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0dc6960f870100c7eb2ac6a40d0ec8d1512ddd68 | wikidoc | HAT medium | HAT medium
HAT Medium (Hypoxanthine Aminopterin Thymidine medium) is a selection medium for mammalian cell culture, which relies on the combination of aminopterin, a drug that acts as a folate metabolism inhibitor by inhibiting dihydrofolate reductase, with hypoxanthine and thymidine, which are intermediates in DNA synthesis - a purine derivative and a deoxynucleoside, respectively. The trick is that aminopterin blocks DNA "de novo" synthesis, which is absolutely required for cell division to proceed, but the other components provide cells with the raw material to evade the blockage (the "salvage pathway") - provided that they have the right enzymes, which means having functioning copies of the genes that encode them.
The enzyme dihydrofolate reductase which produces tetrahydrofolate (THF) by the reduction of dihydrofolate,is specifically blocked by aminopterin. THF, acting in association with specific proteins, can receive single carbon units that are then transferred to specific targets.
One of the important targets for cellular reproduction is thymidylate synthase, which creates thymidine monophosphate (TMP) from uridine monophosphate (dUMP). By additional phosphorylation reactions TMP can be used to make thymidine triphosphate (TTP), one of the four nucleotide precursors that are used by DNA polymerases to create DNA. Without the THF required to convert dUMP, there can be no TTP, and DNA synthesis cannot proceed --- unless TMP can be produced from another source. The alternative source is that thymidine present in HAT medium can be absorbed by the cells and phosphorylated by thymidine kinase (TK) into TMP.
The synthesis of IMP, (precursor to GMP and GTP) also requires THF, and also can be bypassed. In this case hypoxanthine-guanine phosphoribosyltransferase (HGPRT) reacts hypoxanthine absorbed from the medium with PRPP, liberating pyrophosphate, to produce IMP by a salvage pathway.
Thus the use of HAT medium for cell culture is a form of artificial selection for cells containing working TK and HGPRT. Many useful refinements to the scheme are made possible by poisons that kill cells, but to which they are immune if they lack one of these genes. Thus a cell lacking TK is resistant to bromodeoxyuridine (BrdU) and a cell lacking HGPRT is resistant to 6-thioguanine (6-TG) and 8-azaguanine. Thus selection with one of the latter two drugs, followed by HAT medium, will yield revertant colonies.
# Applications
HAT medium is often used for preparation of monoclonal antibodies. This process is called Hybridoma technology. In this method, B cells are fused with HGPRT negative, immortalized myeloma cells using polyethylene glycol or the Sendai virus. Fused cells are incubated in the HAT medium. Aminopterin in the medium blocks the de novo pathway. Hence, unfused myeloma cells die, as they cannot produce nucleotides by de novo or salvage pathway. Unfused B cells die as they have a short life span. In this way, only the B cell-myeloma hybrids survive. These cells produce antibodies (a property of B cells) and are immortal (a property of myeloma cells).
The incubated medium is then diluted into multiwell plates to such an extent that each well contains only 1 cell.
Then the supernatant in each well can be checked for desired antibody. Since the antibodies in a well are produced by the same B cell, they will be directed towards the same epitope, and are known as monoclonal antibodies.
The production of monoclonal anti-bodies was first invented by Cesar Milstein, George Kohler and Niels Kaj Jerne in 1975 | HAT medium
HAT Medium (Hypoxanthine Aminopterin Thymidine medium) is a selection medium for mammalian cell culture, which relies on the combination of aminopterin, a drug that acts as a folate metabolism inhibitor by inhibiting dihydrofolate reductase, with hypoxanthine and thymidine, which are intermediates in DNA synthesis - a purine derivative and a deoxynucleoside, respectively. The trick is that aminopterin blocks DNA "de novo" synthesis, which is absolutely required for cell division to proceed, but the other components provide cells with the raw material to evade the blockage (the "salvage pathway") - provided that they have the right enzymes, which means having functioning copies of the genes that encode them.
The enzyme dihydrofolate reductase which produces tetrahydrofolate (THF) by the reduction of dihydrofolate,is specifically blocked by aminopterin. THF, acting in association with specific proteins, can receive single carbon units that are then transferred to specific targets.
One of the important targets for cellular reproduction is thymidylate synthase, which creates thymidine monophosphate (TMP) from uridine monophosphate (dUMP). By additional phosphorylation reactions TMP can be used to make thymidine triphosphate (TTP), one of the four nucleotide precursors that are used by DNA polymerases to create DNA. Without the THF required to convert dUMP, there can be no TTP, and DNA synthesis cannot proceed --- unless TMP can be produced from another source. The alternative source is that thymidine present in HAT medium can be absorbed by the cells and phosphorylated by thymidine kinase (TK) into TMP.
The synthesis of IMP, (precursor to GMP and GTP) also requires THF, and also can be bypassed. In this case hypoxanthine-guanine phosphoribosyltransferase (HGPRT) reacts hypoxanthine absorbed from the medium with PRPP, liberating pyrophosphate, to produce IMP by a salvage pathway.
Thus the use of HAT medium for cell culture is a form of artificial selection for cells containing working TK and HGPRT. Many useful refinements to the scheme are made possible by poisons that kill cells, but to which they are immune if they lack one of these genes. Thus a cell lacking TK is resistant to bromodeoxyuridine (BrdU) and a cell lacking HGPRT is resistant to 6-thioguanine (6-TG) and 8-azaguanine. Thus selection with one of the latter two drugs, followed by HAT medium, will yield revertant colonies.[1]
# Applications
HAT medium is often used for preparation of monoclonal antibodies. This process is called Hybridoma technology. In this method, B cells are fused with HGPRT negative, immortalized myeloma cells using polyethylene glycol or the Sendai virus. Fused cells are incubated in the HAT medium. Aminopterin in the medium blocks the de novo pathway. Hence, unfused myeloma cells die, as they cannot produce nucleotides by de novo or salvage pathway. Unfused B cells die as they have a short life span. In this way, only the B cell-myeloma hybrids survive. These cells produce antibodies (a property of B cells) and are immortal (a property of myeloma cells).
The incubated medium is then diluted into multiwell plates to such an extent that each well contains only 1 cell.
Then the supernatant in each well can be checked for desired antibody. Since the antibodies in a well are produced by the same B cell, they will be directed towards the same epitope, and are known as monoclonal antibodies.
The production of monoclonal anti-bodies was first invented by Cesar Milstein, George Kohler and Niels Kaj Jerne in 1975 | https://www.wikidoc.org/index.php/HAT_medium | |
e9548167cadba2a003e450cea25022a54564e863 | wikidoc | HFE (gene) | HFE (gene)
Human hemochromatosis protein also known as the HFE protein is a protein which in humans is encoded by the HFE gene.
The HFE gene is located on short arm of chromosome 6 at location 6p21.3. Unusually, the official gene symbol (HFE for High Iron Fe) is not an abbreviation of the official name (hemochromatosis).
# Function
Protein encoded by this gene is a membrane protein that is similar to MHC class I-type proteins and associates with beta-2 microglobulin (beta2M). It is thought that this protein functions to regulate circulating iron uptake by regulating the interaction of the transferrin receptor with transferrin.
The HFE gene contains 7 exons spanning 12 kb. The full-length transcript represents 6 exons.
HFE protein is composed of 343 amino acids. There are several components, in sequence: a signal peptide (initial part of the protein), an extracellular transferrin receptor-binding region (α1 and α2), a portion that resembles immunoglobulin molecules (α3), a transmembrane region that anchors the protein in the cell membrane, and a short cytoplasmic tail.
HFE expression is subjected to alternative splicing. The predominant HFE full-length transcript has ~4.2 kb. Alternative HFE splicing variants may serve as iron regulatory mechanisms in specific cells or tissues.
HFE is prominent in small intestinal absorptive cells, gastric epithelial cells, tissue macrophages, and blood monocytes and granulocytes, and the syncytiotrophoblast, an iron transport tissue in the placenta.
# Clinical significance
The iron storage disorder hereditary hemochromatosis (HHC) is an autosomal recessive genetic disorder that usually results from defects in this gene.
The mutation or polymorphism most commonly associated with hemochromatosis is p. C282Y. About 1/200 of people of Northern European origin have two copies of this variant; they, particularly males, are at high risk of developing hemochromatosis.
Allele frequencies of HFE C282Y in ethnically diverse western European white populations are 5-14% and in North American non-Hispanic whites are 6-7%. C282Y exists as a polymorphism only in Western European white and derivative populations, although C282Y may have arisen independently in non-whites outside Europe.
HFE H63D is cosmopolitan but occurs with greatest frequency in whites of European descent. Allele frequencies of H63D in ethnically diverse western European populations are 10-29%. and in North American non-Hispanic whites are 14-15%.
At least 42 mutations involving HFE introns and exons have been discovered, most of them in persons with hemochromatosis or their family members. Most of these mutations are rare. Many of the mutations cause or probably cause hemochromatosis phenotypes, often in compound heterozygosity with HFE C282Y. Other mutations are either synonymous or their effect on iron phenotypes, if any, has not been demonstrated.
# Interactions
The HFE protein interacts with the transferrin receptor TFRC.
Its primary mode of action is the regulation of the iron storage hormone hepcidin.
# Hfe knockout mice
It is possible to delete part or all of a gene of interest in mice (or other experimental animals) as a means of studying function of the gene and its protein. Such mice are called “knockouts” with respect to the deleted gene. Hfe is the mouse equivalent of the human hemochromatosis gene HFE. The protein encoded by Hfe is Hfe. Mice homozygous (two abnormal gene copies) for a targeted knockout of all six transcribed Hfe exons are designated Hfe−/−. Iron-related traits of Hfe−/− mice, including increased iron absorption and hepatic iron loading, are inherited in an autosomal recessive pattern. Thus, the Hfe−/− mouse model simulates important genetic and physiologic abnormalities of HFE hemochromatosis. Other knockout mice were created to delete the second and third Hfe exons (corresponding to α1 and α2 domains of Hfe). Mice homozygous for this deletion also had increased duodenal iron absorption, elevated plasma iron and transferrin saturation levels, and iron overload, mainly in hepatocytes. Mice have also been created that are homozygous for a missense mutation in Hfe (C282Y). These mice correspond to persons with hemochromatosis who are homozygous for HFE C282Y. These mice develop iron loading that is less severe than that of Hfe−/− mice.
# HFE mutations and iron overload in other animals
Black rhinoceroses (Diceros bicornis) develop iron overload. To determine whether the HFE gene of black rhinoceroses has undergone mutation as an adaptive mechanism to improve iron absorption from iron-poor diets, Beutler et al. sequenced the entire HFE coding region of four species of rhinoceros (two browsing and two grazing species). Although HFE was well conserved across the species, numerous nucleotide differences were found between rhinoceros and human or mouse, some of which changed deduced amino acids. Only one allele, p.S88T in the black rhinoceros, was a candidate that might adversely affect HFE function. p.S88T occurs in a highly conserved region involved in the interaction of HFE and TfR1. | HFE (gene)
Human hemochromatosis protein also known as the HFE protein is a protein which in humans is encoded by the HFE gene.
The HFE gene is located on short arm of chromosome 6 at location 6p21.3. Unusually, the official gene symbol (HFE for High Iron Fe) is not an abbreviation of the official name (hemochromatosis).[1]
# Function
Protein encoded by this gene is a membrane protein that is similar to MHC class I-type proteins and associates with beta-2 microglobulin (beta2M). It is thought that this protein functions to regulate circulating iron uptake by regulating the interaction of the transferrin receptor with transferrin.[2]
The HFE gene contains 7 exons spanning 12 kb.[3] The full-length transcript represents 6 exons.[4]
HFE protein is composed of 343 amino acids. There are several components, in sequence: a signal peptide (initial part of the protein), an extracellular transferrin receptor-binding region (α1 and α2), a portion that resembles immunoglobulin molecules (α3), a transmembrane region that anchors the protein in the cell membrane, and a short cytoplasmic tail.[3]
HFE expression is subjected to alternative splicing. The predominant HFE full-length transcript has ~4.2 kb.[5] Alternative HFE splicing variants may serve as iron regulatory mechanisms in specific cells or tissues.[5]
HFE is prominent in small intestinal absorptive cells,[6][7] gastric epithelial cells, tissue macrophages, and blood monocytes and granulocytes,[7][8] and the syncytiotrophoblast, an iron transport tissue in the placenta.[9]
# Clinical significance
The iron storage disorder hereditary hemochromatosis (HHC) is an autosomal recessive genetic disorder that usually results from defects in this gene.
The mutation or polymorphism most commonly associated with hemochromatosis is p. C282Y. About 1/200 of people of Northern European origin have two copies of this variant; they, particularly males, are at high risk of developing hemochromatosis.[10]
Allele frequencies of HFE C282Y in ethnically diverse western European white populations are 5-14%[11][12] and in North American non-Hispanic whites are 6-7%.[13] C282Y exists as a polymorphism only in Western European white and derivative populations, although C282Y may have arisen independently in non-whites outside Europe.[14]
HFE H63D is cosmopolitan but occurs with greatest frequency in whites of European descent.[15][16] Allele frequencies of H63D in ethnically diverse western European populations are 10-29%.[17] and in North American non-Hispanic whites are 14-15%.[18]
At least 42 mutations involving HFE introns and exons have been discovered, most of them in persons with hemochromatosis or their family members.[19] Most of these mutations are rare. Many of the mutations cause or probably cause hemochromatosis phenotypes, often in compound heterozygosity with HFE C282Y. Other mutations are either synonymous or their effect on iron phenotypes, if any, has not been demonstrated.[19]
# Interactions
The HFE protein interacts with the transferrin receptor TFRC.[20][21]
Its primary mode of action is the regulation of the iron storage hormone hepcidin.[22]
# Hfe knockout mice
It is possible to delete part or all of a gene of interest in mice (or other experimental animals) as a means of studying function of the gene and its protein. Such mice are called “knockouts” with respect to the deleted gene. Hfe is the mouse equivalent of the human hemochromatosis gene HFE. The protein encoded by Hfe is Hfe. Mice homozygous (two abnormal gene copies) for a targeted knockout of all six transcribed Hfe exons are designated Hfe−/−.[23] Iron-related traits of Hfe−/− mice, including increased iron absorption and hepatic iron loading, are inherited in an autosomal recessive pattern. Thus, the Hfe−/− mouse model simulates important genetic and physiologic abnormalities of HFE hemochromatosis.[23] Other knockout mice were created to delete the second and third Hfe exons (corresponding to α1 and α2 domains of Hfe). Mice homozygous for this deletion also had increased duodenal iron absorption, elevated plasma iron and transferrin saturation levels, and iron overload, mainly in hepatocytes.[24] Mice have also been created that are homozygous for a missense mutation in Hfe (C282Y). These mice correspond to persons with hemochromatosis who are homozygous for HFE C282Y. These mice develop iron loading that is less severe than that of Hfe−/− mice.[25]
# HFE mutations and iron overload in other animals
Black rhinoceroses (Diceros bicornis) develop iron overload. To determine whether the HFE gene of black rhinoceroses has undergone mutation as an adaptive mechanism to improve iron absorption from iron-poor diets, Beutler et al. sequenced the entire HFE coding region of four species of rhinoceros (two browsing and two grazing species). Although HFE was well conserved across the species, numerous nucleotide differences were found between rhinoceros and human or mouse, some of which changed deduced amino acids. Only one allele, p.S88T in the black rhinoceros, was a candidate that might adversely affect HFE function. p.S88T occurs in a highly conserved region involved in the interaction of HFE and TfR1.[26] | https://www.wikidoc.org/index.php/HFE_(gene) | |
c95c1f6bb20a70ad3f59c6c3633462b3ff5923e2 | wikidoc | HPN (gene) | HPN (gene)
Serine protease hepsin is an enzyme that in humans is encoded by the HPN gene.
# Function
Hepsin is a cell surface serine protease.
Hepson contains a peptidase S1 domain and an SRCR domain. The SRCR domain is located in the extracellular part of the protein, it is formed primarily by three elements of regular secondary structure: a 12-residue alpha helix, a twisted five-stranded antiparallel beta sheet, and a second, two-stranded, antiparallel sheet. The two beta-sheets lie at roughly right angles to each other, with the helix nestled between the two, adopting an SRCR fold. The exact function of this domain has not been identified, though it probably may serve to orient the protease domain or place it in the vicinity of its substrate.
# Clinical significance
Hepsin expression is unregulated in prostate cancer and correlates with disease progression. | HPN (gene)
Serine protease hepsin is an enzyme that in humans is encoded by the HPN gene.[1][2]
# Function
Hepsin is a cell surface serine protease.[2]
Hepson contains a peptidase S1 domain and an SRCR domain. The SRCR domain is located in the extracellular part of the protein, it is formed primarily by three elements of regular secondary structure: a 12-residue alpha helix, a twisted five-stranded antiparallel beta sheet, and a second, two-stranded, antiparallel sheet. The two beta-sheets lie at roughly right angles to each other, with the helix nestled between the two, adopting an SRCR fold. The exact function of this domain has not been identified, though it probably may serve to orient the protease domain or place it in the vicinity of its substrate.[3]
# Clinical significance
Hepsin expression is unregulated in prostate cancer and correlates with disease progression.[4] | https://www.wikidoc.org/index.php/HPN_(gene) | |
41258cd517d12798545c9a269440789252e94504 | wikidoc | HRB (gene) | HRB (gene)
Arf-GAP domain and FG repeats-containing protein 1 is a protein that in humans is encoded by the AGFG1 gene.
# Function
The protein encoded by this gene is related to nucleoporins, a class of proteins that mediate nucleocytoplasmic transport. This encoded protein binds the Rev activation domain when Rev is assembled onto its RNA target and can significantly enhance Rev activity when overexpressed. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.
# Interactions
HRB (gene) has been shown to interact with EPS15L1 and EPS15. | HRB (gene)
Arf-GAP domain and FG repeats-containing protein 1 is a protein that in humans is encoded by the AGFG1 gene.[1][2]
# Function
The protein encoded by this gene is related to nucleoporins, a class of proteins that mediate nucleocytoplasmic transport. This encoded protein binds the Rev activation domain when Rev is assembled onto its RNA target and can significantly enhance Rev activity when overexpressed. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.[2]
# Interactions
HRB (gene) has been shown to interact with EPS15L1[3] and EPS15.[3] | https://www.wikidoc.org/index.php/HRB_(gene) | |
ad436cae43486063aff15310955ce8ff17eca297 | wikidoc | Haemobilia | Haemobilia
# Overview
Implies bleeding into biliary tree. Can present as acute upper gastrointestinal(UGI) bleeding. It should be considered in upper abdominal pain presenting with UGI bleeding especially when there is a history of liver injury or instrumentation.
- First recorded in 1654 by Francis Glisson, a Cambridge professor.
- Haemobilia occurs when there is a fistula between a vessel of the splanchnic circulation and the intrahepatic or extrahepatic biliary system.
# Causes
- Trauma, accidental or iatrogenic e.g. due to procedures like cholecystectomy
- Instrumentation e.g. after ERCP
- Gallstone
- Inflammatory conditions ranging from ascariasis to PAN
- Vascular malformation
- Tumor
- Coagulopathy
# Clinical feature
Triad of upper abdominal pain, upper gastrointestinal haemorrhage and jaundice is classical but only present in 22% cases.
It can be immediately life threatening in major bleeding. However in minor haemobilia patient is haemodynamically stable despite significant blood loss being apparent .
# Diagnosis
Combination of OGD, CT scan and angiography depending on clinical situation, bearing in mind that haemobilia may present many days after injury. Cholengiography is performed if there is a percutaneous access or if ERCP is undertaken.
The imaging findings are
- Ultrasound: echogenic material in bile ducts.
- Unenhanced CT: High-attenuation clot within the bile ducts.
High density material in the common bile duct is consistent with hemobilia is the patient who is recently s/p cholecystectomy.
# Management
Most bleeding from instrumentation are minor and would settle spontaneously.
When indicated, management is directed towards stopping bleeding and relieving obstruction if present, which is achieved either by surgical ligation of hepatic artery or by endoscopic embolisation. Endoscopic trans-arterial embolisation (TAE) is preferred initially because of high success rate and less complication. TAE involves the selective catheterization of a hepatic artery followed by embolic occlusion. Surgery is indicated when TAE has failed or sepsis present in biliary tree or drainage has failed. | Haemobilia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Implies bleeding into biliary tree. Can present as acute upper gastrointestinal(UGI) bleeding. It should be considered in upper abdominal pain presenting with UGI bleeding especially when there is a history of liver injury or instrumentation.
- First recorded in 1654 by Francis Glisson, a Cambridge professor[1].
- Haemobilia occurs when there is a fistula between a vessel of the splanchnic circulation and the intrahepatic or extrahepatic biliary system.
# Causes
- Trauma, accidental or iatrogenic e.g. due to procedures like cholecystectomy
- Instrumentation e.g. after ERCP
- Gallstone
- Inflammatory conditions ranging from ascariasis to PAN
- Vascular malformation
- Tumor
- Coagulopathy
# Clinical feature
Triad of upper abdominal pain, upper gastrointestinal haemorrhage and jaundice[2] is classical but only present in 22% cases[3].
It can be immediately life threatening in major bleeding. However in minor haemobilia patient is haemodynamically stable despite significant blood loss being apparent [3].
# Diagnosis
Combination of OGD, CT scan and angiography depending on clinical situation, bearing in mind that haemobilia may present many days after injury. Cholengiography is performed if there is a percutaneous access or if ERCP is undertaken.
The imaging findings are
- Ultrasound: echogenic material in bile ducts.
- Unenhanced CT: High-attenuation clot within the bile ducts.
High density material in the common bile duct is consistent with hemobilia is the patient who is recently s/p cholecystectomy.
-
-
# Management
Most bleeding from instrumentation are minor and would settle spontaneously.
When indicated, management is directed towards stopping bleeding and relieving obstruction if present, which is achieved either by surgical ligation of hepatic artery or by endoscopic embolisation. Endoscopic trans-arterial embolisation (TAE) is preferred initially because of high success rate and less complication. TAE involves the selective catheterization of a hepatic artery followed by embolic occlusion. Surgery is indicated when TAE has failed or sepsis present in biliary tree or drainage has failed. | https://www.wikidoc.org/index.php/Haemobilia | |
01ac29e894c1807468fece21e4e4161c65f84379 | wikidoc | Hemostasis | Hemostasis
# Overview
Hemostasis refers to the physiologic process whereby bleeding is halted in most animals with a closed circulatory system. Stopped bleeding is commonly referred to, however, as coagulation, but coagulation is only a part of the hemostatic process.
# Hemostasis in physiology
When a blood vessel is injured, several steps occur to staunch the flow of blood, namely:
- Vasoconstriction constricts the blood vessel, minimizing vessel diameter and slowing bleeding.
- Primary hemostasis occurs, wherein platelets, one of the formed elements of the blood, bind to collagen in the exposed walls of the blood vessel to form a hemostatic plug within seconds after an injury.
- Secondary hemostasis or coagulation occurs. This involves a complex cascade of coagulation factors, ultimately resulting in the transformation of fibrinogen, a blood protein, into polymerized fibrin, making a clot. This process takes several minutes.
- The clot attracts and stimulates the growth of fibroblasts and smooth muscle cells within the vessel wall, and begins the repair process which ultimately results in the dissolution of the clot (fibrinolysis).
Disorders of hemostasis can be roughly divided into platelet disorders, such as idiopathic thrombocytopenic purpura, and disorders of coagulation, such as hemophilia.
Hemostasis may also refer to the complex interaction between vessels, platelets, coagulation factors, coagulation inhibitors and fibrinolytic proteins to maintain the blood within the vascular compartment in a fluid state. The objective of the hemostatic system is to preserve intravascular integrity by achieving a balance between hemorrhage and thrombosis.
Hemostasis can be induced by adenosine diphosphate (ADP) at the site of a mosquito bite to recruit platelets and oppose blood-feeding; however mosquitoes have developed salivary apyrase to degrade ADP to counter this defense.
# Hemostasis by Hemostatic Clamps
Hemostasis may refer to the process of manually clamping a blood vessel, usually with hemostatic clamps, in surgery or dissection, to prevent bleeding from that vessel. This also may be done when an abnormal blood vessel forms, as these vessels may have thin walls and be prone to rupturing. | Hemostasis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Hemostasis refers to the physiologic process whereby bleeding is halted in most animals with a closed circulatory system. Stopped bleeding is commonly referred to, however, as coagulation, but coagulation is only a part of the hemostatic process.
# Hemostasis in physiology
When a blood vessel is injured, several steps occur to staunch the flow of blood, namely:
- Vasoconstriction constricts the blood vessel, minimizing vessel diameter and slowing bleeding.
- Primary hemostasis occurs, wherein platelets, one of the formed elements of the blood, bind to collagen in the exposed walls of the blood vessel to form a hemostatic plug within seconds after an injury.
- Secondary hemostasis or coagulation occurs. This involves a complex cascade of coagulation factors, ultimately resulting in the transformation of fibrinogen, a blood protein, into polymerized fibrin, making a clot. This process takes several minutes.
- The clot attracts and stimulates the growth of fibroblasts and smooth muscle cells within the vessel wall, and begins the repair process which ultimately results in the dissolution of the clot (fibrinolysis).
Disorders of hemostasis can be roughly divided into platelet disorders, such as idiopathic thrombocytopenic purpura, and disorders of coagulation, such as hemophilia.
Hemostasis may also refer to the complex interaction between vessels, platelets, coagulation factors, coagulation inhibitors and fibrinolytic proteins to maintain the blood within the vascular compartment in a fluid state. The objective of the hemostatic system is to preserve intravascular integrity by achieving a balance between hemorrhage and thrombosis.
Hemostasis can be induced by adenosine diphosphate (ADP) at the site of a mosquito bite to recruit platelets and oppose blood-feeding; however mosquitoes have developed salivary apyrase to degrade ADP to counter this defense.
# Hemostasis by Hemostatic Clamps
Hemostasis may refer to the process of manually clamping a blood vessel, usually with hemostatic clamps, in surgery or dissection, to prevent bleeding from that vessel. This also may be done when an abnormal blood vessel forms, as these vessels may have thin walls and be prone to rupturing.
# External links
- http://vam.anest.ufl.edu/hemostasis/index.html A free simulation of perioperative hemostasis
- http://www.hemostasisllc.com/
de:Blutstillung
mk:Хемостаза
nl:Hemostase
no:Hemostase
sq:Hemostaza
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Haemostasis | |
99523507b724dcb0ddc45c504b26915930aec65d | wikidoc | Hair whorl | Hair whorl
# Overview
A Hair whorl is a patch of hair growing in the opposite direction of the rest of the hair. It occurs in most hairy animals. Hair whorls occur on the body as well as on the head.
Hair whorls on the head (parietal whorls) have been intensively studied because of the association indicated between brain development and abnormal hair whorls. (Both brain cells and skin cells are derived from an embryo's ectoderm tissue.) Abnormal hair whorls are used as a preliminary predictor of abnormal temperament in most domesticated animals especially cows, but also in evaluating the mental status of apes and humans.
Parietal whorls which are considered to be normal scalp patterns could be a single whorl or double whorls. Cases of triple parietal scalp whorls are less common but do not necessarily indicate abnormality. Abnormal brain development is usually indicated by the complete absence of hair whorls or abnormal placement of whorls on the scalp. | Hair whorl
# Overview
A Hair whorl is a patch of hair growing in the opposite direction of the rest of the hair. It occurs in most hairy animals. Hair whorls occur on the body as well as on the head.
Hair whorls on the head (parietal whorls) have been intensively studied because of the association indicated between brain development and abnormal hair whorls. (Both brain cells and skin cells are derived from an embryo's ectoderm tissue.) Abnormal hair whorls are used as a preliminary predictor of abnormal temperament in most domesticated animals especially cows, but also in evaluating the mental status of apes and humans.
Parietal whorls which are considered to be normal scalp patterns could be a single whorl or double whorls. Cases of triple parietal scalp whorls are less common but do not necessarily indicate abnormality. Abnormal brain development is usually indicated by the complete absence of hair whorls or abnormal placement of whorls on the scalp.
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Hair_whorl | |
6b70d36e3e325d7970a6bc0f735b1b561c5bffc5 | wikidoc | Halo nevus | Halo nevus
Synonyms and keywords: Leukoderma acquisitum centrifugum, Perinevoid vitiligo, Sutton nevus
# Overview
Halo nevus is a mole that is surrounded by a depigmented ring or 'halo'.:689)
# Pathophysiology
The formation of a halo surrounding a nevi is believed to occur when certain white blood cells called CD8+ T lymphocytes destroy the pigment-producing cells of the skin (melanocytes). The trigger for the autoimmune attack is unknown.
# Epidemiology and Demographics
Halo nevi are estimated to be present in approximately 1% of the general population, and All races and sexes are equally susceptible to this disease, although a familial tendency has been reported. The average age of onset is in a person's teenage years.
# Risk Factors
Halo Nevi are found to be more prevalent in people with vitiligo, malignant melanoma, or Turner syndrome.
# Diagnosis
## Physical Examination
### Skin
Halo nevi are named such because they are a mole (nevi) that is surrounded by an area of depigmentation that resembles a halo.
- Naevus halo. Adapted from Dermatology Atlas.
- Naevus halo. Adapted from Dermatology Atlas.
- Naevus halo. Adapted from Dermatology Atlas.
- Naevus halo. Adapted from Dermatology Atlas.
- Naevus halo. Adapted from Dermatology Atlas.
- Naevus halo. Adapted from Dermatology Atlas.
- Naevus halo. Adapted from Dermatology Atlas.
- Naevus halo. Adapted from Dermatology Atlas.
- Naevus halo. Adapted from Dermatology Atlas.
- Naevus halo. Adapted from Dermatology Atlas.
- Naevus halo. Adapted from Dermatology Atlas.
- Naevus halo. Adapted from Dermatology Atlas.
- Naevus halo. Adapted from Dermatology Atlas.
- Naevus halo. Adapted from Dermatology Atlas.
- Naevus halo. Adapted from Dermatology Atlas.
- Naevus halo. Adapted from Dermatology Atlas.
- Naevus halo. Adapted from Dermatology Atlas.
- Naevus halo. Adapted from Dermatology Atlas.
# Natural History, Prognosis, and Complications
Sometimes the pale (hypopigmented) areas will spontaneous regress, and pigment returns. Although halo nevi are harmless, it is important to monitor the lesion on regular basis. Any changes in appearance of existing or new halo nevi should be noted. If there is any change in appearance or is associated with pain, itch, and infection, a doctor should be consulted immediately to exclude the possibility of melanoma.
# Treatment
As halo nevi are only of cosmetic significance, no treatment is required, and patients will be asymptomatic. | Halo nevus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
Synonyms and keywords: Leukoderma acquisitum centrifugum, Perinevoid vitiligo, Sutton nevus
# Overview
Halo nevus is a mole that is surrounded by a depigmented ring or 'halo'.[1]:689)
# Pathophysiology
The formation of a halo surrounding a nevi is believed to occur when certain white blood cells called CD8+ T lymphocytes destroy the pigment-producing cells of the skin (melanocytes).[2] The trigger for the autoimmune attack is unknown.[3]
# Epidemiology and Demographics
Halo nevi are estimated to be present in approximately 1% of the general population, and All races and sexes are equally susceptible to this disease, although a familial tendency has been reported. The average age of onset is in a person's teenage years.
# Risk Factors
Halo Nevi are found to be more prevalent in people with vitiligo, malignant melanoma,[3] or Turner syndrome.
# Diagnosis
## Physical Examination
### Skin
Halo nevi are named such because they are a mole (nevi) that is surrounded by an area of depigmentation that resembles a halo.
- Naevus halo. Adapted from Dermatology Atlas.[4]
- Naevus halo. Adapted from Dermatology Atlas.[4]
- Naevus halo. Adapted from Dermatology Atlas.[4]
- Naevus halo. Adapted from Dermatology Atlas.[4]
- Naevus halo. Adapted from Dermatology Atlas.[4]
- Naevus halo. Adapted from Dermatology Atlas.[4]
- Naevus halo. Adapted from Dermatology Atlas.[4]
- Naevus halo. Adapted from Dermatology Atlas.[4]
- Naevus halo. Adapted from Dermatology Atlas.[4]
- Naevus halo. Adapted from Dermatology Atlas.[4]
- Naevus halo. Adapted from Dermatology Atlas.[4]
- Naevus halo. Adapted from Dermatology Atlas.[4]
- Naevus halo. Adapted from Dermatology Atlas.[4]
- Naevus halo. Adapted from Dermatology Atlas.[4]
- Naevus halo. Adapted from Dermatology Atlas.[4]
- Naevus halo. Adapted from Dermatology Atlas.[4]
- Naevus halo. Adapted from Dermatology Atlas.[4]
- Naevus halo. Adapted from Dermatology Atlas.[4]
# Natural History, Prognosis, and Complications
Sometimes the pale (hypopigmented) areas will spontaneous regress, and pigment returns. Although halo nevi are harmless, it is important to monitor the lesion on regular basis.[5] Any changes in appearance of existing or new halo nevi should be noted. If there is any change in appearance or is associated with pain, itch, and infection, a doctor should be consulted immediately to exclude the possibility of melanoma.
# Treatment
As halo nevi are only of cosmetic significance, no treatment is required,[6] and patients will be asymptomatic. | https://www.wikidoc.org/index.php/Halo_nevus | |
a050e28a82a4d5fb9bb8fbf28743fa5c33a07ea7 | wikidoc | Haloprogin | Haloprogin
Haloprogin is an antifungal drug used to treat athlete's foot and other fungal infections. It is marketed in creams under the trade names Halotex, Mycanden, Mycilan, and Polik.
# Action
Haloprogin was previously used in 1% topical creams as an antifungal agent. It was marketed over the counter primarily to treat tinea infcections of the skin. The mechanism of action is unknown.
Haloprogin had a high incidence of side effects including: irritation, burning, vesiculation (blisters), scaling, and itching. It has since been discontinued due to the emergence of more modern antifungals with fewer side effects. | Haloprogin
Haloprogin is an antifungal drug used to treat athlete's foot and other fungal infections. It is marketed in creams under the trade names Halotex, Mycanden, Mycilan, and Polik.
# Action
Haloprogin was previously used in 1% topical creams as an antifungal agent. It was marketed over the counter primarily to treat tinea infcections of the skin. The mechanism of action is unknown.[1]
Haloprogin had a high incidence of side effects including: irritation, burning, vesiculation (blisters), scaling, and itching. It has since been discontinued due to the emergence of more modern antifungals with fewer side effects.[2] | https://www.wikidoc.org/index.php/Haloprogin | |
ef4f73db7bef4555e5cc68a14ac7170677fbd81b | wikidoc | Hammer toe | Hammer toe
Synonyms and keywords: Claw toe; hammertoe syndrome; mallet toe
# Overview
A hammer toe is a deformity of the second, third, or fourth toe causing it to be permanently bent at the proximal interphalangeal joint, resembling a hammer. Mallet toe is another name for this condition when affecting the distal interphalangeal joint.
# Pathophysiology
- Hammer toe occurs due to abnormal (permanent) bend at the proximal interphalangeal joint of a toe due to imbalance in the muscles, ligaments, or tendons which normally hold the toe in a straight position
# Risk factors
Common risk factors include:
- Advancing age
- Female sex
- Length of the second toe greater than the big toe
- Osteoarthritis
- Rheumatoid arthritis
- Diabetes
# Complications
Few complications of hammer toe include:
- Permanent bent of the toe if not treated initially when toe is flexible
- Painful corns or calluses due to rubbing of toes against the inside of foot
# Causes
Common causes of muscle, nerve, or joint damage resulting in a hammer toe include:
- Wearing poorly-fit shoes that can force the toe against their tip, such as:
Excessively high heels
Shoes that are too short or narrow for the foot
Osteoarthritis
Rheumatoid arthritis
Stroke
Charcot-Marie-Tooth disease
Diabetes
- Excessively high heels
- Shoes that are too short or narrow for the foot
- Osteoarthritis
- Rheumatoid arthritis
- Stroke
- Charcot-Marie-Tooth disease
- Diabetes
# History and symptoms
- Hammer toe usually involves the second, third, or fourth toe
- Common symptoms include:
Abnormal bend in the joint of one or more toes resembling a hammer
Painful or difficult movement of the affected toe
Painful calluses & corns may form (due to rubbing of hammer toes against the inside of the shoes)
- Abnormal bend in the joint of one or more toes resembling a hammer
- Painful or difficult movement of the affected toe
- Painful calluses & corns may form (due to rubbing of hammer toes against the inside of the shoes)
# Treatment
## Conservative treatment
- In many cases, conservative treatment is enough to resolve the condition such as:
Physical therapy
New shoes with soft, spacious toe boxes
- Physical therapy
- New shoes with soft, spacious toe boxes
## Surgery
- In more severe or longstanding cases, orthopedic surgery may be necessary to correct the deformity
# Prevention
Primary preventive measures for hammer toe include:
- Buying the shoes with following characteristics:
Proper fitting
Low heels
Adequate toe room (avoiding shoes with pointed toes)
More roomier and adjustable (laced or strapped shoes)
- Proper fitting
- Low heels
- Adequate toe room (avoiding shoes with pointed toes)
- More roomier and adjustable (laced or strapped shoes) | Hammer toe
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Sara Mohsin, M.D.[2], Cafer Zorkun, M.D., Ph.D. [3]
Synonyms and keywords: Claw toe; hammertoe syndrome; mallet toe
# Overview
A hammer toe is a deformity of the second, third, or fourth toe causing it to be permanently bent at the proximal interphalangeal joint, resembling a hammer. Mallet toe is another name for this condition when affecting the distal interphalangeal joint.
# Pathophysiology
- Hammer toe occurs due to abnormal (permanent) bend at the proximal interphalangeal joint of a toe due to imbalance in the muscles, ligaments, or tendons which normally hold the toe in a straight position
# Risk factors
Common risk factors include:
- Advancing age
- Female sex
- Length of the second toe greater than the big toe
- Osteoarthritis
- Rheumatoid arthritis
- Diabetes
# Complications
Few complications of hammer toe include:
- Permanent bent of the toe if not treated initially when toe is flexible
- Painful corns or calluses due to rubbing of toes against the inside of foot
# Causes
Common causes of muscle, nerve, or joint damage resulting in a hammer toe include:[1][2]
- Wearing poorly-fit shoes that can force the toe against their tip, such as:
Excessively high heels
Shoes that are too short or narrow for the foot
Osteoarthritis
Rheumatoid arthritis
Stroke
Charcot-Marie-Tooth disease
Diabetes
- Excessively high heels
- Shoes that are too short or narrow for the foot
- Osteoarthritis
- Rheumatoid arthritis
- Stroke
- Charcot-Marie-Tooth disease
- Diabetes
# History and symptoms
- Hammer toe usually involves the second, third, or fourth toe
- Common symptoms include:
Abnormal bend in the joint of one or more toes resembling a hammer
Painful or difficult movement of the affected toe
Painful calluses & corns may form (due to rubbing of hammer toes against the inside of the shoes)
- Abnormal bend in the joint of one or more toes resembling a hammer
- Painful or difficult movement of the affected toe
- Painful calluses & corns may form (due to rubbing of hammer toes against the inside of the shoes)
# Treatment
## Conservative treatment
- In many cases, conservative treatment is enough to resolve the condition such as:
Physical therapy
New shoes with soft, spacious toe boxes
- Physical therapy
- New shoes with soft, spacious toe boxes
## Surgery
- In more severe or longstanding cases, orthopedic surgery may be necessary to correct the deformity[3][4][5][6][7][8][9]
# Prevention
Primary preventive measures for hammer toe include:
- Buying the shoes with following characteristics:
Proper fitting
Low heels
Adequate toe room (avoiding shoes with pointed toes)
More roomier and adjustable (laced or strapped shoes)
- Proper fitting
- Low heels
- Adequate toe room (avoiding shoes with pointed toes)
- More roomier and adjustable (laced or strapped shoes) | https://www.wikidoc.org/index.php/Hammer_toe | |
091f1b6b3a7a109354ecaeb5acbc754b9576b100 | wikidoc | Hantavirus | Hantavirus
# Overview
Hantaviruses belong to the bunyaviridae family of viruses. There are 5 genera within the bunyaviridae family: bunyavirus, phlebovirus, nairovirus, tospovirus, and hantavirus. Each is made up of negative-sensed, single-stranded RNA viruses. All these genera include arthropod-borne viruses, with the exception of hantavirus, which is a genus of rodent-borne agents.
The word hantavirus is derived from the Hantan River, where the Hantaan virus (the etiologic agent of Korean hemorrhagic fever) was first isolated by Dr. Lee Ho-Wang. The disease associated with Hantaan virus is called Korean hemorrhagic fever (a term that is no longer in use) or hemorrhagic fever with renal syndrome (HFRS), a term that is accepted by the World Health Organization.
# History
The Hantaviruses constitute a relatively newly discovered class of virus; the disease entity HFRS was first recognized by Western medicine during the Korean War in the early 1950s. In 1993, a newly-recognized species of hantavirus was found to be behind the Hantavirus cardiopulmonary syndrome (HCPS, also called HPS) caused by the Sin Nombre virus (Spanish for "nameless virus") in New Mexico and other Four Corners states. In addition to Hantaan virus and Sin Nombre virus, several other hantaviruses have been implicated as etiologic agents for either HFRS or HCPS.
# Classification
Hantaviruses can be classified based on the clinical manifestations of hantavirus cardiopulmonary syndrome (HCPS), hemorrhagic fever with renal syndrome (HFRS) and nephropathia epidemica (NE).
*Recreated from VIROLOGICA SINICA.
# Geographic distribution and epidemiology
Regions especially affected by HFRS include China, the Korean Peninsula, Russia (Hantaan, Puumala and Seoul viruses), and northern and western Europe (Puumala and Dobrava viruses). Regions with the highest incidences of HCPS include Patagonian Argentina, Chile, Brazil, the United States, Canada, and Panama, where a milder form of disease that spares the heart has been recognized. The two agents of HCPS in South America are Andes virus (also called Oran, Castelo de Sonhos, Lechiguanas, Juquitiba, Araraquara, and Bermejo viruses, among many other synonyms), which is the only hantavirus that has shown (only in a few clusters of cases) an interpersonal form of transmission, and Laguna Negra virus, an extremely close relative of the previously-known Rio Mamore virus. In the U.S., minor causes of HCPS include New York virus, Bayou virus, and possibly Black Creek Canal virus.
As of July of 2007, six states had reported 30 or more cases of Hantavirus since 1993 - New Mexico (69), Colorado (49), Arizona (46), California (43), Texas (33), and Washington (30). Other states reporting a significant number of cases include Montana (25), Idaho (19), and Utah (24). With only 7 cases, Oregon has a notably lower attack rate overall and relative to population, compared to other Western states.
# Virology
Like other members of the bunyavirus family, hantaviruses are enveloped viruses with a genome that consists of three single-stranded RNA segments designated S (small), M (medium), and L (large). All hantaviral genes are encoded in the negative (genome complementary) sense. The S RNA encodes the nucleocapsid (N) protein. The M RNA encodes a polyprotein that is cotranslationally cleaved to yield the envelope glycoproteins G1 and G2. The L RNA encodes the L protein, which functions as the viral transcriptase/replicase. Within virions, the genomic RNAs of hantaviruses are thought to complex with the N protein to form helical nucleocapsids, the RNA component of which circularizes due to sequence complementarity between the 5' and 3' terminal sequences of each genomic segment.
Hantaviruses replicate exclusively in the host cell cytoplasm. Entry into host cells is thought to occur by attachment of virions to cellular receptors and subsequent endocytosis. Nucleocapsids are introduced into the cytoplasm by pH-dependent fusion of the virion with the endosomal membrane. Transcription of viral genes must be initiated by association of the L protein with the three nucleocapsid species. In addition to transcriptase and replicase functions, the viral L protein is also thought to have an endonuclease activity that cleaves cellular messenger RNAs (mRNAs) for the production of capped primers used to initiate transcription of viral mRNAs. As a result of this "cap snatching," the mRNAs of hantaviruses are capped and contain nontemplated 5' terminal extensions. The G1 (aka Gn) and G2 (Gc) glycoproteins form hetero-oligomers and are then transported from the endoplasmic reticulum to the Golgi complex, where glycosylation is completed. The L protein produces nascent genomes by replication via a positive-sense RNA intermediate. Hantavirus virions are believed to assemble by association of nucleocapsids with glycoproteins embedded in the membranes of the Golgi, followed by budding into the Golgi cisternae. Nascent virions are then transported in secretory vesicles to the plasma membrane and released by exocytosis.
# Symptoms
### Hemorrhagic Fever with Renal Syndrome (HFRS)
Hantavirus has an incubation time of 2-4 weeks in humans, before symptoms of infection occur. These symptoms can be split into five phases:
- Febrile phase: Symptoms include fever, chills, malaise, headaches, nausea, abdominal and back pain, respiratory problems such as the ones common in the influenza virus, as well as gastro-intestinal problems. These symptoms normally occur for 3-7days.
- Hypotensive phase: This occurs when the blood platelet levels drop and symptoms can lead to tachycardia and hypoxemia. This phase can last for 2 days.
- Oliguric phase: This phase lasts for 3-7 days and is characterised by the onset of renal failure and proteinuria occurs.
- Diuretic phase: This is characterized by diuresis of 3-6L per day, which can last for a couple of days up to weeks.
- Convalescent phase: This is normally when recovery occurs and symptoms begin to improve.
### Hantavirus (Cardio-)Pulmonary Syndrome (HPS or HCPS)
Hantavirus pulmonary syndrome (HPS) is a deadly disease transmitted by infected rodents through urine, droppings, or saliva. Humans can contract the disease when they breathe in aerosolized virus. HPS was first recognized in 1993 and has since been identified throughout the United States. Although rare, HPS is potentially deadly. Rodent control in and around the home remains the primary strategy for preventing hantavirus infection.
These symptoms, which are very similar to HFRS, include tachycardia and tachypnoea. Such conditions can lead to a cardiopulmonary phase, where cardiovascular shock can occur, and hospitalization of the patient is required. | Hantavirus
# Overview
Hantaviruses belong to the bunyaviridae family of viruses. There are 5 genera within the bunyaviridae family: bunyavirus, phlebovirus, nairovirus, tospovirus, and hantavirus. Each is made up of negative-sensed, single-stranded RNA viruses. All these genera include arthropod-borne viruses, with the exception of hantavirus, which is a genus of rodent-borne agents.
The word hantavirus is derived from the Hantan River, where the Hantaan virus (the etiologic agent of Korean hemorrhagic fever) was first isolated by Dr. Lee Ho-Wang. The disease associated with Hantaan virus is called Korean hemorrhagic fever (a term that is no longer in use) or hemorrhagic fever with renal syndrome (HFRS), a term that is accepted by the World Health Organization.
# History
The Hantaviruses constitute a relatively newly discovered class of virus; the disease entity HFRS was first recognized by Western medicine during the Korean War in the early 1950s. In 1993, a newly-recognized species of hantavirus was found to be behind the Hantavirus cardiopulmonary syndrome (HCPS, also called HPS) caused by the Sin Nombre virus (Spanish for "nameless virus") in New Mexico and other Four Corners states. In addition to Hantaan virus and Sin Nombre virus, several other hantaviruses have been implicated as etiologic agents for either HFRS or HCPS.
# Classification
Hantaviruses can be classified based on the clinical manifestations of hantavirus cardiopulmonary syndrome (HCPS), hemorrhagic fever with renal syndrome (HFRS) and nephropathia epidemica (NE).
*Recreated from VIROLOGICA SINICA.[1]
# Geographic distribution and epidemiology
Regions especially affected by HFRS include China, the Korean Peninsula, Russia (Hantaan, Puumala and Seoul viruses), and northern and western Europe (Puumala and Dobrava viruses). Regions with the highest incidences of HCPS include Patagonian Argentina, Chile, Brazil, the United States, Canada, and Panama, where a milder form of disease that spares the heart has been recognized. The two agents of HCPS in South America are Andes virus (also called Oran, Castelo de Sonhos, Lechiguanas, Juquitiba, Araraquara, and Bermejo viruses, among many other synonyms), which is the only hantavirus that has shown (only in a few clusters of cases) an interpersonal form of transmission, and Laguna Negra virus, an extremely close relative of the previously-known Rio Mamore virus. In the U.S., minor causes of HCPS include New York virus, Bayou virus, and possibly Black Creek Canal virus.
As of July of 2007, six states had reported 30 or more cases of Hantavirus since 1993 - New Mexico (69), Colorado (49), Arizona (46), California (43), Texas (33), and Washington (30). Other states reporting a significant number of cases include Montana (25), Idaho (19), and Utah (24). With only 7 cases, Oregon has a notably lower attack rate overall and relative to population, compared to other Western states.
# Virology
Like other members of the bunyavirus family, hantaviruses are enveloped viruses with a genome that consists of three single-stranded RNA segments designated S (small), M (medium), and L (large). All hantaviral genes are encoded in the negative (genome complementary) sense. The S RNA encodes the nucleocapsid (N) protein. The M RNA encodes a polyprotein that is cotranslationally cleaved to yield the envelope glycoproteins G1 and G2. The L RNA encodes the L protein, which functions as the viral transcriptase/replicase. Within virions, the genomic RNAs of hantaviruses are thought to complex with the N protein to form helical nucleocapsids, the RNA component of which circularizes due to sequence complementarity between the 5' and 3' terminal sequences of each genomic segment.
Hantaviruses replicate exclusively in the host cell cytoplasm. Entry into host cells is thought to occur by attachment of virions to cellular receptors and subsequent endocytosis. Nucleocapsids are introduced into the cytoplasm by pH-dependent fusion of the virion with the endosomal membrane. Transcription of viral genes must be initiated by association of the L protein with the three nucleocapsid species. In addition to transcriptase and replicase functions, the viral L protein is also thought to have an endonuclease activity that cleaves cellular messenger RNAs (mRNAs) for the production of capped primers used to initiate transcription of viral mRNAs. As a result of this "cap snatching," the mRNAs of hantaviruses are capped and contain nontemplated 5' terminal extensions. The G1 (aka Gn) and G2 (Gc) glycoproteins form hetero-oligomers and are then transported from the endoplasmic reticulum to the Golgi complex, where glycosylation is completed. The L protein produces nascent genomes by replication via a positive-sense RNA intermediate. Hantavirus virions are believed to assemble by association of nucleocapsids with glycoproteins embedded in the membranes of the Golgi, followed by budding into the Golgi cisternae. Nascent virions are then transported in secretory vesicles to the plasma membrane and released by exocytosis.
# Symptoms
### Hemorrhagic Fever with Renal Syndrome (HFRS)
Hantavirus has an incubation time of 2-4 weeks in humans, before symptoms of infection occur. These symptoms can be split into five phases:
- Febrile phase: Symptoms include fever, chills, malaise, headaches, nausea, abdominal and back pain, respiratory problems such as the ones common in the influenza virus, as well as gastro-intestinal problems. These symptoms normally occur for 3-7days.
- Hypotensive phase: This occurs when the blood platelet levels drop and symptoms can lead to tachycardia and hypoxemia. This phase can last for 2 days.
- Oliguric phase: This phase lasts for 3-7 days and is characterised by the onset of renal failure and proteinuria occurs.
- Diuretic phase: This is characterized by diuresis of 3-6L per day, which can last for a couple of days up to weeks.
- Convalescent phase: This is normally when recovery occurs and symptoms begin to improve.
### Hantavirus (Cardio-)Pulmonary Syndrome (HPS or HCPS)
Hantavirus pulmonary syndrome (HPS) is a deadly disease transmitted by infected rodents through urine, droppings, or saliva. Humans can contract the disease when they breathe in aerosolized virus. HPS was first recognized in 1993 and has since been identified throughout the United States. Although rare, HPS is potentially deadly. Rodent control in and around the home remains the primary strategy for preventing hantavirus infection.
These symptoms, which are very similar to HFRS, include tachycardia and tachypnoea. Such conditions can lead to a cardiopulmonary phase, where cardiovascular shock can occur, and hospitalization of the patient is required.
# External links
- "Hantaviruses, with emphasis on Four Corners Hantavirus" by Brian Hjelle, M.D., Department of Pathology, School of Medicine, University of New Mexico
- CDC's Hantavirus Information page
- Kruger DH, Ulrich R, Lundkvist A (2001) "Hantavirus infections and their prevention", Microbes And Infection 3 (13): 1129-1144
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Hantavirosis | |
e7e173f526468d49bfa74e5edca58a6ec25c61dd | wikidoc | Haplogroup | Haplogroup
In the study of molecular evolution, a haplogroup is a large group of haplotypes, which are series of alleles at specific locations on a chromosome.
In human genetics, the haplogroups most commonly studied are Y-chromosome (Y-DNA) haplogroups and mitochondrial DNA (mtDNA) haplogroups, both of which can be used to define genetic populations. Y-DNA has the advantage of being passed solely along the patrilineal line, while mtDNA is passed solely on the matrilineal line.
Classifications of human haplogroups of either sort based on genetic markers, specifically by means of UEPs, have been rapidly evolving over the past several years as new markers are found.
# Haplogroup population genetics
It is usually assumed that there is little natural selection for or against a particular haplotype mutation which has survived to the present day, so apart from mutation rates (which may vary from one marker to another) the main driver of population genetics affecting the proportions of haplotypes in a population is genetic drift - random fluctuation caused by the sampling randomness of which members of the population happen to pass their DNA on to members of the next generation of the appropriate sex. This causes the prevalence of a particular marker in a population to continue to fluctuate, until it either hits 100%, or falls out of the population entirely. In a large population with efficient mixing the rate of genetic drift for common alleles is very slow; however, in a very small interbreeding population the proportions can change much more quickly. The marked geographical variations and concentrations of particular haplotypes and groups of haplotypes therefore witness the distinctive effects of repeated population bottlenecks or founder events followed by population separations and increases.
The lineages which can be traced back from the present will not reflect the full genetic variation of the older population: genetic drift means that some of the variants will have died out. The price of full mtDNA sequence tests has limited the availability of data. Haplotype coalescence times and current geographical prevalences both carry considerable error uncertainties.
## Human Y-chromosome DNA haplogroups
Human Y chromosome DNA (Y-DNA) haplogroups are lettered A through R, and are further subdivided using numbers and lower case letters. Y chromosome haplogroup designations are established by the Y Chromosome Consortium.
Y-chromosomal Adam is the name given by researchers to the male who is the most recent common patrilineal (male-lineage) ancestor of all living humans.
Major Y-chromosome haplogroups, and their geographical regions of occurrence (prior to
the recent European colonization), include: | Haplogroup
In the study of molecular evolution, a haplogroup is a large group of haplotypes, which are series of alleles at specific locations on a chromosome.
In human genetics, the haplogroups most commonly studied are Y-chromosome (Y-DNA) haplogroups and mitochondrial DNA (mtDNA) haplogroups, both of which can be used to define genetic populations. Y-DNA has the advantage of being passed solely along the patrilineal line, while mtDNA is passed solely on the matrilineal line.
Classifications of human haplogroups of either sort based on genetic markers, specifically by means of UEPs, have been rapidly evolving over the past several years as new markers are found.
# Haplogroup population genetics
It is usually assumed that there is little natural selection for or against a particular haplotype mutation which has survived to the present day, so apart from mutation rates (which may vary from one marker to another) the main driver of population genetics affecting the proportions of haplotypes in a population is genetic drift - random fluctuation caused by the sampling randomness of which members of the population happen to pass their DNA on to members of the next generation of the appropriate sex. This causes the prevalence of a particular marker in a population to continue to fluctuate, until it either hits 100%, or falls out of the population entirely. In a large population with efficient mixing the rate of genetic drift for common alleles is very slow; however, in a very small interbreeding population the proportions can change much more quickly. The marked geographical variations and concentrations of particular haplotypes and groups of haplotypes therefore witness the distinctive effects of repeated population bottlenecks or founder events followed by population separations and increases.
The lineages which can be traced back from the present will not reflect the full genetic variation of the older population: genetic drift means that some of the variants will have died out. The price of full mtDNA sequence tests has limited the availability of data. Haplotype coalescence times and current geographical prevalences both carry considerable error uncertainties.
## Human Y-chromosome DNA haplogroups
Human Y chromosome DNA (Y-DNA) haplogroups are lettered A through R, and are further subdivided using numbers and lower case letters. Y chromosome haplogroup designations are established by the Y Chromosome Consortium.
Template:Y-DNA
Y-chromosomal Adam is the name given by researchers to the male who is the most recent common patrilineal (male-lineage) ancestor of all living humans.
Major Y-chromosome haplogroups, and their geographical regions of occurrence (prior to
the recent European colonization), include: | https://www.wikidoc.org/index.php/Haplogroup | |
8e8ac0ceb02b3d3c3068ef5ebe5f946a501a55da | wikidoc | Hatha yoga | Hatha yoga
Hatha yoga (Sanskrit हठयोग Template:IPA), also known as Hatha Vidya (हठविद्या), is a particular system of Yoga introduced by Yogi Swatmarama, a sage of 15th century India, and compiler of the Hatha Yoga Pradipika. In this treatise Swatmarama introduces Hatha Yoga as 'a stairway to the heights of Raja Yoga', hence a preparatory stage of physical purification that renders the body fit for the practice of higher meditation. The Asanas and Pranayama in Raja Yoga were what the Hindu Yogis used to physically train their body for long periods of meditation. This practise is called shatkarma. The word Hatha is a compound of the words Ha and Tha meaning sun and moon ( हकारः कीर्तितः सूर्यष्ठकारश्चंद्र उच्यते | सूर्यचंद्रमसोर्योगाद्धठयोग निगद्यते || ), referring to Praana and Apaana, and also to the principal nadis (energy channels) of the subtle body that must be fully operational to attain a state of dhyana or samadhi. According to the Monier Moneir-Williams Sanskrit Dictionary, the word "hatha" means forceful. It is a strong practice done for purification. In other respects Hatha yoga follows the same principles as the Raaja Yoga of Patanjali including moral restraint yama and spiritual observances niyama. Hatha Yoga is what most people in the West associate with the word "Yoga" and is practiced for mental and physical health throughout the West.
# Origins
The most comprehensive text of Hatha Yoga is the Hatha Yoga Pradipika by Yogi Swatmarama. This work is nonetheless derived from older Sanskrit texts on Yoga besides Yogi Swatmarama's own yogic experiences. It includes information about shatkarma, asana, pranayama, chakras, kundalini, bandhas, kriyas, shakti, nadis, and mudras among other topics.
Traditionally, Lord Shiva (आदिनाथ) is credited with propounding Hatha Yoga. It is said that on a lonely island, assuming nobody else would hear him, he gave the knowledge of Hatha Yoga to Goddess Parvati, but a fish heard the entire discourse, remaining still throughout. Lord Shiva took mercy on the fish (Matsya) and made him a Siddha, who came to be known as Matsyendranaatha. Matsyendranaatha taught Hatha Yoga to Chaurangi, a limbless man who was given hands and feet by Matsyendranaatha just by looking at him. Hatha Yoga Pradipika mentions Adinaatha, Matsyendranaatha, Gorakhanaatah and many other yogis who became famous Hatha Yogis.
Many modern schools of Hatha Yoga derive from the school of Sri Tirumalai Krishnamacharya, who taught from 1924 until his death in 1989. Among his students prominent in popularizing Yoga in the West were Sri K. Pattabhi Jois, famous for popularizing the vigorous Ashtanga Vinyasa Yoga style, B.K.S. Iyengar who emphasizes alignment and the use of props, Indra Devi and Krishnamacharya's son T.K.V. Desikachar who developed the Viniyoga style. Desikachar founded the Krishnamacharya Yoga Mandiram in Chennai, with the aim of making available the heritage of yoga as taught by Krishnamacharya.
Another major stream of influence was Swami Sivananda of Rishikesh (1887-1963) and his many disciples, including Swami Vishnu-Devananda - founder of International Sivananda Yoga Vedanta Centres, Swami Satyananda - of the Bihar School of Yoga, and Swami Satchidananda - of Integral Yoga, among others.
# Concept
Traditional Hatha Yoga is a holistic yogic path, including moral disciplines, physical exercises (e.g., asanas (postures) and Pranayama (breath control)), and meditation. The Hatha yoga predominantly practiced in the West consists of mostly asanas (postures) and exercise.
Hatha Yoga is one of the two branches of Yoga that focus on the physical culture, the other one being Raja Yoga. Both of these are commonly referred to as Ashtanga Yoga, i.e., Yoga of eight parts ('ashta' meaning eight and 'anga' meaning limbs). The eight limbs are described below in detail. The main difference is that Raja Yoga uses asanas to mainly get the body ready for prolonged meditation, and hence focuses more on the meditative asana poses: Lotus Pose (Padmasana), Accomplished Pose (Siddhasana), Easy Pose (Sahajasana) and Pelvic Pose (Vajrasana); Hatha Yoga utilizes most of the asana poses. Similarly, Raja Yoga's use of Pranayama is also devoid of extensive locks (Bandha).
Hatha represents opposing energies: hot and cold (fire and water, following the same concept as the yin-yang), male and female, positive and negative. Hatha yoga attempts to balance mind and body via physical exercises, or "asanas", controlled breathing, and the calming of the mind through relaxation and meditation. Asanas teach poise, balance & strength and are practiced to improve the body's physical health and clear the mind in preparation for meditation in the pursuit of enlightenment.
The Yoga of Patanjali is Ashtanga or composed of 8 limbs, Yama and Niyama, which are ethical obligations, Asana, Pranayama, which is breath control, Pratyahara, which is sense withdrawal, Dharana, which is concentration, Dhyana, which is meditation, and Samadhi, which is the experience of unity with God.. The eight limbs are more precisely viewed as eight levels of progress, each level providing benefits in and of itself and also laying the foundation for the higher levels.
NOTE: In some schools of thought, only Raja Yoga is considered to be Ashtanga Yoga, and Hatha Yoga is thought to consist of six limbs focused on attaining Kundalini. In this scheme, the six limbs of Hatha Yoga are defined as Yama, Niyama, Asana, Pranayama, Mudra (specific postures to help lock in the breath), Nadanusandhana (hearing of the eternal sound within the body), the whole process culminating in the attainment of Kundalini. Due to this, this version of Hatha yoga is also sometimes referred to as Kundalini Yoga.
# Yama and niyama
Yama is a "moral restraint" or rule for living virtuously. Ten yamas are codified in numerous scriptures, including the Hatha Yoga Pradipika compiled by Yogi Swatmarama, while Patanjali lists five yamas, and five niyamas (disciplines) in the Yoga Sutra.
The ten traditional yamas are:
- Ahimsa: Nonviolence. Abstinence from injury, or harm to any living creature in thought, word, or deed. This is the "main" Yama. The other nine are there in support of its accomplishment.
- Satya: Truthfulness in word and thought (in conformity with the facts).
- Asteya: No stealing, no coveting, no entering into debt.
- Brahmacharya: Divine conduct, continence, celibate when single, faithful when married.
- Kshama: Patience, releasing time, functioning in the now.
- Dhriti: Steadfastness, overcoming non-perseverance, fear, and indecision; seeing each task through to completion.
- Daya: Compassion; conquering callous, cruel and insensitive feelings toward all beings.
- Arjava: Honesty, straightforwardness, renouncing deception and wrongdoing.
- Mitahara: Moderate appetite, neither eating too much nor too little; nor consuming meat, fish, shellfish, fowl or eggs.
- Shaucha: Purity, avoidance of impurity in body, mind and speech.
Patanjali's five yamas, or moral restraints, are ahimsa (non-injury), satya (truthfulness), asteya (non-stealing), brahmacharya (continence or chastity) and aparagriha (abstinence from avarice). He also lists five niyamas, or disciplines, which include shauca (purity), samtosha (contentment), tapas (asceticism), svadhyaya (study), and ishvara-pranidhana (devotion to the Lord).
# Asanas (Postures)
Asanas are contemplative in nature and were originally intuited by yogis during meditation; the Kundalini naturally brings forth these postures or movements, called Kriyas, during deep meditation. These movements are meant to help to remove blockages (disease) in the causal, subtle, and physical bodies.
In the ancient author Patanjali's work, Asana is classified as the third rung of 8 in the ladder of the practice of Raja Yoga.
Hatha yoga in the west primarily concerns itself with asanas or postures.
# Pranayama (Breathing)
The words 'Prana' (life-force) and 'Ayama' (to lengthen or regulate) make up Pranayama. Pranayama seeks to lengthen, control & regulate the breath. In one variation, the Rechak (exhaled air),
Poorak (inhalation) and Kumbhak (Retention during normal inhaling and exhaling) are the 3 parts of the breath that are regulated. Pranayama is practiced to develop mental, physical and spiritual strength. Though the beginner's Pranayama is relatively harmless, safely progressing to more advanced practices requires the guidance of a knowledgeable teacher.
# Health Benefits ascribed to Yogasana practice
Different asanas are recommended by practitioners to cure or prevent problems ranging from constipation to cancer. It is known to reduce stress and other mental worries.
See Yoga (alternative medicine)
# Etymology
Hatha yoga, pronounced Template:IPA, is also known as hatha vidya or the "science of hatha" yoga. The word Hatha comes from combining the two Sanskrit terms "ha" meaning sun and "tha" meaning moon. The word "ha" refers to the solar nadi (pingala) in the subtle body and "tha" the lunar channel (ida). However, when the two components of the word are placed together, "hatha" means "forceful", implying that powerful work must be done to purify the body. Yoga to means to yoke, or to join 2 things together, hence hatha yoga is meant to join together our sun (masculine, active) energy with our moon (feminine, receptive) energy, thus producing balance and greater power in an individual.
# In the West
The 2005 "Yoga in America" survey, conducted by Yoga Journal, shows that the number of practitioners in the US increased to 16.5 million with the 18-24 age group showing a 46% increase in one year. | Hatha yoga
Hatha yoga (Sanskrit हठयोग Template:IPA), also known as Hatha Vidya (हठविद्या), is a particular system of Yoga introduced by Yogi Swatmarama, a sage of 15th century India, and compiler of the Hatha Yoga Pradipika. In this treatise Swatmarama introduces Hatha Yoga as 'a stairway to the heights of Raja Yoga', hence a preparatory stage of physical purification that renders the body fit for the practice of higher meditation. The Asanas and Pranayama in Raja Yoga were what the Hindu Yogis used to physically train their body for long periods of meditation. This practise is called shatkarma. The word Hatha is a compound of the words Ha and Tha meaning sun and moon ( हकारः कीर्तितः सूर्यष्ठकारश्चंद्र उच्यते | सूर्यचंद्रमसोर्योगाद्धठयोग निगद्यते || ), referring to Praana and Apaana, and also to the principal nadis (energy channels) of the subtle body that must be fully operational to attain a state of dhyana or samadhi. According to the Monier Moneir-Williams Sanskrit Dictionary, the word "hatha" means forceful. It is a strong practice done for purification. In other respects Hatha yoga follows the same principles as the Raaja Yoga of Patanjali including moral restraint yama and spiritual observances niyama. Hatha Yoga is what most people in the West associate with the word "Yoga" and is practiced for mental and physical health throughout the West.
# Origins
Template:Hinduism small
The most comprehensive text of Hatha Yoga is the Hatha Yoga Pradipika by Yogi Swatmarama. This work is nonetheless derived from older Sanskrit texts on Yoga besides Yogi Swatmarama's own yogic experiences. It includes information about shatkarma, asana, pranayama, chakras, kundalini, bandhas, kriyas, shakti, nadis, and mudras among other topics.
Traditionally, Lord Shiva (आदिनाथ) is credited with propounding Hatha Yoga. It is said that on a lonely island, assuming nobody else would hear him, he gave the knowledge of Hatha Yoga to Goddess Parvati, but a fish heard the entire discourse, remaining still throughout. Lord Shiva took mercy on the fish (Matsya) and made him a Siddha, who came to be known as Matsyendranaatha. Matsyendranaatha taught Hatha Yoga to Chaurangi, a limbless man who was given hands and feet by Matsyendranaatha just by looking at him. Hatha Yoga Pradipika mentions Adinaatha, Matsyendranaatha, Gorakhanaatah and many other yogis who became famous Hatha Yogis.
Many modern schools of Hatha Yoga derive from the school of Sri Tirumalai Krishnamacharya, who taught from 1924 until his death in 1989. Among his students prominent in popularizing Yoga in the West were Sri K. Pattabhi Jois, famous for popularizing the vigorous Ashtanga Vinyasa Yoga style, B.K.S. Iyengar who emphasizes alignment and the use of props, Indra Devi and Krishnamacharya's son T.K.V. Desikachar who developed the Viniyoga style. Desikachar founded the Krishnamacharya Yoga Mandiram in Chennai, with the aim of making available the heritage of yoga as taught by Krishnamacharya.
Another major stream of influence was Swami Sivananda of Rishikesh (1887-1963) and his many disciples, including Swami Vishnu-Devananda - founder of International Sivananda Yoga Vedanta Centres, Swami Satyananda - of the Bihar School of Yoga, and Swami Satchidananda - of Integral Yoga, among others.
# Concept
Traditional Hatha Yoga is a holistic yogic path, including moral disciplines, physical exercises (e.g., asanas (postures) and Pranayama (breath control)), and meditation. The Hatha yoga predominantly practiced in the West consists of mostly asanas (postures) and exercise.
Hatha Yoga is one of the two branches of Yoga that focus on the physical culture, the other one being Raja Yoga. Both of these are commonly referred to as Ashtanga Yoga, i.e., Yoga of eight parts ('ashta' meaning eight and 'anga' meaning limbs). The eight limbs are described below in detail. The main difference is that Raja Yoga uses asanas to mainly get the body ready for prolonged meditation, and hence focuses more on the meditative asana poses: Lotus Pose (Padmasana), Accomplished Pose (Siddhasana), Easy Pose (Sahajasana) and Pelvic Pose (Vajrasana); Hatha Yoga utilizes most of the asana poses. Similarly, Raja Yoga's use of Pranayama is also devoid of extensive locks (Bandha).
Hatha represents opposing energies: hot and cold (fire and water, following the same concept as the yin-yang), male and female, positive and negative. Hatha yoga attempts to balance mind and body via physical exercises, or "asanas", controlled breathing, and the calming of the mind through relaxation and meditation. Asanas teach poise, balance & strength and are practiced to improve the body's physical health and clear the mind in preparation for meditation in the pursuit of enlightenment.
The Yoga of Patanjali is Ashtanga or composed of 8 limbs, Yama and Niyama, which are ethical obligations, Asana, Pranayama, which is breath control, Pratyahara, which is sense withdrawal, Dharana, which is concentration, Dhyana, which is meditation, and Samadhi, which is the experience of unity with God.[1]. The eight limbs are more precisely viewed as eight levels of progress, each level providing benefits in and of itself and also laying the foundation for the higher levels.
NOTE: In some schools of thought, only Raja Yoga is considered to be Ashtanga Yoga, and Hatha Yoga is thought to consist of six limbs focused on attaining Kundalini. In this scheme, the six limbs of Hatha Yoga are defined as Yama, Niyama, Asana, Pranayama, Mudra (specific postures to help lock in the breath), Nadanusandhana (hearing of the eternal sound within the body), the whole process culminating in the attainment of Kundalini. Due to this, this version of Hatha yoga is also sometimes referred to as Kundalini Yoga.
# Yama and niyama
Yama is a "moral restraint" or rule for living virtuously. Ten yamas are codified in numerous scriptures, including the Hatha Yoga Pradipika compiled by Yogi Swatmarama, while Patanjali lists five yamas, and five niyamas (disciplines) in the Yoga Sutra.
The ten traditional yamas are: [2]
- Ahimsa: Nonviolence. Abstinence from injury, or harm to any living creature in thought, word, or deed. This is the "main" Yama. The other nine are there in support of its accomplishment.
- Satya: Truthfulness in word and thought (in conformity with the facts).
- Asteya: No stealing, no coveting, no entering into debt.
- Brahmacharya: Divine conduct, continence, celibate when single, faithful when married.
- Kshama: Patience, releasing time, functioning in the now.
- Dhriti: Steadfastness, overcoming non-perseverance, fear, and indecision; seeing each task through to completion.
- Daya: Compassion; conquering callous, cruel and insensitive feelings toward all beings.
- Arjava: Honesty, straightforwardness, renouncing deception and wrongdoing.
- Mitahara: Moderate appetite, neither eating too much nor too little; nor consuming meat, fish, shellfish, fowl or eggs.
- Shaucha: Purity, avoidance of impurity in body, mind and speech.
Patanjali's five yamas, or moral restraints, are ahimsa (non-injury), satya (truthfulness), asteya (non-stealing), brahmacharya (continence or chastity) and aparagriha (abstinence from avarice). He also lists five niyamas, or disciplines, which include shauca (purity), samtosha (contentment), tapas (asceticism), svadhyaya (study), and ishvara-pranidhana (devotion to the Lord). [3]
# Asanas (Postures)
Asanas are contemplative in nature and were originally intuited by yogis during meditation; the Kundalini naturally brings forth these postures or movements, called Kriyas, during deep meditation. These movements are meant to help to remove blockages (disease) in the causal, subtle, and physical bodies.
In the ancient author Patanjali's work, Asana is classified as the third rung of 8 in the ladder of the practice of Raja Yoga.
Hatha yoga in the west primarily concerns itself with asanas or postures.
# Pranayama (Breathing)
The words 'Prana' (life-force) and 'Ayama' (to lengthen or regulate) make up Pranayama. Pranayama seeks to lengthen, control & regulate the breath. In one variation, the Rechak (exhaled air),
Poorak (inhalation) and Kumbhak (Retention during normal inhaling and exhaling) are the 3 parts of the breath that are regulated. Pranayama is practiced to develop mental, physical and spiritual strength. Though the beginner's Pranayama is relatively harmless, safely progressing to more advanced practices requires the guidance of a knowledgeable teacher.
# Health Benefits ascribed to Yogasana practice
Different asanas are recommended by practitioners to cure or prevent problems ranging from constipation to cancer. It is known to reduce stress and other mental worries.
See Yoga (alternative medicine)
# Etymology
Hatha yoga, pronounced Template:IPA, is also known as hatha vidya or the "science of hatha" yoga. The word Hatha comes from combining the two Sanskrit terms "ha" meaning sun and "tha" meaning moon. The word "ha" refers to the solar nadi (pingala) in the subtle body and "tha" the lunar channel (ida). However, when the two components of the word are placed together, "hatha" means "forceful", implying that powerful work must be done to purify the body. Yoga to means to yoke, or to join 2 things together, hence hatha yoga is meant to join together our sun (masculine, active) energy with our moon (feminine, receptive) energy, thus producing balance and greater power in an individual.
# In the West
The 2005 "Yoga in America" survey, conducted by Yoga Journal, shows that the number of practitioners in the US increased to 16.5 million with the 18-24 age group showing a 46% increase in one year.
# External links
- Yoga of physical poses ( Hatha Yoga) | https://www.wikidoc.org/index.php/Hatha_yoga | |
6666c8d3a2c39fce5d460af4a9e8da12c6067862 | wikidoc | Health 2.0 | Health 2.0
Health 2.0 is a term representing the possiblities between health care, eHealth and Web 2.0, and has come into use after a recent spate of articles in newspapers, and by Physicians and Medical Librarians. A possible explanation for the reason that Health has generated its own "2.0" term are its applications across health care in general, and in particular it limitless potential in public health promotion.
# Level of use of Web 2.0 in Health Care
Little empirical evidence exists to understand how much Web 2.0 is being used in general. Studies suggest the use is extensive, for instance it is estimated that nearly one-third of the 100m Americans who have looked for health information online say that they or people they know have been significantly helped by what they found. This however looks at the broader use of the internet for health management, but other research has suggested that a segment of 245,000 physicians in the U.S are using Web 2.0 for their practice, indicating that use is beyond the stage of the early adopter with regard to physicians and Web 2.0.
# Types of Web 2.0 use in Health Care
Web 2.0 is commonly associated with technologies such as weblogs (blogs), social bookmarking, wikis, podcasts, RSS feeds (and other forms of many-to-many publishing), social software, and web application programming interfaces (APIs) (see main article Web 2.0). As such the commonly identified uses of Web 2.0 in health can be
# Criticism of the use of Web 2.0 in health
Several critcism have been raised in the use of Web 2.0 in health. Firstly, the limitations for Medical Doctors (MDs) to use Google as a diagnostic tool, which may be more effective only for conditions with unique symptoms and signs that can easily be used as search term. Secondly, longheld concerns exist about the effects of patients obtaining information online, such as the idea that petients may delay seeking medical advice. Finally concerns exist about the quality of user generated content leading to mis-information, though empirical research has demonstrated that in certain support groups on 6% of information is factually wrong and that only 3% reported that online advice had caused serious harm. | Health 2.0
Health 2.0 is a term representing the possiblities between health care, eHealth and Web 2.0, and has come into use after a recent spate of articles in newspapers, and by Physicians and Medical Librarians.[1][2] A possible explanation for the reason that Health has generated its own "2.0" term are its applications across health care in general, and in particular it limitless potential in public health promotion.[3]
# Level of use of Web 2.0 in Health Care
Little empirical evidence exists to understand how much Web 2.0 is being used in general. Studies suggest the use is extensive, for instance it is estimated that nearly one-third of the 100m Americans who have looked for health information online say that they or people they know have been significantly helped by what they found.[4] This however looks at the broader use of the internet for health management, but other research has suggested that a segment of 245,000 physicians in the U.S are using Web 2.0 for their practice, indicating that use is beyond the stage of the early adopter with regard to physicians and Web 2.0.[5]
# Types of Web 2.0 use in Health Care
Web 2.0 is commonly associated with technologies such as weblogs (blogs), social bookmarking, wikis, podcasts, RSS feeds (and other forms of many-to-many publishing), social software, and web application programming interfaces (APIs) (see main article Web 2.0). As such the commonly identified uses of Web 2.0 in health can be
# Criticism of the use of Web 2.0 in health
Several critcism have been raised in the use of Web 2.0 in health. Firstly, the limitations for Medical Doctors (MDs) to use Google as a diagnostic tool, which may be more effective only for conditions with unique symptoms and signs that can easily be used as search term.[7] Secondly, longheld concerns exist about the effects of patients obtaining information online, such as the idea that petients may delay seeking medical advice.[8] Finally concerns exist about the quality of user generated content leading to mis-information, though empirical research has demonstrated that in certain support groups on 6% of information is factually wrong and that only 3% reported that online advice had caused serious harm.[9] | https://www.wikidoc.org/index.php/Health_2.0 | |
b40dd2d0c58a74aa233e5423ea36874cdacf445a | wikidoc | Heartsease | Heartsease
Heartsease (Viola tricolor) is a common European wild flower, growing as an annual or short-lived perennial. It has been introduced into North America, where it has spread widely, and is known as the Johnny Jump Up (though this name is also applied to similar species such as the Yellow Pansy). It is the progenitor of the cultivated Pansy, and is therefore sometimes called Wild Pansy; before the cultivated Pansies were developed, "Pansy" was an alternative name for the wild form.
Heartsease is a small plant of creeping habit, reaching at most 15cm in height, with flowers about 1.5 cm in diameter. It grows in short grassland on farms and wasteland, chiefly on acid or neutral soils. It is usually found in partial shade. It flowers from April to September. The flowers can be purple, blue, yellow or white. They are hermaphrodite and self-fertile, pollinated by bees.
As its name implies, Heartsease has a long history of use in herbalism. It has been recommended, among other uses, as a treatment for epilepsy, asthma, skin diseases and eczema. It has expectorant properties, and so has been used in the treatment of chest complaints such as bronchitis and whooping cough. It is also a diuretic, leading to its use in treating rheumatism and cystitis.
The flowers have also been used to make yellow, green and blue-green dyes, while the leaves can be used to make a chemical indicator.
Long before cultivated pansies were developed, Heartsease was associated with thought in the "language of flowers", often by its alternative name of pansy (from the French "pensée" - thought): hence Ophelia's often quoted line in Shakespeare's Hamlet, "There's pansies, that's for thoughts". What Shakespeare had in mind was Heartsease, not a modern garden pansy.
Shakespeare makes a more direct reference to Heartsease in A Midsummer Night's Dream. Oberon sends Puck to gather "a little western flower" that maidens call "Love-in-idleness". Oberon's account is that he diverted an arrow from Cupid's bow aimed at "a fair vestal, throned by the west" (supposedly Queen Elizabeth I) to fall upon the plant "before milk-white, now purple with love's wound". The "imperial vot'ress" passes on "fancy-free", destined never to fall in love. The juice of the heartsease now, claims Oberon, "on sleeping eyelids laid, Will make or man or woman madly dote Upon the next live creature that it sees." Equipped with such powers, Oberon and Puck control the fates of various characters in the play to provide Shakespeare's essential dramatic and comic structure for the play.
Heartsease has a large number of alternative colloquial names, up to two hundred.
Heartsease is also the title of a book in The Changes trilogy, written by Peter Dickinson. | Heartsease
Heartsease (Viola tricolor) is a common European wild flower, growing as an annual or short-lived perennial. It has been introduced into North America, where it has spread widely, and is known as the Johnny Jump Up (though this name is also applied to similar species such as the Yellow Pansy). It is the progenitor of the cultivated Pansy, and is therefore sometimes called Wild Pansy; before the cultivated Pansies were developed, "Pansy" was an alternative name for the wild form.
Heartsease is a small plant of creeping habit, reaching at most 15cm in height, with flowers about 1.5 cm in diameter. It grows in short grassland on farms and wasteland, chiefly on acid or neutral soils. It is usually found in partial shade. It flowers from April to September. The flowers can be purple, blue, yellow or white. They are hermaphrodite and self-fertile, pollinated by bees.
As its name implies, Heartsease has a long history of use in herbalism. It has been recommended, among other uses, as a treatment for epilepsy, asthma, skin diseases and eczema. It has expectorant properties, and so has been used in the treatment of chest complaints such as bronchitis and whooping cough. It is also a diuretic, leading to its use in treating rheumatism and cystitis.
The flowers have also been used to make yellow, green and blue-green dyes, while the leaves can be used to make a chemical indicator.
Long before cultivated pansies were developed, Heartsease was associated with thought in the "language of flowers", often by its alternative name of pansy (from the French "pensée" - thought): hence Ophelia's often quoted line in Shakespeare's Hamlet, "There's pansies, that's for thoughts". What Shakespeare had in mind was Heartsease, not a modern garden pansy.
Shakespeare makes a more direct reference to Heartsease in A Midsummer Night's Dream. Oberon sends Puck to gather "a little western flower" that maidens call "Love-in-idleness". Oberon's account is that he diverted an arrow from Cupid's bow aimed at "a fair vestal, throned by the west" (supposedly Queen Elizabeth I) to fall upon the plant "before milk-white, now purple with love's wound". The "imperial vot'ress" passes on "fancy-free", destined never to fall in love. The juice of the heartsease now, claims Oberon, "on sleeping eyelids laid, Will make or man or woman madly dote Upon the next live creature that it sees." Equipped with such powers, Oberon and Puck control the fates of various characters in the play to provide Shakespeare's essential dramatic and comic structure for the play.
Heartsease has a large number of alternative colloquial names, up to two hundred.
Heartsease is also the title of a book in The Changes trilogy, written by Peter Dickinson.
# External links
- Links to images, collected by the Texas A&M University Bioinformatics Working Group
- Species information in the Plants for a Future database
- Integrated Taxonomic Information System: Viola arvensis
- USDA, Natural Resources Conservation Service: Plants profile - Viola tricolor L. (johnny jumpup)
bg:Трицветна теменуга
cs:Violka trojbarevná
de:Wildes Stiefmütterchen
et:Aaskannike
nl:Driekleurig viooltje
nn:Stemorsblom
se:Gieddeviola
fi:Keto-orvokki
sv:Styvmorsviol
uk:Фіалка триколірна
sr:дан-ноћ (биљка)
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Heartsease | |
ee89b565bfc282f79b3a2120e606ede464781fd4 | wikidoc | Hebephilia | Hebephilia
Hebephilia refers to an adult's sexual preference for pubescent youths; the term was introduced by Glueck (1955). It differs from ephebophilia, which refers to the erotic interest in individuals in mid- to late adolescence, and from pedophilia, which refers to the erotic interest in prepubescent children. While individuals with a sexual preference for adults (i.e., teleiophiles) may have some sexual interest in pubescent-aged individuals, the term hebephilia is reserved for those who prefer pubescent-aged individuals over adults.
# Etiology
As with sexual preference in general, it is not known what causes someone to be sexually interested in pubescent children rather than in adults.
A team of Canada|Canadian sexologists has published a series of research articles comparing biologically relevant characteristics of clinical samples of pedophiles, hebephiles, and teleiophiles (individuals with a sexual preference for adults). In such samples, hebephilic men are midway between pedophilic men and teleiophilic men on average IQ (with pedophiles scoring the lowest), memory test scores (with pedophiles scoring the lowest), rates of non-right-handedness, rates of school grade failures over and above the IQ differences (with pedophiles having the most frequent grade failures), rates of having suffered head injuries in childhood (with pedophiles having the highest rates of injuries), and physical height.
