico: Recluse spider, Brazil - Suero antiloxoscelico: Chilean recluse, Peru - Aracmyn: All species of Loxosceles and Latrodectus, Mexico - Redback spider antivenom: Red-back spider, Australia - Black widow antivenin: Black widow spider, USA - SAIMR Spider antivenom: Button spider, South Africa - Anti Latrodectus antivenom: Black widow spider, Argentina ## Acarids - Tick antivenom: Ixodes holocyclus (Paralysis tick), Australia ## Insects - Soro antilonomico: Lonomia (Lonomia oblique) caterpillar, Brazil ## Scorpions - Alacramyn: Centruroides limpidus, C. noxius, C. suffusus, Mexico - Suero Antialacran: Centruroides limpidus, C. noxius, C. suffusus, Mexico - Tunisian polyvalent antivenom: All Iranian scorpions, Tunisia - Anti-Scorpion Venom Serum I.P.(AScVS): Indian red scorpion, India - Anti-scorpionique: Androctonus spp., Buthus spp., Algeria - Scorpion antivenom: Black scorpion, Buthus occitanus, Morocco - Soro antiescorpionico: Tityus spp., Brazil - SAIMR scorpion antivenom: Parabuthus spp., South Africa - Purified polyvalent Anti-Scorpion Serum(equine): Leiurus spp.& Androctons scorpions, Egypt ## Marine animals - CSL box jellyfish antivenom: Box jellyfish, Australia - CSL stonefish antivenom Stonefish, Australia ## Snakes - Polyvalent snake antivenom: Saw-scaled Viper Echis carinatus, Russell's Viper Daboia Daboia russelli, Spectacled Cobra Naja naja, Common Krait Bungarus caeruleus. India. - Death adder antivenom: Death adder, Australia - Taipan antivenom: Taipan, Australia - Black snake antivenom: Pseudechis\|Pseudechis spp.]] Australia. - Tiger snake antivenom: Austrelaps\|Australian copperheads]], Tiger snakes, Pseudechis spp., Rough scaled snake. Australia - Brown snake antivenom: Pseudonaja\|Brown snakes]]. Australia - Polyvalent snake antivenom: Many Australian snakes. Australia - Sea snake antivenom: Sea snakes, Australia - Vipera tab: Vipera spp. USA - Polyvalent crotalid antivenin (CroFab - Crotalidae Polyvalent Immune Fab (Ovine)): North American pit vipers (all Rattlesnakes, Copperheads, and cottonmouths), USA - Soro antibotropicocrotalico: Pit vipers and Rattlesnakes, Brazil - Antielapidico: Coral snakes, Brazil - Soro anti-elapidico: Coral snakes, Brazil - SAIMR polyvalent antivenom: Mambas, Cobras, Rinkhalses, Puff adders] (Unsuitable small adders: B. worthingtoni, Bitis atropos, Bitis caudalis, Bitis cornuta, Bitis heraldica, Bitis inornata, Bitis peringueyi, Bitis schneideri, Bitis xeropaga), South Africa - SAIMR echis antivenom: Saw-scaled vipers]], South Africa - SAIMR Boomslang antivenom: Boomslang, South Africa - Panamerican serum: anticoral polyvalent serum: Coral snakes, Costa Rica - Anticoral: Coral snakes, Costa Rica - Anti-mipartitus antivenom: Coral snakes, Costa Rica - Anticoral monovalent: Coral snakes, Costa Rica - Antimicrurus: Coral snakes, Argentina - Coralmyn: Coral snakes, Mexico - Anti micruricoscorales: Coral snakes, Colombia # Antivenin sources The following groups assist in locating antivenins: - USA, Miami, Florida: The Miami-Dade Fire Rescue Antivenom Bank: Emergency: 1-786-336-6600 available 24 hours. A list of available antivenins is available at . More information about the bank is available at - USA, The Antivenom Index is a joint project of the The American Zoo and Aquarium Association and the American Association of Poison Control Centers: They maintain a website to help locate rare antivenins. - USA, Colorado: Poisindex central office in Denver, Colorado, USA (1-800-332-3073). - Australia]]: CSL Limited, Parkville, Victoria, Victoria (Australia). - Asia: Haffkine Biopharmaceutical Corporation, Parel, Bombay, India. - Africa: South African Institute for Medical Research, Johannesburg, Republic of South Africa. - Brazil: Instituto Butantan, São Paulo	Antivenom Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Antivenin (or antivenene or antivenom) is a biological product used in the treatment of venomous bites or stings. It is created by injecting a small amount of the targeted venom into an animal such as a horse, sheep, goat, or rabbit; the subject animal will suffer an immune response to the venom, producing antibodies against the venom's active molecule which can then be harvested from the animal's blood and used to treat envenomation in others. Internationally, Snake Venom Antitoxin must carefully meet the standards of Pharmacopoeia and the World Health Organization (WHO). [2] # Therapeutic use The principle of antivenin is based on that of vaccines, developed by Louis Pasteur, however instead of inducing immunity in the patient directly, it is induced in a host animal and the hyperimmunized serum is transfused into the patient. The first antivenin for snakes (called an anti-ophidic serum) was developed by Albert Calmette, a French scientist of the Pasteur Institute working at its Indochine branch in 1895, against the Indian Cobra (Naja naja). Vital Brazil, a Brazilian scientist developed in 1901 the first monovalent and polyvalent antivenins for Central and South American Crotalus, Bothrops and Elaps genera, as well as for certain species of venomous spiders, scorpions, and frogs. They were all developed in a Brazilian institution, the Instituto Butantan, located in São Paulo], Brazil. Antivenins can be classified into monovalent (when they are effective against a given species' venom) or polyvalent (when they are effective against a range of species, or several different species at the same time). Antivenins for therapeutic use are often preserved as freeze-dried ampoules, but some are available only in liquid form and must be kept refrigerated. (They are not immediately inactivated by heat, so a minor gap in the cold chain is not disastrous.) The majority of antivenins (including all snake antivenins) are administered intravenously, however stonefish and red-back spider antivenins are given intramuscularly. The intramuscular route has been questioned in some situations as not uniformly effective.[1] Antivenins bind to and neutralize the venom, halting further damage, but do not reverse damage already done. Thus, they should be administered as soon as possible after the venom has been injected, but are of some benefit as long as venom is present in the body. Since the advent of antivenins, some bites which were previously inevitably fatal have become only rarely fatal provided that the antivenin is administered soon enough. Antivenins are purified by several processes but will still contain other serum proteins that can act as antigens. Some individuals may react to the antivenin with an immediate hypersensitivity reaction (anaphylaxis) or a delayed hypersensitivity (serum sickness) reaction and antivenin should, therefore, be used with caution. Despite this caution, antivenin is typically the sole effective treatment for a life-threatening condition, and once the precautions for managing these reactions are in place, an anaphylactoid reaction is not grounds to refuse to give antivenin if otherwise indicated. Although it is a popular myth that a person allergic to horses "cannot" be given antivenin, the side effects are manageable, and antivenin should be given as rapidly as the side effects can be managed.[2] Sheep are generally used in preference over horses now, however, as the potential for adverse immunological responses in humans from sheep-derived antibodies is generally somewhat less than that from horse-derived antibodies. The use of horses to raise antibodies, in Australia at least, where much antivenin research has been undertaken (by Sutherland and others for example), has been attributed to the research base originally having been comprised of a large number of veterinary officers. These vets had, in many cases, returned from taking part in the Boer and First World Wars and were generally experienced with horses (eg: cavalry). The large animal vets were similarly oriented given the use of horses as a prime source of motive power and transport, especially in the rural setting. The overall experience with horses naturally made them the preferred subject in which to raise antibodies. It was not until later that the immuno-reactivity of certain horse serum proteins was assessed to be sufficiently problematic that alternatives in which to raise antibodies were investigated. # Natural and acquired immunity Although individuals can vary in their physiopathological response and sensitivity to animal venoms, there is no natural immunity to them in humans. Some ophiophagic animals are immune to the venoms produced by some species of venomous snakes, by the presence of antihemorrhagic and antineurotoxic factors in their blood. These animals include king snakes, opossums and hedgehogs. It is quite possible to immunize a person directly with small and graded doses of venom rather than an animal. According to Greek mythology, King Mithridates did this in order to protect himself against attempts of poisoning, therefore this procedure is often called mithridatization. However, unlike a vaccination against disease which must only produce a latent immunity that can be roused in case of infection, to neutralize a sudden and large dose of venom requires maintaining a high level of circulating antibody (a hyperimmunized state), through repeated venom injections (typically every 21 days). The long-term health effects of this process have not been studied. For some large snakes, the total amount of antibody it is possible to maintain in one human being is not enough to neutralize one envenomation. Further, cytotoxic venom components can cause pain and minor scarring at the immunization site. Finally, the resistance is specific to the particular venom used; maintaining resistance to a variety of venoms requires multiple monthly venom injections. Thus, there is no practical purpose or favorable cost/benefit ratio for this, except for people like zoo handlers, researchers, and circus artists who deal closely with venomous animals. Mithridatization has been tried with success in Australia and Brazil and total immunity has been achieved even to multiple bites of extremely venomous cobras and pit vipers. Starting in 1950, Bill Haast successfully immunized himself to the venoms of Cape Cobra, Indian Cobra and King Cobras. Because neurotoxic venoms must travel farther in the body to do harm and are produced in smaller quantities, it is easier to develop resistance to them than directly cytotoxic venoms (such as those of most vipers) that are injected in large quantity and do damage immediately upon injection. # Availability of antivenins Antivenins have been developed for the venoms associated with the following animals:[3] ## Spiders - Funnel web spider antivenom: Sydney funnel-web spider, Australia - Soro antiaracnidico: Brazilian wandering spider, Brazil - Soro antiloxoscelico: Recluse spider, Brazil - Suero antiloxoscelico: Chilean recluse, Peru - Aracmyn: All species of Loxosceles and Latrodectus, Mexico - Redback spider antivenom: Red-back spider, Australia - Black widow antivenin: Black widow spider, USA - SAIMR Spider antivenom: Button spider, South Africa - Anti Latrodectus antivenom: Black widow spider, Argentina ## Acarids - Tick antivenom: Ixodes holocyclus (Paralysis tick), Australia ## Insects - Soro antilonomico: Lonomia (Lonomia oblique) caterpillar, Brazil ## Scorpions - Alacramyn: Centruroides limpidus, C. noxius, C. suffusus, Mexico - Suero Antialacran: Centruroides limpidus, C. noxius, C. suffusus, Mexico - Tunisian polyvalent antivenom: All Iranian scorpions, Tunisia - Anti-Scorpion Venom Serum I.P.(AScVS): Indian red scorpion, India - Anti-scorpionique: Androctonus spp., Buthus spp., Algeria - Scorpion antivenom: Black scorpion, Buthus occitanus, Morocco - Soro antiescorpionico: Tityus spp., Brazil - SAIMR scorpion antivenom: Parabuthus spp., South Africa - Purified polyvalent Anti-Scorpion Serum(equine): Leiurus spp.& Androctons scorpions, Egypt ## Marine animals - CSL box jellyfish antivenom: Box jellyfish, Australia - CSL stonefish antivenom Stonefish, Australia ## Snakes - Polyvalent snake antivenom: Saw-scaled Viper Echis carinatus, Russell's Viper Daboia Daboia russelli, Spectacled Cobra Naja naja, Common Krait Bungarus caeruleus. India. - Death adder antivenom: Death adder, Australia - Taipan antivenom: Taipan, Australia - Black snake antivenom: Pseudechis\|Pseudechis spp.]] Australia. - Tiger snake antivenom: Austrelaps\|Australian copperheads]], Tiger snakes, Pseudechis spp., Rough scaled snake. Australia - Brown snake antivenom: Pseudonaja\|Brown snakes]]. Australia - Polyvalent snake antivenom: Many Australian snakes. Australia - Sea snake antivenom: Sea snakes, Australia - Vipera tab: Vipera spp. USA - Polyvalent crotalid antivenin (CroFab - Crotalidae Polyvalent Immune Fab (Ovine)): North American pit vipers (all Rattlesnakes, Copperheads, and cottonmouths), USA - Soro antibotropicocrotalico: Pit vipers and Rattlesnakes, Brazil - Antielapidico: Coral snakes, Brazil - Soro anti-elapidico: Coral snakes, Brazil - SAIMR polyvalent antivenom: Mambas, Cobras, Rinkhalses, Puff adders] (Unsuitable small adders: B. worthingtoni, Bitis atropos, Bitis caudalis, Bitis cornuta, Bitis heraldica, Bitis inornata, Bitis peringueyi, Bitis schneideri, Bitis xeropaga), South Africa[4] - SAIMR echis antivenom: Saw-scaled vipers]], South Africa - SAIMR Boomslang antivenom: Boomslang, South Africa - Panamerican serum: anticoral polyvalent serum: Coral snakes, Costa Rica - Anticoral: Coral snakes, Costa Rica - Anti-mipartitus antivenom: Coral snakes, Costa Rica - Anticoral monovalent: Coral snakes, Costa Rica - Antimicrurus: Coral snakes, Argentina - Coralmyn: Coral snakes, Mexico - Anti micruricoscorales: Coral snakes, Colombia # Antivenin sources The following groups assist in locating antivenins: - USA, Miami, Florida: The Miami-Dade Fire Rescue Antivenom Bank: Emergency: 1-786-336-6600 available 24 hours. A list of available antivenins is available at [3]. More information about the bank is available at [4] - USA, The Antivenom Index is a joint project of the The American Zoo and Aquarium Association and the American Association of Poison Control Centers: They maintain a website to help locate rare antivenins.[5] - USA, Colorado: Poisindex central office in Denver, Colorado, USA (1-800-332-3073). - Australia]]: CSL Limited, Parkville, Victoria, Victoria (Australia). - Asia: Haffkine Biopharmaceutical Corporation, Parel, Bombay, India. - Africa: South African Institute for Medical Research, Johannesburg, Republic of South Africa. - Brazil: Instituto Butantan, São Paulo	https://www.wikidoc.org/index.php/Antivenom