# Prevalence of hebephilia versus pedophilia
There are clinical and correctional samples of sexual offenders in which hebephilic men outnumber the pedophilic men. Moreover, anonymous surveys of people sexually interested in children more frequently report an erotic interest in pubescent children than in prepubescent children. | Hebephilia
Hebephilia refers to an adult's sexual preference for pubescent youths; the term was introduced by Glueck (1955).[1] It differs from ephebophilia, which refers to the erotic interest in individuals in mid- to late adolescence,[2] and from pedophilia, which refers to the erotic interest in prepubescent children.[3] While individuals with a sexual preference for adults (i.e., teleiophiles) may have some sexual interest in pubescent-aged individuals,[4] the term hebephilia is reserved for those who prefer pubescent-aged individuals over adults.
# Etiology
As with sexual preference in general, it is not known what causes someone to be sexually interested in pubescent children rather than in adults.
A team of Canada|Canadian sexologists has published a series of research articles comparing biologically relevant characteristics of clinical samples of pedophiles, hebephiles, and teleiophiles (individuals with a sexual preference for adults). In such samples, hebephilic men are midway between pedophilic men and teleiophilic men on average IQ (with pedophiles scoring the lowest),[5] memory test scores (with pedophiles scoring the lowest),[5] rates of non-right-handedness,[6] rates of school grade failures over and above the IQ differences (with pedophiles having the most frequent grade failures),[7] rates of having suffered head injuries in childhood (with pedophiles having the highest rates of injuries),[8][9] and physical height.[10]
# Prevalence of hebephilia versus pedophilia
There are clinical and correctional samples of sexual offenders in which hebephilic men outnumber the pedophilic men.[5][11][12] Moreover, anonymous surveys of people sexually interested in children more frequently report an erotic interest in pubescent children than in prepubescent children.[13][14] | https://www.wikidoc.org/index.php/Hebephilia | |
6476903f0d04da3018991232072de84509d4e9da | wikidoc | Heinz body | Heinz body
Heinz bodies (also referred to as "Heinz-Ehrlich bodies") are inclusions within red blood cells composed of denatured hemoglobin.
They are named after Robert Heinz (1865-1924), a German physician who in 1890 described these inclusions in connection with cases of hemolytic anemia.
# Form and appearance
Heinz bodies appear as small round inclusions within the red cell body, though when stained with Romanowsky dyes they may appear as projections from the cell. They appear clearly when supravitally stained (e.g., with methylene blue or bromocresyl green).
# Etiology and associated disorders
Heinz bodies are formed by damage to the hemoglobin component molecules, usually through oxidations, which causes the damaged molecules to precipitate and damage the cell membrane. Damaged cells are attacked by macrophages in the spleen, where the precipitate and damaged membrane is removed, leading to characteristic "bite cells". The denaturing process is irreversible and the continual elimination of damaged cells leads to Heinz body anemia.
There are several pathways leading to the hemoglobin damage. In α-thalassemia the Hemoglobin H molecules, being composed of four beta chains, are unstable and become damaged with time. G6PD (Glucose-6-Phosphate Dehydrogenase) deficiency brought on by administration of oxidant drugs (e.g., primaquine) also can result in Heinz bodies.
In veterinary medicine Heinz bodies are especially associated with the consumptions of onions by cats, dogs, and various primates, and a symptom of paracetamol poisoning in cats. Thiosulfate compounds in the flesh of onions have been identified as the cause.
# Treatment
There is no specific treatment for Heinz bodies; however they are important as a diagnostic indicator for the causative conditions listed above. | Heinz body
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Heinz bodies (also referred to as "Heinz-Ehrlich bodies") are inclusions within red blood cells composed of denatured hemoglobin.[2][3]
They are named after Robert Heinz (1865-1924), a German physician who in 1890 described these inclusions in connection with cases of hemolytic anemia.[4][5]
# Form and appearance
Heinz bodies appear as small round inclusions within the red cell body, though when stained with Romanowsky dyes they may appear as projections from the cell. They appear clearly when supravitally stained (e.g., with methylene blue or bromocresyl green).
# Etiology and associated disorders
Heinz bodies are formed by damage to the hemoglobin component molecules, usually through oxidations, which causes the damaged molecules to precipitate and damage the cell membrane. Damaged cells are attacked by macrophages in the spleen, where the precipitate and damaged membrane is removed, leading to characteristic "bite cells". The denaturing process is irreversible and the continual elimination of damaged cells leads to Heinz body anemia.
There are several pathways leading to the hemoglobin damage. In α-thalassemia the Hemoglobin H molecules, being composed of four beta chains, are unstable and become damaged with time. G6PD (Glucose-6-Phosphate Dehydrogenase) deficiency brought on by administration of oxidant drugs (e.g., primaquine) also can result in Heinz bodies.
In veterinary medicine Heinz bodies are especially associated with the consumptions of onions by cats, dogs, and various primates, and a symptom of paracetamol poisoning in cats. Thiosulfate compounds in the flesh of onions have been identified as the cause.
# Treatment
There is no specific treatment for Heinz bodies; however they are important as a diagnostic indicator for the causative conditions listed above. | https://www.wikidoc.org/index.php/Heinz_bodies | |
4fd41843a8d5dc35e66318668ae1c2bc5ef0f70d | wikidoc | Helium.com | Helium.com
Helium.com, Inc. (formerly known as Helium Knowledge) is a website where writers can contribute articles for payment and visitors can read these articles for free. User generated content in a given category is rated up or down by other writers in a form of peer review system. As with social news sites like Digg or Reddit, user ratings determine the rank of an article. In this case, however, the users are the writers, and multiple answers/articles exist and compete in most topics. In turn, high-rated articles receive more page views and earn more money for writers. Critics have questioned the efficacy of this rating system and raised concerns about plagiarism, censorship, bans and other issues related to Helium.com. According to Alexa's website global traffic rankings, Helium.com's rank has hovered around 10,000 since January 2007. The site had over 5,000 users in October 2006.
# Articles
Contributors to Helium can write an article on any topic. Articles are arranged by categories and sub-categories, e.g. Writing (main category) has sub-topics such as Creative Writing, Writing Tips, and The Business of Writing. Contributors may create their own topic, or post an article to an existing topic (which may have been created by another contributor, or by a Helium staff member), but each writer can only submit one article to any one topic.
If a contributor creates a new topic, it is not published immediately, but instead is held for vetting. If approved, the topic is created and the article appears, usually within a day or two. It is then open for other writers to contribute to. Articles written to existing topics are published immediately and are not vetted or edited by Helium.
Articles within a topic compete with each other for "ratings". Rating is done by contributors on a "rating screen" where the articles are shown anonymously, two at a time, and contributors are asked to vote for the better article. This process is repeated until all the articles in a given topic have been ranked in order. Each time a new article is posted to a topic, the rating process is repeated. Rating is anonymous to prevent bias by contributors.
There is a flagging system which enables contributors to report plagiarism and otherwise poor articles.
# Payment
All articles stay on the site in perpetuity and will continue to earn income so long as the writer is actively contributing to the site. Writers earn a share of the ad revenue from ads appearing with their article, plus an amount based on the rating of their article and the number of times it is read. Helium does not disclose how this formula is calculated.
Earnings vary considerably depending on the categories and topics chosen. New writers can expect to earn only a few cents per article per month. Successful writers typically have hundreds of articles on the site, and/or promote their work heavily elsewhere, and/or make major efforts in contests and the Marketplace (see below).
Writers are encouraged to promote their work by writing blogs which link to Helium, or on MySpace, Facebook, forums and social bookmarking sites - all of which can make a substantial difference to earnings. Writers can also win prizes varying from $25 to $300 in Helium contests, and submit work for purchase by publishers in the Marketplace section. The winner of Helium contests is determined by ratings, however ratings have no bearing in the Marketplace section (although they are still conducted) - instead, the publisher is free to choose their preferred article for publication.
Helium earns money from Google AdSense advertisements displayed on the site, and from commission on articles sold to publishers on Marketplace.
# History
Previously HeliumKnowledge.com, Helium.com was launched in October of 2006. Initial press releases suggested the site was a quick-reference alternative to other sites like Wikipedia and Yahoo! Answers. The article review system for Helium was, from the start, touted by Helium as being significantly different than those of other encyclopedic sites. This review system has been the primary topic of numerous Helium press releases. More recently, Helium has increased rewards for affiliate marketers who bring new writers to the site. At present, according to Helium, the site has approximately 100,000 registered users, 30,000 of which are active contributors, and 300,000 total submitted articles.
# Criticism
Like any commercial website which is in the business of attracting contributors, Helium downplays criticism by contributors on its forums or in articles, and has been known to delete such references from the site. For the same reason, it actively promotes a positive image and contributions which "talk up" their site.
Most contributors agree that the rating system is imperfect, and there are often lively debates on this topic on the site.. Rating other articles benefits a given user, and there is no built-in penalty for giving a positive rating to an article with poor, plagiarized or incorrect content. Helium also does not allow users to flag articles for incorrect content, but only for offensive, plagiarized or poorly structured material.
Concerns have also been raised by writers who claim to have been banned from the site under false pretences. At least one writer has speculated openly that he was banned for raising issues of plagiarism and systematic rating manipulation on Helium. The Helium User Agreement enables Helium to keep all author content on Helium.com after banning an author. Banned authors are also denied the right to edit, remove or earn from content they submitted, including personal information created on their author biography pages. | Helium.com
Template:Infobox Company
Helium.com, Inc. (formerly known as Helium Knowledge) is a website where writers can contribute articles for payment and visitors can read these articles for free. User generated content in a given category is rated up or down by other writers in a form of peer review system. As with social news sites like Digg or Reddit, user ratings determine the rank of an article. In this case, however, the users are the writers, and multiple answers/articles exist and compete in most topics. In turn, high-rated articles receive more page views and earn more money for writers.[1] Critics have questioned the efficacy of this rating system and raised concerns about plagiarism, censorship, bans and other issues related to Helium.com. According to Alexa's website global traffic rankings, Helium.com's rank has hovered around 10,000 since January 2007.[2] The site had over 5,000 users in October 2006.[3]
# Articles
Contributors to Helium can write an article on any topic. Articles are arranged by categories and sub-categories, e.g. Writing (main category) has sub-topics such as Creative Writing, Writing Tips, and The Business of Writing. Contributors may create their own topic, or post an article to an existing topic (which may have been created by another contributor, or by a Helium staff member), but each writer can only submit one article to any one topic.
If a contributor creates a new topic, it is not published immediately, but instead is held for vetting. If approved, the topic is created and the article appears, usually within a day or two. It is then open for other writers to contribute to. Articles written to existing topics are published immediately and are not vetted or edited by Helium.
Articles within a topic compete with each other for "ratings". Rating is done by contributors on a "rating screen" where the articles are shown anonymously, two at a time, and contributors are asked to vote for the better article. This process is repeated until all the articles in a given topic have been ranked in order. Each time a new article is posted to a topic, the rating process is repeated. Rating is anonymous to prevent bias by contributors.
There is a flagging system which enables contributors to report plagiarism and otherwise poor articles.
# Payment
All articles stay on the site in perpetuity and will continue to earn income so long as the writer is actively contributing to the site. Writers earn a share of the ad revenue from ads appearing with their article, plus an amount based on the rating of their article and the number of times it is read. Helium does not disclose how this formula is calculated.
Earnings vary considerably depending on the categories and topics chosen. New writers can expect to earn only a few cents per article per month. Successful writers typically have hundreds of articles on the site, and/or promote their work heavily elsewhere, and/or make major efforts in contests and the Marketplace (see below).
Writers are encouraged to promote their work by writing blogs which link to Helium, or on MySpace, Facebook, forums and social bookmarking sites - all of which can make a substantial difference to earnings. Writers can also win prizes varying from $25 to $300 in Helium contests, and submit work for purchase by publishers in the Marketplace section. The winner of Helium contests is determined by ratings, however ratings have no bearing in the Marketplace section (although they are still conducted) - instead, the publisher is free to choose their preferred article for publication.
Helium earns money from Google AdSense advertisements displayed on the site, and from commission on articles sold to publishers on Marketplace.
# History
Previously HeliumKnowledge.com, Helium.com was launched in October of 2006. Initial press releases suggested the site was a quick-reference alternative to other sites like Wikipedia and Yahoo! Answers. The article review system for Helium was, from the start, touted by Helium as being significantly different than those of other encyclopedic sites. This review system has been the primary topic of numerous Helium press releases.[4] More recently, Helium has increased rewards for affiliate marketers who bring new writers to the site.[5] At present, according to Helium, the site has approximately 100,000 registered users, 30,000 of which are active contributors, and 300,000 total submitted articles.[6]
# Criticism
Template:Bias
Like any commercial website which is in the business of attracting contributors, Helium downplays criticism by contributors on its forums or in articles, and has been known to delete such references from the site.[7] For the same reason, it actively promotes a positive image and contributions which "talk up" their site.[8]
Most contributors agree that the rating system is imperfect, and there are often lively debates on this topic on the site..[9] Rating other articles benefits a given user, and there is no built-in penalty for giving a positive rating to an article with poor, plagiarized or incorrect content. Helium also does not allow users to flag articles for incorrect content, but only for offensive, plagiarized or poorly structured material.[10]
Concerns have also been raised by writers who claim to have been banned from the site under false pretences. At least one writer has speculated openly that he was banned for raising issues of plagiarism and systematic rating manipulation on Helium.[11] The Helium User Agreement enables Helium to keep all author content on Helium.com after banning an author. Banned authors are also denied the right to edit, remove or earn from content they submitted, including personal information created on their author biography pages.[12] | https://www.wikidoc.org/index.php/Helium.com | |
79cd30bf93f6d5a36eabc720fec255c02f1e9906 | wikidoc | Hemiacetal | Hemiacetal
A hemiacetal is a functional group, or a compound containing this functional group, in the form of:
File:Hemiacetal.png
where R and R' are any alkyl groups.
A hemiacetal can react with an alcohol under acidic conditions
to form an acetal, and can dissociate to form an aldehyde and an alcohol.
# Reactions
## Synthesis
In organic synthesis, hemiacetals can be prepared in a number of ways:
- Nucleophilic addition of an alcohol to a carbonyl group of an aldehyde
- Nucleophilic addition of an alcohol to a resonance stabilized hemiacetal cation
- Partial hydrolysis of an acetal
Hemiacetals can be converted into acetals:
- hemiacetal + alcohol + acid (catalyst) ↔ acetal + water
An aldehyde dissolved in water exists in equilibrium with low concentrations of its hydrate, R-CH(OH)2. Similarly, in excess alcohol, the aldehyde, its hemiacetal, and its acetal all exist in solution.
Hemiacetal results from addition of the alcohol's hydroxyl group to the carbon in the C=O bond. Acetals are products of substitution reactions catalyzed by acid. The presence of acid improves the leaving capacity of the hydroxyl group and enables its substitution with an alkoxyl group (-OR). The conversion of a hemiacetal to an acetal is an SN1 reaction.
Ketones give hemiketals and ketals. These do not form as readily as hemiacetals and acetals. To increase yields of ketals or acetals, water formed during the reaction can be removed.
Hemiacetals and hemiketals are generally unstable compounds. In some cases however, stable cyclic hemiacetals and hemiketals can be readily formed. Glucose and many other sugars exist as cyclic hemiacetals. | Hemiacetal
A hemiacetal is a functional group, or a compound containing this functional group, in the form of:
File:Hemiacetal.png
where R and R' are any alkyl groups.
A hemiacetal can react with an alcohol under acidic conditions
to form an acetal, and can dissociate to form an aldehyde and an alcohol.
# Reactions
## Synthesis
In organic synthesis, hemiacetals can be prepared in a number of ways:
- Nucleophilic addition of an alcohol to a carbonyl group of an aldehyde
- Nucleophilic addition of an alcohol to a resonance stabilized hemiacetal cation
- Partial hydrolysis of an acetal
Hemiacetals can be converted into acetals:
- hemiacetal + alcohol + acid (catalyst) ↔ acetal + water
An aldehyde dissolved in water exists in equilibrium with low concentrations of its hydrate, R-CH(OH)2. Similarly, in excess alcohol, the aldehyde, its hemiacetal, and its acetal all exist in solution.
Hemiacetal results from addition of the alcohol's hydroxyl group to the carbon in the C=O bond. Acetals are products of substitution reactions catalyzed by acid. The presence of acid improves the leaving capacity of the hydroxyl group and enables its substitution with an alkoxyl group (-OR). The conversion of a hemiacetal to an acetal is an SN1 reaction.
Ketones give hemiketals and ketals. These do not form as readily as hemiacetals and acetals. To increase yields of ketals or acetals, water formed during the reaction can be removed.
Hemiacetals and hemiketals are generally unstable compounds. In some cases however, stable cyclic hemiacetals and hemiketals can be readily formed. Glucose and many other sugars exist as cyclic hemiacetals. | https://www.wikidoc.org/index.php/Hemiacetal | |
e1f430763720451ab77f54c5d46f283b9148fd11 | wikidoc | Hemocyanin | Hemocyanin
# Overview
Hemocyanins (also spelled haemocyanins) are respiratory proteins in the form of metalloproteins containing two copper atoms that reversibly bind a single oxygen molecule (O2). Oxygenation causes a color change between the colorless Cu(I) deoxygenated form and the blue Cu(II) oxygenated form. Hemocyanins carry oxygen in the blood of most molluscs, and some arthropods such as the horseshoe crab. They are second only to hemoglobin in biological popularity of use in oxygen transport.
# Explanation
Although the respiratory function of hemocyanin is similar to that of hemoglobin, there are a significant number of differences in its molecular structure and mechanism. Whereas hemoglobin carries its iron atoms in porphyrin rings (heme groups), the copper atoms of hemocyanin are bound as prosthetic groups coordinated by histidine residues. Species using hemocyanin for oxygen transportation are commonly crustaceans living in cold environments with low oxygen pressure. Under these circumstances hemoglobin oxygen transportation is less efficient than hemocyanin oxygen transportation.
Most hemocyanins bind with oxygen non-cooperatively and are roughly one-fourth as efficient as hemoglobin at transporting oxygen per amount of blood. Hemoglobin binds oxygen cooperatively due to steric conformation changes in the protein complex, which increases hemoglobin's affinity for oxygen when partially oxygenated. In some hemocyanins of horseshoe crabs and some other species of arthropods, cooperative binding is observed, with Hill coefficients between 1.6-3. Hill constants vary depending on species and laboratory measurement settings. Hemoglobin for comparison has a Hill coefficient of usually 2.8-3. In these cases of cooperative binding hemocyanin was arranged in protein sub-complexes of 6 subunits (hexamer) each with one oxygen binding site, binding of oxygen on one unit in the complex would increase the affinity of the neighboring units. Each hexamer complex was arranged together to form a larger complex of dozens of hexamers. In one study, cooperative binding was found to be dependent on hexamers being arranged together in the larger complex, suggesting cooperative binding between hexamers. Hemocyanin oxygen-binding profile is also affected by dissolve-salt ion levels and pH.
Hemocyanin is made of many individual subunit proteins, each of which contains two copper atoms and can bind one oxygen molecule (O2). Each subunit weighs about 75 kilodaltons (kDa). Subunits may be arranged in dimers or hexamers depending on species, the dimer or hexamer complex is likewise arranged in chains or clusters in weights exceeding 1500 kDa. The subunits are usually homogeneous, or heterogeneous with two variant subunit types. Because of the large size of hemocyanin, it is usually found free-floating in the blood, unlike hemoglobin, which must be contained in cells because its small size would lead it to clog and damage blood-filtering organs such as the kidneys. This free-floating nature can allow for increased hemocyanin density over hemoglobin and increased oxygen carrying capacity. On the other hand, free-floating hemocyanin can increase viscosity and increase the energy expenditure needed to pump blood.
# Structure
Spectroscopy of oxyhemocyanin shows several salient features:
- resonance Raman spectroscopy shows symmetric binding
- UV-Vis spectroscopy shows strong absorbances at 350 and 580 nm.
- OxyHc is EPR-silent indicating the absence of unpaired electrons
- Infrared spectroscopy shows ν(O-O) of 755 cm-1
(1) rules out a mononuclear peroxo complex
(2) does not match with the UV-Vis spectra of mononuclear peroxo and Kenneth Karlin's trans-peroxo models.
(4) shows a considerably weaker O-O bond compared with Karlin's trans-peroxo model.
On the other hand, Nobumasa Kitajima's model shows ν(O-O) of 741 cm-1 and UV-Vis absorbances at 349 and 551 nm, which agree with the experimental observations for oxyHc.
The weak O-O bond of oxyhemocyanin is because of metal-ligand backdonation into the σ- orbitals. The donation of electrons into the O-O antibonding orbitals weakens the O-O bond, giving a lower than expected infrared stretching frequency. | Hemocyanin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Hemocyanins (also spelled haemocyanins) are respiratory proteins in the form of metalloproteins containing two copper atoms that reversibly bind a single oxygen molecule (O2). Oxygenation causes a color change between the colorless Cu(I) deoxygenated form and the blue Cu(II) oxygenated form. Hemocyanins carry oxygen in the blood of most molluscs, and some arthropods such as the horseshoe crab. They are second only to hemoglobin in biological popularity of use in oxygen transport.
# Explanation
Although the respiratory function of hemocyanin is similar to that of hemoglobin, there are a significant number of differences in its molecular structure and mechanism. Whereas hemoglobin carries its iron atoms in porphyrin rings (heme groups), the copper atoms of hemocyanin are bound as prosthetic groups coordinated by histidine residues. Species using hemocyanin for oxygen transportation are commonly crustaceans living in cold environments with low oxygen pressure. Under these circumstances hemoglobin oxygen transportation is less efficient than hemocyanin oxygen transportation.
Most hemocyanins bind with oxygen non-cooperatively and are roughly one-fourth as efficient as hemoglobin at transporting oxygen per amount of blood. Hemoglobin binds oxygen cooperatively due to steric conformation changes in the protein complex, which increases hemoglobin's affinity for oxygen when partially oxygenated. In some hemocyanins of horseshoe crabs and some other species of arthropods, cooperative binding is observed, with Hill coefficients between 1.6-3. Hill constants vary depending on species and laboratory measurement settings. Hemoglobin for comparison has a Hill coefficient of usually 2.8-3. In these cases of cooperative binding hemocyanin was arranged in protein sub-complexes of 6 subunits (hexamer) each with one oxygen binding site, binding of oxygen on one unit in the complex would increase the affinity of the neighboring units. Each hexamer complex was arranged together to form a larger complex of dozens of hexamers. In one study, cooperative binding was found to be dependent on hexamers being arranged together in the larger complex, suggesting cooperative binding between hexamers. Hemocyanin oxygen-binding profile is also affected by dissolve-salt ion levels and pH.
Hemocyanin is made of many individual subunit proteins, each of which contains two copper atoms and can bind one oxygen molecule (O2). Each subunit weighs about 75 kilodaltons (kDa). Subunits may be arranged in dimers or hexamers depending on species, the dimer or hexamer complex is likewise arranged in chains or clusters in weights exceeding 1500 kDa. The subunits are usually homogeneous, or heterogeneous with two variant subunit types. Because of the large size of hemocyanin, it is usually found free-floating in the blood, unlike hemoglobin, which must be contained in cells because its small size would lead it to clog and damage blood-filtering organs such as the kidneys. This free-floating nature can allow for increased hemocyanin density over hemoglobin and increased oxygen carrying capacity. On the other hand, free-floating hemocyanin can increase viscosity and increase the energy expenditure needed to pump blood.
# Structure
Spectroscopy of oxyhemocyanin shows several salient features:
- resonance Raman spectroscopy shows symmetric binding
- UV-Vis spectroscopy shows strong absorbances at 350 and 580 nm.
- OxyHc is EPR-silent indicating the absence of unpaired electrons
- Infrared spectroscopy shows ν(O-O) of 755 cm-1
(1) rules out a mononuclear peroxo complex
(2) does not match with the UV-Vis spectra of mononuclear peroxo and Kenneth Karlin's trans-peroxo models.[1]
(4) shows a considerably weaker O-O bond compared with Karlin's trans-peroxo model.[1]
On the other hand, Nobumasa Kitajima's model shows ν(O-O) of 741 cm-1 and UV-Vis absorbances at 349 and 551 nm, which agree with the experimental observations for oxyHc.[2]
The weak O-O bond of oxyhemocyanin is because of metal-ligand backdonation into the σ* orbitals. The donation of electrons into the O-O antibonding orbitals weakens the O-O bond, giving a lower than expected infrared stretching frequency. | https://www.wikidoc.org/index.php/Hemocyanin | |
a76d40307813422d71bd2e641167de3fca9d1bae | wikidoc | Heparanase | Heparanase
Heparanase, also known as HPSE, is an enzyme that acts both at the cell-surface and within the extracellular matrix to degrade polymeric heparan sulfate molecules into shorter chain length oligosaccharides.
# Synthesis and structure
The protein is originally synthesised in an inactive 65 kDa proheparanase form in the golgi apparatus and transferred to late endosomes/lysosomes for transport to the cell-surface. In the lysosome it is proteolytically processed into its active form. Proteolytic processing results in the production of three products,
- a linker peptide
- an 8 kDa proheparanase fragment and
- a 50 kDa proheparanase fragment
The 8 kDa and 50 kDa fragments form a heterodimer and it is this heterodimer that constitutes the active heparanase molecule. The linker protein is so called because prior to its excision it physically links the 8 kDa and 50 kDa proheparanase fragments. Complete excision of the linker peptide appears to be a prerequisite to the complete activation of the heparanase enzyme.
Crystal structures of both proheparanase and mature heparanase are available, showing that the linker peptide forms a large helical domain which blocks heparan sulfate molecules from interacting with heparanase. Removal of the linker reveals an extended cleft on the enzyme surface, which contains the heparanase active site.
# Function
Heparanase has endoglycosidase activity and cleaves polymeric heparan sulfate molecules at sites which are internal within the polymeric chain. In ocular surface physiology this activity functions as an off/on switch for the prosecretory mitogen lacritin. Lacritin binds the cell surface heparan sulfate proteoglycan syndecan-1 only in the presence of active heparanase. Heparanase partially or completely cleaves heparan sulfate to expose a binding site in the N-terminal 50 amino acids of syndecan-1.
# Clinical significance
The successful penetration of the endothelial cell layer that lines the interior surface of blood vessels is an important process in the formation of blood borne tumour metastases. Heparan sulfate proteoglycans are major constituents of this layer and it has been shown that increased metastatic potential corresponds with increased heparanase activity for a number of cell lines. Due to the contribution of heparanase activity to metastasis and also to angiogenesis, the inhibition of heparanase activity it is considered to be a potential target for anti-cancer therapies.
Heparanase has been shown to promote arterial thrombosis and stent thrombosis in mouse models due to the cleavage of anti-coagulant heparan sulfate proteoglycans. | Heparanase
Heparanase, also known as HPSE, is an enzyme that acts both at the cell-surface and within the extracellular matrix to degrade polymeric heparan sulfate molecules into shorter chain length oligosaccharides.[1][2]
# Synthesis and structure
The protein is originally synthesised in an inactive 65 kDa proheparanase form in the golgi apparatus and transferred to late endosomes/lysosomes for transport to the cell-surface. In the lysosome it is proteolytically processed into its active form. Proteolytic processing results in the production of three products,
- a linker peptide
- an 8 kDa proheparanase fragment and
- a 50 kDa proheparanase fragment
The 8 kDa and 50 kDa fragments form a heterodimer and it is this heterodimer that constitutes the active heparanase molecule.[3] The linker protein is so called because prior to its excision it physically links the 8 kDa and 50 kDa proheparanase fragments. Complete excision of the linker peptide appears to be a prerequisite to the complete activation of the heparanase enzyme.
Crystal structures of both proheparanase and mature heparanase are available, showing that the linker peptide forms a large helical domain which blocks heparan sulfate molecules from interacting with heparanase.[4] Removal of the linker reveals an extended cleft on the enzyme surface, which contains the heparanase active site.[5]
# Function
Heparanase has endoglycosidase activity and cleaves polymeric heparan sulfate molecules at sites which are internal within the polymeric chain.[6] In ocular surface physiology this activity functions as an off/on switch for the prosecretory mitogen lacritin. Lacritin binds the cell surface heparan sulfate proteoglycan syndecan-1 only in the presence of active heparanase. Heparanase partially or completely cleaves heparan sulfate to expose a binding site in the N-terminal 50 amino acids of syndecan-1.[7]
# Clinical significance
The successful penetration of the endothelial cell layer that lines the interior surface of blood vessels is an important process in the formation of blood borne tumour metastases. Heparan sulfate proteoglycans are major constituents of this layer and it has been shown that increased metastatic potential corresponds with increased heparanase activity for a number of cell lines.[8][9] Due to the contribution of heparanase activity to metastasis and also to angiogenesis, the inhibition of heparanase activity it is considered to be a potential target for anti-cancer therapies.[10][11]
Heparanase has been shown to promote arterial thrombosis and stent thrombosis in mouse models due to the cleavage of anti-coagulant heparan sulfate proteoglycans.[12] | https://www.wikidoc.org/index.php/Heparanase | |
6bd19bc847d1044d1dfb57aa5936940a185d02b9 | wikidoc | Oxygenator | Oxygenator
An oxygenator is a medical device that is capable of exchanging oxygen and carbon dioxide in the blood of human patient in surgical procedures that may necessitate the interruption or cessation of blood flow in the body, a critical organ or great blood vessel. These organs can be the heart, lungs or liver, while the great vessels can be the aorta, pulmonary artery, pulmonary veins or vena cava. An oxygenator is typically utilized by a perfusionist in cardiac surgery in conjunction with the heart-lung machine. However, oxygenators can also be utilized in extracorporeal membrane oxygenation in neonatal intensive care units by nurses.
For most cardiac operations such as coronary artery bypass grafting, the cardiopulmonary bypass is performed using a heart-lung machine (or cardiopulmonary bypass machine). The heart-lung machine serves to replace the work of the heart during the open bypass surgery. The machine replaces both the heart's pumping action and the lungs' gas exchange function. Since the heart is stopped during the operation, this permits the surgeon to operate on a bloodless, stationary heart.
One component of the heart-lung machine is the oxygenator. The oxygenator component serves as the lung, and is designed to expose the blood to oxygen and remove carbon dioxide. It is disposable and contains about 2-4 m² of a membrane permeable to gas but impermeable to blood, in the form of hollow fibers. Blood flows on the outside of the hollow fibers, while oxygen flows in the opposite direction on the inside of the fibers. As the blood passes through the oxygenator, the blood comes into intimate contact with the fine surfaces of the device itself. Gas containing oxygen and medical air is delivered to the interface between the blood and the device, permitting the blood cells to absorb oxygen molecules directly.
# Heparin-coated blood oxygenator
## Rationale
Operations which involve uncoated CPB circuits require a high dose of systemic heparin. Although the effects of heparin are reversible by administering protamine, there are a number of side effects associated with this. Side effects can include allergic reaction to heparin resulting in thrombocytopenia, various reactions to the administration of protamine and post-operative hemorrhage due to inadequate reversal of the anticoagulation. Systemic heparin does not completely prevent clotting or the activation of complement, neutrophils, and monocytes, which are the principal mediators of the inflammatory response. This response produces a wide range of cytotoxins, and cell-signaling proteins that circulate throughout the patient's body during surgery and disrupt homeostasis. The inflammatory responses can produce microembolic particles. A greater source of such microemboli are caused by the suction of sugical debris and lipids into the CPB circuit.
Microparticles obstruct arterioles that supply small nests of cells throughout the body and, together with cytotoxins, damage organs and tissues and temporarily disturb organ function. All aspects of cardiopulmonary bypass, including manipulation of the aorta by the surgeon, may be associated with neurological symptoms following perfusion. Physicians refer to such temporary neurological deficits as “pumphead syndrome.” Heparin-coated blood oxygenators are one option available to a surgeon and a perfusionist to decrease morbidity associated with CPB to a limited degree.
Heparin-coated oxygenators are thought to:
- Improve overall biocompatibility and host homeostasis
- Mimic the natural endothelial lining of the vasculature
- Reduce the need for systemic anticoagulation
- Better maintain platelet count
- Reduce adhesion of plasma proteins
- Prevent denaturation and activation of adhered proteins and blood cells
- Avoid complications resulting from an abnormal pressure gradient across the oxygenator
## Surgical outcomes
Heparin coating is reported to result in similar characteristics to the native endothelium. It has been shown to inhibit intrinsic coagulation, inhibit host responses to extracorporeal circulation, and lessen postperfusion, or “pumphead,” syndrome. Several studies have examined the clinical efficacy of these oxygenators.
Mirow et al 2001 examined the effects of heparin-coated cardiopulmonary bypass systems combined with full and low dose systemic heparinization in coronary artery bypass patients. The researchers concluded that:
- Heparin-coated extracorporeal circuits with reduced systemic heparinization lead to significantly increased thrombin generation.
- Postoperative bleeding was reduced with low systemic heparinization, but the reduction was not significant.
Ovrum et al 2001 compared the clinical outcomes of 1336 patients with the Carmeda Bioactive Surface and Duraflo II coatings. The researchers concluded that:
- Duraflo II patients required less heparin to keep the target activated clotting time
- Effects on renal function and platelets were similar
- Incidences of perioperative MI, stroke, and hospital mortality were similar
- Reduced incidence of postoperative atrial fibrillation compared to identical uncoated controls
- Overall clinical results were favorable in both groups
Statistics and conclusions from more studies are available here. Clearly, heparin-coated blood oxygenators exhibit some advantages over non-coated oxygenators. Some hospitals use heparin-coated oxygenators for the large majority of their cases requiring cardiopulmonary bypass. It is unclear whether most surgeons actually reduce the amount of systemic heparin used when their patients are being perfused with heparin-coated oxygenators. Ultimately, each surgeon makes this decision based upon the needs of individual patient.
Although they offer advantages, these oxygenators are not widely regarded by surgeons as revolutionary breakthroughs in cardiopulmonary bypass. This is attibutable to the fact that most of the morbidity associated with CPB is not caused by the contact between the blood with the oxygenator. The leading cause of hemolysis and microemboli is the return of blood suctioned from the surgical field to the CPB circuit. This blood has come into contact with air, lipids and debris that can significantly increase system inflammatory response. Surgeons are instead looking to off-pump cardiac procedures, wherein surgery is performed on beating hearts, as the next “big thing” in open heart surgery. | Oxygenator
An oxygenator is a medical device that is capable of exchanging oxygen and carbon dioxide in the blood of human patient in surgical procedures that may necessitate the interruption or cessation of blood flow in the body, a critical organ or great blood vessel. These organs can be the heart, lungs or liver, while the great vessels can be the aorta, pulmonary artery, pulmonary veins or vena cava. An oxygenator is typically utilized by a perfusionist in cardiac surgery in conjunction with the heart-lung machine. However, oxygenators can also be utilized in extracorporeal membrane oxygenation in neonatal intensive care units by nurses.
For most cardiac operations such as coronary artery bypass grafting, the cardiopulmonary bypass is performed using a heart-lung machine (or cardiopulmonary bypass machine). The heart-lung machine serves to replace the work of the heart during the open bypass surgery. The machine replaces both the heart's pumping action and the lungs' gas exchange function. Since the heart is stopped during the operation, this permits the surgeon to operate on a bloodless, stationary heart.
One component of the heart-lung machine is the oxygenator. The oxygenator component serves as the lung, and is designed to expose the blood to oxygen and remove carbon dioxide. It is disposable and contains about 2-4 m² of a membrane permeable to gas but impermeable to blood, in the form of hollow fibers. Blood flows on the outside of the hollow fibers, while oxygen flows in the opposite direction on the inside of the fibers. As the blood passes through the oxygenator, the blood comes into intimate contact with the fine surfaces of the device itself. Gas containing oxygen and medical air is delivered to the interface between the blood and the device, permitting the blood cells to absorb oxygen molecules directly.
# Heparin-coated blood oxygenator
## Rationale
Operations which involve uncoated CPB circuits require a high dose of systemic heparin. Although the effects of heparin are reversible by administering protamine, there are a number of side effects associated with this. Side effects can include allergic reaction to heparin resulting in thrombocytopenia, various reactions to the administration of protamine and post-operative hemorrhage due to inadequate reversal of the anticoagulation. Systemic heparin does not completely prevent clotting or the activation of complement, neutrophils, and monocytes, which are the principal mediators of the inflammatory response. This response produces a wide range of cytotoxins, and cell-signaling proteins that circulate throughout the patient's body during surgery and disrupt homeostasis. The inflammatory responses can produce microembolic particles. A greater source of such microemboli are caused by the suction of sugical debris and lipids into the CPB circuit[1].
Microparticles obstruct arterioles that supply small nests of cells throughout the body and, together with cytotoxins, damage organs and tissues and temporarily disturb organ function. All aspects of cardiopulmonary bypass, including manipulation of the aorta by the surgeon, may be associated with neurological symptoms following perfusion. Physicians refer to such temporary neurological deficits as “pumphead syndrome.” Heparin-coated blood oxygenators are one option available to a surgeon and a perfusionist to decrease morbidity associated with CPB to a limited degree.
Heparin-coated oxygenators are thought to:
- Improve overall biocompatibility and host homeostasis
- Mimic the natural endothelial lining of the vasculature
- Reduce the need for systemic anticoagulation
- Better maintain platelet count
- Reduce adhesion of plasma proteins
- Prevent denaturation and activation of adhered proteins and blood cells
- Avoid complications resulting from an abnormal pressure gradient across the oxygenator
## Surgical outcomes
Heparin coating is reported to result in similar characteristics to the native endothelium. It has been shown to inhibit intrinsic coagulation, inhibit host responses to extracorporeal circulation, and lessen postperfusion, or “pumphead,” syndrome. Several studies have examined the clinical efficacy of these oxygenators.
Mirow et al 2001 examined the effects of heparin-coated cardiopulmonary bypass systems combined with full and low dose systemic heparinization in coronary artery bypass patients. The researchers concluded that:
- Heparin-coated extracorporeal circuits with reduced systemic heparinization lead to significantly increased thrombin generation.
- Postoperative bleeding was reduced with low systemic heparinization, but the reduction was not significant.
Ovrum et al 2001 compared the clinical outcomes of 1336 patients with the Carmeda Bioactive Surface and Duraflo II coatings. The researchers concluded that:
- Duraflo II patients required less heparin to keep the target activated clotting time
- Effects on renal function and platelets were similar
- Incidences of perioperative MI, stroke, and hospital mortality were similar
- Reduced incidence of postoperative atrial fibrillation compared to identical uncoated controls
- Overall clinical results were favorable in both groups
Statistics and conclusions from more studies are available here. Clearly, heparin-coated blood oxygenators exhibit some advantages over non-coated oxygenators. Some hospitals use heparin-coated oxygenators for the large majority of their cases requiring cardiopulmonary bypass. It is unclear whether most surgeons actually reduce the amount of systemic heparin used when their patients are being perfused with heparin-coated oxygenators. Ultimately, each surgeon makes this decision based upon the needs of individual patient.
Although they offer advantages, these oxygenators are not widely regarded by surgeons as revolutionary breakthroughs in cardiopulmonary bypass. This is attibutable to the fact that most of the morbidity associated with CPB is not caused by the contact between the blood with the oxygenator. The leading cause of hemolysis and microemboli is the return of blood suctioned from the surgical field to the CPB circuit. This blood has come into contact with air, lipids and debris that can significantly increase system inflammatory response. Surgeons are instead looking to off-pump cardiac procedures, wherein surgery is performed on beating hearts, as the next “big thing” in open heart surgery. | https://www.wikidoc.org/index.php/Heparin-coated_blood_oxygenator | |
7afe9cb071b4ccbc94746ba1c25eb7889ca38b02 | wikidoc | Hepatocyte | Hepatocyte
Hepatocytes make up 70-80% of the cytoplasmic mass of the liver. These cells are involved in protein synthesis, protein storage and transformation of carbohydrates, synthesis of cholesterol, bile salts and phospholipids, and detoxification, modification and excretion of exogenous and endogenous substances.
The hepatocyte also initiates the formation and secretion of bile.
# Hepatocyte histology
Hepatocytes display an eosinophilic cytoplasm, reflecting numerous mitochondria, and basophilic stippling due to large amounts of rough endoplasmic reticulum and free ribosomes. Brown lipofuscin granules are also observed (with increasing age) together with irregular unstained areas of cytoplasm; these correspond to cytoplasmic glycogen and lipid stores removed during histological preparation. The average life span of the hepatocyte is 5 months; they are able to regenerate.
Hepatocyte nuclei are round with dispersed chromatin and prominent nucleoli. Anisokaryosis is common and reflects tetraploidy & polyploidy, a normal feature of over 50% of hepatocytes. Binucleate cells are also common.
Hepatocytes are organised into plates separated by vascular channels (sinusoids), an arrangement supported by a reticulin (collagen type III) network. The hepatocyte plates are one cell thick in mammals and two cells thick in the chicken. Sinusoids display a discontinuous, fenestrated endothelial cell lining. The endothelial cells have no basement membrane and are separated from the hepatocytes by the space of Disse which drains lymph into the portal tract lymphatics.
Kupffer cells are scattered between endothelial cells; they are part of the reticuloendothelial system and phagocytose spent erythrocytes. Stellate (Ito) cells store vitamin A and produce extracellular matrix and collagen; they are also distributed amongst endothelial cells but are difficult to visualise by light microscopy.
Hepatocytes are an important physiological example for evalutation of both biological and metabolic effects of xenobiotics. They do not proliferate in culture. Hepatocytes are intensely sensitive to damage during the cycles of cryopreservation including freezing and thawing. Even after the addition of classical cryoprotectants there is still damage done while being cryopreserved.
# Protein synthesis
The hepatocyte is a cell in the body that manufactures serum albumin, fibrinogen, and the prothrombin group of clotting factors.
It is the main site for the synthesis of lipoproteins, ceruloplasmin, transferrin, complement and glycoproteins.
Hepatocytes manufacture their own structural proteins and intracellular enzymes.
Synthesis of proteins is undertaken by the rough endoplasmic reticulum (RER), and both the rough and smooth endoplasmic reticulum (SER) are involved in secretion of the proteins formed.
The endoplasmic reticulum (ER) is involved in conjugation of proteins to lipid and carbohydrate moieties synthesized by, or modified within, the hepatocytes.
# Carbohydrate metabolism
The liver forms fatty acids from carbohydrates and synthesizes triglycerides from fatty acids and glycerol.
Hepatocytes also synthesize apoproteins with which they then assemble and export lipoproteins (VLDL, HDL).
# Lipid metabolism
The liver receives many lipids from the systemic circulation and metabolizes chylomicron remnants.
It also synthesizes cholesterol from acetate and then further synthesizes bile salts.
The liver is the sole site of formation of bile salts.
# Detoxification
Hepatocytes have the ability to metabolize, detoxify, and inactivate exogenous compounds such as drugs and insecticides, and endogenous compounds such as steroids.
The drainage of the intestinal venous blood into the liver requires efficient detoxification of miscellaneous absorbed substances to maintain homeostasis and protect the body against ingested toxins.
One of the detoxifying functions of hepatocytes is to modify ammonia into urea for excretion.
# Additional images
- Schemic diagram of Biliary system | Hepatocyte
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Hepatocytes make up 70-80% of the cytoplasmic mass of the liver. These cells are involved in protein synthesis, protein storage and transformation of carbohydrates, synthesis of cholesterol, bile salts and phospholipids, and detoxification, modification and excretion of exogenous and endogenous substances.
The hepatocyte also initiates the formation and secretion of bile.
# Hepatocyte histology
Hepatocytes display an eosinophilic cytoplasm, reflecting numerous mitochondria, and basophilic stippling due to large amounts of rough endoplasmic reticulum and free ribosomes. Brown lipofuscin granules are also observed (with increasing age) together with irregular unstained areas of cytoplasm; these correspond to cytoplasmic glycogen and lipid stores removed during histological preparation. The average life span of the hepatocyte is 5 months; they are able to regenerate.
Hepatocyte nuclei are round with dispersed chromatin and prominent nucleoli. Anisokaryosis is common and reflects tetraploidy & polyploidy, a normal feature of over 50% of hepatocytes. Binucleate cells are also common.
Hepatocytes are organised into plates separated by vascular channels (sinusoids), an arrangement supported by a reticulin (collagen type III) network. The hepatocyte plates are one cell thick in mammals and two cells thick in the chicken. Sinusoids display a discontinuous, fenestrated endothelial cell lining. The endothelial cells have no basement membrane and are separated from the hepatocytes by the space of Disse which drains lymph into the portal tract lymphatics.
Kupffer cells are scattered between endothelial cells; they are part of the reticuloendothelial system and phagocytose spent erythrocytes. Stellate (Ito) cells store vitamin A and produce extracellular matrix and collagen; they are also distributed amongst endothelial cells but are difficult to visualise by light microscopy.
Hepatocytes are an important physiological example for evalutation of both biological and metabolic effects of xenobiotics. They do not proliferate in culture. Hepatocytes are intensely sensitive to damage during the cycles of cryopreservation including freezing and thawing. Even after the addition of classical cryoprotectants there is still damage done while being cryopreserved. [1]
# Protein synthesis
The hepatocyte is a cell in the body that manufactures serum albumin, fibrinogen, and the prothrombin group of clotting factors.
It is the main site for the synthesis of lipoproteins, ceruloplasmin, transferrin, complement and glycoproteins.
Hepatocytes manufacture their own structural proteins and intracellular enzymes.
Synthesis of proteins is undertaken by the rough endoplasmic reticulum (RER), and both the rough and smooth endoplasmic reticulum (SER) are involved in secretion of the proteins formed.
The endoplasmic reticulum (ER) is involved in conjugation of proteins to lipid and carbohydrate moieties synthesized by, or modified within, the hepatocytes.
# Carbohydrate metabolism
The liver forms fatty acids from carbohydrates and synthesizes triglycerides from fatty acids and glycerol.
Hepatocytes also synthesize apoproteins with which they then assemble and export lipoproteins (VLDL, HDL).
# Lipid metabolism
The liver receives many lipids from the systemic circulation and metabolizes chylomicron remnants.
It also synthesizes cholesterol from acetate and then further synthesizes bile salts.
The liver is the sole site of formation of bile salts.
# Detoxification
Hepatocytes have the ability to metabolize, detoxify, and inactivate exogenous compounds such as drugs and insecticides, and endogenous compounds such as steroids.
The drainage of the intestinal venous blood into the liver requires efficient detoxification of miscellaneous absorbed substances to maintain homeostasis and protect the body against ingested toxins.
One of the detoxifying functions of hepatocytes is to modify ammonia into urea for excretion.
# Additional images
- Schemic diagram of Biliary system | https://www.wikidoc.org/index.php/Hepatocyte | |
fdb17e2d1a69d961a91bcdc974d3f031ce99b841 | wikidoc | Hepatology | Hepatology
# Overview
Hepatology is the branch of medicine that incorporates study of liver, gallbladder, biliary tree and pancreas as well as management of their disorders. Etymologically the word Hepatology is formed of ancient Greek hepar(ηπαρ) or hepato-(ηπατο-) meaning ' liver' and suffix -logia(-λογια) meaning 'word' or 'speech'. Although traditionally considered a sub-specialty of gastroenterology, rapid expansion has led in some countries to doctors specialising solely on this area, who are called hepatologists.
Diseases and complications related to viral hepatitis and alcohol are the main reason for seeking specialist advice. One third of world population has been infected with Hepatitis B virus at some point in their life. Although most of them would clear the virus from the body, approximately 350 million have become persistent carriers. Up to 80% of liver cancers can be attributed to either hepatitis B or Hepatitis C virus. In terms of number of mortality, the former is second only to smoking among known agents causing cancer. Hopefully, widespread implementation of vaccination and strict screening before blood transfusion are going to lower the infection rate in future.
However in many countries overall alcohol intake is on the rise and as one can expect, number of people with cirrhosis and other related complications are increasing.
# Scope of the specialty
As for many medical specialties, patients are most likely to be referred by family physicians( i.e. GP) or by doctors from different disciplines. The reasons might be:
- Jaundice
- Gastrointestinal bleeding from portal hypertension related to liver damage
- Abnormal blood test suggesting liver disease
- Enzyme defects leading to bigger liver in children commonly named storage disease of liver
- Hepatitis virus positivity in blood, perhaps discovered on screening blood tests
- Ascites or swelling of abdomen from fluid accumulation, commonly due to liver disease but can be from other diseases like heart failure
- All patients with advanced liver disease e.g. cirrhosis should be under specialist care
- To undergo ERCP for diagnosing diseases of biliary tree or their management
- Fever with other features suggestive of infection involving mentioned organs. Some exotic tropical diseases like hydatid cyst, kala-azar or schistosomiasis may be suspected. Microbiologists would be involved as well
- Damage to liver from other toxins like drugs. Paracetamol overdose is common
- Systemic diseases affecting liver and biliary tree e.g. haemochromatosis
- Follow up of liver transplant
- Pancreatitis - commonly due to alcohol or gall stone
- Cancer of above organs. Usually multi-disciplinary approach is under taken with involvement of oncologist and other experts.
# History
Evidence from autopsies on Egyptian mummies suggest that liver damage from parasitic infection Bilharziasis was widespread in the ancient society.
It is possible that Greeks might be aware of liver's ability to exponentially duplicate as illustrated by Prometheus story. However knowledge about liver diseases in antiquity was some what sketchy. Most of the important advances in the field were made in last 50 years.
- In 400 BC Hippocrates mentioned liver abscess in apporium .
- Roman anatomist Galen thought liver is the principle organ of the body. He also identified its relationship with gallbladder and spleen.
- Around 100CE Areteus of cappadoca wrote on jaundice
- In mideaval period Avicenna noted the importance of urine in diagnosing liver conditions.
- 1770 French anatomist Antoine Portal, noted bleeding due to oesophageal varices,
- 1844 Gabriel Valentin showed pancreatic juices break down food in digestion.
- 1846 Justus Von Leibig discovered pancreatic juice tyrosine
- 1862 Austin Flint described the production of "stercorin".
- 1875 Victor Charles Hanot described cirrhotic jaundice and other diseases of liver
- In 1958, Moore developed a standard technique for canine orthotopic liver transplantation.
- The first human liver transplant was performed in 1963 by Dr. Thomas E. Starzl on a 3-year-old male afflicted with biliary atresia after perfecting the technique on canine livers.,
- Baruch S. Blumberg discovered Hepatitis B virus in 1966 and developed first vaccine against it 1969. He was awarded the Nobel Prize in Physiology or Medicine 1976.
# Disease classification
1. International Classification of Disease (ICD 2007)/ WHO classification:
- Chapter XI: Diseases of the digestive system
K70-K77 Diseases of liver
K80-K87 Disorders of gallbladder, biliary tract and pancreas
- K70-K77 Diseases of liver
- K80-K87 Disorders of gallbladder, biliary tract and pancreas
2. MeSH (medical subject heading):
- G02.403.776.409.405 same as "Gastroenterology"
- C06.552 Liver Diseases
- C06.130 Biliary Tract Diseases
- C06.689 Pancreatic diseases
3.National Library of Medicine Catalogue (NLM classification 2007):
- WI 700-740 Liver and biliary tree Diseases
- WI 800-830 Pancrease
Also see Hepato-biliary diseases
# Important procedures
- Endoscopic retrograde cholangiopancreatography(ERCP)
- Transhepatic pancreato-cholangiography(TPC)
- Transjugular intrahepatic portosystemic shunt(TIPSS)
# Publication
- The American Journal of Gastroenterology (Journal of the American College of Gastroenterology)
- The American Journal of Physiology - Gastrointestinal and Liver Physiology
- Archives of Gastroenterohepatology
- Comparative Hepatology
- Current Hepatitis Reports
- European Journal of Gastroenterology and Hepatology
- Gastroenterología y Hepatología
- Gastroenterology (journal of the American Gastroenterological Association)
- Hepatobiliary & pancreatic diseases international : HBPD INT (First Affiliated Hospital, Zhejiang University School of Medicine, China)
- Hepatology (journal of the American Association for the Study of Liver Diseases)
- HPB
- Journal of Gastroenterology and Hepatology
- HPB Surgery
- Journal of Hepato-Biliary-Pancreatic Surgery
- Journal of Hepatology (journal of the European Association for the Study of Liver Diseases)
- Journal of Viral Hepatitis
- Liver
- Liver Transplantation (from the American Association for the Study of Liver Diseases)
- Nature clinical practice. Gastroenterology & hepatology.
# Societies
- American Association for the Study of Liver Disease
- American College of Gastroenterology
- American Gastroenterological Association
- American Hepato-Pancreato-Biliary Association
- American Liver Society
- Austrian Society of Gastroenterology and Hepatology
- British Society of Paediatric Gastroenterology, Hepatology and Nutrition
- Canadian Association for the Study of the Liver
- Czech Society of Hepatology
- Danish Association for the Study of the Liver
- European Association for the Study of the Liver
- European Society of Paediatric Gastroenterology, Hepatology and Nutrition
- French Association for the Study of the Liver
- International Hepato-Pancreato-Biliary Association
- International Liver Transplantation Society
- Israel Association for the Study of the Liver
- North American Society for Pediatric Gastroenterology, Hepatology and Nutrition
- Society for Surgery of the Alimentary Tract
- Spanish Society of Pediatric Gastroenterology, Hepatology and Nutrition
- Swiss Association for the Study of the Liver
- Turkish Association for the Study of the Liver | Hepatology
# Overview
Hepatology is the branch of medicine that incorporates study of liver, gallbladder, biliary tree and pancreas as well as management of their disorders. Etymologically the word Hepatology is formed of ancient Greek hepar(ηπαρ) or hepato-(ηπατο-) meaning ' liver' and suffix -logia(-λογια) meaning 'word' or 'speech'. Although traditionally considered a sub-specialty of gastroenterology, rapid expansion has led in some countries to doctors specialising solely on this area, who are called hepatologists.
Diseases and complications related to viral hepatitis and alcohol are the main reason for seeking specialist advice. One third of world population has been infected with Hepatitis B virus at some point in their life. Although most of them would clear the virus from the body, approximately 350 million have become persistent carriers. Up to 80% of liver cancers can be attributed to either hepatitis B or Hepatitis C virus. In terms of number of mortality, the former is second only to smoking among known agents causing cancer. Hopefully, widespread implementation of vaccination and strict screening before blood transfusion are going to lower the infection rate in future.
However in many countries overall alcohol intake is on the rise and as one can expect, number of people with cirrhosis and other related complications are increasing.
# Scope of the specialty
As for many medical specialties, patients are most likely to be referred by family physicians( i.e. GP) or by doctors from different disciplines. The reasons might be:
- Jaundice
- Gastrointestinal bleeding from portal hypertension related to liver damage
- Abnormal blood test suggesting liver disease
- Enzyme defects leading to bigger liver in children commonly named storage disease of liver
- Hepatitis virus positivity in blood, perhaps discovered on screening blood tests
- Ascites or swelling of abdomen from fluid accumulation, commonly due to liver disease but can be from other diseases like heart failure
- All patients with advanced liver disease e.g. cirrhosis should be under specialist care
- To undergo ERCP for diagnosing diseases of biliary tree or their management
- Fever with other features suggestive of infection involving mentioned organs. Some exotic tropical diseases like hydatid cyst, kala-azar or schistosomiasis may be suspected. Microbiologists would be involved as well
- Damage to liver from other toxins like drugs. Paracetamol overdose is common
- Systemic diseases affecting liver and biliary tree e.g. haemochromatosis
- Follow up of liver transplant
- Pancreatitis - commonly due to alcohol or gall stone
- Cancer of above organs. Usually multi-disciplinary approach is under taken with involvement of oncologist and other experts.
# History
Evidence from autopsies on Egyptian mummies suggest that liver damage from parasitic infection Bilharziasis was widespread in the ancient society.[1]
It is possible that Greeks might be aware of liver's ability to exponentially duplicate as illustrated by Prometheus story. However knowledge about liver diseases in antiquity was some what sketchy. Most of the important advances in the field were made in last 50 years.
- In 400 BC Hippocrates mentioned liver abscess in apporium .
- Roman anatomist Galen thought liver is the principle organ of the body. He also identified its relationship with gallbladder and spleen.[2]
- Around 100CE Areteus of cappadoca wrote on jaundice[3]
- In mideaval period Avicenna noted the importance of urine in diagnosing liver conditions.
- 1770 French anatomist Antoine Portal, noted bleeding due to oesophageal varices,[4]
- 1844 Gabriel Valentin showed pancreatic juices break down food in digestion.
- 1846 Justus Von Leibig discovered pancreatic juice tyrosine[3]
- 1862 Austin Flint described the production of "stercorin".
- 1875 Victor Charles Hanot described cirrhotic jaundice and other diseases of liver[5]
- In 1958, Moore developed a standard technique for canine orthotopic liver transplantation.[6]
- The first human liver transplant was performed in 1963 by Dr. Thomas E. Starzl on a 3-year-old male afflicted with biliary atresia after perfecting the technique on canine livers.[7], [8]
- Baruch S. Blumberg discovered Hepatitis B virus in 1966 and developed first vaccine against it 1969. He was awarded the Nobel Prize in Physiology or Medicine 1976.[9]
# Disease classification
1. International Classification of Disease (ICD 2007)/ WHO classification:
- Chapter XI: Diseases of the digestive system [1]
K70-K77 Diseases of liver
K80-K87 Disorders of gallbladder, biliary tract and pancreas
- K70-K77 Diseases of liver
- K80-K87 Disorders of gallbladder, biliary tract and pancreas
2. MeSH (medical subject heading):
- G02.403.776.409.405 same as "Gastroenterology"
- C06.552 Liver Diseases
- C06.130 Biliary Tract Diseases
- C06.689 Pancreatic diseases
3.National Library of Medicine Catalogue (NLM classification 2007):
- WI 700-740 Liver and biliary tree Diseases
- WI 800-830 Pancrease
Also see Hepato-biliary diseases
# Important procedures
- Endoscopic retrograde cholangiopancreatography(ERCP)
- Transhepatic pancreato-cholangiography(TPC)
- Transjugular intrahepatic portosystemic shunt(TIPSS)
# Publication
- The American Journal of Gastroenterology (Journal of the American College of Gastroenterology)
- The American Journal of Physiology - Gastrointestinal and Liver Physiology
- Archives of Gastroenterohepatology
- Comparative Hepatology
- Current Hepatitis Reports
- European Journal of Gastroenterology and Hepatology
- Gastroenterología y Hepatología
- Gastroenterology (journal of the American Gastroenterological Association)
- Hepatobiliary & pancreatic diseases international : HBPD INT (First Affiliated Hospital, Zhejiang University School of Medicine, China)
- Hepatology (journal of the American Association for the Study of Liver Diseases)
- HPB
- Journal of Gastroenterology and Hepatology
- HPB Surgery
- Journal of Hepato-Biliary-Pancreatic Surgery
- Journal of Hepatology (journal of the European Association for the Study of Liver Diseases)
- Journal of Viral Hepatitis
- Liver
- Liver Transplantation (from the American Association for the Study of Liver Diseases)
- Nature clinical practice. Gastroenterology & hepatology.
# Societies
- American Association for the Study of Liver Disease
- American College of Gastroenterology
- American Gastroenterological Association
- American Hepato-Pancreato-Biliary Association
- American Liver Society
- Austrian Society of Gastroenterology and Hepatology
- British Society of Paediatric Gastroenterology, Hepatology and Nutrition
- Canadian Association for the Study of the Liver
- Czech Society of Hepatology
- Danish Association for the Study of the Liver
- European Association for the Study of the Liver
- European Society of Paediatric Gastroenterology, Hepatology and Nutrition
- French Association for the Study of the Liver
- International Hepato-Pancreato-Biliary Association
- International Liver Transplantation Society
- Israel Association for the Study of the Liver
- North American Society for Pediatric Gastroenterology, Hepatology and Nutrition
- Society for Surgery of the Alimentary Tract
- Spanish Society of Pediatric Gastroenterology, Hepatology and Nutrition
- Swiss Association for the Study of the Liver
- Turkish Association for the Study of the Liver | https://www.wikidoc.org/index.php/Hepatological | |
7e7d6cb7d88238b00db501c892190c21a8ec18d3 | wikidoc | Hephaestin | Hephaestin
Hephaestin, also known as HEPH, is a protein which in humans is encoded by the HEPH gene.
# Function
Hephaestin is involved in the metabolism and homeostasis of iron and possibly copper. It is a transmembrane copper-dependent ferroxidase responsible for transporting dietary iron from intestinal enterocytes into the circulatory system. The highest expression of hephaestin is found in small intestine. It is limited to enterocytes of the villi (where the iron absorption takes place), being almost absent in crypt cells. Hephaestin converts iron(II) state, Fe2+, to iron(III) state, Fe3+, and mediates iron efflux most likely in cooperation with the basolateral iron transporter, ferroportin 1. To a lesser extent hephaestin has been detected in colon, spleen, kidney, breast, placenta and bone trabecular cells but its role in these tissues remains to be established. Hephaestin presents homology with ceruloplasmin, a serum dehydrogenase protein involved in copper detoxification and storage.
Hephaestin is a protein of 1135 aminoacids formed from a precursor of 1158 aminoacids and is 130.4 kDa. It is predicted to bind 6 copper ions per monomer.
# Discovery
Hephaestin was first identified by Dr. Christopher D. Vulpe of the University of California, Berkeley in 1999. They named the newfound protein after Hephaestus, the Greek god of metal working.
Much of what is known about hephaestin comes from studying heritable mutants of murine iron metabolism. The protein was discovered and identified through the study of mice with sex-linked anemia, or sla mice, in which there is normal mucosal uptake of dietary iron but impaired transport of iron from the intestinal enterocytes into the circulation. sla mice harbor a partial deletion mutation of the HEPH gene, resulting in the expression of a hephaestin protein that is truncated by 194 amino acids. Studies suggest that this truncated hephaestin protein still retains a minimal, yet detectable and quantifiable level of ferroxidase activity. This raises the possibility that alternative factors may contribute to the decreased efflux of iron seen in the sla phenotype.
In addition to the truncation of the original protein, the iron-deficient sla phenotype may also be explained by the intracellular mislocalization of hephaestin. Wild type hephaestin localizes in a supra nuclear compartment as well as the basolateral surface. In contrast, sla hephaestin seems to localize only in the supranucelar compartment but is largely undetectable in the latter. Given hephaestin's established function in facilitating basolateral iron export, this mislocalization may explain the paradoxical intestinal iron accumulation and systemic iron deficiency observed in sla mice.
Human hephaestin, lacking the putative transmembrane domain, was first recombinantly expressed in 2005 by Drs. Tanya Griffiths, Grant Mauk, and Ross MacGillivray at the University of British Columbia. They demonstrated that recombinant human hephaestin (rhHp) bound copper (determined by inductively coupled plasma mass spectrometry) and exhibited an absorption maximum at ~610 nm consistent with other blue multicopper oxidases such as ceruloplasmin. By using ferrous ammonium sulfate as a substrate, rhHp was shown to have ferroxidase activity with a Km of 2.1 μM for Fe(II).
# Structure
Hephaestin is a member of the family of copper oxidases that includes mammalian ceruloplasmin, yeast fet3 and fet5, and bacterial ascorbate oxidase, among others. While hephaestin shares 50% amino acid sequence identity with its serum homologue ceruloplasmin, the hephaestin protein includes an additional 86 amino acids at the C-terminus, which code for a single transmembrane domain and a short cytoplasmic tail. While the structure and kinetic activity of ceruloplasmin have been studied extensively, hephaestin has yet to be investigated at a similar level. Comparative models of hephaestin's structure have been created using established crystallographic data from ceruloplasmin, and these studies suggest that many of the structural features important in the enzymatic function of the latter are also conserved in the former. In particular, these shared features include cysteine residues involved in disulfide bond formation, histidine residues involved in copper binding, and residues involved in the binding of the iron substrate.
# Regulation
The regulation of hephaestin expression and the protein's role in the larger picture of iron metabolism and homeostasis remain an active area of research. Some studies suggest mechanisms for local and systemic control of intestinal iron transport, in which high dietary iron intake and sufficient iron stores lead to down-regulation of DMT1, ferroportin (Ireg1) and hephaestin protein, thus minimizing iron absorption from the enterocytes into the circulation. Conversely, it is suggested that states of low dietary intake and low iron stores induce up-regulation of DMT1 as well as Ireg1 and hephaestin, thus simultaneously increasing the enterocyte's capacity for dietary iron uptake on the basolateral surface and export into the circulation on the apical surface.
# Relevance in Biology and Disease
Hephaestin has not yet been linked to a human disease. However, when the protein was ablated in murine models, both intestine-specific and whole-body hephaestin knockout (KO) strains exhibited similarly severe accumulation of iron in the duodenal enterocytes and suffered from microcytic, hypochromic anemia, indicative of systemic iron deficiency. The shared phenotype between the two strains suggests that intestinal hephaestin plays an important role in maintaining whole-body iron homeostasis. However, since both strains were viable, it is likely that hephaestin is not essential and other compensatory mechanisms exist to keep these mice alive.
In addition to the transport of iron from the intestine and into the circulation, ferroxidases also seem to play an important role in facilitating iron export from retinal cells. While deficiency in hephaestin or ceruloplasmin alone do not seem to cause iron buildup in the retina, studies done on murine models suggest that the combined deficiency is sufficient to cause age-dependent retinal pigment epithelium and retinal iron accumulation, with features consistent with macular degeneration. Hephaestin has been detected in mouse and human RPE (retinal pigment epithelial) cells as well as in rMC-1 cells (a rat Müller glial cell line), with greatest expression in the Müller endnote next to the internal limiting membrane. | Hephaestin
Hephaestin, also known as HEPH, is a protein which in humans is encoded by the HEPH gene.[1][2][3]
# Function
Hephaestin is involved in the metabolism and homeostasis of iron and possibly copper.[4] It is a transmembrane copper-dependent ferroxidase responsible for transporting dietary iron from intestinal enterocytes into the circulatory system. The highest expression of hephaestin is found in small intestine. It is limited to enterocytes of the villi (where the iron absorption takes place), being almost absent in crypt cells. Hephaestin converts iron(II) state, Fe2+, to iron(III) state, Fe3+, and mediates iron efflux most likely in cooperation with the basolateral iron transporter, ferroportin 1. To a lesser extent hephaestin has been detected in colon, spleen, kidney, breast, placenta and bone trabecular cells but its role in these tissues remains to be established. Hephaestin presents homology with ceruloplasmin, a serum dehydrogenase protein involved in copper detoxification and storage.
Hephaestin is a protein of 1135 aminoacids formed from a precursor of 1158 aminoacids and is 130.4 kDa. It is predicted to bind 6 copper ions per monomer.[5]
# Discovery
Hephaestin was first identified by Dr. Christopher D. Vulpe of the University of California, Berkeley in 1999.[2] They named the newfound protein after Hephaestus, the Greek god of metal working.
Much of what is known about hephaestin comes from studying heritable mutants of murine iron metabolism. The protein was discovered and identified through the study of mice with sex-linked anemia, or sla mice, in which there is normal mucosal uptake of dietary iron but impaired transport of iron from the intestinal enterocytes into the circulation. sla mice harbor a partial deletion mutation of the HEPH gene, resulting in the expression of a hephaestin protein that is truncated by 194 amino acids. Studies suggest that this truncated hephaestin protein still retains a minimal, yet detectable and quantifiable level of ferroxidase activity.[5] This raises the possibility that alternative factors may contribute to the decreased efflux of iron seen in the sla phenotype.
In addition to the truncation of the original protein, the iron-deficient sla phenotype may also be explained by the intracellular mislocalization of hephaestin. Wild type hephaestin localizes in a supra nuclear compartment as well as the basolateral surface.[6] In contrast, sla hephaestin seems to localize only in the supranucelar compartment but is largely undetectable in the latter.[7] Given hephaestin's established function in facilitating basolateral iron export, this mislocalization may explain the paradoxical intestinal iron accumulation and systemic iron deficiency observed in sla mice.
Human hephaestin, lacking the putative transmembrane domain, was first recombinantly expressed in 2005 by Drs. Tanya Griffiths, Grant Mauk, and Ross MacGillivray at the University of British Columbia.[8] They demonstrated that recombinant human hephaestin (rhHp) bound copper (determined by inductively coupled plasma mass spectrometry) and exhibited an absorption maximum at ~610 nm consistent with other blue multicopper oxidases such as ceruloplasmin. By using ferrous ammonium sulfate as a substrate, rhHp was shown to have ferroxidase activity with a Km of 2.1 μM for Fe(II).
# Structure
Hephaestin is a member of the family of copper oxidases that includes mammalian ceruloplasmin, yeast fet3 and fet5, and bacterial ascorbate oxidase, among others. While hephaestin shares 50% amino acid sequence identity with its serum homologue ceruloplasmin, the hephaestin protein includes an additional 86 amino acids at the C-terminus, which code for a single transmembrane domain and a short cytoplasmic tail.[9] While the structure and kinetic activity of ceruloplasmin have been studied extensively,[10] hephaestin has yet to be investigated at a similar level. Comparative models of hephaestin's structure have been created using established crystallographic data from ceruloplasmin, and these studies suggest that many of the structural features important in the enzymatic function of the latter are also conserved in the former. In particular, these shared features include cysteine residues involved in disulfide bond formation, histidine residues involved in copper binding, and residues involved in the binding of the iron substrate.[11]
# Regulation
The regulation of hephaestin expression and the protein's role in the larger picture of iron metabolism and homeostasis remain an active area of research. Some studies suggest mechanisms for local and systemic control of intestinal iron transport, in which high dietary iron intake and sufficient iron stores lead to down-regulation of DMT1, ferroportin (Ireg1) and hephaestin protein, thus minimizing iron absorption from the enterocytes into the circulation. Conversely, it is suggested that states of low dietary intake and low iron stores induce up-regulation of DMT1 as well as Ireg1 and hephaestin, thus simultaneously increasing the enterocyte's capacity for dietary iron uptake on the basolateral surface and export into the circulation on the apical surface.[12]
# Relevance in Biology and Disease
Hephaestin has not yet been linked to a human disease. However, when the protein was ablated in murine models, both intestine-specific and whole-body hephaestin knockout (KO) strains exhibited similarly severe accumulation of iron in the duodenal enterocytes and suffered from microcytic, hypochromic anemia, indicative of systemic iron deficiency. The shared phenotype between the two strains suggests that intestinal hephaestin plays an important role in maintaining whole-body iron homeostasis. However, since both strains were viable, it is likely that hephaestin is not essential and other compensatory mechanisms exist to keep these mice alive.[13]
In addition to the transport of iron from the intestine and into the circulation, ferroxidases also seem to play an important role in facilitating iron export from retinal cells. While deficiency in hephaestin or ceruloplasmin alone do not seem to cause iron buildup in the retina, studies done on murine models suggest that the combined deficiency is sufficient to cause age-dependent retinal pigment epithelium and retinal iron accumulation, with features consistent with macular degeneration.[14] Hephaestin has been detected in mouse and human RPE (retinal pigment epithelial) cells as well as in rMC-1 cells (a rat Müller glial cell line), with greatest expression in the Müller endnote next to the internal limiting membrane.[15] | https://www.wikidoc.org/index.php/Hephaestin | |
1f1d1709716564da78465dbf365fa250de5c8b19 | wikidoc | Heptaminol | Heptaminol
# Overview
Heptaminol is an amino alcohol which is classified as a vasodilator (C01DX08 (WHO)). It is sometimes used in the treatment of low blood pressure, particularly orthostatic hypotension. It is a potent positive inotrope (improving cardiac contraction)
It is classified as a doping substance. In 2008, the cyclist Dmitriy Fofonov was tested positive at the Tour de France. In June 2010, the swimmer Frédérick Bousquet was tested positive for the substance, allegedly for buying a medicine from the pharmacy.
In 2013, the cyclist Sylvain Georges was tested positive at the Giro d'Italia.
In 2014, baseball player Joel Piniero tested positive. | Heptaminol
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Heptaminol is an amino alcohol which is classified as a vasodilator (C01DX08 (WHO)). It is sometimes used in the treatment of low blood pressure, particularly orthostatic hypotension. It is a potent positive inotrope (improving cardiac contraction)
It is classified as a doping substance. In 2008, the cyclist Dmitriy Fofonov was tested positive at the Tour de France.[1] In June 2010, the swimmer Frédérick Bousquet was tested positive for the substance, allegedly for buying a medicine from the pharmacy.[2]
In 2013, the cyclist Sylvain Georges was tested positive at the Giro d'Italia.[3]
In 2014, baseball player Joel Piniero tested positive. [4] | https://www.wikidoc.org/index.php/Heptaminol | |
6b10599f8cd5b9687ecaf321fab3a3cdd09f1c2d | wikidoc | Herbimycin | Herbimycin
Herbimycin is a benzoquinone ansamycin antibiotic that binds to Hsp90 (Heat Shock Protein 90) and alters its function. HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis.
It was originally found by its herbicidal activity, and thus named.
# Synonyms
- Antibiotic Tan 420F
- Herbimycin A
# Biological activity
Herbimycin induces the degradation of proteins that are mutated in tumor cells such as v-Src, Bcr-Abl and p53 preferentially over their normal cellular counterparts. This effect is mediated via HSP90. | Herbimycin
Template:Chembox new
Herbimycin is a benzoquinone ansamycin antibiotic that binds to Hsp90 (Heat Shock Protein 90) and alters its function. HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis.
It was originally found by its herbicidal activity, and thus named.
# Synonyms
- Antibiotic Tan 420F
- Herbimycin A
# Biological activity
Herbimycin induces the degradation of proteins that are mutated in tumor cells such as v-Src, Bcr-Abl and p53 preferentially over their normal cellular counterparts. This effect is mediated via HSP90. | https://www.wikidoc.org/index.php/Herbimycin | |
f9acd5be0b9c7614b7cef170d65135a01e55c08b | wikidoc | Herkinorin | Herkinorin
Herkinorin is an opioid analgesic that is an analogue of the natural product Salvinorin A. It was discovered in 2005 during structure-activity relationship studies into neoclerodane diterpenes, the family of chemical compounds of which Salvinorin A is a member.
Unlike Salvinorin A which is a selective κ-opioid agonist with no significant μ-opioid receptor affinity, herkinorin is a μ-opioid agonist with more than 100x higher μ-opioid affinity and 50x lower κ-opioid affinity compared to Salvinorin A. Herkinorin is a semi-synthetic compound made from Salvinorin B, which is made from Salvinorin A, which is extracted from the plant Salvia divinorum.
Presumably herkinorin produces similar effects to other μ-opioid agonists, such as analgesia and sedation, along with side effects such as nausea, itching, vomiting and respiratory depression which may be harmful or fatal. However unlike most μ-opioid agonists, herkinorin does not promote the recruitment of β-arrestin-2 to the intracellular domain of the μ-opioid receptor, and so does not induce receptor internalisation. This means that herkinorin may not produce tolerance and dependence in the same way as other opioids, although some development of tolerance through other mechanisms has been observed. | Herkinorin
Herkinorin is an opioid analgesic that is an analogue of the natural product Salvinorin A. It was discovered in 2005 during structure-activity relationship studies into neoclerodane diterpenes, the family of chemical compounds of which Salvinorin A is a member.[1]
Unlike Salvinorin A which is a selective κ-opioid agonist with no significant μ-opioid receptor affinity, herkinorin is a μ-opioid agonist with more than 100x higher μ-opioid affinity and 50x lower κ-opioid affinity compared to Salvinorin A.[2][3] Herkinorin is a semi-synthetic compound made from Salvinorin B, which is made from Salvinorin A, which is extracted from the plant Salvia divinorum.[4]
Presumably herkinorin produces similar effects to other μ-opioid agonists, such as analgesia and sedation, along with side effects such as nausea, itching, vomiting and respiratory depression which may be harmful or fatal. However unlike most μ-opioid agonists, herkinorin does not promote the recruitment of β-arrestin-2 to the intracellular domain of the μ-opioid receptor, and so does not induce receptor internalisation.[5] This means that herkinorin may not produce tolerance and dependence in the same way as other opioids, although some development of tolerance through other mechanisms has been observed.[6]
Template:Pharm-stub | https://www.wikidoc.org/index.php/Herkinorin | |
564a146771ea494c3f7e2ac6993fe92480a3c95b | wikidoc | Hetacillin | Hetacillin
# Overview
Hetacillin is a beta-lactam antibiotic that is part of the aminopenicillin family. It is a prodrug and it has no antibacterial activity itself, but quickly splits of acetone in the human body to form ampicillin,which is active against a variety of bacteria.
# Administration
Hetacillin can be administered orally. The potassium salt, hetacillin potassium, is administered by injection, either intravenously or intramuscularly. It is sold under the trade name Hetacin for intramammary injection in veterinary use.
Hetacillin was removed from the market for human use when the discovery was made that it is actually cleaved in the gastrointestinal tract to formaldehyde and had no advantages over ampicillin.
# Chemistry
Hetacillin is prepared from ampicillin and acetone. In aqueous solutions it is unstable, with a half life of 15 to 30 minutes at 37 °C (98.6 °F) and pH 7, quickly releasing acetone again.
As opposed to ampicillin, hetacillin is only marginally broken down by the bacterial enzyme beta-lactamase, at least in vitro. | Hetacillin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Hetacillin is a beta-lactam antibiotic that is part of the aminopenicillin family. It is a prodrug and it has no antibacterial activity itself, but quickly splits of acetone in the human body to form ampicillin,which is active against a variety of bacteria.
# Administration
Hetacillin can be administered orally. The potassium salt, hetacillin potassium, is administered by injection, either intravenously or intramuscularly. It is sold under the trade name Hetacin for intramammary injection in veterinary use.
Hetacillin was removed from the market for human use when the discovery was made that it is actually cleaved in the gastrointestinal tract to formaldehyde and had no advantages over ampicillin.
# Chemistry
Hetacillin is prepared from ampicillin and acetone. In aqueous solutions it is unstable, with a half life of 15 to 30 minutes at 37 °C (98.6 °F) and pH 7, quickly releasing acetone again.
As opposed to ampicillin, hetacillin is only marginally broken down by the bacterial enzyme beta-lactamase, at least in vitro. | https://www.wikidoc.org/index.php/Hetacillin | |
846d7dd65f6d70309f34e87b7257d33d4502cb6e | wikidoc | Percolozoa | Percolozoa
The Percolozoa are a group of colourless protozoa, including many that can transform between amoeboid, flagellate, and encysted stages. These are collectively referred to as schizopyrenids, amoeboflagellates, or vahlkampfids. They also include the acrasids, a group of social amoebae that aggregate to form sporangia. The entire group is usually called the Heterolobosea, but this may be restricted to members with amoeboid stages.
Most Percolozoa are found as bacterivores in soil, freshwater, and on feces. There are a few marine and parasitic forms, including the species Naegleria fowleri, which can become pathogenic in humans and is often fatal. The group is closely related to the Euglenozoa, and share with them the unusual though not unique characteristic of having mitochondria with discoid cristae. The presence of a ventral feeding groove in the flagellate stage, as well as other features, suggests that they are part of the excavate group.
The amoeboid stage is roughly cylindrical, typically around 20-40 μm in length. They are traditionally considered lobose amoebae, but are not related to the others and unlike them do not form true lobose pseudopods. Instead, they advance by eruptive waves, where hemispherical bulges appear from the front margin of the cell, which is clear. The flagellate stage is slightly smaller, with two or four anterior flagella anterior to the feeding groove.
Usually the amoeboid form is taken when food is plentiful, and the flagellate form is used for rapid locomotion. However, not all members are able to assume both forms. The genera Percolomonas, Lyromonas, and Psalteriomonas are known only as flagellates, while Vahlkampfia, Pseudovahlkampfia, and the acrasids do not have flagellate stages. As mentioned above, under unfavourable conditions, the acrasids aggregate to form sporangia. These are superficially similar to the sporangia of the dictyostelids, but the amoebae only aggregate as individuals or in small groups and do not die to form the stalk.
The Heterolobosea were first defined by Page and Blanton in 1985 as a class of amoebae, and so only included those forms with amoeboid stages. Cavalier-Smith created the phylum Percolozoa for the extended group, together with the enigmatic flagellate Stephanopogon. He maintained the Heterolobosea as a class for amoeboid forms, but most others have expanded them to include the flagellates as well. | Percolozoa
The Percolozoa are a group of colourless protozoa, including many that can transform between amoeboid, flagellate, and encysted stages. These are collectively referred to as schizopyrenids, amoeboflagellates, or vahlkampfids. They also include the acrasids, a group of social amoebae that aggregate to form sporangia. The entire group is usually called the Heterolobosea, but this may be restricted to members with amoeboid stages.
Most Percolozoa are found as bacterivores in soil, freshwater, and on feces. There are a few marine and parasitic forms, including the species Naegleria fowleri, which can become pathogenic in humans and is often fatal. The group is closely related to the Euglenozoa, and share with them the unusual though not unique characteristic of having mitochondria with discoid cristae. The presence of a ventral feeding groove in the flagellate stage, as well as other features, suggests that they are part of the excavate group.
The amoeboid stage is roughly cylindrical, typically around 20-40 μm in length. They are traditionally considered lobose amoebae, but are not related to the others and unlike them do not form true lobose pseudopods. Instead, they advance by eruptive waves, where hemispherical bulges appear from the front margin of the cell, which is clear. The flagellate stage is slightly smaller, with two or four anterior flagella anterior to the feeding groove.
Usually the amoeboid form is taken when food is plentiful, and the flagellate form is used for rapid locomotion. However, not all members are able to assume both forms. The genera Percolomonas, Lyromonas, and Psalteriomonas are known only as flagellates, while Vahlkampfia, Pseudovahlkampfia, and the acrasids do not have flagellate stages. As mentioned above, under unfavourable conditions, the acrasids aggregate to form sporangia. These are superficially similar to the sporangia of the dictyostelids, but the amoebae only aggregate as individuals or in small groups and do not die to form the stalk.
The Heterolobosea were first defined by Page and Blanton in 1985[1] as a class of amoebae, and so only included those forms with amoeboid stages. Cavalier-Smith created the phylum Percolozoa for the extended group, together with the enigmatic flagellate Stephanopogon[2]. He maintained the Heterolobosea as a class for amoeboid forms, but most others have expanded them to include the flagellates as well. | https://www.wikidoc.org/index.php/Heterolobosea | |
d982f7562cdcba6654ea9c4c75db37ecd5a42f6c | wikidoc | Hexetidine | Hexetidine
# Overview
Hexetidine (Latin: Hexetidinum) is an anti-bacterial and anti-fungal agent commonly used in both veterinary and human medicine. It is a local anesthetic, astringent and deodorant and has antiplaque effects.
Hexetidine is the medicinal ingredient in Sterisol, which is labelled for "the symptomatic treatment of 'strep' throat, tonsillitis, pharyngitis, laryngitis, gingivitis, ulcerative stomatitis, oral thrush and Vincent's angina; postoperative hygiene following tonsillectomy, throat or oral surgery."
In the UK, Hexetidine is the active ingredient in the medicated mouthwash branded Oraldene. This is produced by Pfizer. Oraldene mouthwash contains 0.1g/100ml of Hexetidine. In some Eastern European countries, the gargle solution Hexoral (by Pfizer) also contains Hexetidine as its active compound. Hexetidine can also be found in the mouthwash Bactidol™ (by Pfizer) which is sold in many Asian countries. | Hexetidine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Hexetidine (Latin: Hexetidinum) is an anti-bacterial and anti-fungal agent commonly used in both veterinary and human medicine. It is a local anesthetic, astringent and deodorant and has antiplaque effects.[1][2]
Hexetidine is the medicinal ingredient in Sterisol, which is labelled for "the symptomatic treatment of 'strep' throat, tonsillitis, pharyngitis, laryngitis, gingivitis, ulcerative stomatitis, oral thrush and Vincent's angina; postoperative hygiene following tonsillectomy, throat or oral surgery."
In the UK, Hexetidine is the active ingredient in the medicated mouthwash branded Oraldene. This is produced by Pfizer. Oraldene mouthwash contains 0.1g/100ml of Hexetidine. In some Eastern European countries, the gargle solution Hexoral (by Pfizer) also contains Hexetidine as its active compound. Hexetidine can also be found in the mouthwash Bactidol™ (by Pfizer) which is sold in many Asian countries.
# External links
- European Agency for the Evaluation of Medicinal Products overview of the medicinal properties
- netDoctor | https://www.wikidoc.org/index.php/Hexetidine | |
6f4c640f2afc3f738e66b2f27220b863f0a7f29e | wikidoc | Hexokinase | Hexokinase
A hexokinase is an enzyme that phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate of hexokinases, and glucose-6-phosphate is the most important product. Hexokinase possesses the ability to transfer an inorganic phosphate group from ATP to a substrate.
Hexokinases should not be confused with glucokinase, which is a specific isoform of hexokinase. All hexokinases are capable of phosphorylating several hexoses but glucokinase acts with a 50-fold lower substrate affinity and its main hexose substrate is glucose.
# Variation
Genes that encode hexokinase have been discovered in every domain of life, and exist among a variety of species that range from bacteria, yeast, and plants to humans and other vertebrates. They are categorized as actin fold proteins, sharing a common ATP binding site core that is surrounded by more variable sequences which determine substrate affinities and other properties.