6a2db4a47f7f7d5af2a90e9497c12f9538249c67	wikidoc	Meclizine	Meclizine # 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 Meclizine is a antiemetic, antihistamine, antivertigo and central nervous system agent that is FDA approved for the treatment of nausea, vomiting and dizziness associated with motion sickness and vertigo. Common adverse reactions include drowsiness, xerostomia, sedation and somnolence. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Based on a review of this drug by the National Academy of Sciences - National Research Council and/or other information, FDA has classified the indications as follows: - Effective: - Management of nausea and vomiting, and dizziness associated with motion sickness. - Possibly Effective: - Management of vertigo associated with diseases affecting the vestibular system. - Final classification of the less than effective indications requires further investigation. ### Dosing Information - For the control of vertigo associated with diseases affecting the vestibular system, the recommended dose is 25 to 100 mg daily, in divided dosage, depending upon clinical response. - The initial dose of 25 to 50 mg of Meclizine should be taken one hour prior to embarkation for protection against motion sickness. Thereafter, the dose may be repeated every 24 hours for the duration of the journey. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Meclizine in adult patients. ### Non–Guideline-Supported Use - Radiation-induced nausea and vomiting; Treatment and Prophylaxis - Dosage 50 mg Oral, 2 to 12 hrs prior to radiotherapy - 50 mg Oral, 2 to 12 hrs prior to radiotherapy - Vomiting of pregnancy - Dosage 25 to 50 mg oral daily - 25 to 50 mg oral daily # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Meclizine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Meclizine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Meclizine in pediatric patients. # Contraindications - Meclizine HCl is contraindicated in individuals who have shown a previous hypersensitivity to it. # Warnings - Since drowsiness may, on occasion, occur with use of this drug, patients should be warned of this possibility and cautioned against driving a car or operating dangerous machinery. - Patients should avoid alcoholic beverages while taking this drug. - Due to its potential anticholinergic action, this drug should be used with caution in patients with asthma, glaucoma, or enlargement of the prostate gland. - Clinical studies establishing safety and effectiveness in children have not been done; therefore, usage is not recommended in children under 12 years of age. # Adverse Reactions ## Clinical Trials Experience - Anaphylactoid reaction, drowsiness, dry mouth, headache, fatigue, vomiting and, on rare occasions, blurred vision have been reported. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Meclizine in the drug label. # Drug Interactions - There may be increased CNS depression when meclizine is administered concurrently with other CNS depressants, including alcohol, tranquilizers, and sedatives. - Based on in-vitro evaluation, meclizine is metabolized by CYP2D6. Therefore there is a possibility for a drug interaction between meclizine and CYP2D6 inhibitors. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproduction studies in rats have shown cleft palates at 25–50 times the human dose. Epidemiological studies in pregnant women, however, do not indicate that meclizine increases the risk of abnormalities when administered during pregnancy. Despite the animal findings, it would appear that the possibility of fetal harm is remote. Nevertheless, meclizine, or any other medication, should be used during pregnancy only if clearly necessary. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Meclizine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Meclizine during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when meclizine is administered to a nursing woman. ### Pediatric Use There is no FDA guidance on the use of Meclizine with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Meclizine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Meclizine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Meclizine with respect to specific racial populations. ### Renal Impairment - The effect of renal impairment on the pharmacokinetics of meclizine has not been evaluated. Due to a potential for drug/metabolite accumulation, meclizine should be administered with caution in patients with renal impairment and in the elderly as renal function generally declines with age. ### Hepatic Impairment - The effect of hepatic impairment on the pharmacokinetics of meclizine has not been evaluated. As meclizine undergoes metabolism, hepatic impairment may result in increased systemic exposure of the drug. Treatment with meclizine should be administered with caution in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Meclizine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Meclizine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Meclizine in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of Meclizine in the drug label. # Overdosage There is limited information regarding Chronic Overdose of Meclizine in the drug label. # Pharmacology ## Mechanism of Action - Meclizine is an antihistamine that shows marked protective activity against nebulized histamine and lethal doses of intravenously injected histamine in guinea pigs. It has a marked effect in blocking the vasodepressor response to histamine, but only a slight blocking action against acetylcholine. Its activity is relatively weak in inhibiting the spasmogenic action of histamine on isolated guinea pig ileum. ## Structure - Chemically, Meclizine HCl is 1-(p-chloro-α-phenylbenzyl)-4-(m-methylbenzyl) piperazine dihydrochloride monohydrate. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Meclizine in the drug label. ## Pharmacokinetics - The available pharmacokinetic information for meclizine following oral administration has been summarized from published literature. - Meclizine is absorbed after oral administration with maximum plasma concentrations reaching at a median Tmax value of 3 hours post-dose (range: 1.5 to 6 hours) for the tablet dosage form. - Drug distribution characteristics for meclizine in humans are unknown. - The metabolic fate of meclizine in humans is unknown. In an in vitro metabolic study using human hepatic microsome and recombinant CYP enzyme, CYP2D6 was found to be the dominant enzyme for metabolism of meclizine. - The genetic polymorphism of CYP2D6 that results in extensive-, poor-, intermediate- and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure. - Meclizine has a plasma elimination half-life of about 5-6 hours in humans. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Meclizine in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Meclizine in the drug label. # How Supplied Antivert: 12.5 mg tablets: Bottles of 100 (NDC 0049-2100-66) Antivert/25: 25 mg tablets: Bottles of 100 (NDC 0049-2110-66) Meclizine/50: 50 mg tablets: Bottles of 100 (NDC 0049-2140-66) ## Storage There is limited information regarding Meclizine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel NDC 0049-2100-66 100 Tablets Meclizine® (meclizine HCl) 12.5 mg Pfizer Distributed by Roerig Division of Pfizer Inc, NY, NY 10017 NDC 0049-2110-66 100 Tablets Antivert® (meclizine HCl) 25 mg Pfizer Distributed by Roerig Division of Pfizer Inc, NY, NY 10017 NDC 0049-2140-66 100 Tablets Antivert® (meclizine HCl) 50 mg Pfizer Distributed by Roerig Division of Pfizer Inc, NY, NY 10017 # Patient Counseling Information There is limited information regarding Patient Counseling Information of Meclizine in the drug label. # Precautions with Alcohol - Alcohol-Meclizine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Antivert® - Antivert/25® - Antivert/50® - Dramamine II® - Meclicot® - Meni-D® - Motion Sickness Relief® - Simply Motion® # Look-Alike Drug Names - Antivert® - Axert® # Drug Shortage Status # Price	Meclizine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Meclizine is a antiemetic, antihistamine, antivertigo and central nervous system agent that is FDA approved for the treatment of nausea, vomiting and dizziness associated with motion sickness and vertigo. Common adverse reactions include drowsiness, xerostomia, sedation and somnolence. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Based on a review of this drug by the National Academy of Sciences - National Research Council and/or other information, FDA has classified the indications as follows: - Effective: - Management of nausea and vomiting, and dizziness associated with motion sickness. - Possibly Effective: - Management of vertigo associated with diseases affecting the vestibular system. - Final classification of the less than effective indications requires further investigation. ### Dosing Information - For the control of vertigo associated with diseases affecting the vestibular system, the recommended dose is 25 to 100 mg daily, in divided dosage, depending upon clinical response. - The initial dose of 25 to 50 mg of Meclizine should be taken one hour prior to embarkation for protection against motion sickness. Thereafter, the dose may be repeated every 24 hours for the duration of the journey. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Meclizine in adult patients. ### Non–Guideline-Supported Use - Radiation-induced nausea and vomiting; Treatment and Prophylaxis - Dosage 50 mg Oral, 2 to 12 hrs prior to radiotherapy - 50 mg Oral, 2 to 12 hrs prior to radiotherapy - Vomiting of pregnancy - Dosage 25 to 50 mg oral daily - 25 to 50 mg oral daily # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Meclizine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Meclizine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Meclizine in pediatric patients. # Contraindications - Meclizine HCl is contraindicated in individuals who have shown a previous hypersensitivity to it. # Warnings - Since drowsiness may, on occasion, occur with use of this drug, patients should be warned of this possibility and cautioned against driving a car or operating dangerous machinery. - Patients should avoid alcoholic beverages while taking this drug. - Due to its potential anticholinergic action, this drug should be used with caution in patients with asthma, glaucoma, or enlargement of the prostate gland. - Clinical studies establishing safety and effectiveness in children have not been done; therefore, usage is not recommended in children under 12 years of age. # Adverse Reactions ## Clinical Trials Experience - Anaphylactoid reaction, drowsiness, dry mouth, headache, fatigue, vomiting and, on rare occasions, blurred vision have been reported. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Meclizine in the drug label. # Drug Interactions - There may be increased CNS depression when meclizine is administered concurrently with other CNS depressants, including alcohol, tranquilizers, and sedatives. - Based on in-vitro evaluation, meclizine is metabolized by CYP2D6. Therefore there is a possibility for a drug interaction between meclizine and CYP2D6 inhibitors. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproduction studies in rats have shown cleft palates at 25–50 times the human dose. Epidemiological studies in pregnant women, however, do not indicate that meclizine increases the risk of abnormalities when administered during pregnancy. Despite the animal findings, it would appear that the possibility of fetal harm is remote. Nevertheless, meclizine, or any other medication, should be used during pregnancy only if clearly necessary. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Meclizine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Meclizine during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when meclizine is administered to a nursing woman. ### Pediatric Use There is no FDA guidance on the use of Meclizine with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Meclizine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Meclizine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Meclizine with respect to specific racial populations. ### Renal Impairment - The effect of renal impairment on the pharmacokinetics of meclizine has not been evaluated. Due to a potential for drug/metabolite accumulation, meclizine should be administered with caution in patients with renal impairment and in the elderly as renal function generally declines with age. ### Hepatic Impairment - The effect of hepatic impairment on the pharmacokinetics of meclizine has not been evaluated. As meclizine undergoes metabolism, hepatic impairment may result in increased systemic exposure of the drug. Treatment with meclizine should be administered with caution in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Meclizine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Meclizine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Meclizine in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of Meclizine in the drug label. # Overdosage There is limited information regarding Chronic Overdose of Meclizine in the drug label. # Pharmacology ## Mechanism of Action - Meclizine is an antihistamine that shows marked protective activity against nebulized histamine and lethal doses of intravenously injected histamine in guinea pigs. It has a marked effect in blocking the vasodepressor response to histamine, but only a slight blocking action against acetylcholine. Its activity is relatively weak in inhibiting the spasmogenic action of histamine on isolated guinea pig ileum. ## Structure - Chemically, Meclizine HCl is 1-(p-chloro-α-phenylbenzyl)-4-(m-methylbenzyl) piperazine dihydrochloride monohydrate. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Meclizine in the drug label. ## Pharmacokinetics - The available pharmacokinetic information for meclizine following oral administration has been summarized from published literature. - Meclizine is absorbed after oral administration with maximum plasma concentrations reaching at a median Tmax value of 3 hours post-dose (range: 1.5 to 6 hours) for the tablet dosage form. - Drug distribution characteristics for meclizine in humans are unknown. - The metabolic fate of meclizine in humans is unknown. In an in vitro metabolic study using human hepatic microsome and recombinant CYP enzyme, CYP2D6 was found to be the dominant enzyme for metabolism of meclizine. - The genetic polymorphism of CYP2D6 that results in extensive-, poor-, intermediate- and ultrarapid metabolizer phenotypes could contribute to large inter-individual variability in meclizine exposure. - Meclizine has a plasma elimination half-life of about 5-6 hours in humans. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Meclizine in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Meclizine in the drug label. # How Supplied Antivert: 12.5 mg tablets: Bottles of 100 (NDC 0049-2100-66) Antivert/25: 25 mg tablets: Bottles of 100 (NDC 0049-2110-66) Meclizine/50: 50 mg tablets: Bottles of 100 (NDC 0049-2140-66) ## Storage There is limited information regarding Meclizine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel NDC 0049-2100-66 100 Tablets Meclizine® (meclizine HCl) 12.5 mg Pfizer Distributed by Roerig Division of Pfizer Inc, NY, NY 10017 NDC 0049-2110-66 100 Tablets Antivert® (meclizine HCl) 25 mg Pfizer Distributed by Roerig Division of Pfizer Inc, NY, NY 10017 NDC 0049-2140-66 100 Tablets Antivert® (meclizine HCl) 50 mg Pfizer Distributed by Roerig Division of Pfizer Inc, NY, NY 10017 # Patient Counseling Information There is limited information regarding Patient Counseling Information of Meclizine in the drug label. # Precautions with Alcohol - Alcohol-Meclizine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Antivert® - Antivert/25® - Antivert/50® - Dramamine II® - Meclicot® - Meni-D® - Motion Sickness Relief® - Simply Motion® # Look-Alike Drug Names - Antivert® - Axert® # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Antivert
4dd7c757342d36492bc51c1089bbf117cbdd6744	wikidoc	Apex beat	Apex beat The apex beat, also called the point of maximum impulse (PMI), is the furthermost point outwards (laterally) and downwards (inferiorly) from the sternum at which the cardiac impulse can be felt. The cardiac impulse is the result of the heart rotating, moving forward and striking against the chest wall during systole. The normal apex beat can be palpated in the precordium left 5th intercostal space, at the point of intersection with the left midclavicular line. In children the apex beat occurs in the fourth rib interspace medial to the nipple. The apex beat may also be found at abnormal locations; in many cases of dextrocardia, the apex beat may be felt on the right side. Lateral and/or inferior displacement of the apex beat usually indicates enlargement of the heart, called cardiomegaly. The apex beat may also be displaced by other conditions: - Pleural or pulmonary diseases - Deformities of the chest wall or the thoracic vertebra Sometimes, the apex beat may not be palpable, either due to a thick chest wall, or conditions where the stroke volume is reduced; such as during ventricular tachycardia or shock. The character of the apex beat may provide vital diagnostic clues: - A forceful impulse indicates pressure overload in the heart (as might occur in hypertension) - An uncoordinated(dyskinetic) apex beat involving a larger area than normal indicates ventricular dysfunction; such as an aneurysm following myocardial infarction CME Category::Cardiology	Apex beat Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The apex beat, also called the point of maximum impulse (PMI), is the furthermost point outwards (laterally) and downwards (inferiorly) from the sternum at which the cardiac impulse can be felt. The cardiac impulse is the result of the heart rotating, moving forward and striking against the chest wall during systole. The normal apex beat can be palpated in the precordium left 5th intercostal space, at the point of intersection with the left midclavicular line. In children the apex beat occurs in the fourth rib interspace medial to the nipple. The apex beat may also be found at abnormal locations; in many cases of dextrocardia, the apex beat may be felt on the right side. Lateral and/or inferior displacement of the apex beat usually indicates enlargement of the heart, called cardiomegaly. The apex beat may also be displaced by other conditions: - Pleural or pulmonary diseases - Deformities of the chest wall or the thoracic vertebra Sometimes, the apex beat may not be palpable, either due to a thick chest wall, or conditions where the stroke volume is reduced; such as during ventricular tachycardia or shock. The character of the apex beat may provide vital diagnostic clues: - A forceful impulse indicates pressure overload in the heart (as might occur in hypertension) - An uncoordinated(dyskinetic) apex beat involving a larger area than normal indicates ventricular dysfunction; such as an aneurysm following myocardial infarction Template:WikiDoc Sources CME Category::Cardiology	https://www.wikidoc.org/index.php/Apex_beat
64f7ae32afa38836544ec21613338847cdcb32b5	wikidoc	Apheresis	Apheresis Apheresis (Greek: "to take away") is a medical technology in which the blood of a donor or patient is passed through an apparatus that separates out one particular constituent and returns the remainder to the circulation. It is thus an extracorporeal therapy. # Method Depending on the substance that is being removed, different processes are employed in apheresis. If separation by weight is required, centrifugation would be the method of choice. Other methods involve absorption onto beads coated with an absorbent material. The centrifugation method can be divided into two basic categories: A. Continuous flow centrifugation (CFC) historically required two venipunctures as the "continuous" means the blood is collected, spun, and returned simultaneously. Newer systems can use a single venipuncture. The main advantage of this system is the low extracorporeal volume (calculated by volume of the apheresis chamber, the donor's hematocrit, and total blood volume of the donor) used in the procedure, which may be advantageous in the elderly and for children. B. Intermittent flow centrifugation works in cycles, taking blood, spinning/processing it and then giving back the unnecessary parts to the donor in a bolus. The main advantage is a single venipuncture site. To stop the blood from coagulating, anticoagulant is automatically mixed with the blood as it is pumped from the body into the apheresis machine. The centrifugation process itself has four variables that can be controlled to selectively remove desired components. The first is spin speed and bowl diameter, the second is "sit time" in centrifuge, the third is solutes added, and the fourth is not as easily controllable: plasma volume and cellular content of the donor. The end product in most cases is the classic sedimented blood sample with the RBC's at the bottom, the "buffy coat" of platelets and WBC's (lymphocytes/granulocytes (PMN's, basophils, eosinophils)/monocytes) in the middle and the plasma on top. It is important to remember that, when the apheresis system is used for therapy, the system is removing relatively small amounts of fluid (not more than 10.5 mL/kg body weight), but that fluid must be replaced to keep correct intravascular volume. The fluid replaced is different at different institutions. If a crystalloid like normal saline is used, the infusion amount should be triple what is removed as the three to one ratio of NS for plasma is needed to keep up oncotic pressure. Some institutions use normal serum albumin, but it is costly and can be difficult to find. Some advocate using FFP, but the dangers including citrate toxicity (from the anticoagulant), ABO incompatibility, bacterial infection, and cellular antigens make this choice less than desirable. # Types of apheresis There are numerous types of apheresis. Blood taken from a healthy donor can be separated into its component parts, where the needed component is collected and the "unused" components are returned to the donor. Fluid replacement is usually not needed in these type of collections. There are large categories of component collections: - Plasmapheresis - blood plasma. Plasmapheresis is useful in collecting FFP (fresh frozen plasma) of a particular ABO group. Commercial uses aside from FFP for this procedure include immune globulin products, plasma derivatives, and collection of rare WBC and RBC antibodies. Consult AABB standards for procedure criteria. FFP may be stored one year at -18 C and seven years at -65 C. After thawing, FFP can be stored for 24 hours at 1-6 C. - Plateletpheresis (thrombapheresis, thrombocytapheresis) - blood platelets. Plateletpheresis, like it sounds, is the collection of platelets by apheresis; while returning the RBC's, WBC's, and component plasma. The yield is normally the equivalent of between six and ten random platelet concentrates. Quality control demands the platelets from apheresis be equal to or greater than 3.0 x 10^11 in number and have a pH of equal to or greater than 6.2 in 90% of the products tested and must be used within five days. ABO compatibility is a good idea. - Leukapheresis - leukocytes (white blood cells). Leukopheresis is the removal of PMN's, basophils, eosinophils for transfusion into patients whose PMN's are ineffective or traditional therapy has failed. There is limited data to suggest the benefit of granulocyte infusion. The complications of this procedure are the difficulty in collection and short shelf life (24 hours at 20 to 24 C). Since the "buffy coat" layer sits directly atop the RBC layer, HES, a sedimenting agent, is employed to improve yield while minimizing RBC collection. Quality control demands the resultant concentrate be 1.0 x 10^10 granulocytes in 75% of the units tested and that the product be irradiated to avoid graft-versus-host disease (inactivate lymphocytes). Irradiation does not affect PMN function. Since there is usually a small amount of RBC's collected, ABO compatibility should be employed when feasible. - Stem cell harvesting - circulating bone marrow cells are harvested to use in bone marrow transplantation. - LDL apheresis - removal of low density lipoprotein in patients with familial hypercholesterolemia. - Photopheresis - Automated Red Cell Collection (2RBC) - removal of two units of red blood cells. Erythrocytaphersis is the collection of RBC's, either two standard units of RBC's or one unit plus either plasma or platelets. The advantage to the donor is the use of smaller needles and saline compensation. The advantage to the blood bankers is the on-line separation into standardized RBC masses with the subsequent reduction in testing, data entry and staffing. - Immunoadsorbtion with Staphylococcal protein A-agarose column - removal of allo- and autoantibodies (in autoimmune diseases, transplant rejection, hemophilia) by directing plasma through protein A-agarose columns. Protein A is a cell wall component produced by several strains of Staphylococcus aureus which binds to the Fc region of IgG. # Uses ## Donation Blood components can be separated from a collected bag of whole blood or from a donor's blood flow before collected to a blood bag. Various blood components are obtained by apheresis from donors. This includes platelets and blood plasma. Intravenous immunoglobulin (IVIG) is a blood product administered intravenously. It contains the pooled IgG immunoglobulins (antibodies extracted from the plasma of thousands of blood donors). IVIG is given as a protein replacement therapy for immune deficient patients which have decreased or abolished antibody production capabilities. IVIG is administered to maintain adequate antibodies levels to prevent infections and confers a passive immunity. IVIG effects last between 2 weeks and 3 months. It is mainly used as treatment in three major categories: Immune deficiencies - Immune deficiencies such as X-linked agammaglobulinemia, hypogammaglobulinemia (Primary immune deficiencies), and acquired compromised immunity conditions (secondary immune deficiencies), featuring low antibody levels. Inflammatory and autoimmune diseases. Acute infections. ## Therapy The various apheresis techniques may be used whenever the removed constituent is causing severe symptoms of disease. Generally, apheresis has to be performed fairly often, and is an invasive process. It is therefore only employed if other means to control a particular disease have failed, or the symptoms are of such a nature that waiting for medication to become effective would cause suffering or risk of complications.	