Several hexokinase isoforms or isozymes that provide different functions can occur in a single species.
# Reaction
The intracellular reactions mediated by hexokinases can be typified as:
where hexose-CH2OH represents any of several hexoses (like glucose) that contain an accessible -CH2OH moiety.
Action of Hexokinase on Glucose
# Consequences of hexose phosphorylation
Phosphorylation of a hexose such as glucose often limits it to a number of intracellular metabolic processes, such as glycolysis or glycogen synthesis. This is because phosphorylated hexoses are charged, and thus more difficult to transport out of a cell.
In patients with essential fructosuria, metabolism of fructose by hexokinase to fructose-6-phosphate is the primary method of metabolizing dietary fructose; this pathway is not significant in normal individuals.
# Size of different isoforms
Most bacterial hexokinases are approximately 50 kD in size. Multicellular organisms including plants and animals often have more than one hexokinase isoform. Most are about 100 kD in size and consist of two halves (N and C terminal), which share much sequence homology. This suggests an evolutionary origin by duplication and fusion of a 50kD ancestral hexokinase similar to those of bacteria.
# Types of mammalian hexokinase
There are four important mammalian hexokinase isozymes (EC 2.7.1.1) that vary in subcellular locations and kinetics with respect to different substrates and conditions, and physiological function. They are designated hexokinases I, II, III, and IV or hexokinases A, B, C, and D.
## Hexokinases I, II, and III
Hexokinases I, II, and III are referred to as "low-Km" isozymes because of a high affinity for glucose (below 1 mM). Hexokinases I and II follow Michaelis-Menten kinetics at physiologic concentrations of substrates. All three are strongly inhibited by their product, glucose-6-phosphate. Molecular weights are around 100 kD. Each consists of two similar 50kD halves, but only in hexokinase II do both halves have functional active sites.
- Hexokinase I/A is found in all mammalian tissues, and is considered a "housekeeping enzyme," unaffected by most physiological, hormonal, and metabolic changes.
- Hexokinase II/B constitutes the principal regulated isoform in many cell types and is increased in many cancers. It is the hexokinase found in muscle and heart. Hexokinase II is also located at the mitochondria outer membrane so it can have direct access to ATP.
- Hexokinase III/C is substrate-inhibited by glucose at physiologic concentrations. Little is known about the regulatory characteristics of this isoform.
## Hexokinase IV ("glucokinase")
Mammalian hexokinase IV, also referred to as glucokinase, differs from other hexokinases in kinetics and functions.
The location of the phosphorylation on a subcellular level occurs when glucokinase translocates between the cytoplasm and nucleus of liver cells. Glucokinase can only phosphorylate glucose if the concentration of this substrate is high enough; its Km for glucose is 100 times higher than that of hexokinases I, II, and III.
Hexokinase IV is monomeric, about 50kD, displays positive cooperativity with glucose, and is not allosterically inhibited by its product, glucose-6-phosphate.
Hexokinase IV is present in the liver, pancreas, hypothalamus, small intestine, and perhaps certain other neuroendocrine cells, and plays an important regulatory role in carbohydrate metabolism. In the beta cells of the pancreatic islets, it serves as a glucose sensor to control insulin release, and similarly controls glucagon release in the alpha cells. In hepatocytes of the liver, glucokinase responds to changes of ambient glucose levels by increasing or reducing glycogen synthesis.
# In glycolysis
Glucose is unique in that it can be used to produce ATP by all cells in both the presence and absence of molecular oxygen (O2). The first step in glycolysis is the phosphorylation of glucose by hexokinase.
Compound C00031 at KEGG Pathway Database. Enzyme 2.7.1.1 at KEGG Pathway Database. Compound C00668 at KEGG Pathway Database. Reaction R01786 at KEGG Pathway Database.
By catalyzing the phosphorylation of glucose to yield glucose 6-phosphate, hexokinases maintain the downhill concentration gradient that favors the facilitated transport of glucose into cells. This reaction also initiates all physiologically relevant pathways of glucose utilization, including glycolysis and the pentose phosphate pathway. The addition of a charged phosphate group at the 6-position of hexoses also ensures 'trapping' of glucose and 2-deoxyhexose glucose analogs (e.g. 2-deoxyglucose, and 2-fluoro-2-deoxyglucose) within cells, as charged hexose phosphates cannot easily cross the cell membrane.
# Association with mitochondria
Hexokinases I and II can associate physically to the outer surface of the external membrane of mitochondria through specific binding to a porin, or voltage dependent anion channel. This association confers hexokinase direct access to ATP generated by mitochondria, which is one of the two substrates of hexokinase. Mitochondrial hexokinase is highly elevated in rapidly growing malignant tumor cells, with levels up to 200 times higher than normal tissues. Mitochondrially bound hexokinase has been demonstrated to be the driving force for the extremely high glycolytic rates that take place aerobically in tumor cells (the so-called Warburg effect described by Otto Heinrich Warburg in 1930).
# Hydropathy plot
The potential transmembrane portions of a protein can be detected by hydropathy analysis. A hydropathy analysis uses an algorithm that quantifies the hydrophobic character at each position along the polypeptide chain. One of the accepted hydropathy scales is that of Kyte and Doolittle which relies on the generation of hydropathy plots. In these plots, the negative numbers represent hydrophilic regions and the positive numbers represent hydrophobic regions on the y-axis. A potential transmembrane domain is about 20 amino acids long on the x-axis.
A hydropathy analysis of hexokinase in yeast has been created by these standards. It appears as if hexokinase possesses a single potential transmembrane domain located around amino acid 400. Therefore, hexokinase is most likely not an integral membrane protein in yeast.
# Deficiency
Hexokinase deficiency is a genetic autosomal recessive disease that causes Chronic Haemolytic Anaemia. Chronic Haemolytic Anaemia is caused by a mutation in the HK gene, which codes for the HK enzyme. The mutation causes a reduction of the HK activity, which causes hexokinase deficiency. | Hexokinase
A hexokinase is an enzyme that phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate of hexokinases, and glucose-6-phosphate is the most important product. Hexokinase possesses the ability to transfer an inorganic phosphate group from ATP to a substrate.
Hexokinases should not be confused with glucokinase, which is a specific isoform of hexokinase. All hexokinases are capable of phosphorylating several hexoses but glucokinase acts with a 50-fold lower substrate affinity and its main hexose substrate is glucose.
# Variation
Genes that encode hexokinase have been discovered in every domain of life, and exist among a variety of species that range from bacteria, yeast, and plants to humans and other vertebrates. They are categorized as actin fold proteins, sharing a common ATP binding site core that is surrounded by more variable sequences which determine substrate affinities and other properties.
Several hexokinase isoforms or isozymes that provide different functions can occur in a single species.
# Reaction
The intracellular reactions mediated by hexokinases can be typified as:
where hexose-CH2OH represents any of several hexoses (like glucose) that contain an accessible -CH2OH moiety.
Action of Hexokinase on Glucose
# Consequences of hexose phosphorylation
Phosphorylation of a hexose such as glucose often limits it to a number of intracellular metabolic processes, such as glycolysis or glycogen synthesis. This is because phosphorylated hexoses are charged, and thus more difficult to transport out of a cell.
In patients with essential fructosuria, metabolism of fructose by hexokinase to fructose-6-phosphate is the primary method of metabolizing dietary fructose; this pathway is not significant in normal individuals.
# Size of different isoforms
Most bacterial hexokinases are approximately 50 kD in size. Multicellular organisms including plants and animals often have more than one hexokinase isoform. Most are about 100 kD in size and consist of two halves (N and C terminal), which share much sequence homology. This suggests an evolutionary origin by duplication and fusion of a 50kD ancestral hexokinase similar to those of bacteria.
# Types of mammalian hexokinase
There are four important mammalian hexokinase isozymes (EC 2.7.1.1) that vary in subcellular locations and kinetics with respect to different substrates and conditions, and physiological function. They are designated hexokinases I, II, III, and IV or hexokinases A, B, C, and D.
## Hexokinases I, II, and III
Hexokinases I, II, and III are referred to as "low-Km" isozymes because of a high affinity for glucose (below 1 mM). Hexokinases I and II follow Michaelis-Menten kinetics at physiologic concentrations of substrates.[citation needed] All three are strongly inhibited by their product, glucose-6-phosphate. Molecular weights are around 100 kD. Each consists of two similar 50kD halves, but only in hexokinase II do both halves have functional active sites.
- Hexokinase I/A is found in all mammalian tissues, and is considered a "housekeeping enzyme," unaffected by most physiological, hormonal, and metabolic changes.
- Hexokinase II/B constitutes the principal regulated isoform in many cell types and is increased in many cancers. It is the hexokinase found in muscle and heart. Hexokinase II is also located at the mitochondria outer membrane so it can have direct access to ATP.[2]
- Hexokinase III/C is substrate-inhibited by glucose at physiologic concentrations. Little is known about the regulatory characteristics of this isoform.
## Hexokinase IV ("glucokinase")
Mammalian hexokinase IV, also referred to as glucokinase, differs from other hexokinases in kinetics and functions.
The location of the phosphorylation on a subcellular level occurs when glucokinase translocates between the cytoplasm and nucleus of liver cells. Glucokinase can only phosphorylate glucose if the concentration of this substrate is high enough; its Km for glucose is 100 times higher than that of hexokinases I, II, and III.
Hexokinase IV is monomeric, about 50kD, displays positive cooperativity with glucose, and is not allosterically inhibited by its product, glucose-6-phosphate.
Hexokinase IV is present in the liver, pancreas, hypothalamus, small intestine, and perhaps certain other neuroendocrine cells, and plays an important regulatory role in carbohydrate metabolism. In the beta cells of the pancreatic islets, it serves as a glucose sensor to control insulin release, and similarly controls glucagon release in the alpha cells. In hepatocytes of the liver, glucokinase responds to changes of ambient glucose levels by increasing or reducing glycogen synthesis.
# In glycolysis
Glucose is unique in that it can be used to produce ATP by all cells in both the presence and absence of molecular oxygen (O2). The first step in glycolysis is the phosphorylation of glucose by hexokinase.
Compound C00031 at KEGG Pathway Database. Enzyme 2.7.1.1 at KEGG Pathway Database. Compound C00668 at KEGG Pathway Database. Reaction R01786 at KEGG Pathway Database.
By catalyzing the phosphorylation of glucose to yield glucose 6-phosphate, hexokinases maintain the downhill concentration gradient that favors the facilitated transport of glucose into cells. This reaction also initiates all physiologically relevant pathways of glucose utilization, including glycolysis and the pentose phosphate pathway.[3] The addition of a charged phosphate group at the 6-position of hexoses also ensures 'trapping' of glucose and 2-deoxyhexose glucose analogs (e.g. 2-deoxyglucose, and 2-fluoro-2-deoxyglucose) within cells, as charged hexose phosphates cannot easily cross the cell membrane.
# Association with mitochondria
Hexokinases I and II can associate physically to the outer surface of the external membrane of mitochondria through specific binding to a porin, or voltage dependent anion channel. This association confers hexokinase direct access to ATP generated by mitochondria, which is one of the two substrates of hexokinase. Mitochondrial hexokinase is highly elevated in rapidly growing malignant tumor cells, with levels up to 200 times higher than normal tissues. Mitochondrially bound hexokinase has been demonstrated to be the driving force[4] for the extremely high glycolytic rates that take place aerobically in tumor cells (the so-called Warburg effect described by Otto Heinrich Warburg in 1930).
# Hydropathy plot
The potential transmembrane portions of a protein can be detected by hydropathy analysis. A hydropathy analysis uses an algorithm that quantifies the hydrophobic character at each position along the polypeptide chain. One of the accepted hydropathy scales is that of Kyte and Doolittle which relies on the generation of hydropathy plots. In these plots, the negative numbers represent hydrophilic regions and the positive numbers represent hydrophobic regions on the y-axis. A potential transmembrane domain is about 20 amino acids long on the x-axis.
A hydropathy analysis of hexokinase in yeast has been created by these standards. It appears as if hexokinase possesses a single potential transmembrane domain located around amino acid 400. Therefore, hexokinase is most likely not an integral membrane protein in yeast.[5]
# Deficiency
Hexokinase deficiency is a genetic autosomal recessive disease that causes Chronic Haemolytic Anaemia. Chronic Haemolytic Anaemia is caused by a mutation in the HK gene, which codes for the HK enzyme. The mutation causes a reduction of the HK activity, which causes hexokinase deficiency. [6] | https://www.wikidoc.org/index.php/Hexokinase | |
ff4247e803f64caffbe8245326ca752b4c663e80 | wikidoc | Hikikomori | Hikikomori
# Background
# Definition
Although there are versions where the hikikomori may venture outdoors, the Japanese Ministry of Health, Labour and Welfare defines hikikomori as individuals who refuse to leave their parents' house, and isolate themselves away from society and family in a single room for a period exceeding six months. While the severity of the phenomenon varies depending on the individual, some youths remain in isolation for years, or in rare cases, decades. Often hikikomori start out as school refusals, or tōkōkyohi (登校拒否) in Japanese.
# Situation
## Japan
According to psychologist Tamaki Saito, who first coined the phrase, there may be one million hikikomori in Japan, twenty percent of all male adolescents in Japan, or one percent of the total Japanese population. Saito later admitted in his autobiography (Hakushi no kimyo na shishunki) that he made up this number to draw attention to the problem and that it had no factual basis. He had based the figure on the number of schizophrenics found in Japanese society. His clinical work had convinced him that there were at least that many hikikomori. After the syndrome was officially recognized, the number of reported cases turned out to be in the low thousands. However, it must be remembered that like any social stigma, the actual number of cases may be significantly higher than what gets reported.
Though acute social withdrawal in Japan appears to affect both genders equally, due to differing social expectations for maturing boys and girls, the most widely reported cases of hikikomori are from Japanese families with male children who seek outside intervention when a son, usually the eldest, refuses to leave the family home.
## Worldwide
While total social withdrawal has been claimed to be mainly a Japanese phenomenon, there are reports of similar phenomena developing in South Korea, Taiwan and China. When a BBC program claiming that hikikomori was a Japanese phenomenon was aired in Britain, the BBC home page received numerous messages from viewers in the United Kingdom saying that they had personal experience with hikikomori and that it was hardly a phenomenon particular to Japan. Even the most casual search of anglophonic materials will show that essentially the same phenomenon is found in the United States, Australia, Canada, Britain, etc.
# Causes
## General causes
Sometimes referred to as a kind of social problem in Japanese discourse, the hikikomori phenomenon has a number of possible contributing factors. Young adults may feel overwhelmed by modern Japanese society, or be unable to fulfill their expected social roles as they have not yet formulated a sense of personal tatemae (the public facade) and honne (the "true self") – both of which are needed to cope with the daily paradoxes of adulthood.
The dominant nexus of the hikikomori issue centers on the transformation from young life to the responsibilities and expectations of adult life — indications are that advanced capitalist societies such as modern Japan fail to provide sufficient meaningful transformation rituals for promoting certain susceptible types of youth into mature roles within society.
As with many advanced capitalist meritocracies, there exists a great deal of pressure on adolescents in Japan to be successful and perpetuate the existing social status-quo. A traditionally strong emphasis on complex social conduct, rigid hierarchies and the resulting, potentially intimidating multitude of social expectations, responsibilities and duties in Japanese society contribute to this pressure on young adults. Historically, Confucian teachings de-emphasizing the individual and favoring a conformist stance to ensure social harmony in a rigidly hierarchized society have shaped much of the Sinosphere, possibly explaining the emergence of the hikikomori phenomenon in other East-Asian countries.
In general, the prevalence of hikikomori tendencies in Japan may be encouraged and facilitated by three primary factors:
- Middle class affluence in a post-industrial society such as Japan allows parents to support and feed an adult child indefinitely in the home. Lower income families do not have hikikomori children because a socially withdrawing youth is forced to work outside the home if he cannot finish school, and for this reason isolation in the room stops at an early stage.
- The inability of Japanese parents to recognize and act upon the youth's slide into isolation, soft parenting, or even a codependent collusion between mother and son known as amae in Japanese. When a youth withdraws from life, parents can act or respond in such a way that causes the child to become even more seclusionary.
- A decade of flat economic indicators and a shaky job market in Japan makes the pre-existing system requiring years of competitive schooling for elite jobs a pointless effort. While Japanese fathers of the current generation of youth still enjoy lifetime employment at multinational corporations, incoming employees in Japan enjoy no such job guarantees in today's job market (See Freeters and NEET for more on this). Young Japanese people are savvy enough to see that the system in place for their grandfathers and fathers no longer works, and for some the lack of a clear life goal makes them susceptible to social withdrawal as a hikikomori.
Lastly, it should be noted that the hikikomori phenomenon is similar to the symptoms exhibited by people with Pervasive Developmental Disorders in western cultures. Japan has the highest incidence of Pervasive Developmental Disorders, a group of disorders including autism and Asperger’s syndrome, in the developed world. In Japan, PDDs are some 2.95 times more common than in western countries. Some 3.3% of Japanese males have PDD compared with approximately 1% in Europe and the US. This has led some western commentators to suggest that people with hikikomori are affected by PDDs or disorders that affect social competence, but that their disorders are altered from their typical western presentation by the social and cultural pressures unique to Japan.
According to Michael Zielenziger's book, Shutting out the Sun: How Japan Created its Own Lost Generation, the syndrome is more closely related to Post Tramatic Stress Disorder or PTSD. The hikikomori studied and interviewed for Zielenziger's book were not autistic, but bright intelligent people who have discovered independent thinking and a sense of self that the current Japanese environment cannot accommodate. For the most part they have no one to talk to. They are victims of the social and cultural pressures of Japan.
## The education system
The Japanese education system, like those found in China, Singapore, Taiwan, and South Korea, and similar to the school systems in India, puts great demands upon youth. A multitude of expectations, high emphasis on competition, and the rote memorization of facts and figures for the purpose of passing entrance exams into the next tier of education in what could be termed a rigid pass-or-fail ideology, induce a high level of stress. Echoing the traditional Confucian values of society, the educational system is still viewed as playing an important part in society's overall productivity and success. In this social frame, students often face significant pressure from parents and the society in general to conform to its dictates and doctrines. These doctrines, while part of modern Japanese society, are increasingly being rejected by Japanese youth in varying ways such as hikikomori, freeter, NEET (Not currently engaged in Employment, Education, or Training), and parasite singles.
Beginning in the 1960s, the pressure on Japanese youth to succeed began successively earlier in their lives, sometimes starting before pre-school, where even toddlers had to compete through an entrance exam for the privilege of attending one of the best pre-schools. This was said to prepare children for the entrance exam of the best kindergarten, which in turn prepared the child for the entrance exam of the best primary school, junior high school, high school, and eventually for their university entrance exam. Many adolescents take one year off after high school to study exclusively for the university entrance exam. The higher the prestige of the university, the more difficult the exam, the most prestigious university with the most difficult exam being the University of Tokyo.
Since 1996, the Japanese Ministry of Education has taken steps to address this 'pressure-cooker' educational environment and instill greater creative thought in Japanese youth by significantly relaxing the school schedule from six day weeks to five day weeks and dropping two subjects from the daily schedule, with new academic curricula more comparable to Western educational models. However this may be too little too late, as highly competitive Japanese parents are sending their children to private cram schools to 'make up' for the newly lax curricula in the Japanese public schools.
After graduating from high school or university, Japanese youth also have to face a very difficult job market in Japan, often finding only part-time employment and ending up as freeters with little income, unable to start a family.
Another source of pressure is from their co-students, who may harass and bully some students for a variety of reasons, including physical appearance (especially if they are overweight or have severe acne problems), wealth, educational or athletic performance, or even having lived overseas for a short period. Some have been punished for bullying or truancy, bringing shame to their families.
# Symptoms
While many people feel the pressure of the outside world, and may feel uncomfortable in public (or "social anxiety"), a hikikomori reacts by complete social withdrawal to avoid all outside pressure. In some cases, they may lock themselves into their bedroom or another room of their parent's house for prolonged periods of time, sometimes measured in years. They usually have few, or no friends. A hikikomori's days are characterized by long spells of sleeping, while their nighttime hours are often spent watching TV, extensively playing computer games, surfing the Internet, reading, trading the stock, forex, derivatives markets (i.e. stock future indices) or other non-social activities. One of the most prominent cases of an isolated trader who lived in his parents home is the Japanese individual who traded the JASDAQ Securities Exchange with 1 million yen (apr. US$10,000) as capital, whose alias is B.N.F (J-Com man). Starting in 2003 he managed to exponentially grow his account 10,000 fold in three years up to 10 billion yen (apr. US$100 million). He first gained fame on the Japanese mass media when he managed to profit 2 billion yen (apr. US$20 million) in a window of 10 minutes on 8 December 2005 from a Mizuho Securities order misplacement blunder. Although rare, ironically some of the adult-onset hikikomori people have succeeded in becoming extremely wealthy and in achieving financial freedom, in contrast to their more conformist salaryman counterparts.
Refusal to participate in society and fulfill their expected roles makes hikikomori an extreme subset of a much larger group of the younger Japanese generation that includes parasite singles and freeters. All three groups seem to be rejecting the current social norms society has placed upon them in their own unique ways, with lifestyles considered deviant by society at large.
The withdrawal from society usually starts gradually. Affected individuals may appear unhappy, lose their friends, become insecure, shy, and talk less. Those in their teens may be bullied at school, which, atop the already high pressures of school and family, may be the final trigger for the withdrawal.
Hikikomori often set their own sleep schedule, typically waking in the afternoon and going to bed in the early morning. While they are awake, they may engage in a variety of activities shared with other people of their age, including listening to music, surfing the Internet or actively posting in Internet forums like 2channel, which has become famous for its hikikomori population. While hikikomori favor indoor activities, most of them do venture outdoors on occasion, though they may prefer to do that at night.
# Effects
## On the individual
The lack of social contact and prolonged solitude has a profound effect on the mentality of the hikikomori, who gradually lose their social skills, social references and mores necessary to interact with the outside world. They may immerse themselves into the fantasy worlds of manga, anime and video games, which in turn become their only frame of reference. Due to a lack of interpersonal stimulus the hikikomori may developmentally stagnate into routine behaviors as time passes, sleeping all day and staying up all night only to sneak out into the kitchen for food when the family is asleep. In extreme cases, the hikikomori eventually abandons all diversions of books and TV and simply stares into space for hours at a time.
Should a hikikomori decide to give up his seclusion, whether on his own or through the aid of a care worker, they may face the problem of lacking social skills and years of education that their peers already possess through normal daily interaction with society. Also making reentry into society difficult is the recent social stigma that has come to be attached to the condition due to mass media attention since 1998. As a result, some former hikikomori might be afraid that others will discover their past, adding to their feeling of insecurity around people, especially strangers, in how they should act. Also detrimental is the fact they lack a work history, making anything beyond menial jobs difficult to acquire.
## On the family
Having a hikikomori in the family is often considered embarrassing, so usually it is acknowledged as an internal private matter of the family, and many parents wait for a long time before seeking help from a third party within the hikikomori support industry. Also, in Japan the education of the children is traditionally done by the mother, and the father may leave the problem of a hikikomori to the mother, who feels very protective of her child. Initially, most parents simply wait and hope that the child will eventually overcome his problems and return to society by his own will. They see it as a phase the child has to overcome. Also, many parents are uncertain about what to do with a hikikomori, and wait simply due to lack of other options. An aggressive approach by the parents forcing the child back into society is usually not taken or only after a considerable waiting period.
In some cases, school homeroom teachers and social workers make inquiries, but usually do not get involved with the situation. In recent years, due to widespread media attention, having a family member who is a hikikomori has come to have a social stigma attached to the condition akin to mental illness. Due to this stigma and the resultant shame, many families strive to keep their child's hikikomori condition a secret from those in the community, thus further delaying parents from seeking outside intervention for their child.
# Controversy
Hikikomori gained increased worldwide attention when the media attributed a number of high profile crimes to it a few years ago. In 2000, a 17-year-old labeled as a hikikomori by the press hijacked a bus and killed one passenger. In fact, it was discovered later that the hijacker had originally been a hikikomori, but his parents, in frustration, had committed him to a mental hospital for two months of observation. Allegedly, the boy felt betrayed by his parents as a result of his hospital admission, and some argue that the violence during the bus hijacking was directed at his mother by proxy. In the ensuing days, the media characterized other extremely violent crimes as having been perpetrated by hikikomori, such as one man who kidnapped ten-year-old Sano Fusako and held her captive for nine years and two months, or Tsutomu Miyazaki, who in 1989 killed four young girls. As a result of this negative media attention, hikikomori acquired a social stigma of being violent and mentally ill that persists to this day.
In 2004, 29-year-old Japanese-Dutch film school student Danyael Sugawara made a film based on hikikomori called “Tamago" ("Egg").
The hikikomoris' fear of social pressure and concurrent inability to effect change in their situation may turn into frustration or even anger. Some hikikomori have physically attacked their parents, though most of the time anger manifests in other ways, such as nightly harassment by banging on walls while the rest of the family sleeps.
This hostility often arises when parents continue to exert pressure on the hikikomori to come out of their rooms after many months of isolation, despite the fact that a status quo has been allowed to develop between the parents, usually the mother, and the hikikomori. This status quo, called the Strange Peace, occurs because parents passively allow their child to stay withdrawn. It can have many causes but mostly centers on an amae relationship between mother and son, the fear and social stigma of the local community knowing the family has a hikikomori, and the notion that it is better to have the child in the house even in isolation than as a runaway.
When hikikomori came into the public spotlight, mass media sources initially argued that the loss of a social frame of reference might lead hikikomori to commit violent or criminal acts. However, hikikomori experts maintain that true hikikomori are too socially withdrawn and timid to venture outside of their rooms, let alone go outside the home and attack someone. If hikikomori physically attack anyone, it is usually family members.
# Reaction
## Treatment
There are different opinions about the treatment of a hikikomori, and the opinions often split into a Japanese and a western point of view. Japanese experts usually suggest waiting until the hikikomori reemerges, whereas western doctors suggest dragging the hikikomori back into society, by force if necessary.
While there are a growing number of doctors and clinics specialized in helping hikikomori, many hikikomori and their parents still feel a lack of support for their problems on an institutional level and feel that society at large has been slow to react to the hikikomori crisis. In the last several years, a hikikomori support industry has sprung up in Japan, each with its own style or philosophy in treating hikikomori cases. Despite this diversity, there seem to be two general camps for treatment:
- The psychological approach suggests psychological help is needed for these isolated young people, as many parents are overwhelmed with the problems of a hikikomori child whom they don’t understand. The standard psychological approach to hikikomori behavior in a youth is to treat the condition as a behavioral or mental disorder and so admit the child to a hospital ward in order to administer counseling, observation, and drug therapy using standard institutional procedures.
- The socialization approach to hikikomori treatment views the problem as one of socialization rather than mental illness. Instead of clinical treatment in a hospital, the hikikomori is removed from the original environment of the home into a shared living environment and encouraged to reintegrate into social groups through daily activities with other hikikomori who are already in various states of recovery; this approach shows the person that they are not alone in their condition and appears to be successful for most cases.
- Hikikomori may not find a free space to express himself as an individual because some feel Japanese culture doesn't provide such a frame. In that instance, a possible way of treatment is to encourage a Hikikomori to share social experiences outside Japan, for a short or long period.
## Acceptance
In contrast to the approach of treatment, some may argue that the Hikikomori status is a personality type or lifestyle to be accepted, or resolved, within the respective families, as long as this choice doesn't lead to criminal or violent behaviour. Some argue that there is a tendency in societies — especially those, like Japanese society, that emphasize conformity — to label people who differ from the norm "pathologically ill," and urge greater concern for the wishes of the individual. (Similar issues have been raised about Asperger Syndrome and Schizoid Personality Disorder.)
In some cases a Hikikomori partially or completely recovers in time when given a free house or apartment of his own.
# References in pop culture
- The light novel, manga and anime series Welcome to the NHK! created by Tatsuhiko Takimoto and illustrated by Kenji Oiwa, currently serialized in the magazine Monthly Shōnen Ace deals with hikikomori as a central theme.
- In the manga and anime, Rozen Maiden, the main character, Jun Sakurada, suffers from hikikomori after cracking under the pressure of entrance exams. In the manga, his reasoning is different.
- Episode 2 of the live action TV series Jigoku Shōjo (based on the popular anime series of the same name) tells a short story of a hikikomori who exacts revenge against the person who led his father to commit suicide.
- Endrance, one of the major characters of .hack//G.U., is a hikikomori outside of the game, spending most of his time playing it.
- In the 2002 film Moon Overflowing (Koboreru Tsuki), one of the main characters is a hikikomori.
- The 2004 film Hikikomori: Tokyo Plastic by director Adario Strange.
- 2004 film The Quiet One by Danyael Sugawara
- In the film Densha Otoko, the main character is given advice over the Internet by a hikikomori.
- In the 2006 South Korean horror film APT.
- In the drama Ikebukuro West Gate Park, the minor character Kazunori gradually recovers from his hikikomori status.
- In the 2007 summer anime called Hayate no Gotoku, the main female lead Nagi Sanzen'in is a hikikomori, although her family is very rich and prestigious, however she herself has her own huge fortune without ever needing her family's fortune or inheritance.
- In the manga and anime series Sayonara Zetsubou Sensei, one recurring character, Kiri Komori, is a hikikomori.
- In the dorama Seito Shokun!, one of the students in class 2–3, Shirai Naoki, became a hikikomori after a mountain climbing accident, after which his teacher left his class alone on the mountain to die. He finally comes out of his room in episode 4. | Hikikomori
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
Template:Nihongo is a Japanese term to refer to the phenomenon of reclusive individuals who have chosen to withdraw from social life, often seeking extreme degrees of isolation and confinement due to various personal and social factors in their lives. The term hikikomori refers to both the sociological phenomenon in general as well as to individuals belonging to this societal group.
# Definition
Although there are versions where the hikikomori may venture outdoors, [1] the Japanese Ministry of Health, Labour and Welfare defines hikikomori as individuals who refuse to leave their parents' house, and isolate themselves away from society and family in a single room for a period exceeding six months.[citation needed] While the severity of the phenomenon varies depending on the individual, some youths remain in isolation for years, or in rare cases, decades. Often hikikomori start out as school refusals, or tōkōkyohi (登校拒否) in Japanese.
# Situation
## Japan
According to psychologist Tamaki Saito, who first coined the phrase, there may be one million hikikomori in Japan, twenty percent of all male adolescents in Japan, or one percent of the total Japanese population. Saito later admitted in his autobiography (Hakushi no kimyo na shishunki) that he made up this number to draw attention to the problem and that it had no factual basis. He had based the figure on the number of schizophrenics found in Japanese society. His clinical work had convinced him that there were at least that many hikikomori. After the syndrome was officially recognized, the number of reported cases turned out to be in the low thousands.[citation needed] However, it must be remembered that like any social stigma, the actual number of cases may be significantly higher than what gets reported.
Though acute social withdrawal in Japan appears to affect both genders equally, due to differing social expectations for maturing boys and girls, the most widely reported cases of hikikomori are from Japanese families with male children who seek outside intervention when a son, usually the eldest, refuses to leave the family home.
## Worldwide
While total social withdrawal has been claimed to be mainly a Japanese phenomenon, there are reports of similar phenomena developing in South Korea, Taiwan and China.[citation needed] When a BBC program claiming that hikikomori was a Japanese phenomenon was aired in Britain, the BBC home page received numerous messages from viewers in the United Kingdom saying that they had personal experience with hikikomori and that it was hardly a phenomenon particular to Japan. Even the most casual search of anglophonic materials will show that essentially the same phenomenon is found in the United States, Australia, Canada, Britain, etc.[citation needed]
# Causes
## General causes
Sometimes referred to as a kind of social problem in Japanese discourse, the hikikomori phenomenon has a number of possible contributing factors. Young adults may feel overwhelmed by modern Japanese society, or be unable to fulfill their expected social roles as they have not yet formulated a sense of personal tatemae (the public facade) and honne (the "true self") – both of which are needed to cope with the daily paradoxes of adulthood.
The dominant nexus of the hikikomori issue centers on the transformation from young life to the responsibilities and expectations of adult life — indications are that advanced capitalist societies such as modern Japan fail to provide sufficient meaningful transformation rituals for promoting certain susceptible types of youth into mature roles within society.
As with many advanced capitalist meritocracies, there exists a great deal of pressure on adolescents in Japan to be successful and perpetuate the existing social status-quo. A traditionally strong emphasis on complex social conduct, rigid hierarchies and the resulting, potentially intimidating multitude of social expectations, responsibilities and duties in Japanese society contribute to this pressure on young adults. Historically, Confucian teachings de-emphasizing the individual and favoring a conformist stance to ensure social harmony in a rigidly hierarchized society have shaped much of the Sinosphere, possibly explaining the emergence of the hikikomori phenomenon in other East-Asian countries.
In general, the prevalence of hikikomori tendencies in Japan may be encouraged and facilitated by three primary factors:
- Middle class affluence in a post-industrial society such as Japan allows parents to support and feed an adult child indefinitely in the home. Lower income families do not have hikikomori children because a socially withdrawing youth is forced to work outside the home if he cannot finish school, and for this reason isolation in the room stops at an early stage.
- The inability of Japanese parents to recognize and act upon the youth's slide into isolation, soft parenting, or even a codependent collusion between mother and son known as amae in Japanese. When a youth withdraws from life, parents can act or respond in such a way that causes the child to become even more seclusionary.
- A decade of flat economic indicators and a shaky job market in Japan makes the pre-existing system requiring years of competitive schooling for elite jobs a pointless effort. While Japanese fathers of the current generation of youth still enjoy lifetime employment at multinational corporations, incoming employees in Japan enjoy no such job guarantees in today's job market (See Freeters and NEET for more on this). Young Japanese people are savvy enough to see that the system in place for their grandfathers and fathers no longer works, and for some the lack of a clear life goal makes them susceptible to social withdrawal as a hikikomori.
Lastly, it should be noted that the hikikomori phenomenon is similar to the symptoms exhibited by people with Pervasive Developmental Disorders in western cultures. Japan has the highest incidence of Pervasive Developmental Disorders, a group of disorders including autism and Asperger’s syndrome, in the developed world.[citation needed] In Japan, PDDs are some 2.95 times more common than in western countries.[citation needed] Some 3.3% of Japanese males have PDD compared with approximately 1% in Europe and the US.[citation needed] This has led some western commentators to suggest that people with hikikomori are affected by PDDs or disorders that affect social competence, but that their disorders are altered from their typical western presentation by the social and cultural pressures unique to Japan.[citation needed]
According to Michael Zielenziger's book, Shutting out the Sun: How Japan Created its Own Lost Generation, the syndrome is more closely related to Post Tramatic Stress Disorder or PTSD. The hikikomori studied and interviewed for Zielenziger's book were not autistic, but bright intelligent people who have discovered independent thinking and a sense of self that the current Japanese environment cannot accommodate. For the most part they have no one to talk to. They are victims of the social and cultural pressures of Japan.
## The education system
The Japanese education system, like those found in China, Singapore, Taiwan, and South Korea, and similar to the school systems in India, puts great demands upon youth. A multitude of expectations, high emphasis on competition, and the rote memorization of facts and figures for the purpose of passing entrance exams into the next tier of education in what could be termed a rigid pass-or-fail ideology, induce a high level of stress. Echoing the traditional Confucian values of society, the educational system is still viewed as playing an important part in society's overall productivity and success. In this social frame, students often face significant pressure from parents and the society in general to conform to its dictates and doctrines. These doctrines, while part of modern Japanese society, are increasingly being rejected by Japanese youth in varying ways such as hikikomori, freeter, NEET (Not currently engaged in Employment, Education, or Training), and parasite singles.
Beginning in the 1960s, the pressure on Japanese youth to succeed began successively earlier in their lives, sometimes starting before pre-school, where even toddlers had to compete through an entrance exam for the privilege of attending one of the best pre-schools. This was said to prepare children for the entrance exam of the best kindergarten, which in turn prepared the child for the entrance exam of the best primary school, junior high school, high school, and eventually for their university entrance exam. Many adolescents take one year off after high school to study exclusively for the university entrance exam. The higher the prestige of the university, the more difficult the exam, the most prestigious university with the most difficult exam being the University of Tokyo.
Since 1996, the Japanese Ministry of Education has taken steps to address this 'pressure-cooker' educational environment and instill greater creative thought in Japanese youth by significantly relaxing the school schedule from six day weeks to five day weeks and dropping two subjects from the daily schedule, with new academic curricula more comparable to Western educational models. However this may be too little too late, as highly competitive Japanese parents are sending their children to private cram schools to 'make up' for the newly lax curricula in the Japanese public schools.
After graduating from high school or university, Japanese youth also have to face a very difficult job market in Japan, often finding only part-time employment and ending up as freeters with little income, unable to start a family.
Another source of pressure is from their co-students, who may harass and bully some students for a variety of reasons, including physical appearance (especially if they are overweight or have severe acne problems), wealth, educational or athletic performance, or even having lived overseas for a short period. Some have been punished for bullying or truancy, bringing shame to their families.
# Symptoms
While many people feel the pressure of the outside world, and may feel uncomfortable in public (or "social anxiety"), a hikikomori reacts by complete social withdrawal to avoid all outside pressure. In some cases, they may lock themselves into their bedroom or another room of their parent's house for prolonged periods of time, sometimes measured in years. They usually have few, or no friends. A hikikomori's days are characterized by long spells of sleeping, while their nighttime hours are often spent watching TV, extensively playing computer games, surfing the Internet, reading, trading the stock, forex, derivatives markets (i.e. stock future indices) or other non-social activities. One of the most prominent cases of an isolated trader who lived in his parents home is the Japanese individual who traded the JASDAQ Securities Exchange with 1 million yen (apr. US$10,000) as capital, whose alias is B.N.F (J-Com man). Starting in 2003 he managed to exponentially grow his account 10,000 fold in three years up to 10 billion yen (apr. US$100 million). [2] He first gained fame on the Japanese mass media when he managed to profit 2 billion yen (apr. US$20 million) in a window of 10 minutes on 8 December 2005 from a Mizuho Securities order misplacement blunder.[3] Although rare, ironically some of the adult-onset hikikomori people have succeeded in becoming extremely wealthy and in achieving financial freedom, in contrast to their more conformist salaryman counterparts.
Refusal to participate in society and fulfill their expected roles makes hikikomori an extreme subset of a much larger group of the younger Japanese generation that includes parasite singles and freeters. All three groups seem to be rejecting the current social norms society has placed upon them in their own unique ways, with lifestyles considered deviant by society at large.
The withdrawal from society usually starts gradually. Affected individuals may appear unhappy, lose their friends, become insecure, shy, and talk less. Those in their teens may be bullied at school, which, atop the already high pressures of school and family, may be the final trigger for the withdrawal.
Hikikomori often set their own sleep schedule, typically waking in the afternoon and going to bed in the early morning. While they are awake, they may engage in a variety of activities shared with other people of their age, including listening to music, surfing the Internet or actively posting in Internet forums like 2channel, which has become famous for its hikikomori population. While hikikomori favor indoor activities, most of them do venture outdoors on occasion, though they may prefer to do that at night.
# Effects
## On the individual
The lack of social contact and prolonged solitude has a profound effect on the mentality of the hikikomori, who gradually lose their social skills, social references and mores necessary to interact with the outside world. They may immerse themselves into the fantasy worlds of manga, anime and video games, which in turn become their only frame of reference. Due to a lack of interpersonal stimulus the hikikomori may developmentally stagnate into routine behaviors as time passes, sleeping all day and staying up all night only to sneak out into the kitchen for food when the family is asleep. In extreme cases, the hikikomori eventually abandons all diversions of books and TV and simply stares into space for hours at a time.[citation needed]
Should a hikikomori decide to give up his seclusion, whether on his own or through the aid of a care worker, they may face the problem of lacking social skills and years of education that their peers already possess through normal daily interaction with society. Also making reentry into society difficult is the recent social stigma that has come to be attached to the condition due to mass media attention since 1998. As a result, some former hikikomori might be afraid that others will discover their past, adding to their feeling of insecurity around people, especially strangers, in how they should act. Also detrimental is the fact they lack a work history, making anything beyond menial jobs difficult to acquire.
## On the family
Having a hikikomori in the family is often considered embarrassing, so usually it is acknowledged as an internal private matter of the family, and many parents wait for a long time before seeking help from a third party within the hikikomori support industry. Also, in Japan the education of the children is traditionally done by the mother, and the father may leave the problem of a hikikomori to the mother, who feels very protective of her child. Initially, most parents simply wait and hope that the child will eventually overcome his problems and return to society by his own will. They see it as a phase the child has to overcome. Also, many parents are uncertain about what to do with a hikikomori, and wait simply due to lack of other options. An aggressive approach by the parents forcing the child back into society is usually not taken or only after a considerable waiting period.
In some cases, school homeroom teachers and social workers make inquiries, but usually do not get involved with the situation. In recent years, due to widespread media attention, having a family member who is a hikikomori has come to have a social stigma attached to the condition akin to mental illness. Due to this stigma and the resultant shame, many families strive to keep their child's hikikomori condition a secret from those in the community, thus further delaying parents from seeking outside intervention for their child.
# Controversy
Hikikomori gained increased worldwide attention when the media attributed a number of high profile crimes to it a few years ago. In 2000, a 17-year-old labeled as a hikikomori by the press hijacked a bus and killed one passenger. In fact, it was discovered later that the hijacker had originally been a hikikomori, but his parents, in frustration, had committed him to a mental hospital for two months of observation. Allegedly, the boy felt betrayed by his parents as a result of his hospital admission, and some argue that the violence during the bus hijacking was directed at his mother by proxy. In the ensuing days, the media characterized other extremely violent crimes as having been perpetrated by hikikomori, such as one man who kidnapped ten-year-old Sano Fusako and held her captive for nine years and two months, or Tsutomu Miyazaki, who in 1989 killed four young girls. As a result of this negative media attention, hikikomori acquired a social stigma of being violent and mentally ill that persists to this day.
In 2004, 29-year-old Japanese-Dutch film school student Danyael Sugawara[4] made a film based on hikikomori called “Tamago" ("Egg"). [2]
The hikikomoris' fear of social pressure and concurrent inability to effect change in their situation may turn into frustration or even anger. Some hikikomori have physically attacked their parents, though most of the time anger manifests in other ways, such as nightly harassment by banging on walls while the rest of the family sleeps.
This hostility often arises when parents continue to exert pressure on the hikikomori to come out of their rooms after many months of isolation, despite the fact that a status quo has been allowed to develop between the parents, usually the mother, and the hikikomori. This status quo, called the Strange Peace, occurs because parents passively allow their child to stay withdrawn. It can have many causes but mostly centers on an amae relationship between mother and son, the fear and social stigma of the local community knowing the family has a hikikomori, and the notion that it is better to have the child in the house even in isolation than as a runaway.
When hikikomori came into the public spotlight, mass media sources initially argued that the loss of a social frame of reference might lead hikikomori to commit violent or criminal acts. However, hikikomori experts maintain that true hikikomori are too socially withdrawn and timid to venture outside of their rooms, let alone go outside the home and attack someone. If hikikomori physically attack anyone, it is usually family members.
# Reaction
## Treatment
There are different opinions about the treatment of a hikikomori, and the opinions often split into a Japanese and a western point of view. Japanese experts usually suggest waiting until the hikikomori reemerges, whereas western doctors suggest dragging the hikikomori back into society, by force if necessary.
While there are a growing number of doctors and clinics specialized in helping hikikomori, many hikikomori and their parents still feel a lack of support for their problems on an institutional level and feel that society at large has been slow to react to the hikikomori crisis. In the last several years, a hikikomori support industry has sprung up in Japan, each with its own style or philosophy in treating hikikomori cases. Despite this diversity, there seem to be two general camps for treatment:
- The psychological approach suggests psychological help is needed for these isolated young people, as many parents are overwhelmed with the problems of a hikikomori child whom they don’t understand. The standard psychological approach to hikikomori behavior in a youth is to treat the condition as a behavioral or mental disorder and so admit the child to a hospital ward in order to administer counseling, observation, and drug therapy using standard institutional procedures.
- The socialization approach to hikikomori treatment views the problem as one of socialization rather than mental illness. Instead of clinical treatment in a hospital, the hikikomori is removed from the original environment of the home into a shared living environment and encouraged to reintegrate into social groups through daily activities with other hikikomori who are already in various states of recovery; this approach shows the person that they are not alone in their condition and appears to be successful for most cases.
- Hikikomori may not find a free space to express himself as an individual because some feel Japanese culture doesn't provide such a frame. In that instance, a possible way of treatment is to encourage a Hikikomori to share social experiences outside Japan, for a short or long period.
## Acceptance
In contrast to the approach of treatment, some may argue that the Hikikomori status is a personality type or lifestyle to be accepted, or resolved, within the respective families, as long as this choice doesn't lead to criminal or violent behaviour. Some argue that there is a tendency in societies — especially those, like Japanese society, that emphasize conformity — to label people who differ from the norm "pathologically ill," and urge greater concern for the wishes of the individual. (Similar issues have been raised about Asperger Syndrome and Schizoid Personality Disorder.)
In some cases a Hikikomori partially or completely recovers in time when given a free house or apartment of his own.
# References in pop culture
- The light novel, manga and anime series Welcome to the NHK! created by Tatsuhiko Takimoto and illustrated by Kenji Oiwa, currently serialized in the magazine Monthly Shōnen Ace deals with hikikomori as a central theme.
- In the manga and anime, Rozen Maiden, the main character, Jun Sakurada, suffers from hikikomori after cracking under the pressure of entrance exams. In the manga, his reasoning is different.
- Episode 2 of the live action TV series Jigoku Shōjo (based on the popular anime series of the same name) tells a short story of a hikikomori who exacts revenge against the person who led his father to commit suicide.
- Endrance, one of the major characters of .hack//G.U., is a hikikomori outside of the game, spending most of his time playing it.
- In the 2002 film Moon Overflowing (Koboreru Tsuki), one of the main characters is a hikikomori.
- The 2004 film Hikikomori: Tokyo Plastic by director Adario Strange.
- 2004 film The Quiet One by Danyael Sugawara
- In the film Densha Otoko, the main character is given advice over the Internet by a hikikomori.
- In the 2006 South Korean horror film APT.
- In the drama Ikebukuro West Gate Park, the minor character Kazunori gradually recovers from his hikikomori status.
- In the 2007 summer anime called Hayate no Gotoku, the main female lead Nagi Sanzen'in is a hikikomori, although her family is very rich and prestigious, however she herself has her own huge fortune without ever needing her family's fortune or inheritance.
- In the manga and anime series Sayonara Zetsubou Sensei, one recurring character, Kiri Komori, is a hikikomori.
- In the dorama Seito Shokun!, one of the students in class 2–3, Shirai Naoki, became a hikikomori after a mountain climbing accident, after which his teacher left his class alone on the mountain to die. He finally comes out of his room in episode 4. | https://www.wikidoc.org/index.php/Hikikomori | |
acb4913445f65f82b3a8800922cc106eb9af612e | wikidoc | Histiocyte | Histiocyte
A histiocyte is a cell that is part of the human immune system; a tissue macrophage cell ("histo-" = "tissue", and "-cyte" = "cell".) Some sources also consider Langerhans cell derivatives to be histocytes.
All categories of histiocytes are derived from the bone marrow by multiplication from a stem cell. The derived cells migrate from the bone marrow to the blood as monocytes. They circulate through the body and stop in various organs where they undergo differentiation into histiocytes which are part of the mononuclear phagocytic system (MPS).
# Overview
Histiocytes have common histological and immunophenotypical characteristics (demonstrated by immunostains). Their cytoplasm is eosinophilic and contains variable amounts of lysosomes. They bear membrane receptors for opsonins, such as IgG and the fragment C3b of complement. They express LCAs (leucocyte common antigens) CD45, CD14, CD33 and CD4 (also expressed by T Helper Cells). These histiocytes are part of the immune system by way of two distinct functions: phagocytosis and antigen presentation. Phagocytosis is the main process of macrophages and antigen presentation the main property of dendritic cells (so called because of their star-like cytoplasmic processes). Macrophages and dendritic cells are derived from common bone marrow precursor cells that have undergone different differentiation (as histiocytes) under the influence of various environmental (tissue location) and growth factors such as GM-CSF, TNF and IL-4. The various categories of histocytes are distinguishable by their morphology, phenotype and size.
Macrophages are highly variable in size and morphology, their cytoplasm contains numerous acid phosphatase laden lysosomes - in relation to their specialised phagocytic function. They express CD68.
Dendritic cells have an indented (bean shaped) nucleus and cytoplasm with thin processes (dendritic). Their main activity is antigen presentation, they express Factor XIIIa, CD1c and Class II HLA antigens.
A subset of cells differentiates into Langerhans cells; this maturation occurs in the squamous epithelium, lymph nodes, spleen, and bronchiolar epithelium. Langerhans cells are antigen presenting cells but have undergone further differentiation. Skin Langerhans cells express CD1a as do cortical thymocytes (cells of the cortex of the thymus gland). They also express S-100, and their nucleus contains tennis-racket like ultra-structural inclusions called Birbeck granules.
Histiocytoses describe neoplasias where the proliferative cell is the histiocyte. | Histiocyte
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A histiocyte is a cell that is part of the human immune system; a tissue macrophage cell[1][2][3] ("histo-" = "tissue", and "-cyte" = "cell".) Some sources also consider Langerhans cell derivatives to be histocytes.[4]
All categories of histiocytes are derived from the bone marrow by multiplication from a stem cell. The derived cells migrate from the bone marrow to the blood as monocytes. They circulate through the body and stop in various organs where they undergo differentiation into histiocytes which are part of the mononuclear phagocytic system (MPS).
# Overview
Histiocytes have common histological and immunophenotypical characteristics (demonstrated by immunostains). Their cytoplasm is eosinophilic and contains variable amounts of lysosomes. They bear membrane receptors for opsonins, such as IgG and the fragment C3b of complement. They express LCAs (leucocyte common antigens) CD45, CD14, CD33 and CD4 (also expressed by T Helper Cells). These histiocytes are part of the immune system by way of two distinct functions: phagocytosis and antigen presentation. Phagocytosis is the main process of macrophages and antigen presentation the main property of dendritic cells (so called because of their star-like cytoplasmic processes). Macrophages and dendritic cells are derived from common bone marrow precursor cells that have undergone different differentiation (as histiocytes) under the influence of various environmental (tissue location) and growth factors such as GM-CSF, TNF and IL-4. The various categories of histocytes are distinguishable by their morphology, phenotype and size.
Macrophages are highly variable in size and morphology, their cytoplasm contains numerous acid phosphatase laden lysosomes - in relation to their specialised phagocytic function. They express CD68.
Dendritic cells have an indented (bean shaped) nucleus and cytoplasm with thin processes (dendritic). Their main activity is antigen presentation, they express Factor XIIIa, CD1c and Class II HLA antigens.
A subset of cells differentiates into Langerhans cells; this maturation occurs in the squamous epithelium, lymph nodes, spleen, and bronchiolar epithelium. Langerhans cells are antigen presenting cells but have undergone further differentiation. Skin Langerhans cells express CD1a as do cortical thymocytes (cells of the cortex of the thymus gland). They also express S-100, and their nucleus contains tennis-racket like ultra-structural inclusions called Birbeck granules.
Histiocytoses describe neoplasias where the proliferative cell is the histiocyte. | https://www.wikidoc.org/index.php/Histiocyte | |
e924ae5b8e54e3be3bd6fecf8162e414620b1704 | wikidoc | Histone H1 | Histone H1
# Overview
Histone H1 is one of the 5 main histone proteins involved in the structure of chromatin in eukaryotic cells. A variant of the histone H1 protein is the histone H5, which has a similar structure and function.
Featuring a central globular domain and long C and N terminal tails H1 is involved with the packing of the 'beads on a string' structure into the '30nm solenoid' structure.
H1 is present in half the amount of the other four histones. This is because unlike the other histones, H1 does not make up the nucleosome 'bead'. Instead, it sits on top of the structure, keeping in place the DNA that has wrapped around the nucleosome. Specifically, the H1 protein binds to the linker DNA (approximately 80 nucleotides in length) region between the histone beads, helping stabilize the zig-zagged 30nm chromatin fiber.
H1 histone seals off the nucleosome at the location at which the linker DNA enters and leaves.
hu:H1
de:Histon H1 | Histone H1
# Overview
Histone H1 is one of the 5 main histone proteins involved in the structure of chromatin in eukaryotic cells. A variant of the histone H1 protein is the histone H5, which has a similar structure and function.
Featuring a central globular domain and long C and N terminal tails H1 is involved with the packing of the 'beads on a string' structure into the '30nm solenoid' structure.
H1 is present in half the amount of the other four histones. This is because unlike the other histones, H1 does not make up the nucleosome 'bead'. Instead, it sits on top of the structure, keeping in place the DNA that has wrapped around the nucleosome. Specifically, the H1 protein binds to the linker DNA (approximately 80 nucleotides in length) region between the histone beads, helping stabilize the zig-zagged 30nm chromatin fiber.
H1 histone seals off the nucleosome at the location at which the linker DNA enters and leaves.
hu:H1
de:Histon H1
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Histone_H1 | |
ef6a29141c2e6b159521b4f37bf53172c3dc2a71 | wikidoc | Histone H3 | Histone H3
Histone H3 is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal tail, H3 is involved with the structure of the nucleosomes of the 'beads on a string' structure. Histone proteins are highly post-translationally modified however Histone H3 is the most extensively modified of the five histones. The term "Histone H3" alone is purposely ambiguous in that it does not distinguish between sequence variants or modification state. Histone H3 is an important protein in the emerging field of epigenetics, where its sequence variants and variable modification states are thought to play a role in the dynamic and long term regulation of genes.
# Epigenetics and post-translational modifications
The N-terminal tail of histone H3 protrudes from the globular nucleosome core and can undergo several different types of post-translational modification that influence cellular processes. These modifications include the covalent attachment of methyl or acetyl groups to lysine and arginine amino acids and the phosphorylation of serine or threonine. Di- and Tri-methylation of Lysine 9 are associated with repression and heterochromatin, while mono-methylation of K4 (K4 corresponds to lysine residue at 4th position) is associated with active genes. Acetylation of histone H3 occurs at several different lysine positions in the histone tail and is performed by a family of enzymes known as histone acetyltransferases (HATs). Acetylation of lysine14 is commonly seen in genes that are being actively transcribed into RNA.
# Sequence variants
Mammalian cells have seven known sequence variants of histone H3. These are denoted as Histone H3.1, Histone H3.2, Histone H3.3, Histone H3.4 (H3T), Histone H3.5, Histone H3.X and Histone H3.Y but have highly conserved sequences differing only by a few amino acids. Histone H3.3 has been found to play an important role in maintaining genome integrity during mammalian development. Histone variants from different organisms, their classification and variant specific features can be found in "HistoneDB - with Variants" database.
# Genetics
Histone H3s are coded by several genes in the human genome, including:
- H3.1: HIST1H3A, HIST1H3B, HIST1H3C, HIST1H3D, HIST1H3E, HIST1H3F, HIST1H3G, HIST1H3H, HIST1H3I, HIST1H3J
- H3.2: HIST2H3A, HIST2H3C, HIST2H3D
- H3.3: H3F3A, H3F3B
# Addiction
Epigenetic modifications of histone tails in specific regions of the brain are of central importance in addictions, and much of the work on addiction has focused on histone H3 epigenetic post-translational modifications. Once particular epigenetic alterations occur, they appear to be long lasting "molecular scars" that may account for the persistence of addictions.
Cigarette smokers (about 21% of the US population) are usually addicted to nicotine. After 7 days of nicotine treatment of mice, acetylation of both histone H3 and histone H4 was increased at the FosB promoter in the nucleus accumbens of the brain, causing 61% increase in FosB expression. This would also increase expression of the splice variant Delta FosB. In the nucleus accumbens of the brain, Delta FosB functions as a "sustained molecular switch" and "master control protein" in the development of an addiction.
About 7% of the US population is addicted to alcohol. In rats exposed to alcohol for up to 5 days, there was an increase in histone 3 lysine 9 acetylation in the pronociceptin promoter in the brain amygdala complex. This acetylation is an activating mark for pronociceptin. The nociceptin/nociceptin opioid receptor system is involved in the reinforcing or conditioning effects of alcohol.
Cocaine addiction occurs in about 0.5% of the US population. Repeated cocaine administration in mice induces hyperacetylation of Histone H3 or Histone H4 at 1,696 genes in one brain "reward" region and deacetylation at 206 genes. At least 45 genes, shown in previous studies to be upregulated in the nucleus accumbens of mice after chronic cocaine exposure, were found to be associated with hyperacetylation of H3 or H4. Many of these individual genes are directly related to aspects of addiction associated with cocaine exposure.
Walker et al. in 2015 tabulated a large number histone H3 acetylations and methylations occurring in various regions of the brain due to drug or alcohol abuse and affecting expression of genes with roles in addiction.
In rodent models, many agents causing addiction, including nicotine, alcohol, cocaine, heroin and methampheamine, cause DNA damage in the brain. During repair of DNA damages some individual repair events may alter the acetylations or methylations of histones at the sites of damage, or cause other epigenetic alterations, and thus leave an epigenetic scar on chromatin. Such epigenetic scars likely contribute to the persistent epigenetic changes found in addictions.
In 2013, 22.7 million persons aged 12 or older needed treatment for an illicit drug or alcohol use problem (8.6 percent of persons aged 12 or older). | Histone H3
Histone H3 is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells.[1][2] Featuring a main globular domain and a long N-terminal tail, H3 is involved with the structure of the nucleosomes of the 'beads on a string' structure. Histone proteins are highly post-translationally modified however Histone H3 is the most extensively modified of the five histones. The term "Histone H3" alone is purposely ambiguous in that it does not distinguish between sequence variants or modification state. Histone H3 is an important protein in the emerging field of epigenetics, where its sequence variants and variable modification states are thought to play a role in the dynamic and long term regulation of genes.
# Epigenetics and post-translational modifications
The N-terminal tail of histone H3 protrudes from the globular nucleosome core and can undergo several different types of post-translational modification that influence cellular processes. These modifications include the covalent attachment of methyl or acetyl groups to lysine and arginine amino acids and the phosphorylation of serine or threonine. Di- and Tri-methylation of Lysine 9 are associated with repression and heterochromatin, while mono-methylation of K4 (K4 corresponds to lysine residue at 4th position) is associated with active genes.[3][4] Acetylation of histone H3 occurs at several different lysine positions in the histone tail and is performed by a family of enzymes known as histone acetyltransferases (HATs). Acetylation of lysine14 is commonly seen in genes that are being actively transcribed into RNA.
# Sequence variants
Mammalian cells have seven known sequence variants of histone H3. These are denoted as Histone H3.1, Histone H3.2, Histone H3.3, Histone H3.4 (H3T), Histone H3.5, Histone H3.X and Histone H3.Y but have highly conserved sequences differing only by a few amino acids.[5][6] Histone H3.3 has been found to play an important role in maintaining genome integrity during mammalian development.[7] Histone variants from different organisms, their classification and variant specific features can be found in "HistoneDB - with Variants" database.
# Genetics
Histone H3s are coded by several genes in the human genome, including:
- H3.1: HIST1H3A, HIST1H3B, HIST1H3C, HIST1H3D, HIST1H3E, HIST1H3F, HIST1H3G, HIST1H3H, HIST1H3I, HIST1H3J
- H3.2: HIST2H3A, HIST2H3C, HIST2H3D
- H3.3: H3F3A, H3F3B
# Addiction
Epigenetic modifications of histone tails in specific regions of the brain are of central importance in addictions, and much of the work on addiction has focused on histone H3 epigenetic post-translational modifications.[8][9] Once particular epigenetic alterations occur, they appear to be long lasting "molecular scars" that may account for the persistence of addictions.[10][11]
Cigarette smokers (about 21% of the US population[12]) are usually addicted to nicotine.[13] After 7 days of nicotine treatment of mice, acetylation of both histone H3 and histone H4 was increased at the FosB promoter in the nucleus accumbens of the brain, causing 61% increase in FosB expression.[14] This would also increase expression of the splice variant Delta FosB. In the nucleus accumbens of the brain, Delta FosB functions as a "sustained molecular switch" and "master control protein" in the development of an addiction.[15][16]
About 7% of the US population is addicted to alcohol. In rats exposed to alcohol for up to 5 days, there was an increase in histone 3 lysine 9 acetylation in the pronociceptin promoter in the brain amygdala complex. This acetylation is an activating mark for pronociceptin. The nociceptin/nociceptin opioid receptor system is involved in the reinforcing or conditioning effects of alcohol.[17]
Cocaine addiction occurs in about 0.5% of the US population. Repeated cocaine administration in mice induces hyperacetylation of Histone H3 or Histone H4 at 1,696 genes in one brain "reward" region [the nucleus accumbens] and deacetylation at 206 genes.[18][19] At least 45 genes, shown in previous studies to be upregulated in the nucleus accumbens of mice after chronic cocaine exposure, were found to be associated with hyperacetylation of H3 or H4. Many of these individual genes are directly related to aspects of addiction associated with cocaine exposure.[19][20]
Walker et al.[21] in 2015 tabulated a large number histone H3 acetylations and methylations occurring in various regions of the brain due to drug or alcohol abuse and affecting expression of genes with roles in addiction.
In rodent models, many agents causing addiction, including nicotine,[22][23] alcohol,[24] cocaine,[25] heroin[26] and methampheamine,[27][28] cause DNA damage in the brain. During repair of DNA damages some individual repair events may alter the acetylations or methylations of histones at the sites of damage, or cause other epigenetic alterations, and thus leave an epigenetic scar on chromatin.[11][10] Such epigenetic scars likely contribute to the persistent epigenetic changes found in addictions.
In 2013, 22.7 million persons aged 12 or older needed treatment for an illicit drug or alcohol use problem (8.6 percent of persons aged 12 or older).[12] | https://www.wikidoc.org/index.php/Histone_H3 | |
fcb80ffc2443be34c49eb15c8922b83043cefdd1 | wikidoc | Histone H4 | Histone H4
Histone H4 is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal tail, H4 is involved with the structure of the nucleosome of the 'beads on a string' organization. Histone proteins are highly post-translationally modified. Covalently bonded modifications include acetylation and methylation of the N-terminal tails. These modifications may alter expression of genes located on DNA associated with its parent histone octamer. Histone H4 is an important protein in the structure and function of chromatin, where its sequence variants and variable modification states are thought to play a role in the dynamic and long term regulation of genes.
# Genetics
Histone H4 is encoded in multiple genes at different loci including:
HIST1H4A, HIST1H4B, HIST1H4C, HIST1H4D, HIST1H4E, HIST1H4F, HIST1H4G, HIST1H4H, HIST1H4I, HIST1H4J, HIST1H4K, HIST1H4L, HIST2H4A, HIST2H4B, HIST4H4.
# Evolution
Histone proteins are among the most highly conserved eukaryotic proteins. For example, the amino acid sequence of histone H4 from a pea and cow differ at only 2 out of the 102 positions. This evolutionary conservation suggests that the functions of histone proteins involve nearly all of their amino acids so that any change is deleterious to the cell. Most changes in histone sequences are lethal; the few that are not lethal cause changes in the pattern of gene expression as well as other abnormalities.
# Structure
Histone H4 is a 102 to 135 amino acid protein which shares a structural motif, known as the histone fold, formed from three a-helices connected by two loops. Histone proteins H3 and H4 bind to form a H3-H4 dimer, two of these H3-H4 dimers combine to form a tetramer. This tetramer further combines with two H2a-H2b dimers to form the compact Histone octamer core.
# Sequence Variants
Histone H4 is one of the slowest evolving proteins, and there appear to be no known sequence variants of histone H4. However, there are H4 genes that are constitutively expressed throughout the cell cycle that encode for proteins that are identical in sequence to the major H4. The reason for a lack of sequence variants remains unclear.
# Post-Translational Modifications
Eukaryotic organisms can produce small amounts of specialized variant core histones that differ in amino acid sequence from the main ones. These variants with a variety of covalent modifications on the N-terminal can be added to histones making possible different chromatin structures that are required for DNA function in higher eukaryotes. Potential modifications include methylation (mono-, di-, or tri-methylation) or acetylation on the tails.
# Methylation
Histone methylation occurs on arginine, lysine and histidine amino acids residues. Mono-, di- or tri-methylation has been discovered on histone H2A, H3 and H4. Histone methylation has been associated with various cellular functions such as transcription, DNA replication, and DNA damage response including repair, heterochromatin formation, and somatic cell reprogramming. Among these biological functions, transcriptional repression and activation are the most studied. Studies have shown that H4R3 methylation by PRMT1 (a histone methyltransferase) appears to be essential in vivo for the establishment or maintenance of a wide range of “active” chromatin modifications. Also methylation of histone H4 by PRMT1 was sufficient to permit subsequent acetylation on the N-terminal tail. However, acetylation of H4 inhibits its methylation by PRMT1.
# Acetylation
Acetylation of histones is thought to relax condensed heterochromatin as the negative charge of acetyl groups can repel the DNA phosphate backbone charges, thus reducing the histone binding affinity for DNA. This hypothesis was validated by the discovery of the histone acetyltransferase (HAT) activity of several transcriptional activator complexes. Histone acetylation influences chromatin structure in several ways. First, it can provide a tag for the binding of proteins that contain areas which recognize the acetylated tails. Secondly, it can block the function of chromatin remodelers. Thirdly, it neutralizes the positive charge on lysines. Acetylation of histone H4 on lysine 16 (H4K16Ac) is especially important for chromatin structure and function in a variety of eukaryotes and is catalyzed by specific histone lysine acetyltransferases (HATs). H4K16 is particularly interesting because this is the only acetylatable site of the H4 N-terminal tail, and can influence the formation of a compact higher-order chromatin structure. H4K16Ac also has roles in transcriptional activation and the maintenance of euchromatin. | Histone H4
Histone H4 is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal tail, H4 is involved with the structure of the nucleosome of the 'beads on a string' organization. Histone proteins are highly post-translationally modified. Covalently bonded modifications include acetylation and methylation of the N-terminal tails. These modifications may alter expression of genes located on DNA associated with its parent histone octamer.[1][2] Histone H4 is an important protein in the structure and function of chromatin, where its sequence variants and variable modification states are thought to play a role in the dynamic and long term regulation of genes.
# Genetics
Histone H4 is encoded in multiple genes at different loci including:
HIST1H4A, HIST1H4B, HIST1H4C, HIST1H4D, HIST1H4E, HIST1H4F, HIST1H4G, HIST1H4H, HIST1H4I, HIST1H4J, HIST1H4K, HIST1H4L, HIST2H4A, HIST2H4B, HIST4H4.
# Evolution
Histone proteins are among the most highly conserved eukaryotic proteins. For example, the amino acid sequence of histone H4 from a pea and cow differ at only 2 out of the 102 positions. This evolutionary conservation suggests that the functions of histone proteins involve nearly all of their amino acids so that any change is deleterious to the cell. Most changes in histone sequences are lethal; the few that are not lethal cause changes in the pattern of gene expression as well as other abnormalities.[3]
# Structure
Histone H4 is a 102 to 135 amino acid protein which shares a structural motif, known as the histone fold, formed from three a-helices connected by two loops. Histone proteins H3 and H4 bind to form a H3-H4 dimer, two of these H3-H4 dimers combine to form a tetramer. This tetramer further combines with two H2a-H2b dimers to form the compact Histone octamer core.[3]
# Sequence Variants
Histone H4 is one of the slowest evolving proteins, and there appear to be no known sequence variants of histone H4. However, there are H4 genes that are constitutively expressed throughout the cell cycle that encode for proteins that are identical in sequence to the major H4.[4] The reason for a lack of sequence variants remains unclear.
# Post-Translational Modifications
Eukaryotic organisms can produce small amounts of specialized variant core histones that differ in amino acid sequence from the main ones. These variants with a variety of covalent modifications on the N-terminal can be added to histones making possible different chromatin structures that are required for DNA function in higher eukaryotes. Potential modifications include methylation (mono-, di-, or tri-methylation) or acetylation on the tails.[3]
# Methylation
Histone methylation occurs on arginine, lysine and histidine amino acids residues. Mono-, di- or tri-methylation has been discovered on histone H2A, H3 and H4.[5] Histone methylation has been associated with various cellular functions such as transcription, DNA replication, and DNA damage response including repair, heterochromatin formation, and somatic cell reprogramming. Among these biological functions, transcriptional repression and activation are the most studied.[5] Studies have shown that H4R3 methylation by PRMT1 (a histone methyltransferase) appears to be essential in vivo for the establishment or maintenance of a wide range of “active” chromatin modifications. Also methylation of histone H4 by PRMT1 was sufficient to permit subsequent acetylation on the N-terminal tail. However, acetylation of H4 inhibits its methylation by PRMT1.[6]
# Acetylation
Acetylation of histones is thought to relax condensed heterochromatin as the negative charge of acetyl groups can repel the DNA phosphate backbone charges, thus reducing the histone binding affinity for DNA. This hypothesis was validated by the discovery of the histone acetyltransferase (HAT) activity of several transcriptional activator complexes.[5] Histone acetylation influences chromatin structure in several ways. First, it can provide a tag for the binding of proteins that contain areas which recognize the acetylated tails. Secondly, it can block the function of chromatin remodelers.[7] Thirdly, it neutralizes the positive charge on lysines.[7] Acetylation of histone H4 on lysine 16 (H4K16Ac) is especially important for chromatin structure and function in a variety of eukaryotes and is catalyzed by specific histone lysine acetyltransferases (HATs). H4K16 is particularly interesting because this is the only acetylatable site of the H4 N-terminal tail, and can influence the formation of a compact higher-order chromatin structure.[7] H4K16Ac also has roles in transcriptional activation and the maintenance of euchromatin.[8] | https://www.wikidoc.org/index.php/Histone_H4 | |
6bff9eccd8321a648c6f8b01c1d4e61fc7b342e8 | wikidoc | Hoechst AG | Hoechst AG
Hoechst AG was a German life-sciences company that became Aventis after its merger with Rhône-Poulenc S.A. in 1999. It has been called "The pharmacy of the world" due to its important role in the world's drug market.
# History
The company was founded in 1863 as "Teerfarbenfabrik Meister, Lucius & Co." in Höchst, near Frankfurt and changed its name some years later to "Teerfarbenfabrik Meister Lucius & Brüning". In 1880 it became a stock company "Farbwerke vorm. Meister Lucius & Brüning AG". For the international market the name was simplified to "Farbwerke Hoechst AG". Until 1925 the Hoechst AG was independent. The Hoechst AG was one of the co-founders. of IG Farben, founded 1916, a pressure group of Germany's chemicals industry to gain industrial power during WW I and afterwards. In 1925 the IG Farben turned from a pressure group into a the well known conglomerate and was split up in 1951 into its founder companies. The Hoechst AG was re-founded on December 7, 1951 in Frankfurt. The original capitalization of the company was 100,000 Deutsche Mark.
1987 - Hoechst acquired the American chemical company Celanese and formed a new Hoechst subsidiary in the US, Hoechst Celanese.
1994 - The U.S. National Right to Life Committee announced a U.S. boycott of all Hoechst pharmaceutical products including Altace.
1994 (September 17) - Pharmacists For Life International joins the international boycott, "...against the American subsidiary of Hoechst, AG Hoechst-Roussel, Hoechst-Celanese, its generic subsidiary Coply Pharmaceuticals and the agricultural Hoechst subsidiary" while asking U.S. consumers to "focus on key Hoechst drugs which have the most economic impact rather than taking an across-the-board shotgun approach" and specifically listing Altace as a boycott list item.
1995 - Hoechst mergers with Marion Merrill Dow of Kansas City, Missouri forming U.S. subsidiary Hoechst Marion Roussel (HMR). Altace was bringing in under $90 million in revenues for Hoechst and Hoechst had stopped promoting Altace within the United States.
1995 - The King Pharmaceuticals President Jefferson "Jeff" Gregory first begins negotiations with Hoechst to acquire U.S. distribution rights to Altace.
1997 - Hoechst underwent a realignment wherein its various businesses were transferred to independent companies, including Nutrinova and Clariant.
1997 (April 2) - The anti-abortion group Concerned Women For America announces at a National Right To Life Committee press briefing at the National Press Club that the anti-RU486 boycott against the U.S. subsidiaries of Hoechst AG & Roussel Uclaf by the NRTLC "...will be more narrowly focused onto the HMR prescription drugs Allegra, Cardizem, Seldane, Claforan, Lasix, DiaBeta, and Nicoderm" - and Altace is auspiciously no longer included by Concerned Women For Americas as a boycotted Hoechst Marion Roussel product.
1998 (December 18) - The King Pharmaceuticals wholly owned subsidiary Monarch Pharmaceuticals, Inc. acquires ownership of U.S. distribution rights to Altace and other Hoechst products from Hoechst AG subsidiary Hoechst Marion Roussel of Kansas City, Missouri.
1999 (December 7) - Hoechst and Rhone-Poulenc Settle Federal Trade Commission charges that merger would violate U.S. antitrust laws;
1999 - Aventis was formed when Hoechst AG merged with Rhône-Poulenc S.A. The merged company was based in Strasbourg, France. As part of the merger, the company demerged many of its industrial businesses into Celanese, which became an independent company again. | Hoechst AG
Hoechst AG was a German life-sciences company that became Aventis after its merger with Rhône-Poulenc S.A. in 1999. It has been called "The pharmacy of the world" due to its important role in the world's drug market.
# History
The company was founded in 1863 as "Teerfarbenfabrik Meister, Lucius & Co." in Höchst, near Frankfurt and changed its name some years later to "Teerfarbenfabrik Meister Lucius & Brüning". In 1880 it became a stock company "Farbwerke vorm. Meister Lucius & Brüning AG". For the international market the name was simplified to "Farbwerke Hoechst AG". Until 1925 the Hoechst AG was independent. The Hoechst AG was one of the co-founders. of IG Farben, founded 1916, a pressure group of Germany's chemicals industry to gain industrial power during WW I and afterwards. In 1925 the IG Farben turned from a pressure group into a the well known conglomerate and was split up in 1951 into its founder companies. The Hoechst AG was re-founded on December 7, 1951 in Frankfurt. The original capitalization of the company was 100,000 Deutsche Mark.
1987 - Hoechst acquired the American chemical company Celanese and formed a new Hoechst subsidiary in the US, Hoechst Celanese.
1994 - The U.S. National Right to Life Committee announced a U.S. boycott of all Hoechst pharmaceutical products including Altace.
1994 (September 17) - Pharmacists For Life International joins the international boycott, "...against the American subsidiary of Hoechst, AG Hoechst-Roussel, Hoechst-Celanese, its generic subsidiary Coply Pharmaceuticals and the agricultural Hoechst subsidiary" while asking U.S. consumers to "focus on key Hoechst drugs which have the most economic impact rather than taking an across-the-board shotgun approach" and specifically listing Altace as a boycott list item.[1]
1995 - Hoechst mergers with Marion Merrill Dow of Kansas City, Missouri forming U.S. subsidiary Hoechst Marion Roussel (HMR). Altace was bringing in under $90 million in revenues for Hoechst and Hoechst had stopped promoting Altace within the United States.[2]
1995 - The King Pharmaceuticals President Jefferson "Jeff" Gregory first begins negotiations with Hoechst to acquire U.S. distribution rights to Altace.[3]
1997 - Hoechst underwent a realignment wherein its various businesses were transferred to independent companies, including Nutrinova and Clariant.
1997 (April 2) - The anti-abortion group Concerned Women For America announces at a National Right To Life Committee press briefing at the National Press Club that the anti-RU486 boycott against the U.S. subsidiaries of Hoechst AG & Roussel Uclaf by the NRTLC "...will be more narrowly focused onto the HMR prescription drugs Allegra, Cardizem, Seldane, Claforan, Lasix, DiaBeta, and Nicoderm" - and Altace is auspiciously no longer included by Concerned Women For Americas as a boycotted Hoechst Marion Roussel product.[4]
1998 (December 18) - The King Pharmaceuticals wholly owned subsidiary Monarch Pharmaceuticals, Inc. acquires ownership of U.S. distribution rights to Altace and other Hoechst products from Hoechst AG subsidiary Hoechst Marion Roussel of Kansas City, Missouri.[5]
1999 (December 7) - Hoechst and Rhone-Poulenc Settle Federal Trade Commission charges that merger would violate U.S. antitrust laws;
1999 - Aventis was formed when Hoechst AG merged with Rhône-Poulenc S.A. The merged company was based in Strasbourg, France. As part of the merger, the company demerged many of its industrial businesses into Celanese, which became an independent company again. | https://www.wikidoc.org/index.php/Hoechst_AG | |
d61eeaf44965dad8395294cdffdc033c3262622a | wikidoc | Holography | Holography
Holography (from the Greek, όλος-hòlòs whole + γραφή-grafè writing, drawing) is the science of producing holograms. It is a technique that allows the light scattered from an object to be recorded and later reconstructed so that it appears as if the object is in the same position relative to the recording medium as it was when recorded. The image changes as the position and orientation of the viewing system changes in exactly the same way is if the object were still present. Holograms can also be made using other types of waves.
The technique of holography can also be used to optically store, retrieve, and process information. It is common to confuse volumetric displays with holograms, particularly in science fiction works such as Star Trek, Star Wars, Red Dwarf, and Quantum Leap, although now with many advances in commercial and possibly government technology (most likely secret - Area 22) the concept of holographic entertainment and communication does not seem far off.
# Overview
Holography was invented in 1947 by Hungarian physicist Dennis Gabor (Hungarian name: Gábor Dénes) (1900–1979), work for which he received the Nobel Prize in physics in 1971. It was made possible by pioneering work in the field of physics by other scientists like Mieczysław Wolfke who resolved technical issues that previously made advancements impossible. The discovery was an unexpected result of research into improving electron microscopes at the British Thomson-Houston Company in Rugby, England. The British Thomson-Houston company filed a patent in December 1947(patent GB685286), but the field did not really advance until the development of the laser in 1960.
The first holograms that recorded 3D objects were made in 1962 by Yuri Denisyuk in the Soviet Union; and by Emmett Leith and Juris Upatnieks in University of Michigan, USA. Advances in photochemical processing techniques, to produce high-quality display holograms were achieved by Nicholas J. Phillips.
Several types of holograms can be made. Transmission holograms, such as those produced by Leith and Upatnieks, are viewed by shining laser light through them and looking at the reconstructed image from the side of the hologram opposite the source. A later refinement, the "rainbow transmission" hologram allows more convenient illumination by white light rather than by lasers or other monochromatic sources. Rainbow holograms are commonly seen today on credit cards as a security feature and on product packaging. These versions of the rainbow transmission hologram are commonly formed as surface relief patterns in a plastic film, and they incorporate a reflective aluminium coating which provides the light from "behind" to reconstruct their imagery.
Another kind of common hologram, the reflection or Denisyuk hologram, is capable of multicolour image reproduction using a white light illumination source on the same side of the hologram as the viewer.
One of the most promising recent advances in the short history of holography has been the mass production of low-cost solid-state lasers—typically used by the millions in DVD recorders and other applications, but which are sometimes also useful for holography. These cheap, compact, solid-state lasers can under some circumstances compete well with the large, expensive gas lasers previously required to make holograms, and are already helping to make holography much more accessible to low-budget researchers, artists, and dedicated hobbyists.
# How it works
Though holography is often referred to as 3D photography, this is a misconception. A better analogy is sound recording where the sound field is encoded in such a way that it can later be reproduced. In holography, some of the light scattered from an object or a set of objects falls on the recording medium. A second light beam, known as the reference beam, also illuminates the recording medium, so that interference occurs between the two beams. The resulting light field is an apparently random pattern of varying intensity which is the hologram. It can be shown that if the hologram is illuminated by the original reference beam, a light field is diffracted by the reference beam which is identical to the light field which was scattered by the object or objects. Thus, someone looking into the hologram 'sees' the objects even though they may no longer be present. There are a variety of recording materials which can be used, including photographic film.
## Holography explained in terms of interference and diffraction
Interference occurs when one or more wavefronts are superimposed. Diffraction occurs whenever a wavefront encounters an object. The process of producing a holographic reconstruction is explained below purely in terms of interference and diffraction. It is somewhat simplistic, but is accurate enough to provide an understanding of how the holographic process works.
### A hologram of a plane wavefront
A diffraction grating is a structure with a repeating pattern. A simple example is a metal plate with slits cut at regular intervals. Light rays travelling through it are bent at an angle determined by λ, the wavelength of the light and d, the distance between the slits and is given by sinθ = λ/d.
A very simple hologram can be made by superimposing two plane waves from the same light source. One(the reference beam)hits the photographic plate normally and the other one (the object beam) hits the plate at an angle θ. The relative phase between the two beams varies across the photographic plate as 2π y sinθ/λ where y is the distance along the photographic plate. The two beams interfere with one another to form an interference pattern. The relative phase changes by 2π at intervals of d = λ/sinθ so the spacing of the interference fringes is given by d. Thus, the relative phase of object and reference beam is encoded as the maxima and minima of the fringe pattern.
When the photographic plate is developed, the fringe pattern acts as a diffraction grating and when the reference beam is incident upon the photographic plate, it is partly diffracted into the same angle θ at which the original object beam was incident. Thus, the object beam has been re-constructed. The diffraction grating created by the two waves interfering has reconstructed the "object beam" and it is therefore a hologram as defined above.
### A hologram of a point source
A slightly more complicated hologram can be made using a point source of light as object beam and a plane wave as reference beam to illuminate the photographic plate. An interference pattern is formed which in this case is in the form of curves of decreasing separation with increasing distance from the centre.
The photographic plate is developed giving a complicated pattern which can be considered to be made up of a diffraction pattern of varying spacing. When the plate is illuminated by the reference beam alone, it is diffracted by the grating into different angles which depend on the local spacing of the pattern on the plate. It can be shown that the net effect of this it to re-construct the object beam, so that it appears that light is coming from a point source behind the plate, even when the source has been removed. The light emerging from the photographic plate is identical to the light emerging when the point source which used to be there. An observer looking into the plate from the other side will 'see' a point source of light whether the original source of light is there or not.
This sort of hologram is effectively a concave lens, since it 'converts' a plane wavefront into a divergent wavefront. It will also increase the divergence of any wave which is incident on it in exactly the same way as a normal lens does. Its focal length is the distance between the point source and the plate.
### A hologram of a complex object which can be considered to be a set of point sources
The diagram on the right shows the optical arrangement for making a hologram of a complex object. The laser beam is split in two by the beam splitter. One beam illuminates the object which then scatters light onto the recording medium. The second (reference) beam illuminates the recording medium directly.
According to diffraction theory, each point in the object acts as a point source of light. Each of these point sources interferes with the reference beam, giving rise to an interference pattern. The resulting pattern is the sum of a large number (strictly speaking, an infinite number) of point source + reference beam interference patterns.
The diagram on the left shows the optical arrangement for re-constructing the object beam. The object is no longer present, and the hologram is illuminated by the reference beam. Each point source diffraction grating will diffract part of the reference beam to re-construct the wavefront from its point source. These individual wavefronts add together to recontstruct the whole of the object beam.
The viewer perceives a wavefront which is identical to the wavefront scattered by the object, so that it appears to him/her that the object is still in place. This image is known as a 'virtual' image as it is generated even though the object is no longer there.
This explains, albeit in somewhat simplistic terms, how transmission holograms work. Other holograms, such as rainbow and Denisyuk holgrams are somewhat more complex but the principles are the same
## Holography - the theory
A light wave can be modelled by a complex number U which represents the electric or magnetic field of the light wave. The amplitude and phase of the light are represented by the absolute value and angle of the complex number. The object and reference waves at any point in the holographic system are given by UO and UR. The combined beam is given be UO + UR. The energy of the combined beams is proportional to the square of magnitude of the electric wave:
|U_O + U_R|^2=U_O U_R^*+|U_R|^2+|U_O|^2+ U_O^*U_R
If a photographic plate is exposed to the two beams, and then developed, its transmittance, T, is proportional to the light energy which was incident on the plate, and is given by
T=k
where k is a constant. When the developed plate is illuminated by the reference beam, the light transmitted through the plate, UH is
U_H=TU_R=kU_R=k
It can be seen that UH has four terms. The first of these is kUO, since URUR- is equal to one, and this is the re-constructed object beam. The second term represents the reference beam whose amplitude has been modifed by UR2. The third also represent the reference beam which has had its amplitude modifed by UO2; this modification will cause the reference beam to be diffracted around its central direction. The fourth term is know as the 'conjugate object beam'. It has the reverse curvature to the object beam itself, and forms a real image of the object in the space beyond the holographic plate.
Early holograms had both the object and reference beams illuminating the recording medium normally which meant that all the four beams emerging from the holgram were superimposed on one another. The off-axis hologram was developed by Leith and Upatnieks to overcome this problem. The object and reference beams are incident at well-separated angles onto the holographic recording medium and the virtual, real and reference wavefronts all emerge at different angles enabling the re-constructed object beam to be imaged clearly.