Apheresis Template:Otheruses4 Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Apheresis (Greek: "to take away") is a medical technology in which the blood of a donor or patient is passed through an apparatus that separates out one particular constituent and returns the remainder to the circulation. It is thus an extracorporeal therapy. # Method Depending on the substance that is being removed, different processes are employed in apheresis. If separation by weight is required, centrifugation would be the method of choice. Other methods involve absorption onto beads coated with an absorbent material. The centrifugation method can be divided into two basic categories: A. Continuous flow centrifugation (CFC) historically required two venipunctures as the "continuous" means the blood is collected, spun, and returned simultaneously. Newer systems can use a single venipuncture. The main advantage of this system is the low extracorporeal volume (calculated by volume of the apheresis chamber, the donor's hematocrit, and total blood volume of the donor) used in the procedure, which may be advantageous in the elderly and for children. B. Intermittent flow centrifugation works in cycles, taking blood, spinning/processing it and then giving back the unnecessary parts to the donor in a bolus. The main advantage is a single venipuncture site. To stop the blood from coagulating, anticoagulant is automatically mixed with the blood as it is pumped from the body into the apheresis machine. The centrifugation process itself has four variables that can be controlled to selectively remove desired components. The first is spin speed and bowl diameter, the second is "sit time" in centrifuge, the third is solutes added, and the fourth is not as easily controllable: plasma volume and cellular content of the donor. The end product in most cases is the classic sedimented blood sample with the RBC's at the bottom, the "buffy coat" of platelets and WBC's (lymphocytes/granulocytes (PMN's, basophils, eosinophils)/monocytes) in the middle and the plasma on top. It is important to remember that, when the apheresis system is used for therapy, the system is removing relatively small amounts of fluid (not more than 10.5 mL/kg body weight), but that fluid must be replaced to keep correct intravascular volume. The fluid replaced is different at different institutions. If a crystalloid like normal saline is used, the infusion amount should be triple what is removed as the three to one ratio of NS for plasma is needed to keep up oncotic pressure. Some institutions use normal serum albumin, but it is costly and can be difficult to find. Some advocate using FFP, but the dangers including citrate toxicity (from the anticoagulant), ABO incompatibility, bacterial infection, and cellular antigens make this choice less than desirable. # Types of apheresis There are numerous types of apheresis. Blood taken from a healthy donor can be separated into its component parts, where the needed component is collected and the "unused" components are returned to the donor. Fluid replacement is usually not needed in these type of collections. There are large categories of component collections: - Plasmapheresis - blood plasma. Plasmapheresis is useful in collecting FFP (fresh frozen plasma) of a particular ABO group. Commercial uses aside from FFP for this procedure include immune globulin products, plasma derivatives, and collection of rare WBC and RBC antibodies. Consult AABB standards for procedure criteria. FFP may be stored one year at -18 C and seven years at -65 C. After thawing, FFP can be stored for 24 hours at 1-6 C. - Plateletpheresis (thrombapheresis, thrombocytapheresis) - blood platelets. Plateletpheresis, like it sounds, is the collection of platelets by apheresis; while returning the RBC's, WBC's, and component plasma. The yield is normally the equivalent of between six and ten random platelet concentrates. Quality control demands the platelets from apheresis be equal to or greater than 3.0 x 10^11 in number and have a pH of equal to or greater than 6.2 in 90% of the products tested and must be used within five days. ABO compatibility is a good idea. - Leukapheresis - leukocytes (white blood cells). Leukopheresis is the removal of PMN's, basophils, eosinophils for transfusion into patients whose PMN's are ineffective or traditional therapy has failed. There is limited data to suggest the benefit of granulocyte infusion. The complications of this procedure are the difficulty in collection and short shelf life (24 hours at 20 to 24 C). Since the "buffy coat" layer sits directly atop the RBC layer, HES, a sedimenting agent, is employed to improve yield while minimizing RBC collection. Quality control demands the resultant concentrate be 1.0 x 10^10 granulocytes in 75% of the units tested and that the product be irradiated to avoid graft-versus-host disease (inactivate lymphocytes). Irradiation does not affect PMN function. Since there is usually a small amount of RBC's collected, ABO compatibility should be employed when feasible. - Stem cell harvesting - circulating bone marrow cells are harvested to use in bone marrow transplantation. - LDL apheresis - removal of low density lipoprotein in patients with familial hypercholesterolemia. - Photopheresis - Automated Red Cell Collection (2RBC) - removal of two units of red blood cells. Erythrocytaphersis is the collection of RBC's, either two standard units of RBC's or one unit plus either plasma or platelets. The advantage to the donor is the use of smaller needles and saline compensation. The advantage to the blood bankers is the on-line separation into standardized RBC masses with the subsequent reduction in testing, data entry and staffing. - Immunoadsorbtion with Staphylococcal protein A-agarose column - removal of allo- and autoantibodies (in autoimmune diseases, transplant rejection, hemophilia) by directing plasma through protein A-agarose columns. Protein A is a cell wall component produced by several strains of Staphylococcus aureus which binds to the Fc region of IgG. # Uses ## Donation Blood components can be separated from a collected bag of whole blood or from a donor's blood flow before collected to a blood bag. Various blood components are obtained by apheresis from donors. This includes platelets and blood plasma. Intravenous immunoglobulin (IVIG) is a blood product administered intravenously. It contains the pooled IgG immunoglobulins (antibodies extracted from the plasma of thousands of blood donors). IVIG is given as a protein replacement therapy for immune deficient patients which have decreased or abolished antibody production capabilities. IVIG is administered to maintain adequate antibodies levels to prevent infections and confers a passive immunity. IVIG effects last between 2 weeks and 3 months. It is mainly used as treatment in three major categories: Immune deficiencies - Immune deficiencies such as X-linked agammaglobulinemia, hypogammaglobulinemia (Primary immune deficiencies), and acquired compromised immunity conditions (secondary immune deficiencies), featuring low antibody levels. Inflammatory and autoimmune diseases. Acute infections. ## Therapy The various apheresis techniques may be used whenever the removed constituent is causing severe symptoms of disease. Generally, apheresis has to be performed fairly often, and is an invasive process. It is therefore only employed if other means to control a particular disease have failed, or the symptoms are of such a nature that waiting for medication to become effective would cause suffering or risk of complications.	https://www.wikidoc.org/index.php/Apheresis
de623a114e91937fc63ed4eab735b49692d805c9	wikidoc	Apophenia	Apophenia # Overview Apophenia is the experience of seeing patterns or connections in random or meaningless data. The term was coined in 1958 by Klaus Conrad, who defined it as the "unmotivated seeing of connections" accompanied by a "specific experience of an abnormal meaningfulness". "While observations of relevant work environments and human behaviors in these environments is a very important first step in coming to understand any new domain, this activity is in and of its self not sufficient to constitute scientific research. It is fraught with problems of subjective bias in the observer. We (like the experts we study) often see what we expect to see, we interpret the world through our own personal lens. Thus we are extraordinarily open to the trap of apophenia." In statistics, apophenia would be classed as a Type I error (false positive, false alarm, caused by an excess in sensitivity). Apophenia is often used as an explanation of some paranormal and religious claims, and can also be used to explain the tendency of humans to believe pseudoscience such as Intelligent design. Apophenia may be linked to psychosis and creativity. # Origins Conrad originally described this phenomenon in relation to the distortion of reality present in psychosis, but it has become more widely used to describe this tendency in healthy individuals without necessarily implying the presence of neurological or mental illness. # Examples ## Pareidolia Pareidolia is a type of apophenia involving the finding of images or sounds in random stimuli. ## Discordianism The Principia Discordia refers to the act of seeing order which does not really exist as the Aneristic Illusion, and avoiding this illusion is a major tenet of the Discordian religion. The Principia illustrates this with a drawing of five pebbles, and gives several possibilities for the shape (a pentagon, or a star, or disorder). It goes on to state that "an Illuminated Mind can see all of these, yet he does not insist that any one is really true, or that none at all is true". ## Dark Side of the Rainbow When the album Dark Side of the Moon by Pink Floyd is played simultaneously with the 1939 film The Wizard of Oz, numerous images from the film appear to synchronise with the music and lyrics. All band members (save Roger Waters), and engineer Alan Parsons, have firmly stated that the phenomenon is a coincidence. This effect has often been called Dark Side of the Rainbow. Arguably, playing any two media together will produce an impression of a striking amount of coincidence, which is an example of apophenia. ## Fiction Postmodern novelists and film-makers have reflected on apophenia-related phenomena, such as paranoid narrativization or fuzzy plotting (e.g., Vladimir Nabokov's "Signs and Symbols", Thomas Pynchon's The Crying of Lot 49 and V., Alan Moore's Watchmen, Umberto Eco's The Name of the Rose and Foucault's Pendulum, William Gibson's Pattern Recognition, James Curcio's Join My Cult, Arturo Pérez-Reverte's The Club Dumas, The Illuminatus! Trilogy by Robert Shea and Robert Anton Wilson, and the films Conspiracy Theory, Darren Aronofsky's π, A Beautiful Mind and The Number 23). As narrative is one of our major cognitive instruments for structuring reality, there is some common ground between apophenia and narrative fallacies such as hindsight bias. Since pattern recognition may be related to plans, goals, and ideology, and may be a matter of group ideology rather than a matter of solitary delusion, the interpreter attempting to diagnose or identify apophenia may have to face a conflict of interpretations. The Question, who is portrayed as a conspiracy theorist in the animated television series Justice League Unlimited, was mentioned to have apophenia. He claimed to see connections between the Girl Scouts and the crop circle phenomenon as well as spy satellites and fluoridated toothpaste.	Apophenia # Overview Apophenia is the experience of seeing patterns or connections in random or meaningless data. The term was coined in 1958 by Klaus Conrad, who defined it as the "unmotivated seeing of connections" accompanied by a "specific experience of an abnormal meaningfulness". "While observations of relevant work environments and human behaviors in these environments is a very important first step in coming to understand any new domain, this activity is in and of its self not sufficient to constitute scientific research. It is fraught with problems of subjective bias in the observer. We (like the experts we study) often see what we expect to see, we interpret the world through our own personal lens. Thus we are extraordinarily open to the trap of apophenia."[1] In statistics, apophenia would be classed as a Type I error (false positive, false alarm, caused by an excess in sensitivity). Apophenia is often used as an explanation of some paranormal and religious claims, and can also be used to explain the tendency of humans to believe pseudoscience such as Intelligent design[2]. Apophenia may be linked to psychosis and creativity. # Origins Conrad originally described this phenomenon in relation to the distortion of reality present in psychosis, but it has become more widely used to describe this tendency in healthy individuals without necessarily implying the presence of neurological or mental illness. # Examples ## Pareidolia Pareidolia is a type of apophenia involving the finding of images or sounds in random stimuli. ## Discordianism The Principia Discordia refers to the act of seeing order which does not really exist as the Aneristic Illusion, and avoiding this illusion is a major tenet of the Discordian religion. The Principia illustrates this with a drawing of five pebbles, and gives several possibilities for the shape (a pentagon, or a star, or disorder). It goes on to state that "an Illuminated Mind can see all of these, yet he does not insist that any one is really true, or that none at all is true". ## Dark Side of the Rainbow When the album Dark Side of the Moon by Pink Floyd is played simultaneously with the 1939 film The Wizard of Oz, numerous images from the film appear to synchronise with the music and lyrics. All band members (save Roger Waters), and engineer Alan Parsons, have firmly stated that the phenomenon is a coincidence.[2] This effect has often been called Dark Side of the Rainbow. Arguably, playing any two media together will produce an impression of a striking amount of coincidence, which is an example of apophenia. ## Fiction Postmodern novelists and film-makers have reflected on apophenia-related phenomena, such as paranoid narrativization or fuzzy plotting (e.g., Vladimir Nabokov's "Signs and Symbols", Thomas Pynchon's The Crying of Lot 49 and V., Alan Moore's Watchmen, Umberto Eco's The Name of the Rose and Foucault's Pendulum, William Gibson's Pattern Recognition, James Curcio's Join My Cult, Arturo Pérez-Reverte's The Club Dumas, The Illuminatus! Trilogy by Robert Shea and Robert Anton Wilson, and the films Conspiracy Theory, Darren Aronofsky's π, A Beautiful Mind and The Number 23). As narrative is one of our major cognitive instruments for structuring reality, there is some common ground between apophenia and narrative fallacies such as hindsight bias. Since pattern recognition may be related to plans, goals, and ideology, and may be a matter of group ideology rather than a matter of solitary delusion, the interpreter attempting to diagnose or identify apophenia may have to face a conflict of interpretations. The Question, who is portrayed as a conspiracy theorist in the animated television series Justice League Unlimited, was mentioned to have apophenia. He claimed to see connections between the Girl Scouts and the crop circle phenomenon as well as spy satellites and fluoridated toothpaste.	https://www.wikidoc.org/index.php/Apophenia
159bdb4587f3ec99e822e22ee63854d591e20753	wikidoc	Apoptosis	Apoptosis Apoptosis (/̩æ.pəpˈtō.səs/) is a form of programmed cell death in multicellular organisms. It is one of the main types of programmed cell death (PCD) and involves a series of biochemical events leading to a characteristic cell morphology and death, in more specific terms, a series of biochemical events that lead to a variety of morphological changes, including blebbing, changes to the cell membrane such as loss of membrane asymmetry and attachment, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation (1-4). Processes of disposal of cellular debris whose results do not damage the organism differentiate apoptosis from necrosis. In contrast to necrosis, which is a form of traumatic cell death that results from acute cellular injury, apoptosis, in general, confers advantages during an organism's life cycle. For example, the differentiation of fingers and toes in a developing human embryo occurs because cells between the fingers apoptose; the result is that the digits are separate. Between 50 billion and 70 billion cells die each day due to apoptosis in the average human adult. For an average child between the ages of 8 and 14, approximately 20 billion to 30 billion cells die a day. In a year, this amounts to the proliferation and subsequent destruction of a mass of cells equal to an individual's body weight. Research on apoptosis has increased substantially since the early 1990s. In addition to its importance as a biological phenomenon, defective apoptotic processes have been implicated in an extensive variety of diseases. Excessive apoptosis causes hypotrophy, such as in ischemic damage, whereas an insufficient amount results in uncontrolled cell proliferation, such as cancer. # Discovery and etymology That cell death is a completely normal process in living organisms was already discovered by scientists more than 100 years ago. The German scientist Carl Vogt was first to describe the principle of apoptosis in 1842. In 1885, anatomist Walther Flemming delivered a more precise description of the process of programmed cell death. However, it was not until 1965 that the topic was resurrected. Apoptosis (Greek: apo - from, ptosis - falling; thus etymologically correct pronunciation is Template:IPA) was distinguished from traumatic cell death by John Foxton Ross Kerr while he was studying tissues using electron microscopy at the University of Queensland Pathology Department in Brisbane. Following publication of this paper, Kerr was invited to join Professor Alastair R Currie and Andrew Wyllie, Currie's PhD student at the time, at the University of Aberdeen to continue his research. In 1972, the trio published a seminal article in the British Journal of Cancer. Kerr had originally used the term "programmed cell necrosis" to describe the phenomenon but in the 1972 article this process of natural cell death was called apoptosis. Kerr, Wylie and Currie credited Professor James Cormack (Department of Greek, University of Aberdeen) with suggesting the term apoptosis. In Greek, apoptosis means "dropping off" of petals or leaves from plants or trees. Cormack reintroduced the term for medical use as it had a medical meaning for the Greeks over two thousand years before. Hippocrates used the term to mean "the falling off of the bones". Galen extended its meaning to "the dropping of the scabs". Cormack was no doubt aware of this usage when he suggested the name. Debate continues over the correct pronunciation, with opinion divided between a pronunciation with a silent p (Template:PronEng) and the p spelt out (Template:PronEng), as in the original Greek. In English, the p of the Greek -pt- consonant cluster is typically silent at the beginning of a word (e.g. pterodactyl), but articulated when used in combining forms preceded by a vowel, as in helicopter or the orders of insects: diptera, lepidoptera, etc. John Foxton Ross Kerr, Emeritus Professor of Pathology at the University of Queensland, received the Paul Ehrlich and Ludwig Darmstaedter Prize on March 14 2000, for his description of apoptosis. He shared the prize with Boston biologist Robert Horvitz. # Functions ## Cell termination Apoptosis can occur when a cell is damaged beyond repair, infected with a virus, or undergoing stress conditions such as starvation. DNA damage from ionizing radiation or toxic chemicals can also induce apoptosis via the actions of the tumour-suppressing gene p53. The "decision" for apoptosis can come from the cell itself, from the surrounding tissue, or from a cell that is part of the immune system. In these cases apoptosis functions to remove the damaged cell, preventing it from sapping further nutrients from the organism, or to prevent the spread of viral infection. Apoptosis also plays a role in preventing cancer; if a cell is unable to undergo apoptosis, due to mutation or biochemical inhibition, it can continue dividing and develop into a tumour. For example, infection by papillomaviruses causes a viral gene to interfere with the cell's p53 protein, an important member of the apoptotic pathway. This interference in the apoptotic capability of the cell plays a critical role in the development of cervical cancer. ## Homeostasis In the adult organism, the number of cells is kept relatively constant through cell death and division. Cells must be replaced when they become diseased or malfunctioning; but proliferation must be compensated by cell death. This balancing process is part of the homeostasis required by living organisms to maintain their internal states within certain limits. Some scientists have suggested homeodynamics as a more accurate term. The related term allostasis reflects a balance of a more complex nature by the body. Homeostasis is achieved when the rate of mitosis (cell division) in the tissue is balanced by cell death. If this equilibrium is disturbed, one of two potentially fatal disorders occurs: - The cells are dividing faster than they die, effectively developing a tumor. - The cells are dividing slower than they die, which results in a disorder of cell loss. The organism must orchestrate a complex series of controls to keep homeostasis tightly controlled, a process that is ongoing for the life of the organism and involves many different types of cell signaling. Impairment of any one of these controls can lead to a diseased state; for example, dysregulation of signaling pathway has been implicated in several forms of cancer. The pathway, which conveys an anti-apoptotic signal, has been found to be activated in pancreatic adenocarcinoma tissues. ## Development Programmed cell death is an integral part of both plant and animal tissue development. Development of an organ or tissue is often preceded by the extensive division and differentiation of a particular cell, the resultant mass is then "pruned" into the correct form by apoptosis. Unlike cellular death caused by injury, apoptosis results in cell shrinkage and fragmentation. This allows the cells to be efficiently phagocytosed and their components reused without releasing potentially harmful intracellular substances (such as hydrolytic enzymes, for example) into the surrounding tissue. Research on chick embryos has suggested how selective cell proliferation, combined with selective apoptosis, sculpts developing tissues in vertebrates. During vertebrate embryo development, structures called the notochord and the floor plate secrete a gradient of the signaling molecule (Shh), and it is this gradient that directs cells to form patterns in the embryonic neural tube: cells that receive Shh in a receptor in their membranes called Patched1 (Ptc1) survive and proliferate; but, in the absence of Shh, one of the ends of this same Ptc1 receptor (the carboxyl-terminal, inside the membrane) is cleaved by caspase-3, an action that exposes an apoptosis-producing domain. During development, apoptosis is tightly regulated and different tissues use different signals for inducing apoptosis. In birds, bone morphogenetic proteins (BMP) signaling is used to induce apoptosis in the interdigital tissue. In Drosophila flies, steroid hormones regulate cell death. Developmental cues can also induce apoptosis, such as the sex-specific cell death of hermaphrodite specific neurons in C. elegans males through low TRA-1 transcription factor activity (TRA-1 helps prevent cell death). ## Lymphocyte interactions The development of B lymphocytes and the development of T lymphocytes in the human body is a complex process that effectively creates a large pool of diverse cells to begin with, then weeds out those potentially damaging to the body. Apoptosis is the mechanism by which the body removes both the ineffective and the potentially-damaging immature cells, and in T-cells is initiated by the withdrawal of survival signals. Cytotoxic T-cells are able to directly induce apoptosis in cells by opening up pores in the target's membrane and releasing chemicals that bypass the normal apoptotic pathway. The pores are created by the action of secreted perforin, and the granules contain granzyme B, a serine protease that activates a variety of caspases by cleaving aspartate residues. # Process The process of apoptosis is controlled by a diverse range of cell signals, which may originate either extracellularly (extrinsic inducers) or intracellularly (intrinsic inducers). Extracellular signals may include hormones, growth factors, nitric oxide or cytokines, and therefore must either cross the plasma membrane or transduce to effect a response. These signals may positively or negatively induce apoptosis; in this context the binding and subsequent initiation of apoptosis by a molecule is termed positive, whereas the active repression of apoptosis by a molecule is termed negative. Intracellular apoptotic signalling is a response initiated by a cell in response to stress, and may ultimately result in cell suicide. The binding of nuclear receptors by glucocorticoids, heat, radiation, nutrient deprivation, viral infection, and hypoxia are all factors that can lead to the release of intracellular apoptotic signals by a damaged cell. A number of cellular components, such as poly ADP ribose polymerase, may also help regulate