# Viewing the hologram
The picture on the right is a photograph, taken against a diffuse light background, of a hologram recorded on photographic emulsion. The area shown is about 8mmx8mm. The holographic recording is the random variation in intensity which is an objective speckle pattern, and not the regular lines which are likely to be due to interference arising from multiple reflections in the glass plate on which the photographic emulsion is mounted. It is no more possible to discern the subject of the hologram from this than it is to identify the music on a gramophone record by looking at the structure of the tracks. When this hologram is illuminated by a divergent laser beam, the viewer will see the object used to make it (in this case, a toy van) because the light is diffracted by the hologram to re-construct the light which was scattered from the object.
When you look at a scene, each eye captures a portion of the light scattered from the scene, and the lens of the eye forms an image of the scene on the retina, in which light from each angular position is focused to a specific angular position in the image plane. Since the hologram reconstructs the whole of the scattered light field which was incident on the hologram, the viewer sees the same image whether this is derived from the light field scattered from the object, or the reconstructed light field produced by the hologram and is unable to tell whether he/she is looking at the real or the virtual object. If the viewer moves about, the object will appear to move in exactly the same way whether he/she is looking at the original light field or the reconstructed light field. If there are several objects in the scene, they will exhibit parallax. If the viewer is using both eyes (stereoscopic vision), he/she will get depth information when viewing the hologram in exactly the same way as when he/she is viewing the real scene.
It should be clear from this why a hologram is not a 3D photograph. A photograph records an image of the recorded scene from a single viewpoint, which is defined by the position of the camera lens. The hololgram is not an image, but an encoding system which enables the scattered light field to be reconstructed. Images can then be formed from any point in the reconstructed beam either with a camera or by eye. It was very common in the early days of holography to use a chess board as the object, and then take photographs at several different angles using the reconstructed light to show how the relative positions of the chess-pieces appeared to change.
Since each point in the hologram contains light from the whole of the original scene, the whole scene can, in principle, be re-constructed from a single point in the hologram. To demonstrate this concept, you can break the hologram into small pieces and you can still see the entire object from each small piece. If you envisage the hologram as a 'window' on the object, then each small piece of hologram is just a part of the window from which you can still view the object even if the rest of the window is blocked off.
You do, however, lose resolution as you decrease the size of the hologram - the image becomes 'fuzzier'. This is a result of diffraction and arises in the same way as the resolution of an imaging system is ultimately limited by diffraction where the resolution becomes coarser as the lens or lens aperture diameter decreases.
# Practical requirements for making and viewing a hologram
The object and the reference beams must be able to produce an interference pattern which is stable during the time in which the holographic recording is made. To do this, they must have the same frequency and the same relative phase during this time, that is, they must be mutually coherent. Many laser beams satisfy this condition, and lasers have been used to make holograms since their invention, though it should be noted that the first holograms by Gabor used 'quasi-chromatic' light sources. In principle, two separate light sources could be used if the coherence condition could be satisfied, but in practice a single laser is always used.
In addition, the medium used to record the fringe pattern must be able to resolve the fringe patterns and some of the more common media used are listed below. The spacing of the fringes depends on the angle between object and reference beam. For example, if this angle is 45o, and the wavelength of the light is 0.5μm, the fringe spacing is about 0.7μm or 1300 lines/mm. A working hologram can be obtained even if all the fringes are not resolved, but the resolution of the image is reduced as the resolution of the recording medium reduces.
Mechanical stability is also very important when making a hologram. Any relative phase change between the object and reference beams due to vibration or air movement will cause the fringes on the recording medium to move, and if the phase changes is greater than π, the fringe pattern is averaged out, and no holographic recording is obtained. Recording time can be several seconds or more, and given that a phase change of π is equivalent to a movement of λ/2 this is quite a stringent stability equirement.
Generally, the coherence length of the light determines the maximum depth in the scene of interest which can be recorded holographically. A good holography laser will typically have a coherence length of several meters, ample for a deep hologram. Certain pen laser pointers have been used to make small holograms (see External links). The size of these holograms is not restricted by the coherence length of the laser pointers (which can exceed several meters), but by their low power of below 5 mW.
The objects which form the scene must, in general, have optically rough surfaces so that they scatter light over a wide range of angles. A specularly reflecting (or shiny) surface reflects the light in only one direction at each point on its surface, so in general, most of the light will not be incident on the recording medium. It should be noted that the light scattered from objects with a rough surface forms an objective speckle pattern which has random amplitude and phase.
The reference beam is not normally a plane wavefront; it is usually a divergent wavefront which is formed by placing a convex lens in the path of the laser beam.
To re-construct the object exactly from a transmission holgram, the reference beam must have the same wavelength, the same curvature, and must illuminate the hologram at the same angle as the original reference beam. Any slight departure from any of these conditions will give a distorted re-construction, and if the difference between the reconstruction and original reference beam is too great, no re-construction is obtained.
Exact re-construction is achieved in holographic interferometry where the holographically re-constructed wavefront interferes with the live wavefront, to map out any displacement of the live object, and gives a null fringe if the object has not moved.
# Holographic recording media
The recording medium must be able to resolve the interference fringes as discussed above. It must also be sufficiently sensitive to record the fringe pattern in a time period short enough for the system to remain optically stable, i.e any relative movement of the two beams must be significantly less than λ/2.
The recording medium has to convert the interference pattern into an optical element which modifies either the amplitude or the phase of a light beam which is incident upon it.
These are known as amplitude and phase holograms respectively. In amplitude holograms the modulation is in the varying absorption of the light by the hologram, as in a developed photographic emulsion which is less or more absorptive depending on the intensity of the light which illuminated it. In phase holograms, the optical distance (i.e. the refractive index or in some cases the thickness) in the material is modulated.
Most materials used for phase holograms reach the theoretical diffraction efficiency for holograms, which is 100% for thick holograms (Bragg diffraction regime) and 33.9% for thin holograms (Raman-Nath diffraction regime, holographic films of typically some μm thickness). Amplitude holograms have a lower efficiency than phase holograms and are therefore used more rarely.
The table below shows the principal materials for holographic recording. Note that these do not include the materials used in the mass replication of an existing hologram. The resolution limit given in the table indicates the maximal number of interference lines per mm of the gratings. The required exposure is for a long exposure. Short exposure times (less than 1/1000th of second, such as with a pulsed laser) require a higher exposure due to reciprocity failure.
It is also possible to make holographic recordings using digital cameras - see digital holography
# Mass replication of holograms
An existing hologram can be replicated, either in an optical way similar to holographic recording, or in the case of surface relief holograms, by embossing. Surface relief holograms are recorded in photoresists or photothermoplastics, and allow cheap mass reproduction. Such embossed holograms are now widely used, for instance as security features on credit cards or quality merchandise. The Royal Canadian Mint even produces holographic gold and silver coinage through a complex stamping process. The first book to feature a hologram on the front cover was The Skook (Warner Books, 1984) by JP Miller, featuring an illustration by Miller.
The first step in the embossing process is to make a stamper by electrodeposition of nickel on the relief image recorded on the photoresist or photothermoplastic. When the nickel layer is thick enough, it is separated from the master hologram and mounted on a metal backing plate. The material used to make embossed copies consists of a polyester base film, a resin separation layer and a thermoplastic film constituting the holographic layer.
The embossing process can be carried out with a simple heated press. The bottom layer of the duplicating film (the thermoplastic layer) is heated above its softening point and pressed against the stamper so that it takes up its shape. This shape is retained when the film is cooled and removed from the press. In order to permit the viewing of embossed holograms in reflection, an additional reflecting layer of aluminium is usually added on the hologram recording layer.
# Applications of optical holography
## Holographic data storage
Holography can be put to a variety of uses other than recording images. Holographic data storage is a technique that can store information at high density inside crystals or photopolymers. The ability to store large amounts of information in some kind of media is of great importance, as many electronic products incorporate storage devices. As current storage techniques such as Blu-ray reach the denser limit of possible data density (due to the diffraction-limited size of the writing beams), holographic storage has the potential to become the next generation of popular storage media.The advantage of this type of data storage is that the volume of the recording media is used instead of just the surface.
Currently available SLMs can produce about 1000 different images a second at 1024×1024-bit resolution. With the right type of media (probably polymers rather than something like LiNbO3), this would result in about 1 gigabit per second writing speed. Read speeds can surpass this and experts believe 1-terabit per second readout is possible.
In 2005, companies such as Optware and Maxell have produced a 120 mm disc that uses a holographic layer to store data to a potential 3.9 TB (terabyte), which they plan to market under the name Holographic Versatile Disc. Another company, InPhase Technologies, is developing a competing format.
While many holographic data storage models have used "page-based" storage, where each recorded hologram holds a large amount of data, more recent research into using submicrometre-sized "microholograms" has resulted in several potential 3D optical data storage solutions. While this approach to data storage can not attain the high data rates of page-based storage, the tolerances, technological hurdles, and cost of producing a commercial product are significantly lower.
## Holographic Interferometry
Holographic interferometry (HI)is a technique which enables static and dynamic displacements of objects with optically rough surfaces to be measured to optical interferometric precision (i.e to fractions of a wavelength of light). It can also be used to detect optical path length variations in transparent media, which enables, for example, fluid flow to be visualised and analysed. It can also be used to generate contours representing the form of the surface.
It has been widely used to measure stress, strain, and vibration in engineering structures
## Security holograms
Security holograms are very difficult to forge because they are replicated from a master hologram which requires expensive, specialized and technologically advanced equipment. They are used widely in many currencies such as the Brazilian real 20 note, British pound 5/10/20 notes, Canadian dollar 5/10/20/50/100 notes, Euro 5/10/20/50/100/200/500 notes, South Korean won 5000/10000 notes, Japanese yen 5000/10000 notes, etc. They are also used in credit and bank cards as well as quality products.
## Interferometric microscopy
The hologram keeps the information on the amplitude and phase of the field. Several holograms may keep information about the same distribution of light,
emitted to various directions. The numerical analysis of such holograms allows one to emulate large numerical aperture which, in turn, enables enhancement of the resolution of optical microscopy.
The corresponding technique is called interferometric microscopy. Recent achievements of interferometric microscopy allow one to approach the quarter-wavelength limit of resolution.
## Dynamic holography
The discussion above describes static holography, in which recording, developing and reconstructing occur sequentially and a permanent hologram is produced.
There exist also holographic materials which don't need the developing process and can record a hologram in a very short time. This allows to use holography to perform some simple operations in an all-optical way. Examples of applications of such real-time holograms include phase-conjugate mirrors ("time-reversal" of light), optical cache memories, image processing (pattern recognition of time-varying images), and optical computing.
The amount of processed information can be very high (terabit/s), since the operation is performed in parallel on a whole image. This compensates the fact that the recording time, which is in the order of a µs, is still very long compared to the processing time of an electronic computer. The optical processing performed by a dynamic hologram is also much less flexible than electronic processing. On one side one has to perform the operation always on the whole image, and on the other side the operation a hologram can perform is basically either a multiplication or a phase conjugation. But remember that in optics, addition and Fourier transform are already easily performed in linear materials, the second simply by a lens. This enables some applications like a device that compares images in an optical way.
The search for novel nonlinear optical materials for dynamic holography is an active area of research. The most common materials are photorefractive crystals, but also in semiconductors or semiconductor heterostructures (such as quantum wells), atomic vapors and gases, plasmas and even liquids it was possible to generate holograms.
A particularly promising application is optical phase conjugation. It allows the removal of the wavefront distortions a light beam receives when passing through an aberrating medium, by sending it back through the same aberrating medium with a conjugated phase. This is useful for example in free-space optical communications to compensate for atmospheric turbulence (the phenomenon that gives rise to the twinkling of starlight).
## Holography in art
Early on artists saw the potential of holography as a medium and gained access to science laboratories to create their work. Holographic art is often the result of collaborations between scientists and artists, although some holographers would regard themselves as both an artist and scientist.
Salvador Dalí claimed to have been the first to employ holography artistically. He was certainly the first and most notorious surrealist to do so, but the 1972 New York exhibit of Dalí holograms had been preceded by the holographic art exhibition which was held at the Cranbrook Academy of Art in Michigan in 1968 and by the one at the Finch College gallery in New York in 1970, which attracted national media attention.
During the 1970's a number of arts studios and schools were established, each with their particular approach to holography. Notably there was the San Francisco School of holography established by Llyod Cross, The Museum of Holography in New York founded by Rosemary (Possie) H. Jackson, the Royal College of Art in London and the Lake Forrest College Symposiums organised by Tung Jeong (T.J). None of these studios still exist, however there is the Center for the Holographic Arts in New York and the HOLOcenter in Seoul which offer artists a place to create and exhibit work.
A small but active group of artist use holography as their main medium and many more artists integrate holographic elements into their work.
The MIT Museum and Jonathan Ross both have extensive collections of holography and on-line catalogues of art holograms.
## Holography as a hobby
Since the beginning of holography experimenters have explored the uses of holography. Starting in 1971 Lloyd Cross started the San Francisco School of Holography and started to teach amateurs the methods of making holograms with inexpensive equipment. This method relied on the use of a large table of deep sand (invented by Jerry Pethic) to hold the optics rigid and dampen vibrations that would destroy the image.
Many of these holographers would go on to produce art holograms. In 1983, Fred Unterseher published the Holography Handbook, a remarkably easy to read description of making holograms at home. This brought in a new wave of holographers and gave simple methods to use the then available AGFA silver halide recording materials.
In 2000 Frank DeFreitas published the Shoebox Holography Book and introduced using inexpensive laser pointers to countless hobbiests. This was a very important development for amateurs as it took the cost for a 5mw laser from $1200 to $5. Now there are hundreds to thousands of amateur holographers worldwide.
In 2006 a large number of surplus Holography Quality Green Lasers (Coherent C315) became available and put Dichromated Gelatin (DCG) within the reach of the amateur holographer. The holography community was surprised at the amazing sensitivity of DCG to green light. It had been assumed that the sensitivity would be non existent. Jeff Blythe responded with the G307 formulation of DCG to increase the speed and sensitivity to these new lasers.
Many film suppliers have come and gone from the silver halide market. While more film manufactures have filled in the voids, many amateurs are now making their own film. The favorite formulations are Dichromated Gelatin, Methelene Blue Sensitised Dichromated Gelatin and Diffusion Method Silver Halide preparations. Jeff Blythe has published very accurate methods for making film in a small lab or garage.
A small group of amateurs are even constructing their own pulsed lasers to make holograms of moving objects.
Jeff Blythe's Film Formulations
# Non-optical holography
In principle, it is possible to make a hologram for any wave.
## Electron holography
Electron holography is the application of holography techniques to electron waves rather than light waves.
Electron holography was invented by Dennis Gabor to improve the resolution and avoid the aberrations of the transmission electron microscope. Today it is commonly used to study electric and magnetic fields in thin films, as magnetic and electric fields can shift the phase of the interfering wave passing through the sample.
The principle of electron holography can also be applied to interference lithography.
## Acoustic holography
Acoustic Holography is the method for registering sound waves.
## Atom holography
Atomic holography has evolved out of the development of the basic elements of atom optics. With the Fresnel diffraction lens and atomic mirrors atomic holography follows a natural step in the development of the physics (and applications) of atomic beams. Recent developments including atomic mirrors and especially ridged mirrors have provided the tools necessary for the creation of atomic holograms., although such holograms have not yet been commercialized.
# Holographic theories of brain function
An analogy between the distributed information in holograms and the distributed information in brains gave rise to a speculative idea termed holonomic brain theory. | Holography
Holography (from the Greek, όλος-hòlòs whole + γραφή-grafè writing, drawing) is the science of producing holograms. It is a technique that allows the light scattered from an object to be recorded and later reconstructed so that it appears as if the object is in the same position relative to the recording medium as it was when recorded. The image changes as the position and orientation of the viewing system changes in exactly the same way is if the object were still present. Holograms can also be made using other types of waves.
The technique of holography can also be used to optically store, retrieve, and process information. It is common to confuse volumetric displays with holograms, particularly in science fiction works such as Star Trek, Star Wars, Red Dwarf, and Quantum Leap, although now with many advances in commercial and possibly government technology (most likely secret - Area 22) the concept of holographic entertainment and communication does not seem far off.
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# Overview
Holography was invented in 1947 by Hungarian physicist Dennis Gabor (Hungarian name: Gábor Dénes) (1900–1979)[1], work for which he received the Nobel Prize in physics in 1971. It was made possible by pioneering work in the field of physics by other scientists like Mieczysław Wolfke who resolved technical issues that previously made advancements impossible. The discovery was an unexpected result of research into improving electron microscopes at the British Thomson-Houston Company in Rugby, England. The British Thomson-Houston company filed a patent in December 1947(patent GB685286), but the field did not really advance until the development of the laser in 1960.
The first holograms that recorded 3D objects were made in 1962 by Yuri Denisyuk in the Soviet Union;[2] and by Emmett Leith and Juris Upatnieks in University of Michigan, USA.[3] Advances in photochemical processing techniques, to produce high-quality display holograms were achieved by Nicholas J. Phillips[4].
Several types of holograms can be made. Transmission holograms, such as those produced by Leith and Upatnieks, are viewed by shining laser light through them and looking at the reconstructed image from the side of the hologram opposite the source. A later refinement, the "rainbow transmission" hologram allows more convenient illumination by white light rather than by lasers or other monochromatic sources. Rainbow holograms are commonly seen today on credit cards as a security feature and on product packaging. These versions of the rainbow transmission hologram are commonly formed as surface relief patterns in a plastic film, and they incorporate a reflective aluminium coating which provides the light from "behind" to reconstruct their imagery.
Another kind of common hologram, the reflection or Denisyuk hologram, is capable of multicolour image reproduction using a white light illumination source on the same side of the hologram as the viewer.
One of the most promising recent advances in the short history of holography has been the mass production of low-cost solid-state lasers—typically used by the millions in DVD recorders and other applications, but which are sometimes also useful for holography. These cheap, compact, solid-state lasers can under some circumstances compete well with the large, expensive gas lasers previously required to make holograms, and are already helping to make holography much more accessible to low-budget researchers, artists, and dedicated hobbyists.
# How it works
Though holography is often referred to as 3D photography, this is a misconception. A better analogy is sound recording where the sound field is encoded in such a way that it can later be reproduced. In holography, some of the light scattered from an object or a set of objects falls on the recording medium. A second light beam, known as the reference beam, also illuminates the recording medium, so that interference occurs between the two beams. The resulting light field is an apparently random pattern of varying intensity which is the hologram. It can be shown that if the hologram is illuminated by the original reference beam, a light field is diffracted by the reference beam which is identical to the light field which was scattered by the object or objects. Thus, someone looking into the hologram 'sees' the objects even though they may no longer be present. There are a variety of recording materials which can be used, including photographic film.
## Holography explained in terms of interference and diffraction
Interference occurs when one or more wavefronts are superimposed. Diffraction occurs whenever a wavefront encounters an object. The process of producing a holographic reconstruction is explained below purely in terms of interference and diffraction. It is somewhat simplistic, but is accurate enough to provide an understanding of how the holographic process works.
### A hologram of a plane wavefront
A diffraction grating is a structure with a repeating pattern. A simple example is a metal plate with slits cut at regular intervals. Light rays travelling through it are bent at an angle determined by λ, the wavelength of the light and d, the distance between the slits and is given by sinθ = λ/d.
A very simple hologram can be made by superimposing two plane waves from the same light source. One(the reference beam)hits the photographic plate normally and the other one (the object beam) hits the plate at an angle θ. The relative phase between the two beams varies across the photographic plate as 2π y sinθ/λ where y is the distance along the photographic plate. The two beams interfere with one another to form an interference pattern. The relative phase changes by 2π at intervals of d = λ/sinθ so the spacing of the interference fringes is given by d. Thus, the relative phase of object and reference beam is encoded as the maxima and minima of the fringe pattern.
When the photographic plate is developed, the fringe pattern acts as a diffraction grating and when the reference beam is incident upon the photographic plate, it is partly diffracted into the same angle θ at which the original object beam was incident. Thus, the object beam has been re-constructed. The diffraction grating created by the two waves interfering has reconstructed the "object beam" and it is therefore a hologram as defined above.
### A hologram of a point source
A slightly more complicated hologram can be made using a point source of light as object beam and a plane wave as reference beam to illuminate the photographic plate. An interference pattern is formed which in this case is in the form of curves of decreasing separation with increasing distance from the centre.
The photographic plate is developed giving a complicated pattern which can be considered to be made up of a diffraction pattern of varying spacing. When the plate is illuminated by the reference beam alone, it is diffracted by the grating into different angles which depend on the local spacing of the pattern on the plate. It can be shown that the net effect of this it to re-construct the object beam, so that it appears that light is coming from a point source behind the plate, even when the source has been removed. The light emerging from the photographic plate is identical to the light emerging when the point source which used to be there. An observer looking into the plate from the other side will 'see' a point source of light whether the original source of light is there or not.
This sort of hologram is effectively a concave lens, since it 'converts' a plane wavefront into a divergent wavefront. It will also increase the divergence of any wave which is incident on it in exactly the same way as a normal lens does. Its focal length is the distance between the point source and the plate.
### A hologram of a complex object which can be considered to be a set of point sources
The diagram on the right shows the optical arrangement for making a hologram of a complex object. The laser beam is split in two by the beam splitter. One beam illuminates the object which then scatters light onto the recording medium. The second (reference) beam illuminates the recording medium directly.
According to diffraction theory, each point in the object acts as a point source of light. Each of these point sources interferes with the reference beam, giving rise to an interference pattern. The resulting pattern is the sum of a large number (strictly speaking, an infinite number) of point source + reference beam interference patterns.
The diagram on the left shows the optical arrangement for re-constructing the object beam. The object is no longer present, and the hologram is illuminated by the reference beam. Each point source diffraction grating will diffract part of the reference beam to re-construct the wavefront from its point source. These individual wavefronts add together to recontstruct the whole of the object beam.
The viewer perceives a wavefront which is identical to the wavefront scattered by the object, so that it appears to him/her that the object is still in place. This image is known as a 'virtual' image as it is generated even though the object is no longer there.
This explains, albeit in somewhat simplistic terms, how transmission holograms work. Other holograms, such as rainbow and Denisyuk holgrams are somewhat more complex but the principles are the same
## Holography - the theory
A light wave can be modelled by a complex number U which represents the electric or magnetic field of the light wave. The amplitude and phase of the light are represented by the absolute value and angle of the complex number. The object and reference waves at any point in the holographic system are given by UO and UR. The combined beam is given be UO + UR. The energy of the combined beams is proportional to the square of magnitude of the electric wave:
<math>|U_O + U_R|^2=U_O U_R^*+|U_R|^2+|U_O|^2+ U_O^*U_R</math>
If a photographic plate is exposed to the two beams, and then developed, its transmittance, T, is proportional to the light energy which was incident on the plate, and is given by
<math>T=k[U_O U_R^*+|U_R|^2+|U_O|^2+ U_O^*U_R]</math>
where k is a constant. When the developed plate is illuminated by the reference beam, the light transmitted through the plate, UH is
<math>U_H=TU_R=k[U_O U_R^*+|U_R|^2+|U_O|^2+ U_O^*U_R]U_R=k[U_O+|U_R|^2U_R+|U_O|^2U_R+ U_O^*U_R^2]</math>
It can be seen that UH has four terms. The first of these is kUO, since URUR* is equal to one, and this is the re-constructed object beam. The second term represents the reference beam whose amplitude has been modifed by UR2. The third also represent the reference beam which has had its amplitude modifed by UO2; this modification will cause the reference beam to be diffracted around its central direction. The fourth term is know as the 'conjugate object beam'. It has the reverse curvature to the object beam itself, and forms a real image of the object in the space beyond the holographic plate.
Early holograms had both the object and reference beams illuminating the recording medium normally which meant that all the four beams emerging from the holgram were superimposed on one another. The off-axis hologram was developed by Leith and Upatnieks to overcome this problem. The object and reference beams are incident at well-separated angles onto the holographic recording medium and the virtual, real and reference wavefronts all emerge at different angles enabling the re-constructed object beam to be imaged clearly.
# Viewing the hologram
The picture on the right is a photograph, taken against a diffuse light background, of a hologram recorded on photographic emulsion. The area shown is about 8mmx8mm. The holographic recording is the random variation in intensity which is an objective speckle pattern, and not the regular lines which are likely to be due to interference arising from multiple reflections in the glass plate on which the photographic emulsion is mounted. It is no more possible to discern the subject of the hologram from this than it is to identify the music on a gramophone record by looking at the structure of the tracks. When this hologram is illuminated by a divergent laser beam, the viewer will see the object used to make it (in this case, a toy van) because the light is diffracted by the hologram to re-construct the light which was scattered from the object.
When you look at a scene, each eye captures a portion of the light scattered from the scene, and the lens of the eye forms an image of the scene on the retina, in which light from each angular position is focused to a specific angular position in the image plane. Since the hologram reconstructs the whole of the scattered light field which was incident on the hologram, the viewer sees the same image whether this is derived from the light field scattered from the object, or the reconstructed light field produced by the hologram and is unable to tell whether he/she is looking at the real or the virtual object. If the viewer moves about, the object will appear to move in exactly the same way whether he/she is looking at the original light field or the reconstructed light field. If there are several objects in the scene, they will exhibit parallax. If the viewer is using both eyes (stereoscopic vision), he/she will get depth information when viewing the hologram in exactly the same way as when he/she is viewing the real scene.
It should be clear from this why a hologram is not a 3D photograph. A photograph records an image of the recorded scene from a single viewpoint, which is defined by the position of the camera lens. The hololgram is not an image, but an encoding system which enables the scattered light field to be reconstructed. Images can then be formed from any point in the reconstructed beam either with a camera or by eye. It was very common in the early days of holography to use a chess board as the object, and then take photographs at several different angles using the reconstructed light to show how the relative positions of the chess-pieces appeared to change.
Since each point in the hologram contains light from the whole of the original scene, the whole scene can, in principle, be re-constructed from a single point in the hologram. To demonstrate this concept, you can break the hologram into small pieces and you can still see the entire object from each small piece. If you envisage the hologram as a 'window' on the object, then each small piece of hologram is just a part of the window from which you can still view the object even if the rest of the window is blocked off.
You do, however, lose resolution as you decrease the size of the hologram - the image becomes 'fuzzier'. This is a result of diffraction and arises in the same way as the resolution of an imaging system is ultimately limited by diffraction where the resolution becomes coarser as the lens or lens aperture diameter decreases.
# Practical requirements for making and viewing a hologram
The object and the reference beams must be able to produce an interference pattern which is stable during the time in which the holographic recording is made. To do this, they must have the same frequency and the same relative phase during this time, that is, they must be mutually coherent. Many laser beams satisfy this condition, and lasers have been used to make holograms since their invention, though it should be noted that the first holograms by Gabor used 'quasi-chromatic' light sources. In principle, two separate light sources could be used if the coherence condition could be satisfied, but in practice a single laser is always used.
In addition, the medium used to record the fringe pattern must be able to resolve the fringe patterns and some of the more common media used are listed below. The spacing of the fringes depends on the angle between object and reference beam. For example, if this angle is 45o, and the wavelength of the light is 0.5μm, the fringe spacing is about 0.7μm or 1300 lines/mm. A working hologram can be obtained even if all the fringes are not resolved, but the resolution of the image is reduced as the resolution of the recording medium reduces.
Mechanical stability is also very important when making a hologram. Any relative phase change between the object and reference beams due to vibration or air movement will cause the fringes on the recording medium to move, and if the phase changes is greater than π, the fringe pattern is averaged out, and no holographic recording is obtained. Recording time can be several seconds or more, and given that a phase change of π is equivalent to a movement of λ/2 this is quite a stringent stability equirement.
Generally, the coherence length of the light determines the maximum depth in the scene of interest which can be recorded holographically. A good holography laser will typically have a coherence length of several meters, ample for a deep hologram. Certain pen laser pointers have been used to make small holograms (see External links). The size of these holograms is not restricted by the coherence length of the laser pointers (which can exceed several meters), but by their low power of below 5 mW.
The objects which form the scene must, in general, have optically rough surfaces so that they scatter light over a wide range of angles. A specularly reflecting (or shiny) surface reflects the light in only one direction at each point on its surface, so in general, most of the light will not be incident on the recording medium. It should be noted that the light scattered from objects with a rough surface forms an objective speckle pattern which has random amplitude and phase.
The reference beam is not normally a plane wavefront; it is usually a divergent wavefront which is formed by placing a convex lens in the path of the laser beam.
To re-construct the object exactly from a transmission holgram, the reference beam must have the same wavelength, the same curvature, and must illuminate the hologram at the same angle as the original reference beam. Any slight departure from any of these conditions will give a distorted re-construction, and if the difference between the reconstruction and original reference beam is too great, no re-construction is obtained.
Exact re-construction is achieved in holographic interferometry where the holographically re-constructed wavefront interferes with the live wavefront, to map out any displacement of the live object, and gives a null fringe if the object has not moved.
# Holographic recording media
The recording medium must be able to resolve the interference fringes as discussed above. It must also be sufficiently sensitive to record the fringe pattern in a time period short enough for the system to remain optically stable, i.e any relative movement of the two beams must be significantly less than λ/2.
The recording medium has to convert the interference pattern into an optical element which modifies either the amplitude or the phase of a light beam which is incident upon it.
These are known as amplitude and phase holograms respectively. In amplitude holograms the modulation is in the varying absorption of the light by the hologram, as in a developed photographic emulsion which is less or more absorptive depending on the intensity of the light which illuminated it. In phase holograms, the optical distance (i.e. the refractive index or in some cases the thickness) in the material is modulated.
Most materials used for phase holograms reach the theoretical diffraction efficiency for holograms, which is 100% for thick holograms (Bragg diffraction regime) and 33.9% for thin holograms (Raman-Nath diffraction regime, holographic films of typically some μm thickness). Amplitude holograms have a lower efficiency than phase holograms and are therefore used more rarely.
The table below shows the principal materials for holographic recording. Note that these do not include the materials used in the mass replication of an existing hologram. The resolution limit given in the table indicates the maximal number of interference lines per mm of the gratings. The required exposure is for a long exposure. Short exposure times (less than 1/1000th of second, such as with a pulsed laser) require a higher exposure due to reciprocity failure.
It is also possible to make holographic recordings using digital cameras - see digital holography[6]
# Mass replication of holograms
An existing hologram can be replicated, either in an optical way similar to holographic recording, or in the case of surface relief holograms, by embossing. Surface relief holograms are recorded in photoresists or photothermoplastics, and allow cheap mass reproduction. Such embossed holograms are now widely used, for instance as security features on credit cards or quality merchandise. The Royal Canadian Mint even produces holographic gold and silver coinage through a complex stamping process.[7] The first book to feature a hologram on the front cover was The Skook (Warner Books, 1984) by JP Miller, featuring an illustration by Miller.
The first step in the embossing process is to make a stamper by electrodeposition of nickel on the relief image recorded on the photoresist or photothermoplastic. When the nickel layer is thick enough, it is separated from the master hologram and mounted on a metal backing plate. The material used to make embossed copies consists of a polyester base film, a resin separation layer and a thermoplastic film constituting the holographic layer.
The embossing process can be carried out with a simple heated press. The bottom layer of the duplicating film (the thermoplastic layer) is heated above its softening point and pressed against the stamper so that it takes up its shape. This shape is retained when the film is cooled and removed from the press. In order to permit the viewing of embossed holograms in reflection, an additional reflecting layer of aluminium is usually added on the hologram recording layer.
# Applications of optical holography
## Holographic data storage
Holography can be put to a variety of uses other than recording images. Holographic data storage is a technique that can store information at high density inside crystals or photopolymers. The ability to store large amounts of information in some kind of media is of great importance, as many electronic products incorporate storage devices. As current storage techniques such as Blu-ray reach the denser limit of possible data density (due to the diffraction-limited size of the writing beams), holographic storage has the potential to become the next generation of popular storage media.The advantage of this type of data storage is that the volume of the recording media is used instead of just the surface.
Currently available SLMs can produce about 1000 different images a second at 1024×1024-bit resolution. With the right type of media (probably polymers rather than something like LiNbO3), this would result in about 1 gigabit per second writing speed. Read speeds can surpass this and experts believe 1-terabit per second readout is possible.
In 2005, companies such as Optware and Maxell have produced a 120 mm disc that uses a holographic layer to store data to a potential 3.9 TB (terabyte), which they plan to market under the name Holographic Versatile Disc. Another company, InPhase Technologies, is developing a competing format.
While many holographic data storage models have used "page-based" storage, where each recorded hologram holds a large amount of data, more recent research into using submicrometre-sized "microholograms" has resulted in several potential 3D optical data storage solutions. While this approach to data storage can not attain the high data rates of page-based storage, the tolerances, technological hurdles, and cost of producing a commercial product are significantly lower.
## Holographic Interferometry
Holographic interferometry (HI)[8][9]is a technique which enables static and dynamic displacements of objects with optically rough surfaces to be measured to optical interferometric precision (i.e to fractions of a wavelength of light). It can also be used to detect optical path length variations in transparent media, which enables, for example, fluid flow to be visualised and analysed. It can also be used to generate contours representing the form of the surface.
It has been widely used to measure stress, strain, and vibration in engineering structures
## Security holograms
Security holograms are very difficult to forge because they are replicated from a master hologram which requires expensive, specialized and technologically advanced equipment. They are used widely in many currencies such as the Brazilian real 20 note, British pound 5/10/20 notes, Canadian dollar 5/10/20/50/100 notes, Euro 5/10/20/50/100/200/500 notes, South Korean won 5000/10000 notes, Japanese yen 5000/10000 notes, etc. They are also used in credit and bank cards as well as quality products.
## Interferometric microscopy
The hologram keeps the information on the amplitude and phase of the field. Several holograms may keep information about the same distribution of light,
emitted to various directions. The numerical analysis of such holograms allows one to emulate large numerical aperture which, in turn, enables enhancement of the resolution of optical microscopy.
The corresponding technique is called interferometric microscopy. Recent achievements of interferometric microscopy allow one to approach the quarter-wavelength limit of resolution.[10]
## Dynamic holography
The discussion above describes static holography, in which recording, developing and reconstructing occur sequentially and a permanent hologram is produced.
There exist also holographic materials which don't need the developing process and can record a hologram in a very short time. This allows to use holography to perform some simple operations in an all-optical way. Examples of applications of such real-time holograms include phase-conjugate mirrors ("time-reversal" of light), optical cache memories, image processing (pattern recognition of time-varying images), and optical computing.
The amount of processed information can be very high (terabit/s), since the operation is performed in parallel on a whole image. This compensates the fact that the recording time, which is in the order of a µs, is still very long compared to the processing time of an electronic computer. The optical processing performed by a dynamic hologram is also much less flexible than electronic processing. On one side one has to perform the operation always on the whole image, and on the other side the operation a hologram can perform is basically either a multiplication or a phase conjugation. But remember that in optics, addition and Fourier transform are already easily performed in linear materials, the second simply by a lens. This enables some applications like a device that compares images in an optical way.[11]
The search for novel nonlinear optical materials for dynamic holography is an active area of research. The most common materials are photorefractive crystals, but also in semiconductors or semiconductor heterostructures (such as quantum wells), atomic vapors and gases, plasmas and even liquids it was possible to generate holograms.
A particularly promising application is optical phase conjugation. It allows the removal of the wavefront distortions a light beam receives when passing through an aberrating medium, by sending it back through the same aberrating medium with a conjugated phase. This is useful for example in free-space optical communications to compensate for atmospheric turbulence (the phenomenon that gives rise to the twinkling of starlight).
## Holography in art
Early on artists saw the potential of holography as a medium and gained access to science laboratories to create their work. Holographic art is often the result of collaborations between scientists and artists, although some holographers would regard themselves as both an artist and scientist.
Salvador Dalí claimed to have been the first to employ holography artistically. He was certainly the first and most notorious surrealist to do so, but the 1972 New York exhibit of Dalí holograms had been preceded by the holographic art exhibition which was held at the Cranbrook Academy of Art in Michigan in 1968 and by the one at the Finch College gallery in New York in 1970, which attracted national media attention.[12]
During the 1970's a number of arts studios and schools were established, each with their particular approach to holography. Notably there was the San Francisco School of holography established by Llyod Cross, The Museum of Holography in New York founded by Rosemary (Possie) H. Jackson, the Royal College of Art in London and the Lake Forrest College Symposiums organised by Tung Jeong (T.J). None of these studios still exist, however there is the Center for the Holographic Arts in New York [1] and the HOLOcenter in Seoul [2] which offer artists a place to create and exhibit work.
A small but active group of artist use holography as their main medium and many more artists integrate holographic elements into their work.
The MIT Museum [3] and Jonathan Ross [4] both have extensive collections of holography and on-line catalogues of art holograms.
## Holography as a hobby
Since the beginning of holography experimenters have explored the uses of holography. Starting in 1971 Lloyd Cross started the San Francisco School of Holography and started to teach amateurs the methods of making holograms with inexpensive equipment. This method relied on the use of a large table of deep sand (invented by Jerry Pethic) to hold the optics rigid and dampen vibrations that would destroy the image.
Many of these holographers would go on to produce art holograms. In 1983, Fred Unterseher published the Holography Handbook, a remarkably easy to read description of making holograms at home. This brought in a new wave of holographers and gave simple methods to use the then available AGFA silver halide recording materials.
In 2000 Frank DeFreitas published the Shoebox Holography Book and introduced using inexpensive laser pointers to countless hobbiests. This was a very important development for amateurs as it took the cost for a 5mw laser from $1200 to $5. Now there are hundreds to thousands of amateur holographers worldwide.
In 2006 a large number of surplus Holography Quality Green Lasers (Coherent C315) became available and put Dichromated Gelatin (DCG) within the reach of the amateur holographer. The holography community was surprised at the amazing sensitivity of DCG to green light. It had been assumed that the sensitivity would be non existent. Jeff Blythe responded with the G307 formulation of DCG to increase the speed and sensitivity to these new lasers.
Many film suppliers have come and gone from the silver halide market. While more film manufactures have filled in the voids, many amateurs are now making their own film. The favorite formulations are Dichromated Gelatin, Methelene Blue Sensitised Dichromated Gelatin and Diffusion Method Silver Halide preparations. Jeff Blythe has published very accurate methods for making film in a small lab or garage.
A small group of amateurs are even constructing their own pulsed lasers to make holograms of moving objects.
Jeff Blythe's Film Formulations
# Non-optical holography
In principle, it is possible to make a hologram for any wave.
## Electron holography
Electron holography is the application of holography techniques to electron waves rather than light waves.
Electron holography was invented by Dennis Gabor to improve the resolution and avoid the aberrations of the transmission electron microscope. Today it is commonly used to study electric and magnetic fields in thin films, as magnetic and electric fields can shift the phase of the interfering wave passing through the sample.[13]
The principle of electron holography can also be applied to interference lithography.[14]
## Acoustic holography
Acoustic Holography is the method for registering sound waves.
## Atom holography
Atomic holography has evolved out of the development of the basic elements of atom optics. With the Fresnel diffraction lens and atomic mirrors atomic holography follows a natural step in the development of the physics (and applications) of atomic beams. Recent developments including atomic mirrors and especially ridged mirrors have provided the tools necessary for the creation of atomic holograms.[15], although such holograms have not yet been commercialized.
# Holographic theories of brain function
An analogy between the distributed information in holograms and the distributed information in brains gave rise to a speculative idea termed holonomic brain theory. | https://www.wikidoc.org/index.php/Hologram | |
3437b9514922f646e14d2e783de55d00bb1e952d | wikidoc | Home birth | Home birth
# Background
Home birth is childbirth that occurs outside a hospital or birthing center setting, usually in the home of the mother. Most home births are assisted by midwives, but some home births are physician assisted. Others have no medical assistance at all. This is known as unassisted childbirth or freebirth.
In most Western countries, home birth declined over the 20th century, although there was some revival of the practice in 1970s. In The Netherlands, about 30% of all births occur at home, but this number is falling. In countries where midwives are the main carers for pregnant women, home birth is more prevalent.
# Types of home birth
## Assisted home birth
For low-risk pregnancies, a number of studies have shown that planned, assisted home births are at least as safe as hospital births. There are fewer medical interventions, such as cesarean sections, forceps or ventouse deliveries, episiotomies and administration of pain medication such as epidurals, all of which may pose some risk to the health of the mother and baby of which a homebirth can help minimise.
## Unassisted home birth
Main article: Unassisted childbirth
There have been no formal studies on unassisted birth. A mother having an unassisted home birth can do so in the environment in which she feels most comfortable.
Many mothers choose a "couple's birth" where the birthing mother and her spouse or partner are the only ones present while she gives birth. Other children may be sleeping, or busy elsewhere in the house. Advocates of unassisted birth believe that couple's birth is an intimate extension of babymaking.
# Differing opinions
Proponents of home birth prefer the atmosphere and safety of a home birth. The mother has more control over her surroundings, and can eat and move around, sleep and do anything she pleases – activities which may be discouraged in a hospital setting. The mother is often more comfortable in her own home and increased comfort contributes to shorter labor. Antibiotic resistant pathogens commonly found in hospitals , such as staph (methicillin-resistant Staphylococcus aureus and others), are less likely to be transferred to the mother or child when the birth takes place at home. However, in the case of emergencies such as cord prolapse, breathing problems with the infant, inverted uterus, or bleeding of the mother, there is less access to life-saving equipment. Properly trained midwives can manage such emergencies until the woman can be transferred to a hospital.
Conversely, some mothers are more comfortable in a hospital setting because they implicitly trust the medical system and because they prefer to be closer to an operating room should an emergency arise. Most hospitals have a policy of trying to deliver the baby within 30 minutes of determining a caesarean is required, however, owing to the theatre preparation time, this goal is only achieved 66% of the time. Despite this, there is no statistical increase in morbidity or mortality when it takes longer than 30 minutes. This generally fits with the view that very few obstetric emergencies require immediate action.
# Safety
The safety of home birth has been questioned by some obstetricians and general practitioners, but designing randomized controlled trials to test the safety of home birth compared to hospital birth has significant ethical problems. Studies of safety have differing conclusions.
A recent study in the British Medical Journal, "Outcomes of planned home births with certified professional midwives: large prospective study in North America" (Johnson & Daviss, June 2005), concluded that outcomes were just as good and "medical intervention rates (such as epidural, episiotomy, forceps, ventouse, and caesarean section) were substantially lower than for low risk US women having hospital births." For example, amongst the home birth women, 3.7% ended up having a caesarean section compared to 19% for the US as a whole (for a similar risk profile) . The intrapartum and neonatal mortality was 1.7 deaths per 1000 low risk intended home births after planned breeches and twins (not considered low risk) were excluded.
The National Center for Health and Clinical Excellence, a healthcare watchdog organization in the UK, has recently performed a comprehensive review of homebirth literature and concluded that high-quality research is lacking, specifically with regard to the number of babies who die at home births versus hospital births, but feel that women should be given the choice of where to birth:
“The quality of evidence available is not as good as it should be for such an important healthcare issue and most studies do not report complete or consistent outcome data. Planning birth outside an obstetric unit seems to be associated with an increase in spontaneous vaginal births, an increase in women with an intact perineum and improved maternal satisfaction.
“Of particular concern is the lack of reliable data, relating to relatively rare but serious outcomes such as IPPM in all places of birth. Uncontrolled confounding and selection bias are particular methodological limitations of most studies. The GDG was unable to reassure itself that planning birth in a non-obstetric setting is as safe in this respect as birth in an obstetric unit.
“Women should be offered the choice of planning birth at home, in a midwifery unit or in an obstetric unit. Women should be reassured that intrapartum-related perinatal mortality is low in all settings. Before making their choice, women should be informed of the variable quality of the information comparing the potential risks and benefits of each birth setting.”
According to Enkin et al in the work A Guide To Effective Care in Pregnancy and Childbirth; "Women with low risk pregnancies considering out of hospital birth should not be discouraged."
# Legal situation in the United States
No state prosecutes mothers for giving birth outside of a hospital. However, midwives who assist at such births may be prosecuted in some areas.
In the early and mid 1900s, physicians pushed to have midwifery banned throughout the United States. Childbirth became very clinical with the mother generally subdued with leather straps and ether. In 37 states it is once again legal to acquire the services of a midwife. Many midwives continue to attend mothers in states where it is illegal, while efforts are underway to change the law.
Practicing as a direct-entry midwife is still (as of May 2006) illegal under certain circumstances in Washington, D.C. and the following states: Alabama, Georgia, Hawaii, Illinois, Indiana, Iowa, Kentucky, Maryland, Missouri, North Carolina, South Dakota and Wyoming. However, Certified Nurse Midwives can legally practice in these areas.
People wishing to have a midwife-assisted home birth in the United States should always research the applicable laws in their home state.
# Legal situation in Australia
Whilst there is no restriction on having homebirths in Australia, it is illegal for midwives to practice in some Australian States and Territories, because they are unable to obtain professional indemnity insurance. Medical practitioners in some Australian jurisdictions must have insurance before they can practice. After the collapse of the large Australian insurer HIH, the remaining Australian insurance companies ceased offering insurance to home birth midwives, as they claimed that the pool of midwives requiring insurance was too small to make it commercially viable. Without insurance, many independently practicing midwives have elected to discontinue providing independent services, even though they are qualified health professionals and are allowed to practice within hospitals.
When several large insurance companies threatened to withdraw insurance for obstetricians in 2002, the Australian Government immediately responded and provided a A$600 million dollar (over 4 years) subsidy to the obstetricians to allow them to continue to practice legally.
Some State Governments have now introduced government funded home birth services, including the Northern Territory, Western Australia, New South Wales and South Australia. In April 2007, the Western Australian Government announced that it would be expanding birth at home across the State.
# Additional reading
- A Good Birth, A Safe Birth : Choosing and Having the Childbirth Experience You Want. (1992), Korte, Diana, Boston, MA: USA, The Harvard Common Press.
- Birthing From Within: An Extra-Ordinary Guide to Childbirth Preparation. (1998), England, Horowitz NM: USA, Partera Press.
- A Wise Birth. Bringing together the best of natural childbirth with modern medicine, Armstrong P & Feldman S, 1990, reissued 2007, Pinter & Martin, ISBN 978-1-905177-03-5
- Having a Great Birth in Australia Ed David Vernon, Australian College of Midwives, Canberra, 2005 ISBN 0-9751674-3-X
- Men at Birth Ed David Vernon, Australian College of Midwives, Canberra, 2006, ISBN 0-9751674-4-8
- Home Birth: A Practical Guide, Wesson, Nicky, 2006, Pinter & Martin, ISBN 978-1-905177-06-6
- The Thinking Woman's Guide to a Better Birth, by Henci Goer
- Lamaze Institute for Normal Birth
- The American Way of Birth, Jessica Mitford
- The birthjunkie site has an unassisted childbirth forum where you can discuss unassisted and minimally assisted childbirth with others. You can also read birth stories from unassisted births, including an 11.25 pound (5.1 kg) baby born without tearing.
- The MANA state-by-state chart shows midwife certification requirements in the USA and reimbursement by Medicaid. It is common for private insurance to reimburse according to the Medicaid rules.
- Summary of Medical Studies on Homebirth
- Home Midwifery Association Queensland
- Joyous Birth forums | Home birth
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
Home birth is childbirth that occurs outside a hospital or birthing center setting, usually in the home of the mother. Most home births are assisted by midwives, but some home births are physician assisted. Others have no medical assistance at all. This is known as unassisted childbirth or freebirth.
In most Western countries, home birth declined over the 20th century, although there was some revival of the practice in 1970s. In The Netherlands, about 30% of all births occur at home, but this number is falling. In countries where midwives are the main carers for pregnant women, home birth is more prevalent.[citation needed]
# Types of home birth
## Assisted home birth
For low-risk pregnancies, a number of studies have shown that planned, assisted home births are at least as safe as hospital births. There are fewer medical interventions, such as cesarean sections, forceps or ventouse deliveries, episiotomies and administration of pain medication such as epidurals, all of which may pose some risk to the health of the mother and baby of which a homebirth can help minimise.
## Unassisted home birth
Main article: Unassisted childbirth
There have been no formal studies on unassisted birth. A mother having an unassisted home birth can do so in the environment in which she feels most comfortable.
Many mothers choose a "couple's birth" where the birthing mother and her spouse or partner are the only ones present while she gives birth. Other children may be sleeping, or busy elsewhere in the house. Advocates of unassisted birth believe that couple's birth is an intimate extension of babymaking.
# Differing opinions
Proponents of home birth prefer the atmosphere and safety of a home birth. The mother has more control over her surroundings, and can eat and move around, sleep and do anything she pleases – activities which may be discouraged in a hospital setting. The mother is often more comfortable in her own home and increased comfort contributes to shorter labor. [1] Antibiotic resistant pathogens commonly found in hospitals [2] [3], such as staph (methicillin-resistant Staphylococcus aureus and others), are less likely to be transferred to the mother or child when the birth takes place at home. However, in the case of emergencies such as cord prolapse, breathing problems with the infant, inverted uterus, or bleeding of the mother, there is less access to life-saving equipment. Properly trained midwives can manage such emergencies until the woman can be transferred to a hospital.
Conversely, some mothers are more comfortable in a hospital setting because they implicitly trust the medical system and because they prefer to be closer to an operating room should an emergency arise. Most hospitals have a policy of trying to deliver the baby within 30 minutes of determining a caesarean is required, however, owing to the theatre preparation time, this goal is only achieved 66% of the time. Despite this, there is no statistical increase in morbidity or mortality when it takes longer than 30 minutes. This generally fits with the view that very few obstetric emergencies require immediate action. [4]
# Safety
The safety of home birth has been questioned by some obstetricians and general practitioners, but designing randomized controlled trials to test the safety of home birth compared to hospital birth has significant ethical problems. Studies of safety have differing conclusions.
A recent study in the British Medical Journal, "Outcomes of planned home births with certified professional midwives: large prospective study in North America" (Johnson & Daviss, June 2005), concluded that outcomes were just as good and "medical intervention rates (such as epidural, episiotomy, forceps, ventouse, and caesarean section) were substantially lower than for low risk US women having hospital births." For example, amongst the home birth women, 3.7% ended up having a caesarean section compared to 19% for the US as a whole (for a similar risk profile) [2000 data]. The intrapartum and neonatal mortality was 1.7 deaths per 1000 low risk intended home births after planned breeches and twins (not considered low risk) were excluded.[5]
The National Center for Health and Clinical Excellence, a healthcare watchdog organization in the UK, has recently performed a comprehensive review of homebirth literature and concluded that high-quality research is lacking, specifically with regard to the number of babies who die at home births versus hospital births, but feel that women should be given the choice of where to birth:
“The quality of evidence available is not as good as it should be for such an important healthcare issue and most studies do not report complete or consistent outcome data. Planning birth outside an obstetric unit seems to be associated with an increase in spontaneous vaginal births, an increase in women with an intact perineum and improved maternal satisfaction.
“Of particular concern is the lack of reliable data, relating to relatively rare but serious outcomes such as IPPM [intrapartum-related perinatal mortality] in all places of birth. Uncontrolled confounding and selection bias are particular methodological limitations of most studies. The GDG was unable to reassure itself that planning birth in a non-obstetric setting is as safe in this respect as birth in an obstetric unit.
“Women should be offered the choice of planning birth at home, in a midwifery unit or in an obstetric unit. Women should be reassured that intrapartum-related perinatal mortality is low in all settings. Before making their choice, women should be informed of the variable quality of the information comparing the potential risks and benefits of each birth setting.”[6]
According to Enkin et al in the work A Guide To Effective Care in Pregnancy and Childbirth; "Women with low risk pregnancies considering out of hospital birth should not be discouraged."[7]
# Legal situation in the United States
No state prosecutes mothers for giving birth outside of a hospital. However, midwives who assist at such births may be prosecuted in some areas.
In the early and mid 1900s, physicians pushed to have midwifery banned throughout the United States. Childbirth became very clinical with the mother generally subdued with leather straps and ether. In 37 states it is once again legal to acquire the services of a midwife. Many midwives continue to attend mothers in states where it is illegal, while efforts are underway to change the law.
Practicing as a direct-entry midwife is still (as of May 2006) illegal under certain circumstances in Washington, D.C. and the following states: Alabama, Georgia, Hawaii, Illinois, Indiana, Iowa, Kentucky, Maryland, Missouri, North Carolina, South Dakota and Wyoming.[8] However, Certified Nurse Midwives can legally practice in these areas.
People wishing to have a midwife-assisted home birth in the United States should always research the applicable laws in their home state.
# Legal situation in Australia
Whilst there is no restriction on having homebirths in Australia, it is illegal for midwives to practice in some Australian States and Territories, because they are unable to obtain professional indemnity insurance. Medical practitioners in some Australian jurisdictions must have insurance before they can practice. After the collapse of the large Australian insurer HIH, the remaining Australian insurance companies ceased offering insurance to home birth midwives, as they claimed that the pool of midwives requiring insurance was too small to make it commercially viable. Without insurance, many independently practicing midwives have elected to discontinue providing independent services, even though they are qualified health professionals and are allowed to practice within hospitals.
When several large insurance companies threatened to withdraw insurance for obstetricians in 2002, the Australian Government immediately responded and provided a A$600 million dollar (over 4 years) subsidy to the obstetricians to allow them to continue to practice legally.
Some State Governments have now introduced government funded home birth services, including the Northern Territory, Western Australia, New South Wales and South Australia. In April 2007, the Western Australian Government announced that it would be expanding birth at home across the State. [9]
# Additional reading
- A Good Birth, A Safe Birth : Choosing and Having the Childbirth Experience You Want. (1992), Korte, Diana, Boston, MA: USA, The Harvard Common Press.
- Birthing From Within: An Extra-Ordinary Guide to Childbirth Preparation. (1998), England, Horowitz NM: USA, Partera Press.
- A Wise Birth. Bringing together the best of natural childbirth with modern medicine, Armstrong P & Feldman S, 1990, reissued 2007, Pinter & Martin, ISBN 978-1-905177-03-5
- Having a Great Birth in Australia Ed David Vernon, Australian College of Midwives, Canberra, 2005 ISBN 0-9751674-3-X
- Men at Birth Ed David Vernon, Australian College of Midwives, Canberra, 2006, ISBN 0-9751674-4-8
- Home Birth: A Practical Guide, Wesson, Nicky, 2006, Pinter & Martin, ISBN 978-1-905177-06-6
- The Thinking Woman's Guide to a Better Birth, by Henci Goer
- Lamaze Institute for Normal Birth
- The American Way of Birth, Jessica Mitford
- The birthjunkie site has an unassisted childbirth forum where you can discuss unassisted and minimally assisted childbirth with others. You can also read birth stories from unassisted births, including an 11.25 pound (5.1 kg) baby born without tearing.
- The MANA state-by-state chart shows midwife certification requirements in the USA and reimbursement by Medicaid. It is common for private insurance to reimburse according to the Medicaid rules.
- Summary of Medical Studies on Homebirth
- Home Midwifery Association Queensland
- Joyous Birth forums | https://www.wikidoc.org/index.php/Home_birth | |
2a7b4350dae443ca5ac5f1cdbfac8d103e77fb04 | wikidoc | Homeopathy | Homeopathy
Homeopathy (also homœopathy or homoeopathy; from the Greek ὅμοιος, hómoios, "similar" + πάθος, páthos, "suffering" or "disease") is a form of alternative medicine first defined by Samuel Hahnemann in the 18th century. Homeopathic practitioners contend that an ill person can be treated using a substance that can produce, in a healthy person, symptoms similar to those of the illness. According to homeopaths, serial dilution, with shaking between each dilution, removes the toxic effects of the remedy while the qualities of the substance are retained by the diluent (water, sugar, or alcohol). The end product is often so diluted that materially it is indistinguishable from pure water, sugar or alcohol. Practitioners select treatments according to a patient consultation that explores the physical and psychological state of the patient, both of which are considered important to selecting the remedy.
Claims for efficacy of homeopathic treatment beyond the placebo effect are unsupported by scientific and clinical studies, although meta-analyses of homeopathy, which compare the results of many studies, face difficulty in controlling for the combination of publication bias and the fact that most of these studies suffer from serious shortcomings in their methods. The ideas behind homeopathy are scientifically implausible and "diametrically opposed to modern pharmaceutical knowledge". The lack of convincing scientific evidence supporting its efficacy, and its contradiction of basic scientific principles, have caused homeopathy to be regarded as pseudoscience, or, in the words of a 1998 medical review, as "placebo therapy at best and quackery at worst".
Current usage around the world varies from two percent of people in Britain and the United States using homeopathy in any one year, to 15 percent in India, where homeopathy is now considered part of Indian traditional medicine. Homeopathic remedies are generally considered safe, with rare exceptions; however, homeopaths have been criticised for putting patients at risk by advising them to avoid conventional medicine, such as vaccinations, anti-malarial drugs and antibiotics. In many countries, the laws that govern regulation and testing of conventional drugs often do not apply to homeopathic remedies.
# History
## 18th-century medicine
At the time of the inception of homeopathy, the late 1700s, mainstream medicine employed such measures as bloodletting and purging, the use of laxatives and enemas, and the administration of complex mixtures, such as theriac, which was made from 64 substances including opium, myrrh, and viper's flesh. Such measures often worsened symptoms and sometimes proved fatal. While the virtues of these treatments had been extolled for centuries, Hahnemann rejected such methods as irrational and unadvisable. Instead, he favored the use of single drugs at lower doses and promoted an immaterial, vitalistic view of how living organisms function, believing that diseases have spiritual, as well as physical causes. (At the time, vitalism was part of mainstream science; in the twentieth century, however, medicine discarded vitalism, with the development of microbiology, the germ theory of disease, and advances in chemistry.) Hahnemann also advocated various lifestyle improvements to his patients, including exercise, diet, and cleanliness.
## Hahnemann's concept
Samuel Hahnemann conceived of homeopathy while translating a medical treatise by Scottish physician and chemist William Cullen into German. Being sceptical of Cullen’s theory concerning cinchona’s action in malaria, Hahnemann ingested some of the bark specifically to see if it cured fever "by virtue of its effect of strengthening the stomach".
Upon ingesting the bark, he noticed few stomach symptoms, but did experience fever, shivering and joint pain, symptoms similar to some of the early symptoms of malaria, the disease that the bark was ordinarily used to treat. From this, Hahnemann came to believe that all effective drugs produce symptoms in healthy individuals similar to those of the diseases that they can treat. This later became known as the "law of similars", the most important concept of homeopathy. The term "homeopathy" was coined by Hahnemann and first appeared in print in 1807, although he began outlining his theories of "medical similars" in a series of articles and monographs in 1796.
Hahnemann began to test what effects substances produced in humans, a procedure which would later become known as "proving". These time-consuming tests required subjects to clearly record all of their symptoms as well as the ancillary conditions under which they appeared. Hahnemann saw this data as a way of identifying substances suitable for the treatment of particular diseases. The first collection of provings was published in 1805 and a second collection of 65 remedies appeared in his book, Materia Medica Pura, in 1810. Hahnemann believed that large doses of drugs that caused similar symptoms would only aggravate illness, and so he advocated extreme dilutions of the substances; he devised a technique for making dilutions that he believed would preserve a substance's therapeutic properties while removing its harmful effects, proposing that this process aroused and enhanced "spirit-like medicinal powers held within a drug". He gathered and published a complete overview of his new medical system in his 1810 book, The Organon of the Healing Art, whose 6th edition, published in 1921, is still used by homeopaths today.
## Rise to popularity and early criticism
During the 19th century homeopathy grew in popularity. In 1830, the first homeopathic schools opened, and throughout the 19th century dozens of homeopathic institutions appeared in Europe and the United States. Because of mainstream medicine's reliance on blood-letting and untested, often dangerous medicines, patients of homeopaths often had better outcomes than those of mainstream doctors. Homeopathic treatments, even if ineffective, would almost surely cause no harm, making the users of homeopathic medicine less likely to be killed by the medicine that was supposed to be helping them. The relative success of homeopathy in the 18th century may have led to the abandonment of the ineffective and harmful treatments of bloodletting and purging and to have begun the move towards more effective, scientific medicine.
In the early 19th century, homeopathy began to be criticised. Sir John Forbes, physician to Queen Victoria, said the extremely small doses of homeopathy were regularly derided as useless, laughably ridiculous and "an outrage to human reason". Professor Sir James Young Simpson said of the highly diluted drugs: "No poison, however strong or powerful, the billionth or decillionth of which would in the least degree affect a man or harm a fly." Nineteenth century American physician and author Oliver Wendell Holmes, Sr. was also a vocal critic of homeopathy and published an essay in 1842 entitled Homœopathy, and its Kindred Delusions. The last school in the U.S. exclusively teaching homeopathy closed in 1920.
# General philosophy
Homeopathy is a vitalist philosophy in that it regards diseases and sickness to be caused by disturbances in a hypothetical vital force or life force in humans and that these disturbances manifest themselves as unique symptoms. Homeopathy contends that the vital force has the ability to react and adapt to internal and external causes, which homeopaths refer to as the "law of susceptibility". The law of susceptibility states that a negative state of mind can attract hypothetical disease entities called "miasms" to invade the body and produce symptoms of diseases. However, Hahnemann rejected the notion of a disease as a separate thing or invading entity and insisted that it was always part of the "living whole".
## Law of similars
Hahnemann observed from his experiments with cinchona bark, used as a treatment for malaria, that the effects he experienced from ingesting the bark were similar to the symptoms of malaria. He therefore reasoned that cure proceeds through similarity, and that treatments must be able to produce symptoms in healthy individuals similar to those of the disease being treated. Through further experiments with other substances, Hahnemann conceived of the "law of similars", otherwise known as "like cures like" (Template:Lang-la) as a fundamental healing principle. He believed that by inducing a disease through use of drugs, the artificial symptoms empowered the vital force to neutralise and expel the original disease and that this artificial disturbance would naturally subside when the dosing ceased.
## Miasms and disease
Hahnemann found as early as 1816 that the patients he treated through homeopathy still suffered from chronic diseases that he was unable to cure. In 1828, he introduced the concept of miasms, which he regarded as underlying causes for many known diseases. A miasm is often defined by homeopaths as an imputed "peculiar morbid derangement of our vital force". Hahnemann associated each miasm with specific diseases, with each miasm seen as the root cause of several diseases. According to Hahnemann, initial exposure to miasms causes local symptoms, such as skin or venereal diseases, but if these symptoms are suppressed by medication, the cause goes deeper and begins to manifest itself as diseases of the internal organs. Homeopathy contends that treating diseases by directly opposing their symptoms, as is sometimes done in conventional medicine, is not so effective because all "disease can generally be traced to some latent, deep-seated, underlying chronic, or inherited tendency". The underlying imputed miasm still remains, and deep-seated ailments can only be corrected by removing the deeper disturbance of the vital force.
Hahnemann's miasm theory remains disputed and controversial within homeopathy even in modern times. In 1978, Anthony Campbell, then a consultant physician at The Royal London Homeopathic Hospital, criticised statements by George Vithoulkas claiming that syphilis, when treated with antibiotics, would develop into secondary and tertiary syphilis with involvement of the central nervous system. This conflicts with scientific studies, which indicate that penicillin treatment produces a complete cure of syphilis in more than 90% of cases. Campbell described this as "a thoroughly irresponsible statement which could mislead an unfortunate layman into refusing orthodox treatment".
Originally Hahnemann presented only three miasms, of which the most important was "psora" (Greek for itch), described as being related to any itching diseases of the skin, supposed to be derived from suppressed scabies, and claimed to be the foundation of many further disease conditions. Hahnemann claimed psora to be the cause of such diseases as epilepsy, cancer, jaundice, deafness, and cataracts. Since Hahnemann's time, other miasms have been proposed, some replacing one or more of psora's proposed functions, including tubercular miasms and cancer miasms.
# Preparation of remedies
## Dilution and succussion
In producing treatments for diseases, homeopaths use a process called "dynamisation" or "potentisation" whereby the remedy is diluted with alcohol or water and then vigorously shaken by ten hard strikes against an elastic body in a process called "succussion". Hahnemann thought that the use of remedies which present symptoms similar to those of disease in healthy individuals would only intensify the symptoms and exacerbate the condition, so he advocated the dilution of the remedies. During the process of potentisation, homeopaths believe that the vital energy of the diluted substance is activated and its energy released by vigorous shaking of the substance. For this purpose, Hahnemann had a saddle maker construct a special wooden striking board covered in leather on one side and stuffed with horsehair. Insoluble solids, such as quartz and oyster shell, are diluted by grinding them with lactose (trituration).
Three potency scales are in regular use in homeopathy. Hahnemann pioneered and always favoured the centesimal or "C scale", diluting a substance 1 part in a hundred of diluent at each stage. A 2C dilution requires a substance to be diluted to one part in one hundred, then some of that diluted solution is diluted by one part in one hundred. This works out to one part of the original solution to ten thousand parts (100x100) of diluent. A 6C dilution repeats the process six times, ending up with one part in 1,000,000,000,000. (100 × 100 × 100 × 100 × 100 × 100, or 1006) Other dilutions follow the same pattern. In homeopathy, a solution is described as higher potency the more dilute it is. Higher potencies - that is more dilute substances - are considered to be stronger deep-acting remedies.
Hahnemann advocated carrying out provings of remedies using 30C dilutions and a common homeopathic treatment for the flu is a 200C dilution of duck liver, called Oscillococcinum in homeopathy. Comparing these levels of dilution to the number of molecules present in the initial solution, 50 mL of a 12C solution of Natrum muriaticum (sodium chloride) contains on average only about one molecule of the original substance. The chances of a single molecule of the original substance remaining in a 15C dilution would be roughly 1 in 2 million, and less than one in a billion billion billion billion (1036) for a 30C solution. For a perspective on these numbers, there are on the order of 1032 molecules of water in an Olympic-size swimming pool and if such a pool were filled with a 15C homeopathic remedy, to have a 63% chance of consuming at least one molecule from the original substance, one would need to swallow 1% of the volume of such a pool, or roughly 25 metric tons of water.
For more perspective, 1 ml of a solution which has gone through a 30C dilution would have been diluted into a volume of water equal to that of a cube of 1,000,000,000,000,000,000 metres per side, or about 106 light years. Thus, homeopathic remedies of standard dilutions contain, with overwhelming probability, only water (or alcohol). Practitioners of homeopathy believe that this water retains some "essential property" of the original substance, due to the shaking after each dilution. Hahnemann believed that the dynamisation or shaking of the solution caused a "spirit-like" healing force to be released from within the substance. He thought that even after every molecule of the previous substance has been removed from the water, the spiritual healing force still remained.
Some homeopaths developed a decimal scale (D or X), diluting the substance to ten times its original volume each stage. The D or X scale dilution is therefore half that of the same value of the C scale; for example, "12X" is the same level of dilution as "6C". Hahnemann never used this scale but it was very popular throughout the 19th century and still is in Europe. This potency scale appears to have been introduced in the 1830s by the American homeopath, Dr. Constantine Hering. In the last ten years of his life, Hahnemann also developed a quintamillesimal (Q) or LM scale diluting the drug 1 part in 50,000 parts of diluent. A Q scale dilution is 2.35 times that of a C scale one, for example "20Q" is the same potency as "47C".
Not all homeopaths advocate extremely high dilutions. Many of the early homeopaths were originally doctors and generally tended to use lower dilutions such as "3X" or "6X", rarely going beyond "12X". The split between lower and higher dilutions followed ideological lines with the former stressing pathology and a strong link to conventional medicine, while the latter emphasised vital force, miasms and a spiritual interpretation of disease.
### Coverage in the mainstream press
The BBC's Horizon and ABC's 20/20 broadcast programs described scientific testing of homeopathic dilutions that were unable to differentiate these dilutions from water.
## Provings
In order to determine which specific remedies could be used to treat which diseases, Hahnemann experimented on himself and others for several years, before using remedies on patients. His experiments did not initially consist of giving remedies to the sick, because he thought that the most similar remedy, by virtue of its ability to induce symptoms similar to the disease itself, would make it impossible to determine which symptoms came from the remedy and which from the disease itself. Therefore, sick people were excluded from the provings. The method used for determining which remedies were suitable for specific diseases was called "proving". A homeopathic proving is the method by which the profile of a homeopathic remedy is determined. The word "proving" derives from the German word "Prüfung" meaning "test".
During the process of proving, Hahnemann used healthy volunteers who were given remedies, often in molecular doses, although he later advocated proving with remedies at a 30C dilution, and the resulting symptoms were compiled by observers into a "Drug Picture". During the process the volunteers were observed for months at a time and were made to keep extensive journals detailing all of their symptoms at specific times during the day. During the tests volunteers were forbidden from consuming coffee, tea, spices, or wine. They were also not allowed to play chess, because Hahnemann considered it to be "too exciting", though they were allowed to drink beer and were encouraged to moderately exercise. After the experiments were over, Hahnemann made the volunteers offer their hands and take an oath swearing that what they reported in their journals was the truth, at which time he would interrogate them extensively concerning their symptoms.
Provings have been described as important in the development of the clinical trial, due to their early use of simple control groups, systematic and quantitative procedures, and some of the first application of statistics in medicine. The lengthy records of self-experimentation by homeopaths have occasionally proven useful in the development of modern drugs: For example, evidence nitroglycerin might be useful as a treatment for angina was discovered by looking through homeopathic provings, though homeopaths themselves never used it for that purpose at that time.
The first recorded provings were published by Hahnemann in his 1796 Essay on a New Principle. His Fragmenta de viribus (1805) contained the results of 27 provings, and his 1810 Materia Medica Pura contained 65. 217 remedies underwent provings for James Tyler Kent's 1905 Lectures on Homoeopathic Materia Medica, and newer substances are continually added to contemporary versions.
## Repertory
A compilation of reports of many homeopathic provings is known as a homeopathic materia medica. In practice the usefulness of such a compilation is limited because a practitioner does not need to look up the symptoms for a particular remedy, but rather to explore the remedies for a particular symptom. This need is filled by the homeopathic repertory, which is an index of symptoms, listing after each symptom those remedies that are associated with it. Repertories are often very extensive and may include data from clinical experience in addition to provings. There is often lively debate among the compilers of a repertory and interested practitioners over the veracity of a particular inclusion. The first symptomatic index of the homeopathic materia medica was arranged by Hahnemann. Soon after, one of his students Clemens von Bönninghausen, created the Therapautic Pocket Book, another homeopathic repertory. The first such Homeopathic Repertory was Dr. George Jahr's Repertory, published in 1835 in German and then again in 1838 in English and edited by Dr. Constantine Hering. This version was less focused on disease categories and would be the forerunner to Kent's later works. It consisted of three large volumes. Such repertories increased in size and detail as time progressed.
# Treatments
Homeopathic treatments generally begin with a detailed examinations of their patients' histories, including questions regarding their physical, mental and emotional states, their one's life circumstances and any physical/emotional illnesses. The homeopath then translates this information into a complex formula of mental and physical symptoms, including likes, dislikes, innate predispositions and even body type. The goal is to develop a comprehensive representation of each individual's overall health. This information can then be compared with similar established data in the drug provings found in the homeopathic materia medica. Assisted by further dialogues with the patient, the homeopath then aims to find the one drug most closely matching the "symptom totality" of the patient. There are many methods for determining the most-similar remedy (the simillimum), and homeopaths sometimes disagree. This is partly due to the complexity of the "totality of symptoms" concept. That is, homeopaths do not use all symptoms, but decide which are the most characteristic. This subjective evaluation of case analysis relies on knowledge and experience of the homeopath doing the diagnosis.
Some diversity in approaches to treatments exists among homeopaths. So called "classical" homeopathy generally involves detailed examinations of a patient's history and infrequent doses of a single remedy as the patient is monitored for improvements in symptoms. While "clinical" homeopathy involves combinations of remedies to address the various symptoms of an illness.
## Remedies
"Remedy" is a technical term used in homeopathy to refer to a substance prepared with a particular procedure and intended for treating patients. Homeopathic practitioners rely on two types of reference when prescribing remedies. The Homeopathic Materia Medicae which is comprised of alphabetical indexes of "drug pictures" organised by remedy and describe the symptom patterns associated with individual remedies. They also rely on homeopathic repertories which consist of indexes of symptoms of diseases and listing remedies associated with specific symptoms.
Homeopathy uses many animal, plant, mineral, and synthetic substances in its remedies. Examples include Natrum muriaticum (sodium chloride or table salt), Lachesis muta (the venom of the bushmaster snake), Opium, and Thyroidinum (thyroid hormone). Homeopaths also use treatments called nosodes (from the Greek nosos, disease) made from diseased or pathological products such as fecal, urinary, and respiratory discharges, blood, and tissue. Homeopathic remedies prepared from healthy specimens are called Sarcodes.
Some modern homeopaths have considered more esoteric substances, known as "imponderables" because they do not originate from a material but from electromagnetic energy presumed to have been "captured" by alcohol or lactose. Examples include X-rays, sunlight, and electricity. Recent ventures by homeopaths into even more esoteric substances include thunderstorms (prepared from collected rainwater). Today there are about 3,000 different remedies commonly used in homeopathy. Some homeopaths also use techniques that are regarded by other practitioners as controversial. These include paper remedies, where the substance and dilution are written on a piece of paper and either pinned to the patient's clothing, put in their pocket, or placed under a glass of water that is then given to the patient, as well as the use of radionics to prepare remedies. Such practices have been strongly criticised by classical homeopaths as unfounded, speculative and verging upon magic and superstition.
## Isopathy
Isopathy is a therapy derived from homeopathy and was invented by Johann Joseph Wilhelm Lux in the 1830s. Isopathy differs from homeopathy in general in that the remedies are made up either from things that cause the disease, or from products of the disease, such as pus. Many so-called "homeopathic vaccines" are a form of isopathy.
## Tautopathy
Tautopathy is a practice of alternative medicine that is similar to homeopathy in that it uses very diluted substances to treat illness. However, tautopathy does not rely on the "law of similars", as homeopathy does. According to practitioners of Tautopathy, dilute solutions of lead and arsenic can cause the body to secrete excess amounts of these toxic metals.
## Flower remedies
Flower remedies are produced by placing flowers in water and exposing them to sunlight. The most famous of these are the Bach flower remedies, which were developed by the homeopath Edward Bach. The relationship between these remedies and homeopathy is controversial. On the one hand, the proponents of these remedies share homeopathy's vitalist world-view and the remedies are claimed to act through the same hypothetical "vital force". However, although many of the same plants are used as in homeopathy, the method of preparation is somewhat different, with Bach flower therapies supposedly being prepared in "gentler" ways, such as placing flowers in bowls of sunlit water, and so on. There is no convincing scientific or clinical evidence for flower remedies being effective.
## Veterinary use
The idea of using homeopathy as a treatment for other animals, termed veterinary homeopathy, dates back to the inception of homeopathy as Hahnemann himself wrote and spoke of the use of homeopathy in animals other than humans. In the USA veterinary homeopathy is used by veterinarian members of the Academy for Veterinary Homeopathy and/or the American Holistic Veterinary Medical Association. The FDA has not approved homeopathic products as veterinary medicine in the US. In the UK, veterinary surgeons who use homeopathy belong to the Faculty of Homeopathy and/or to the British Association of Homeopathic Veterinary Surgeons. Animals may only be treated by qualified veterinary surgeons in the UK and some other countries. Internationally, the body that supports and represents homeopathic veterinarians is the International Association for Veterinary Homeopathy. The use of homeopathy in veterinary medicine is controversial, as there has been little scientific investigation and current research in the field is not of a high enough standard to provide reliable data. Other studies have also found that giving animals placebos can play active roles in influencing pet owners to believe in the effectiveness of the treatment when none exists.
# Medical and scientific analysis
Homeopathy is unsupported by modern scientific research. The extreme dilutions used in homeopathic preparations usually leave none of the active ingredient (atoms, ions or molecules) in the final product. The idea that any biological effects could be produced by these preparations is inconsistent with the observed dose-response relationships of conventional drugs. The proposed rationale for these extreme dilutions - that the water contains the "memory" or "vibration" from the diluted ingredient - is also counter to the laws of chemistry and physics. Thus critics contend that any positive results obtained from homeopathic remedies are purely due to the placebo effect. Critics cite the lack of viable scientific studies for the effectiveness of homeopathic remedies as evidence that they are not effective and that any positive effects are due to the placebo effect. Critics also contend that homeopathy is inherently dangerous, because homeopaths offer a false hope that may discourage or delay proper treatment.
## High dilutions
The extremely high dilutions in homeopathy have been a main point of criticism. Homeopaths believe that the methodical dilution of a substance, beginning with a 10% or lower solution and working downwards, with shaking after each dilution, produces a therapeutically active "remedy", in contrast to therapeutically inert water. However, homeopathic remedies are usually diluted to the point where there are no molecules from the original solution left in a dose of the final remedy. Since even the longest-lived noncovalent structures in liquid water at room temperature are only stable for a few picoseconds, critics have concluded that any effect that might have been present from the original substance can no longer exist. Furthermore, since water will have been in contact with millions of different substances throughout its history, critics point out that any glass of water is therefore an extreme dilution of almost any conceivable substance, and so by drinking water one would, according to homeopathic principles, receive treatment for every imaginable condition. Proponents of homeopathy, including Rustum Roy, maintain that water has a memory effect beyond the presence of individual molecules of the dissolved substance, but this is unsupported by experimental evidence.
Homeopathy contends that higher dilutions (fewer potential molecules in each dose) result in stronger medicinal effects. This idea is inconsistent with the observed dose-response relationships of conventional drugs, where the effects are dependent on the concentration of the active ingredient in the body. This dose-response relationship has been confirmed in thousands of experiments on organisms as diverse as nematodes, rats, and humans.
Physicist Robert L. Park, former executive director of the American Physical Society, has noted that "since the least amount of a substance in a solution is one molecule, a 30C solution would have to have at least one molecule of the original substance dissolved in a minimum of 1,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000 molecules of water. This would require a container more than 30,000,000,000 times the size of the Earth." Park has also noted that "to expect to get even one molecule of the 'medicinal' substance allegedly present in 30X pills, it would be necessary to take some two billion of them, which would total about a thousand tons of lactose plus whatever impurities the lactose contained". The laws of chemistry state that there is a limit to the dilution that can be made without losing the original substance altogether. This limit, which is related to Avogadro's number, corresponds to homeopathic potencies of 12C or 24X (1 part in 1024).Template:Ref label
## Research on medical effectiveness
The medical effectiveness of homeopathy has been a point of contention since its inception, and researchers have subjected the system to close scrutiny. One of the earliest studies concerning homeopathic medicine was sponsored by the British government during World War II in which volunteers tested the effectiveness of homeopathic remedies against diluted mustard gas burns. More recent controlled clinical trials on homeopathy have shown poor results, showing slight-to-no differences between homeopathic remedies and placebo.
Meta-analyses, which analyse large groups of studies and draw conclusions based on the results as a whole, have been used to evaluate the effectiveness of homeopathy. Early meta-analyses investigating homeopathic remedies showed slightly positive results among the studies examined, but such studies have warned that it was impossible to draw conclusions due to low methodological quality and difficulty in controlling for publication bias in the studies reviewed. One of the positive meta-analyses, by Linde, et al, was later corrected by the authors, who wrote:
A recent meta-analysis of clinical trials on the effectiveness of homeopathy has shown that earlier clinical trials showed signs of major weakness in methodology and reporting, and that homeopathy trials were less randomized and reported less on dropouts than other types of trials.
In 2005 The Lancet medical journal published a meta-analysis of 110 placebo-controlled homeopathy trials and 110 matched conventional-medicine trials based upon the Swiss government's Program for Evaluating Complementary Medicine, or PEK. The study concluded that its findings were compatible with the notion that the clinical effects of homeopathy are nothing more than placebo effects. However, this last study has been criticised "for being methodologically flawed on many levels." "Of particular concern, the researchers eliminated 102 of 110 homeopathic trials and based their conclusions on only the 8 largest high-quality trials without clearly identifying the criteria by which these trials were selected or the identity of these trials. Odds ratios calculated before the exclusions (on all 110 trials) do not support their ultimate conclusion that homeopathic interventions are no better than placebo"
A 2006 meta-analysis of six trials evaluating homeopathic treatments to reduce cancer therapy side effects following radiotherapy and chemotherapy found "encouraging but not convincing" evidence in support of homeopathic treatment. However, variability in the methodological quality of the six studies provided "insufficient evidence to support clinical efficacy of homeopathic therapy in cancer care".
Since homeopathic remedies at dilutions higher than about D23 (10-23) contain no ingredients apart from the diluent (water, alcohol or sugar), there is no chemical basis for them to have any medicinal action. Newer randomized, double-blind, placebo-controlled trials using highly-diluted homeopathic preparations also fail to find clinical effects of the substances.
The Cochrane Library found insufficient clinical evidence to evaluate the efficacy of homeopathic treatments for asthma or dementia, or for the use of homeopathy in induction of labor. Other researchers found no evidence that homeopathy is beneficial for osteoarthritis, migraines or delayed-onset muscle soreness.
Health organisations such as UK's National Health Service, the American Medical Association, and the FASEB have issued statements of their conclusion that there is no convincing scientific evidence to support the use of homeopathic treatments in medicine.
Clinical studies of the medical efficacy of homeopathy have been criticised by some homeopaths as being irrelevant because they do not test "classical homeopathy". There have, however, been a number of clinical trials that have tested individualized homeopathy. A 1998 review
found 32 trials that met their inclusion criteria, 19 of which were placebo-controlled and provided enough data for meta-analysis. These 19 studies showed a pooled odds ratio of 1.17 to 2.23 in favor of individualized homeopathy over the placebo, but no difference was seen when the analysis was restricted to the methodologically best trials. The authors concluded "that the results of the available randomized trials suggest that individualized homeopathy has an effect over placebo. The evidence, however, is not convincing because of methodological shortcomings and inconsistencies."
Dr. Jack Killen, acting deputy director of the National Center for Complementary and Alternative Medicine, says homeopathy "goes beyond current understanding of chemistry and physics". He adds, "There is, to my knowledge, no condition for which homeopathy has been proven to be an effective treatment."
# Research on effects in other biological systems
While some articles have suggested that homeopathic solutions of high dilution can have statistically significant effects on organic processes including the growth of grain, histamine release by leukocytes, and enzyme reactions, such evidence is disputed since attempts to replicate them have failed.
In 1987, French immunologist Jacques Benveniste submitted a paper to the journal Nature while working at INSERM. The paper purported to have discovered that basophils released histamine when exposed to a homeopathic dilution of anti-immunoglobulin E, a type of white blood cell. The journal editors, sceptical of the results, requested that the study be replicated in a separate laboratory. Upon replication in four separate laboratories the study was published. Still sceptical of the findings, Nature assembled an independent investigative team to determine the accuracy of the research, consisting of Nature editor and physicist Sir John Maddox, American scientific fraud investigator and chemist Walter Stewart, and sceptic and magician James Randi. After investigating the findings and methodology of the experiment, the team found that the experiments were "statistically ill-controlled", "interpretation has been clouded by the exclusion of measurements in conflict with the claim", and concluded, "We believe that experimental data have been uncritically assessed and their imperfections inadequately reported." James Randi stated that he doubted that there had been any conscious fraud, but that the researchers had allowed "wishful thinking" to influence their interpretation of the data.
## Ethical and safety issues
As homeopathic remedies usually contain only water and/or alcohol, they are thought to be generally safe. Only in rare cases are the original ingredients present at detectable levels. In one such case, an unusually undiluted (1:100 or "2X") solution of zinc gluconate, marketed as Zicam Nasal Spray, allegedly caused a small percentage of users to lose their sense of smell. There were 340 cases settled out of court for 12 million U.S. dollars.
Critics of homeopathy have cited other concerns over homeopathic remedies, most seriously, cases of patients of homeopathy failing to receive proper treatment for diseases that it is claimed could have been diagnosed or cured with conventional medicine. Several surveys demonstrate that some (particularly non-physician) homoeopaths advise their patients against immunisation. Some homeopaths suggest that vaccines be replaced with homeopathically diluted "nosodes", created from dilutions of biological agents - including material such as vomit, feces or infected human tissues. While Hahnemann was opposed to such preparations, modern homeopaths often use them and there is no evidence to indicate they have any beneficial effects. Cases of homeopaths advising against the use of anti-malarial drugs have been identified. This puts visitors to the tropics who take this advice in severe danger, since homeopathic remedies are completely ineffective against the malaria parasite. Also, in one case in 2004, a homeopath instructed one of his patients to stop taking conventional medication for a heart condition, writing in his advice, "She just cannot take ANY drugs – I have suggested some homeopathic remedies. I feel confident that if she follows the advice she will regain her health." The patient suffered a fatal heart attack four months later, caused by this stoppage of her medication.
In 1978, Anthony Campbell, then a consultant physician at The Royal London Homeopathic Hospital, criticised statements made by George Vithoulkas to promote his homeopathic treatments. Vithoulkas stated that syphilis, when treated with antibiotics, would develop into secondary and tertiary syphilis with involvement of the central nervous system. Campbell described this as a thoroughly irresponsible statement which could mislead an unfortunate layman into refusing conventional medical treatment. This claim echoes the idea that treating a disease with external medication used to treat the symptoms would only drive it deeper into the body and conflicts with scientific studies, which indicate that penicillin treatment produces a complete cure of syphilis in more than 90% of cases.