apoptosis. Before the actual process of cell death is carried out by enzymes, apoptotic signals must be connected to the actual death pathway by way of regulatory proteins. This step allows apoptotic signals to either culminate in cell death, or be aborted should the cell no longer need to die. Several proteins are involved, however two main methods of achieving regulation have been identified; targeting mitochondria functionality, or directly transducing the signal via adapter proteins to the apoptotic mechanisms. The whole preparation process requires energy and functioning cell machinery. ## Mitochondrial regulation The mitochondria are essential to multicellular life. Without them, a cell ceases to respire aerobically and quickly dies - a fact exploited by some apoptotic pathways. Apoptotic proteins that target mitochondria affect them in different ways; they may cause mitochondrial swelling through the formation of membrane pores, or they may increase the permeability of the mitochondrial membrane and cause apoptotic effectors to leak out. There is also a growing body of evidence that indicates that nitric oxide (NO) is able to induce apoptosis by helping to dissipate the membrane potential of mitochondria and therefore make it more permeable. Mitochondrial proteins known as SMACs (second mitochondria-derived activator of caspases) are released into the cytosol following an increase in permeability. SMAC binds to inhibitor of apoptosis proteins (IAPs) and deactivates them, preventing the IAPs from arresting the apoptotic process and therefore allowing apoptosis to proceed. IAP also normally suppresses the activity of a group of cysteine proteases called caspases, which carry out the degradation of the cell, therefore the actual degradation enzymes can be seen to be indirectly regulated by mitochondrial permeability. Cytochrome c is also released from mitochondria due to formation of a channel, MAC, in the outer mitochondrial membrane, and serves a regulatory function as it precedes morphological change associated with apoptosis. Once cytochrome c is released it binds with Apaf-1 and ATP, which then bind to pro-caspase-9 to create a protein complex known as an apoptosome. The apoptosome cleaves the pro-caspase to its active form of caspase-9, which in turn activates the effector caspase-3. MAC is itself subject to regulation by various proteins, such as those encoded by the mammalian Bcl-2 family of anti-apoptopic genes, the homologs of the ced-9 gene found in C. elegans. Bcl-2 proteins are able to promote or inhibit apoptosis either by direct action on MAC or indirectly through other proteins. It is important to note that the actions of some Bcl-2 proteins are able to halt apoptosis even if cytochrome c has been released by the mitochondria. ## Direct signal transduction File:TFN-signalling.png File:Fas-signalling.png Two important examples of the direct initiation of apoptotic mechanisms in mammals include the TNF-induced (tumour necrosis factor) model and the Fas-Fas ligand-mediated model, both involving receptors of the TNF receptor (TNFR) family coupled to extrinsic signals. TNF is a cytokine produced mainly by activated macrophages, and is the major extrinsic mediator of apoptosis. Most cells in the human body have two receptors for TNF: TNF-R1 and TNF-R2. The binding of TNF to TNF-R1 has been shown to initiate the pathway that leads to caspase activation via the intermediate membrane proteins TNF receptor-associated death domain (TRADD) and Fas-associated death domain protein (FADD). Binding of this receptor can also indirectly lead to the activation of transcription factors involved in cell survival and inflammatory responses. The link between TNF and apoptosis shows why an abnormal production of TNF plays a fundamental role in several human diseases, especially in autoimmune diseases. The Fas receptor (also known as Apo-1 or CD95) binds the Fas ligand (FasL), a transmembrane protein part of the TNF family. The interaction between Fas and FasL results in the formation of the death-inducing signaling complex (DISC), which contains the FADD, caspase-8 and caspase-10. In some types of cells (type I), processed caspase-8 directly activates other members of the caspase family, and triggers the execution of apoptosis. In other types of cells (type II), the Fas-DISC starts a feedback loop that spirals into increasing release of pro-apoptotic factors from mitochondria and the amplified activation of caspase-8. Following TNF-R1 and Fas activation in mammalian cells a balance between pro-apoptotic (BAX, BID, BAK, or BAD) and anti-apoptotic (Bcl-Xl and Bcl-2) members of the Bcl-2 family is established. This balance is the proportion of pro-apoptotic homodimers that form in the outer-membrane of the mitochondrion. The pro-apoptotic homodimers are required to make the mitochondrial membrane permeable for the release of caspase activators such as cytochrome c and SMAC. Control of pro-apoptotic proteins under normal cell conditions of non-apoptotic cells is incompletely understood, but it has been found that a mitochondrial outer-membrane protein, VDAC2, interacts with BAK to keep this potentially-lethal apoptotic effector under control. When the death signal is received, products of the activation cascade displace VDAC2 and BAK is able to be activated. There also exists a caspase-independent apoptotic pathway that is mediated by AIF (apoptosis-inducing factor). For more information, see the article of the author Susin in Nature of 1999 and also reference 21 mentioned below. ## Execution Although many pathways and signals lead to apoptosis, there is only one mechanism that actually causes the death of the cell in this process; after the appropriate stimulus has been received by the cell and the necessary controls exerted, a cell will undergo the organized degradation of cellular organelles by activated proteolytic caspases. A cell undergoing apoptosis shows a characteristic morphology that can be observed with a microscope: - Cell shrinkage and rounding due to the breakdown of the proteinaceous cytoskeleton by caspases. - The cytoplasm appears dense, and the organelles appear tightly packed. - Chromatin undergoes condensation into compact patches against the nuclear envelope in a process known as pyknosis, a hallmark of apoptosis. - The nuclear envelope becomes discontinuous and the DNA inside it is fragmented in a process referred to as karyorrhexis. The nucleus breaks into several discrete chromatin bodies or nucleosomal units due to the degradation of DNA. - The cell membrane shows irregular buds known as blebs. - The cell breaks apart into several vesicles called apoptotic bodies, which are then phagocytosed. Apoptosis progresses quickly and its products are quickly removed, making it difficult to detect or visualize. During karyorrhexis, endonuclease activation leaves short DNA fragments, regularly spaced in size. These give a characteristic "laddered" appearance on agar gel after electrophoresis. Tests for DNA laddering differentiate apoptosis from ischemic or toxic cell death. ## Removal of dead cells Dying cells that undergo the final stages of apoptosis display phagocytotic molecules, such as phosphatidylserine, on their cell surface. Phosphatidylserine is normally found on the cytosolic surface of the plasma membrane, but is redistributed during apoptosis to the extracellular surface by a hypothetical protein known as scramblase. These molecules mark the cell for phagocytosis by cells possessing the appropriate receptors, such as macrophages. Upon recognition, the phagocyte reorganizes its cytoskeleton for engulfment of the cell. The removal of dying cells by phagocytes occurs in an orderly manner without eliciting an inflammatory response. # Implication in disease ## Defective apoptotic pathways The many different types of apoptotic pathways contain a multitude of different biochemical components, many of them not yet understood. As a pathway is more or less sequential in nature it is a victim of causality; removing or modifying one component leads to an effect in another. In a living organism this can have disastrous effects, often in the form of disease or disorder. A discussion of every disease caused by modification of the various apoptotic pathways would be impractical, but the concept overlying each one is the same: the normal functioning of the pathway has been disrupted in such a way as to impair the ability of the cell to undergo normal apoptosis. This results in a cell that lives past its "use-by-date" and is able to replicate and pass on any faulty machinery to its progeny, increasing the likelihood of the cell becoming cancerous or diseased. A recently-described example of this concept in action can be seen in the development of a lung cancer called NCI-H460. The X-linked inhibitor of apoptosis protein (XIAP) is overexpressed in cells of the H460 cell line. XIAPs bind to the processed form of caspase-9, and suppress the activity of apoptotic activator cytochrome c, therefore overexpression leads to a decrease in the amount of pro-apoptotic agonists. As a consequence, the balance of anti-apoptotic and pro-apoptotic effectors is upset in favour of the former, and the damaged cells continue to replicate despite being directed to die. ## p53 disregulation The tumor-suppressor protein p53 accumulates when DNA is damaged due to a chain of biochemical reactions. Part of this pathway includes interferon-alpha and interferon-beta, which induce transcription of the p53 gene and result in the increase of p53 protein level and enhancement of cancer cell-apoptosis. p53 prevents the cell from replicating by stopping the cell cycle at G1, or interphase, to give the cell time to repair, however it will induce apoptosis if damage is extensive and repair efforts fail. Any disruption to the regulation of the p53 or interferon genes will result in impaired apoptosis and the possible formation of tumors. ## HIV progression The progression of the human immunodeficiency virus (HIV) to AIDS is primarily due to the depletion of CD4+ T-helper lymphocytes, which leads to a compromised immune system. One of the mechanisms by which T-helper cells are depleted is apoptosis, which can be the end-product of multiple biochemical pathways: - HIV enzymes inactivate anti-apoptotic Bcl-2 and simultaneously activate pro-apoptotic procaspase-8. This does not directly cause cell death but primes the cell for apoptosis should the appropriate signal be received. - HIV products may increase levels of cellular proteins which have a promotive effect on Fas-mediated apoptosis. - HIV proteins decrease the amount of CD4 glycoprotein marker present on the cell membrane. - Released viral particles and proteins present in extracellular fluid are able to induce apoptosis in nearby "bystander" T-helper cells. - HIV decreases the production of molecules involved in marking the cell for apoptosis, giving the virus time to replicate and continue releasing apoptotic agents and virions into the surrounding tissue. - The infected CD4+ cell may also receive the death signal from a cytotoxic T cell, leading to apoptosis. In addition to apoptosis, infected cells may also die as a direct consequence of the viral infection. ## Viral infection Viruses can trigger apoptosis of infected cells via a range of mechanisms including: - Receptor binding. - Activation of protein kinase R (PKR). - Interaction with p53. - Expression of viral proteins coupled to MHC proteins on the surface of the infected cell, allowing recognition by cells of the immune system (such as Natural Killer and cytotoxic T cells) that then induce the infected cell to undergo apoptosis. Most viruses encode proteins that can inhibit apoptosis. Several viruses encode viral homologs of Bcl-2. These homologs can inhibit pro-apoptotic proteins such as BAX and BAK, which are essential for the activation of apoptosis. Examples of viral Bcl-2 proteins include the Epstein-Barr virus BHRF1 protein and the adenovirus E1B 19K protein. Some viruses express caspase inhibitors that inhibit caspase activity and an example is the CrmA protein of cowpox viruses. Whilst a number of viruses can block the effects of TNF and Fas. For example the M-T2 protein of myxoma viruses can bind TNF preventing it from binding the TNF receptor and inducing a response. Furthermore, many viruses express p53 inhibitors that can bind p53 and inhibit its transcriptional transactivation activity. Consequently p53 cannot induce apoptosis since it cannot induce the expression of pro-apoptotic proteins. The adenovirus E1B-55K protein and the hepatitis B virus HBx protein are examples of viral proteins that can perform such a function. Interestingly, viruses can remain intact from apoptosis particularly in the latter stages of infection. They can be exported in the apoptotic bodies that pinch off from the surface of the dying cell and the fact that they are engulfed by phagocytes prevents the initiation of a host response. This favours the spread of the virus.	Apoptosis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Apoptosis (/̩æ.pəpˈtō.səs/[1]) is a form of programmed cell death in multicellular organisms. It is one of the main types of programmed cell death (PCD) and involves a series of biochemical events leading to a characteristic cell morphology and death, in more specific terms, a series of biochemical events that lead to a variety of morphological changes, including blebbing, changes to the cell membrane such as loss of membrane asymmetry and attachment, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation (1-4). Processes of disposal of cellular debris whose results do not damage the organism differentiate apoptosis from necrosis. In contrast to necrosis, which is a form of traumatic cell death that results from acute cellular injury, apoptosis, in general, confers advantages during an organism's life cycle. For example, the differentiation of fingers and toes in a developing human embryo occurs because cells between the fingers apoptose; the result is that the digits are separate. Between 50 billion and 70 billion cells die each day due to apoptosis in the average human adult. For an average child between the ages of 8 and 14, approximately 20 billion to 30 billion cells die a day. In a year, this amounts to the proliferation and subsequent destruction of a mass of cells equal to an individual's body weight. Research on apoptosis has increased substantially since the early 1990s. In addition to its importance as a biological phenomenon, defective apoptotic processes have been implicated in an extensive variety of diseases. Excessive apoptosis causes hypotrophy, such as in ischemic damage, whereas an insufficient amount results in uncontrolled cell proliferation, such as cancer. # Discovery and etymology That cell death is a completely normal process in living organisms was already discovered by scientists more than 100 years ago. The German scientist Carl Vogt was first to describe the principle of apoptosis in 1842. In 1885, anatomist Walther Flemming delivered a more precise description of the process of programmed cell death. However, it was not until 1965 that the topic was resurrected. Apoptosis (Greek: apo - from, ptosis - falling; thus etymologically correct pronunciation is Template:IPA) was distinguished from traumatic cell death by John Foxton Ross Kerr while he was studying tissues using electron microscopy at the University of Queensland Pathology Department in Brisbane. [2] Following publication of this paper, Kerr was invited to join Professor Alastair R Currie and Andrew Wyllie, Currie's PhD student at the time,[3] at the University of Aberdeen to continue his research. In 1972, the trio published a seminal article in the British Journal of Cancer.[4] Kerr had originally used the term "programmed cell necrosis" to describe the phenomenon but in the 1972 article this process of natural cell death was called apoptosis. Kerr, Wylie and Currie credited Professor James Cormack (Department of Greek, University of Aberdeen) with suggesting the term apoptosis. In Greek, apoptosis means "dropping off" of petals or leaves from plants or trees. Cormack reintroduced the term for medical use as it had a medical meaning for the Greeks over two thousand years before. Hippocrates used the term to mean "the falling off of the bones". Galen extended its meaning to "the dropping of the scabs". Cormack was no doubt aware of this usage when he suggested the name. Debate continues over the correct pronunciation, with opinion divided between a pronunciation with a silent p (Template:PronEng) and the p spelt out (Template:PronEng),[5][6] as in the original Greek. In English, the p of the Greek -pt- consonant cluster is typically silent at the beginning of a word (e.g. pterodactyl), but articulated when used in combining forms preceded by a vowel, as in helicopter or the orders of insects: diptera, lepidoptera, etc. John Foxton Ross Kerr, Emeritus Professor of Pathology at the University of Queensland, received the Paul Ehrlich and Ludwig Darmstaedter Prize on March 14 2000, for his description of apoptosis. He shared the prize with Boston biologist Robert Horvitz.[7] # Functions ## Cell termination Apoptosis can occur when a cell is damaged beyond repair, infected with a virus, or undergoing stress conditions such as starvation. DNA damage from ionizing radiation or toxic chemicals can also induce apoptosis via the actions of the tumour-suppressing gene p53. The "decision" for apoptosis can come from the cell itself, from the surrounding tissue, or from a cell that is part of the immune system. In these cases apoptosis functions to remove the damaged cell, preventing it from sapping further nutrients from the organism, or to prevent the spread of viral infection. Apoptosis also plays a role in preventing cancer; if a cell is unable to undergo apoptosis, due to mutation or biochemical inhibition, it can continue dividing and develop into a tumour. For example, infection by papillomaviruses causes a viral gene to interfere with the cell's p53 protein, an important member of the apoptotic pathway. This interference in the apoptotic capability of the cell plays a critical role in the development of cervical cancer. ## Homeostasis In the adult organism, the number of cells is kept relatively constant through cell death and division. Cells must be replaced when they become diseased or malfunctioning; but proliferation must be compensated by cell death.[8] This balancing process is part of the homeostasis required by living organisms to maintain their internal states within certain limits. Some scientists have suggested homeodynamics as a more accurate term.[9] The related term allostasis reflects a balance of a more complex nature by the body. Homeostasis is achieved when the rate of mitosis (cell division) in the tissue is balanced by cell death. If this equilibrium is disturbed, one of two potentially fatal disorders occurs: - The cells are dividing faster than they die, effectively developing a tumor. - The cells are dividing slower than they die, which results in a disorder of cell loss. The organism must orchestrate a complex series of controls to keep homeostasis tightly controlled, a process that is ongoing for the life of the organism and involves many different types of cell signaling. Impairment of any one of these controls can lead to a diseased state; for example, dysregulation of signaling pathway has been implicated in several forms of cancer. The pathway, which conveys an anti-apoptotic signal, has been found to be activated in pancreatic adenocarcinoma tissues. ## Development Programmed cell death is an integral part of both plant and animal tissue development. Development of an organ or tissue is often preceded by the extensive division and differentiation of a particular cell, the resultant mass is then "pruned" into the correct form by apoptosis. Unlike cellular death caused by injury, apoptosis results in cell shrinkage and fragmentation. This allows the cells to be efficiently phagocytosed and their components reused without releasing potentially harmful intracellular substances (such as hydrolytic enzymes, for example) into the surrounding tissue. Research on chick embryos has suggested how selective cell proliferation, combined with selective apoptosis, sculpts developing tissues in vertebrates. During vertebrate embryo development, structures called the notochord and the floor plate secrete a gradient of the signaling molecule (Shh), and it is this gradient that directs cells to form patterns in the embryonic neural tube: cells that receive Shh in a receptor in their membranes called Patched1 (Ptc1) survive and proliferate; but, in the absence of Shh, one of the ends of this same Ptc1 receptor (the carboxyl-terminal, inside the membrane) is cleaved by caspase-3, an action that exposes an apoptosis-producing domain.[10][11] During development, apoptosis is tightly regulated and different tissues use different signals for inducing apoptosis. In birds, bone morphogenetic proteins (BMP) signaling is used to induce apoptosis in the interdigital tissue. In Drosophila flies, steroid hormones regulate cell death. Developmental cues can also induce apoptosis, such as the sex-specific cell death of hermaphrodite specific neurons in C. elegans males through low TRA-1 transcription factor activity (TRA-1 helps prevent cell death). ## Lymphocyte interactions The development of B lymphocytes and the development of T lymphocytes in the human body is a complex process that effectively creates a large pool of diverse cells to begin with, then weeds out those potentially damaging to the body. Apoptosis is the mechanism by which the body removes both the ineffective and the potentially-damaging immature cells, and in T-cells is initiated by the withdrawal of survival signals.[12] Cytotoxic T-cells are able to directly induce apoptosis in cells by opening up pores in the target's membrane and releasing chemicals that bypass the normal apoptotic pathway. The pores are created by the action of secreted perforin, and the granules contain granzyme B, a serine protease that activates a variety of caspases by cleaving aspartate residues.[13] # Process The process of apoptosis is controlled by a diverse range of cell signals, which may originate either extracellularly (extrinsic inducers) or intracellularly (intrinsic inducers). Extracellular signals may include hormones, growth factors, nitric oxide[14] or cytokines, and therefore must either cross the plasma membrane or transduce to effect a response. These signals may positively or negatively induce apoptosis; in this context the binding and subsequent initiation of apoptosis by a molecule is termed positive, whereas the active repression of apoptosis by a molecule is termed negative. Intracellular apoptotic signalling is a response initiated by a cell in response to stress, and may ultimately result in cell suicide. The binding of nuclear receptors by glucocorticoids, heat, radiation, nutrient deprivation, viral infection, and hypoxia are all factors that can lead to the release of intracellular apoptotic signals by a damaged cell.[13] A number of cellular components, such as poly ADP ribose polymerase, may also help regulate apoptosis.[15] Before the actual process of cell death is carried out by enzymes, apoptotic signals must be connected to the actual death pathway by way of regulatory proteins. This step allows apoptotic signals to either culminate in cell death, or be aborted should the cell no longer need to die. Several proteins are involved, however two main methods of achieving regulation have been identified; targeting mitochondria functionality, or directly transducing the signal via adapter proteins to the apoptotic mechanisms. The whole preparation process requires energy and functioning cell machinery. ## Mitochondrial regulation The mitochondria are essential to multicellular life. Without them, a cell ceases to respire aerobically and quickly dies - a fact exploited by some apoptotic pathways. Apoptotic proteins that target mitochondria affect them in different ways; they may cause mitochondrial swelling through the formation of membrane pores, or they may increase the permeability of the mitochondrial membrane and cause apoptotic effectors to leak out.[13] There is also a growing body of evidence that indicates that nitric oxide (NO) is able to induce apoptosis by helping to dissipate the membrane potential of mitochondria and therefore make it more permeable.[14] Mitochondrial proteins known as SMACs (second mitochondria-derived activator of caspases) are released into the cytosol following an increase in permeability. SMAC binds to inhibitor of apoptosis proteins (IAPs) and deactivates them, preventing the IAPs from arresting the apoptotic process and therefore allowing apoptosis to proceed. IAP also normally suppresses the activity of a group of cysteine proteases called caspases,[16] which carry out the degradation of the cell, therefore the actual degradation enzymes can be seen to be indirectly regulated by mitochondrial permeability. Cytochrome c is also released from mitochondria due to formation of a channel, MAC, in the outer mitochondrial membrane[17], and serves a regulatory function as it precedes morphological change associated with apoptosis.[13] Once cytochrome c is released it binds with Apaf-1 and ATP, which then bind to pro-caspase-9 to create a protein complex known as an apoptosome. The apoptosome cleaves the pro-caspase to its active form of caspase-9, which in turn activates the effector caspase-3. MAC is itself subject to regulation by various proteins, such as those encoded by the mammalian Bcl-2 family of anti-apoptopic genes, the homologs of the ced-9 gene found in C. elegans.[18][19] Bcl-2 proteins are able to promote or inhibit apoptosis either by direct action on MAC or indirectly through other proteins. It is important to note that the actions of some Bcl-2 proteins are able to halt apoptosis even if cytochrome c has been released by the mitochondria.[13] ## Direct signal transduction File:TFN-signalling.png File:Fas-signalling.png Two important examples of the direct initiation of apoptotic mechanisms in mammals include the TNF-induced (tumour necrosis factor) model and the Fas-Fas ligand-mediated model, both involving receptors of the TNF receptor (TNFR) family[20] coupled to extrinsic signals. TNF is a cytokine produced mainly by activated macrophages, and is the major extrinsic mediator of apoptosis. Most cells in the human body have two receptors for TNF: TNF-R1 and TNF-R2. The binding of TNF to TNF-R1 has been shown to initiate the pathway that leads to caspase activation via the intermediate membrane proteins TNF receptor-associated death domain (TRADD) and Fas-associated death domain protein (FADD).