A 2006 review by W. Steven Pray of the College of Pharmacy at Southwestern Oklahoma State University recommends that pharmacy colleges include a required course in unproven medications and therapies, that ethical dilemmas inherent in recommending products lacking proven safety and efficacy data be discussed, and that students should be taught where unproven systems such as homeopathy depart from evidence-based medicine.
# Prevalence and legal trends
Homeopathic medicine is fairly common in some countries while being uncommon in others; is highly regulated in some countries and mostly unregulated in others. Regulations vary in Europe depending on the country. In some countries, there are no specific legal regulations concerning the use of homeopathy, while in others, licenses or degrees in conventional medicine from accredited universities are required. In Austria and Germany, no specific regulations exist, while France and Denmark mandate licenses to diagnose any illness or dispense of any product whose purpose is to treat any illness. Some homeopathic treatment is covered by the national insurance coverage of several European countries, including France, the United Kingdom, Denmark, and Luxembourg. In other countries, such as Belgium, homeopathy is not covered. In Austria, public insurance requires scientific proof of effectiveness in order to reimburse medical treatments, but exceptions are made for homeopathy. Two countries which formerly offered homeopathy under their public health insurance schemes have withdrawn this privilege. At the start of 2004, homeopathic medications, with some exceptions, were no longer covered by German public health insurance, and in June 2005, the Swiss Government, after a 5-year trial, withdrew insurance coverage for homeopathy and four other complementary treatments, stating that they did not meet efficacy and cost-effectiveness criteria, though additional insurance can be bought to cover such treatments provided by a medical doctor.
## Outline of past prevalence in Great Britain
In Britain homeopathy was first established by Dr. Frederick Quin around 1827, although two Italian homeopathic doctors (Drs Romani and Roberta) had been employed two years previously by the Earl of Shrewsbury based at Alton Towers in North Staffordshire. Homeopathy in Britain quickly became the preferred medical treatment of the upper classes, as well as the aristocracy and retained an elite clientele, including members of the royal family.
At its peak in the 1870s, Britain had numerous homeopathic dispensaries and small hospitals as well as large busy hospitals in Liverpool, Birmingham, Glasgow, London and Bristol.
## Contemporary prevalence
### United Kingdom
The NHS currently operates five homeopathic hospitals. The largest organisation of homeopaths in the United Kingdom, the Society of Homeopaths, was founded in 1978. The London-based Faculty of Homeopathy has over 1,400 members and was incorporated by an Act of Parliament in 1950. According to a 2006 study, forty nine percent of Scottish medical practices prescribed homeopathic remedies. During the study period, 0.22% of patients were prescribed at least one homeopathic remedy; of that number, 16 percent were children. The study concluded that critical review of Homeopathy's role in the Scottish branch of the national health care system was needed.
### Australia
According to one study, about 4.4% of Australian adults have used homeopathic remedies at least once in their lives, including 1.2% that sought treatment exclusively from homeopathic practitioners.
### Canada
In Canada, a study detailing the use of alternative medicines by children in Quebec found that 11% of the sampled 1911 children used alternative medicines, and 25% of those who did use alternative medicines used homeopathy. The study also pointed out that homeopathy is more commonly used in children in Canada than in adults, of whom only 19% of alternative medicine users used homeopathy. Homeopathy is not officially recognised by Federal Food and Drugs Act in Canada and physicians who choose to use alternative medicines such as homeopathy must follow guidelines set by their province's College of Physicians and Surgeons. Provincial health care generally does not cover homeopathy.
### South America
Some countries in South America, such as Argentina, allow only professional doctors who are qualified and have graduated from a recognised medical school to practice homeopathy. Homeopathy has been regulated in other South American countries, such as Colombia, since the beginning of the 20th century. In Brazil, homeopathy is included in the national health system, and since 1991, physicians who want to practice homeopathy must complete 2,300 hours of education prior to receiving the proper licenses.
### Mexico
In Mexico, homeopathy is currently integrated into the national health care system. In 1985, a presidential decree established the first homeopathic school as well as regulations specifying training requirements for homeopathic doctors. Of those individuals who use complementary alternative medicines, over 26% use homeopathy.
### United States
In the United States, homeopathy is much less common, where the percentage of people seeking homeopathic treatment declined from 3.4% in 1997 to 1.7% in 2002. Homeopathy was first established in the United States by Dr. Hans Burch Gram in 1825 and rapidly gained popularity, partly because conventional medicine of the time was inherently risky. The height of its influence was the end of the 19th century where hardly any city with over 50,000 people was without a homeopathic hospital. In 1890, there were 93 regular schools, 14 of them were fully homeopathic and 8 of them were eclectic. In 1900, there were 121 regular schools, with 22 of them being homeopathic and 10 eclectic. The use of homeopathy in the United States among adults is about 0.3%. According to one study, in 1990, 0.7% of individuals used homeopathy in the year prior to being questioned; in 1997, 3.4% had used homeopathy at least once in the previous year. According to the same study, of those who used homeopathy, 31.7% had seen a homeopathic practitioner in the past year in 1990 and the number dropped to 16.5 by 1997.
In the United States, homeopathic remedies, like all health-care products, are regulated by the Food and Drug Administration. However, the FDA treats homeopathic remedies very differently from conventional medicines. Homeopathic products do not need FDA approval before sale; they do have to be proven safe per the Dietary Supplement Health and Education Act of 1994, but they do not have to prove efficacy. Homeopathic remedies do not have to be labeled with an expiration date, and they do not have to undergo finished product testing to verify contents and strength. All of these are voluntary actions done by the manufacturer. The manufacturer is required to have all ingredients on the label; however, it might not specify which ones are active. In the USA, only homeopathic medicines that claim to treat self-limiting conditions may be sold over-the-counter; homeopathic medicines that claim to treat a serious disease can be sold only by prescription. A memorandum, written in 1985 by attorneys for the American Association of Homeopathic Manufacturers, describes a meeting between the AAHP attorneys and high-ranking FDA officials to discuss whether homeopathic products must be proven effective to remain legally marketable. Such negotiations led to the issuance in 1988 (revised in 1995) of an FDA Compliance Policy Guide that permits homeopathic products "intended solely for self-limiting disease conditions amenable to self-diagnosis (of symptoms) and treatment" to be marketed as nonprescription drugs. In 2001, the FDA published a comprehensive review of mercury compounds in homeopathic drugs. This report indicated that nearly all examined compounds derived from the use of mercury. However, due to the extreme dilution of materials, the presence of mercury in the finished product would be minimal. At present the FDA Health Fraud Division only pursues claims which may cause direct harm to consumers through their use. Homeopathic drugs, largely regarded as equivalent to placebos, are not considered under these guidelines. Due to the significant dilution of the products, the agents become practically immeasurable: the harmful effects of homeopathic drugs is more likely to be that patients avoid conventional treatments.
### Asia
In Asia, the use of homeopathic treatments is increasing, especially in India. Homeopathy arrived in India with Dr John Martin Honigberger in Lahore, in 1829–1830. India has the largest homeopathic infrastructure in the world, with low estimates at about 64,000, but going as high as 300,000 practising homeopaths. In addition, there are 180 colleges teaching courses, and 7500 government clinics and 307 hospitals which dispense homeopathic remedies. In Malaysia, homeopathy was introduced during World War II and was brought by Indians via the British army.
### Africa
In South Africa, homeopathy is regulated by the Associated Health Service Professions Act of 1982, which was set up to provide a registration and licensing framework for health professions. During the 1960s, all homeopathic colleges were closed by the South African Medical Council. However, conventional medical doctors retained the right to use homeopathic treatments. | Homeopathy
Homeopathy (also homœopathy or homoeopathy; from the Greek ὅμοιος, hómoios, "similar" + πάθος, páthos, "suffering" or "disease") is a form of alternative medicine first defined by Samuel Hahnemann in the 18th century.[1] Homeopathic practitioners contend that an ill person can be treated using a substance that can produce, in a healthy person, symptoms similar to those of the illness. According to homeopaths, serial dilution, with shaking between each dilution, removes the toxic effects of the remedy while the qualities of the substance are retained by the diluent (water, sugar, or alcohol). The end product is often so diluted that materially it is indistinguishable from pure water, sugar or alcohol.[2][3][4] Practitioners select treatments according to a patient consultation that explores the physical and psychological state[5] of the patient, both of which are considered important to selecting the remedy.[6]
Claims for efficacy of homeopathic treatment beyond the placebo effect are unsupported by scientific and clinical studies,[7][8][9][10] although meta-analyses of homeopathy, which compare the results of many studies, face difficulty in controlling for the combination of publication bias and the fact that most of these studies suffer from serious shortcomings in their methods.[11][12][13] The ideas behind homeopathy are scientifically implausible and "diametrically opposed to modern pharmaceutical knowledge".[14][15][16] The lack of convincing scientific evidence supporting its efficacy,[17] and its contradiction of basic scientific principles, have caused homeopathy to be regarded as pseudoscience,[18][19][20][21] or, in the words of a 1998 medical review, as "placebo therapy at best and quackery at worst".[22]
Current usage around the world varies from two percent of people in Britain and the United States using homeopathy in any one year,[23][24] to 15 percent in India, where homeopathy is now considered part of Indian traditional medicine.[25] Homeopathic remedies are generally considered safe, with rare exceptions;[26][27] however, homeopaths have been criticised for putting patients at risk by advising them to avoid conventional medicine, such as vaccinations,[28] anti-malarial drugs[29] and antibiotics.[30] In many countries, the laws that govern regulation and testing of conventional drugs often do not apply to homeopathic remedies.[31]
Template:Alternative medical systems
# History
## 18th-century medicine
At the time of the inception of homeopathy, the late 1700s, mainstream medicine employed such measures as bloodletting and purging, the use of laxatives and enemas, and the administration of complex mixtures, such as theriac, which was made from 64 substances including opium, myrrh, and viper's flesh.[32][33] Such measures often worsened symptoms and sometimes proved fatal.[34] While the virtues of these treatments had been extolled for centuries,[35] Hahnemann rejected such methods as irrational and unadvisable.[36] Instead, he favored the use of single drugs at lower doses and promoted an immaterial, vitalistic view of how living organisms function, believing that diseases have spiritual, as well as physical causes.[37][38][39] (At the time, vitalism was part of mainstream science; in the twentieth century, however, medicine discarded vitalism, with the development of microbiology, the germ theory of disease,[40] and advances in chemistry.[41][42]) Hahnemann also advocated various lifestyle improvements to his patients, including exercise, diet, and cleanliness.[36][43]
## Hahnemann's concept
Samuel Hahnemann conceived of homeopathy while translating a medical treatise by Scottish physician and chemist William Cullen into German.[1] Being sceptical of Cullen’s theory concerning cinchona’s action in malaria, Hahnemann ingested some of the bark specifically to see if it cured fever "by virtue of its effect of strengthening the stomach".
[44] Upon ingesting the bark, he noticed few stomach symptoms, but did experience fever, shivering and joint pain, symptoms similar to some of the early symptoms of malaria, the disease that the bark was ordinarily used to treat. From this, Hahnemann came to believe that all effective drugs produce symptoms in healthy individuals similar to those of the diseases that they can treat. This later became known as the "law of similars", the most important concept of homeopathy.[1] The term "homeopathy" was coined by Hahnemann and first appeared in print in 1807, although he began outlining his theories of "medical similars" in a series of articles and monographs in 1796.[45]
Hahnemann began to test what effects substances produced in humans, a procedure which would later become known as "proving".[46] These time-consuming tests required subjects to clearly record all of their symptoms as well as the ancillary conditions under which they appeared. Hahnemann saw this data as a way of identifying substances suitable for the treatment of particular diseases.[46] The first collection of provings was published in 1805 and a second collection of 65 remedies appeared in his book, Materia Medica Pura, in 1810.[47] Hahnemann believed that large doses of drugs that caused similar symptoms would only aggravate illness, and so he advocated extreme dilutions of the substances; he devised a technique for making dilutions that he believed would preserve a substance's therapeutic properties while removing its harmful effects,[48] proposing that this process aroused and enhanced "spirit-like medicinal powers held within a drug".[49] He gathered and published a complete overview of his new medical system in his 1810 book, The Organon of the Healing Art, whose 6th edition, published in 1921, is still used by homeopaths today.[1]
## Rise to popularity and early criticism
During the 19th century homeopathy grew in popularity. In 1830, the first homeopathic schools opened, and throughout the 19th century dozens of homeopathic institutions appeared in Europe and the United States.[50] Because of mainstream medicine's reliance on blood-letting and untested, often dangerous medicines, patients of homeopaths often had better outcomes than those of mainstream doctors.[51] Homeopathic treatments, even if ineffective, would almost surely cause no harm, making the users of homeopathic medicine less likely to be killed by the medicine that was supposed to be helping them.[1] The relative success of homeopathy in the 18th century may have led to the abandonment of the ineffective and harmful treatments of bloodletting and purging and to have begun the move towards more effective, scientific medicine.[34]
In the early 19th century, homeopathy began to be criticised. Sir John Forbes, physician to Queen Victoria, said the extremely small doses of homeopathy were regularly derided as useless, laughably ridiculous and "an outrage to human reason".[52] Professor Sir James Young Simpson said of the highly diluted drugs: "No poison, however strong or powerful, the billionth or decillionth of which would in the least degree affect a man or harm a fly."[53] Nineteenth century American physician and author Oliver Wendell Holmes, Sr. was also a vocal critic of homeopathy and published an essay in 1842 entitled Homœopathy, and its Kindred Delusions.[54] The last school in the U.S. exclusively teaching homeopathy closed in 1920.[1]
# General philosophy
Homeopathy is a vitalist philosophy in that it regards diseases and sickness to be caused by disturbances in a hypothetical vital force or life force in humans and that these disturbances manifest themselves as unique symptoms. Homeopathy contends that the vital force has the ability to react and adapt to internal and external causes, which homeopaths refer to as the "law of susceptibility". The law of susceptibility states that a negative state of mind can attract hypothetical disease entities called "miasms" to invade the body and produce symptoms of diseases.[1] However, Hahnemann rejected the notion of a disease as a separate thing or invading entity[55] and insisted that it was always part of the "living whole".[56]
## Law of similars
Hahnemann observed from his experiments with cinchona bark, used as a treatment for malaria, that the effects he experienced from ingesting the bark were similar to the symptoms of malaria. He therefore reasoned that cure proceeds through similarity, and that treatments must be able to produce symptoms in healthy individuals similar to those of the disease being treated. Through further experiments with other substances, Hahnemann conceived of the "law of similars", otherwise known as "like cures like" (Template:Lang-la) as a fundamental healing principle. He believed that by inducing a disease through use of drugs, the artificial symptoms empowered the vital force to neutralise and expel the original disease and that this artificial disturbance would naturally subside when the dosing ceased.[1]
## Miasms and disease
Hahnemann found as early as 1816 that the patients he treated through homeopathy still suffered from chronic diseases that he was unable to cure.[57] In 1828,[58] he introduced the concept of miasms, which he regarded as underlying causes for many known diseases. A miasm is often defined by homeopaths as an imputed "peculiar morbid derangement of our vital force".[59] Hahnemann associated each miasm with specific diseases, with each miasm seen as the root cause of several diseases. According to Hahnemann, initial exposure to miasms causes local symptoms, such as skin or venereal diseases, but if these symptoms are suppressed by medication, the cause goes deeper and begins to manifest itself as diseases of the internal organs.[60] Homeopathy contends that treating diseases by directly opposing their symptoms, as is sometimes done in conventional medicine, is not so effective because all "disease can generally be traced to some latent, deep-seated, underlying chronic, or inherited tendency".[61] The underlying imputed miasm still remains, and deep-seated ailments can only be corrected by removing the deeper disturbance of the vital force.[62]
Hahnemann's miasm theory remains disputed and controversial within homeopathy even in modern times. In 1978, Anthony Campbell, then a consultant physician at The Royal London Homeopathic Hospital, criticised statements by George Vithoulkas claiming that syphilis, when treated with antibiotics, would develop into secondary and tertiary syphilis with involvement of the central nervous system. This conflicts with scientific studies, which indicate that penicillin treatment produces a complete cure of syphilis in more than 90% of cases.[63] Campbell described this as "a thoroughly irresponsible statement which could mislead an unfortunate layman into refusing orthodox treatment".[64]
Originally Hahnemann presented only three miasms, of which the most important was "psora" (Greek for itch), described as being related to any itching diseases of the skin, supposed to be derived from suppressed scabies, and claimed to be the foundation of many further disease conditions. Hahnemann claimed psora to be the cause of such diseases as epilepsy, cancer, jaundice, deafness, and cataracts.[38] Since Hahnemann's time, other miasms have been proposed, some replacing one or more of psora's proposed functions, including tubercular miasms and cancer miasms.[60]
# Preparation of remedies
## Dilution and succussion
In producing treatments for diseases, homeopaths use a process called "dynamisation" or "potentisation" whereby the remedy is diluted with alcohol or water and then vigorously shaken by ten hard strikes against an elastic body in a process called "succussion". Hahnemann thought that the use of remedies which present symptoms similar to those of disease in healthy individuals would only intensify the symptoms and exacerbate the condition, so he advocated the dilution of the remedies. During the process of potentisation, homeopaths believe that the vital energy of the diluted substance is activated and its energy released by vigorous shaking of the substance. For this purpose, Hahnemann had a saddle maker construct a special wooden striking board covered in leather on one side and stuffed with horsehair.[65][66] Insoluble solids, such as quartz and oyster shell, are diluted by grinding them with lactose (trituration).
Three potency scales are in regular use in homeopathy. Hahnemann pioneered and always favoured the centesimal or "C scale", diluting a substance 1 part in a hundred of diluent at each stage. A 2C dilution requires a substance to be diluted to one part in one hundred, then some of that diluted solution is diluted by one part in one hundred. This works out to one part of the original solution to ten thousand parts (100x100) of diluent. A 6C dilution repeats the process six times, ending up with one part in 1,000,000,000,000. (100 × 100 × 100 × 100 × 100 × 100, or 1006) Other dilutions follow the same pattern. In homeopathy, a solution is described as higher potency the more dilute it is. Higher potencies - that is more dilute substances - are considered to be stronger deep-acting remedies.
Hahnemann advocated carrying out provings of remedies using 30C dilutions[67](a dilution by a factor of 1060) and a common homeopathic treatment for the flu is a 200C dilution of duck liver, called Oscillococcinum in homeopathy. Comparing these levels of dilution to the number of molecules present in the initial solution, 50 mL of a 12C solution of Natrum muriaticum (sodium chloride) contains on average only about one molecule of the original substance. The chances of a single molecule of the original substance remaining in a 15C dilution would be roughly 1 in 2 million, and less than one in a billion billion billion billion (1036) for a 30C solution. For a perspective on these numbers, there are on the order of 1032 molecules of water in an Olympic-size swimming pool and if such a pool were filled with a 15C homeopathic remedy, to have a 63% chance of consuming at least one molecule from the original substance, one would need to swallow 1% of the volume of such a pool, or roughly 25 metric tons of water.[68][69]
For more perspective, 1 ml of a solution which has gone through a 30C dilution would have been diluted into a volume of water equal to that of a cube of 1,000,000,000,000,000,000 metres per side, or about 106 light years. Thus, homeopathic remedies of standard dilutions contain, with overwhelming probability, only water (or alcohol). Practitioners of homeopathy believe that this water retains some "essential property" of the original substance, due to the shaking after each dilution.[70] Hahnemann believed that the dynamisation or shaking of the solution caused a "spirit-like" healing force to be released from within the substance. He thought that even after every molecule of the previous substance has been removed from the water, the spiritual healing force still remained.[69]
Some homeopaths developed a decimal scale (D or X), diluting the substance to ten times its original volume each stage. The D or X scale dilution is therefore half that of the same value of the C scale; for example, "12X" is the same level of dilution as "6C". Hahnemann never used this scale but it was very popular throughout the 19th century and still is in Europe. This potency scale appears to have been introduced in the 1830s by the American homeopath, Dr. Constantine Hering.[71] In the last ten years of his life, Hahnemann also developed a quintamillesimal (Q) or LM scale diluting the drug 1 part in 50,000 parts of diluent.[72] A Q scale dilution is 2.35 times that of a C scale one, for example "20Q" is the same potency as "47C".
Not all homeopaths advocate extremely high dilutions. Many of the early homeopaths were originally doctors and generally tended to use lower dilutions such as "3X" or "6X", rarely going beyond "12X". The split between lower and higher dilutions followed ideological lines with the former stressing pathology and a strong link to conventional medicine, while the latter emphasised vital force, miasms and a spiritual interpretation of disease.[73][74]
### Coverage in the mainstream press
The BBC's Horizon and ABC's 20/20 broadcast programs described scientific testing of homeopathic dilutions that were unable to differentiate these dilutions from water.[66][75]
## Provings
In order to determine which specific remedies could be used to treat which diseases, Hahnemann experimented on himself and others for several years, before using remedies on patients. His experiments did not initially consist of giving remedies to the sick, because he thought that the most similar remedy, by virtue of its ability to induce symptoms similar to the disease itself, would make it impossible to determine which symptoms came from the remedy and which from the disease itself. Therefore, sick people were excluded from the provings. The method used for determining which remedies were suitable for specific diseases was called "proving". A homeopathic proving is the method by which the profile of a homeopathic remedy is determined.[76] The word "proving" derives from the German word "Prüfung" meaning "test".
During the process of proving, Hahnemann used healthy volunteers who were given remedies, often in molecular doses, although he later advocated proving with remedies at a 30C dilution[77], and the resulting symptoms were compiled by observers into a "Drug Picture". During the process the volunteers were observed for months at a time and were made to keep extensive journals detailing all of their symptoms at specific times during the day. During the tests volunteers were forbidden from consuming coffee, tea, spices, or wine. They were also not allowed to play chess, because Hahnemann considered it to be "too exciting", though they were allowed to drink beer and were encouraged to moderately exercise. After the experiments were over, Hahnemann made the volunteers offer their hands and take an oath swearing that what they reported in their journals was the truth, at which time he would interrogate them extensively concerning their symptoms.
Provings have been described as important in the development of the clinical trial, due to their early use of simple control groups, systematic and quantitative procedures, and some of the first application of statistics in medicine.[78] The lengthy records of self-experimentation by homeopaths have occasionally proven useful in the development of modern drugs: For example, evidence nitroglycerin might be useful as a treatment for angina was discovered by looking through homeopathic provings, though homeopaths themselves never used it for that purpose at that time.[79]
The first recorded provings were published by Hahnemann in his 1796 Essay on a New Principle. His Fragmenta de viribus (1805)[80] contained the results of 27 provings, and his 1810 Materia Medica Pura contained 65.[81] 217 remedies underwent provings for James Tyler Kent's 1905 Lectures on Homoeopathic Materia Medica, and newer substances are continually added to contemporary versions.
## Repertory
A compilation of reports of many homeopathic provings is known as a homeopathic materia medica. In practice the usefulness of such a compilation is limited because a practitioner does not need to look up the symptoms for a particular remedy, but rather to explore the remedies for a particular symptom. This need is filled by the homeopathic repertory, which is an index of symptoms, listing after each symptom those remedies that are associated with it. Repertories are often very extensive and may include data from clinical experience in addition to provings. There is often lively debate among the compilers of a repertory and interested practitioners over the veracity of a particular inclusion. The first symptomatic index of the homeopathic materia medica was arranged by Hahnemann. Soon after, one of his students Clemens von Bönninghausen, created the Therapautic Pocket Book, another homeopathic repertory.[82] The first such Homeopathic Repertory was Dr. George Jahr's Repertory, published in 1835 in German and then again in 1838 in English and edited by Dr. Constantine Hering. This version was less focused on disease categories and would be the forerunner to Kent's later works.[83] It consisted of three large volumes. Such repertories increased in size and detail as time progressed.
# Treatments
Homeopathic treatments generally begin with a detailed examinations of their patients' histories, including questions regarding their physical, mental and emotional states, their one's life circumstances and any physical/emotional illnesses. The homeopath then translates this information into a complex formula of mental and physical symptoms, including likes, dislikes, innate predispositions and even body type.[84] The goal is to develop a comprehensive representation of each individual's overall health. This information can then be compared with similar established data in the drug provings found in the homeopathic materia medica. Assisted by further dialogues with the patient, the homeopath then aims to find the one drug most closely matching the "symptom totality" of the patient. There are many methods for determining the most-similar remedy (the simillimum), and homeopaths sometimes disagree. This is partly due to the complexity of the "totality of symptoms" concept. That is, homeopaths do not use all symptoms, but decide which are the most characteristic. This subjective evaluation of case analysis relies on knowledge and experience of the homeopath doing the diagnosis.
Some diversity in approaches to treatments exists among homeopaths. So called "classical" homeopathy generally involves detailed examinations of a patient's history and infrequent doses of a single remedy as the patient is monitored for improvements in symptoms. While "clinical" homeopathy involves combinations of remedies to address the various symptoms of an illness.[85]
## Remedies
"Remedy" is a technical term used in homeopathy to refer to a substance prepared with a particular procedure and intended for treating patients. Homeopathic practitioners rely on two types of reference when prescribing remedies. The Homeopathic Materia Medicae which is comprised of alphabetical indexes of "drug pictures" organised by remedy and describe the symptom patterns associated with individual remedies. They also rely on homeopathic repertories which consist of indexes of symptoms of diseases and listing remedies associated with specific symptoms.[86]
Homeopathy uses many animal, plant, mineral, and synthetic substances in its remedies. Examples include Natrum muriaticum (sodium chloride or table salt), Lachesis muta (the venom of the bushmaster snake), Opium, and Thyroidinum (thyroid hormone). Homeopaths also use treatments called nosodes (from the Greek nosos, disease) made from diseased or pathological products such as fecal, urinary, and respiratory discharges, blood, and tissue.[87] Homeopathic remedies prepared from healthy specimens are called Sarcodes.
Some modern homeopaths have considered more esoteric substances, known as "imponderables" because they do not originate from a material but from electromagnetic energy presumed to have been "captured" by alcohol or lactose. Examples include X-rays, sunlight,[88] and electricity.[89] Recent ventures by homeopaths into even more esoteric substances include thunderstorms (prepared from collected rainwater).[90] Today there are about 3,000 different remedies commonly used in homeopathy.[91] Some homeopaths also use techniques that are regarded by other practitioners as controversial. These include paper remedies, where the substance and dilution are written on a piece of paper and either pinned to the patient's clothing, put in their pocket, or placed under a glass of water that is then given to the patient, as well as the use of radionics to prepare remedies. Such practices have been strongly criticised by classical homeopaths as unfounded, speculative and verging upon magic and superstition.[92][93]
## Isopathy
Isopathy is a therapy derived from homeopathy and was invented by Johann Joseph Wilhelm Lux in the 1830s.[83] Isopathy differs from homeopathy in general in that the remedies are made up either from things that cause the disease, or from products of the disease, such as pus. Many so-called "homeopathic vaccines" are a form of isopathy.[94]
## Tautopathy
Tautopathy is a practice of alternative medicine that is similar to homeopathy in that it uses very diluted substances to treat illness. However, tautopathy does not rely on the "law of similars", as homeopathy does. According to practitioners of Tautopathy, dilute solutions of lead and arsenic can cause the body to secrete excess amounts of these toxic metals.[95]
## Flower remedies
Flower remedies are produced by placing flowers in water and exposing them to sunlight. The most famous of these are the Bach flower remedies, which were developed by the homeopath Edward Bach. The relationship between these remedies and homeopathy is controversial. On the one hand, the proponents of these remedies share homeopathy's vitalist world-view and the remedies are claimed to act through the same hypothetical "vital force". However, although many of the same plants are used as in homeopathy, the method of preparation is somewhat different, with Bach flower therapies supposedly being prepared in "gentler" ways, such as placing flowers in bowls of sunlit water, and so on.[96] There is no convincing scientific or clinical evidence for flower remedies being effective.[97]
## Veterinary use
The idea of using homeopathy as a treatment for other animals, termed veterinary homeopathy, dates back to the inception of homeopathy as Hahnemann himself wrote and spoke of the use of homeopathy in animals other than humans.[98] In the USA veterinary homeopathy is used by veterinarian members of the Academy for Veterinary Homeopathy and/or the American Holistic Veterinary Medical Association. The FDA has not approved homeopathic products as veterinary medicine in the US. In the UK, veterinary surgeons who use homeopathy belong to the Faculty of Homeopathy and/or to the British Association of Homeopathic Veterinary Surgeons. Animals may only be treated by qualified veterinary surgeons in the UK and some other countries. Internationally, the body that supports and represents homeopathic veterinarians is the International Association for Veterinary Homeopathy. The use of homeopathy in veterinary medicine is controversial, as there has been little scientific investigation and current research in the field is not of a high enough standard to provide reliable data.[99] Other studies have also found that giving animals placebos can play active roles in influencing pet owners to believe in the effectiveness of the treatment when none exists.[99]
# Medical and scientific analysis
Homeopathy is unsupported by modern scientific research. The extreme dilutions used in homeopathic preparations usually leave none of the active ingredient (atoms, ions or molecules) in the final product.[100][101] The idea that any biological effects could be produced by these preparations is inconsistent with the observed dose-response relationships of conventional drugs.[102] The proposed rationale for these extreme dilutions - that the water contains the "memory" or "vibration" from the diluted ingredient - is also counter to the laws of chemistry and physics.[100] Thus critics contend that any positive results obtained from homeopathic remedies are purely due to the placebo effect.[103][104] Critics cite the lack of viable scientific studies for the effectiveness of homeopathic remedies as evidence that they are not effective and that any positive effects are due to the placebo effect. Critics also contend that homeopathy is inherently dangerous, because homeopaths offer a false hope that may discourage or delay proper treatment.
## High dilutions
The extremely high dilutions in homeopathy have been a main point of criticism. Homeopaths believe that the methodical dilution of a substance, beginning with a 10% or lower solution and working downwards, with shaking after each dilution, produces a therapeutically active "remedy", in contrast to therapeutically inert water. However, homeopathic remedies are usually diluted to the point where there are no molecules from the original solution left in a dose of the final remedy.[101] Since even the longest-lived noncovalent structures in liquid water at room temperature are only stable for a few picoseconds,[105] critics have concluded that any effect that might have been present from the original substance can no longer exist.[106] Furthermore, since water will have been in contact with millions of different substances throughout its history, critics point out that any glass of water is therefore an extreme dilution of almost any conceivable substance, and so by drinking water one would, according to homeopathic principles, receive treatment for every imaginable condition.[107] Proponents of homeopathy, including Rustum Roy, maintain that water has a memory effect beyond the presence of individual molecules of the dissolved substance,[108] but this is unsupported by experimental evidence.
Homeopathy contends that higher dilutions (fewer potential molecules in each dose) result in stronger medicinal effects. This idea is inconsistent with the observed dose-response relationships of conventional drugs, where the effects are dependent on the concentration of the active ingredient in the body.[102] This dose-response relationship has been confirmed in thousands of experiments on organisms as diverse as nematodes,[109] rats,[110] and humans.[111]
Physicist Robert L. Park, former executive director of the American Physical Society, has noted that "since the least amount of a substance in a solution is one molecule, a 30C solution would have to have at least one molecule of the original substance dissolved in a minimum of 1,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000 molecules of water. This would require a container more than 30,000,000,000 times the size of the Earth." Park has also noted that "to expect to get even one molecule of the 'medicinal' substance allegedly present in 30X pills, it would be necessary to take some two billion of them, which would total about a thousand tons of lactose plus whatever impurities the lactose contained". The laws of chemistry state that there is a limit to the dilution that can be made without losing the original substance altogether.[15] This limit, which is related to Avogadro's number, corresponds to homeopathic potencies of 12C or 24X (1 part in 1024).[103][69]Template:Ref label
## Research on medical effectiveness
The medical effectiveness of homeopathy has been a point of contention since its inception, and researchers have subjected the system to close scrutiny. One of the earliest studies concerning homeopathic medicine was sponsored by the British government during World War II in which volunteers tested the effectiveness of homeopathic remedies against diluted mustard gas burns.[112] More recent controlled clinical trials on homeopathy have shown poor results, showing slight-to-no differences between homeopathic remedies and placebo.[113]
Meta-analyses, which analyse large groups of studies and draw conclusions based on the results as a whole, have been used to evaluate the effectiveness of homeopathy. Early meta-analyses investigating homeopathic remedies showed slightly positive results among the studies examined, but such studies have warned that it was impossible to draw conclusions due to low methodological quality and difficulty in controlling for publication bias in the studies reviewed.[114][11][12] One of the positive meta-analyses, by Linde, et al,[12] was later corrected by the authors, who wrote:
A recent meta-analysis of clinical trials on the effectiveness of homeopathy has shown that earlier clinical trials showed signs of major weakness in methodology and reporting, and that homeopathy trials were less randomized and reported less on dropouts than other types of trials.[11]
In 2005 The Lancet medical journal published a meta-analysis of 110 placebo-controlled homeopathy trials and 110 matched conventional-medicine trials based upon the Swiss government's Program for Evaluating Complementary Medicine, or PEK. The study concluded that its findings were compatible with the notion that the clinical effects of homeopathy are nothing more than placebo effects.[14] However, this last study has been criticised[116] "for being methodologically flawed on many levels."[16] "Of particular concern, the researchers eliminated 102 of 110 homeopathic trials and based their conclusions on only the 8 largest high-quality trials without clearly identifying the criteria by which these trials were selected or the identity of these trials. Odds ratios calculated before the exclusions (on all 110 trials) do not support their ultimate conclusion that homeopathic interventions are no better than placebo"[16]
A 2006 meta-analysis of six trials evaluating homeopathic treatments to reduce cancer therapy side effects following radiotherapy and chemotherapy found "encouraging but not convincing" evidence in support of homeopathic treatment. However, variability in the methodological quality of the six studies provided "insufficient evidence to support clinical efficacy of homeopathic therapy in cancer care".[117]
Since homeopathic remedies at dilutions higher than about D23 (10-23) contain no ingredients apart from the diluent (water, alcohol or sugar), there is no chemical basis for them to have any medicinal action. Newer randomized, double-blind, placebo-controlled trials using highly-diluted homeopathic preparations also fail to find clinical effects of the substances.[118]
The Cochrane Library found insufficient clinical evidence to evaluate the efficacy of homeopathic treatments for asthma[8] or dementia,[9] or for the use of homeopathy in induction of labor.[119] Other researchers found no evidence that homeopathy is beneficial for osteoarthritis,[120] migraines[121] or delayed-onset muscle soreness.[85]
Health organisations such as UK's National Health Service,[122] the American Medical Association,[123] and the FASEB[106] have issued statements of their conclusion that there is no convincing scientific evidence to support the use of homeopathic treatments in medicine.
Clinical studies of the medical efficacy of homeopathy have been criticised by some homeopaths as being irrelevant because they do not test "classical homeopathy".[124][125] There have, however, been a number of clinical trials that have tested individualized homeopathy. A 1998 review[126]
found 32 trials that met their inclusion criteria, 19 of which were placebo-controlled and provided enough data for meta-analysis. These 19 studies showed a pooled odds ratio of 1.17 to 2.23 in favor of individualized homeopathy over the placebo, but no difference was seen when the analysis was restricted to the methodologically best trials. The authors concluded "that the results of the available randomized trials suggest that individualized homeopathy has an effect over placebo. The evidence, however, is not convincing because of methodological shortcomings and inconsistencies."
Dr. Jack Killen, acting deputy director of the National Center for Complementary and Alternative Medicine, says homeopathy "goes beyond current understanding of chemistry and physics". He adds, "There is, to my knowledge, no condition for which homeopathy has been proven to be an effective treatment."[17]
# Research on effects in other biological systems
While some articles have suggested that homeopathic solutions of high dilution can have statistically significant effects on organic processes including the growth of grain,[127] histamine release by leukocytes,[128] and enzyme reactions, such evidence is disputed since attempts to replicate them have failed.[129][130][131][132][133]
In 1987, French immunologist Jacques Benveniste submitted a paper to the journal Nature while working at INSERM. The paper purported to have discovered that basophils released histamine when exposed to a homeopathic dilution of anti-immunoglobulin E, a type of white blood cell. The journal editors, sceptical of the results, requested that the study be replicated in a separate laboratory. Upon replication in four separate laboratories the study was published. Still sceptical of the findings, Nature assembled an independent investigative team to determine the accuracy of the research, consisting of Nature editor and physicist Sir John Maddox, American scientific fraud investigator and chemist Walter Stewart, and sceptic and magician James Randi. After investigating the findings and methodology of the experiment, the team found that the experiments were "statistically ill-controlled", "interpretation has been clouded by the exclusion of measurements in conflict with the claim", and concluded, "We believe that experimental data have been uncritically assessed and their imperfections inadequately reported."[134][135][136] James Randi stated that he doubted that there had been any conscious fraud, but that the researchers had allowed "wishful thinking" to influence their interpretation of the data.[135]
## Ethical and safety issues
As homeopathic remedies usually contain only water and/or alcohol, they are thought to be generally safe. Only in rare cases are the original ingredients present at detectable levels. In one such case, an unusually undiluted (1:100 or "2X") solution of zinc gluconate, marketed as Zicam Nasal Spray, allegedly caused a small percentage of users to lose their sense of smell.[137] There were 340 cases settled out of court for 12 million U.S. dollars.[138]
Critics of homeopathy have cited other concerns over homeopathic remedies, most seriously, cases of patients of homeopathy failing to receive proper treatment for diseases that it is claimed could have been diagnosed or cured with conventional medicine. Several surveys demonstrate that some (particularly non-physician) homoeopaths advise their patients against immunisation.[139][28][140] Some homeopaths suggest that vaccines be replaced with homeopathically diluted "nosodes", created from dilutions of biological agents - including material such as vomit, feces or infected human tissues. While Hahnemann was opposed to such preparations, modern homeopaths often use them and there is no evidence to indicate they have any beneficial effects.[141][142] Cases of homeopaths advising against the use of anti-malarial drugs have been identified.[143][144][29] This puts visitors to the tropics who take this advice in severe danger, since homeopathic remedies are completely ineffective against the malaria parasite.[143][144][29] Also, in one case in 2004, a homeopath instructed one of his patients to stop taking conventional medication for a heart condition, writing in his advice, "She just cannot take ANY drugs – I have suggested some homeopathic remedies. I feel confident that if she follows the advice she will regain her health." The patient suffered a fatal heart attack four months later, caused by this stoppage of her medication.[145][146]
In 1978, Anthony Campbell, then a consultant physician at The Royal London Homeopathic Hospital, criticised statements made by George Vithoulkas to promote his homeopathic treatments. Vithoulkas stated that syphilis, when treated with antibiotics, would develop into secondary and tertiary syphilis with involvement of the central nervous system. Campbell described this as a thoroughly irresponsible statement which could mislead an unfortunate layman into refusing conventional medical treatment.[147] This claim echoes the idea that treating a disease with external medication used to treat the symptoms would only drive it deeper into the body and conflicts with scientific studies, which indicate that penicillin treatment produces a complete cure of syphilis in more than 90% of cases.[63]
A 2006 review by W. Steven Pray of the College of Pharmacy at Southwestern Oklahoma State University recommends that pharmacy colleges include a required course in unproven medications and therapies, that ethical dilemmas inherent in recommending products lacking proven safety and efficacy data be discussed, and that students should be taught where unproven systems such as homeopathy depart from evidence-based medicine.[148]
# Prevalence and legal trends
Homeopathic medicine is fairly common in some countries while being uncommon in others; is highly regulated in some countries and mostly unregulated in others. Regulations vary in Europe depending on the country. In some countries, there are no specific legal regulations concerning the use of homeopathy, while in others, licenses or degrees in conventional medicine from accredited universities are required. In Austria and Germany, no specific regulations exist, while France and Denmark mandate licenses to diagnose any illness or dispense of any product whose purpose is to treat any illness.[31] Some homeopathic treatment is covered by the national insurance coverage of several European countries, including France, the United Kingdom, Denmark, and Luxembourg. In other countries, such as Belgium, homeopathy is not covered. In Austria, public insurance requires scientific proof of effectiveness in order to reimburse medical treatments, but exceptions are made for homeopathy.[31] Two countries which formerly offered homeopathy under their public health insurance schemes have withdrawn this privilege. At the start of 2004, homeopathic medications, with some exceptions, were no longer covered by German public health insurance, and in June 2005, the Swiss Government, after a 5-year trial, withdrew insurance coverage for homeopathy and four other complementary treatments, stating that they did not meet efficacy and cost-effectiveness criteria, though additional insurance can be bought to cover such treatments provided by a medical doctor.[149]
## Outline of past prevalence in Great Britain
In Britain homeopathy was first established by Dr. Frederick Quin around 1827, although two Italian homeopathic doctors (Drs Romani and Roberta) had been employed two years previously by the Earl of Shrewsbury based at Alton Towers in North Staffordshire. Homeopathy in Britain quickly became the preferred medical treatment of the upper classes,[150] as well as the aristocracy[151] and retained an elite clientele, including members of the royal family.[152]
At its peak in the 1870s, Britain had numerous homeopathic dispensaries and small hospitals as well as large busy hospitals in Liverpool, Birmingham,[153] Glasgow, London and Bristol.
## Contemporary prevalence
### United Kingdom
The NHS currently operates five homeopathic hospitals. The largest organisation of homeopaths in the United Kingdom, the Society of Homeopaths, was founded in 1978. The London-based Faculty of Homeopathy has over 1,400 members and was incorporated by an Act of Parliament in 1950.[154] According to a 2006 study, forty nine percent of Scottish medical practices prescribed homeopathic remedies. During the study period, 0.22% of patients were prescribed at least one homeopathic remedy; of that number, 16 percent were children. The study concluded that critical review of Homeopathy's role in the Scottish branch of the national health care system was needed.[155]
### Australia
According to one study, about 4.4% of Australian adults have used homeopathic remedies at least once in their lives, including 1.2% that sought treatment exclusively from homeopathic practitioners.[156]
### Canada
In Canada, a study detailing the use of alternative medicines by children in Quebec found that 11% of the sampled 1911 children used alternative medicines, and 25% of those who did use alternative medicines used homeopathy. The study also pointed out that homeopathy is more commonly used in children in Canada than in adults, of whom only 19% of alternative medicine users used homeopathy.[157] Homeopathy is not officially recognised by Federal Food and Drugs Act in Canada and physicians who choose to use alternative medicines such as homeopathy must follow guidelines set by their province's College of Physicians and Surgeons. Provincial health care generally does not cover homeopathy.[31]
### South America
Some countries in South America, such as Argentina, allow only professional doctors who are qualified and have graduated from a recognised medical school to practice homeopathy. Homeopathy has been regulated in other South American countries, such as Colombia, since the beginning of the 20th century. In Brazil, homeopathy is included in the national health system, and since 1991, physicians who want to practice homeopathy must complete 2,300 hours of education prior to receiving the proper licenses.[31]
### Mexico
In Mexico, homeopathy is currently integrated into the national health care system. In 1985, a presidential decree established the first homeopathic school as well as regulations specifying training requirements for homeopathic doctors.[31] Of those individuals who use complementary alternative medicines, over 26% use homeopathy.[158]
### United States
In the United States, homeopathy is much less common, where the percentage of people seeking homeopathic treatment declined from 3.4% in 1997 to 1.7% in 2002.[23] Homeopathy was first established in the United States by Dr. Hans Burch Gram[159] in 1825 and rapidly gained popularity, partly because conventional medicine of the time was inherently risky.[160] The height of its influence was the end of the 19th century where hardly any city with over 50,000 people was without a homeopathic hospital. In 1890, there were 93 regular schools, 14 of them were fully homeopathic and 8 of them were eclectic. In 1900, there were 121 regular schools, with 22 of them being homeopathic and 10 eclectic.[161] The use of homeopathy in the United States among adults is about 0.3%. According to one study, in 1990, 0.7% of individuals used homeopathy in the year prior to being questioned; in 1997, 3.4% had used homeopathy at least once in the previous year. According to the same study, of those who used homeopathy, 31.7% had seen a homeopathic practitioner in the past year in 1990 and the number dropped to 16.5 by 1997.[162]
In the United States, homeopathic remedies, like all health-care products, are regulated by the Food and Drug Administration. However, the FDA treats homeopathic remedies very differently from conventional medicines. Homeopathic products do not need FDA approval before sale; they do have to be proven safe per the Dietary Supplement Health and Education Act of 1994, but they do not have to prove efficacy. Homeopathic remedies do not have to be labeled with an expiration date, and they do not have to undergo finished product testing to verify contents and strength. All of these are voluntary actions done by the manufacturer. The manufacturer is required to have all ingredients on the label; however, it might not specify which ones are active. In the USA, only homeopathic medicines that claim to treat self-limiting conditions may be sold over-the-counter; homeopathic medicines that claim to treat a serious disease can be sold only by prescription.[163] A memorandum, written in 1985 by attorneys for the American Association of Homeopathic Manufacturers, describes a meeting between the AAHP attorneys and high-ranking FDA officials to discuss whether homeopathic products must be proven effective to remain legally marketable.[164] Such negotiations led to the issuance in 1988 (revised in 1995) of an FDA Compliance Policy Guide that permits homeopathic products "intended solely for self-limiting disease conditions amenable to self-diagnosis (of symptoms) and treatment" to be marketed as nonprescription drugs.[165] In 2001, the FDA published a comprehensive review of mercury compounds in homeopathic drugs. This report indicated that nearly all examined compounds derived from the use of mercury. However, due to the extreme dilution of materials, the presence of mercury in the finished product would be minimal.[166] At present the FDA Health Fraud Division only pursues claims which may cause direct harm to consumers through their use. Homeopathic drugs, largely regarded as equivalent to placebos, are not considered under these guidelines. Due to the significant dilution of the products, the agents become practically immeasurable: the harmful effects of homeopathic drugs is more likely to be that patients avoid conventional treatments.[167]
### Asia
In Asia, the use of homeopathic treatments is increasing, especially in India. Homeopathy arrived in India with Dr John Martin Honigberger in Lahore, in 1829–1830.[168][169] India has the largest homeopathic infrastructure in the world, with low estimates at about 64,000, but going as high as 300,000 practising homeopaths. In addition, there are 180 colleges teaching courses, and 7500 government clinics and 307 hospitals which dispense homeopathic remedies.[170][171] In Malaysia, homeopathy was introduced during World War II and was brought by Indians via the British army.
### Africa
In South Africa, homeopathy is regulated by the Associated Health Service Professions Act of 1982, which was set up to provide a registration and licensing framework for health professions. During the 1960s, all homeopathic colleges were closed by the South African Medical Council. However, conventional medical doctors retained the right to use homeopathic treatments.[31] | https://www.wikidoc.org/index.php/Homeopathic | |
e5adda2e778d0a80f983efc66e5dd1a4e0ffcbb4 | wikidoc | HomoloGene | HomoloGene
# Overview
HomoloGene, a tool of the National Center for Biotechnology Information (NCBI), is a system for automated detection of homologs (similarity attributable to descent from a common ancestor) among the annotated genes of several completely sequenced eukaryotic genomes.
The HomoloGene processing consists of the protein analysis from the input organisms. Sequences are compared using blastp, then matched up and put into groups, using a taxonomic tree built from sequence similarity, where closer related organisms are matched up first, and then further organisms are added to the tree. The protein alignments are mapped back to their corresponding DNA sequences, and then distance metrics as molecular distances Jukes and Cantor (1969), Ka/Ks ratio can be calculated.
The sequences are matched up by using a heuristic algorithm for maximizing the score globally, rather than locally, in a bipartite matching (see complete bipartite graph). And then it calculates the statistical significance of each match. Cutoffs are made per position and Ks values are set to prevent false "orthologs" from being grouped together. “Paralogs” are identified by finding sequences that are closer within species than other species.
# Input Organisms
Homo sapiens, Mus musculus, Danio rerio, Rattus norvegicus, Pan troglodytes, Canis lupus familiaris, Arabidopsis thaliana, Gallus gallus, Oryza sativa, Anopheles gambiae, Drosophila melanogaster, Magnaporthe grisea, Neurospora crassa, Caenorhabditis elegans, Saccharomyces cerevisiae, Kluyveromyces lactis, Eremothecium gossypii, Schizosaccharomyces pombe and Plasmodium falciparum.
# Interface
The HomoloGene is linked to all Entrez databases and based on homology and phenotype information of these links:
- Mouse Genome Informatics (MGI),
- Zebrafish Information Network (ZFIN),
- Saccharomyces Genome Database (SGD),
- Clusters of Orthologous Groups (COG),
- FlyBase,
- Online Mendelian Inheritance in Man (OMIM)
As a result HomoloGene displays information about Genes, Proteins, Phenotypes, and Conserved Domains. | HomoloGene
# Overview
HomoloGene[1], a tool of the National Center for Biotechnology Information (NCBI)[2], is a system for automated detection of homologs (similarity attributable to descent from a common ancestor) among the annotated genes of several completely sequenced eukaryotic genomes.
The HomoloGene processing consists of the protein analysis from the input organisms. Sequences are compared using blastp[3], then matched up and put into groups, using a taxonomic tree built from sequence similarity, where closer related organisms are matched up first, and then further organisms are added to the tree. The protein alignments are mapped back to their corresponding DNA sequences, and then distance metrics as molecular distances Jukes and Cantor (1969), Ka/Ks ratio can be calculated.
The sequences are matched up by using a heuristic algorithm for maximizing the score globally, rather than locally, in a bipartite matching (see complete bipartite graph). And then it calculates the statistical significance of each match. Cutoffs are made per position and Ks values are set to prevent false "orthologs" from being grouped together. “Paralogs” are identified by finding sequences that are closer within species than other species.
# Input Organisms
Homo sapiens, Mus musculus, Danio rerio, Rattus norvegicus, Pan troglodytes, Canis lupus familiaris, Arabidopsis thaliana, Gallus gallus, Oryza sativa, Anopheles gambiae, Drosophila melanogaster, Magnaporthe grisea, Neurospora crassa, Caenorhabditis elegans, Saccharomyces cerevisiae, Kluyveromyces lactis, Eremothecium gossypii, Schizosaccharomyces pombe and Plasmodium falciparum.
# Interface
The HomoloGene is linked to all Entrez databases and based on homology and phenotype information of these links:
- Mouse Genome Informatics (MGI),
- Zebrafish Information Network (ZFIN),
- Saccharomyces Genome Database (SGD),
- Clusters of Orthologous Groups (COG),
- FlyBase,
- Online Mendelian Inheritance in Man (OMIM)
As a result HomoloGene displays information about Genes, Proteins, Phenotypes, and Conserved Domains.
# External links
- Bioinformatic Harvester is a meta search engine that uses, among others, Homologene: [4]
- NCBI
- OMIM
- ZFIN
- SGD
- COG
- FlyBase
- MGI
- Rat Genome Database
Template:Harvesternavi
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/HomoloGene | |
23c72a7af2be65f34355767ae5e652264994fc18 | wikidoc | Houttuynia | Houttuynia
Houttuynia cordata (Template:Zh-cpl; Vietnamese: giấp cá), the sole species in the genus Houttuynia, is a flowering plant native to Japan, southern China and Southeast Asia, where it grows in moist, shady places.
Houttuynia is a herbaceous perennial plant growing to between 20 and 80 cm. The proximal part of the stem is trailing and produces adventitious roots, while the distal part of the stem grows vertically. The leaves are alternate, broadly heart-shaped, 4-9 cm long and 3-8 cm broad. Flowers are greenish-yellow, borne on a terminal spike 2-3 cm long with 4-6 large white basal bracts.
# Cultivation
The plant grows well in moist to wet soil and even slightly submerged in water in partial or full sun. Plants can become invasive in gardens and difficult to eradicate. Propagation is via division.
Houttuynia in temperate gardens is usually in one of its cultivated forms, including: Chameleon (synonymous with H.c. 'Court Jester', H.c. 'Tricolour', H.c. 'Variegata') this variety is slightly less vigorous than the species and has leaves broadly edged in yellow and flecked with red; Flore Pleno has masses of white bracts and the vigour of the parent species.
# Medicinal and culinary use
Grown as a leaf vegetable, particularly in Vietnam, where it is called giấp cá or diếp cá and is used as a fresh herbal garnish. The leaf has an unusual taste that is often described as fishy (earning it the nickname "fish mint"), so it is not enjoyed as universally as basil, mint, or other more commonly used herbs.
Houttuynia is also used in herbal medicine. The beverage dokudami cha (Japanese: ドクダミ茶; literally "Houttuynia cordata tea") is an infusion made from Houttuynia cordata leaves, Oolong tea leaves, and Job's Tears.
In the southwestern Chinese provinces of Yunnan, Guizhou, and Sichuan, roots are used as a root vegetable. English names include heartleaf and lizardtail.
# Invasive Weed
Lizard Tail is an invasive species in many areas in the United States. Even the less vigorous forms will spread beyond an apt gardener's control if planted in any moderately moist soil. To prevent this, try planting in an old pot, sunk down into the garden soil.
# References and external links
- ↑ Template:Citeweb
- Flora of China: Houttuynia
- Asian Vegetables (with photo)
- Flora, The Gardener's Bible, ABC Publishing, Ultimo, NSW, Australia, 2006 ISBN 0 7333 1439 2 | Houttuynia
Houttuynia cordata (Template:Zh-cpl; Vietnamese: giấp cá), the sole species in the genus Houttuynia, is a flowering plant native to Japan, southern China and Southeast Asia, where it grows in moist, shady places.
Houttuynia is a herbaceous perennial plant growing to between 20 and 80 cm. The proximal part of the stem is trailing and produces adventitious roots, while the distal part of the stem grows vertically. The leaves are alternate, broadly heart-shaped, 4-9 cm long and 3-8 cm broad. Flowers are greenish-yellow, borne on a terminal spike 2-3 cm long with 4-6 large white basal bracts.
# Cultivation
The plant grows well in moist to wet soil and even slightly submerged in water in partial or full sun. Plants can become invasive in gardens and difficult to eradicate. Propagation is via division.
Houttuynia in temperate gardens is usually in one of its cultivated forms, including: Chameleon (synonymous with H.c. 'Court Jester', H.c. 'Tricolour', H.c. 'Variegata') this variety is slightly less vigorous than the species and has leaves broadly edged in yellow and flecked with red; Flore Pleno has masses of white bracts and the vigour of the parent species.
# Medicinal and culinary use
Grown as a leaf vegetable, particularly in Vietnam, where it is called giấp cá or diếp cá and is used as a fresh herbal garnish. The leaf has an unusual taste that is often described as fishy (earning it the nickname "fish mint"), so it is not enjoyed as universally as basil, mint, or other more commonly used herbs.
Houttuynia is also used in herbal medicine. The beverage dokudami cha (Japanese: ドクダミ茶; literally "Houttuynia cordata tea") is an infusion made from Houttuynia cordata leaves, Oolong tea leaves, and Job's Tears.[1]
In the southwestern Chinese provinces of Yunnan, Guizhou, and Sichuan, roots are used as a root vegetable. English names include heartleaf and lizardtail.
# Invasive Weed
Lizard Tail is an invasive species in many areas in the United States. Even the less vigorous forms will spread beyond an apt gardener's control if planted in any moderately moist soil. To prevent this, try planting in an old pot, sunk down into the garden soil.
# References and external links
- ↑ Template:Citeweb
- Flora of China: Houttuynia
- Asian Vegetables (with photo)
- Flora, The Gardener's Bible, ABC Publishing, Ultimo, NSW, Australia, 2006 ISBN 0 7333 1439 2
Template:Herbs & spices
Template:Vegetable-stub | https://www.wikidoc.org/index.php/Houttuynia | |
5a9f4ca333907b6d33c1e94b00e04e471a011883 | wikidoc | Human lung | Human lung
The human lungs are the human organs of respiration.
Humans have two lungs, with the left being divided into two lobes and the right into three lobes. Together, the lungs contain approximately 1500 miles (2,400 km) of airways and 300 to 500 million alveoli, having a total surface area of about 75 m2 in adults — roughly the same area as a tennis court. Furthermore, if all of the capillaries that surround the alveoli were unwound and laid end to end, they would extend for about 620 miles.
# Organization
- The conducting zone contains the trachea, the bronchi, the bronchioles, and the terminal bronchioles
- The respiratory zone contains the respiratory bronchioles, the alveolar ducts, and the alveoli.
The conducting zone and the respiratory zone (but not the alveoli) are made up of airways.
The conducting zone has no gas exchange with the blood, and is reinforced with cartilage and smooth muscle, which are very strong. Smooth muscle has variable resistance to air flow. The conducting zone warms the air to 37 degrees Celsius and humidifies the air. It also cleanses the air by removing particles.
The respiratory zone is the site of gas exchange with blood.
The smooth muscle tone in bronchioles, and therefore bronchiolar diameter, is controlled by:
- the sympathetic nervous system via noradrenaline acting on the beta receptors and causes bronchodilation
- the parasympathetic nervous system via acetylcholine which acts on the muscarinic receptors and causes bronchoconstriction
- many other non-autonomic nervous and biochemical stimuli including, for example, carbon dioxide.
The intrapleural space is the potential space between the pleura lining the inner wall of the thoracic cage and the pleura lining the lungs.
# Physiology
Total lung capacity (TLC) includes inspiratory reserve volume, tidal volume, expiratory reserve volume, and residual volume. The total lung capacity depends on the person's age, height, weight, sex, and normally ranges between 4,000 and 6,000 cm3 (4 to 6 L). For example, females tend to have a 20–25% lower capacity than males. Tall people tend to have a larger total lung capacity than shorter people. Smokers have a lower capacity than nonsmokers. Lung capacity is also affected by altitude. People who are born and live at sea level will have a smaller lung capacity than people who spend their lives at a high altitude. In addition to the total lung capacity, one also measures the tidal volume, the volume breathed in with an average breath, about 500 cm3. For a detailed discussion of the various lung volumes, see the article on lung volumes.
Typical resting adult respiratory rates are 10–20 breaths per minute with 1/3 of the breath time in inspiration.
Human lungs are to a certain extent 'overbuilt' and have a tremendous reserve volume as compared to the oxygen exchange requirements when at rest. This is the reason that individuals can smoke for years without having a noticeable decrease in lung function while still or moving slowly; in situations like these only a small portion of the lungs are actually perfused with blood for gas exchange. As oxygen requirements increase due to exercise, a greater volume of the lungs is perfused, allowing the body to reach its CO2/O2 exchange requirements.
# Diseases
The following is a list of important medical conditions involving the lung. Many of these are caused or worsened by smoking.
- Lung cancer
- Emphysema is an enlargement of the air spaces in the lung, making it hard to breathe.
- Asthma is an immunological disease which causes the bronchioles to narrow by inflammation and spasm of the lining of the airway wall.
- Cystic fibrosis is a hereditary disease which causes the lung to produce abnormally viscous mucus.
- A pulmonary embolism occurs when a blood clot obstructs an artery leading to the lung.
- Tuberculosis is a transmittable bacterial infection of the lung, the most common infectious disease today.
- Pneumonia is an infection of the lung, caused by bacteria, viruses or fungi.
- Bronchitis is an inflammation of the bronchi.
- A collapsed lung (pneumothorax) can occur when one or both walls of the pleural cavity are penetrated by injury, allowing air to enter.
- In pulmonary edema fluid from the capillaries enters the alveoli. This can be caused by weakness of the left side of the heart (resulting in a blood holdup in the lung), altitude sickness, or rarely inhaling toxic gases.
- Lung pinprick condition is a hereditary disease which results in decreased lung capacity and occasional shortness of breath.
Transplantation now allows for a person to have a single lung transplant, a double-lung transplant, or a transplant of both the heart and lungs.
# Modification of substances
The lungs convert angiotensin I to angiotensin II. In addition, they remove several blood-bourne substances, e.g. PGE1, PGE2, PGF2α, leukotrienes, serotonin, bradykinin. | Human lung
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The human lungs are the human organs of respiration.
Humans have two lungs, with the left being divided into two lobes and the right into three lobes. Together, the lungs contain approximately 1500 miles (2,400 km) of airways and 300 to 500 million alveoli, having a total surface area of about 75 m2 in adults — roughly the same area as a tennis court.[1] Furthermore, if all of the capillaries that surround the alveoli were unwound and laid end to end, they would extend for about 620 miles.
# Organization
- The conducting zone contains the trachea, the bronchi, the bronchioles, and the terminal bronchioles
- The respiratory zone contains the respiratory bronchioles, the alveolar ducts, and the alveoli.
The conducting zone and the respiratory zone (but not the alveoli) are made up of airways.
The conducting zone has no gas exchange with the blood, and is reinforced with cartilage and smooth muscle, which are very strong. Smooth muscle has variable resistance to air flow. The conducting zone warms the air to 37 degrees Celsius and humidifies the air. It also cleanses the air by removing particles.
The respiratory zone is the site of gas exchange with blood.
The smooth muscle tone in bronchioles, and therefore bronchiolar diameter, is controlled by:
- the sympathetic nervous system via noradrenaline acting on the beta receptors and causes bronchodilation
- the parasympathetic nervous system via acetylcholine which acts on the muscarinic receptors and causes bronchoconstriction
- many other non-autonomic nervous and biochemical stimuli including, for example, carbon dioxide.
The intrapleural space is the potential space between the pleura lining the inner wall of the thoracic cage and the pleura lining the lungs.
# Physiology
Total lung capacity (TLC) includes inspiratory reserve volume, tidal volume, expiratory reserve volume, and residual volume.[2] The total lung capacity depends on the person's age, height, weight, sex, and normally ranges between 4,000 and 6,000 cm3 (4 to 6 L). For example, females tend to have a 20–25% lower capacity than males. Tall people tend to have a larger total lung capacity than shorter people. Smokers have a lower capacity than nonsmokers. Lung capacity is also affected by altitude. People who are born and live at sea level will have a smaller lung capacity than people who spend their lives at a high altitude. In addition to the total lung capacity, one also measures the tidal volume, the volume breathed in with an average breath, about 500 cm3. For a detailed discussion of the various lung volumes, see the article on lung volumes.
Typical resting adult respiratory rates are 10–20 breaths per minute with 1/3 of the breath time in inspiration.
Human lungs are to a certain extent 'overbuilt' and have a tremendous reserve volume as compared to the oxygen exchange requirements when at rest. This is the reason that individuals can smoke for years without having a noticeable decrease in lung function while still or moving slowly; in situations like these only a small portion of the lungs are actually perfused with blood for gas exchange. As oxygen requirements increase due to exercise, a greater volume of the lungs is perfused, allowing the body to reach its CO2/O2 exchange requirements.
# Diseases
The following is a list of important medical conditions involving the lung. Many of these are caused or worsened by smoking.
- Lung cancer
- Emphysema is an enlargement of the air spaces in the lung, making it hard to breathe.
- Asthma is an immunological disease which causes the bronchioles to narrow by inflammation and spasm of the lining of the airway wall.
- Cystic fibrosis is a hereditary disease which causes the lung to produce abnormally viscous mucus.
- A pulmonary embolism occurs when a blood clot obstructs an artery leading to the lung.
- Tuberculosis is a transmittable bacterial infection of the lung, the most common infectious disease today.
- Pneumonia is an infection of the lung, caused by bacteria, viruses or fungi.
- Bronchitis is an inflammation of the bronchi.
- A collapsed lung (pneumothorax) can occur when one or both walls of the pleural cavity are penetrated by injury, allowing air to enter.
- In pulmonary edema fluid from the capillaries enters the alveoli. This can be caused by weakness of the left side of the heart (resulting in a blood holdup in the lung), altitude sickness, or rarely inhaling toxic gases.
- Lung pinprick condition is a hereditary disease which results in decreased lung capacity and occasional shortness of breath.
Transplantation now allows for a person to have a single lung transplant, a double-lung transplant, or a transplant of both the heart and lungs.
# Modification of substances
The lungs convert angiotensin I to angiotensin II. In addition, they remove several blood-bourne substances, e.g. PGE1, PGE2, PGF2α, leukotrienes, serotonin, bradykinin. [3] | https://www.wikidoc.org/index.php/Human_lung | |
1b60f370b0b7ca3e65601699c497769711060fc7 | wikidoc | Human nose | Human nose
The visible part of the human nose is the protruding part of the face that bears the nostrils. The shape of the nose is determined by the ethmoid bone and the nasal septum, which consists mostly of cartilage and which separates the nostrils.
# Associated health risks
Because of the special nature of the blood supply to the human nose and surrounding area, it is possible for retrograde infections from the nasal area to spread to the brain. For this reason, the area from the corners of the mouth to the bridge of the nose, including the nose and maxilla, is known to doctors as the danger triangle of the face.
# Shapes of the human nose
Human noses can take many different shapes. Several attempts have been made towards a classification of noses. The following examples are from Nasology by Eden Warwick (pseudonym of George Jabet). This 19th century tract associated nose shapes with character traits in a way akin to phrenology, in a somewhat ironic way, as the booklet was intended to mock the popular but highly controversial subject of phrenology.
- Class I: The Roman, or Aquiline nose, which is rather convex, but undulating as its name aquiline imports. (See: Hooknose)
- Class II: The Greek or Straight nose, which is perfectly straight
- Class III: The Nubian, or Wide-nostrilled nose, wide at the end, thick and broad, gradually widening from below the bridge. The other noses are seen in profile, but this one in full face.
- Class IV: The Hawk nose, which is very convex, and preserves its convexity like a bow. It is thin and sharp
- Class V: The Snub nose
- Class VI: The Turn-up or Celestial nose, with a continuous concavity from the eyes to the tip
- Class I
- Class II
- Class III
- Class IV
- Class V
- Class VI
# Culture
In the Western world, some people choose to get rhinoplasty to change the aesthetic appearance of their nose. Nose piercings are also common, such as nostril, septum or bridge.
In New Zealand, nose pressing ("hongi") is a traditional greeting amongst Maori people, however is now generally confined to certain traditional celebrations.
# People famous for their noses
- Barbara Streisand
- John Barrymore known as "The Great Profile"
- Cyrano de Bergerac
- Adrien Brody
- Tom Cruise was offered rhinoplasty in his earlier career, but passed.
- Jimmy Durante Cartoonist Al Hirschfeld questioned the size of Durante's schnozz. In The World of Hirschfeld (1966) he illustrated the point by taking a picture of Durante and adding white hair, a cigar, and a few other features, and leaving the nose untouched--and he came up with an uncanny likeness of former governor of New York, Alfred E. Smith.
- Nanette Fabray (for her small nose)
- Jamie Farr, who played Klinger on M*A*S*H. Many gags about Klinger's nose were written into the episodes.
- Jennifer Grey
- W.C. Fields
- Pinocchio, whose nose grew whenever he told a lie.
- Bob Hope ("ski-nose")
- Michael Jackson known for having multiple plastic surgery on his nose .
- Major Kovalyov in Nikolai Gogol's novel The Nose.
- Barry Manilow known for his large nose, often parodied ,
- Al Molinaro (Al from Happy Days)
- Jack Nicholson in the film Chinatown (1974) by Roman Polanski
- Richard Nixon
- Danny Thomas
- Duke of Wellington - The first Duke of Wellington was so renowned for his large hooked nose that his troops gave him the nickname of 'Nosey'.
- Owen Wilson
- Tycho Brahe lost his nose in a duel and wore a prosthetic nose made of gold and silver
- Severus Snape in J.K. Rowling's Harry Potter series
- Gonzo in The Muppets
- Hector Sepúlveda In Colegio De San José | Human nose
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The visible part of the human nose is the protruding part of the face that bears the nostrils. The shape of the nose is determined by the ethmoid bone and the nasal septum, which consists mostly of cartilage and which separates the nostrils.
# Associated health risks
Because of the special nature of the blood supply to the human nose and surrounding area, it is possible for retrograde infections from the nasal area to spread to the brain. For this reason, the area from the corners of the mouth to the bridge of the nose, including the nose and maxilla, is known to doctors as the danger triangle of the face.
# Shapes of the human nose
Human noses can take many different shapes. Several attempts have been made towards a classification of noses. The following examples are from Nasology by Eden Warwick (pseudonym of George Jabet). This 19th century tract associated nose shapes with character traits in a way akin to phrenology, in a somewhat ironic way, as the booklet was intended to mock the popular but highly controversial subject of phrenology.
- Class I: The Roman, or Aquiline nose, which is rather convex, but undulating as its name aquiline imports. (See: Hooknose)
- Class II: The Greek or Straight nose, which is perfectly straight
- Class III: The Nubian, or Wide-nostrilled nose, wide at the end, thick and broad, gradually widening from below the bridge. The other noses are seen in profile, but this one in full face.
- Class IV: The Hawk nose, which is very convex, and preserves its convexity like a bow. It is thin and sharp
- Class V: The Snub nose
- Class VI: The Turn-up or Celestial nose, with a continuous concavity from the eyes to the tip
- Class I
- Class II
- Class III
- Class IV
- Class V
- Class VI
# Culture
In the Western world, some people choose to get rhinoplasty to change the aesthetic appearance of their nose. Nose piercings are also common, such as nostril, septum or bridge.
In New Zealand, nose pressing ("hongi") is a traditional greeting amongst Maori people, however is now generally confined to certain traditional celebrations.
# People famous for their noses
- Barbara Streisand
- John Barrymore known as "The Great Profile"
- Cyrano de Bergerac
- Adrien Brody
- Tom Cruise was offered rhinoplasty in his earlier career, but passed.
- Jimmy Durante Cartoonist Al Hirschfeld questioned the size of Durante's schnozz. In The World of Hirschfeld (1966) he illustrated the point by taking a picture of Durante and adding white hair, a cigar, and a few other features, and leaving the nose untouched--and he came up with an uncanny likeness of former governor of New York, Alfred E. Smith.
- Nanette Fabray (for her small nose)
- Jamie Farr, who played Klinger on M*A*S*H. Many gags about Klinger's nose were written into the episodes.
- Jennifer Grey
- W.C. Fields
- Pinocchio, whose nose grew whenever he told a lie.
- Bob Hope ("ski-nose")
- Michael Jackson known for having multiple plastic surgery on his nose [1].
- Major Kovalyov in Nikolai Gogol's novel The Nose.
- Barry Manilow known for his large nose, often parodied [2], [3]
- Al Molinaro (Al from Happy Days)
- Jack Nicholson in the film Chinatown (1974) by Roman Polanski
- Richard Nixon
- Danny Thomas
- Duke of Wellington - The first Duke of Wellington was so renowned for his large hooked nose that his troops gave him the nickname of 'Nosey'.
- Owen Wilson
- Tycho Brahe lost his nose in a duel and wore a prosthetic nose made of gold and silver
- Severus Snape in J.K. Rowling's Harry Potter series
- Gonzo in The Muppets
- Hector Sepúlveda In Colegio De San José | https://www.wikidoc.org/index.php/Human_nose | |
b0f7403780d3f4ee75b0e648634d47e36cf3e59b | wikidoc | Huntingtin | Huntingtin
The huntingtin gene, also called the HTT or HD (Huntington disease) gene, is the IT15 ("interesting transcript 15") gene, which codes for a protein called the huntingtin protein. The gene and its product are under heavy investigation as part of Huntington's disease clinical research and the suggested role for huntingtin in long-term memory storage.
It is variable in its structure, as the many polymorphisms of the gene can lead to variable numbers of glutamine residues present in the protein. In its wild-type (normal) form, it contains 6-35 glutamine residues. However, in individuals affected by Huntington's disease (an autosomal dominant genetic disorder), it contains more than 36 glutamine residues (highest reported repeat length is about 250). Its commonly used name is derived from this disease; previously, the IT15 label was commonly used.
The mass of huntingtin protein is dependent largely on the number of glutamine residues it has, the predicted mass is around 350 kDa. Normal huntingtin is generally accepted to be 3144 amino acids in size. The exact function of this protein is not known, but it plays an important role in nerve cells. Within cells, huntingtin may be involved in signaling, transporting materials, binding proteins and other structures, and protecting against programmed cell death (apoptosis). The huntingtin protein is required for normal development before birth. It is expressed in many tissues in the body, with the highest levels of expression seen in the brain.
# Gene
The 5' end of the HD gene has a sequence of three DNA bases, cytosine-adenine-guanine (CAG), coding for the amino acid glutamine, that is repeated multiple times. This region is called a trinucleotide repeat. Normal persons have a CAG repeat count of between seven and 35 repeats.
The HD gene is located on the short (p) arm of chromosome 4 at position 16.3, from base pair 3,074,510 to base pair 3,243,960.
# Protein
## Function
The function of huntingtin is unclear. It is essential for development, and absence of huntingtin is lethal in mice. The protein has no sequence homology with other proteins and is highly expressed in neurons and testes in humans and rodents. Huntingtin upregulates the expression of Brain Derived Neurotrophic Factor (BDNF) at the transcription level, but the mechanism by which huntingtin regulates gene expression has not been determined. From immunohistochemistry, electron microscopy, and subcellular fractionation studies of the molecule, it has been found that huntingtin is primarily associated with vesicles and microtubules. These appear to indicate a functional role in cytoskeletal anchoring or transport of mitochondria. The Htt protein is involved in vesicle trafficking as it interacts with HIP1, a clathrin-binding protein, to mediate endocytosis, the trafficking of materials into a cell. Huntingtin has also been shown to have a role in the establishment in epithelial polarity through its interaction with RAB11A.
## Interactions
Huntingtin has been found to interact directly with at least 19 other proteins, of which six are used for transcription, four for transport, three for cell signalling, and six others of unknown function (HIP5, HIP11, HIP13, HIP15, HIP16, and CGI-125). Over 100 interacting proteins have been found, such as huntingtin-associated protein 1 (HAP1) and huntingtin interacting protein 1 (HIP1), these were typically found using two-hybrid screening and confirmed using immunoprecipitation.
Huntingtin has also been shown to interact with:
- HIP2,
- MAP3K10,
- OPTN,
- PRPF40A,
- RASA1,
- SETD2,
- TRIP10,
- ZDHHC17.
# Mitochondrial dysfunction
Mutant Huntingtin protein plays a key role in mitochondrial dysfunction involving inhibition of mitochondrial electron transport, higher levels of reactive oxygen species and increased oxidative stress. Mutant huntingtin protein also promotes oxidative damage to DNA that may contribute to Huntington disease pathology.
# Clinical significance
Huntington's disease (HD) is caused by a mutated form of the huntingtin gene, where excessive (more than 36) CAG repeats result in formation of an unstable protein. These expanded repeats lead to production of a huntingtin protein that contains an abnormally long polyglutamine tract at the N-terminus. This makes it part of a class of neurodegenerative disorders known as trinucleotide repeat disorders or polyglutamine disorders. The key sequence which is found in Huntington's disease is a trinucleotide repeat expansion of glutamine residues beginning at the 18th amino acid. In unaffected individuals, this contains between 9 and 35 glutamine residues with no adverse effects. However, 36 or more residues produce an erroneous form of Htt, mHtt (standing for mutant Htt). Reduced penetrance is found in counts 36-39.
Enzymes in the cell often cut this elongated protein into fragments. The protein fragments form abnormal clumps, known as neuronal intranuclear inclusions (NIIs), inside nerve cells, and may attract other, normal proteins into the clumps. The presence of these clumps was once thought to play a causal role in Huntington disease. Further research undermined this conclusion by showing the presence of NIIs actually extended the life of neurons and acted to reduce intracellular mutant huntingtin in neighboring neurons. Thus, the likelihood of neuronal death can be predicted by accounting for two factors: (1) the length of CAG repeats in the Huntingtin gene and (2) the neuron's exposure to diffuse intracellular mutant huntingtin protein. NIIs (protein clumping) can thereby be construed as a coping mechanism—as opposed to a pathogenic mechanism—to stem neuronal death by decreasing the amount of diffuse huntingtin. This process is particularly likely to occur in the striatum (a part of the brain that coordinates movement) primarily, and the frontal cortex (a part of the brain that controls thinking and emotions).
People with 36 to 40 CAG repeats may or may not develop the signs and symptoms of Huntington disease, while people with more than 40 repeats will develop the disorder during a normal lifetime. When there are more than 60 CAG repeats, the person develops a severe form of HD known as juvenile HD. Therefore, the number of CAG (the sequence coding for the amino acid glutamine) repeats influences the age of onset of the disease. No case of HD has been diagnosed with a count less than 36.
As the altered gene is passed from one generation to the next, the size of the CAG repeat expansion can change; it often increases in size, especially when it is inherited from the father. People with 28 to 35 CAG repeats have not been reported to develop the disorder, but their children are at risk of having the disease if the repeat expansion increases. | Huntingtin
The huntingtin gene, also called the HTT or HD (Huntington disease) gene, is the IT15 ("interesting transcript 15") gene, which codes for a protein called the huntingtin protein.[1] The gene and its product are under heavy investigation as part of Huntington's disease clinical research and the suggested role for huntingtin in long-term memory storage.[2]
It is variable in its structure, as the many polymorphisms of the gene can lead to variable numbers of glutamine residues present in the protein. In its wild-type (normal) form, it contains 6-35 glutamine residues. However, in individuals affected by Huntington's disease (an autosomal dominant genetic disorder), it contains more than 36 glutamine residues (highest reported repeat length is about 250).[3] Its commonly used name is derived from this disease; previously, the IT15 label was commonly used.
The mass of huntingtin protein is dependent largely on the number of glutamine residues it has, the predicted mass is around 350 kDa. Normal huntingtin is generally accepted to be 3144 amino acids in size. The exact function of this protein is not known, but it plays an important role in nerve cells. Within cells, huntingtin may be involved in signaling, transporting materials, binding proteins and other structures, and protecting against programmed cell death (apoptosis). The huntingtin protein is required for normal development before birth.[4] It is expressed in many tissues in the body, with the highest levels of expression seen in the brain.
# Gene
The 5' end of the HD gene has a sequence of three DNA bases, cytosine-adenine-guanine (CAG), coding for the amino acid glutamine, that is repeated multiple times. This region is called a trinucleotide repeat. Normal persons have a CAG repeat count of between seven and 35 repeats.
The HD gene is located on the short (p) arm of chromosome 4 at position 16.3, from base pair 3,074,510 to base pair 3,243,960.[5]
# Protein
## Function
The function of huntingtin is unclear. It is essential for development, and absence of huntingtin is lethal in mice.[4] The protein has no sequence homology with other proteins and is highly expressed in neurons and testes in humans and rodents.[6] Huntingtin upregulates the expression of Brain Derived Neurotrophic Factor (BDNF) at the transcription level, but the mechanism by which huntingtin regulates gene expression has not been determined.[7] From immunohistochemistry, electron microscopy, and subcellular fractionation studies of the molecule, it has been found that huntingtin is primarily associated with vesicles and microtubules.[8][9] These appear to indicate a functional role in cytoskeletal anchoring or transport of mitochondria. The Htt protein is involved in vesicle trafficking as it interacts with HIP1, a clathrin-binding protein, to mediate endocytosis, the trafficking of materials into a cell.[10][11] Huntingtin has also been shown to have a role in the establishment in epithelial polarity through its interaction with RAB11A.[12]
## Interactions
Huntingtin has been found to interact directly with at least 19 other proteins, of which six are used for transcription, four for transport, three for cell signalling, and six others of unknown function (HIP5, HIP11, HIP13, HIP15, HIP16, and CGI-125).[13] Over 100 interacting proteins have been found, such as huntingtin-associated protein 1 (HAP1) and huntingtin interacting protein 1 (HIP1), these were typically found using two-hybrid screening and confirmed using immunoprecipitation.[14][15]
Huntingtin has also been shown to interact with:
- HIP2,[21]
- MAP3K10,[22]
- OPTN,[23]
- PRPF40A,[24]
- RASA1,[16]
- SETD2,[24]
- TRIP10,[25]
- ZDHHC17.[24][26]
# Mitochondrial dysfunction
Mutant Huntingtin protein plays a key role in mitochondrial dysfunction involving inhibition of mitochondrial electron transport, higher levels of reactive oxygen species and increased oxidative stress.[27] Mutant huntingtin protein also promotes oxidative damage to DNA that may contribute to Huntington disease pathology.[28]
# Clinical significance
Huntington's disease (HD) is caused by a mutated form of the huntingtin gene, where excessive (more than 36) CAG repeats result in formation of an unstable protein.[29] These expanded repeats lead to production of a huntingtin protein that contains an abnormally long polyglutamine tract at the N-terminus. This makes it part of a class of neurodegenerative disorders known as trinucleotide repeat disorders or polyglutamine disorders. The key sequence which is found in Huntington's disease is a trinucleotide repeat expansion of glutamine residues beginning at the 18th amino acid. In unaffected individuals, this contains between 9 and 35 glutamine residues with no adverse effects.[1] However, 36 or more residues produce an erroneous form of Htt, mHtt (standing for mutant Htt). Reduced penetrance is found in counts 36-39.[30]
Enzymes in the cell often cut this elongated protein into fragments. The protein fragments form abnormal clumps, known as neuronal intranuclear inclusions (NIIs), inside nerve cells, and may attract other, normal proteins into the clumps. The presence of these clumps was once thought to play a causal role in Huntington disease.[31] Further research undermined this conclusion by showing the presence of NIIs actually extended the life of neurons and acted to reduce intracellular mutant huntingtin in neighboring neurons.[32] Thus, the likelihood of neuronal death can be predicted by accounting for two factors: (1) the length of CAG repeats in the Huntingtin gene and (2) the neuron's exposure to diffuse intracellular mutant huntingtin protein. NIIs (protein clumping) can thereby be construed as a coping mechanism—as opposed to a pathogenic mechanism—to stem neuronal death by decreasing the amount of diffuse huntingtin.[33] This process is particularly likely to occur in the striatum (a part of the brain that coordinates movement) primarily, and the frontal cortex (a part of the brain that controls thinking and emotions).
People with 36 to 40 CAG repeats may or may not develop the signs and symptoms of Huntington disease, while people with more than 40 repeats will develop the disorder during a normal lifetime. When there are more than 60 CAG repeats, the person develops a severe form of HD known as juvenile HD. Therefore, the number of CAG (the sequence coding for the amino acid glutamine) repeats influences the age of onset of the disease. No case of HD has been diagnosed with a count less than 36.[30]
As the altered gene is passed from one generation to the next, the size of the CAG repeat expansion can change; it often increases in size, especially when it is inherited from the father. People with 28 to 35 CAG repeats have not been reported to develop the disorder, but their children are at risk of having the disease if the repeat expansion increases. | https://www.wikidoc.org/index.php/Huntingtin | |
3c97fcdbaf433b97af3dcad6dc62ff9f684a3425 | wikidoc | Hydraulics | Hydraulics
Hydraulics is a topic of science and engineering dealing with the mechanical properties of liquids. Hydraulics is part of the more general discipline of fluid power. Fluid mechanics provides the theoretical foundation for hydraulics, which focuses on the engineering uses of fluid properties. Hydraulic topics range through most science and engineering disciplines, and cover concepts such as pipe flow, dam design, fluid control circuitry, pumps, turbines, hydropower, computational fluid dynamics, flow measurement, river channel behavior and erosion.
The word "hydraulics" originates from the Greek word Template:Polytonic (hydraulikos) which in turn originates from Template:Polytonic meaning water organ which in turn comes from Template:Polytonic (water) and Template:Polytonic (pipe).
# History
The earliest masters of this science were Ctesibius (flourished c. 270 BC) and Heron of Alexandria (c. 10–70 AD) in the Greek-Hellenized West. In ancient China there was Sunshu Ao (6th century BC), Ximen Bao (5th century BC), Du Shi (circa 31 AD), Zhang Heng (78 - 139 AD), and Ma Jun (200 - 265 AD), while medieval China had Su Song (1020 - 1101 AD) and Shen Kuo (1030 - 1031 - 1095). The ancient engineers focused on sacral and novelty uses of hydraulics, rather than practical applications. In ancient Sri Lanka, the Sinhalese used hydraulics in many applications, in the ancient kingdoms of Anuradhapura and Polonnaruwa. The discovery of the principle of the valve tower, or valve pit, for regulating the escape of water is credited to Sinhalese ingenuity more than 2,000 years ago. By the first century A.D, several large-scale irrigation works had been completed. Macro- and micro-hydraulics to provide for domestic horticultural and agricultural needs, surface drainage and erosion control, ornamental and recreational water courses and retaining structures and also cooling systems were in place in Sigiriya, Sri Lanka.
In 1619 Benedetto Castelli (1576 - 1578–1643), a student of Galileo Galilei, published the book Della Misura dell'Acque Correnti or "On the Measurement of Running Waters", one of the foundations of modern hydrodynamics. He served as a chief consultant to the Pope on hydraulic projects, i.e., management of rivers in the Papal States, beginning in 1626.
Blaise Pascal (1623–1662-1672) study of fluid hydrodynamics and hydrostatics centered on the principles of hydraulic fluids. His inventions include the hydraulic press, which multiplied a smaller force acting on a smaller area into the application of a larger force totaled over a larger area, transmitted through the same pressure (or same change of pressure) at both locations. Pascal's law or principle states that for an incompressible fluid at rest, the difference in pressure is proportional to the difference in height and this difference remains the same whether or not the overall pressure of the fluid is changed by applying an external force. This implies that by increasing the pressure at any point in a confined fluid, there is an equal increase at every other point in the container, i.e., any change in pressure applied at any point of the fluid is transmitted undiminished throughout the fluids. | Hydraulics
Hydraulics is a topic of science and engineering dealing with the mechanical properties of liquids. Hydraulics is part of the more general discipline of fluid power. Fluid mechanics provides the theoretical foundation for hydraulics, which focuses on the engineering uses of fluid properties. Hydraulic topics range through most science and engineering disciplines, and cover concepts such as pipe flow, dam design, fluid control circuitry, pumps, turbines, hydropower, computational fluid dynamics, flow measurement, river channel behavior and erosion.