[21] Binding of this receptor can also indirectly lead to the activation of transcription factors involved in cell survival and inflammatory responses.[22] The link between TNF and apoptosis shows why an abnormal production of TNF plays a fundamental role in several human diseases, especially in autoimmune diseases. The Fas receptor (also known as Apo-1 or CD95) binds the Fas ligand (FasL), a transmembrane protein part of the TNF family.[20] The interaction between Fas and FasL results in the formation of the death-inducing signaling complex (DISC), which contains the FADD, caspase-8 and caspase-10. In some types of cells (type I), processed caspase-8 directly activates other members of the caspase family, and triggers the execution of apoptosis. In other types of cells (type II), the Fas-DISC starts a feedback loop that spirals into increasing release of pro-apoptotic factors from mitochondria and the amplified activation of caspase-8.[23] Following TNF-R1 and Fas activation in mammalian cells a balance between pro-apoptotic (BAX,[24] BID, BAK, or BAD) and anti-apoptotic (Bcl-Xl and Bcl-2) members of the Bcl-2 family is established. This balance is the proportion of pro-apoptotic homodimers that form in the outer-membrane of the mitochondrion. The pro-apoptotic homodimers are required to make the mitochondrial membrane permeable for the release of caspase activators such as cytochrome c and SMAC. Control of pro-apoptotic proteins under normal cell conditions of non-apoptotic cells is incompletely understood, but it has been found that a mitochondrial outer-membrane protein, VDAC2, interacts with BAK to keep this potentially-lethal apoptotic effector under control.[25] When the death signal is received, products of the activation cascade displace VDAC2 and BAK is able to be activated. There also exists a caspase-independent apoptotic pathway that is mediated by AIF (apoptosis-inducing factor). For more information, see the article of the author Susin in Nature of 1999 and also reference 21 mentioned below. ## Execution Although many pathways and signals lead to apoptosis, there is only one mechanism that actually causes the death of the cell in this process; after the appropriate stimulus has been received by the cell and the necessary controls exerted, a cell will undergo the organized degradation of cellular organelles by activated proteolytic caspases. A cell undergoing apoptosis shows a characteristic morphology that can be observed with a microscope: - Cell shrinkage and rounding due to the breakdown of the proteinaceous cytoskeleton by caspases. - The cytoplasm appears dense, and the organelles appear tightly packed. - Chromatin undergoes condensation into compact patches against the nuclear envelope in a process known as pyknosis, a hallmark of apoptosis.[26][27] - The nuclear envelope becomes discontinuous and the DNA inside it is fragmented in a process referred to as karyorrhexis. The nucleus breaks into several discrete chromatin bodies or nucleosomal units due to the degradation of DNA.[28] - The cell membrane shows irregular buds known as blebs. - The cell breaks apart into several vesicles called apoptotic bodies, which are then phagocytosed. Apoptosis progresses quickly and its products are quickly removed, making it difficult to detect or visualize. During karyorrhexis, endonuclease activation leaves short DNA fragments, regularly spaced in size. These give a characteristic "laddered" appearance on agar gel after electrophoresis. Tests for DNA laddering differentiate apoptosis from ischemic or toxic cell death.[29] ## Removal of dead cells Dying cells that undergo the final stages of apoptosis display phagocytotic molecules, such as phosphatidylserine, on their cell surface.[30] Phosphatidylserine is normally found on the cytosolic surface of the plasma membrane, but is redistributed during apoptosis to the extracellular surface by a hypothetical protein known as scramblase.[31] These molecules mark the cell for phagocytosis by cells possessing the appropriate receptors, such as macrophages.[32] Upon recognition, the phagocyte reorganizes its cytoskeleton for engulfment of the cell. The removal of dying cells by phagocytes occurs in an orderly manner without eliciting an inflammatory response. # Implication in disease ## Defective apoptotic pathways The many different types of apoptotic pathways contain a multitude of different biochemical components, many of them not yet understood.[8] As a pathway is more or less sequential in nature it is a victim of causality; removing or modifying one component leads to an effect in another. In a living organism this can have disastrous effects, often in the form of disease or disorder. A discussion of every disease caused by modification of the various apoptotic pathways would be impractical, but the concept overlying each one is the same: the normal functioning of the pathway has been disrupted in such a way as to impair the ability of the cell to undergo normal apoptosis. This results in a cell that lives past its "use-by-date" and is able to replicate and pass on any faulty machinery to its progeny, increasing the likelihood of the cell becoming cancerous or diseased. A recently-described example of this concept in action can be seen in the development of a lung cancer called NCI-H460.[33] The X-linked inhibitor of apoptosis protein (XIAP) is overexpressed in cells of the H460 cell line. XIAPs bind to the processed form of caspase-9, and suppress the activity of apoptotic activator cytochrome c, therefore overexpression leads to a decrease in the amount of pro-apoptotic agonists. As a consequence, the balance of anti-apoptotic and pro-apoptotic effectors is upset in favour of the former, and the damaged cells continue to replicate despite being directed to die. ## p53 disregulation The tumor-suppressor protein p53 accumulates when DNA is damaged due to a chain of biochemical reactions. Part of this pathway includes interferon-alpha and interferon-beta, which induce transcription of the p53 gene and result in the increase of p53 protein level and enhancement of cancer cell-apoptosis.[34] p53 prevents the cell from replicating by stopping the cell cycle at G1, or interphase, to give the cell time to repair, however it will induce apoptosis if damage is extensive and repair efforts fail. Any disruption to the regulation of the p53 or interferon genes will result in impaired apoptosis and the possible formation of tumors. ## HIV progression The progression of the human immunodeficiency virus (HIV) to AIDS is primarily due to the depletion of CD4+ T-helper lymphocytes, which leads to a compromised immune system. One of the mechanisms by which T-helper cells are depleted is apoptosis, which can be the end-product of multiple biochemical pathways:[35] - HIV enzymes inactivate anti-apoptotic Bcl-2 and simultaneously activate pro-apoptotic procaspase-8. This does not directly cause cell death but primes the cell for apoptosis should the appropriate signal be received. - HIV products may increase levels of cellular proteins which have a promotive effect on Fas-mediated apoptosis. - HIV proteins decrease the amount of CD4 glycoprotein marker present on the cell membrane. - Released viral particles and proteins present in extracellular fluid are able to induce apoptosis in nearby "bystander" T-helper cells. - HIV decreases the production of molecules involved in marking the cell for apoptosis, giving the virus time to replicate and continue releasing apoptotic agents and virions into the surrounding tissue. - The infected CD4+ cell may also receive the death signal from a cytotoxic T cell, leading to apoptosis. In addition to apoptosis, infected cells may also die as a direct consequence of the viral infection. ## Viral infection Viruses can trigger apoptosis of infected cells via a range of mechanisms including: - Receptor binding. - Activation of protein kinase R (PKR). - Interaction with p53. - Expression of viral proteins coupled to MHC proteins on the surface of the infected cell, allowing recognition by cells of the immune system (such as Natural Killer and cytotoxic T cells) that then induce the infected cell to undergo apoptosis.[36] Most viruses encode proteins that can inhibit apoptosis.[37] Several viruses encode viral homologs of Bcl-2. These homologs can inhibit pro-apoptotic proteins such as BAX and BAK, which are essential for the activation of apoptosis. Examples of viral Bcl-2 proteins include the Epstein-Barr virus BHRF1 protein and the adenovirus E1B 19K protein.[38] Some viruses express caspase inhibitors that inhibit caspase activity and an example is the CrmA protein of cowpox viruses. Whilst a number of viruses can block the effects of TNF and Fas. For example the M-T2 protein of myxoma viruses can bind TNF preventing it from binding the TNF receptor and inducing a response.[39] Furthermore, many viruses express p53 inhibitors that can bind p53 and inhibit its transcriptional transactivation activity. Consequently p53 cannot induce apoptosis since it cannot induce the expression of pro-apoptotic proteins. The adenovirus E1B-55K protein and the hepatitis B virus HBx protein are examples of viral proteins that can perform such a function.[40] Interestingly, viruses can remain intact from apoptosis particularly in the latter stages of infection. They can be exported in the apoptotic bodies that pinch off from the surface of the dying cell and the fact that they are engulfed by phagocytes prevents the initiation of a host response. This favours the spread of the virus.[39]	https://www.wikidoc.org/index.php/Apoptosis
b208763a6f843fbf7fdc5013f9336d8636e76474	wikidoc	Appendage	Appendage # Overview An appendage in the broadest sense is an additional or subsidiary part existing on, or added to, something which can generally still function if the appendage has never existed or is later provided or grown, or will still perform a primary function if the appendage is removed. # Biological context An appendage is an external body part, or natural prolongation, that protrudes from an organism's body, such as a vertebrate's limbs. In invertebrate biology, "appendage" is a general term that covers any of the homologous body parts that may extend from a body segment. These include antennae, mouthparts (including mandibles, maxillae and maxillipeds), wings, elytra, gills, walking legs (pereiopods), swimming legs (pleopods), sexual organs (gonopods), and parts of the tail (uropods). Typically, each body segment carries one pair of appendages. Appendages may be uniramous, as in insects and centipedes, where each appendage comprises a single series of segments, or it may be biramous, as in many crustaceans, where each appendage branches into two sections. Triramous (branching into three) appendages are also possible. All arthropod appendages are variations of the same basic structure (homologous), and which structure is produced is controlled by "homeobox" genes. Changes to these genes have allowed scientists to produce animals (chiefly Drosophila melanogaster) with modified appendages, such as legs instead of antennae. # Linguistic context In British English, depending on the surrounding context, "appendage" might infer that the added words to which it refers give a more precise meaning to a name or description or else it might be used in a derogatory sense to describe an addition which appears to serve no useful function.	Appendage Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview An appendage in the broadest sense is an additional or subsidiary part existing on, or added to, something which can generally still function if the appendage has never existed or is later provided or grown, or will still perform a primary function if the appendage is removed. # Biological context An appendage is an external body part, or natural prolongation, that protrudes from an organism's body, such as a vertebrate's limbs. In invertebrate biology, "appendage" is a general term that covers any of the homologous body parts that may extend from a body segment. These include antennae, mouthparts (including mandibles, maxillae and maxillipeds), wings, elytra, gills, walking legs (pereiopods), swimming legs (pleopods), sexual organs (gonopods), and parts of the tail (uropods). Typically, each body segment carries one pair of appendages. Appendages may be uniramous, as in insects and centipedes, where each appendage comprises a single series of segments, or it may be biramous, as in many crustaceans, where each appendage branches into two sections. Triramous (branching into three) appendages are also possible. All arthropod appendages are variations of the same basic structure (homologous), and which structure is produced is controlled by "homeobox" genes. Changes to these genes have allowed scientists to produce animals (chiefly Drosophila melanogaster) with modified appendages, such as legs instead of antennae. # Linguistic context In British English, depending on the surrounding context, "appendage" might infer that the added words to which it refers give a more precise meaning to a name or description or else it might be used in a derogatory sense to describe an addition which appears to serve no useful function.[citation needed] Template:WS	https://www.wikidoc.org/index.php/Appendage

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