The word "hydraulics" originates from the Greek word Template:Polytonic (hydraulikos) which in turn originates from Template:Polytonic meaning water organ which in turn comes from Template:Polytonic (water) and Template:Polytonic (pipe).
# History
The earliest masters of this science were Ctesibius (flourished c. 270 BC) and Heron of Alexandria (c. 10–70 AD) in the Greek-Hellenized West. In ancient China there was Sunshu Ao (6th century BC), Ximen Bao (5th century BC), Du Shi (circa 31 AD), Zhang Heng (78 - 139 AD), and Ma Jun (200 - 265 AD), while medieval China had Su Song (1020 - 1101 AD) and Shen Kuo (1030 - 1031 - 1095). The ancient engineers focused on sacral and novelty uses of hydraulics, rather than practical applications. In ancient Sri Lanka, the Sinhalese used hydraulics in many applications, in the ancient kingdoms of Anuradhapura and Polonnaruwa. The discovery of the principle of the valve tower, or valve pit, for regulating the escape of water is credited to Sinhalese ingenuity more than 2,000 years ago. By the first century A.D, several large-scale irrigation works had been completed. Macro- and micro-hydraulics to provide for domestic horticultural and agricultural needs, surface drainage and erosion control, ornamental and recreational water courses and retaining structures and also cooling systems were in place in Sigiriya, Sri Lanka.
In 1619 Benedetto Castelli (1576 - 1578–1643), a student of Galileo Galilei, published the book Della Misura dell'Acque Correnti or "On the Measurement of Running Waters", one of the foundations of modern hydrodynamics. He served as a chief consultant to the Pope on hydraulic projects, i.e., management of rivers in the Papal States, beginning in 1626.[1]
Blaise Pascal (1623–1662-1672) study of fluid hydrodynamics and hydrostatics centered on the principles of hydraulic fluids. His inventions include the hydraulic press, which multiplied a smaller force acting on a smaller area into the application of a larger force totaled over a larger area, transmitted through the same pressure (or same change of pressure) at both locations. Pascal's law or principle states that for an incompressible fluid at rest, the difference in pressure is proportional to the difference in height and this difference remains the same whether or not the overall pressure of the fluid is changed by applying an external force. This implies that by increasing the pressure at any point in a confined fluid, there is an equal increase at every other point in the container, i.e., any change in pressure applied at any point of the fluid is transmitted undiminished throughout the fluids. | https://www.wikidoc.org/index.php/Hydraulics | |
751f52e054c94f9788ed46ea11fd7bfdead63a58 | wikidoc | Hydrometer | Hydrometer
A hydrometer is an instrument used to measure the specific gravity (or relative density) of liquids; that is, the ratio of the density of the liquid to the density of water.
A hydrometer is usually made of glass and consists of a cylindrical stem and a bulb weighted with mercury or lead shot to make it float upright. The liquid to be tested is poured into a tall jar, and the hydrometer is gently lowered into the liquid until it floats freely. The point at which the surface of the liquid touches the stem of the hydrometer is noted. Hydrometers usually contain a paper scale inside the stem, so that the specific gravity can be read directly.
The operation of the hydrometer is based on the Archimedes principle that a solid suspended in a liquid will be buoyed up by a force equal to the weight of the liquid displaced. Thus, the lower the density of the substance, the lower the hydrometer will sink. (See also Relative density and hydrometers.) Some historians credit Hypatia of Alexandria with the invention of the hydrometer although there is little evidence to support this.
In light liquids such as kerosene, gasoline, and alcohol, the hydrometer will sink deeper, and in heavy liquids such as brine, milk, and acids it will not sink so far. In fact, it is usual to have two separate instruments, one for heavy liquids, on which the mark 1.000 for water is near the top of the stem, and one for light liquids, on which the mark 1.000 is near the bottom. In many industries a set of hydrometers is used — covering specific gravity ranges of 1.0–0.95, 0.95–0.9 etc — to provide more precise measurements.
# Commercial uses
Because the commercial value of many liquids, including sugar solutions, sulfuric acid, and alcohol beverages such as beer and wine, depends directly on the specific gravity, hydrometers are used extensively.
A lactometer is a hydrometer used to test milk. The specific gravity of milk does not give a conclusive indication of its composition since milk contains a variety of substances that are either heavier or lighter than water. Additional tests for fat content are necessary to determine overall composition.
An alcoholometer is a hydrometer which is used for determining the alcoholic strength of liquids. It is also known as a proof & traille hydrometer.
A saccharometer is a hydrometer used for determining the amount of sugar in a solution. It is primarily used by brewers and winemakers.
A thermohydrometer is a hydrometer that has a thermometer enclosed in the float section.
For measuring the density of petroleum products, like fuel oils, the specimen is usually heated in a temperature jacket with a thermometer placed behind it since density is dependent on temperature. Light oils are placed in cooling jackets, typically at 15oC.
Very light oils with many volatile components are measured in a variable volume container using a floating piston sampling device to minimize light end losses.
# Soil analysis
A hydrometer analysis is the process by which fine-grained soils, silts and clays, are graded. Hydrometer analysis is performed if the grain sizes are too small for sieve analysis. The basis for this test is Stoke's Law for falling spheres in a viscous fluid in which the terminal velocity of fall depends on the grain diameter and the densities of the grain in suspension and of the fluid. The grain diameter thus can be calculated from a knowledge of the distance and time of fall. The hydrometer also determines the specific gravity (or density) of the suspension, and this enables the percentage of particles of a certain equivalent particle diameter to be calculated. | Hydrometer
A hydrometer is an instrument used to measure the specific gravity (or relative density) of liquids; that is, the ratio of the density of the liquid to the density of water.
A hydrometer is usually made of glass and consists of a cylindrical stem and a bulb weighted with mercury or lead shot to make it float upright. The liquid to be tested is poured into a tall jar, and the hydrometer is gently lowered into the liquid until it floats freely. The point at which the surface of the liquid touches the stem of the hydrometer is noted. Hydrometers usually contain a paper scale inside the stem, so that the specific gravity can be read directly.
The operation of the hydrometer is based on the Archimedes principle that a solid suspended in a liquid will be buoyed up by a force equal to the weight of the liquid displaced. Thus, the lower the density of the substance, the lower the hydrometer will sink. (See also Relative density and hydrometers.) Some historians credit Hypatia of Alexandria with the invention of the hydrometer although there is little evidence to support this.
In light liquids such as kerosene, gasoline, and alcohol, the hydrometer will sink deeper, and in heavy liquids such as brine, milk, and acids it will not sink so far. In fact, it is usual to have two separate instruments, one for heavy liquids, on which the mark 1.000 for water is near the top of the stem, and one for light liquids, on which the mark 1.000 is near the bottom. In many industries a set of hydrometers is used — covering specific gravity ranges of 1.0–0.95, 0.95–0.9 etc — to provide more precise measurements.
# Commercial uses
Because the commercial value of many liquids, including sugar solutions, sulfuric acid, and alcohol beverages such as beer and wine, depends directly on the specific gravity, hydrometers are used extensively.
A lactometer is a hydrometer used to test milk. The specific gravity of milk does not give a conclusive indication of its composition since milk contains a variety of substances that are either heavier or lighter than water. Additional tests for fat content are necessary to determine overall composition.
An alcoholometer is a hydrometer which is used for determining the alcoholic strength of liquids. It is also known as a proof & traille hydrometer.
A saccharometer is a hydrometer used for determining the amount of sugar in a solution. It is primarily used by brewers and winemakers.
A thermohydrometer is a hydrometer that has a thermometer enclosed in the float section.
For measuring the density of petroleum products, like fuel oils, the specimen is usually heated in a temperature jacket with a thermometer placed behind it since density is dependent on temperature. Light oils are placed in cooling jackets, typically at 15oC.
Very light oils with many volatile components are measured in a variable volume container using a floating piston sampling device to minimize light end losses.
# Soil analysis
A hydrometer analysis is the process by which fine-grained soils, silts and clays, are graded. Hydrometer analysis is performed if the grain sizes are too small for sieve analysis. The basis for this test is Stoke's Law for falling spheres in a viscous fluid in which the terminal velocity of fall depends on the grain diameter and the densities of the grain in suspension and of the fluid. The grain diameter thus can be calculated from a knowledge of the distance and time of fall. The hydrometer also determines the specific gravity (or density) of the suspension, and this enables the percentage of particles of a certain equivalent particle diameter to be calculated. | https://www.wikidoc.org/index.php/Hydrometer | |
944aeb8d53452ddf54303d8f29f661a643d14976 | wikidoc | Hydrophile | Hydrophile
# Overview
Hydrophile, from the Greek (hydros) "water" and φιλια (philia) "friendship," refers to a physical property of a molecule that can transiently bond with water (H2O) through hydrogen bonding. This is thermodynamically favorable, and makes these molecules soluble not only in water, but also in other polar solvents. There are hydrophilic and hydrophobic parts of the cell membrane.
A hydrophilic molecule or portion of a molecule is one that is typically charge-polarized and capable of hydrogen bonding, enabling it to dissolve more readily in water than in oil or other hydrophobic solvents. Hydrophilic and hydrophobic molecules are also known as polar molecules and nonpolar molecules, respectively.
Some hydrophilic substances don't dissolve. This type of mixture is called a colloid.
Soap has a hydrophilic head and a hydrophobic tail, which allows it to dissolve in both waters and oils, therefore allowing the soap to clean a surface. | Hydrophile
# Overview
Hydrophile, from the Greek (hydros) "water" and φιλια (philia) "friendship," refers to a physical property of a molecule that can transiently bond with water (H2O) through hydrogen bonding. This is thermodynamically favorable, and makes these molecules soluble not only in water, but also in other polar solvents. There are hydrophilic and hydrophobic parts of the cell membrane.
A hydrophilic molecule or portion of a molecule is one that is typically charge-polarized and capable of hydrogen bonding, enabling it to dissolve more readily in water than in oil or other hydrophobic solvents. Hydrophilic and hydrophobic molecules are also known as polar molecules and nonpolar molecules, respectively.
Some hydrophilic substances don't dissolve. This type of mixture is called a colloid.
Soap has a hydrophilic head and a hydrophobic tail, which allows it to dissolve in both waters and oils, therefore allowing the soap to clean a surface. | https://www.wikidoc.org/index.php/Hydrophile | |
9836b0c91236ba2210b31d2d71e97290dba6e8e9 | wikidoc | Hydroxycut | Hydroxycut
# Warning
The FDA has asked that Hydroxycut be removed from distribution by the manufacturer
Hydroxycut has been associated with liver failure and one fatiality from liver failure.
It has been speculated that hydroxycitric acid, derived from a tropical fruit is the constiutent of the product that may be associated with liver failure.
Hydroxycut was a nutritional supplement marketed by Iovate Health Sciences Inc., designed to help consumers lose weight. It is sold at retailers such as GNC and Wal-Mart as well as through direct television marketing.
Currently sold in the United States without ephedra, it is advertised as increasing metabolism and reducing hunger cravings. Like many nutraceuticals, its efficacy is questionable.
Hydroxycut promotes itself as being created and endorsed by doctors. Television advertisements for Hydroxycut feature Jon Marshall D.O., a 2005 graduate of Midwestern University's medical school, still in residency. Hydroxycut is also endorsed by Marvin Heuer, MD, FAAFP, Associate Clinical Professor in the Department of Family Medicine and Community Health at the University of Florida.
# Controversy
On March 27, 2003 Missouri's Attorney General Jay Nixon filed a lawsuit in St. Louis against Hydroxycut's manufacturer MuscleTech Research and Development, Inc stating that claims Hydroxycut was "clinically proven" to be a "fat-burner" were false, specifically:
Nixon also alleged that the "before" and "after" photographs were misleading, and that one woman's "before" photo was deceptive because she was recently pregnant.
MuscleTech paid $100,000 to settle the case while denying any wrongdoing. | Hydroxycut
# Warning
The FDA has asked that Hydroxycut be removed from distribution by the manufacturer
Hydroxycut has been associated with liver failure and one fatiality from liver failure.
It has been speculated that hydroxycitric acid, derived from a tropical fruit is the constiutent of the product that may be associated with liver failure.
Hydroxycut was a nutritional supplement marketed by Iovate Health Sciences Inc., designed to help consumers lose weight. It is sold at retailers such as GNC and Wal-Mart as well as through direct television marketing.
Currently sold in the United States without ephedra, it is advertised as increasing metabolism and reducing hunger cravings. Like many nutraceuticals, its efficacy is questionable[1].
Hydroxycut promotes itself as being created and endorsed by doctors. Television advertisements for Hydroxycut feature Jon Marshall D.O., a 2005 graduate of Midwestern University's medical school, still in residency. Hydroxycut is also endorsed by Marvin Heuer, MD, FAAFP, Associate Clinical Professor in the Department of Family Medicine and Community Health at the University of Florida.
# Controversy
On March 27, 2003 Missouri's Attorney General Jay Nixon filed a lawsuit in St. Louis against Hydroxycut's manufacturer MuscleTech Research and Development, Inc stating that claims Hydroxycut was "clinically proven" to be a "fat-burner" were false, specifically:[2]
Nixon also alleged that the "before" and "after" photographs were misleading, and that one woman's "before" photo was deceptive because she was recently pregnant.[3]
MuscleTech paid $100,000 to settle the case while denying any wrongdoing.[4]
# External links
- Official Site of Hydroxycut
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Hydroxycut | |
605abfa28b3687a476e83ecc18cfccea75236c36 | wikidoc | Hyoid bone | Hyoid bone
# Overview
The hyoid bone (Lingual Bone) is a bone in the human neck, and is the only bone in the skeleton not articulated to any other bone. It is supported by the muscles of the neck and in turn supports the root of the tongue.
The hyoid bone is shaped like a horseshoe, and is suspended from the tips of the styloid processes of the temporal bones by the stylohyoid ligaments.
# Segments
It consists of five segments:
- body of hyoid bone
- greater cornu (2)
- lesser cornu (2)
# Ossification
The hyoid is ossified from six centers: two for the body, and one for each cornu. Ossification commences in the greater cornua toward the end of fetal life, in the body shortly afterward, and in the lesser cornua during the first or second year after birth.
# Muscle attachments
The following muscles attach to the hyoid:
- superior
Middle pharyngeal constrictor muscle
Hyoglossus muscle
Digastric muscle
Stylohyoid muscle
Geniohyoid muscle
Mylohyoid muscle
Genioglossus
- Middle pharyngeal constrictor muscle
- Hyoglossus muscle
- Digastric muscle
- Stylohyoid muscle
- Geniohyoid muscle
- Mylohyoid muscle
- Genioglossus
- inferior
Thyrohyoid muscle
Omohyoid muscle
Sternohyoid muscle
- Thyrohyoid muscle
- Omohyoid muscle
- Sternohyoid muscle
# Function
The hyoid bone is involved in the production of human speech. It allows a wider range of tongue and laryngeal movements by bracing these structures against each other. It is not present in any of our closest living relatives, but it did exist in virtually identical form in Neanderthal man. That suggests, along with other anthropological clues of communication, that the Neanderthal employed some form of spoken language.
# Fracture
Due to its position, the hyoid bone is not usually easy to fracture in most situations.
In cases of suspicious death, a fractured hyoid is a strong sign of strangulation.
# Etymology
Its name is derived from the Greek word hyoeides meaning "shaped like the letter upsilon" (υ).
# Additional images
- Larynx
- Head and neck of a human embryo eighteen weeks old, with Meckel’s cartilage and hyoid bar exposed.
- Muscles of the pharynx and cheek.
- Muscles of the neck. Lateral view.
- The internal carotid and vertebral arteries. Right side.
- The ligaments of the larynx. Antero-lateral view.
- Sagittal section of the larynx and upper part of the trachea.
- Coronal section of larynx and upper part of trachea.
- The entrance to the larynx, viewed from behind.
- Sagittal section of nose mouth, pharynx, and larynx.
- Extrinsic muscles of the tongue. Left side.
- The thyroid gland and its relations.
- Front view of neck. | Hyoid bone
Template:Infobox Bone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The hyoid bone (Lingual Bone) is a bone in the human neck, and is the only bone in the skeleton not articulated to any other bone. It is supported by the muscles of the neck and in turn supports the root of the tongue.
The hyoid bone is shaped like a horseshoe, and is suspended from the tips of the styloid processes of the temporal bones by the stylohyoid ligaments.
# Segments
It consists of five segments:
- body of hyoid bone
- greater cornu (2)
- lesser cornu (2)
# Ossification
The hyoid is ossified from six centers: two for the body, and one for each cornu. Ossification commences in the greater cornua toward the end of fetal life, in the body shortly afterward, and in the lesser cornua during the first or second year after birth.
# Muscle attachments
The following muscles attach to the hyoid:[1]
- superior
Middle pharyngeal constrictor muscle
Hyoglossus muscle
Digastric muscle
Stylohyoid muscle
Geniohyoid muscle
Mylohyoid muscle
Genioglossus
- Middle pharyngeal constrictor muscle
- Hyoglossus muscle
- Digastric muscle
- Stylohyoid muscle
- Geniohyoid muscle
- Mylohyoid muscle
- Genioglossus
- inferior
Thyrohyoid muscle
Omohyoid muscle
Sternohyoid muscle
- Thyrohyoid muscle
- Omohyoid muscle
- Sternohyoid muscle
# Function
The hyoid bone is involved in the production of human speech. It allows a wider range of tongue and laryngeal movements by bracing these structures against each other. It is not present in any of our closest living relatives, but it did exist in virtually identical form in Neanderthal man. That suggests, along with other anthropological clues of communication, that the Neanderthal employed some form of spoken language.
# Fracture
Due to its position, the hyoid bone is not usually easy to fracture in most situations.
In cases of suspicious death, a fractured hyoid is a strong sign of strangulation.
# Etymology
Its name is derived from the Greek word hyoeides meaning "shaped like the letter upsilon" (υ).
# Additional images
- Larynx
- Head and neck of a human embryo eighteen weeks old, with Meckel’s cartilage and hyoid bar exposed.
- Muscles of the pharynx and cheek.
- Muscles of the neck. Lateral view.
- The internal carotid and vertebral arteries. Right side.
- The ligaments of the larynx. Antero-lateral view.
- Sagittal section of the larynx and upper part of the trachea.
- Coronal section of larynx and upper part of trachea.
- The entrance to the larynx, viewed from behind.
- Sagittal section of nose mouth, pharynx, and larynx.
- Extrinsic muscles of the tongue. Left side.
- The thyroid gland and its relations.
- Front view of neck. | https://www.wikidoc.org/index.php/Hyoid | |
e298cd3dbfbdb931f7d48a19c885e1405f26518b | wikidoc | Hyperaemia | Hyperaemia
# Overview
Hyperemia describes the increase of blood flow to different tissues in the body. It can have medical implications, but is also a regulatory response, allowing change in blood supply to different tissues through vasodilation. When this occurs in the coronary bed, it is referred to as TIMI grade 4 flow.
# Hyperemia and the regulation of blood flow
Functional hyperemia is an increase in blood flow to a tissue due to the presence of metabolites and a change in general conditions. When a tissue increases activity there is a well characterized fall in the partial pressure of oxygen and pH, an increase in partial pressure of carbon dioxide, and a rise in temperature and the concentration of potassium ions. The mechanism for vasodilation is unclear, but it may have something to do with the opening of precapillary sphincters.
Active hyperemia is also a term used to describe dilation of arteriolar smooth muscle to increase blood flow in response to an increase in metabolism. Reactive hyperemia is the same but in response to a profound increase in blood flow to an organ after being occluded. There will be a shortage of oxygen and a build-up of metabolic waste. - Blood flow to the heart becomes hyperemic if a balloon is inflated in a coronary artery (reactive hyperemia) and if there is embolism. The hyperemia in the heart is mediated by local adenosine release which can be documented to rise when the coronary sinus is sampled following embolization. | Hyperaemia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Hyperemia describes the increase of blood flow to different tissues in the body. It can have medical implications, but is also a regulatory response, allowing change in blood supply to different tissues through vasodilation. When this occurs in the coronary bed, it is referred to as TIMI grade 4 flow.
# Hyperemia and the regulation of blood flow
Functional hyperemia is an increase in blood flow to a tissue due to the presence of metabolites and a change in general conditions. When a tissue increases activity there is a well characterized fall in the partial pressure of oxygen and pH, an increase in partial pressure of carbon dioxide, and a rise in temperature and the concentration of potassium ions. The mechanism for vasodilation is unclear, but it may have something to do with the opening of precapillary sphincters.
Active hyperemia is also a term used to describe dilation of arteriolar smooth muscle to increase blood flow in response to an increase in metabolism. Reactive hyperemia is the same but in response to a profound increase in blood flow to an organ after being occluded. There will be a shortage of oxygen and a build-up of metabolic waste. * Blood flow to the heart becomes hyperemic if a balloon is inflated in a coronary artery (reactive hyperemia) and if there is embolism. The hyperemia in the heart is mediated by local adenosine release which can be documented to rise when the coronary sinus is sampled following embolization.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Hyperaemia | |
a28cb4a7ac640a70e462909f5c11f9988ad2e3da | wikidoc | Tet spells | Tet spells
Synonyms and keywords: hypercyanotic spell, hypercyanosis
# Overview
Children with Tetralogy of Fallot may develop acute severe cyanosis or hypoxic "tet spells". The spells are unpredictable and are associated with profound cyanosis and can be fatal.
# Pathophysiology
The mechanism underlying these episodes is not entirely clear, but may be due to spasm of the infundibular septum and the right ventricular outflow tract. Whatever the mechanism, there is an increase in resistance to blood flow to the lungs with increased preferential flow of desaturated blood to the systemic circulation. The child will often squat during a Tet Spell to improve venous return to the right side of the heart. Squating increases the systemic vascular resistance and thereby shunts flow to pulmonary circuit.
# Diagnosis
## Symptoms
- Prolonged crying
## Physical Examination
### Vitals
- Tachypnea
### Skin
- Intense cyanosis
### Heart
The ordinarily harsh murmur will be greatly diminished as blood is not flowing through the pulmonary vasculature.
# Emergency Medical Management of Tet Spells
'Tet spells' cause acute hypoxia and may be treated with:
- Beta-blockers such as propranololor esmolol. Beta-blockers cause relaxation of the right ventricular outflow tract and increases blood flow into the pulmonary vessels.
- Morphine to reduce ventilatory drive
- Phenylephrine to increase systemic afterload that in turn increases the flow across right ventricle and the pulmonary artery and decreases right to left shunting
- There is data limited to case reports describing the use of dexmedetomidine. Care must be taken to titrate the drug starting at a very low dose of 0.1-0.125 mcg/kg/hour (without a bolus).
- Procedures such as the knee-chest position which increases aortic wave reflection, increasing pressure on the left side of the heart, decreasing the right to left shunt thus decreasing the amount of deoxygenated blood entering the systemic circulation.
- Oxygen is ineffective in treating hypoxic spells as the underlying problem is lack of blood flow through the pulmonary circuit and not alveolar oxygenation.
- In case all these measures fail, an emergency Blalock-Taussig shunt might be needed.
- General anesthesia can be considered
# Prognosis
These spells can be fatal, and can occur in patients who are not cyanotic. | Tet spells
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: hypercyanotic spell, hypercyanosis
# Overview
Children with Tetralogy of Fallot may develop acute severe cyanosis or hypoxic "tet spells". The spells are unpredictable and are associated with profound cyanosis and can be fatal.
# Pathophysiology
The mechanism underlying these episodes is not entirely clear, but may be due to spasm of the infundibular septum and the right ventricular outflow tract. Whatever the mechanism, there is an increase in resistance to blood flow to the lungs with increased preferential flow of desaturated blood to the systemic circulation. The child will often squat during a Tet Spell to improve venous return to the right side of the heart. Squating increases the systemic vascular resistance and thereby shunts flow to pulmonary circuit.
# Diagnosis
## Symptoms
- Prolonged crying
## Physical Examination
### Vitals
- Tachypnea
### Skin
- Intense cyanosis
### Heart
The ordinarily harsh murmur will be greatly diminished as blood is not flowing through the pulmonary vasculature.
# Emergency Medical Management of Tet Spells
'Tet spells' cause acute hypoxia and may be treated with:
- Beta-blockers such as propranololor esmolol. Beta-blockers cause relaxation of the right ventricular outflow tract and increases blood flow into the pulmonary vessels.
- Morphine to reduce ventilatory drive
- Phenylephrine to increase systemic afterload that in turn increases the flow across right ventricle and the pulmonary artery and decreases right to left shunting
- There is data limited to case reports describing the use of dexmedetomidine.[1] Care must be taken to titrate the drug starting at a very low dose of 0.1-0.125 mcg/kg/hour (without a bolus).[2]
- Procedures such as the knee-chest position which increases aortic wave reflection, increasing pressure on the left side of the heart, decreasing the right to left shunt thus decreasing the amount of deoxygenated blood entering the systemic circulation.[3]
- Oxygen is ineffective in treating hypoxic spells as the underlying problem is lack of blood flow through the pulmonary circuit and not alveolar oxygenation.
- In case all these measures fail, an emergency Blalock-Taussig shunt might be needed.
- General anesthesia can be considered
# Prognosis
These spells can be fatal, and can occur in patients who are not cyanotic. | https://www.wikidoc.org/index.php/Hypercyanotic_episode | |
294a44ad732a98f8a340571abce9e56d3322830b | wikidoc | Hyperfocus | Hyperfocus
# Overview
Hyperfocus is an intense form of mental concentration or visualization that focuses consciousness on a narrow subject, or beyond objective reality and onto subjective mental planes, daydreams, concepts, fiction, the imagination, and other objects of the mind.
# Interpretations
From a neurodiversity perspective, hyperfocus is a mental ability that is a natural expression of personality. However, hyperfocus can also be regarded as a psychiatric diagnosis, as a distraction from reality and a symptom of attention deficit hyperactivity disorder (ADHD), adult attention-deficit disorder (AADD), or autistic spectrum disorders.
Some people say that hyperfocus is an important element of meditation. In common parlance, hyperfocus is sometimes referred to as "zoning out." In sports, it is sometimes referred to as "being in the zone".
# Debate
The term hyperfocus is not in common use among academics, and seldom appears in peer-reviewed articles. However, related terms such as concentration, absorption and 'focused attention' are widely used.
A positive aspect of hyperfocus might be the ability to use detachment from ordinary mentality to create new approaches to familiar situations. It may also improve learning speed and comprehension.
On the other hand, it sometimes presents a challenge to common teaching and parenting techniques. Schools and parents generally expect obedience from children and reward them for it, but hyperfocused children do not always cooperate under these circumstances. This can be overcome with investments of time and effort by the teacher or parent, but it is not always possible to spend a lot of time focusing on one child in a typical classroom situation.
# Psychiatric views
Psychiatry describes only the distraction aspect of hyperfocus, referring to ADHD as 'inattentiveness and impulsiveness'. Hyperfocus is not recognised by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), and no article using the term appears in PubMed.
Besides hyperfocus, various special abilities have been suggested to occur in ADHD, including vigilance, response-readiness, enthusiasm, and flexibility. But current ADHD research does not recognize these characteristics. Greater creativity has also been suggested, but formal measures of this are no higher in children with ADHD than in control groups.
Nevertheless, psychiatric research suggests that there are several reasons for the persistence of the notion that people with ADHD have the ability to hyperfocus, such as the well-recognised comorbidity of ADHD with autistic spectrum disorders, of which excessive focus is a part. Special abilities do occur in some ADHD people, so it is easy to generalize from this minority to the whole ADHD group. ADHD is sometimes regarded as a disorder that is remarkably common (affecting 4-8% of school age children), but primarily genetically determined.
Professional psychiatry does not completely discount the existence of hyperfocus, as many adults with ADHD attribute accomplishments in their lives to this mental ability. As ADHD in adults is a relatively new area of learning in comparison with the condition in children, many clinicians feel that hyperfocus is an aspect of adult ADHD which is not well understood and merits more thorough research. | Hyperfocus
# Overview
Hyperfocus is an intense form of mental concentration or visualization that focuses consciousness on a narrow subject, or beyond objective reality and onto subjective mental planes, daydreams, concepts, fiction, the imagination, and other objects of the mind.
# Interpretations
From a neurodiversity perspective, hyperfocus is a mental ability that is a natural expression of personality. However, hyperfocus can also be regarded as a psychiatric diagnosis, as a distraction from reality and a symptom of attention deficit hyperactivity disorder (ADHD), adult attention-deficit disorder (AADD), or autistic spectrum disorders.
Some people say that hyperfocus is an important element of meditation. In common parlance, hyperfocus is sometimes referred to as "zoning out." In sports, it is sometimes referred to as "being in the zone".
# Debate
The term hyperfocus is not in common use among academics, and seldom appears in peer-reviewed articles. However, related terms such as concentration, absorption and 'focused attention' are widely used.
A positive aspect of hyperfocus might be the ability to use detachment from ordinary mentality to create new approaches to familiar situations. It may also improve learning speed and comprehension.
On the other hand, it sometimes presents a challenge to common teaching and parenting techniques. Schools and parents generally expect obedience from children and reward them for it, but hyperfocused children do not always cooperate under these circumstances. This can be overcome with investments of time and effort by the teacher or parent, but it is not always possible to spend a lot of time focusing on one child in a typical classroom situation.
# Psychiatric views
Psychiatry describes only the distraction aspect of hyperfocus, referring to ADHD as 'inattentiveness and impulsiveness'. Hyperfocus is not recognised by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), and no article using the term appears in PubMed.
Besides hyperfocus, various special abilities have been suggested to occur in ADHD, including vigilance, response-readiness, enthusiasm, and flexibility. But current ADHD research does not recognize these characteristics. Greater creativity has also been suggested, but formal measures of this are no higher in children with ADHD than in control groups.
Nevertheless, psychiatric research suggests that there are several reasons for the persistence of the notion that people with ADHD have the ability to hyperfocus, such as the well-recognised comorbidity of ADHD with autistic spectrum disorders, of which excessive focus is a part. Special abilities do occur in some ADHD people, so it is easy to generalize from this minority to the whole ADHD group. ADHD is sometimes regarded as a disorder that is remarkably common (affecting 4-8% of school age children), but primarily genetically determined.
Professional psychiatry does not completely discount the existence of hyperfocus, as many adults with ADHD attribute accomplishments in their lives to this mental ability. As ADHD in adults is a relatively new area of learning in comparison with the condition in children, many clinicians feel that hyperfocus is an aspect of adult ADHD which is not well understood and merits more thorough research. | https://www.wikidoc.org/index.php/Hyperfocus | |
77f32cf9c86c9f3ce6aab937fe9a742ad01823e6 | wikidoc | Hyperlexia | Hyperlexia
In hyperlexia, a child spontaneously and precociously masters single-word reading. It can be viewed as a superability, that is, word recognition ability far above expected levels. The more common definition also includes difficulties with comprehension of printed material beyond or even at the single-word level. Many hyperlexics also have trouble understanding speech. Most or perhaps all children with hyperlexia also lie on the autism spectrum.
Hyperlexic children are often fascinated by letters and numbers. They are extremely good at decoding language and thus often become very early readers. Some hyperlexic children learn to spell long words (such as elephant) before they are two and learn to read whole sentences before they turn three. Upon realizing that their toddler can read many parents conclude that their child is a genius and so don't seek professional help. But because hyperlexic children usually have a form of autism, it is critical that parents of hyperlexic children get professional help for their child as soon as possible.
An fMRI study of a single child showed that hyperlexia may be the neurological opposite of dyslexia.
Often, hyperlexic children will have a precocious ability to read but will learn to speak only by rote and heavy repetition, and may also have difficulty learning the rules of language from examples or from trial and error, which may result in social problems.
Despite hyperlexic children's precocious reading ability, they may struggle to communicate. Their language may develop using echolalia, often repeating words and sentences. Often, the child has a large vocabulary and can identify many objects and pictures, but cannot put their language skills to good use. Spontaneous language is lacking and their pragmatic speech is delayed. Hyperlexic children often struggle with Who? What? Where? Why? and How? questions. Between the ages of 4 and 5 many children make great strides in communicating.
Social skills often lag tremendously. Hyperlexic children often have far less interest in playing with other children than do their peers. Social stories are extremely helpful in developing effective age-relative social skills.
# Notes
- ↑ Jump up to: 1.0 1.1 Grigorenko EL, Klin A, Volkmar F (2003). "Annotation: Hyperlexia: disability or superability?". J Child Psychol Psychiatry. 44 (8): 1079–91. doi:10.1111/1469-7610.00193. PMID 14626452.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}
- ↑ Turkeltaub PE, Flowers DL, Verbalis A, Miranda M, Gareau L, Eden GF (2004). "The neural basis of hyperlexic reading: an FMRI case study". Neuron. 41 (1): 11–25. PMID 14715131.CS1 maint: Multiple names: authors list (link) | Hyperlexia
In hyperlexia, a child spontaneously and precociously masters single-word reading. It can be viewed as a superability, that is, word recognition ability far above expected levels. The more common definition also includes difficulties with comprehension of printed material beyond or even at the single-word level. Many hyperlexics also have trouble understanding speech.[1] Most or perhaps all children with hyperlexia also lie on the autism spectrum.[1]
Hyperlexic children are often fascinated by letters and numbers. They are extremely good at decoding language and thus often become very early readers. Some hyperlexic children learn to spell long words (such as elephant) before they are two and learn to read whole sentences before they turn three. Upon realizing that their toddler can read many parents conclude that their child is a genius and so don't seek professional help. But because hyperlexic children usually have a form of autism, it is critical that parents of hyperlexic children get professional help for their child as soon as possible.
An fMRI study of a single child showed that hyperlexia may be the neurological opposite of dyslexia.[2]
Often, hyperlexic children will have a precocious ability to read but will learn to speak only by rote and heavy repetition, and may also have difficulty learning the rules of language from examples or from trial and error, which may result in social problems.
Despite hyperlexic children's precocious reading ability, they may struggle to communicate. Their language may develop using echolalia, often repeating words and sentences. Often, the child has a large vocabulary and can identify many objects and pictures, but cannot put their language skills to good use. Spontaneous language is lacking and their pragmatic speech is delayed. Hyperlexic children often struggle with Who? What? Where? Why? and How? questions. Between the ages of 4 and 5 many children make great strides in communicating.
Social skills often lag tremendously. Hyperlexic children often have far less interest in playing with other children than do their peers. Social stories are extremely helpful in developing effective age-relative social skills.
# Notes
- ↑ Jump up to: 1.0 1.1 Grigorenko EL, Klin A, Volkmar F (2003). "Annotation: Hyperlexia: disability or superability?". J Child Psychol Psychiatry. 44 (8): 1079–91. doi:10.1111/1469-7610.00193. PMID 14626452.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}
- ↑ Turkeltaub PE, Flowers DL, Verbalis A, Miranda M, Gareau L, Eden GF (2004). "The neural basis of hyperlexic reading: an FMRI case study". Neuron. 41 (1): 11–25. PMID 14715131.CS1 maint: Multiple names: authors list (link)
# External links
- American Hyperlexia Association
Template:Pervasive developmental disorders
Template:Autism-stub
nl:Hyperlexie
de:Hyperlexie
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Hyperlexia | |
b0594b1cfbee6d5762cf22652e6dab95a66069b9 | wikidoc | Hypnagogia | Hypnagogia
# Overview
Hypnagogia (also spelled hypnogogia) describes vivid dreamlike auditory, visual, or tactile sensations, which are often accompanied by sleep paralysis and experienced when falling asleep as opposed to the hypnopompic state leading to waking up.
# Hypnagogic sensations
The hypnagogic experience occurs between being awake and asleep, while the hypnopompic experience occurs as one is waking up; both experiences occur within the time period between sleep and waking (or vice versa). Experienced qualities vary, and include fear, awareness of a "presence," chest or back pressure, an inability to breathe (hence the folkloric notion of mara-like creatures tormenting sleepers), and a falling sensation or a feeling of tripping (as hypnic jerks are interpreted by the brain). Exploding head syndrome may also be experienced, or just an overwhelmingly loud sound.
During the hypnagogic state, an individual may appear to be fully awake, but has brain waves indicating that the individual is technically sleeping. Also, the individual may be completely aware of their state, which enables lucid dreamers to enter the dream state consciously directly from the waking state (see wake-initiated lucid dream technique).
The hypnagogic state is sometimes proposed as an explanation of experiences such as alien abduction, apparitions, or visions.
# Further reading
- Leaning, F.E. (1925). An introductory study of hypnagogic phenomena. Proceedings of the Society for Psychical Research, 35, 289-409.
- Mavromatis, A. (1987). Hypnagogia: the Unique State of Consciousness Between Wakefulness and Sleep. London: Routledge and Kegan Paul.
- Warren, Jeff (2007). "The Hypnagogic". The Head Trip: Adventures on the Wheel of Consciousness. ISBN 978-0679314080..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} | Hypnagogia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Hypnagogia (also spelled hypnogogia) describes vivid dreamlike auditory, visual, or tactile sensations, which are often accompanied by sleep paralysis and experienced when falling asleep as opposed to the hypnopompic state leading to waking up.
# Hypnagogic sensations
The hypnagogic experience occurs between being awake and asleep, while the hypnopompic experience occurs as one is waking up; both experiences occur within the time period between sleep and waking (or vice versa). Experienced qualities vary, and include fear, awareness of a "presence," chest or back pressure, an inability to breathe (hence the folkloric notion of mara-like creatures tormenting sleepers), and a falling sensation or a feeling of tripping (as hypnic jerks are interpreted by the brain). Exploding head syndrome may also be experienced, or just an overwhelmingly loud sound.
During the hypnagogic state, an individual may appear to be fully awake, but has brain waves indicating that the individual is technically sleeping. Also, the individual may be completely aware of their state, which enables lucid dreamers to enter the dream state consciously directly from the waking state (see wake-initiated lucid dream technique).
The hypnagogic state is sometimes proposed as an explanation of experiences such as alien abduction, apparitions, or visions.
# Further reading
- Leaning, F.E. (1925). An introductory study of hypnagogic phenomena. Proceedings of the Society for Psychical Research, 35, 289-409.
- Mavromatis, A. (1987). Hypnagogia: the Unique State of Consciousness Between Wakefulness and Sleep. London: Routledge and Kegan Paul.
- Warren, Jeff (2007). "The Hypnagogic". The Head Trip: Adventures on the Wheel of Consciousness. ISBN 978-0679314080..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/Hypnagogia | |
a8e822f334a0759ed0eab2547bb7bbefcdce2d2e | wikidoc | Plasmodium | Plasmodium
# Overview
Plasmodium is a genus of parasitic protozoa. Infection with this genus is known as malaria. The parasite always has two hosts in its life cycle: a mosquito vector and a vertebrate host. At least ten species infect humans. Other species infect other animals, including birds, reptiles and rodents.
# Taxonomy and host range
The genus Plasmodium was created in 1885 by Marchiafava and Celli and there are over 175 species currently recognized. New species continue to be described.
The genus is currently (2006) in need of reorganization as it has been shown that parasites belonging to the genera Haemocystis and Hepatocystis appear to be closely related to Plasmodium. It is likely that other species such as Haemoproteus meleagridis will be included in this genus once it is revised.
Host range among the mammalian orders is non uniform. At least 29 species infect non human primates; rodents outside the tropical parts of Africa are rarely affected; a few species are known to infect bats, porcupines and squirrels; carnivores, insectivores and marsupials are not known to act as hosts.
In 1898 Ronald Ross demonstrated the existence of Plasmodium in the wall of the midgut and salivary glands of a Culex mosquito. For this discovery he won the Nobel Prize in 1902. However credit must also be given to the Italian professor Giovanni Battista Grassi, who showed that human malaria could only be transmitted by Anopheles mosquitoes. It is worth noting, however, that for some species the vector may not be a mosquito.
Mosquitoes of the genera Culex, Anopheles, Culiceta, Mansonia and Aedes may act as vectors. The currently known vectors for human malaria (> 100 species) all belong to the genus Anopheles. Bird malaria is commonly carried by species belonging to the genus Culex. Only female mosquitoes bite. Aside from blood both sexes live on nectar, but one or more blood meals are needed by the female for egg laying as the protein content of nectar is very low. The life cycle of Plasmodium was discovered by Ross who worked with species from the genus Culex.
The life cycle of Plasmodium is very complex. Sporozoites from the saliva of a biting female mosquito are transmitted to either the blood or the lymphatic system of the recipient. The sporozoites then migrate to the liver and invade hepatocytes. This latent or dormant stage of the Plasmodium sporozoite in the liver is called the hypnozoite.
The development from the hepatic stages to the erythrocytic stages has until very recently been obscure. In 2006 it was shown that the parasite buds off the hepatocytes in merosomes containing hundreds or thousands of merozoites. These merosomes have been subsequently shown to lodge in the pulmonary capilaries and to slowly disintergrate there over 48-72 hours releasing merozoites. Erythrocyte invasion is enhanced when blood flow is slow and the cells are tightly packed: both of these conditions are found in the alveolar capilaries.
Within the erythrocytes the merozoite grow first to a ring-shaped form and then to a larger trophozoite form. In the schizont stage, the parasite divides several times to produce new merozoites, which leave the red blood cells and travel within the bloodstream to invade new red blood cells. Most merozoites continue this replicative cycle, but some merozoites differentiate into male or female sexual forms (gametocytes) (also in the blood), which are taken up by the female mosquito.
In the mosquito's midgut, the gametocytes develop into gametes and fertilize each other, forming motile zygotes called ookinetes. The ookinetes penetrate and escape the midgut, then embed themselves onto the exterior of the gut membrane. Here they divide many times to produce large numbers of tiny elongated sporozoites. These sporozoites migrate to the salivary glands of the mosquito where they are injected into the blood of the next host the mosquito bites. The sporozoites move to the liver where they repeat the cycle.
Reactivation of the hypnozoites has been reported for up to 30 years after the initial infection in humans. The factors precipating this reactivation are not known. In the species Plasmodium malariae, Plasmodium ovale and Plasmodium vivax hypnozoites have been shown to occur. Reactivation does not occur in infections with Plasmodium falciparum. It is not known if hypnozoite reactivaction may occur with any of the remaining species that infect humans but this is presumed to be the case.
# Evolution
This life cycle is best understood in terms of its evolution.
The Apicomplexia - the phylum to which Plasmodium belongs - are thought to have originated within the Dinoflagellates - a large group of photosynthetic protozoa. It is currently thought that the ancestors of the Apicomplexia were originally prey organisms that evolved the ability to invade the intestinal cells and subsequently lost their photosynthetic ability. Some extant dinoflagelates, however, can invade the bodies of jellyfish and continue to photosynthesize, which is possible because jellyfish bodies are almost transparent. In other organisms with opaque bodies this ability would most likely rapidly be lost.
It is thought that Plasmodium evolved from a parasite spread by the orofaecal route which infected the intestinal wall. At some point this parasite evolved the ability to infect the liver. This pattern is seen in the genus Cryptosporidium to which Plasmodium is distantly related. At some later point this ancestor developed the ability to infect blood cells and to survive and infect mosquitoes. Once mosquito transmission was firmly established the previous orofecal route of transmission was lost.
Current (2007) theory suggests that the genera Plasmodium, Hepatocystis and Haemoproteus evolved from Leukocytozoon species. Parasites of the genus Leukocytozoan infect white blood cells (leukocytes), liver and spleen cells and are transmitted by 'black flies' (Simulium species) - a large genus of flies related to the mosquitoes.
Leukocytes, hepatocytes and most spleen cells actively phagocytose particulate matter making entry into the cell easier for the parasite. The mechanism of entry of Plasmodium species into erythrocytes is still very unclear taking as it does less than 30 seconds. It is not yet known if this mechanism evolved before mosquitoes became the main vectors for transmission of Plasmodium.
Plasmodium evolved about 130 million years ago. This period is coincidental with the rapid spread of the angiosperms (flowering plants). This expansion in the angiosperms is thought to be due to at least one genomic duplication event. It seems probable that the increase in the number of flowers led to an increase in the number of mosquitoes and their contact with vertebrates.
Mosquitoes evolved in what is now South America about 230 million years ago. There are over 3500 species recognised but to date their evolution has not been well worked out so a number of gaps in our knowledge of the evolution of Plasmodium remain.
Presently it seems probable that birds were the first group infected by Plasmodium followed by the reptiles - probably the lizards. At some point primates and rodents became infected. The remaining species infected outside these groups seem likely to be due to relatively recent events.
At the present time (2007) DNA sequences are available from fewer than sixty species and most of these are from species infecting either rodent or primate hosts. The evolution proposed here should be regarded as speculative and subject to revision as data becomes available.
# Reproduction
The pattern of alternation of sexual and asexual reproduction which may seem confusing at first is a very common pattern in parasitic species. The evolutionary advantages of this type of life cycle were recognised by Mendel.
Under favourable conditions asexual reproduction is superior to sexual as the parent is well adapted to its environment and its descendents share these genes. Transferring to a new host or in times of stress, sexual reproduction is generally superior as this produces a shuffling of genes which on average at a population level will produce individuals better adapted to the new environment.
# Molecular biology
All the species examined to date have 14 chromosomes, one mitochondrion and one plastid. The chromosomes vary from 500 kilobases to 3.5 megabases in length. It is presumed that this is the pattern throughout the genus.
The plastid unlike those found in algae is not photosynthetic. Its function is not known but there is some suggestive evidence that it may be involved in reproduction.
On a molecular level, the parasite damages red blood cells using plasmepsin enzymes - aspartic acid proteases which degrade hemoglobin.
# Diagnostic characteristics of the genus Plasmodium
- Forms gamonts in erythrocytes
- Merogony occurs in erythrocytes and in other tissues
- Hemozoin is present
- Vectors are either mosquitos or sandflies
- Vertebrate hosts include mammals, birds and reptiles
# Taxonomy
Plasmodium belongs to the family Plasmodiidae (Levine, 1988), order Haemosporidia and phylum Apicomplexia. There are currently 450 recognised species in this order. Many species of this order are undergoing reexamination of their taxonomy with DNA analysis. It seems likely that many of these species will be re assigned after these studies have been completed. For this reason the entire order is outlined here.
Notes:
The genera Plasmodium, Fallisia and Saurocytozoon all cause malaria in lizards. All are carried by Dipteria (roughly speaking the flies). Pigment is absent in the Garnia. Non pigmented gametocytes are typically the only forms found in Saurocytozoon: pigmented forms may be found in the leukocytes occasionally. Fallisia produce non pigmented asexual and gametocyte forms in leukocytes and thrombocytes.
# Subgenera
The full taxonomic name of a species includes the subgenus but this is often omitted. The full name indicates some features of the morphology and type of host species.
The only two species in the sub genus Laverania are P. falciparum and P. reichenowi.
Species infecting monkeys and apes (the higher primates) with the exceptions of P. falciparum and P. reichenowi are classified in the subgenus Plasmodium.
Parasites infecting other mammals including lower primates (lemurs and others) are classified in the subgenus Vinckeia.
The distinction between P. falciparum and P. reichenowi and the other species infecting higher primates was based on the morphological findings but have since been confirmed by DNA analysis. Vinckeia while previously considered to be something of a taxonomic 'rag bag' has been recently shown - perhaps rather surprisingly - to form a coherent grouping.
The remaining groupings here are based on the morphology of the parasites. Revisions to this system are likely to occur in the future as more species are subject to analysis of their DNA.
The four subgenera Giovannolaia, Haemamoeba, Huffia and Novyella were created by Corradetti et al for the known avian malarial species. A fifth - Bennettinia - was created in 1997 by Valkiunas. The relationships between the subgenera are the matter of current investigation. Martinsen et al 's recent (2006) paper outlines what is currently (2007) known.
P. juxtanucleare is currently (2007) the only known member of the subgenus Bennettinia.
Unlike the mammalian and bird malarias those affecting reptiles have been more difficult to classify. In 1966 Garnham classified those with large schizonts as Sauramoeba, those with small schizonts as Carinamoeba and the single then known species infecting snakes (Plasmodium wenyoni) as Ophidiella. He was aware of the arbitrariness of this system and that it might not prove to be biologically valid. Telford in 1988 used this scheme as the basis for the currently accepted (2007) system.
Classification criteria
Species in the subgenus Bennettinia have the following characteristics:
- Schizonts contain scant cytoplasm, are often round, do not exceed the size of the host nucleus and stick to it.
- Gametocytes while varying in shape tend to be round or oval, do not exceed the size of the nucleus and stick to it.
Species in the subgenus Giovanolaia have the following characteristics:
- Schizonts contain plentiful cytoplasm, are larger than the host cell nucleus and frequently displace it. They are found only in mature erythrocytes.
- Gametocytes are elongated.
- Exoerythrocytic schizogony occurs in the mononuclear phagocyte system.
Species in the subgenus Haemamoeba have the following characteristics:
- Mature schizonts are larger than the host cell nucleus and commonly displace it.
- Gametocytes are large, round, oval or irregular in shape and are substantially larger than the host nucleus.
Species in the subgenus Huffia have the following characteristics:
- Mature schizonts, while varying in shape and size, contain plentiful cytoplasm and are commonly found in immature erthryocytes.
- Gametocytes are elongated.
Species in the subgenus Novyella have the following characteristics:
- Mature schisonts are either smaller than or only slightly larger than the host nucleus. They contain scanty cytoplasm.
- Gametocytes are elongated. Sexual stages in this subgenus resemble those of Haemoproteus.
- Exoerythrocytic schizogony occurs in the mononuclear phagocyte system
Species in the subgenus Carinamoeba have the following characteristics:
- Infect lizards
- Schizonts normally give rise to less than 8 merozoites
Species in the subgenus Sauramoeba have the following characteristics:
- Infect lizards
- Schizonts normally give rise to more than 8 merozoites
Notes
- The erythrocytes of both reptiles and birds retain their nucleus, unlike those of mammals. The reason for the loss of the nucleus in mammalian erythocytes remains unknown.
- The presence of elongated gametocytes in several of the avian subgenera and in Laverania in addition to a number of clinical features suggested that these might be closely related. This is is no longer thought to be the case.
- Plasmodium falciparum (the cause of malignant tertian malaria)
- Plasmodium vivax (the most frequent cause of benign tertian malaria)
- Plasmodium ovale (the other, less frequent, cause of benign tertian malaria)
- Plasmodium malariae (the cause of benign quartan malaria)
- Plasmodium knowlesi
- Plasmodium brasilianum
- Plasmodium cynomolgi
- Plasmodium cynomolgi bastianellii
- Plasmodium inui
- Plasmodium rhodiani
- Plasmodium schweitzi
- Plasmodium semiovale
- Plasmodium simium
The first four listed here are the most common species that infect humans. With the use of the polymerase chain reaction additional species have been and are still being identified that infect humans.
One possible experimental infection has been reported with Plasmodium eylesi. Fever and low grade parasitemia were apparent at 15 days. The volunteer (Dr Bennett) had previously been infected by Plasmodium cynomolgi and the infection was not transferable to a gibbon (P. eylesi 's natural host) so this cannot be regarded as definitive evidence of its ability to infect humans. A second case has been reported that may have been a case of P. eylesi but the author was not certain of the infecting species.
A possible infection with Plasmodium tenue has been reported. This report described a case of malaria in a three year old black girl from Georgia, USA who had never been outside the US. She suffered from both P. falciparum and P. vivax malaria and while forms similar to those described for P. tenue were found in her blood even the author was skeptical about the validity of the diagnosis.
Confusingly Plasmodium tenue was proposed in the same year (1914) for a species found in birds. The human species is now considered to be likely to have been a misdiagnosis and the bird species is described on the Plasmodium tenue page.
Notes:
The only known host of P. falciparum are humans; neither is any other host currently known for P. malariae.
P. vivax will infect chimpanzees. Infection tends to be low grade but may be persistent and remain as source of parasites for humans for some time.
P. vivax is also known to infect orangutans.
Like P. vivax, P. ovale has been shown to be transmittable to chimpanzees. P. ovale has a unusual distribution pattern being found in Africa, the Philippines and New Guinea. In spite of its admittedly poor transmission to chimpanzees given its discontigous spread, it is suspected that P. ovale may in fact be a zooenosis with an as yet unidentified host. If this is actually the case, the host seems likely to be a primate.
The remaining species capable of infecting humans all have other primate hosts.
Plasmodium shortii and Plasmodium osmaniae are now considered to be junior synonyms of Plasmodium inui
Species no longer recognised as valid
Taxonomy in parasitology until the advent of DNA based methods has always been a problem and revisions in this area are continuing. A number of synonoms have been given for the species infecting humans that are no longer recognised as valid. Since perusal of the older literature may be confusing some of these are listed here...
The species that infect primates other than humans include: P. bouillize, P. brasilianum, P. bucki, P. cercopitheci,P. coatneyi, P. coulangesi, P. cynomolgi, P. eylesi, P. fieldi, P. foleyi, P. fragile, P. girardi, P. georgesi, P. gonderi, P. hylobati, P. inui, P. jefferyi, P. joyeuxi,P. knowlesi, P. lemuris, P. percygarnhami, P. petersi, P. reichenowi, P. rodhaini, P. sandoshami, P. semnopitheci, P. silvaticum, P. simiovale, P. simium, P. uilenbergi, P. vivax and P. youngei.
Host records - Most if not all Plasmodium species infect more than one host: the host records shown here should be regarded as being incomplete. | Plasmodium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Plasmodium is a genus of parasitic protozoa. Infection with this genus is known as malaria. The parasite always has two hosts in its life cycle: a mosquito vector and a vertebrate host. At least ten species infect humans. Other species infect other animals, including birds, reptiles and rodents.
# Taxonomy and host range
The genus Plasmodium was created in 1885 by Marchiafava and Celli and there are over 175 species currently recognized. New species continue to be described. [1]
The genus is currently (2006) in need of reorganization as it has been shown that parasites belonging to the genera Haemocystis and Hepatocystis appear to be closely related to Plasmodium. It is likely that other species such as Haemoproteus meleagridis will be included in this genus once it is revised.
Host range among the mammalian orders is non uniform. At least 29 species infect non human primates; rodents outside the tropical parts of Africa are rarely affected; a few species are known to infect bats, porcupines and squirrels; carnivores, insectivores and marsupials are not known to act as hosts.
In 1898 Ronald Ross demonstrated the existence of Plasmodium in the wall of the midgut and salivary glands of a Culex mosquito. For this discovery he won the Nobel Prize in 1902. However credit must also be given to the Italian professor Giovanni Battista Grassi, who showed that human malaria could only be transmitted by Anopheles mosquitoes. It is worth noting, however, that for some species the vector may not be a mosquito.
Mosquitoes of the genera Culex, Anopheles, Culiceta, Mansonia and Aedes may act as vectors. The currently known vectors for human malaria (> 100 species) all belong to the genus Anopheles. Bird malaria is commonly carried by species belonging to the genus Culex. Only female mosquitoes bite. Aside from blood both sexes live on nectar, but one or more blood meals are needed by the female for egg laying as the protein content of nectar is very low. The life cycle of Plasmodium was discovered by Ross who worked with species from the genus Culex.
The life cycle of Plasmodium is very complex. Sporozoites from the saliva of a biting female mosquito are transmitted to either the blood or the lymphatic system[2] of the recipient. The sporozoites then migrate to the liver and invade hepatocytes. This latent or dormant stage of the Plasmodium sporozoite in the liver is called the hypnozoite.
The development from the hepatic stages to the erythrocytic stages has until very recently been obscure. In 2006[3] it was shown that the parasite buds off the hepatocytes in merosomes containing hundreds or thousands of merozoites. These merosomes have been subsequently shown[4] to lodge in the pulmonary capilaries and to slowly disintergrate there over 48-72 hours releasing merozoites. Erythrocyte invasion is enhanced when blood flow is slow and the cells are tightly packed: both of these conditions are found in the alveolar capilaries.
Within the erythrocytes the merozoite grow first to a ring-shaped form and then to a larger trophozoite form. In the schizont stage, the parasite divides several times to produce new merozoites, which leave the red blood cells and travel within the bloodstream to invade new red blood cells. Most merozoites continue this replicative cycle, but some merozoites differentiate into male or female sexual forms (gametocytes) (also in the blood), which are taken up by the female mosquito.
In the mosquito's midgut, the gametocytes develop into gametes and fertilize each other, forming motile zygotes called ookinetes. The ookinetes penetrate and escape the midgut, then embed themselves onto the exterior of the gut membrane. Here they divide many times to produce large numbers of tiny elongated sporozoites. These sporozoites migrate to the salivary glands of the mosquito where they are injected into the blood of the next host the mosquito bites. The sporozoites move to the liver where they repeat the cycle.
Reactivation of the hypnozoites has been reported for up to 30 years after the initial infection in humans. The factors precipating this reactivation are not known. In the species Plasmodium malariae, Plasmodium ovale and Plasmodium vivax hypnozoites have been shown to occur. Reactivation does not occur in infections with Plasmodium falciparum. It is not known if hypnozoite reactivaction may occur with any of the remaining species that infect humans but this is presumed to be the case.
# Evolution
This life cycle is best understood in terms of its evolution.
The Apicomplexia - the phylum to which Plasmodium belongs - are thought to have originated within the Dinoflagellates - a large group of photosynthetic protozoa. It is currently thought that the ancestors of the Apicomplexia were originally prey organisms that evolved the ability to invade the intestinal cells and subsequently lost their photosynthetic ability. Some extant dinoflagelates, however, can invade the bodies of jellyfish and continue to photosynthesize, which is possible because jellyfish bodies are almost transparent. In other organisms with opaque bodies this ability would most likely rapidly be lost.
It is thought that Plasmodium evolved from a parasite spread by the orofaecal route which infected the intestinal wall. At some point this parasite evolved the ability to infect the liver. This pattern is seen in the genus Cryptosporidium to which Plasmodium is distantly related. At some later point this ancestor developed the ability to infect blood cells and to survive and infect mosquitoes. Once mosquito transmission was firmly established the previous orofecal route of transmission was lost.
Current (2007) theory suggests that the genera Plasmodium, Hepatocystis and Haemoproteus evolved from Leukocytozoon species. Parasites of the genus Leukocytozoan infect white blood cells (leukocytes), liver and spleen cells and are transmitted by 'black flies' (Simulium species) - a large genus of flies related to the mosquitoes.
Leukocytes, hepatocytes and most spleen cells actively phagocytose particulate matter making entry into the cell easier for the parasite. The mechanism of entry of Plasmodium species into erythrocytes is still very unclear taking as it does less than 30 seconds. It is not yet known if this mechanism evolved before mosquitoes became the main vectors for transmission of Plasmodium.
Plasmodium evolved about 130 million years ago. This period is coincidental with the rapid spread of the angiosperms (flowering plants). This expansion in the angiosperms is thought to be due to at least one genomic duplication event. It seems probable that the increase in the number of flowers led to an increase in the number of mosquitoes and their contact with vertebrates.
Mosquitoes evolved in what is now South America about 230 million years ago. There are over 3500 species recognised but to date their evolution has not been well worked out so a number of gaps in our knowledge of the evolution of Plasmodium remain.
Presently it seems probable that birds were the first group infected by Plasmodium followed by the reptiles - probably the lizards. At some point primates and rodents became infected. The remaining species infected outside these groups seem likely to be due to relatively recent events.
At the present time (2007) DNA sequences are available from fewer than sixty species and most of these are from species infecting either rodent or primate hosts. The evolution proposed here should be regarded as speculative and subject to revision as data becomes available.
# Reproduction
The pattern of alternation of sexual and asexual reproduction which may seem confusing at first is a very common pattern in parasitic species. The evolutionary advantages of this type of life cycle were recognised by Mendel.
Under favourable conditions asexual reproduction is superior to sexual as the parent is well adapted to its environment and its descendents share these genes. Transferring to a new host or in times of stress, sexual reproduction is generally superior as this produces a shuffling of genes which on average at a population level will produce individuals better adapted to the new environment.
# Molecular biology
All the species examined to date have 14 chromosomes, one mitochondrion and one plastid. The chromosomes vary from 500 kilobases to 3.5 megabases in length. It is presumed that this is the pattern throughout the genus.
The plastid unlike those found in algae is not photosynthetic. Its function is not known but there is some suggestive evidence that it may be involved in reproduction.
On a molecular level, the parasite damages red blood cells using plasmepsin enzymes - aspartic acid proteases which degrade hemoglobin.
# Diagnostic characteristics of the genus Plasmodium
- Forms gamonts in erythrocytes
- Merogony occurs in erythrocytes and in other tissues
- Hemozoin is present
- Vectors are either mosquitos or sandflies
- Vertebrate hosts include mammals, birds and reptiles
# Taxonomy
Plasmodium belongs to the family Plasmodiidae (Levine, 1988), order Haemosporidia and phylum Apicomplexia. There are currently 450 recognised species in this order. Many species of this order are undergoing reexamination of their taxonomy with DNA analysis. It seems likely that many of these species will be re assigned after these studies have been completed.[5][6] For this reason the entire order is outlined here.
Notes:
The genera Plasmodium, Fallisia and Saurocytozoon all cause malaria in lizards. All are carried by Dipteria (roughly speaking the flies). Pigment is absent in the Garnia. Non pigmented gametocytes are typically the only forms found in Saurocytozoon: pigmented forms may be found in the leukocytes occasionally. Fallisia produce non pigmented asexual and gametocyte forms in leukocytes and thrombocytes.
# Subgenera
The full taxonomic name of a species includes the subgenus but this is often omitted. The full name indicates some features of the morphology and type of host species.
The only two species in the sub genus Laverania are P. falciparum and P. reichenowi.
Species infecting monkeys and apes (the higher primates) with the exceptions of P. falciparum and P. reichenowi are classified in the subgenus Plasmodium.
Parasites infecting other mammals including lower primates (lemurs and others) are classified in the subgenus Vinckeia.
The distinction between P. falciparum and P. reichenowi and the other species infecting higher primates was based on the morphological findings but have since been confirmed by DNA analysis. Vinckeia while previously considered to be something of a taxonomic 'rag bag' has been recently shown - perhaps rather surprisingly - to form a coherent grouping.
The remaining groupings here are based on the morphology of the parasites. Revisions to this system are likely to occur in the future as more species are subject to analysis of their DNA.
The four subgenera Giovannolaia, Haemamoeba, Huffia and Novyella were created by Corradetti et al[7] for the known avian malarial species. A fifth - Bennettinia - was created in 1997 by Valkiunas.[8] The relationships between the subgenera are the matter of current investigation. Martinsen et al 's recent (2006) paper outlines what is currently (2007) known.[9]
P. juxtanucleare is currently (2007) the only known member of the subgenus Bennettinia.
Unlike the mammalian and bird malarias those affecting reptiles have been more difficult to classify. In 1966 Garnham classified those with large schizonts as Sauramoeba, those with small schizonts as Carinamoeba and the single then known species infecting snakes (Plasmodium wenyoni) as Ophidiella.[10] He was aware of the arbitrariness of this system and that it might not prove to be biologically valid. Telford in 1988 used this scheme as the basis for the currently accepted (2007) system.[11]
Classification criteria
Species in the subgenus Bennettinia have the following characteristics:
- Schizonts contain scant cytoplasm, are often round, do not exceed the size of the host nucleus and stick to it.
- Gametocytes while varying in shape tend to be round or oval, do not exceed the size of the nucleus and stick to it.
Species in the subgenus Giovanolaia have the following characteristics:
- Schizonts contain plentiful cytoplasm, are larger than the host cell nucleus and frequently displace it. They are found only in mature erythrocytes.
- Gametocytes are elongated.
- Exoerythrocytic schizogony occurs in the mononuclear phagocyte system.
Species in the subgenus Haemamoeba have the following characteristics:
- Mature schizonts are larger than the host cell nucleus and commonly displace it.
- Gametocytes are large, round, oval or irregular in shape and are substantially larger than the host nucleus.
Species in the subgenus Huffia have the following characteristics:
- Mature schizonts, while varying in shape and size, contain plentiful cytoplasm and are commonly found in immature erthryocytes.
- Gametocytes are elongated.
Species in the subgenus Novyella have the following characteristics:
- Mature schisonts are either smaller than or only slightly larger than the host nucleus. They contain scanty cytoplasm.
- Gametocytes are elongated. Sexual stages in this subgenus resemble those of Haemoproteus.
- Exoerythrocytic schizogony occurs in the mononuclear phagocyte system
Species in the subgenus Carinamoeba have the following characteristics:
- Infect lizards
- Schizonts normally give rise to less than 8 merozoites
Species in the subgenus Sauramoeba have the following characteristics:
- Infect lizards
- Schizonts normally give rise to more than 8 merozoites
Notes
- The erythrocytes of both reptiles and birds retain their nucleus, unlike those of mammals. The reason for the loss of the nucleus in mammalian erythocytes remains unknown.
- The presence of elongated gametocytes in several of the avian subgenera and in Laverania in addition to a number of clinical features suggested that these might be closely related. This is is no longer thought to be the case.
- Plasmodium falciparum (the cause of malignant tertian malaria)
- Plasmodium vivax (the most frequent cause of benign tertian malaria)
- Plasmodium ovale (the other, less frequent, cause of benign tertian malaria)
- Plasmodium malariae (the cause of benign quartan malaria)
- Plasmodium knowlesi
- Plasmodium brasilianum
- Plasmodium cynomolgi
- Plasmodium cynomolgi bastianellii
- Plasmodium inui
- Plasmodium rhodiani
- Plasmodium schweitzi
- Plasmodium semiovale
- Plasmodium simium
The first four listed here are the most common species that infect humans. With the use of the polymerase chain reaction additional species have been and are still being identified that infect humans.
One possible experimental infection has been reported with Plasmodium eylesi. Fever and low grade parasitemia were apparent at 15 days. The volunteer (Dr Bennett) had previously been infected by Plasmodium cynomolgi and the infection was not transferable to a gibbon (P. eylesi 's natural host) so this cannot be regarded as definitive evidence of its ability to infect humans. A second case has been reported that may have been a case of P. eylesi but the author was not certain of the infecting species.[12]
A possible infection with Plasmodium tenue has been reported. [13] This report described a case of malaria in a three year old black girl from Georgia, USA who had never been outside the US. She suffered from both P. falciparum and P. vivax malaria and while forms similar to those described for P. tenue were found in her blood even the author was skeptical about the validity of the diagnosis.
Confusingly Plasmodium tenue was proposed in the same year (1914) for a species found in birds. The human species is now considered to be likely to have been a misdiagnosis and the bird species is described on the Plasmodium tenue page.
Notes:
The only known host of P. falciparum are humans; neither is any other host currently known for P. malariae.
P. vivax will infect chimpanzees. Infection tends to be low grade but may be persistent and remain as source of parasites for humans for some time.
P. vivax is also known to infect orangutans.[14]
Like P. vivax, P. ovale has been shown to be transmittable to chimpanzees. P. ovale has a unusual distribution pattern being found in Africa, the Philippines and New Guinea. In spite of its admittedly poor transmission to chimpanzees given its discontigous spread, it is suspected that P. ovale may in fact be a zooenosis with an as yet unidentified host. If this is actually the case, the host seems likely to be a primate.
The remaining species capable of infecting humans all have other primate hosts.
Plasmodium shortii and Plasmodium osmaniae are now considered to be junior synonyms of Plasmodium inui
Species no longer recognised as valid
Taxonomy in parasitology until the advent of DNA based methods has always been a problem and revisions in this area are continuing. A number of synonoms have been given for the species infecting humans that are no longer recognised as valid.[15] Since perusal of the older literature may be confusing some of these are listed here...
The species that infect primates other than humans include: P. bouillize, P. brasilianum, P. bucki, P. cercopitheci,P. coatneyi, P. coulangesi, P. cynomolgi, P. eylesi, P. fieldi, P. foleyi, P. fragile, P. girardi, P. georgesi, P. gonderi, P. hylobati, P. inui, P. jefferyi, P. joyeuxi,P. knowlesi, P. lemuris, P. percygarnhami, P. petersi, P. reichenowi, P. rodhaini, P. sandoshami, P. semnopitheci, P. silvaticum, P. simiovale, P. simium, P. uilenbergi, P. vivax and P. youngei.
Host records - Most if not all Plasmodium species infect more than one host: the host records shown here should be regarded as being incomplete. | https://www.wikidoc.org/index.php/Hypnozoite | |
f4fea3092cfb6645cf54cdf4ba616f221c56bb16 | wikidoc | Hypocapnia | Hypocapnia
# Overview
Hypocapnia, sometimes incorrectly called acapnia, is a state of reduced carbon dioxide in the blood. Hypocapnia usually results from deep or rapid breathing, known as hyperventilation.
Even when severe, hypocapnia is normally well tolerated. However, hypocapnia causes cerebral vasoconstriction, leading to cerebral hypoxia and this can cause transient dizziness, visual disturbances, and anxiety. A low partial pressure of carbon dioxide in the blood also causes alkalosis (because CO2 is acidic in solution), leading to lowered plasma calcium ions and nerve and muscle excitability. This explains the other common symptoms of hyperventilation —pins and needles, muscle cramps and tetany in the extremities, especially hands and feet.
Hypocapnia is sometimes induced in the treatment of the medical emergencies, such as intracranial hypertension and hyperkalaemia.
Because the brain stem monitors the level of blood CO2 in blood to regulate breathing, hypocapnia can suppress breathing to the point of blackout from cerebral hypoxia. Self-induced hypocapnia through hyperventilation is the basis for the deadly schoolyard choking game. Deliberate hyperventilation has been unwisely used by underwater breath-hold divers to extend dive time but at the risk of shallow water blackout, which is a significant cause of drowning. | Hypocapnia
# Overview
Hypocapnia, sometimes incorrectly called acapnia, is a state of reduced carbon dioxide in the blood. Hypocapnia usually results from deep or rapid breathing, known as hyperventilation.
Even when severe, hypocapnia is normally well tolerated. However, hypocapnia causes cerebral vasoconstriction, leading to cerebral hypoxia and this can cause transient dizziness, visual disturbances, and anxiety. A low partial pressure of carbon dioxide in the blood also causes alkalosis (because CO2 is acidic in solution), leading to lowered plasma calcium ions and nerve and muscle excitability. This explains the other common symptoms of hyperventilation —pins and needles, muscle cramps and tetany in the extremities, especially hands and feet.
Hypocapnia is sometimes induced in the treatment of the medical emergencies, such as intracranial hypertension and hyperkalaemia.
Because the brain stem monitors the level of blood CO2 in blood to regulate breathing, hypocapnia can suppress breathing to the point of blackout from cerebral hypoxia. Self-induced hypocapnia through hyperventilation is the basis for the deadly schoolyard choking game. Deliberate hyperventilation has been unwisely used by underwater breath-hold divers to extend dive time but at the risk of shallow water blackout, which is a significant cause of drowning. | https://www.wikidoc.org/index.php/Hypocapnea | |
a6941e35e1f0775321ce3c77e0e4b8ec5043e81f | wikidoc | Hypodontia | Hypodontia
# Overview
In dentistry, hypodontia is the condition at which the patient has missing teeth as a result of their failure to develop. Hypodontia describes a situation where the patient is missing up to 6 teeth, excluding the 3rd molars. Missing third molars occur in 9-30% of population. In primary dentition the maxilla is more affected, with the condition usually involving the maxillary lateral incisor.
# Classification
The condition of missing over 6 teeth, excluding 3rd molars or wisdom teeth, is called oligodontia. The condition for missing all teeth, either primary and/or permanent), is called anodontia. A similar condition is hyperdontia, in which there are more than the usual number of teeth.
Many other terms to describe a reduction in number of teeth appear in the literature: oligodontia, anodontia, aplasia of teeth, congenitally missing teeth, absence of teeth, agenesis of teeth and lack of teeth.
# Pathophysiology
The cause of isolated missing teeth remains unclear, but the condition is believed to be associated with genetic or environmental factors during dental development. Missing teeth have been reported in association with increased maternal age, low birth weight, multiple births and rubella virus infection during embryonic life.
There is a possible correlation between tooth agenesis and innervation. A relationship was also postulated between abnormalities of the brainstem and the presence of agenesis.
Hypodontia is often familial, and can also be associated with genetic disorders such as ectodermal dysplasia or Down syndrome. Hypodontia can also been seen in people with cleft lip and palate.
Among the possible causes are mentioned genetic, hormonal, environmental and infectious.
Etiology due to hormonal defects: idiopathic hypoparathyroidism and pseudohypoparathyroidism. Exists the possibility that this defect depends on a moniliasis (candidiasis, candida endocrinopathy syndrome).
Environmental causes involving exposure to PCBs (ex.dioxin), radiation, anticancer chemotherapeutic agents, allergy and toxic epidermal necrolysis after drug.
Infectious causes of hypodontia: rubella, candida.
The Journal of the American Dental Association published preliminary data suggesting a statistical association between hypodontia of the permanent teeth and epithelial ovarian cancer (EOC). The study shows that women with EOC are 8.1 times more likely to have hypodontia than are women without EOC. The suggestion therefore is that hypodontia can serve as a "marker" for potential risk of EOC in women.
Also the increased frequency of hypodontia in twins and low birth weight in twins with hypodontia suggests that environmental factors during perinatal are responsible hypodontia.
## Genetics
Genetic causes also involve the genes MSX1 and PAX9. But MSX1 and MSX2 are excluded as candidate genes for hypodontia.
Genetic associations for selective tooth agenesis ("STHAG") include:
==Epidemiology and Demographics
In caucasians, the most common missing teeth are the wisdom teeth (25-35%), the upper lateral incisors (2%) the lower second premolars (3%), or the upper second premolar, with a 4:1 female to male ratio. The prevalence of missing primary teeth is found at 0.1-0.9%, with a 1:1 male to female ratio. Excluding the third molars, missing permanent dentition accounts for 3.5-6.5%. Similar trends of missing teeth can be seen in approximately 3-10% of orthodontic patients.
30-50% of people with missing primary teeth will have missing permanent teeth, as well. | Hypodontia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In dentistry, hypodontia is the condition at which the patient has missing teeth as a result of their failure to develop. Hypodontia describes a situation where the patient is missing up to 6 teeth, excluding the 3rd molars. Missing third molars occur in 9-30% of population. In primary dentition the maxilla is more affected, with the condition usually involving the maxillary lateral incisor.
# Classification
The condition of missing over 6 teeth, excluding 3rd molars or wisdom teeth, is called oligodontia. The condition for missing all teeth, either primary and/or permanent), is called anodontia. A similar condition is hyperdontia, in which there are more than the usual number of teeth.
Many other terms to describe a reduction in number of teeth appear in the literature: oligodontia, anodontia, aplasia of teeth, congenitally missing teeth, absence of teeth, agenesis of teeth and lack of teeth.[1]
# Pathophysiology
The cause of isolated missing teeth remains unclear, but the condition is believed to be associated with genetic or environmental factors during dental development. Missing teeth have been reported in association with increased maternal age, low birth weight, multiple births and rubella virus infection during embryonic life.[citation needed]
There is a possible correlation between tooth agenesis and innervation.[2][3][4][5][6] A relationship was also postulated between abnormalities of the brainstem and the presence of agenesis.[7]
Hypodontia is often familial, and can also be associated with genetic disorders such as ectodermal dysplasia or Down syndrome. Hypodontia can also been seen in people with cleft lip and palate.
Among the possible causes are mentioned genetic, hormonal, environmental and infectious.
Etiology due to hormonal defects: idiopathic hypoparathyroidism and pseudohypoparathyroidism.[8][9] Exists the possibility that this defect depends on a moniliasis (candidiasis, candida endocrinopathy syndrome).[8][10][11]
Environmental causes involving exposure to PCBs (ex.dioxin),[12][13][14] radiation,[15][16][17] anticancer chemotherapeutic agents,[18] allergy [19] and toxic epidermal necrolysis after drug.[20]
Infectious causes of hypodontia: rubella,[21] candida.[22]
The Journal of the American Dental Association published preliminary data suggesting a statistical association between hypodontia of the permanent teeth and epithelial ovarian cancer (EOC). The study shows that women with EOC are 8.1 times more likely to have hypodontia than are women without EOC. The suggestion therefore is that hypodontia can serve as a "marker" for potential risk of EOC in women.[23]
Also the increased frequency of hypodontia in twins and low birth weight in twins with hypodontia suggests that environmental factors during perinatal are responsible hypodontia.[24][25]
## Genetics
Genetic causes also involve the genes MSX1 and PAX9.[26][27] But MSX1 and MSX2 are excluded as candidate genes for hypodontia.[28]
Genetic associations for selective tooth agenesis ("STHAG") include:
==Epidemiology and Demographics
In caucasians, the most common missing teeth are the wisdom teeth (25-35%), the upper lateral incisors (2%) the lower second premolars (3%), or the upper second premolar, with a 4:1 female to male ratio. The prevalence of missing primary teeth is found at 0.1-0.9%, with a 1:1 male to female ratio. Excluding the third molars, missing permanent dentition accounts for 3.5-6.5%. Similar trends of missing teeth can be seen in approximately 3-10% of orthodontic patients.[29] [30]
30-50% of people with missing primary teeth will have missing permanent teeth, as well. | https://www.wikidoc.org/index.php/Hypodontia | |
5c183351f3c15914261186c831263dc953eb2f19 | wikidoc | Hypoplasia | Hypoplasia
# Overview
Hypoplasia is an incomplete or arrested development of an organ or a part . It is descriptive of many medical conditions such as:
- Underdeveloped breasts during puberty.
- Underdeveloped testes in Klinefelter's syndrome.
- Underdeveloped thymus in DiGeorge syndrome.
- Underdeveloped labia majora in popliteal pterygium syndrome.
- Underdeveloped cerebellum caused by mutation in the Reelin gene.
- Underdeveloped tooth caused by oral pathology, such as Turner's hypoplasia.
- Underdeveloped chambers of the heart in hypoplastic left heart syndrome and hypoplastic right heart syndrome
- Underdeveloped optic nerve in optic nerve hypoplasia
- Underdeveloped sacrum in sacral agenesis
- Underdeveloped facial muscle in asymmetric crying facies
# Related Chapters
- Aplasia
- Atrophy. | Hypoplasia
# Overview
Hypoplasia is an incomplete or arrested development of an organ or a part [1]. It is descriptive of many medical conditions such as:
- Underdeveloped breasts during puberty.
- Underdeveloped testes in Klinefelter's syndrome.
- Underdeveloped thymus in DiGeorge syndrome.
- Underdeveloped labia majora in popliteal pterygium syndrome.
- Underdeveloped cerebellum caused by mutation in the Reelin gene.
- Underdeveloped tooth caused by oral pathology, such as Turner's hypoplasia.
- Underdeveloped chambers of the heart in hypoplastic left heart syndrome and hypoplastic right heart syndrome
- Underdeveloped optic nerve in optic nerve hypoplasia
- Underdeveloped sacrum in sacral agenesis
- Underdeveloped facial muscle in asymmetric crying facies
# Related Chapters
- Aplasia
- Atrophy.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Hypoplasia | |
1541bb5532e7c6fd885ccd820f6606a8b6f04a13 | wikidoc | Hypothesis | Hypothesis
# Overview
A hypothesis (from Greek Template:Polytonic) consists either of a suggested explanation for a phenomenon or of a reasoned proposal suggesting a possible correlation between multiple phenomena. The term derives from the Greek, hypotithenai meaning "to put under" or "to suppose." The scientific method requires that one can test a scientific hypothesis. Scientists generally base such hypotheses on previous observations or on extensions of scientific theories.
# Usage
In early usage, scholars often referred to a clever idea or to a convenient mathematical approach that simplified cumbersome calculations as a hypothesis; when used this way, the word did not necessarily have any specific meaning. Cardinal Bellarmine gave a famous example of the older sense of the word in the warning issued to Galileo in the early 17th century: that he must not treat the motion of the Earth as a reality, but merely as a hypothesis.
In common usage in the 21st century, a hypothesis refers to a provisional idea whose merit needs evaluation. For proper evaluation, the framer of a hypothesis needs to define specifics in operational terms. A hypothesis requires more work by the researcher in order to either confirm or disprove it. In due course, a confirmed hypothesis may become part of a theory or occasionally may grow to become a theory itself. Normally, scientific hypotheses have the form of a mathematical model. Sometimes, but not always, one can also formulate them as existential statements, stating that some particular instance of the phenomenon under examination has some characteristic and causal explanations, which have the general form of universal statements, stating that every instance of the phenomenon has a particular characteristic.
Any useful hypothesis will enable predictions by reasoning (including deductive reasoning). It might predict the outcome of an experiment in a laboratory setting or the observation of a phenomenon in nature. The prediction may also invoke statistics and only talk about probabilities. Karl Popper, following others, has argued that a hypothesis must be falsifiable, and that one cannot regard a proposition or theory as scientific if it does not admit the possibility of being shown false. To meet this additional criterion, it must at least in principle be possible to make an observation that would disprove the proposition as false, even if one has not actually (yet) made that observation. A falsifiable hypothesis can greatly simplify the process of testing to determine whether the hypothesis has instances in which it is false. The scientific method involves experimentation on the basis of falsifiable hypotheses in order to answer questions and explore observations.
In framing a hypothesis, the investigator must not currently know the outcome of a potentially falsifying test or that it remains reasonably under continuing investigation. Only in such cases does the experiment, test or study potentially increase the probability of showing the truth of a hypothesis. If the researcher already knows the outcome, it counts as a "consequence" — and the researcher should have already considered this while formulating the hypothesis. If one cannot assess the predictions by observation or by experience, the hypothesis classes as not yet useful, and must wait for others who might come afterward to make possible the needed observations. For example, a new technology or theory might make the necessary experiments feasible.
In the United States of America, teachers of science in primary schools have often simplified the meaning of the term "hypothesis" by describing a hypothesis as "an educated guess". Overemphasizing this aspect fails to convey the explanatory or predictive quality of scientific hypotheses. To define a hypothesis as "an educated guess" resembles describing a tricycle is a "vehicle with three". The definition omits the concept's most important and characteristic feature: the purpose of hypotheses. People generate hypotheses as early attempts to explain patterns observed in nature or to predict the outcomes of experiments. For example, in science, one could correctly call the following statement a hypothesis: identical twins can have different personalities because the environment influences personality. In contrast, although one might have informed one's self about the qualifications of various political candidates, making an educated guess about the outcome of an election would not qualify as a scientific hypothesis: the guess lacks an underpinning generic explanation.
# Types of hypothesis
A proposition may take the form of asserting a causal relationship (such as "A causes B"). A proposition often (but not necessarily) involves an assertion of causation. For example, if a particular independent variable changes, then a certain dependent variable also changes. This formulation, also known as an "If and Then" statement, applies whether or not a proposition asserts a direct cause-and-effect relationship.
A hypothesis about possible correlation does not stipulate the cause and effect per se, only stating that "A is related to B". Investigators may have more difficulty in verifying causal relationships than other correlations, because quite commonly intervening variables also become involved, possibly giving rise to the appearance of a possibly direct cause-and-effect relationship, but which (upon further investigation) turn out to have some other, more direct causal factor not mentioned in the proposition. Also, a mere observation of a change in one variable, when correlated with a change in another variable, can actually mistake the effect for the cause, and vice-versa (i.e., potentially get the hypothesized cause and effect backwards).
Empirical hypotheses that experimenters have repeatedly verified may become sufficiently dependable that, at some point in time, they become considered as "proven". Some people may succumb to the temptation to term such hypotheses laws, but they would do so mistakenly, since by definition a hypothesis explains and a law describes (for example, a law can state: "Matter can neither be created or destroyed, only changed in form"). More accurately, one could refer to repeatedly verified hypotheses simply as "adequately verified", or as "dependable".
Statistics features a rather more general concept of a hypothesis: this involves making assertions about the probability distributions or likelihoods of events.
Statisticians use two kinds of hypothesis: first, the null hypothesis or H0; secondly, the alternative hypothesis or H1. To give the simplest non-trivial example, one might formulate two hypotheses about tossing a coin:
- H0: coin-tossing operates "fairly" (equally likely to fall "Heads" or "Tails")
- H1: coin-tossing operates in a biased manner to give a 90% probability of falling "Heads"
No finite sequence of results could utterly falsify either hypothesis. However, various statistical approaches (such as Bayesian statistics and classical statistics (i.e. t-tests)) can quantify the strong intuition that H1 appears much less likely than H0 if, in 1,000 tosses, 495 came out "Heads" — and much more likely if 895 came out "Heads". In more complex sciences, researchers generally evaluate experiments statistically rather than as simple verifications or falsifications.
# Evaluating hypotheses
The hypothetico-deductive method demands falsifiable hypotheses, framed in such a manner that the scientific community can prove them false (usually by observation). (Note that confirming (or failing to falsify) a hypothesis does not necessarily prove that hypothesis: the hypothesis remains provisional.)
For example: someone who enters a new country and observes only white sheep might form the hypothesis that all sheep in that country are white. It can be considered a hypothesis, as it is falsifiable. Anyone could falsify the hypothesis by observing a single black sheep. Provided that the experimental uncertainties remain small (for example, provided that one can fairly reliably distinguish the observed black sheep from (say) a goat), and provided that the experimenter has correctly interpreted the statement of the hypothesis (for example, does the meaning of "sheep" include rams?), finding a black sheep falsifies the "white sheep only" hypothesis. However, one cannot consider failure to find non-white sheep as proof that no non-white sheep exist.
# Scientific hypothesis
People refer to a trial solution to a problem as a hypothesis — often called an "educated guess" — because it provides a suggested solution based on the evidence. Experimenters may test and reject several hypotheses before solving the problem.
According to Schick and Vaughn,
researchers weighing up alternative hypotheses may take into consideration:
- Testability (compare falsifiability as discussed above)
- Simplicity (as in the application of "Occam's Razor", discouraging the postulation of excessive numbers of entities
- Scope - the apparent application of the hypothesis to multiple cases of phenomena
- Fruitfulness - the prospect that a hypothesis may explain further phenomena in the future
- Conservatism - the degree of "fit" with existing recognised knowledge-systems | Hypothesis
# Overview
A hypothesis (from Greek Template:Polytonic) consists either of a suggested explanation for a phenomenon or of a reasoned proposal suggesting a possible correlation between multiple phenomena. The term derives from the Greek, hypotithenai meaning "to put under" or "to suppose." The scientific method requires that one can test a scientific hypothesis. Scientists generally base such hypotheses on previous observations or on extensions of scientific theories.
# Usage
In early usage, scholars often referred to a clever idea or to a convenient mathematical approach that simplified cumbersome calculations as a hypothesis; when used this way, the word did not necessarily have any specific meaning. Cardinal Bellarmine gave a famous example of the older sense of the word in the warning issued to Galileo in the early 17th century: that he must not treat the motion of the Earth as a reality, but merely as a hypothesis.
In common usage in the 21st century, a hypothesis refers to a provisional idea whose merit needs evaluation. For proper evaluation, the framer of a hypothesis needs to define specifics in operational terms. A hypothesis requires more work by the researcher in order to either confirm or disprove it. In due course, a confirmed hypothesis may become part of a theory or occasionally may grow to become a theory itself. Normally, scientific hypotheses have the form of a mathematical model. Sometimes, but not always, one can also formulate them as existential statements, stating that some particular instance of the phenomenon under examination has some characteristic and causal explanations, which have the general form of universal statements, stating that every instance of the phenomenon has a particular characteristic.
Any useful hypothesis will enable predictions by reasoning (including deductive reasoning). It might predict the outcome of an experiment in a laboratory setting or the observation of a phenomenon in nature. The prediction may also invoke statistics and only talk about probabilities. Karl Popper, following others, has argued that a hypothesis must be falsifiable, and that one cannot regard a proposition or theory as scientific if it does not admit the possibility of being shown false. To meet this additional criterion, it must at least in principle be possible to make an observation that would disprove the proposition as false, even if one has not actually (yet) made that observation. A falsifiable hypothesis can greatly simplify the process of testing to determine whether the hypothesis has instances in which it is false. The scientific method involves experimentation on the basis of falsifiable hypotheses in order to answer questions and explore observations.
In framing a hypothesis, the investigator must not currently know the outcome of a potentially falsifying test or that it remains reasonably under continuing investigation. Only in such cases does the experiment, test or study potentially increase the probability of showing the truth of a hypothesis. If the researcher already knows the outcome, it counts as a "consequence" — and the researcher should have already considered this while formulating the hypothesis. If one cannot assess the predictions by observation or by experience, the hypothesis classes as not yet useful, and must wait for others who might come afterward to make possible the needed observations. For example, a new technology or theory might make the necessary experiments feasible.
In the United States of America, teachers of science in primary schools have often simplified the meaning of the term "hypothesis" by describing a hypothesis as "an educated guess". Overemphasizing this aspect fails to convey the explanatory or predictive quality of scientific hypotheses. To define a hypothesis as "an educated guess" resembles describing a tricycle is a "vehicle with three". The definition omits the concept's most important and characteristic feature: the purpose of hypotheses. People generate hypotheses as early attempts to explain patterns observed in nature or to predict the outcomes of experiments. For example, in science, one could correctly call the following statement a hypothesis: identical twins can have different personalities because the environment influences personality. In contrast, although one might have informed one's self about the qualifications of various political candidates, making an educated guess about the outcome of an election would not qualify as a scientific hypothesis: the guess lacks an underpinning generic explanation.
# Types of hypothesis
A proposition may take the form of asserting a causal relationship (such as "A causes B"). A proposition often (but not necessarily) involves an assertion of causation. For example, if a particular independent variable changes, then a certain dependent variable also changes. This formulation, also known as an "If and Then" statement, applies whether or not a proposition asserts a direct cause-and-effect relationship.[1]
A hypothesis about possible correlation does not stipulate the cause and effect per se, only stating that "A is related to B". Investigators may have more difficulty in verifying causal relationships than other correlations, because quite commonly intervening variables also become involved, possibly giving rise to the appearance of a possibly direct cause-and-effect relationship, but which (upon further investigation) turn out to have some other, more direct causal factor not mentioned in the proposition. Also, a mere observation of a change in one variable, when correlated with a change in another variable, can actually mistake the effect for the cause, and vice-versa (i.e., potentially get the hypothesized cause and effect backwards).
Empirical hypotheses that experimenters have repeatedly verified may become sufficiently dependable that, at some point in time, they become considered as "proven". Some people may succumb to the temptation to term such hypotheses laws, but they would do so mistakenly, since by definition a hypothesis explains and a law describes (for example, a law can state: "Matter can neither be created or destroyed, only changed in form"). More accurately, one could refer to repeatedly verified hypotheses simply as "adequately verified", or as "dependable".
Statistics features a rather more general concept of a hypothesis: this involves making assertions about the probability distributions or likelihoods of events.
Statisticians use two kinds of hypothesis: first, the null hypothesis or H0; secondly, the alternative hypothesis or H1. To give the simplest non-trivial example, one might formulate two hypotheses about tossing a coin:
- H0: coin-tossing operates "fairly" (equally likely to fall "Heads" or "Tails")
- H1: coin-tossing operates in a biased manner to give a 90% probability of falling "Heads"
No finite sequence of results could utterly falsify either hypothesis. However, various statistical approaches (such as Bayesian statistics and classical statistics (i.e. t-tests)) can quantify the strong intuition that H1 appears much less likely than H0 if, in 1,000 tosses, 495 came out "Heads" — and much more likely if 895 came out "Heads". In more complex sciences, researchers generally evaluate experiments statistically rather than as simple verifications or falsifications.
# Evaluating hypotheses
The hypothetico-deductive method demands falsifiable hypotheses, framed in such a manner that the scientific community can prove them false (usually by observation). (Note that confirming (or failing to falsify) a hypothesis does not necessarily prove that hypothesis: the hypothesis remains provisional.)
For example: someone who enters a new country and observes only white sheep might form the hypothesis that all sheep in that country are white. It can be considered a hypothesis, as it is falsifiable. Anyone could falsify the hypothesis by observing a single black sheep. Provided that the experimental uncertainties remain small (for example, provided that one can fairly reliably distinguish the observed black sheep from (say) a goat), and provided that the experimenter has correctly interpreted the statement of the hypothesis (for example, does the meaning of "sheep" include rams?), finding a black sheep falsifies the "white sheep only" hypothesis. However, one cannot consider failure to find non-white sheep as proof that no non-white sheep exist.
# Scientific hypothesis
People refer to a trial solution to a problem as a hypothesis — often called an "educated guess" — because it provides a suggested solution based on the evidence. Experimenters may test and reject several hypotheses before solving the problem.
According to Schick and Vaughn,[2]
researchers weighing up alternative hypotheses may take into consideration:
- Testability (compare falsifiability as discussed above)
- Simplicity (as in the application of "Occam's Razor", discouraging the postulation of excessive numbers of entities
- Scope - the apparent application of the hypothesis to multiple cases of phenomena
- Fruitfulness - the prospect that a hypothesis may explain further phenomena in the future
- Conservatism - the degree of "fit" with existing recognised knowledge-systems | https://www.wikidoc.org/index.php/Hypothesis | |
196867756cd238026b7a0191bfe1b7daa6ee00cb | wikidoc | Hyracoidea | Hyracoidea
A hyrax (from Greek Template:Polytonic 'shrewmouse'; Afrikaans: klipdassie, from Dutch: klipdas 'rockbadger') is any of four species of fairly small, thickset, herbivorous mammals in the order Hyracoidea. They live in Africa and the Middle East.
Hyraxes are well-furred rotund creatures with a mere stump for a tail. They are about the size of a Corgi; most measure between about 30 and 70 cm long and weigh between 2 and 5 kg. From a distance, a hyrax could be mistaken for a very well-fed rabbit or guinea pig.
# Characteristics
Hyraxes retain a number of early mammal characteristics; in particular they have poorly developed internal temperature regulation (which they deal with by huddling together for warmth, and by basking in the sun like reptiles). Unlike other browsing and grazing animals, they do not use the incisors at the front of the jaw for slicing off leaves and grass, and use the molar teeth at the side of the jaw instead. The incisors are nonetheless large, and grow continuously through life, in a similar manner to those of rodents. There is a short diastema between the incisors and the cheek teeth. The dental formula for hyraxes is:Template:Dentition2
Unlike the even-toed ungulates and some of the macropods, hyraxes do not chew cud to help extract nutrients from coarse, low-grade leaves and grasses. They do, however, have complex, multi-chambered stomachs which allow symbiotic bacteria to break down tough plant materials, and their overall ability to digest fibre is similar to that of the ungulates.
Hyraxes inhabit rocky terrain across sub-Saharan Africa. Their feet have rubbery pads with numerous sweat glands, which help the animal maintain its grip when moving fast up steep rocky surfaces. They also have efficient kidneys, retaining water so that they can survive in arid environments.
Female hyraxes give birth to up to four young after a gestation period of between seven and eight months, depending on the species. The young are weaned at one to five months of age, and reach sexual maturity at sixteen to seventeen months.
Hyraxes live in small family groups, dominated by a single male who aggressively defends the territory from rivals. Where there is abundant living space, the male may dominate multiple groups of females, each with their own range. The remaining males live solitary lives, often on the periphery of areas controlled by larger males, and mate only with younger females
# Historical accounts
Early Phoenician navigators mistook the rabbits of the Iberian Peninsula for hyraxes (Hebrew Shaphan); hence they named it I-Shapan-im, meaning "land of the hyraxes", which possibly became the Latin word "Hispania", the root of Spain's modern Spanish name España and the English name Spain.
The word "rabbit, or "hare" was used instead of "hyrax" many times in some earlier English Bible translations. European translators of those times had no knowledge of the hyrax (Hebrew שָּׁפָן Shaphan), and therefore no name for them. There are references to hyraxes in the Old Testament which describe hyraxes and rabbits as cud-chewing animals, but the Hebrew phrase means literally, "raising up what has been swallowed." and they are not true cud chewers in the modern sense of the term, but rather coprophages. After eating, they ferment and partially digest their food; their cecum plays a similar role in this process to a cow's rumen. After passing this partially-digested food, they re-ingest it and complete the digestive process. Once digestion is complete, they pass feces of a different texture which they do not re-ingest.
# Evolution
Hyraxes are sometimes described as being the closest living relative to the elephant. This is because they may share an ancestor in the distant past when hyraxes were larger and more diverse. However, the details of their relationship remain open to debate.
All modern hyraxes are members of the family Procaviidae (the only living family within the Hyracoidea) and are found only in Africa and the Middle East. In the past, however, hyraxes were more diverse and widespread. The order first appears in the fossil record over 40 million years ago, and for many millions of years hyraxes were the primary terrestrial herbivore in Africa, just as odd-toed ungulates were in the Americas. There were many different species, the largest of them about the weight of a small horse, the smallest the size of a mouse. During the Miocene, however, competition from the newly-developed bovids—very efficient grazers and browsers—pushed the hyraxes out of the prime territory and into marginal niches. Nevertheless, the order remained widespread, diverse and successful as late as the end of the Pliocene (about two million years ago) with representatives throughout most of Africa, Europe and Asia.
The descendants of the giant hyracoids evolved in different ways. Some became smaller, and gave rise to the modern hyrax family. Others appear to have taken to the water (perhaps like the modern capybara), and ultimately gave rise to the elephant family, and perhaps also the Sirenians (dugongs and manatees). DNA evidence supports this hypothesis, and the small modern hyraxes share numerous features with elephants, such as toenails, excellent hearing, sensitive pads on their feet, small tusks, good memory, high brain functions compared to other similar mammals, and the shape of some of their bones.
Not all scientists support the proposal that hyraxes are the closest living relative of the elephant. Recent morphological and molecular based classifications reveal the Sirenians to be the closest living relatives of elephants, while hyraxes are closely related but form an outgroup to the assemblage of elephants, sirenians, and extinct orders like Embrithopoda and Desmostylia..
## List of extinct species
- Pliohyracidae
Geniohyinae
Seggeurius
Geniohyus
Saghatheriinae
Microhyrax
Meroehyrax
Selenohyrax
Bunohyrax
Pachyhyrax
Megalohyrax
Saghatherium
Thyrohyrax
Titanohyracinae
Antilohyrax
Titanohyrax
Pliohyracinae
Sogdohyrax
Kvabebihyrax
Prohyrax
Parapliohyrax
Pliohyrax
Postschizotherium
- Geniohyinae
Seggeurius
Geniohyus
- Seggeurius
- Geniohyus
- Saghatheriinae
Microhyrax
Meroehyrax
Selenohyrax
Bunohyrax
Pachyhyrax
Megalohyrax
Saghatherium
Thyrohyrax
- Microhyrax
- Meroehyrax
- Selenohyrax
- Bunohyrax
- Pachyhyrax
- Megalohyrax
- Saghatherium
- Thyrohyrax
- Titanohyracinae
Antilohyrax
Titanohyrax
- Antilohyrax
- Titanohyrax
- Pliohyracinae
Sogdohyrax
Kvabebihyrax
Prohyrax
Parapliohyrax
Pliohyrax
Postschizotherium
- Sogdohyrax
- Kvabebihyrax
- Prohyrax
- Parapliohyrax
- Pliohyrax
- Postschizotherium
- Procaviidae
Procaviinae
Gigantohyrax
Procavia (Cape Hyrax)
Procavia antigua
Procavia transvaalensis
- Procaviinae
Gigantohyrax
Procavia (Cape Hyrax)
Procavia antigua
Procavia transvaalensis
- Gigantohyrax
- Procavia (Cape Hyrax)
Procavia antigua
Procavia transvaalensis
- Procavia antigua
- Procavia transvaalensis
# Living species
Scientists have recently reduced the number of distinct species of hyrax recognized. As recently as 1995 there were eleven or more recognized species; only four are recognized today. The remaining species are regarded as subspecies of the remaining four. There are over 50 recognized subspecies and species, many of which are considered highly endangered.
- ORDER HYRACOIDEA
Family Procaviidae
Genus Dendrohyrax
Southern Tree Hyrax, Dendrohyrax arboreus
Western Tree Hyrax, Dendrohyrax dorsalis
Genus Heterohyrax
Yellow-spotted Rock Hyrax, Heterohyrax brucei
Genus Procavia
Cape Hyrax, Procavia capensis
- Family Procaviidae
Genus Dendrohyrax
Southern Tree Hyrax, Dendrohyrax arboreus
Western Tree Hyrax, Dendrohyrax dorsalis
Genus Heterohyrax
Yellow-spotted Rock Hyrax, Heterohyrax brucei
Genus Procavia
Cape Hyrax, Procavia capensis
- Genus Dendrohyrax
Southern Tree Hyrax, Dendrohyrax arboreus
Western Tree Hyrax, Dendrohyrax dorsalis
- Southern Tree Hyrax, Dendrohyrax arboreus
- Western Tree Hyrax, Dendrohyrax dorsalis
- Genus Heterohyrax
Yellow-spotted Rock Hyrax, Heterohyrax brucei
- Yellow-spotted Rock Hyrax, Heterohyrax brucei
- Genus Procavia
Cape Hyrax, Procavia capensis
- Cape Hyrax, Procavia capensis | Hyracoidea
A hyrax (from Greek Template:Polytonic 'shrewmouse'; Afrikaans: klipdassie, from Dutch: klipdas 'rockbadger') is any of four species of fairly small, thickset, herbivorous mammals in the order Hyracoidea. They live in Africa and the Middle East.
Hyraxes are well-furred rotund creatures with a mere stump for a tail. They are about the size of a Corgi; most measure between about 30 and 70 cm long and weigh between 2 and 5 kg. From a distance, a hyrax could be mistaken for a very well-fed rabbit or guinea pig.
# Characteristics
Hyraxes retain a number of early mammal characteristics; in particular they have poorly developed internal temperature regulation (which they deal with by huddling together for warmth, and by basking in the sun like reptiles). Unlike other browsing and grazing animals, they do not use the incisors at the front of the jaw for slicing off leaves and grass, and use the molar teeth at the side of the jaw instead. The incisors are nonetheless large, and grow continuously through life, in a similar manner to those of rodents. There is a short diastema between the incisors and the cheek teeth. The dental formula for hyraxes is:Template:Dentition2
Unlike the even-toed ungulates and some of the macropods, hyraxes do not chew cud to help extract nutrients from coarse, low-grade leaves and grasses. They do, however, have complex, multi-chambered stomachs which allow symbiotic bacteria to break down tough plant materials, and their overall ability to digest fibre is similar to that of the ungulates.
Hyraxes inhabit rocky terrain across sub-Saharan Africa. Their feet have rubbery pads with numerous sweat glands, which help the animal maintain its grip when moving fast up steep rocky surfaces. They also have efficient kidneys, retaining water so that they can survive in arid environments.
Female hyraxes give birth to up to four young after a gestation period of between seven and eight months, depending on the species. The young are weaned at one to five months of age, and reach sexual maturity at sixteen to seventeen months.
Hyraxes live in small family groups, dominated by a single male who aggressively defends the territory from rivals. Where there is abundant living space, the male may dominate multiple groups of females, each with their own range. The remaining males live solitary lives, often on the periphery of areas controlled by larger males, and mate only with younger females[1]
.
# Historical accounts
Early Phoenician navigators mistook the rabbits of the Iberian Peninsula for hyraxes (Hebrew Shaphan); hence they named it I-Shapan-im, meaning "land of the hyraxes", which possibly became the Latin word "Hispania", the root of Spain's modern Spanish name España and the English name Spain.[citation needed]
The word "rabbit, or "hare" was used instead of "hyrax" many times in some earlier English Bible translations. European translators of those times had no knowledge of the hyrax (Hebrew שָּׁפָן Shaphan[2]), and therefore no name for them. There are references to hyraxes in the Old Testament[3] which describe hyraxes and rabbits as cud-chewing animals, but the Hebrew phrase means literally, "raising up what has been swallowed."[4] and they are not true cud chewers in the modern sense of the term, but rather coprophages. After eating, they ferment and partially digest their food; their cecum plays a similar role in this process to a cow's rumen. After passing this partially-digested food, they re-ingest it and complete the digestive process. Once digestion is complete, they pass feces of a different texture which they do not re-ingest.
# Evolution
Hyraxes are sometimes described as being the closest living relative to the elephant. This is because they may share an ancestor in the distant past when hyraxes were larger and more diverse. However, the details of their relationship remain open to debate.
All modern hyraxes are members of the family Procaviidae (the only living family within the Hyracoidea) and are found only in Africa and the Middle East. In the past, however, hyraxes were more diverse and widespread. The order first appears in the fossil record over 40 million years ago, and for many millions of years hyraxes were the primary terrestrial herbivore in Africa, just as odd-toed ungulates were in the Americas. There were many different species, the largest of them about the weight of a small horse, the smallest the size of a mouse. During the Miocene, however, competition from the newly-developed bovids—very efficient grazers and browsers—pushed the hyraxes out of the prime territory and into marginal niches. Nevertheless, the order remained widespread, diverse and successful as late as the end of the Pliocene (about two million years ago) with representatives throughout most of Africa, Europe and Asia.
The descendants of the giant hyracoids evolved in different ways. Some became smaller, and gave rise to the modern hyrax family. Others appear to have taken to the water (perhaps like the modern capybara), and ultimately gave rise to the elephant family, and perhaps also the Sirenians (dugongs and manatees). DNA evidence supports this hypothesis, and the small modern hyraxes share numerous features with elephants, such as toenails, excellent hearing, sensitive pads on their feet, small tusks, good memory, high brain functions compared to other similar mammals, and the shape of some of their bones.[5]
Not all scientists support the proposal that hyraxes are the closest living relative of the elephant. Recent morphological and molecular based classifications reveal the Sirenians to be the closest living relatives of elephants, while hyraxes are closely related but form an outgroup to the assemblage of elephants, sirenians, and extinct orders like Embrithopoda and Desmostylia.[6].
## List of extinct species
- Pliohyracidae
Geniohyinae
Seggeurius
Geniohyus
Saghatheriinae
Microhyrax
Meroehyrax
Selenohyrax
Bunohyrax
Pachyhyrax
Megalohyrax
Saghatherium
Thyrohyrax
Titanohyracinae
Antilohyrax
Titanohyrax
Pliohyracinae
Sogdohyrax
Kvabebihyrax
Prohyrax
Parapliohyrax
Pliohyrax
Postschizotherium
- Geniohyinae
Seggeurius
Geniohyus
- Seggeurius
- Geniohyus
- Saghatheriinae
Microhyrax
Meroehyrax
Selenohyrax
Bunohyrax
Pachyhyrax
Megalohyrax
Saghatherium
Thyrohyrax
- Microhyrax
- Meroehyrax
- Selenohyrax
- Bunohyrax
- Pachyhyrax
- Megalohyrax
- Saghatherium
- Thyrohyrax
- Titanohyracinae
Antilohyrax
Titanohyrax
- Antilohyrax
- Titanohyrax
- Pliohyracinae
Sogdohyrax
Kvabebihyrax
Prohyrax
Parapliohyrax
Pliohyrax
Postschizotherium
- Sogdohyrax
- Kvabebihyrax
- Prohyrax
- Parapliohyrax
- Pliohyrax
- Postschizotherium
- Procaviidae
Procaviinae
Gigantohyrax
Procavia (Cape Hyrax)
Procavia antigua
Procavia transvaalensis
- Procaviinae
Gigantohyrax
Procavia (Cape Hyrax)
Procavia antigua
Procavia transvaalensis
- Gigantohyrax
- Procavia (Cape Hyrax)
Procavia antigua
Procavia transvaalensis
- Procavia antigua
- Procavia transvaalensis
# Living species
Scientists have recently reduced the number of distinct species of hyrax recognized. As recently as 1995 there were eleven or more recognized species; only four are recognized today. The remaining species are regarded as subspecies of the remaining four. There are over 50 recognized subspecies and species, many of which are considered highly endangered.[7]
- ORDER HYRACOIDEA
Family Procaviidae
Genus Dendrohyrax
Southern Tree Hyrax, Dendrohyrax arboreus
Western Tree Hyrax, Dendrohyrax dorsalis
Genus Heterohyrax
Yellow-spotted Rock Hyrax, Heterohyrax brucei
Genus Procavia
Cape Hyrax, Procavia capensis
- Family Procaviidae
Genus Dendrohyrax
Southern Tree Hyrax, Dendrohyrax arboreus
Western Tree Hyrax, Dendrohyrax dorsalis
Genus Heterohyrax
Yellow-spotted Rock Hyrax, Heterohyrax brucei
Genus Procavia
Cape Hyrax, Procavia capensis
- Genus Dendrohyrax
Southern Tree Hyrax, Dendrohyrax arboreus
Western Tree Hyrax, Dendrohyrax dorsalis
- Southern Tree Hyrax, Dendrohyrax arboreus
- Western Tree Hyrax, Dendrohyrax dorsalis
- Genus Heterohyrax
Yellow-spotted Rock Hyrax, Heterohyrax brucei
- Yellow-spotted Rock Hyrax, Heterohyrax brucei
- Genus Procavia
Cape Hyrax, Procavia capensis
- Cape Hyrax, Procavia capensis | https://www.wikidoc.org/index.php/Hyracoidea | |
8fcc48cf282983ed858dca35a08c49605c53c78d | wikidoc | ID3 (gene) | ID3 (gene)
DNA-binding protein inhibitor ID-3 is a protein that in humans is encoded by the ID3 gene.
# Function
Members of the ID family of helix-loop-helix (HLH) proteins lack a basic DNA-binding domain and inhibit transcription through formation of nonfunctional dimers that are incapable of binding to DNA.
# Interactions
ID3 (gene) has been shown to interact with TCF3.
# Repressors of ID3
BTG2 binds to the promoter of Id3 and represses its activity. By this mechanism, the upregulation of Id3 in the hippocampus caused by BTG2 ablation prevents terminal differentiation of hippocampal neurons. | ID3 (gene)
DNA-binding protein inhibitor ID-3 is a protein that in humans is encoded by the ID3 gene.[1][2]
# Function
Members of the ID family of helix-loop-helix (HLH) proteins lack a basic DNA-binding domain and inhibit transcription through formation of nonfunctional dimers that are incapable of binding to DNA.[supplied by OMIM][2]
# Interactions
ID3 (gene) has been shown to interact with TCF3.[3][4]
# Repressors of ID3
BTG2 binds to the promoter of Id3 and represses its activity. By this mechanism, the upregulation of Id3 in the hippocampus caused by BTG2 ablation prevents terminal differentiation of hippocampal neurons.[5] | https://www.wikidoc.org/index.php/ID3_(gene) | |
bb26b6f9e6736b216813f5eed058f7ad7752f828 | wikidoc | ITK (gene) | ITK (gene)
Tyrosine-protein kinase ITK/TSK also known as interleukin-2-inducible T-cell kinase or simply ITK, is a protein that in humans is encoded by the ITK gene. ITK is a member of the TEC family of kinases and is highly expressed in T cells.
# Function
This gene encodes an intracellular tyrosine kinase expressed in T-cells. The protein is thought to play a role in T-cell proliferation and differentiation. ITK is functionally important for the development and effector function of Th2 and Th17 cells.
Mice lacking ITK were shown to not be susceptible to asthma.
# Structure
This protein contains the following domains, which are often found in intracellular kinases:
- N-terminus – PH (pleckstrin homology domain)
- TH – Tec family homology domain (including Bruton's tyrosine kinase Cys-rich motif and Proline rich region)
- SH3 – (Src homology 3)
- SH2 – (Src homology 2)
- C-terminus – tyrosine kinase, catalytic domain
# Interactions
ITK (gene) has been shown to interact with:
- FYN,
- Grb2 and
- KHDRBS1,
- KPNA2,
- LAT,
- LCP2,
- PLCG1,
- PPIA, and
- WAS. | ITK (gene)
Tyrosine-protein kinase ITK/TSK also known as interleukin-2-inducible T-cell kinase or simply ITK, is a protein that in humans is encoded by the ITK gene.[1] ITK is a member of the TEC family of kinases and is highly expressed in T cells.[2]
# Function
This gene encodes an intracellular tyrosine kinase expressed in T-cells. The protein is thought to play a role in T-cell proliferation and differentiation.[3][4] ITK is functionally important for the development and effector function of Th2 and Th17 cells.[2]
Mice lacking ITK were shown to not be susceptible to asthma.[5]
# Structure
This protein contains the following domains, which are often found in intracellular kinases:[6]
- N-terminus – PH (pleckstrin homology domain)
- TH – Tec family homology domain (including Bruton's tyrosine kinase Cys-rich motif and Proline rich region)
- SH3 – (Src homology 3)
- SH2 – (Src homology 2)
- C-terminus – tyrosine kinase, catalytic domain
# Interactions
ITK (gene) has been shown to interact with:
- FYN,[7][8]
- Grb2[7][9] and
- KHDRBS1,[8][9][10]
- KPNA2,[11]
- LAT,[12][13]
- LCP2,[7][14]
- PLCG1,[10][15]
- PPIA,[16] and
- WAS.[8][17] | https://www.wikidoc.org/index.php/ITK_(gene) | |
6ff049a8f356a10dd65910e2422621b34c006cd3 | wikidoc | Ibalizumab | Ibalizumab
# 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
Ibalizumab is a CD4-directed post-attachment HIV-1 inhibitor that is FDA approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen. Common adverse reactions include diarrhea, dizziness, nausea, and rash.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Ibalizumab, in combination with other antiretroviral(s), is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen.
- Ibalizumab is available in a single-dose, 2 mL vial containing 150 mg/mL of Ibalizumab-uiyk. Each vial delivers approximately 1.33 mL containing 200 mg of Ibalizumab-uiyk.
- Ibalizumab is administered intravenously (IV), after diluting the appropriate number of vials in 250 mL of 0.9% Sodium Chloride Injection, USP. Patients should receive a single loading dose of 2,000 mg followed by a maintenance dose of 800 mg every 2 weeks.
- Dose modifications of Ibalizumab are not required when administered with any other antiretroviral or any other treatments.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Ibalizumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Ibalizumab 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 Ibalizumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Ibalizumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Ibalizumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None
# Warnings
- Immune reconstitution inflammatory syndrome has been reported in one patient treated with Ibalizumab in combination with other antiretrovirals. During the initial phase of combination antiretroviral therapies, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections, which may necessitate further evaluation and treatment.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- A total of 292 patients with HIV-1 infection have been exposed to Ibalizumab IV infusion.
Trial TMB-301
- The primary safety assessment of Ibalizumab is based on 24 weeks of data from Trial TMB-301. TMB-301 was a single-arm trial of Ibalizumab which enrolled 40 heavily treatment-experienced subjects with multidrug resistant HIV-1 on a failing HIV treatment regimen. Subjects received a single 2,000 mg IV loading dose of Ibalizumab followed seven days later by the initiation of an optimized background regimen (OBR) including at least one agent to which the subjects virus was susceptible. Two weeks after the Ibalizumab loading dose, 800 mg of Ibalizumab was administered IV. The IV administration of Ibalizumab 800 mg was continued every 2 weeks through Week 25.
- The most common adverse reactions (all Grades) reported in at least 5% of subjects were diarrhea, dizziness, nausea, and rash. Table 2 shows the frequency of adverse reactions occurring in 5% or more of subjects.
- Most (90%) of the adverse reactions reported were mild or moderate in severity. Two subjects experienced severe adverse reactions: one subject had a severe rash and one subject developed immune reconstitution inflammatory syndrome manifested as an exacerbation of progressive multifocal leukoencephalopathy.
Laboratory Abnormalities
- Table 3 shows the frequency of laboratory abnormalities (≥ Grade 3) in Trial TMB-301.
- As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Ibalizumab-uiyk in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
- All subjects enrolled in clinical trial TMB-301 and trial TMB-202 (a Phase 2b clinical trial that studied Ibalizumab administered intravenously as 2,000 mg every 4 weeks or 800 mg every 2 weeks; the safety and effectiveness of this dosing regimen has not been established), were tested for the presence of anti-Ibalizumab antibodies throughout their participation. One sample tested positive with low titer anti-Ibalizumab antibodies. No adverse reaction or reduced efficacy was attributed to the positive sample reported in this subject.
## Postmarketing Experience
There is limited information regarding Ibalizumab Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Ibalizumab Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Exposure Registry
- There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Ibalizumab during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1–800–258–4263.
Risk Summary
- No adequate human data are available to establish whether or not Ibalizumab poses a risk to pregnancy outcomes. Animal reproductive toxicology studies with Ibalizumab-uiyk have not been conducted. Monoclonal antibodies, such as Ibalizumab-uiyk, are transported across the placenta as pregnancy progresses; therefore, Ibalizumab-uiyk has the potential to be transmitted from the mother to the developing fetus. The 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.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ibalizumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ibalizumab during labor and delivery.
### Nursing Mothers
Risk Summary
- The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid the risk of postnatal transmission of HIV-1 infection. No data are available regarding the presence of Ibalizumab in human milk, the effects on the breastfed child, or the effects on milk production. Human IgG is present in human milk, although published data indicate that antibodies in breast milk do not enter the neonatal or infant circulation system in substantial amounts. Because of the potential for HIV-1 transmission, instruct mothers not to breastfeed if they are receiving Ibalizumab.
### Pediatric Use
- The safety and effectiveness of Ibalizumab in pediatric patients have not been established.
### Geriatic Use
- No studies have been conducted with Ibalizumab in geriatric patients.
### Gender
There is no FDA guidance on the use of Ibalizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ibalizumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ibalizumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ibalizumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ibalizumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ibalizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Diluted Ibalizumab solution should be administered by a trained medical professional.
- Administer Ibalizumab as an IV infusion in the cephalic vein of the patient’s right or left arm. If this vein is not accessible, an appropriate vein located elsewhere can be used. Do not administer Ibalizumab as an intravenous push or bolus.
- The duration of the first infusion (loading dose) should be no less than 30 minutes. If no infusion-associated adverse reactions have occurred, the duration of the subsequent infusions (maintenance doses) can be decreased to no less than 15 minutes.
- After the infusion is complete, flush with 30 mL of 0.9% Sodium Chloride Injection, USP.
- All patients must be observed for 1 hour after completion of Ibalizumab administration for at least the first infusion. If the patient does not experience an infusion-associated adverse reaction, the post-infusion observation time can be reduced to 15 minutes thereafter.
- If a maintenance dose (800 mg) of Ibalizumab is missed by 3 days or longer beyond the scheduled dosing day, a loading dose (2,000 mg) should be administered as early as possible. Resume maintenance dosing (800 mg) every 14 days thereafter.
### Monitoring
- Viral load: At baseline and with modification of antiretroviral (ARV) treatment, at 2 to 8 weeks until values are below the limit of detection (less than 200 copies/mL), then every 3 to 4 months; monitoring may be extended to every 6 months for patients who are immunologically stable, adherent, and with suppressed viral loads for more than 2 years.
- CD4 cells counts: At baseline and with modification of ARV treatment, then every 3 to 6 months during at least the first 2 years of treatment and if the CD4 counts are less than 33 cell/mm(3) or viremia develops; after 2 years monitoring may be extended to every 12 months for patients who are clinically stable with suppressed viral loads.
- Hepatitis B screening: Baseline and with modification of ARV treatment; may repeat screening every 12 months if hepatitis B surface antigen or antibody are negative at baseline.
- Hepatitis C antibody testing: Prior to initiation or modification of ARV treatment; may repeat screening every 12 months in high-risk patients if results are negative at baseline.
- ALT, AST, and total bilirubin: At baseline and with modification of ARV treatment, at 2 to 8 weeks, then every 3 to 6 months.
- Basic chemistry including serum, sodium, potassium, bicarbonate, chloride, BUN, creatinine, and creatinine-based estimated glomerular filtration rate: At baseline and with modification of ARV treatment, at 2 to 8 weeks, then every 3 to 6 months.
- CBC with a differential: At baseline and with modification of ARV treatment, 6 months thereafter or every 3 to 6 months if CD4 testing is done.
- Fasting blood glucose or HbA1c: At baseline and with modification of ARV treatment, then every 3 to 6 months in patients with abnormal values or every 12 months in patients with normal values.
- Fasting lipid profile: At baseline and with modification of ARV treatment, then every 6 months in patients with abnormal values or annually in patients with normal values.
- Urinalysis: At baseline or modification of therapy, then every 6 months.
- Pregnancy Test: In women of reproductive potential; prior to therapy initiation.
- Infusion-related reaction: 1 hour after completion of first infusion. If no reaction is observed, the post-infusion observation time can be reduced to 15 minutes thereafter.
# IV Compatibility
There is limited information regarding the compatibility of Ibalizumab and IV administrations.
# Overdosage
There is limited information regarding Ibalizumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Ibalizumab-uiyk is an HIV-1 antiretroviral drug.
## Structure
There is limited information regarding Ibalizumab Structure in the drug label.
## Pharmacodynamics
- A clear trend was identified between exposure and response rate for the Phase 2b trial (TMB-202) which studied two different intravenous doses given at two different dosing intervals (every 4 weeks vs. every 2 weeks). The recommended intravenous dosing regimen consisting of a 2,000 mg loading dose followed by a maintenance dose of 800 mg every 2 weeks was selected on the basis of these results.
## Pharmacokinetics
- Ibalizumab-uiyk administered as a single agent exhibits nonlinear pharmacokinetics. Following single-dose administrations of Ibalizumab-uiyk as 0.5 to 1.5-hour infusions, the area under the concentration-time curve increased in a greater than dose-proportional manner, clearance decreased from 9.54 to 0.36 mL/h/kg and elimination half-life increased from 2.7 to 64 hours as the dose increased from 0.3 to 25 mg/kg. The volume of distribution of Ibalizumab-uiyk was approximately that of serum volume, at 4.8 L.
- Following the recommended dose regimen (a single loading dose of 2,000 mg followed by a maintenance dose of 800 mg every 2 weeks), Ibalizumab-uiyk concentrations reached steady-state levels after the first 800 mg maintenance dose with mean concentrations over 30 mcg/mL throughout the dosing interval.
Specific Populations
- A population pharmacokinetic analysis was performed to explore the potential effects of selected covariates (age, body weight, sex, baseline CD4+ cell count) on Ibalizumab-uiyk pharmacokinetics. The result suggests that Ibalizumab-uiyk concentration decreases as body weight increases; however, the effect is unlikely to impact virologic outcome and does not warrant a dose adjustment.
- Pediatric/Geriatric Patients: Ibalizumab-uiyk pharmacokinetics have not been evaluated in pediatric or geriatric patients.
- Renal/Hepatic Impairment: No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of Ibalizumab-uiyk. Renal impairment is not anticipated to impact the pharmacokinetics of Ibalizumab-uiyk.
Drug Interaction studies
- No drug interaction studies have been conducted with Ibalizumab-uiyk. Based on Ibalizumab-uiyk’s mechanism of action and target-mediated drug disposition, drug-drug interactions are not expected.
## Nonclinical Toxicology
- Carcinogenesis, mutagenesis, and reproductive toxicology studies with Ibalizumab-uiyk have not been conducted.
# Clinical Studies
- Trial TMB-301 was a single arm, multicenter clinical trial conducted in 40 heavily treatment-experienced HIV-infected subjects with multidrug resistant HIV-1. Subjects were required to have a viral load greater than 1,000 copies/mL and documented resistance to at least one antiretroviral medication from each of three classes of antiretroviral medications as measured by resistance testing. Subjects must have been treated with antiretrovirals for at least 6 months and be failing or had recently failed (i.e., in the last 8 weeks) therapy.
- The trial was composed of three discrete periods:
- Control period (Day 0 to Day 6): Subjects were either monitored on their current failing therapy or received no therapy if they had failed and discontinued treatment within the 8 weeks preceding screening. This was an observational period to establish baseline HIV viral load.
- Functional monotherapy period (Day 7 to Day 13): All subjects received a 2,000 mg loading dose of Ibalizumab on Day 7. Subjects on a failing ART regimen continued to receive their failing regimen in addition to the loading dose of Ibalizumab. This period was to establish the virologic activity of Ibalizumab.
- Maintenance period (Day 14 to Week 25): On Day 14 of the treatment period, viral load was assessed for the primary endpoint, and thereafter the background regimen was optimized to include at least one drug to which the subjects virus was susceptible. The use of an investigational drug(s) as a component of the optimized background regimen was allowed. Beginning at Day 21, an 800 mg maintenance dose of Ibalizumab was administered every two weeks through Week 25. This period was to establish the safety and durability of virologic suppression of Ibalizumab when used in combination with an optimized background regimen.
- The majority of subjects in Trial TMB-301 were male (85%), white (55%) and between 23 and 65 years of age (mean age: 50.5 years). At Baseline, median viral load and CD4+ T cell counts were 35,350 copies/mL and 73 cells/mm3, respectively. The subjects were heavily treatment-experienced: 53% of participants had been treated with 10 or more antiretroviral drugs prior to trial enrollment; 98% percent had been treated with NRTIs, 98% with PIs, 80% with NNRTIs, 78% with INSTIs, 30% with gp41 fusion inhibitors, and 20% with CCR5 co-receptor antagonists.
- The primary efficacy endpoint was the proportion of subjects achieving a 0.5 log10 decrease in viral load from the beginning to the end of the Functional monotherapy period as compared to the proportion of subjects achieving a 0.5 log10 decrease from the beginning to the end of the Control period, as defined above. The results of the primary endpoint analysis are shown in Table 4 below.
- p < 0.0001 based on McNemars test comparing the proportion of subjects achieving 0.5 log10 decrease in viral load at the end of the control and functional monotherapy periods.
- At Week 25, viral load <50 and <200 HIV-1 RNA copies/mL was achieved in 43% and 50% of subjects, respectively. Fifty-five percent of subjects had a 1 log10 reduction in viral load, and 48% of subjects had a 2 log10 reduction in viral load at Week 25. An increase in the mean and median number of CD4+ T-cells (44 cells/mm3 and 17 cells/mm3, respectively) was observed from Baseline to Week 25. Week 25 outcomes are shown in Table 5 and Table 6.
# How Supplied
- Ibalizumab (Ibalizumab-uiyk) injection is a sterile colorless to slightly yellow and clear to slightly opalescent solution with no visible particles for intravenous infusion. It is packaged in a single-dose 2 mL clear glass vial containing 200 mg/1.33 mL (150 mg/mL) of Ibalizumab-uiyk.
- Ibalizumab is available in a carton containing two single-dose vials (NDC 62064-122-02).
- Store vials under refrigeration at 2 to 8ºC (36-46 ºF). Do not freeze and protect from light.
- Once diluted, the Ibalizumab solution should be administered immediately.
## Storage
There is limited information regarding Ibalizumab Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Immune Reconstitution Syndrome
- Immune Reconstitution Inflammatory Syndrome: Advise patients that immune reconstitution syndrome has been reported in a patient receiving Ibalizumab and to inform their health care provider immediately of any symptoms of infection.
Important Administration Information
- Advise the patient it is important to receive Ibalizumab injections every two weeks as recommended by their healthcare professional and not to change the dosing schedule of Ibalizumab or any antiretroviral medication without consulting their healthcare provider. Advise the patient to contact their healthcare provider immediately if they stop taking Ibalizumab or any other drug in their antiretroviral regimen.
Pregnancy Exposure Registry
- Inform patients that there is an antiretroviral pregnancy registry that monitors fetal outcomes of pregnant women exposed to Ibalizumab.
Lactation
- Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.
# Precautions with Alcohol
Alcohol-Ibalizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Trogarzo
# Look-Alike Drug Names
There is limited information regarding Ibalizumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Ibalizumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[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
Ibalizumab is a CD4-directed post-attachment HIV-1 inhibitor that is FDA approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen. Common adverse reactions include diarrhea, dizziness, nausea, and rash.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Ibalizumab, in combination with other antiretroviral(s), is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen.
- Ibalizumab is available in a single-dose, 2 mL vial containing 150 mg/mL of Ibalizumab-uiyk. Each vial delivers approximately 1.33 mL containing 200 mg of Ibalizumab-uiyk.
- Ibalizumab is administered intravenously (IV), after diluting the appropriate number of vials in 250 mL of 0.9% Sodium Chloride Injection, USP. Patients should receive a single loading dose of 2,000 mg followed by a maintenance dose of 800 mg every 2 weeks.
- Dose modifications of Ibalizumab are not required when administered with any other antiretroviral or any other treatments.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Ibalizumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Ibalizumab 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 Ibalizumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Ibalizumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Ibalizumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None
# Warnings
- Immune reconstitution inflammatory syndrome has been reported in one patient treated with Ibalizumab in combination with other antiretrovirals. During the initial phase of combination antiretroviral therapies, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections, which may necessitate further evaluation and treatment.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- A total of 292 patients with HIV-1 infection have been exposed to Ibalizumab IV infusion.
Trial TMB-301
- The primary safety assessment of Ibalizumab is based on 24 weeks of data from Trial TMB-301. TMB-301 was a single-arm trial of Ibalizumab which enrolled 40 heavily treatment-experienced subjects with multidrug resistant HIV-1 on a failing HIV treatment regimen. Subjects received a single 2,000 mg IV loading dose of Ibalizumab followed seven days later by the initiation of an optimized background regimen (OBR) including at least one agent to which the subjects virus was susceptible. Two weeks after the Ibalizumab loading dose, 800 mg of Ibalizumab was administered IV. The IV administration of Ibalizumab 800 mg was continued every 2 weeks through Week 25.
- The most common adverse reactions (all Grades) reported in at least 5% of subjects were diarrhea, dizziness, nausea, and rash. Table 2 shows the frequency of adverse reactions occurring in 5% or more of subjects.
- Most (90%) of the adverse reactions reported were mild or moderate in severity. Two subjects experienced severe adverse reactions: one subject had a severe rash and one subject developed immune reconstitution inflammatory syndrome manifested as an exacerbation of progressive multifocal leukoencephalopathy.
Laboratory Abnormalities
- Table 3 shows the frequency of laboratory abnormalities (≥ Grade 3) in Trial TMB-301.
- As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Ibalizumab-uiyk in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
- All subjects enrolled in clinical trial TMB-301 and trial TMB-202 (a Phase 2b clinical trial that studied Ibalizumab administered intravenously as 2,000 mg every 4 weeks or 800 mg every 2 weeks; the safety and effectiveness of this dosing regimen has not been established), were tested for the presence of anti-Ibalizumab antibodies throughout their participation. One sample tested positive with low titer anti-Ibalizumab antibodies. No adverse reaction or reduced efficacy was attributed to the positive sample reported in this subject.
## Postmarketing Experience
There is limited information regarding Ibalizumab Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Ibalizumab Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Exposure Registry
- There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Ibalizumab during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1–800–258–4263.
Risk Summary
- No adequate human data are available to establish whether or not Ibalizumab poses a risk to pregnancy outcomes. Animal reproductive toxicology studies with Ibalizumab-uiyk have not been conducted. Monoclonal antibodies, such as Ibalizumab-uiyk, are transported across the placenta as pregnancy progresses; therefore, Ibalizumab-uiyk has the potential to be transmitted from the mother to the developing fetus. The 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.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ibalizumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ibalizumab during labor and delivery.
### Nursing Mothers
Risk Summary
- The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid the risk of postnatal transmission of HIV-1 infection. No data are available regarding the presence of Ibalizumab in human milk, the effects on the breastfed child, or the effects on milk production. Human IgG is present in human milk, although published data indicate that antibodies in breast milk do not enter the neonatal or infant circulation system in substantial amounts. Because of the potential for HIV-1 transmission, instruct mothers not to breastfeed if they are receiving Ibalizumab.
### Pediatric Use
- The safety and effectiveness of Ibalizumab in pediatric patients have not been established.
### Geriatic Use
- No studies have been conducted with Ibalizumab in geriatric patients.
### Gender
There is no FDA guidance on the use of Ibalizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ibalizumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ibalizumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ibalizumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ibalizumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ibalizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Diluted Ibalizumab solution should be administered by a trained medical professional.
- Administer Ibalizumab as an IV infusion in the cephalic vein of the patient’s right or left arm. If this vein is not accessible, an appropriate vein located elsewhere can be used. Do not administer Ibalizumab as an intravenous push or bolus.
- The duration of the first infusion (loading dose) should be no less than 30 minutes. If no infusion-associated adverse reactions have occurred, the duration of the subsequent infusions (maintenance doses) can be decreased to no less than 15 minutes.
- After the infusion is complete, flush with 30 mL of 0.9% Sodium Chloride Injection, USP.
- All patients must be observed for 1 hour after completion of Ibalizumab administration for at least the first infusion. If the patient does not experience an infusion-associated adverse reaction, the post-infusion observation time can be reduced to 15 minutes thereafter.
- If a maintenance dose (800 mg) of Ibalizumab is missed by 3 days or longer beyond the scheduled dosing day, a loading dose (2,000 mg) should be administered as early as possible. Resume maintenance dosing (800 mg) every 14 days thereafter.
### Monitoring
- Viral load: At baseline and with modification of antiretroviral (ARV) treatment, at 2 to 8 weeks until values are below the limit of detection (less than 200 copies/mL), then every 3 to 4 months; monitoring may be extended to every 6 months for patients who are immunologically stable, adherent, and with suppressed viral loads for more than 2 years.
- CD4 cells counts: At baseline and with modification of ARV treatment, then every 3 to 6 months during at least the first 2 years of treatment and if the CD4 counts are less than 33 cell/mm(3) or viremia develops; after 2 years monitoring may be extended to every 12 months for patients who are clinically stable with suppressed viral loads.
- Hepatitis B screening: Baseline and with modification of ARV treatment; may repeat screening every 12 months if hepatitis B surface antigen or antibody are negative at baseline.
- Hepatitis C antibody testing: Prior to initiation or modification of ARV treatment; may repeat screening every 12 months in high-risk patients if results are negative at baseline.
- ALT, AST, and total bilirubin: At baseline and with modification of ARV treatment, at 2 to 8 weeks, then every 3 to 6 months.
- Basic chemistry including serum, sodium, potassium, bicarbonate, chloride, BUN, creatinine, and creatinine-based estimated glomerular filtration rate: At baseline and with modification of ARV treatment, at 2 to 8 weeks, then every 3 to 6 months.
- CBC with a differential: At baseline and with modification of ARV treatment, 6 months thereafter or every 3 to 6 months if CD4 testing is done.
- Fasting blood glucose or HbA1c: At baseline and with modification of ARV treatment, then every 3 to 6 months in patients with abnormal values or every 12 months in patients with normal values.
- Fasting lipid profile: At baseline and with modification of ARV treatment, then every 6 months in patients with abnormal values or annually in patients with normal values.
- Urinalysis: At baseline or modification of therapy, then every 6 months.
- Pregnancy Test: In women of reproductive potential; prior to therapy initiation.
- Infusion-related reaction: 1 hour after completion of first infusion. If no reaction is observed, the post-infusion observation time can be reduced to 15 minutes thereafter.
# IV Compatibility
There is limited information regarding the compatibility of Ibalizumab and IV administrations.
# Overdosage
There is limited information regarding Ibalizumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Ibalizumab-uiyk is an HIV-1 antiretroviral drug.
## Structure
There is limited information regarding Ibalizumab Structure in the drug label.
## Pharmacodynamics
- A clear trend was identified between exposure and response rate for the Phase 2b trial (TMB-202) which studied two different intravenous doses given at two different dosing intervals (every 4 weeks vs. every 2 weeks). The recommended intravenous dosing regimen consisting of a 2,000 mg loading dose followed by a maintenance dose of 800 mg every 2 weeks was selected on the basis of these results.
## Pharmacokinetics
- Ibalizumab-uiyk administered as a single agent exhibits nonlinear pharmacokinetics. Following single-dose administrations of Ibalizumab-uiyk as 0.5 to 1.5-hour infusions, the area under the concentration-time curve increased in a greater than dose-proportional manner, clearance decreased from 9.54 to 0.36 mL/h/kg and elimination half-life increased from 2.7 to 64 hours as the dose increased from 0.3 to 25 mg/kg. The volume of distribution of Ibalizumab-uiyk was approximately that of serum volume, at 4.8 L.
- Following the recommended dose regimen (a single loading dose of 2,000 mg followed by a maintenance dose of 800 mg every 2 weeks), Ibalizumab-uiyk concentrations reached steady-state levels after the first 800 mg maintenance dose with mean concentrations over 30 mcg/mL throughout the dosing interval.
Specific Populations
- A population pharmacokinetic analysis was performed to explore the potential effects of selected covariates (age, body weight, sex, baseline CD4+ cell count) on Ibalizumab-uiyk pharmacokinetics. The result suggests that Ibalizumab-uiyk concentration decreases as body weight increases; however, the effect is unlikely to impact virologic outcome and does not warrant a dose adjustment.
- Pediatric/Geriatric Patients: Ibalizumab-uiyk pharmacokinetics have not been evaluated in pediatric or geriatric patients.
- Renal/Hepatic Impairment: No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of Ibalizumab-uiyk. Renal impairment is not anticipated to impact the pharmacokinetics of Ibalizumab-uiyk.
Drug Interaction studies
- No drug interaction studies have been conducted with Ibalizumab-uiyk. Based on Ibalizumab-uiyk’s mechanism of action and target-mediated drug disposition, drug-drug interactions are not expected.
## Nonclinical Toxicology
- Carcinogenesis, mutagenesis, and reproductive toxicology studies with Ibalizumab-uiyk have not been conducted.
# Clinical Studies
- Trial TMB-301 was a single arm, multicenter clinical trial conducted in 40 heavily treatment-experienced HIV-infected subjects with multidrug resistant HIV-1. Subjects were required to have a viral load greater than 1,000 copies/mL and documented resistance to at least one antiretroviral medication from each of three classes of antiretroviral medications as measured by resistance testing. Subjects must have been treated with antiretrovirals for at least 6 months and be failing or had recently failed (i.e., in the last 8 weeks) therapy.
- The trial was composed of three discrete periods:
- Control period (Day 0 to Day 6): Subjects were either monitored on their current failing therapy or received no therapy if they had failed and discontinued treatment within the 8 weeks preceding screening. This was an observational period to establish baseline HIV viral load.
- Functional monotherapy period (Day 7 to Day 13): All subjects received a 2,000 mg loading dose of Ibalizumab on Day 7. Subjects on a failing ART regimen continued to receive their failing regimen in addition to the loading dose of Ibalizumab. This period was to establish the virologic activity of Ibalizumab.
- Maintenance period (Day 14 to Week 25): On Day 14 of the treatment period, viral load was assessed for the primary endpoint, and thereafter the background regimen was optimized to include at least one drug to which the subjects virus was susceptible. The use of an investigational drug(s) as a component of the optimized background regimen was allowed. Beginning at Day 21, an 800 mg maintenance dose of Ibalizumab was administered every two weeks through Week 25. This period was to establish the safety and durability of virologic suppression of Ibalizumab when used in combination with an optimized background regimen.
- The majority of subjects in Trial TMB-301 were male (85%), white (55%) and between 23 and 65 years of age (mean [SD] age: 50.5 [11.0] years). At Baseline, median viral load and CD4+ T cell counts were 35,350 copies/mL and 73 cells/mm3, respectively. The subjects were heavily treatment-experienced: 53% of participants had been treated with 10 or more antiretroviral drugs prior to trial enrollment; 98% percent had been treated with NRTIs, 98% with PIs, 80% with NNRTIs, 78% with INSTIs, 30% with gp41 fusion inhibitors, and 20% with CCR5 co-receptor antagonists.
- The primary efficacy endpoint was the proportion of subjects achieving a 0.5 log10 decrease in viral load from the beginning to the end of the Functional monotherapy period as compared to the proportion of subjects achieving a 0.5 log10 decrease from the beginning to the end of the Control period, as defined above. The results of the primary endpoint analysis are shown in Table 4 below.
- p < 0.0001 based on McNemars test comparing the proportion of subjects achieving 0.5 log10 decrease in viral load at the end of the control and functional monotherapy periods.
- At Week 25, viral load <50 and <200 HIV-1 RNA copies/mL was achieved in 43% and 50% of subjects, respectively. Fifty-five percent of subjects had a 1 log10 reduction in viral load, and 48% of subjects had a 2 log10 reduction in viral load at Week 25. An increase in the mean and median number of CD4+ T-cells (44 cells/mm3 and 17 cells/mm3, respectively) was observed from Baseline to Week 25. Week 25 outcomes are shown in Table 5 and Table 6.
# How Supplied
- Ibalizumab (Ibalizumab-uiyk) injection is a sterile colorless to slightly yellow and clear to slightly opalescent solution with no visible particles for intravenous infusion. It is packaged in a single-dose 2 mL clear glass vial containing 200 mg/1.33 mL (150 mg/mL) of Ibalizumab-uiyk.
- Ibalizumab is available in a carton containing two single-dose vials (NDC 62064-122-02).
- Store vials under refrigeration at 2 to 8ºC (36-46 ºF). Do not freeze and protect from light.
- Once diluted, the Ibalizumab solution should be administered immediately.
## Storage
There is limited information regarding Ibalizumab Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Immune Reconstitution Syndrome
- Immune Reconstitution Inflammatory Syndrome: Advise patients that immune reconstitution syndrome has been reported in a patient receiving Ibalizumab and to inform their health care provider immediately of any symptoms of infection.
Important Administration Information
- Advise the patient it is important to receive Ibalizumab injections every two weeks as recommended by their healthcare professional and not to change the dosing schedule of Ibalizumab or any antiretroviral medication without consulting their healthcare provider. Advise the patient to contact their healthcare provider immediately if they stop taking Ibalizumab or any other drug in their antiretroviral regimen.
Pregnancy Exposure Registry
- Inform patients that there is an antiretroviral pregnancy registry that monitors fetal outcomes of pregnant women exposed to Ibalizumab.
Lactation
- Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.
# Precautions with Alcohol
Alcohol-Ibalizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Trogarzo
# Look-Alike Drug Names
There is limited information regarding Ibalizumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Ibalizumab | |
54b6b81b9f7960641c4c48067b77ff1682e0f98d | wikidoc | Icodextrin | Icodextrin
# Overview
Icodextrin (INN, USAN) is a colloid osmotic agent, derived from maltodextrin, used in form of an aqueous solution for peritoneal dialysis under the trade name Extraneal, and after gynecological laparoscopic surgery for the reduction of post-surgical adhesions (fibrous bands that form between tissues and organs) under the trade name Adept.
# Physical and chemical properties
Icodextrin is a starch-derived, branched, water-soluble glucose polymer linked by α-(1→4) and less than 10% α-(1→6) glycosidic bonds, making it a type of dextrin. Its weight-average molecular weight is between 13,000 and 19,000 Daltons and its number-average molecular weight between 5,000 and 6,500 Daltons. The substance is a white to off-white solid, and the solution is clear and colourless to pale yellow.
# Mechanism of action
The osmotic activity of icodextrin keeps the solution inside the peritoneum for three to four days, separating tissues and thus reducing adhesion between them when fibrin is formed after a surgery. In other words, the tissues are kept from gluing together.
When used for peritoneal dialysis, the icodextrin solution absorbs waste products from the blood, and is removed from the peritoneum after a few hours together with the waste.
# Pharmacokinetics
Icodextrin is not significantly metabolised inside the peritoneum. Instead, it is absorbed slowly (40% after 12 hours) into the bloodstream via the lymph vessels. There it is broken down into oligosaccharides by the enzyme alpha-amylase. In patients with intact kidney function, both icodextrin and its fragments are excreted via the kidney by glomerular filtration.
# Contraindications
Icodextrin is contraindicated in patients with cornstarch allergy, maltose or isomaltose intolerance, glycogen storage disease, or severe lactic acidosis.
# Adverse effects
Adverse effects include peritonitis, respiratory infection, hypertension (high blood pressure), rashes, and headache. Of these side effects, only hypertension and rashes occurred significantly more often than under glucose solution; the other events seem to be related to peritoneal dialysis in general.
# Interactions
Icodextrin can mimic increased blood glucose levels, depending on the used testing system. Specifically, glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase (GDO) based tests can erroneously show high blood glucose in patients that have been treated with icodextrin. | Icodextrin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Icodextrin (INN, USAN) is a colloid osmotic agent, derived from maltodextrin,[1] used in form of an aqueous solution for peritoneal dialysis under the trade name Extraneal,[2] and after gynecological laparoscopic surgery for the reduction of post-surgical adhesions (fibrous bands that form between tissues and organs) under the trade name Adept.[3]
# Physical and chemical properties
Icodextrin is a starch-derived, branched, water-soluble glucose polymer linked by α-(1→4) and less than 10% α-(1→6) glycosidic bonds, making it a type of dextrin. Its weight-average molecular weight is between 13,000 and 19,000 Daltons and its number-average molecular weight between 5,000 and 6,500 Daltons. The substance is a white to off-white solid, and the solution is clear and colourless to pale yellow.[3]
# Mechanism of action
The osmotic activity of icodextrin keeps the solution inside the peritoneum for three to four days, separating tissues and thus reducing adhesion between them when fibrin is formed after a surgery. In other words, the tissues are kept from gluing together.[3]
When used for peritoneal dialysis, the icodextrin solution absorbs waste products from the blood, and is removed from the peritoneum after a few hours together with the waste.[4]
# Pharmacokinetics
Icodextrin is not significantly metabolised inside the peritoneum. Instead, it is absorbed slowly (40% after 12 hours) into the bloodstream via the lymph vessels. There it is broken down into oligosaccharides by the enzyme alpha-amylase. In patients with intact kidney function, both icodextrin and its fragments are excreted via the kidney by glomerular filtration.[2][3]
# Contraindications
Icodextrin is contraindicated in patients with cornstarch allergy, maltose or isomaltose intolerance, glycogen storage disease, or severe lactic acidosis.[5]
# Adverse effects
Adverse effects include peritonitis, respiratory infection, hypertension (high blood pressure), rashes, and headache. Of these side effects, only hypertension and rashes occurred significantly more often than under glucose solution; the other events seem to be related to peritoneal dialysis in general.[5]
# Interactions
Icodextrin can mimic increased blood glucose levels, depending on the used testing system. Specifically, glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase (GDO) based tests can erroneously show high blood glucose in patients that have been treated with icodextrin.[5] | https://www.wikidoc.org/index.php/Icodextrin | |
c7d2d55d0bb07dc39622f56b56ea5c25e960a926 | wikidoc | Idelalisib | Idelalisib
# 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
Idelalisib is an antineoplastic agent that is FDA approved for the treatment of relapsed chronic lymphocytic leukemia, relapsed follicular b-cell non-hodgkin lymphoma and relapsed small lymphocytic lymphoma. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hyperglycemia, hypertriglyceridemia, abdominal pain, nausea, neutropenia, cough, fatigue, fever and shivering.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Recommended Dose
- The recommended maximum starting dose of Idelalisib is 150 mg administered orally twice daily.
- Idelalisib can be taken with or without food. Tablets should be swallowed whole.
- Continue treatment until disease progression or unacceptable toxicity. The optimal and safe dosing regimen for patients who receive treatment longer than several months is unknown.
### Dose Modification
- See the table below for dose modification instructions for specific toxicities related to Idelalisib.
- For other severe or life-threatening toxicities related to Idelalisib, withhold drug until toxicity is resolved. If resuming Idelalisib after interruption for other severe or life-threatening toxicities, reduce the dose to 100 mg twice daily. Recurrence of other severe or life-threatening Idelalisib-related toxicity upon rechallenge should result in permanent discontinuation of Idelalisib.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Idelalisib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Idelalisib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Idelalisib 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 Idelalisib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Idelalisib in pediatric patients.
# Contraindications
- History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis.
# Warnings
### Hepatotoxicity
- Fatal and/or serious hepatotoxicity occurred in 14% of patients treated with Idelalisib. Elevations in ALT or AST greater than 5 times the upper limit of normal have occurred. These findings were generally observed within the first 12 weeks of treatment and were reversible with dose interruption. After resumption of treatment at a lower dose, 26% of patients had recurrence of ALT and AST elevations. Discontinue Idelalisib for recurrent hepatotoxicity.
- Avoid concurrent use of Idelalisib with other drugs that may cause liver toxicity.
- Monitor ALT and AST in all patients every 2 weeks for the first 3 months of treatment, every 4 weeks for the next 3 months, then every 1 to 3 months thereafter. Monitor weekly for liver toxicity if the ALT or AST rises above 3 times the upper limit of normal until resolved. Withhold Idelalisib if the ALT or AST is greater than 5 times the upper limit of normal, and continue to monitor AST, ALT and total bilirubin weekly until the abnormality is resolved.
### Severe Diarrhea or Colitis
- Severe diarrhea or colitis (Grade 3 or higher) occurred in 14% of Idelalisib-treated patients across clinical trials. Diarrhea can occur at any time. Avoid concurrent use of Idelalisib and other drugs that cause diarrhea. Diarrhea due to Idelalisib responds poorly to antimotility agents. Median time to resolution ranged between 1 week and 1 month across trials, following interruption of Idelalisib therapy and in some instances, use of corticosteroids.
### Pneumonitis
- Fatal and serious pneumonitis occurred in patients treated with Idelalisib. Patients taking Idelalisib who present with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on a radiologic exam, or a decline by more than 5% in oxygen saturation should be evaluated for pneumonitis. If pneumonitis is suspected, interrupt Idelalisib until the etiology of the pulmonary symptoms has been determined. Patients with pneumonitis thought to be caused by Idelalisib have been treated with discontinuation of Idelalisib and administration of corticosteroids.
### Intestinal Perforation
- Fatal and serious intestinal perforation occurred in Idelalisib-treated patients. At the time of perforation, some patients had moderate to severe diarrhea. Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting. Discontinue Idelalisib permanently in patients who experience intestinal perforation.
### Severe Cutaneous Reactions
- One case of toxic epidermal necrolysis (TEN) occurred in a study of Idelalisib in combination with rituximab and bendamustine. Other severe or life-threatening (Grade ≥3) cutaneous reactions, including dermatitis exfoliative, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, papular rash, pruritic rash, exfoliative rash, and skin disorder, have been reported in Idelalisib-treated patients. Monitor patients for the development of severe cutaneous reactions and discontinue Idelalisib.
### Anaphylaxis
- Serious allergic reactions, including anaphylaxis, have been reported in patients on Idelalisib. In patients who develop serious allergic reactions, discontinue Idelalisib permanently and institute appropriate supportive measures.
### Neutropenia
- Treatment-emergent Grade 3 or 4 neutropenia occurred in 31% of Idelalisib-treated patients across clinical trials. Monitor blood counts at least every two weeks for the first 3 months of therapy, and at least weekly in patients while neutrophil counts are less than 1.0 Gi/L.
### Embryo-fetal Toxicity
- Based on findings in animals, Idelalisib may cause fetal harm when administered to a pregnant woman. Idelalisib is teratogenic in rats, at systemic exposures 12 times those reported in patients at the recommended dose of 150 mg twice daily. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
- Advise females of reproductive potential to avoid becoming pregnant while taking Idelalisib If contraceptive methods are being considered, use effective contraception during treatment, and for at least 1 month after the last dose of Idelalisib.
# Adverse Reactions
## Clinical Trials Experience
### Summary of Clinical Trials in Chronic Lymphocytic Leukemia
- The safety data reflect subject exposure to Idelalisib from Study 1, in which 218 subjects with relapsed CLL received up to 8 doses of rituximab with or without Idelalisib 150 mg twice daily. The median duration of exposure to Idelalisib was 5 months.
- Serious adverse reactions were reported in 54 (49%) subjects treated with Idelalisib + rituximab. The most frequent (≥2%) serious adverse reactions reported for subjects treated with Idelalisib were pneumonia (17%), pyrexia (9%), sepsis (8%), febrile neutropenia (5%) and diarrhea (5%). Adverse reactions that led to discontinuation of Idelalisib occurred in 11 (10%) subjects. The most common adverse reactions that led to treatment discontinuations were hepatotoxicity and diarrhea/colitis.
- Thirty-nine subjects (35%) had dose interruptions and sixteen subjects (15%) had dose reductions due to adverse reactions or laboratory abnormalities. The most common reasons for dose reductions were elevated transaminases, diarrhea or colitis, and rash.
- Table 2 and Table 3 summarize common adverse reactions and laboratory abnormalities reported for Idelalisib + rituximab and placebo + rituximab arms.
### Summary of Clinical Trials in Indolent Non-Hodgkin Lymphoma
- The safety data reflect exposure to Idelalisib in 146 adults with indolent non-Hodgkin lymphoma treated with Idelalisib 150 mg twice daily in clinical trials. The median duration of exposure was 6.1 months (range 0.3 to 26.4 months).
- Serious adverse reactions were reported in 73 (50%) subjects. The most frequent serious adverse reactions that occurred were pneumonia (15%), diarrhea (11%), and pyrexia (9%).
- Adverse reactions resulted in interruption or discontinuation for 78 (53%) subjects. The most common reasons for interruption or discontinuations were diarrhea (11%), pneumonia (11%), and elevated transaminases (10%).
Table 4 provides the adverse reactions occurring in at least 10% of subjects receiving Idelalisib monotherapy, and Table 5 provides the treatment-emergent laboratory abnormalities.
## Postmarketing Experience
There is limited information regarding Idelalisib Postmarketing Experience in the drug label.
# Drug Interactions
### Effects of Other Drugs on Idelalisib
- The AUC of idelalisib was reduced by 75% when Idelalisib was coadministered with a strong CYP3A inducer. Avoid coadministration of Idelalisib with strong CYP3A inducers, such as rifampin, phenytoin, St. John's wort, or carbamazepine.
- The AUC of idelalisib was increased 1.8-fold when Idelalisib was coadministered with a strong CYP3A inhibitor. If patients are taking concomitant strong CYP3A inhibitors, monitor for signs of Idelalisib toxicity. Follow dose modifications for adverse reactions.
### Effects of Idelalisib on Other Drugs
- Idelalisib is a strong CYP3A inhibitor. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when Idelalisib was coadministered with a sensitive CYP3A substrate. Avoid coadministration of Idelalisib with CYP3A substrates.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Based on findings in animals, Idelalisib may cause fetal harm when administered to a pregnant woman. Idelalisib was teratogenic in animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Idelalisib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Idelalisib during labor and delivery.
### Nursing Mothers
- It is not known whether idelalisib 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 Idelalisib, a decision should be made whether to discontinue nu
### Pediatric Use
- Safety and effectiveness of Idelalisib in children less than 18 years of age have not been established.
### Geriatic Use
- In clinical trials of Idelalisib in patients with FL, SLL, and CLL, 131/208 (63%) patients were age 65 and older. No major differences in effectiveness were observed. In patients 65 years of age or older with indolent non-Hodgkin lymphoma in comparison to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (28% vs 20%), higher incidence of serious adverse reactions (64% vs 37%), and higher incidence of death (11% vs 5%). In patients 65 years of age or older with CLL in comparison to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (11% vs 5%), higher incidence of serious adverse reactions (51% vs 43%), and higher incidence of death (3% vs 0%).
### Gender
There is no FDA guidance on the use of Idelalisib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Idelalisib with respect to specific racial populations.
### Renal Impairment
- No dose adjustment of Idelalisib is necessary for patients with creatinine clearance (CLcr) ≥ 15 mL/min
### Hepatic Impairment
- The AUC of idelalisib increased up to 1.7-fold in subjects with ALT or AST or bilirubin greater than the upper limit of normal (ULN) compared to healthy subjects with normal ALT or AST or bilirubin values. Safety and efficacy data are not available in patients with baseline ALT or AST values greater than 2.5 × ULN or bilirubin values greater than 1.5 × ULN, as these patients were excluded from Studies 1 and 2. Patients with baseline hepatic impairment should be monitored for signs of Idelalisib toxicity. Follow dose modifications for adverse reactions
### Females of Reproductive Potential and Males
### Contraception
- Idelalisib may cause fetal harm when administered during pregnancy. Advise females of reproductive potential to avoid becoming pregnant while taking Idelalisib If contraceptive methods are being considered, use effective contraception while taking Idelalisib and for at least one month after taking the last dose of Idelalisib Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Idelalisib.
### Immunocompromised Patients
There is no FDA guidance one the use of Idelalisib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Idelalisib Administration in the drug label.
### Monitoring
There is limited information regarding Idelalisib Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Idelalisib and IV administrations.
# Overdosage
There is limited information regarding Idelalisib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Idelalisib is an inhibitor of PI3Kδ kinase, which is expressed in normal and malignant B-cells. Idelalisib induced apoptosis and inhibited proliferation in cell lines derived from malignant B-cells and in primary tumor cells. Idelalisib inhibits several cell signaling pathways, including B-cell receptor (BCR) signaling and the CXCR4 and CXCR5 signaling, which are involved in trafficking and homing of B-cells to the lymph nodes and bone marrow. Treatment of lymphoma cells with idelalisib resulted in inhibition of chemotaxis and adhesion, and reduced cell viability.
## Structure
- It has a molecular formula of C22H18FN7O and a molecular weight of 415.42 g/mol. Idelalisib has the following structural formula:
## Pharmacodynamics
### Electrocardiographic Effects
- The effect of Idelalisib (150 mg and 400 mg) on the QT/QTc interval was evaluated in a placebo- and positive-controlled (moxifloxacin 400 mg) crossover study in 46 healthy subjects. At a dose 2.7 times the maximum recommended dose, Idelalisib did not prolong the QT/QTc interval (i.e., not greater than or equal to 10 ms).
## Pharmacokinetics
### Absorption
- Following oral administration of a single dose of Idelalisib in the fasted state, the median Tmax was observed at 1.5 hours.
- Idelalisib exposure increased in a less than dose-proportional manner over a dose range of 50 mg to 350 mg twice daily in the fasted state.
- Relative to fasting conditions, the administration of a single dose of Idelalisib with a high-fat meal increased idelalisib AUC 1.4-fold. Idelalisib can be administered without regard to food.
### Distribution
- Idelalisib is greater than 84% bound to human plasma proteins with no concentration dependence. The mean blood-to-plasma ratio was 0.7. The population apparent central volume of distribution at steady state is 23 L.
### Metabolism and Elimination
- Idelalisib is metabolized to its major metabolite GS-563117 via aldehyde oxidase and CYP3A. GS-563117 is inactive against PI3Kδ in vitro. Idelalisib undergoes minor metabolism by UGT1A4.
- The population apparent systemic clearance at steady-state is 14.9 L/hr. The population terminal elimination half-life of idelalisib is 8.2 hours. Following a single dose of 150 mg of idelalisib, 78% and 14% of the radioactivity was excreted in feces and urine, respectively. GS-563117 accounted for 49% of the radioactivity in the urine and 44% in the feces.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenicity studies with idelalisib have not been conducted.
- Idelalisib did not induce mutations in the bacterial mutagenesis (Ames) assay and was not clastogenic in the in vitro chromosome aberration assay using human peripheral blood lymphocytes. Idelalisib was genotoxic in males in the in vivo rat micronucleus study at a high dose of 2000 mg/kg.
- Idelalisib may impair fertility in humans. In a fertility study, treated male rats (25, 50, or 100 mg/kg/day of idelalisib) were mated with untreated females. Decreased epididymidal and testicular weights were observed at all dose levels and reduced sperm concentration at the mid- and high doses; however, there were no adverse effects on fertility parameters. The low dose in males resulted in an exposure (AUC) that is approximately 50% of the exposure in patients at the recommended dose of 150 mg twice daily.
- In a separate fertility study, treated female rats (25, 50, or 100 mg/kg/day of idelalisib) were mated with untreated males. There were no adverse effects on fertility parameters; however, there was a decrease in the number of live embryos at the high dose. The high dose in females resulted in an exposure (AUC) that is approximately 17-fold the exposure in patients at the recommended dose of 150 mg twice daily.
### Animal Pharmacology and/or Toxicology
- Toxicities observed in animals and not reported in patients include cardiac toxicity (cardiomyopathy, inflammation, and increased heart weight) and pancreatic findings (inflammation, hemorrhage, and low-incidence acinar degeneration and hyperplasia). These findings were observed in Sprague-Dawley rats in toxicology studies at exposures (AUCs) higher than those reported in patients at the recommended dose of 150 mg twice daily. Cardiac inflammation was mainly seen in a 28-day study in rats, the other findings were observed in the 13-week and/or 6-month studies.
# Clinical Studies
### Relapsed Chronic Lymphocytic Leukemia
Idelalisib was evaluated in a randomized, double-blind, placebo-controlled study (Study 1) in 220 subjects with relapsed CLL who required treatment and were unable to tolerate standard chemoimmunotherapy due to coexisting medical conditions, reduced renal function as measured by creatinine clearance <60 mL/min, or NCI CTCAE Grade ≥3 neutropenia or Grade ≥3 thrombocytopenia resulting from myelotoxic effects of prior therapy with cytotoxic agents. Subjects were randomized 1:1 to receive 8 doses of rituximab (first dose at 375 mg/m2, subsequent doses at 500 mg/m2 every 2 weeks for 4 infusions and every 4 weeks for an additional 4 infusions) in combination with either an oral placebo twice daily or with Idelalisib 150 mg taken twice daily until disease progression or unacceptable toxicity.
- In Study 1, the median age was 71 (range 47, 92) with 78% over 65, 66% were male, and 90% were Caucasian. The median time since diagnosis was 8.5 years. The median number of prior therapies was 3. Nearly all (96%) subjects had received prior anti-CD20 monoclonal antibodies. The most common (>15%) prior regimens were: bendamustine + rituximab (98 subjects, 45%), fludarabine + cyclophosphamide + rituximab (75 subjects, 34%), single-agent rituximab (67 subjects, 31%), fludarabine + rituximab (37 subjects, 17%), and chlorambucil (36 subjects, 16%).
- The primary endpoint was progression free survival (PFS), as assessed by an independent review committee (IRC). The trial was stopped for efficacy following the first pre-specified interim analysis. Results of a second interim analysis continued to show a statistically significant improvement for Idelalisib + rituximab over placebo + rituximab for the primary endpoint of PFS (HR: 0.18, 95% CI , p < 0.0001). The efficacy results are shown in Table 6 and the Kaplan-Meier curve for PFS is shown in Figure 1.
### Relapsed Follicular B-cell non-Hodgkin Lymphoma
- The safety and efficacy of Idelalisib in patients with FL was evaluated in a single-arm, multicenter clinical trial which included 72 patients with follicular B-cell non-Hodgkin lymphoma who had relapsed within 6 months following rituximab and an alkylating agent and had received at least 2 prior treatments. The median age was 62 years (range 33 to 84), 54% were male, and 90% were Caucasian. At enrollment, 92% of patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 4.7 years and the median number of prior treatments was 4 (range 2 to 12). The most common prior combination regimens were R-CHOP (49%), BR (50%), and R-CVP (28%). At baseline, 33% of patients had extranodal involvement and 26% had bone marrow involvement.
- Patients received 150 mg of Idelalisib orally twice daily until evidence of disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group response criteria for malignant lymphoma. The primary endpoint was Independent Review Committee-assessed overall response rate (ORR). Efficacy results are summarized in Table 7.
### Relapsed Small Lymphocytic Lymphoma
- The safety and efficacy of Idelalisib in patients with SLL was evaluated in a single-arm, multicenter clinical trial which included 26 patients with small lymphocytic lymphoma who had relapsed within 6 months following rituximab and an alkylating agent and had received at least 2 prior treatments. The median age was 65 years (range 50 to 87), 73% were male, and 81% were Caucasian. At enrollment, 96% of patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 6.7 years and the median number of prior treatments was 4 (range 2 to 9). The most common prior combination regimens were BR (81%), FCR (62%) and R-CHOP (35%). At baseline, 27% of patients had extranodal involvement.
- Subjects received 150 mg of Idelalisib orally twice daily until evidence of disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group response criteria for malignant lymphoma. The primary endpoint was Independent Review Committee-assessed overall response rate (ORR). Efficacy results are summarized in Table 8.
# How Supplied
Idelalisib tablets supplied as follows:
## Storage
Store between 20–30 °C (68–86 °F) with excursions permitted 15–30 ºC (59–86 ºF).
- Dispense only in original container.
- Do not use if seal over bottle opening is broken or missing.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Idelalisib Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Idelalisib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Zydelig
# Look-Alike Drug Names
There is limited information regarding Idelalisib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Idelalisib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
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# Black Box Warning
# Overview
Idelalisib is an antineoplastic agent that is FDA approved for the treatment of relapsed chronic lymphocytic leukemia, relapsed follicular b-cell non-hodgkin lymphoma and relapsed small lymphocytic lymphoma. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hyperglycemia, hypertriglyceridemia, abdominal pain, nausea, neutropenia, cough, fatigue, fever and shivering.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Recommended Dose
- The recommended maximum starting dose of Idelalisib is 150 mg administered orally twice daily.
- Idelalisib can be taken with or without food. Tablets should be swallowed whole.
- Continue treatment until disease progression or unacceptable toxicity. The optimal and safe dosing regimen for patients who receive treatment longer than several months is unknown.
### Dose Modification
- See the table below for dose modification instructions for specific toxicities related to Idelalisib.
- For other severe or life-threatening toxicities related to Idelalisib, withhold drug until toxicity is resolved. If resuming Idelalisib after interruption for other severe or life-threatening toxicities, reduce the dose to 100 mg twice daily. Recurrence of other severe or life-threatening Idelalisib-related toxicity upon rechallenge should result in permanent discontinuation of Idelalisib.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Idelalisib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Idelalisib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Idelalisib 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 Idelalisib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Idelalisib in pediatric patients.
# Contraindications
- History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis.
# Warnings
### Hepatotoxicity
- Fatal and/or serious hepatotoxicity occurred in 14% of patients treated with Idelalisib. Elevations in ALT or AST greater than 5 times the upper limit of normal have occurred. These findings were generally observed within the first 12 weeks of treatment and were reversible with dose interruption. After resumption of treatment at a lower dose, 26% of patients had recurrence of ALT and AST elevations. Discontinue Idelalisib for recurrent hepatotoxicity.
- Avoid concurrent use of Idelalisib with other drugs that may cause liver toxicity.
- Monitor ALT and AST in all patients every 2 weeks for the first 3 months of treatment, every 4 weeks for the next 3 months, then every 1 to 3 months thereafter. Monitor weekly for liver toxicity if the ALT or AST rises above 3 times the upper limit of normal until resolved. Withhold Idelalisib if the ALT or AST is greater than 5 times the upper limit of normal, and continue to monitor AST, ALT and total bilirubin weekly until the abnormality is resolved.
### Severe Diarrhea or Colitis
- Severe diarrhea or colitis (Grade 3 or higher) occurred in 14% of Idelalisib-treated patients across clinical trials. Diarrhea can occur at any time. Avoid concurrent use of Idelalisib and other drugs that cause diarrhea. Diarrhea due to Idelalisib responds poorly to antimotility agents. Median time to resolution ranged between 1 week and 1 month across trials, following interruption of Idelalisib therapy and in some instances, use of corticosteroids.
### Pneumonitis
- Fatal and serious pneumonitis occurred in patients treated with Idelalisib. Patients taking Idelalisib who present with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on a radiologic exam, or a decline by more than 5% in oxygen saturation should be evaluated for pneumonitis. If pneumonitis is suspected, interrupt Idelalisib until the etiology of the pulmonary symptoms has been determined. Patients with pneumonitis thought to be caused by Idelalisib have been treated with discontinuation of Idelalisib and administration of corticosteroids.
### Intestinal Perforation
- Fatal and serious intestinal perforation occurred in Idelalisib-treated patients. At the time of perforation, some patients had moderate to severe diarrhea. Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting. Discontinue Idelalisib permanently in patients who experience intestinal perforation.
### Severe Cutaneous Reactions
- One case of toxic epidermal necrolysis (TEN) occurred in a study of Idelalisib in combination with rituximab and bendamustine. Other severe or life-threatening (Grade ≥3) cutaneous reactions, including dermatitis exfoliative, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, papular rash, pruritic rash, exfoliative rash, and skin disorder, have been reported in Idelalisib-treated patients. Monitor patients for the development of severe cutaneous reactions and discontinue Idelalisib.
### Anaphylaxis
- Serious allergic reactions, including anaphylaxis, have been reported in patients on Idelalisib. In patients who develop serious allergic reactions, discontinue Idelalisib permanently and institute appropriate supportive measures.
### Neutropenia
- Treatment-emergent Grade 3 or 4 neutropenia occurred in 31% of Idelalisib-treated patients across clinical trials. Monitor blood counts at least every two weeks for the first 3 months of therapy, and at least weekly in patients while neutrophil counts are less than 1.0 Gi/L.
### Embryo-fetal Toxicity
- Based on findings in animals, Idelalisib may cause fetal harm when administered to a pregnant woman. Idelalisib is teratogenic in rats, at systemic exposures 12 times those reported in patients at the recommended dose of 150 mg twice daily. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
- Advise females of reproductive potential to avoid becoming pregnant while taking Idelalisib If contraceptive methods are being considered, use effective contraception during treatment, and for at least 1 month after the last dose of Idelalisib.
# Adverse Reactions
## Clinical Trials Experience
### Summary of Clinical Trials in Chronic Lymphocytic Leukemia
- The safety data reflect subject exposure to Idelalisib from Study 1, in which 218 subjects with relapsed CLL received up to 8 doses of rituximab with or without Idelalisib 150 mg twice daily. The median duration of exposure to Idelalisib was 5 months.
- Serious adverse reactions were reported in 54 (49%) subjects treated with Idelalisib + rituximab. The most frequent (≥2%) serious adverse reactions reported for subjects treated with Idelalisib were pneumonia (17%), pyrexia (9%), sepsis (8%), febrile neutropenia (5%) and diarrhea (5%). Adverse reactions that led to discontinuation of Idelalisib occurred in 11 (10%) subjects. The most common adverse reactions that led to treatment discontinuations were hepatotoxicity and diarrhea/colitis.
- Thirty-nine subjects (35%) had dose interruptions and sixteen subjects (15%) had dose reductions due to adverse reactions or laboratory abnormalities. The most common reasons for dose reductions were elevated transaminases, diarrhea or colitis, and rash.
- Table 2 and Table 3 summarize common adverse reactions and laboratory abnormalities reported for Idelalisib + rituximab and placebo + rituximab arms.
### Summary of Clinical Trials in Indolent Non-Hodgkin Lymphoma
- The safety data reflect exposure to Idelalisib in 146 adults with indolent non-Hodgkin lymphoma treated with Idelalisib 150 mg twice daily in clinical trials. The median duration of exposure was 6.1 months (range 0.3 to 26.4 months).
- Serious adverse reactions were reported in 73 (50%) subjects. The most frequent serious adverse reactions that occurred were pneumonia (15%), diarrhea (11%), and pyrexia (9%).
- Adverse reactions resulted in interruption or discontinuation for 78 (53%) subjects. The most common reasons for interruption or discontinuations were diarrhea (11%), pneumonia (11%), and elevated transaminases (10%).
Table 4 provides the adverse reactions occurring in at least 10% of subjects receiving Idelalisib monotherapy, and Table 5 provides the treatment-emergent laboratory abnormalities.
## Postmarketing Experience
There is limited information regarding Idelalisib Postmarketing Experience in the drug label.
# Drug Interactions
### Effects of Other Drugs on Idelalisib
- The AUC of idelalisib was reduced by 75% when Idelalisib was coadministered with a strong CYP3A inducer. Avoid coadministration of Idelalisib with strong CYP3A inducers, such as rifampin, phenytoin, St. John's wort, or carbamazepine.
- The AUC of idelalisib was increased 1.8-fold when Idelalisib was coadministered with a strong CYP3A inhibitor. If patients are taking concomitant strong CYP3A inhibitors, monitor for signs of Idelalisib toxicity. Follow dose modifications for adverse reactions.
### Effects of Idelalisib on Other Drugs
- Idelalisib is a strong CYP3A inhibitor. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when Idelalisib was coadministered with a sensitive CYP3A substrate. Avoid coadministration of Idelalisib with CYP3A substrates.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Based on findings in animals, Idelalisib may cause fetal harm when administered to a pregnant woman. Idelalisib was teratogenic in animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Idelalisib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Idelalisib during labor and delivery.
### Nursing Mothers
- It is not known whether idelalisib 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 Idelalisib, a decision should be made whether to discontinue nu
### Pediatric Use
- Safety and effectiveness of Idelalisib in children less than 18 years of age have not been established.
### Geriatic Use
- In clinical trials of Idelalisib in patients with FL, SLL, and CLL, 131/208 (63%) patients were age 65 and older. No major differences in effectiveness were observed. In patients 65 years of age or older with indolent non-Hodgkin lymphoma in comparison to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (28% vs 20%), higher incidence of serious adverse reactions (64% vs 37%), and higher incidence of death (11% vs 5%). In patients 65 years of age or older with CLL in comparison to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (11% vs 5%), higher incidence of serious adverse reactions (51% vs 43%), and higher incidence of death (3% vs 0%).
### Gender
There is no FDA guidance on the use of Idelalisib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Idelalisib with respect to specific racial populations.
### Renal Impairment
- No dose adjustment of Idelalisib is necessary for patients with creatinine clearance (CLcr) ≥ 15 mL/min
### Hepatic Impairment
- The AUC of idelalisib increased up to 1.7-fold in subjects with ALT or AST or bilirubin greater than the upper limit of normal (ULN) compared to healthy subjects with normal ALT or AST or bilirubin values. Safety and efficacy data are not available in patients with baseline ALT or AST values greater than 2.5 × ULN or bilirubin values greater than 1.5 × ULN, as these patients were excluded from Studies 1 and 2. Patients with baseline hepatic impairment should be monitored for signs of Idelalisib toxicity. Follow dose modifications for adverse reactions
### Females of Reproductive Potential and Males
### Contraception
- Idelalisib may cause fetal harm when administered during pregnancy. Advise females of reproductive potential to avoid becoming pregnant while taking Idelalisib If contraceptive methods are being considered, use effective contraception while taking Idelalisib and for at least one month after taking the last dose of Idelalisib Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Idelalisib.
### Immunocompromised Patients
There is no FDA guidance one the use of Idelalisib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Idelalisib Administration in the drug label.
### Monitoring
There is limited information regarding Idelalisib Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Idelalisib and IV administrations.
# Overdosage
There is limited information regarding Idelalisib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Idelalisib is an inhibitor of PI3Kδ kinase, which is expressed in normal and malignant B-cells. Idelalisib induced apoptosis and inhibited proliferation in cell lines derived from malignant B-cells and in primary tumor cells. Idelalisib inhibits several cell signaling pathways, including B-cell receptor (BCR) signaling and the CXCR4 and CXCR5 signaling, which are involved in trafficking and homing of B-cells to the lymph nodes and bone marrow. Treatment of lymphoma cells with idelalisib resulted in inhibition of chemotaxis and adhesion, and reduced cell viability.
## Structure
- It has a molecular formula of C22H18FN7O and a molecular weight of 415.42 g/mol. Idelalisib has the following structural formula:
## Pharmacodynamics
### Electrocardiographic Effects
- The effect of Idelalisib (150 mg and 400 mg) on the QT/QTc interval was evaluated in a placebo- and positive-controlled (moxifloxacin 400 mg) crossover study in 46 healthy subjects. At a dose 2.7 times the maximum recommended dose, Idelalisib did not prolong the QT/QTc interval (i.e., not greater than or equal to 10 ms).
## Pharmacokinetics
### Absorption
- Following oral administration of a single dose of Idelalisib in the fasted state, the median Tmax was observed at 1.5 hours.
- Idelalisib exposure increased in a less than dose-proportional manner over a dose range of 50 mg to 350 mg twice daily in the fasted state.
- Relative to fasting conditions, the administration of a single dose of Idelalisib with a high-fat meal increased idelalisib AUC 1.4-fold. Idelalisib can be administered without regard to food.
### Distribution
- Idelalisib is greater than 84% bound to human plasma proteins with no concentration dependence. The mean blood-to-plasma ratio was 0.7. The population apparent central volume of distribution at steady state is 23 L.
### Metabolism and Elimination
- Idelalisib is metabolized to its major metabolite GS-563117 via aldehyde oxidase and CYP3A. GS-563117 is inactive against PI3Kδ in vitro. Idelalisib undergoes minor metabolism by UGT1A4.
- The population apparent systemic clearance at steady-state is 14.9 L/hr. The population terminal elimination half-life of idelalisib is 8.2 hours. Following a single dose of 150 mg of [14C] idelalisib, 78% and 14% of the radioactivity was excreted in feces and urine, respectively. GS-563117 accounted for 49% of the radioactivity in the urine and 44% in the feces.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenicity studies with idelalisib have not been conducted.
- Idelalisib did not induce mutations in the bacterial mutagenesis (Ames) assay and was not clastogenic in the in vitro chromosome aberration assay using human peripheral blood lymphocytes. Idelalisib was genotoxic in males in the in vivo rat micronucleus study at a high dose of 2000 mg/kg.
- Idelalisib may impair fertility in humans. In a fertility study, treated male rats (25, 50, or 100 mg/kg/day of idelalisib) were mated with untreated females. Decreased epididymidal and testicular weights were observed at all dose levels and reduced sperm concentration at the mid- and high doses; however, there were no adverse effects on fertility parameters. The low dose in males resulted in an exposure (AUC) that is approximately 50% of the exposure in patients at the recommended dose of 150 mg twice daily.
- In a separate fertility study, treated female rats (25, 50, or 100 mg/kg/day of idelalisib) were mated with untreated males. There were no adverse effects on fertility parameters; however, there was a decrease in the number of live embryos at the high dose. The high dose in females resulted in an exposure (AUC) that is approximately 17-fold the exposure in patients at the recommended dose of 150 mg twice daily.
### Animal Pharmacology and/or Toxicology
- Toxicities observed in animals and not reported in patients include cardiac toxicity (cardiomyopathy, inflammation, and increased heart weight) and pancreatic findings (inflammation, hemorrhage, and low-incidence acinar degeneration and hyperplasia). These findings were observed in Sprague-Dawley rats in toxicology studies at exposures (AUCs) higher than those reported in patients at the recommended dose of 150 mg twice daily. Cardiac inflammation was mainly seen in a 28-day study in rats, the other findings were observed in the 13-week and/or 6-month studies.
# Clinical Studies
### Relapsed Chronic Lymphocytic Leukemia
Idelalisib was evaluated in a randomized, double-blind, placebo-controlled study (Study 1) in 220 subjects with relapsed CLL who required treatment and were unable to tolerate standard chemoimmunotherapy due to coexisting medical conditions, reduced renal function as measured by creatinine clearance <60 mL/min, or NCI CTCAE Grade ≥3 neutropenia or Grade ≥3 thrombocytopenia resulting from myelotoxic effects of prior therapy with cytotoxic agents. Subjects were randomized 1:1 to receive 8 doses of rituximab (first dose at 375 mg/m2, subsequent doses at 500 mg/m2 every 2 weeks for 4 infusions and every 4 weeks for an additional 4 infusions) in combination with either an oral placebo twice daily or with Idelalisib 150 mg taken twice daily until disease progression or unacceptable toxicity.
- In Study 1, the median age was 71 (range 47, 92) with 78% over 65, 66% were male, and 90% were Caucasian. The median time since diagnosis was 8.5 years. The median number of prior therapies was 3. Nearly all (96%) subjects had received prior anti-CD20 monoclonal antibodies. The most common (>15%) prior regimens were: bendamustine + rituximab (98 subjects, 45%), fludarabine + cyclophosphamide + rituximab (75 subjects, 34%), single-agent rituximab (67 subjects, 31%), fludarabine + rituximab (37 subjects, 17%), and chlorambucil (36 subjects, 16%).
- The primary endpoint was progression free survival (PFS), as assessed by an independent review committee (IRC). The trial was stopped for efficacy following the first pre-specified interim analysis. Results of a second interim analysis continued to show a statistically significant improvement for Idelalisib + rituximab over placebo + rituximab for the primary endpoint of PFS (HR: 0.18, 95% CI [0.10, 0.32], p < 0.0001). The efficacy results are shown in Table 6 and the Kaplan-Meier curve for PFS is shown in Figure 1.
### Relapsed Follicular B-cell non-Hodgkin Lymphoma
- The safety and efficacy of Idelalisib in patients with FL was evaluated in a single-arm, multicenter clinical trial which included 72 patients with follicular B-cell non-Hodgkin lymphoma who had relapsed within 6 months following rituximab and an alkylating agent and had received at least 2 prior treatments. The median age was 62 years (range 33 to 84), 54% were male, and 90% were Caucasian. At enrollment, 92% of patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 4.7 years and the median number of prior treatments was 4 (range 2 to 12). The most common prior combination regimens were R-CHOP (49%), BR (50%), and R-CVP (28%). At baseline, 33% of patients had extranodal involvement and 26% had bone marrow involvement.
- Patients received 150 mg of Idelalisib orally twice daily until evidence of disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group response criteria for malignant lymphoma. The primary endpoint was Independent Review Committee-assessed overall response rate (ORR). Efficacy results are summarized in Table 7.
### Relapsed Small Lymphocytic Lymphoma
- The safety and efficacy of Idelalisib in patients with SLL was evaluated in a single-arm, multicenter clinical trial which included 26 patients with small lymphocytic lymphoma who had relapsed within 6 months following rituximab and an alkylating agent and had received at least 2 prior treatments. The median age was 65 years (range 50 to 87), 73% were male, and 81% were Caucasian. At enrollment, 96% of patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 6.7 years and the median number of prior treatments was 4 (range 2 to 9). The most common prior combination regimens were BR (81%), FCR (62%) and R-CHOP (35%). At baseline, 27% of patients had extranodal involvement.
- Subjects received 150 mg of Idelalisib orally twice daily until evidence of disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group response criteria for malignant lymphoma. The primary endpoint was Independent Review Committee-assessed overall response rate (ORR). Efficacy results are summarized in Table 8.
# How Supplied
Idelalisib tablets supplied as follows:
## Storage
Store between 20–30 °C (68–86 °F) with excursions permitted 15–30 ºC (59–86 ºF).
- Dispense only in original container.
- Do not use if seal over bottle opening is broken or missing.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Idelalisib Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Idelalisib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Zydelig
# Look-Alike Drug Names
There is limited information regarding Idelalisib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Idelalisib | |
b18612c5e481651c8030bd6d08ee9d91fa69f2da | wikidoc | Idiopathic | Idiopathic
# Overview
Idiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios (one's own) + παθος, pathos (suffering), it means approximately "a disease of its own kind."
It is technically a term from nosology, the classification of disease. For most medical conditions, one or more causes are somewhat understood, but in a certain percentage of people with the condition, the cause may not be readily apparent or characterized. In these cases, the origin of the condition is said to be "idiopathic."
With some medical conditions, the medical community cannot establish a root cause for a large percentage of all cases (e.g. Focal segmental glomerulosclerosis, the majority of which are idiopathic); with other conditions, however, idiopathic cases account for a small percentage (e.g., pulmonary fibrosis). As medical and scientific advances are made with relation to a particular condition or disease, more root causes are discovered, and the percentage of cases designated as idiopathic shrinks.
In his book The Human Body, Isaac Asimov noted a comment about the term "idiopathic" made in the 20th edition of Stedman's Medical Dictionary: "A high-flown term to conceal ignorance." | Idiopathic
# Overview
Idiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios (one's own) + παθος, pathos (suffering), it means approximately "a disease of its own kind."
It is technically a term from nosology, the classification of disease. For most medical conditions, one or more causes are somewhat understood, but in a certain percentage of people with the condition, the cause may not be readily apparent or characterized. In these cases, the origin of the condition is said to be "idiopathic."
With some medical conditions, the medical community cannot establish a root cause for a large percentage of all cases (e.g. Focal segmental glomerulosclerosis, the majority of which are idiopathic);[1] with other conditions, however, idiopathic cases account for a small percentage (e.g., pulmonary fibrosis).[2] As medical and scientific advances are made with relation to a particular condition or disease, more root causes are discovered, and the percentage of cases designated as idiopathic shrinks.
In his book The Human Body, Isaac Asimov noted a comment about the term "idiopathic" made in the 20th edition of Stedman's Medical Dictionary: "A high-flown term to conceal ignorance." | https://www.wikidoc.org/index.php/Idiopathic | |
1cdb77a5bbcd3bc36b944617a52346c1641b0bc8 | wikidoc | Ifosfamide | Ifosfamide
# 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
Ifosfamide is an alkylating agent that is FDA approved for the treatment of germ cell testicular cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include alopecia, nausea and vomiting, leukopenia, anemia, CNS toxicity, hematuria, and infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Ifosfamide is indicated for use in combination with certain other approved antineoplastic agents for third-line chemotherapy of germ cell testicular cancer.
- Dosage:
- 1.2 grams per m2 per day for 5 consecutive days
- Treatment is repeated every 3 weeks or after recovery from hematologic toxicity
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ifosfamide in adult patients.
### Non–Guideline-Supported Use
- Acute lymphoid leukemia
- Breast cancer
- Carcinoma of bladder
- Cervical cancer
- Endometrial carcinoma
- Ewing's sarcoma of bone
- Germ cell tumor
- Germ cell tumor of ovary
- Gestational trophoblastic neoplasia
- Head and neck cancer
- Hodgkin's disease
- Combinations therapy: Ifosfamide and mesna (3000 mg/m(2) each, infused daily as a continuous infusion on days 1 through 4), and vinorelbine (25 mg/m(2) as a rapid IV injection on days 1 and 5). The cycle was repeated every 21 days for a median of 6 cycles.
- Liver carcinoma
- Malignant tumor of thymus
- Metastatic cerebral tumor
- Multiple myeloma
- Nephroblastoma
- Neuroblastoma
- Non-Hodgkin's lymphoma
- Non-small cell lung cancer
- Osteosarcoma of bone
- Ovarian cancer
- Sarcoma of soft tissue
- Combination therapy: 5 cycles of epirubicin (60 mg/m(2)/day on days 1 and 2) and ifosfamide (1.8 g/m(2)/day on days 1 through 5) repeated every 3 weeks. Mesna was administered at 20% of the ifosfamide dose before and 4 and 8 hours after ifosfamide.
- Small cell carcinoma of lung
- Testicular cancer
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in children have not been established
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ifosfamide in pediatric patients.
### Non–Guideline-Supported Use
- Ewing's sarcoma of bone
- Non-Hodgkin's lymphoma
- Osteosarcoma of bone
- Sarcoma of soft tissue
# Contraindications
Ifosfamide for Injection is contraindicated in patients with:
- Known hypersensitivity to administration of ifosfamide
- Urinary outflow obstruction
# Warnings
Treatment with ifosfamide may cause myelosuppression and significant suppression of immune responses, which can lead to severe infections. Fatal outcomes of ifosfamide-associated myelosuppression have been reported. Ifosfamide-induced myelosuppression can cause leukopenia, neutropenia, thrombocytopenia (associated with a higher risk of bleeding events), and anemia. The nadir of the leukocyte count tends to be reached approximately during the second week after administration. When Ifosfamide for Injection is given in combination with other chemotherapeutic/hematotoxic agents and/or radiation therapy, severe myelosuppression is frequently observed. The risk of myelosuppression is dose-dependent and is increased with administration of a single high dose compared with fractionated administration. The risk of myelosuppression is also increased in patients with reduced renal function.
Severe immunosuppression has led to serious, sometimes fatal, infections. Sepsis and septic shock also have been reported. Infections reported with ifosfamide include pneumonias, as well as other bacterial, fungal, viral, and parasitic infections. Latent infections can be reactivated. In patients treated with ifosfamide, reactivation has been reported for various viral infections. Infections must be treated appropriately. Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing physician. In case of neutropenic fever, antibiotics and/or antimycotics must be given. Close hematologic monitoring is recommended. White blood cell (WBC) count, platelet count and hemoglobin should be obtained prior to each administration and at appropriate intervals after administration. Unless clinically essential, Ifosfamide for Injection should not be given to patients with a WBC count below 2000/µL and/or a platelet count below 50,000/µL.
Ifosfamide for Injection should be given cautiously, if at all, to patients with presence of an infection, severe immunosuppression or compromised bone marrow reserve, as indicated by leukopenia, granulocytopenia, extensive bone marrow metastases, prior radiation therapy, or prior therapy with other cytotoxic agents.
Administration of ifosfamide can cause CNS toxicity and other neurotoxic effects. The risk of CNS toxicity and other neurotoxic effects necessitates careful monitoring of the patient. Neurologic manifestations consisting of somnolence, confusion, hallucinations, blurred vision, psychotic behavior, extrapyramidal symptoms, urinary incontinence, seizures, and in some instances, coma, have been reported following Ifosfamide for Injection therapy. There have also been reports of peripheral neuropathy associated with ifosfamide use.
Ifosfamide neurotoxicity may become manifest within a few hours to a few days after first administration and in most cases resolves within 48 to 72 hours of ifosfamide discontinuation. Symptoms may persist for longer periods of time. Supportive therapy should be maintained until their complete resolution. Occasionally, recovery has been incomplete. Fatal outcomes of CNS toxicity have been reported. Recurrence of CNS toxicity after several uneventful treatment courses has been reported. If encephalopathy develops, administration of ifosfamide should be discontinued.
Due to the potential for additive effects, drugs acting on the CNS (such as antiemetics, sedatives, narcotics, or antihistamines) must be used with particular caution or, if necessary, be discontinued in case of ifosfamide-induced encephalopathy.
Manifestations of CNS toxicity may impair a patient’s ability to operate an automobile or other heavy machinery.
Ifosfamide is both nephrotoxic and urotoxic. Glomerular and tubular kidney function must be evaluated before commencement of therapy as well as during and after treatment. Monitor urinary sediment regularly for the presence of erythrocytes and other signs of uro/nephrotoxicity.
Monitor serum and urine chemistries, including phosphorus and potassium regularly. Administer appropriate replacement therapy as indicated. Renal parenchymal and tubular necrosis have been reported in patients treated with ifosfamide. Acute tubular necrosis, acute renal failure, and chronic renal failure secondary to ifosfamide therapy have been reported, and fatal outcome from nephrotoxicity has been documented.
Disorders of renal function, (glomerular and tubular) following ifosfamide administration are very common. Manifestations include a decrease in glomerular filtration rate, increased serum creatinine, proteinuria, enzymuria, cylindruria, aminoaciduria, phosphaturia, and glycosuria as well as tubular acidosis. Fanconi syndrome, renal rickets, and growth retardation in children as well as osteomalacia in adults also have been reported. Development of a syndrome resembling SIADH (syndrome of inappropriate antidiuretic hormone secretion) has been reported with ifosfamide.
Tubular damage may become apparent during therapy, months or even years after cessation of treatment. Glomerular or tubular dysfunction may resolve with time, remain stable, or progress over a period of months or years, even after completion of ifosfamide treatment.
The risk and expected benefits of ifosfamide therapy should be carefully weighed when considering the use of ifosfamide in patients with preexisting renal impairment or reduced nephron reserve.
Urotoxic side effects, especially hemorrhagic cystitis, have been very commonly associated with the use of Ifosfamide for Injection. These urotoxic effects can be reduced by prophylactic use of mesna.
Hemorrhagic cystitis requiring blood transfusion has been reported with ifosfamide. The risk of hemorrhagic cystitis is dose-dependent and increased with administration of single high doses compared to fractionated administration. Hemorrhagic cystitis after a single dose of ifosfamide has been reported. Past or concomitant radiation of the bladder or busulfan treatment may increase the risk for hemorrhagic cystitis.
Before starting treatment, it is necessary to exclude or correct any urinary tract obstructions.
During or immediately after administration, adequate amounts of fluid should be ingested or infused to force dieresis in order to reduce the risk of urinary tract toxicity. Obtain a urinalysis prior to each dose of Ifosfamide for Injection. If microscopic hematuria (greater than 10 RBCs per high power field) is present, then subsequent administration should be withheld until complete resolution. Further administration of Ifosfamide for Injection should be given with vigorous oral or parenteral hydration.
Ifosfamide should be used with caution, if at all, in patients with active urinary tract infections.
Manifestations of cardiotoxicity reported with ifosfamide treatment include:
- Supraventricular or ventricular arrhythmias, including atrial/supraventricular tachycardia, atrial fibrillation, pulseless ventricular tachycardia
- Decreased QRS voltage and ST-segment or T-wave changes
- Toxic cardiomyopathy leading to heart failure with congestion and hypotension
- Pericardial effusion, fibrinous pericarditis, and epicardial fibrosis
Fatal outcome of ifosfamide-associated cardiotoxicity has been reported.
The risk of developing cardiotoxic effects is dose-dependent. It is increased in patients with prior or concomitant treatment with other cardiotoxic agents or radiation of the cardiac region and, possibly, renal impairment.
Particular caution should be exercised when ifosfamide is used in patients with risk factors for cardiotoxicity and in patients with preexisting cardiac disease.
Interstitial pneumonitis, pulmonary fibrosis, and other forms of pulmonary toxicity have been reported with ifosfamide treatment. Pulmonary toxicity leading to respiratory failure as well as fatal outcome has also been reported. Monitor for signs and symptoms of pulmonary toxicity and treat as clinically indicated.
Treatment with ifosfamide involves the risk of secondary tumors and their precursors as late sequelae. The risk of myelodysplastic alterations, some progressing to acute leukemias, is increased. Other malignancies reported after use of ifosfamide or regimens with ifosfamide include lymphoma, thyroid cancer, and sarcomas.
The secondary malignancy may develop several years after chemotherapy has been discontinued.
Veno-occlusive liver disease has been reported with chemotherapy that included ifosfamide.
Anaphylactic/anaphylactoid reactions have been reported in association with ifosfamide. Cross-sensitivity between oxazaphosphorine cytotoxic agents has been reported.
Ifosfamide may interfere with normal wound healing.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted from 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 adverse reactions and frequencies below are based on 30 publications describing clinical experience with fractionated administration of ifosfamide as monotherapy with a total dose of 4 to 12 g/m2 per course.
## Postmarketing Experience
The following adverse reactions have been reported in the post-marketing experience, listed by MedDRA System Organ Class (SOC), then by Preferred Term in order of severity, where feasible. 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.
The following manifestations have been associated with myelosuppression and immunosuppression caused by ifosfamide: increased risk for and severity of infections†, pneumonias†, sepsis and septic shock (including fatal outcomes), as well as reactivation of latent infections, including viral hepatitis†, Pneumocystis jiroveci†, herpes zoster, Strongyloides, progressive multifocal leukoencephalopathy†, and other viral and fungal infections.
† Severe immunosuppression has led to serious, sometimes fatal, infections.
As treatment-related secondary malignancy*, Acute leukemia- (Acute myeloid leukemia)*, Acute promyelocytic leukemia*, Acute lymphocytic leukemia*, Myelodysplastic syndrome, Lymphoma (Non-Hodgkin’s lymphoma), Sarcomas*, Renal cell carcinoma, Thyroid cancer.
Hematotoxicity*, Myelosuppression manifested as Bone marrow failure, Agranulocytosis; Febrile bone marrow aplasia; Disseminated intravascular coagulation, Hemolytic uremic syndrome, Hemolytic anemia, Neonatal anemia, Methemoglobinemia.
Angioedema*, Anaphylactic reaction, Immunosuppression, Urticaria, Hypersensitivity reaction.
Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Tumor lysis syndrome, Metabolic acidosis, Hypokalemia, Hypocalcemia, Hypophosphatemia, Hyperglycemia, Polydipsia.
Panic attack, Catatonia, Mania, Paranoia, Delusion, Delirium, Bradyphrenia, Mutism, Mental status change, Echolalia, Logorrhea, Perseveration, Amnesia.
Convulsion*, Status epilepticus (convulsive and nonconvulsive), reversible posterior leukoencephalopathy syndrome, Leukoencephalopathy, Extrapyramidal disorder, Asterixis, Movement disorder, Polyneuropathy, Dysesthesia, Hypothesia, Paresthesia, Neuralgia, Gait disturbance, Fecal incontinence, Dysarthria.
Visual impairment, Vision blurred, Conjunctivitis, Eye irritation
Deafness, Hypoacusis, Vertigo, Tinnitus
Cardiotoxicity*, Cardiac arrest*, Ventricular fibrillation*, Ventricular tachycardia*, Cardiogenic shock*, Myocardial infarction*, Cardiac failure*, Bundle branch block left, Bundle branch block right, Pericardial effusion, Myocardial hemorrhage, Angina pectoris, Left ventricular failure, Cardiomyopathy*, Congestive cardiomyopathy, Myocarditis*, Arrhythmia*, Pericarditis, Atrial fibrillation, Atrial flutter, Bradycardia, Supraventricular extrasystoles, Premature atrial contractions, Ventricular extrasystoles, Myocardial depression, Palpitations, Ejection fraction decreased*, Electrocardiogram ST-segment abnormal, Electrocardiogram T-wave inversion, Electrocardiogram QRS complex abnormal
Pulmonary embolism, Deep vein thrombosis, Capillary leak syndrome, Vasculitis, Hypertension, Flushing, Blood pressure decreased
Respiratory failure*, Acute respiratory distress syndrome*, Pulmonary hypertension*, Interstitial lung disease- as manifested by Pulmonary fibrosis*, Alveolitis allergic, Interstitial pneumonitis, Pneumonitis*, Pulmonary edema*,Pleural effusion, Bronchospasm, Dyspnea, Hypoxia, Cough
Cecitis, Colitis, Enterocolitis, Pancreatitis, Ileus, Gastrointestinal hemorrhage, Mucosal ulceration, Constipation, Abdominal pain, Salivary hypersecretion.
Hepatic failure*, Hepatitis fulminant*, Veno-occlusive liver disease, Portal vein thrombosis, Cytolytic hepatitis, Cholestasis
Toxic epidermal necrolysis, Stevens-Johnson syndrome, Palmar-plantar erythrodysesthesia syndrome, Radiation recall dermatitis, Skin necrosis, Facial swelling, Petechiae, Macular rash, Rash, Pruritus, Erythema, Skin hyperpigmentation, Hyperhidrosis, nail disorder.
Rhabdomyolysis, Osteomalacia, Rickets, Growth retardation, Myalgia, Arthralgia, Pain in extremity, Muscle twitching
Fanconi syndrome, Tubulointerstitial nephritis, Nephrogenic diabetes insipidus, Phosphaturia, Aminoaciduria, Polyuria, Enuresis, Feeling of residual urine
Fatal outcomes from acute and chronic renal failure have been documented.
Infertility, Ovarian failure, Premature menopause, Amenorrhea, Ovarian disorder, Ovulation disorder, Azoospermia, Oligospermia, Impairment of spermatogenesis, Blood estrogen decreased, Blood gonadotrophin increased
Fetal growth retardation
Multi-organ failure*, General physical deterioration, Injection/Infusion site reactions including swelling, inflammation, pain, erythema, tenderness, pruritus; Chest pain, Edema, Mucosal inflammation, Pain, Pyrexia, Chills
- Including fatal outcomes
# Drug Interactions
Ifosfamide is a substrate for both CYP3A4 and CYP2B6.
CYP3A4 inducers (e.g., carbamazepine, phenytoin, fosphenytoin, phenobarbital, rifampin, St. John Wort) may increase the metabolism of ifosfamide to its active alkylating metabolites. CYP3A4 inducers may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde. Closely monitor patients taking ifosfamide with CYP3A4 inducers for toxicities and consider dose adjustment.
CYP3A4 inhibitors (e.g., ketoconazole, fluconazole, itraconazole, sorafenib, aprepitant, fosaprepitant, grapefruit, grapefruit juice) may decrease the metabolism of ifosfamide to its active alkylating metabolites, perhaps decreasing the effectiveness of ifosfamide treatment.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
Ifosfamide for Injection can cause fetal harm when administered to a pregnant woman. Fetal growth retardation and neonatal anemia have been reported following exposure to ifosfamide-containing chemotherapy regimens during pregnancy.
Animal studies indicate that ifosfamide is capable of causing gene mutations and chromosomal damage in vivo. In pregnant mice, resorptions increased and anomalies were present at day 19 after a 30 mg/m2 dose of ifosfamide was administered on day 11 of gestation. Embryo-lethal effects were observed in rats following the administration of 54 mg/m2 doses of ifosfamide from the 6th through the 15th day of gestation and embryotoxic effects were apparent after dams received 18 mg/m2 doses over the same dosing period. Ifosfamide is embryotoxic to rabbits receiving 88 mg/m2/day doses from the 6th through the 18th day after mating. The number of anomalies was also significantly increased over the control group.
Women should not become pregnant and men should not father a child during therapy with ifosfamide. Further, men should not father a child for up to 6 months after the end of therapy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug or after treatment, the patient should be apprised of the potential hazard to a fetus.
Pregnancy Category (AUS): D
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ifosfamide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ifosfamide during labor and delivery.
### Nursing Mothers
Ifosfamide is excreted in breast milk. Because of the potential for serious adverse events and the tumorigenicity shown for ifosfamide in animal studies, 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. Women must not breastfeed during treatment with ifosfamide.
### Pediatric Use
Safety and effectiveness have not been established in pediatric patients.
### Geriatic Use
In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
A study of patients 40 to 71 years of age indicated that elimination half-life appears to increase with advancing age. This apparent increase in half-life appeared to be related to increases in volume of distribution of ifosfamide with age. No significant changes in total plasma clearance or renal or non-renal clearance with age were reported.
Ifosfamide and its metabolites are 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 Ifosfamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ifosfamide with respect to specific racial populations.
### Renal Impairment
No formal studies were conducted in patients with renal impairment. Ifosfamide and its metabolites are known to be excreted by the kidneys and may accumulate in plasma with decreased renal function. Patients with renal impairment should be closely monitored for toxicity and dose reduction may be considered. Ifosfamide and its metabolites are dialyzable.
### Hepatic Impairment
No formal studies were conducted in patients with hepatic impairment. Ifosfamide is extensively metabolized in the liver and forms both efficacious and toxic metabolites. Ifosfamide for Injection should be given cautiously to patients with impaired hepatic function.
### Females of Reproductive Potential and Males
Ifosfamide interferes with oogenesis and spermatogenesis. Amenorrhea, azoospermia, and sterility in both sexes have been reported. Development of sterility appears to depend on the dose of ifosfamide, duration of therapy, and state of gonadal function at the time of treatment. Sterility may be irreversible in some patients.
Female Patients
Amenorrhea has been reported in patients treated with ifosfamide. The risk of permanent chemotherapy-induced amenorrhea increases with age. Pediatric patients treated with ifosfamide during prepubescence subsequently may not conceive and those who retain ovarian function after completing treatment are at increased risk of developing premature menopause.
Male Patients
Men treated with ifosfamide may develop oligospermia or azoospermia. Pediatric patients treated with ifosfamide during prepubescence might not develop secondary sexual characteristics normally, but may have oligospermia or azoospermia. Azoospermia may be reversible in some patients, though the reversibility may not occur for several years after cessation of therapy. Sexual function and libido are generally unimpaired in these patients. Some degree of testicular atrophy may occur. Patients treated with ifosfamide have subsequently fathered children.
### Immunocompromised Patients
There is no FDA guidance one the use of Ifosfamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Intravenous
### Monitoring
There is limited information regarding Ifosfamide Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Ifosfamide and IV administrations.
# Overdosage
- No specific antidote for Ifosfamide for Injection is known.
- Patients who receive an overdose should be closely monitored for the development of toxicities. Serious consequences of overdosage include manifestations of dose-dependent toxicities such as CNS toxicity, nephrotoxicity, myelosuppression, and mucositis.
- Management of overdosage would include general supportive measures to sustain the patient through any period of toxicity that might occur, including appropriate state-of-the-art treatment for any concurrent infection, myelosuppression, or other toxicity. Ifosfamide as well as ifosfamide metabolites are dialyzable.
- Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with overdose.
# Pharmacology
## Mechanism of Action
Ifosfamide is a prodrug that requires metabolic activation by hepatic cytochrome P450 isoenzymes to exert its cytotoxic activity. Activation occurs by hydroxylation at the ring carbon atom forming the unstable intermediate 4-hydroxyifosfamide and its ring-opened aldo tautomer, which decomposes to yield the cytotoxic and urotoxic compound acrolein and an alkylating isophosphoramide mustard as well as multiple other nontoxic products. The exact mechanism of action of ifosfamide has not been determined, but its cytotoxic action is primarily through DNA crosslinks caused by alkylation by the isophosphoramide mustard at guanine N-7 positions. The formation of inter- and intra-strand cross-links in the DNA results in cell death.
## Structure
The molecular formula is C7H15Cl2N2O2P and its molecular weight is 261.1. Its structural formula is:
## Pharmacodynamics
There is limited information regarding Ifosfamide Pharmacodynamics in the drug label.
## Pharmacokinetics
Ifosfamide exhibits dose-dependent pharmacokinetics in humans. At single doses of 3.8 to 5.0 g/m2, the plasma concentrations decay biphasically and the mean terminal elimination half-life is about 15 hours. At doses of 1.6 to 2.4 g/m2/day, the plasma decay is monoexponential and the terminal elimination half-life is about 7 hours.
Ifosfamide exhibits time-dependent pharmacokinetics in humans. Following intravenous administration of 1.5 g/m2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, a decrease in the median elimination half-life from 7.2 hour on Day 1 to 4.6 hours on Day 5 occurred with a concomitant increase in the median clearance from 66 mL/min on Day 1 to 115 mL/min on Day 5. There was no significant change in the volume of distribution on Day 5 compared with Day 1.
Ifosfamide volume of distribution (Vd) approximates the total body water volume, suggesting that distribution takes place with minimal tissue binding. Following intravenous administration of 1.5 g/m2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, the median Vd of ifosfamide was 0.64 L/kg on Day 1 and 0.72 L/kg on Day 5. Ifosfamide shows little plasma protein binding. Ifosfamide and its active metabolites are extensively bound by red blood cells. Ifosfamide is not a substrate for P-glycoprotein.
Ifosfamide is extensively metabolized in humans through two metabolic pathways: ring oxidation ("activation") to form the active metabolite, 4-hydroxy-ifosfamide and side-chain oxidation to form the inactive metabolites, 3-dechloro-ethylifosfamide or 2-dechloroethylifosfamide with liberation of the toxic metabolite, chloroacetaldehyde. Small quantities (nmol/mL) of ifosfamide mustard and 4-hydroxyifosfamide are detectable in human plasma. Metabolism of ifosfamide is required for the generation of the biologically active species and while metabolism is extensive, it is also quite variable among patients.
After administration of doses of 5 g/m2 of 14C-labeled ifosfamide, from 70% to 86% of the dosed radioactivity was recovered in urine as metabolites, with about 61% of the dose excreted as parent compound. At doses of 1.6 to 2.4 g/m2 only 12% to 18% of the dose was excreted in the urine as unchanged drug within 72 hours. Two different dechloroethylated derivatives of ifosfamide, 4-carboxyifosfamide, thiodiacetic acid and cysteine conjugates of chloroacetic acid have been identified as the major urinary metabolites of ifosfamide in humans and only small amounts of 4-hydroxyifosfamide and acrolein are present.
## Nonclinical Toxicology
Ifosfamide has been shown to be carcinogenic in rats when administered by intraperitoneal injection at 6 mg/kg (37 mg/m2, or about 3% of the daily human dose on a mg/m2 basis) 3 times a week for 52 weeks. Female rats had a significantly higher incidence of uterine leiomyosarcomas and mammary fibroadenomas than vehicle controls.
The mutagenic potential of ifosfamide has been documented in bacterial systems in vitro and mammalian cells in vivo. In vivo, ifosfamide has induced mutagenic effects in mice and Drosophila melanogaster germ cells, and has induced a significant increase in dominant lethal mutations in male mice as well as recessive sex-linked lethal mutations in Drosophila.
# Clinical Studies
Patients with refractory testicular cancer (n=59) received a combination of ifosfamide, cisplatin, and either etoposide (VePesid) or vinblastine (VIP) as third-line therapy or later. The selection of etoposide or vinblastine (“V” in the VIP regimen) was guided by the therapeutic effect achieved with prior regimens. The contribution of ifosfamide to the VIP combination was determined in patients treated with cisplatin-etoposide prior to ifosfamide- cisplatin-etoposide or those who received cisplatin-vinblastine prior to ifosfamide-cisplatin-vinblastine.
A total of 59 patients received a third-line salvage regimen which consisted of ifosfamide 1.2 g/m2/day intravenously on days 1 to 5, cisplatin 20 mg/m2/day intravenously on days 1 to 5, and either etoposide 75 mg/m2/day intravenously on days 1 to 5 or vinblastine 0.22 mg/kg intravenously on day 1. Efficacy results with the VIP regimen were compared to data pooled from six single agent phase II trials conducted between August 1980 and October 1985 including a total of 90 patients of whom 65 were eligible as controls of this study. Twenty-three patients in the VIP regimen became free of disease with VIP alone or VIP plus surgery, whereas a single patient in the historical control group achieved complete response. The median survival time exceeded two years in the VIP group versus less than one year in the control group. Performance status ≥ 80, embryonal carcinoma and minimal disease were favorable prognostic factors for survival. In all prognostic categories, the difference between VIP and historical controls remained highly significant.
In a study, 50 fully evaluable patients with germ cell testicular cancer were treated with Ifosfamide for Injection in combination with cisplatin and either vinblastine or etoposide after failing (47 of 50 patients) at least two prior chemotherapy regimens consisting of cisplatin/vinblastine/bleomycin, (PVB), cisplatin/vinblastine/actinomycin D/bleomycin/cyclophosphamide, (VAB6), or the combination of cisplatin and etoposide. Patients were selected for remaining cisplatin sensitivity because they had previously responded to a cisplatin containing regimen and had not progressed while on the cisplatin containing regimen or within 3 weeks of stopping it. Patients served as their own control based on the premise that long term complete responses could not be achieved by retreatment with a regimen to which they had previously responded and subsequently relapsed.
Ten of 50 fully evaluable patients were still alive 2 to 5 years after treatment. Four of the 10 long term survivors were rendered free of cancer by surgical resection after treatment with the ifosfamide regimen; median survival for the entire group of 50 fully evaluable patients was 53 weeks.
# How Supplied
- Ifosfamide for injection 1 gr.
- NDC 0338-3991-01
- Single-Dose Vial
- Ifosfamide for injection 3 gr.
- NDC 0338-3993-01
- Single-Dose Vial
## Storage
Store at 20°C to 25°C (68°F to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Inform patients of the risks associated with the use of Ifosfamide for Injection as well as the plan for regular blood monitoring during therapy.
Specifically inform patients of the following:
- Treatment with ifosfamide may cause myelosuppression which can be severe and lead to fatal outcome. Significant suppression of immune responses can also occur which can lead to severe infections. Latent infections can be reactivated. Patients should report fever or other symptoms of an infection.
- The risk of bleeding and anemia.
- The risk of CNS toxicity and other neurotoxic effects with fatal outcome.
- The risk of bladder and kidney toxicity. Patients should be aware of the need to increase fluid intake and frequent voiding to prevent accumulation in the bladder.
- The risk of cardiotoxicity and fatal outcome. Patients should report preexisting cardiac disease.
- The risk of pulmonary toxicity leading to respiratory failure with fatal outcome.
- The risk of secondary malignancies due to therapy.
- The risk of veno-occlusive liver disease.
- The potential hazard to a fetus if a patient becomes pregnant or fathers a child during therapy and for up to 6 months after therapy. Effective methods of contraception should be used during therapy and for up to 6 months after therapy.
- The potential for serious adverse reactions and tumorigenicity when children are breastfed during therapy.
- The risk of amenorrhea, premature menopause, and sterility.
- The risk of alopecia, wound healing, and other serious skin and subcutaneous tissue disorders.
- Therapy may cause gastrointestinal disorders and alcohol may increase nausea and vomiting.
- The risk of stomatitis and the importance of proper oral hygiene.
- The risk of eye disorders such as visual impairment, blurred vision, and eye irritation.
- The risk of ear and labyrinth disorders such as deafness, vertigo, and tinnitus.
# Precautions with Alcohol
Alcohol-Ifosfamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Ifex
# Look-Alike Drug Names
There is limited information regarding Ifosfamide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ifosfamide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]
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# Black Box Warning
# Overview
Ifosfamide is an alkylating agent that is FDA approved for the treatment of germ cell testicular cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include alopecia, nausea and vomiting, leukopenia, anemia, CNS toxicity, hematuria, and infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Ifosfamide is indicated for use in combination with certain other approved antineoplastic agents for third-line chemotherapy of germ cell testicular cancer.
- Dosage:
- 1.2 grams per m2 per day for 5 consecutive days
- Treatment is repeated every 3 weeks or after recovery from hematologic toxicity
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ifosfamide in adult patients.
### Non–Guideline-Supported Use
- Acute lymphoid leukemia
- Breast cancer
- Carcinoma of bladder
- Cervical cancer
- Endometrial carcinoma
- Ewing's sarcoma of bone
- Germ cell tumor
- Germ cell tumor of ovary
- Gestational trophoblastic neoplasia
- Head and neck cancer
- Hodgkin's disease
- Combinations therapy: Ifosfamide and mesna (3000 mg/m(2) each, infused daily as a continuous infusion on days 1 through 4), and vinorelbine (25 mg/m(2) as a rapid IV injection on days 1 and 5). The cycle was repeated every 21 days for a median of 6 cycles. [1]
- Liver carcinoma
- Malignant tumor of thymus
- Metastatic cerebral tumor
- Multiple myeloma
- Nephroblastoma
- Neuroblastoma
- Non-Hodgkin's lymphoma
- Non-small cell lung cancer
- Osteosarcoma of bone
- Ovarian cancer
- Sarcoma of soft tissue
- Combination therapy: 5 cycles of epirubicin (60 mg/m(2)/day on days 1 and 2) and ifosfamide (1.8 g/m(2)/day on days 1 through 5) repeated every 3 weeks. Mesna was administered at 20% of the ifosfamide dose before and 4 and 8 hours after ifosfamide. [2]
- Small cell carcinoma of lung
- Testicular cancer
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in children have not been established
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ifosfamide in pediatric patients.
### Non–Guideline-Supported Use
- Ewing's sarcoma of bone
- Non-Hodgkin's lymphoma
- Osteosarcoma of bone
- Sarcoma of soft tissue
# Contraindications
Ifosfamide for Injection is contraindicated in patients with:
- Known hypersensitivity to administration of ifosfamide
- Urinary outflow obstruction
# Warnings
Treatment with ifosfamide may cause myelosuppression and significant suppression of immune responses, which can lead to severe infections. Fatal outcomes of ifosfamide-associated myelosuppression have been reported. Ifosfamide-induced myelosuppression can cause leukopenia, neutropenia, thrombocytopenia (associated with a higher risk of bleeding events), and anemia. The nadir of the leukocyte count tends to be reached approximately during the second week after administration. When Ifosfamide for Injection is given in combination with other chemotherapeutic/hematotoxic agents and/or radiation therapy, severe myelosuppression is frequently observed. The risk of myelosuppression is dose-dependent and is increased with administration of a single high dose compared with fractionated administration. The risk of myelosuppression is also increased in patients with reduced renal function.
Severe immunosuppression has led to serious, sometimes fatal, infections. Sepsis and septic shock also have been reported. Infections reported with ifosfamide include pneumonias, as well as other bacterial, fungal, viral, and parasitic infections. Latent infections can be reactivated. In patients treated with ifosfamide, reactivation has been reported for various viral infections. Infections must be treated appropriately. Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing physician. In case of neutropenic fever, antibiotics and/or antimycotics must be given. Close hematologic monitoring is recommended. White blood cell (WBC) count, platelet count and hemoglobin should be obtained prior to each administration and at appropriate intervals after administration. Unless clinically essential, Ifosfamide for Injection should not be given to patients with a WBC count below 2000/µL and/or a platelet count below 50,000/µL.
Ifosfamide for Injection should be given cautiously, if at all, to patients with presence of an infection, severe immunosuppression or compromised bone marrow reserve, as indicated by leukopenia, granulocytopenia, extensive bone marrow metastases, prior radiation therapy, or prior therapy with other cytotoxic agents.
Administration of ifosfamide can cause CNS toxicity and other neurotoxic effects. The risk of CNS toxicity and other neurotoxic effects necessitates careful monitoring of the patient. Neurologic manifestations consisting of somnolence, confusion, hallucinations, blurred vision, psychotic behavior, extrapyramidal symptoms, urinary incontinence, seizures, and in some instances, coma, have been reported following Ifosfamide for Injection therapy. There have also been reports of peripheral neuropathy associated with ifosfamide use.
Ifosfamide neurotoxicity may become manifest within a few hours to a few days after first administration and in most cases resolves within 48 to 72 hours of ifosfamide discontinuation. Symptoms may persist for longer periods of time. Supportive therapy should be maintained until their complete resolution. Occasionally, recovery has been incomplete. Fatal outcomes of CNS toxicity have been reported. Recurrence of CNS toxicity after several uneventful treatment courses has been reported. If encephalopathy develops, administration of ifosfamide should be discontinued.
Due to the potential for additive effects, drugs acting on the CNS (such as antiemetics, sedatives, narcotics, or antihistamines) must be used with particular caution or, if necessary, be discontinued in case of ifosfamide-induced encephalopathy.
Manifestations of CNS toxicity may impair a patient’s ability to operate an automobile or other heavy machinery.
Ifosfamide is both nephrotoxic and urotoxic. Glomerular and tubular kidney function must be evaluated before commencement of therapy as well as during and after treatment. Monitor urinary sediment regularly for the presence of erythrocytes and other signs of uro/nephrotoxicity.
Monitor serum and urine chemistries, including phosphorus and potassium regularly. Administer appropriate replacement therapy as indicated. Renal parenchymal and tubular necrosis have been reported in patients treated with ifosfamide. Acute tubular necrosis, acute renal failure, and chronic renal failure secondary to ifosfamide therapy have been reported, and fatal outcome from nephrotoxicity has been documented.
Disorders of renal function, (glomerular and tubular) following ifosfamide administration are very common. Manifestations include a decrease in glomerular filtration rate, increased serum creatinine, proteinuria, enzymuria, cylindruria, aminoaciduria, phosphaturia, and glycosuria as well as tubular acidosis. Fanconi syndrome, renal rickets, and growth retardation in children as well as osteomalacia in adults also have been reported. Development of a syndrome resembling SIADH (syndrome of inappropriate antidiuretic hormone secretion) has been reported with ifosfamide.
Tubular damage may become apparent during therapy, months or even years after cessation of treatment. Glomerular or tubular dysfunction may resolve with time, remain stable, or progress over a period of months or years, even after completion of ifosfamide treatment.
The risk and expected benefits of ifosfamide therapy should be carefully weighed when considering the use of ifosfamide in patients with preexisting renal impairment or reduced nephron reserve.
Urotoxic side effects, especially hemorrhagic cystitis, have been very commonly associated with the use of Ifosfamide for Injection. These urotoxic effects can be reduced by prophylactic use of mesna.
Hemorrhagic cystitis requiring blood transfusion has been reported with ifosfamide. The risk of hemorrhagic cystitis is dose-dependent and increased with administration of single high doses compared to fractionated administration. Hemorrhagic cystitis after a single dose of ifosfamide has been reported. Past or concomitant radiation of the bladder or busulfan treatment may increase the risk for hemorrhagic cystitis.
Before starting treatment, it is necessary to exclude or correct any urinary tract obstructions.
During or immediately after administration, adequate amounts of fluid should be ingested or infused to force dieresis in order to reduce the risk of urinary tract toxicity. Obtain a urinalysis prior to each dose of Ifosfamide for Injection. If microscopic hematuria (greater than 10 RBCs per high power field) is present, then subsequent administration should be withheld until complete resolution. Further administration of Ifosfamide for Injection should be given with vigorous oral or parenteral hydration.
Ifosfamide should be used with caution, if at all, in patients with active urinary tract infections.
Manifestations of cardiotoxicity reported with ifosfamide treatment include:
- Supraventricular or ventricular arrhythmias, including atrial/supraventricular tachycardia, atrial fibrillation, pulseless ventricular tachycardia
- Decreased QRS voltage and ST-segment or T-wave changes
- Toxic cardiomyopathy leading to heart failure with congestion and hypotension
- Pericardial effusion, fibrinous pericarditis, and epicardial fibrosis
Fatal outcome of ifosfamide-associated cardiotoxicity has been reported.
The risk of developing cardiotoxic effects is dose-dependent. It is increased in patients with prior or concomitant treatment with other cardiotoxic agents or radiation of the cardiac region and, possibly, renal impairment.
Particular caution should be exercised when ifosfamide is used in patients with risk factors for cardiotoxicity and in patients with preexisting cardiac disease.
Interstitial pneumonitis, pulmonary fibrosis, and other forms of pulmonary toxicity have been reported with ifosfamide treatment. Pulmonary toxicity leading to respiratory failure as well as fatal outcome has also been reported. Monitor for signs and symptoms of pulmonary toxicity and treat as clinically indicated.
Treatment with ifosfamide involves the risk of secondary tumors and their precursors as late sequelae. The risk of myelodysplastic alterations, some progressing to acute leukemias, is increased. Other malignancies reported after use of ifosfamide or regimens with ifosfamide include lymphoma, thyroid cancer, and sarcomas.
The secondary malignancy may develop several years after chemotherapy has been discontinued.
Veno-occlusive liver disease has been reported with chemotherapy that included ifosfamide.
Anaphylactic/anaphylactoid reactions have been reported in association with ifosfamide. Cross-sensitivity between oxazaphosphorine cytotoxic agents has been reported.
Ifosfamide may interfere with normal wound healing.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted from 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 adverse reactions and frequencies below are based on 30 publications describing clinical experience with fractionated administration of ifosfamide as monotherapy with a total dose of 4 to 12 g/m2 per course.
## Postmarketing Experience
The following adverse reactions have been reported in the post-marketing experience, listed by MedDRA System Organ Class (SOC), then by Preferred Term in order of severity, where feasible. 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.
The following manifestations have been associated with myelosuppression and immunosuppression caused by ifosfamide: increased risk for and severity of infections†, pneumonias†, sepsis and septic shock (including fatal outcomes), as well as reactivation of latent infections, including viral hepatitis†, Pneumocystis jiroveci†, herpes zoster, Strongyloides, progressive multifocal leukoencephalopathy†, and other viral and fungal infections.
† Severe immunosuppression has led to serious, sometimes fatal, infections.
As treatment-related secondary malignancy*, Acute leukemia* (Acute myeloid leukemia)*, Acute promyelocytic leukemia*, Acute lymphocytic leukemia*, Myelodysplastic syndrome, Lymphoma (Non-Hodgkin’s lymphoma), Sarcomas*, Renal cell carcinoma, Thyroid cancer.
Hematotoxicity*, Myelosuppression manifested as Bone marrow failure, Agranulocytosis; Febrile bone marrow aplasia; Disseminated intravascular coagulation, Hemolytic uremic syndrome, Hemolytic anemia, Neonatal anemia, Methemoglobinemia.
Angioedema*, Anaphylactic reaction, Immunosuppression, Urticaria, Hypersensitivity reaction.
Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Tumor lysis syndrome, Metabolic acidosis, Hypokalemia, Hypocalcemia, Hypophosphatemia, Hyperglycemia, Polydipsia.
Panic attack, Catatonia, Mania, Paranoia, Delusion, Delirium, Bradyphrenia, Mutism, Mental status change, Echolalia, Logorrhea, Perseveration, Amnesia.
Convulsion*, Status epilepticus (convulsive and nonconvulsive), reversible posterior leukoencephalopathy syndrome, Leukoencephalopathy, Extrapyramidal disorder, Asterixis, Movement disorder, Polyneuropathy, Dysesthesia, Hypothesia, Paresthesia, Neuralgia, Gait disturbance, Fecal incontinence, Dysarthria.
Visual impairment, Vision blurred, Conjunctivitis, Eye irritation
Deafness, Hypoacusis, Vertigo, Tinnitus
Cardiotoxicity*, Cardiac arrest*, Ventricular fibrillation*, Ventricular tachycardia*, Cardiogenic shock*, Myocardial infarction*, Cardiac failure*, Bundle branch block left, Bundle branch block right, Pericardial effusion, Myocardial hemorrhage, Angina pectoris, Left ventricular failure, Cardiomyopathy*, Congestive cardiomyopathy, Myocarditis*, Arrhythmia*, Pericarditis, Atrial fibrillation, Atrial flutter, Bradycardia, Supraventricular extrasystoles, Premature atrial contractions, Ventricular extrasystoles, Myocardial depression, Palpitations, Ejection fraction decreased*, Electrocardiogram ST-segment abnormal, Electrocardiogram T-wave inversion, Electrocardiogram QRS complex abnormal
Pulmonary embolism, Deep vein thrombosis, Capillary leak syndrome, Vasculitis, Hypertension, Flushing, Blood pressure decreased
Respiratory failure*, Acute respiratory distress syndrome*, Pulmonary hypertension*, Interstitial lung disease* as manifested by Pulmonary fibrosis*, Alveolitis allergic, Interstitial pneumonitis, Pneumonitis*, Pulmonary edema*,Pleural effusion, Bronchospasm, Dyspnea, Hypoxia, Cough
Cecitis, Colitis, Enterocolitis, Pancreatitis, Ileus, Gastrointestinal hemorrhage, Mucosal ulceration, Constipation, Abdominal pain, Salivary hypersecretion.
Hepatic failure*, Hepatitis fulminant*, Veno-occlusive liver disease, Portal vein thrombosis, Cytolytic hepatitis, Cholestasis
Toxic epidermal necrolysis, Stevens-Johnson syndrome, Palmar-plantar erythrodysesthesia syndrome, Radiation recall dermatitis, Skin necrosis, Facial swelling, Petechiae, Macular rash, Rash, Pruritus, Erythema, Skin hyperpigmentation, Hyperhidrosis, nail disorder.
Rhabdomyolysis, Osteomalacia, Rickets, Growth retardation, Myalgia, Arthralgia, Pain in extremity, Muscle twitching
Fanconi syndrome, Tubulointerstitial nephritis, Nephrogenic diabetes insipidus, Phosphaturia, Aminoaciduria, Polyuria, Enuresis, Feeling of residual urine
Fatal outcomes from acute and chronic renal failure have been documented.
Infertility, Ovarian failure, Premature menopause, Amenorrhea, Ovarian disorder, Ovulation disorder, Azoospermia, Oligospermia, Impairment of spermatogenesis, Blood estrogen decreased, Blood gonadotrophin increased
Fetal growth retardation
Multi-organ failure*, General physical deterioration, Injection/Infusion site reactions including swelling, inflammation, pain, erythema, tenderness, pruritus; Chest pain, Edema, Mucosal inflammation, Pain, Pyrexia, Chills
- Including fatal outcomes
# Drug Interactions
Ifosfamide is a substrate for both CYP3A4 and CYP2B6.
CYP3A4 inducers (e.g., carbamazepine, phenytoin, fosphenytoin, phenobarbital, rifampin, St. John Wort) may increase the metabolism of ifosfamide to its active alkylating metabolites. CYP3A4 inducers may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde. Closely monitor patients taking ifosfamide with CYP3A4 inducers for toxicities and consider dose adjustment.
CYP3A4 inhibitors (e.g., ketoconazole, fluconazole, itraconazole, sorafenib, aprepitant, fosaprepitant, grapefruit, grapefruit juice) may decrease the metabolism of ifosfamide to its active alkylating metabolites, perhaps decreasing the effectiveness of ifosfamide treatment.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
Ifosfamide for Injection can cause fetal harm when administered to a pregnant woman. Fetal growth retardation and neonatal anemia have been reported following exposure to ifosfamide-containing chemotherapy regimens during pregnancy.
Animal studies indicate that ifosfamide is capable of causing gene mutations and chromosomal damage in vivo. In pregnant mice, resorptions increased and anomalies were present at day 19 after a 30 mg/m2 dose of ifosfamide was administered on day 11 of gestation. Embryo-lethal effects were observed in rats following the administration of 54 mg/m2 doses of ifosfamide from the 6th through the 15th day of gestation and embryotoxic effects were apparent after dams received 18 mg/m2 doses over the same dosing period. Ifosfamide is embryotoxic to rabbits receiving 88 mg/m2/day doses from the 6th through the 18th day after mating. The number of anomalies was also significantly increased over the control group.
Women should not become pregnant and men should not father a child during therapy with ifosfamide. Further, men should not father a child for up to 6 months after the end of therapy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug or after treatment, the patient should be apprised of the potential hazard to a fetus.
Pregnancy Category (AUS): D
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ifosfamide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ifosfamide during labor and delivery.
### Nursing Mothers
Ifosfamide is excreted in breast milk. Because of the potential for serious adverse events and the tumorigenicity shown for ifosfamide in animal studies, 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. Women must not breastfeed during treatment with ifosfamide.
### Pediatric Use
Safety and effectiveness have not been established in pediatric patients.
### Geriatic Use
In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
A study of patients 40 to 71 years of age indicated that elimination half-life appears to increase with advancing age. This apparent increase in half-life appeared to be related to increases in volume of distribution of ifosfamide with age. No significant changes in total plasma clearance or renal or non-renal clearance with age were reported.
Ifosfamide and its metabolites are 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 Ifosfamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ifosfamide with respect to specific racial populations.
### Renal Impairment
No formal studies were conducted in patients with renal impairment. Ifosfamide and its metabolites are known to be excreted by the kidneys and may accumulate in plasma with decreased renal function. Patients with renal impairment should be closely monitored for toxicity and dose reduction may be considered. Ifosfamide and its metabolites are dialyzable.
### Hepatic Impairment
No formal studies were conducted in patients with hepatic impairment. Ifosfamide is extensively metabolized in the liver and forms both efficacious and toxic metabolites. Ifosfamide for Injection should be given cautiously to patients with impaired hepatic function.
### Females of Reproductive Potential and Males
Ifosfamide interferes with oogenesis and spermatogenesis. Amenorrhea, azoospermia, and sterility in both sexes have been reported. Development of sterility appears to depend on the dose of ifosfamide, duration of therapy, and state of gonadal function at the time of treatment. Sterility may be irreversible in some patients.
Female Patients
Amenorrhea has been reported in patients treated with ifosfamide. The risk of permanent chemotherapy-induced amenorrhea increases with age. Pediatric patients treated with ifosfamide during prepubescence subsequently may not conceive and those who retain ovarian function after completing treatment are at increased risk of developing premature menopause.
Male Patients
Men treated with ifosfamide may develop oligospermia or azoospermia. Pediatric patients treated with ifosfamide during prepubescence might not develop secondary sexual characteristics normally, but may have oligospermia or azoospermia. Azoospermia may be reversible in some patients, though the reversibility may not occur for several years after cessation of therapy. Sexual function and libido are generally unimpaired in these patients. Some degree of testicular atrophy may occur. Patients treated with ifosfamide have subsequently fathered children.
### Immunocompromised Patients
There is no FDA guidance one the use of Ifosfamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Intravenous
### Monitoring
There is limited information regarding Ifosfamide Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Ifosfamide and IV administrations.
# Overdosage
- No specific antidote for Ifosfamide for Injection is known.
- Patients who receive an overdose should be closely monitored for the development of toxicities. Serious consequences of overdosage include manifestations of dose-dependent toxicities such as CNS toxicity, nephrotoxicity, myelosuppression, and mucositis.
- Management of overdosage would include general supportive measures to sustain the patient through any period of toxicity that might occur, including appropriate state-of-the-art treatment for any concurrent infection, myelosuppression, or other toxicity. Ifosfamide as well as ifosfamide metabolites are dialyzable.
- Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with overdose.
# Pharmacology
## Mechanism of Action
Ifosfamide is a prodrug that requires metabolic activation by hepatic cytochrome P450 isoenzymes to exert its cytotoxic activity. Activation occurs by hydroxylation at the ring carbon atom forming the unstable intermediate 4-hydroxyifosfamide and its ring-opened aldo tautomer, which decomposes to yield the cytotoxic and urotoxic compound acrolein and an alkylating isophosphoramide mustard as well as multiple other nontoxic products. The exact mechanism of action of ifosfamide has not been determined, but its cytotoxic action is primarily through DNA crosslinks caused by alkylation by the isophosphoramide mustard at guanine N-7 positions. The formation of inter- and intra-strand cross-links in the DNA results in cell death.
## Structure
The molecular formula is C7H15Cl2N2O2P and its molecular weight is 261.1. Its structural formula is:
## Pharmacodynamics
There is limited information regarding Ifosfamide Pharmacodynamics in the drug label.
## Pharmacokinetics
Ifosfamide exhibits dose-dependent pharmacokinetics in humans. At single doses of 3.8 to 5.0 g/m2, the plasma concentrations decay biphasically and the mean terminal elimination half-life is about 15 hours. At doses of 1.6 to 2.4 g/m2/day, the plasma decay is monoexponential and the terminal elimination half-life is about 7 hours.
Ifosfamide exhibits time-dependent pharmacokinetics in humans. Following intravenous administration of 1.5 g/m2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, a decrease in the median elimination half-life from 7.2 hour on Day 1 to 4.6 hours on Day 5 occurred with a concomitant increase in the median clearance from 66 mL/min on Day 1 to 115 mL/min on Day 5. There was no significant change in the volume of distribution on Day 5 compared with Day 1.
Ifosfamide volume of distribution (Vd) approximates the total body water volume, suggesting that distribution takes place with minimal tissue binding. Following intravenous administration of 1.5 g/m2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, the median Vd of ifosfamide was 0.64 L/kg on Day 1 and 0.72 L/kg on Day 5. Ifosfamide shows little plasma protein binding. Ifosfamide and its active metabolites are extensively bound by red blood cells. Ifosfamide is not a substrate for P-glycoprotein.
Ifosfamide is extensively metabolized in humans through two metabolic pathways: ring oxidation ("activation") to form the active metabolite, 4-hydroxy-ifosfamide and side-chain oxidation to form the inactive metabolites, 3-dechloro-ethylifosfamide or 2-dechloroethylifosfamide with liberation of the toxic metabolite, chloroacetaldehyde. Small quantities (nmol/mL) of ifosfamide mustard and 4-hydroxyifosfamide are detectable in human plasma. Metabolism of ifosfamide is required for the generation of the biologically active species and while metabolism is extensive, it is also quite variable among patients.
After administration of doses of 5 g/m2 of 14C-labeled ifosfamide, from 70% to 86% of the dosed radioactivity was recovered in urine as metabolites, with about 61% of the dose excreted as parent compound. At doses of 1.6 to 2.4 g/m2 only 12% to 18% of the dose was excreted in the urine as unchanged drug within 72 hours. Two different dechloroethylated derivatives of ifosfamide, 4-carboxyifosfamide, thiodiacetic acid and cysteine conjugates of chloroacetic acid have been identified as the major urinary metabolites of ifosfamide in humans and only small amounts of 4-hydroxyifosfamide and acrolein are present.
## Nonclinical Toxicology
Ifosfamide has been shown to be carcinogenic in rats when administered by intraperitoneal injection at 6 mg/kg (37 mg/m2, or about 3% of the daily human dose on a mg/m2 basis) 3 times a week for 52 weeks. Female rats had a significantly higher incidence of uterine leiomyosarcomas and mammary fibroadenomas than vehicle controls.
The mutagenic potential of ifosfamide has been documented in bacterial systems in vitro and mammalian cells in vivo. In vivo, ifosfamide has induced mutagenic effects in mice and Drosophila melanogaster germ cells, and has induced a significant increase in dominant lethal mutations in male mice as well as recessive sex-linked lethal mutations in Drosophila.
# Clinical Studies
Patients with refractory testicular cancer (n=59) received a combination of ifosfamide, cisplatin, and either etoposide (VePesid) or vinblastine (VIP) as third-line therapy or later. The selection of etoposide or vinblastine (“V” in the VIP regimen) was guided by the therapeutic effect achieved with prior regimens. The contribution of ifosfamide to the VIP combination was determined in patients treated with cisplatin-etoposide prior to ifosfamide- cisplatin-etoposide or those who received cisplatin-vinblastine prior to ifosfamide-cisplatin-vinblastine.
A total of 59 patients received a third-line salvage regimen which consisted of ifosfamide 1.2 g/m2/day intravenously on days 1 to 5, cisplatin 20 mg/m2/day intravenously on days 1 to 5, and either etoposide 75 mg/m2/day intravenously on days 1 to 5 or vinblastine 0.22 mg/kg intravenously on day 1. Efficacy results with the VIP regimen were compared to data pooled from six single agent phase II trials conducted between August 1980 and October 1985 including a total of 90 patients of whom 65 were eligible as controls of this study. Twenty-three patients in the VIP regimen became free of disease with VIP alone or VIP plus surgery, whereas a single patient in the historical control group achieved complete response. The median survival time exceeded two years in the VIP group versus less than one year in the control group. Performance status ≥ 80, embryonal carcinoma and minimal disease were favorable prognostic factors for survival. In all prognostic categories, the difference between VIP and historical controls remained highly significant.
In a study, 50 fully evaluable patients with germ cell testicular cancer were treated with Ifosfamide for Injection in combination with cisplatin and either vinblastine or etoposide after failing (47 of 50 patients) at least two prior chemotherapy regimens consisting of cisplatin/vinblastine/bleomycin, (PVB), cisplatin/vinblastine/actinomycin D/bleomycin/cyclophosphamide, (VAB6), or the combination of cisplatin and etoposide. Patients were selected for remaining cisplatin sensitivity because they had previously responded to a cisplatin containing regimen and had not progressed while on the cisplatin containing regimen or within 3 weeks of stopping it. Patients served as their own control based on the premise that long term complete responses could not be achieved by retreatment with a regimen to which they had previously responded and subsequently relapsed.
Ten of 50 fully evaluable patients were still alive 2 to 5 years after treatment. Four of the 10 long term survivors were rendered free of cancer by surgical resection after treatment with the ifosfamide regimen; median survival for the entire group of 50 fully evaluable patients was 53 weeks.
# How Supplied
- Ifosfamide for injection 1 gr.
- NDC 0338-3991-01
- Single-Dose Vial
- Ifosfamide for injection 3 gr.
- NDC 0338-3993-01
- Single-Dose Vial
## Storage
Store at 20°C to 25°C (68°F to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Inform patients of the risks associated with the use of Ifosfamide for Injection as well as the plan for regular blood monitoring during therapy.
Specifically inform patients of the following:
- Treatment with ifosfamide may cause myelosuppression which can be severe and lead to fatal outcome. Significant suppression of immune responses can also occur which can lead to severe infections. Latent infections can be reactivated. Patients should report fever or other symptoms of an infection.
- The risk of bleeding and anemia.
- The risk of CNS toxicity and other neurotoxic effects with fatal outcome.
- The risk of bladder and kidney toxicity. Patients should be aware of the need to increase fluid intake and frequent voiding to prevent accumulation in the bladder.
- The risk of cardiotoxicity and fatal outcome. Patients should report preexisting cardiac disease.
- The risk of pulmonary toxicity leading to respiratory failure with fatal outcome.
- The risk of secondary malignancies due to therapy.
- The risk of veno-occlusive liver disease.
- The potential hazard to a fetus if a patient becomes pregnant or fathers a child during therapy and for up to 6 months after therapy. Effective methods of contraception should be used during therapy and for up to 6 months after therapy.
- The potential for serious adverse reactions and tumorigenicity when children are breastfed during therapy.
- The risk of amenorrhea, premature menopause, and sterility.
- The risk of alopecia, wound healing, and other serious skin and subcutaneous tissue disorders.
- Therapy may cause gastrointestinal disorders and alcohol may increase nausea and vomiting.
- The risk of stomatitis and the importance of proper oral hygiene.
- The risk of eye disorders such as visual impairment, blurred vision, and eye irritation.
- The risk of ear and labyrinth disorders such as deafness, vertigo, and tinnitus.
# Precautions with Alcohol
Alcohol-Ifosfamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Ifex [3]
# Look-Alike Drug Names
There is limited information regarding Ifosfamide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ifex | |
37547cbf07a75394144ece76a97363f52adde1f2 | wikidoc | Iliac vein | Iliac vein
# Overview
In human anatomy, iliac vein refers to several anatomical structures located in the pelvis:
- External iliac vein - terminates at the common iliac vein, drains the femoral vein.
- Internal iliac vein - terminates at the common iliac vein, drains pelvic organs and perineum.
- Common iliac vein - formed by the external and internal iliac veins, drains into the inferior vena cava. | Iliac vein
# Overview
In human anatomy, iliac vein refers to several anatomical structures located in the pelvis:
- External iliac vein - terminates at the common iliac vein, drains the femoral vein.
- Internal iliac vein - terminates at the common iliac vein, drains pelvic organs and perineum.
- Common iliac vein - formed by the external and internal iliac veins, drains into the inferior vena cava. | https://www.wikidoc.org/index.php/Iliac_vein | |
4fa87ca4ee2d91d720b006364a466dd3533669cb | wikidoc | Imidazenil | Imidazenil
Imidazenil is an anxiolytic drug which is derived from the benzodiazepine family, and is most closely related to other imidazobenzodiazepines such as midazolam, flumazenil and bretazenil.
Imidazenil is a GABAA partial agonist with an unusual profile of effects, producing some of the effects associated with normal benzodiazepines such as anticonvulsant and anxiolytic effects, yet without any notable sedative or amnestic effects. In fact, imidazenil blocks the sedative effects of diazepam, yet without lowering the convulsion threshold, and so potentially could be a more flexible antidote than the antagonist flumazenil which is commonly used to treat benzodiazepine overdose at present.
This unusual profile of effects makes imidazenil potentially a very useful drug. In animal studies it has been shown to be an effective anxiolytic and strong anticonvulsant, yet without many of the side effects associated with other benzodiazepines; it does not produce tolerance or dependence, reverses the amnestic effects of conventional benzodiazepines, and does not potentiate the effects of alcohol.
Imidazenil has not yet been developed commercially for use in humans, however it has been suggested as a safe and effective treatment for anxiety, a potent yet non-sedating anticonvulsant which might be particularly useful in the treatment of poisoning with organophosphate nerve agents, and as a novel treatment for schizophrenia. | Imidazenil
Imidazenil is an anxiolytic drug which is derived from the benzodiazepine family, and is most closely related to other imidazobenzodiazepines such as midazolam, flumazenil and bretazenil.
Imidazenil is a GABAA partial agonist[1] with an unusual profile of effects, producing some of the effects associated with normal benzodiazepines such as anticonvulsant and anxiolytic effects, yet without any notable sedative[2] or amnestic[3] effects. In fact, imidazenil blocks the sedative effects of diazepam, yet without lowering the convulsion threshold,[4] and so potentially could be a more flexible antidote than the antagonist flumazenil which is commonly used to treat benzodiazepine overdose at present.
This unusual profile of effects makes imidazenil potentially a very useful drug. In animal studies it has been shown to be an effective anxiolytic and strong anticonvulsant, yet without many of the side effects associated with other benzodiazepines; it does not produce tolerance[5] or dependence,[6] reverses the amnestic effects of conventional benzodiazepines, and does not potentiate the effects of alcohol.[7][8]
Imidazenil has not yet been developed commercially for use in humans, however it has been suggested as a safe and effective treatment for anxiety,[9] a potent yet non-sedating anticonvulsant which might be particularly useful in the treatment of poisoning with organophosphate nerve agents,[10][11] and as a novel treatment for schizophrenia.[12] | https://www.wikidoc.org/index.php/Imidazenil | |
1efae0d8842c4dbc7270435d54f15d3c5543bca3 | wikidoc | Imipramine | Imipramine
# 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
Imipramine is a Tricyclic antidepressant that is FDA approved for the {{{indicationType}}} of depression, nocturnal enuresis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include weight gain, bloating symptom, constipation, xerostomia, asthenia, dizziness, headache, somnolence, blurred vision, urinary retention, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Hospitalized patients
- 100 mg orally per day in divided doses; may increase up to a max of 300 mg/day
- Outpatients
- 75 mg orally per day; may increase up to a max of 200 mg/day; usual maintenance dose, 50 to 150 mg/day
- 25 mg orally at bedtime, may increase in 25 mg increments to max dose of 150mg at bedtime
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Imipramine in adult patients
### Non–Guideline-Supported Use
There is limited information about Off-Label Non-Guideline-Supported Use of Imipramine in adult patients
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Children 6 to 12 y
- Initial, 25 mg orally 1 h before bedtime, may increase in 25 mg increments to max dose of 50 mg/d or 2.5 mg/kg/d
- Children over 12 y
- Initial, 25 mg orally 1 h before bedtime, may increase in 25 mg increments to max dose of 75 mg/d or 2.5 mg/kg/d
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Imipramine in pediatric patients
### Non–Guideline-Supported Use
There is limited information about Off-Label Non-Guideline-Supported Use of Imipramine in pediatric patients
# Contraindications
- Concomitant use of monoamine oxidase inhibiting compounds
- Acute recovery period after a myocardial infarction
- Hypersensitivity
# Warnings
- 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.
- 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 imipramine hydrochloride should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
- 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 imipramine hydrochloride is not approved for use in treating bipolar depression.
- A dose of 2.5 mg/kg/day of imipramine hydrochloride should not be exceeded in childhood. ECG changes of unknown significance have been reported in pediatric patients with doses twice this amount.
- Extreme caution should be used when this drug is given to:
- Patients with cardiovascular disease because of the possibility of conduction defects, arrhythmias, congestive heart failure, myocardial infarction, strokes, and tachycardia. These patients require cardiac surveillance at all dosage levels of the drug; patients with increased intraocular pressure, history of urinary retention, or history of narrow-angle glaucoma because of the drug’s anticholinergic properties; hyperthyroid patients or those on thyroid medication because of the possibility of cardiovascular toxicity;patients with a history of seizure disorder because this drug has been shown to lower the seizure threshold; patients receiving guanethidine, clonidine, or similar agents, since imipramine hydrochloride may block the pharmacologic effects of these drugs.
- Patients receiving methylphenidate hydrochloride. Since methylphenidate hydrochloride may inhibit the metabolism of imipramine, downward dosage adjustment of imipramine hydrochloride may be required when given concomitantly with methylphenidate hydrochloride.
- Imipramine may enhance the CNS depressant effects of alcohol. Therefore, it should be borne in mind that the dangers inherent in a suicide attempt or accidental overdosage with the drug may be increased for the patient who uses excessive amounts of alcohol.
- Since imipramine hydrochloride may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned accordingly.
# Adverse Reactions
## Clinical Trials Experience
### Central Nervous System
- Orthostatic hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, ECG changes, precipitation of congestive heart failure, stroke
- Nausea and vomiting, anorexia, epigastric distress, diarrhea; peculiar taste, stomatitis, abdominal cramps, black tongue.
- Skin rash, petechiae, urticaria, itching, photosensitization, edema (general or of face and tongue); drug fever, cross-sensitivity with desipramine.
- Jaundice (simulating obstructive); altered liver function; weight gain or loss; perspiration; flushing; urinary frequency; drowsiness, dizziness, weakness and fatigue; headache; parotid swelling; alopecia; proneness to falling.
## Postmarketing Experience
There is limited information about adverse reactions reported from postmarketing experience of Imipramine.
# Drug Interactions
- 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 interaction 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.
- The plasma concentration of imipramine may increase when the drug is given concomitantly with hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and decrease by concomitant administration with hepatic enzyme inducers (e.g., barbiturates, phenytoin), and adjustment of the dosage of imipramine may therefore be necessary.
- In occasional susceptible patients or in those receiving anticholinergic drugs (including antiparkinsonism agents) in addition, the atropine-like effects may become more pronounced (e.g., paralytic ileus). Close supervision and careful adjustment of dosage is required when imipramine hydrochloride is administered concomitantly with anticholinergic drugs.
- Avoid the use of preparations, such as decongestants and local anesthetics, that contain any sympathomimetic amine (e.g., epinephrine, norepinephrine), since it has been reported that tricyclic antidepressants can potentiate the effects of catecholamines.
- Caution should be exercised when imipramine hydrochloride is used with agents that lower blood pressure. Imipramine hydrochloride may potentiate the effects of CNS depressant drugs.
- Patients should be warned that imipramine hydrochloride may enhance the CNS depressant effects of alcohol.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Animal reproduction studies have yielded inconclusive results (see also Animal Pharmacology& Toxicology)
There have been no well-controlled studies conducted with pregnant women to determine the effect of imipramine hydrochloride on the fetus. However, there have been clinical reports of congenital malformations associated with the use of the drug. Although a causal relationship between these effects and the drug could not be established, the possibility of fetal risk from the maternal ingestion of imipramine hydrochloride cannot be excluded. Therefore, imipramine hydrochloride should be used in women who are or might become pregnant only if the clinical condition clearly justifies potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Imipramine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Imipramine during labor and delivery.
### Nursing Mothers
- Limited data suggest that imipramine hydrochloride is likely to be excreted in human breast milk. As a general rule, a woman taking a drug should not nurse since the possibility exists that the drug may be excreted in breast milk and be harmful to the child.
### Pediatric Use
- Safety and effectiveness in the pediatric population other than pediatric patients with nocturnal enuresis have not been established (see Box Warning and Warnings: Clinical Worsening and Suicide Risk). Anyone considering the use of imipramine hydrochloride in a child or adolescent must balance the potential risks with the clinical need.
- The safety and effectiveness of the drug as temporary adjunctive therapy for nocturnal enuresis in pediatric patients less than 6 years of age has not been established.
- The safety of the drug for long-term, chronic use as adjunctive therapy for nocturnal enuresis in pediatric patients 6 years of age or older has not been established; consideration should be given to instituting a drug-free period following an adequate therapeutic trial with a favorable response.
- A dose of 2.5 mg/kg/day should not be exceeded in childhood. ECG changes of unknown significance have been reported in pediatric patients with doses twice this amount.
### Geriatic Use
- In the literature, there were four well-controlled, randomized, double-blind, parallel group comparison clinical studies done with imipramine in the elderly population. There was a total number of 651 subjects included in these studies. These studies did not provide a comparison to younger subjects. There were no additional adverse experiences identified in the elderly.
- Clinical studies of imipramine in the original application did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Post-marketing clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for the elderly should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. (See also Dosage and Administration:Adolescents and Geriatric Patients.) (See also Precautions: General)
### Gender
There is no FDA guidance on the use of Imipramine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Imipramine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Imipramine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Imipramine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Imipramine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Imipramine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Imipramine Administration in the drug label.
### Monitoring
There is limited information regarding Imipramine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Imipramine and IV administrations.
# Overdosage
- Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic overdose. Therefore, hospital monitoring is required as soon as possible.
- Children have been reported to be more sensitive than adults to an acute overdosage of imipramine hydrochloride. An acute overdose of any amount in infants or young children, especially, must be considered serious and potentially fatal.
- These may vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the interval between drug ingestion and the start of treatment. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity.
Other CNS manifestations may include drowsiness, stupor, ataxia, restlessness, agitation, hyperactive reflexes, muscle rigidity, athetoid and choreiform movements.
Cardiac abnormalities may include tachycardia and signs of congestive failure. Respiratory depression, cyanosis, shock, vomiting, hyperpyrexia, mydriasis, and diaphoresis may also be present.
- Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient.
- Gastrointestinal Decontamination
- All patients suspected of tricyclic overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated.
- Cardiovascular
- A maximal limb-lead QRS duration of ≥0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH>7.60 or a pCO2<20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium, or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide).
- In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic poisoning.
- CNS
- In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center.
- Psychiatric Follow-up
- Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate.
- Pediatric Management
- The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.
# Pharmacology
## Mechanism of Action
- The mechanism of action of imipramine hydrochloride is not definitely known. However, it does not act primarily by stimulation of the central nervous system. The clinical effect is hypothesized as being due to potentiation of adrenergic synapses by blocking uptake of norepinephrine at nerve endings. The mode of action of the drug in controlling childhood enuresis is thought to be apart from its antidepressant effect.
## Structure
- Imipramine hydrochloride, the original tricyclic antidepressant, is a member of the dibenzazepine group of compounds. It is designated 5--10, 11-dihydro-5H-dibenz -azepine monohydrochloride. Structurally, it may be represented as follows:
- Imipramine hydrochloride USP is a white to off-white, odorless, or practically odorless crystalline powder. It is freely soluble in water and in alcohol, soluble in acetone, and insoluble in ether and in benzene. It melts at 170-174°C.
- Each tablet, for oral administration, contains 10 mg, 25 mg or 50 mg imipramine hydrochloride USP. Inactive ingredients for 10 mg include: corn starch, D & C Yellow #10 Aluminum Lake, FD & C Red #30 Aluminum Lake, hydroxypropyl cellulose, hypromellose, lactose (anhydrous), magnesium stearate, polyethylene glycol, povidone and titanium dioxide; for 25 mg: corn starch, D & C Yellow #10 Aluminum Lake, FD & C Blue #2 Aluminum Lake, FD & C Red #40 Aluminum Lake, hydroxypropyl cellulose, hypromellose, lactose (anhydrous), magnesium stearate, polyethylene glycol, povidone and titanium dioxide; for 50 mg: corn starch, D & C Yellow #10 Aluminum Lake, FD & C Blue #1 Aluminum Lake, FD & C Red #40 Aluminum Lake, hydroxypropyl cellulose, hypromellose, lactose (anhydrous), magnesium stearate, polyethylene glycol, povidone and titanium dioxide.
## Pharmacodynamics
There is limited information information related to the pharmacodynamics of Imipramine.
## Pharmacokinetics
There is limited information information related to the pharmacodynamics of Imipramine.
## Nonclinical Toxicology
There is limited information regarding Imipramine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Imipramine Clinical Studies in the drug label.
# How Supplied
- Imipramine hydrochloride tablets USP for oral administration are available as:
- 10 mg: Round, film-coated, yellow tablets, debossed GG on one side and 41 on the reverse side, and supplied as:
- NDC 0781-1762-31 bottles of 30
- NDC 0781-1762-01 bottles of 100
- NDC 0781-1762-10 bottles of 1000
- 25 mg: Round, film-coated, beige tablets, debossed GG on one side and 47 on the reverse side, and supplied as:
- NDC 0781-1764-31 bottles of 30
- NDC 0781-1764-01 bottles of 100
- NDC 0781-1764-10 bottles of 1000
- NDC 0781-1764-13 unit dose packages of 100
- 50 mg: Round, film-coated, green tablets, debossed GG on one side and 42 on the reverse side, and supplied as:
- NDC 0781-1766-31 bottles of 30
- NDC 0781-1766-01 bottles of 100
- NDC 0781-1766-10 bottles of 1000
- NDC 0781-1766-13 unit dose packages of 100
## Storage
- Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature).
- Dispense in a tight, light-resistant container.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about:
- All risks and benefits of treatment with antidepressant medicines
- All treatment choices for depression or other serious mental illness
- Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
- Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions.
- Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
- Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
- Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.
- Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:
- Thoughts about suicide or dying
- Attempts to commit suicide
- New or worse depression
- New or worse anxiety
- Feeling very agitated or restless
- Panic attacks
- Trouble sleeping (insomnia)
- New or worse irritability
- Acting aggressive, being angry, or violent
- Acting on dangerous impulses
- An extreme increase in activity and talking (mania)
- Other unusual changes in behavior or mood
- Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
- Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
- Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
- Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
- Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.
# Precautions with Alcohol
Alcohol-Imipramine 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 Imipramine Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Imipramine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Imipramine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
# Disclaimer
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# Black Box Warning
# Overview
Imipramine is a Tricyclic antidepressant that is FDA approved for the {{{indicationType}}} of depression, nocturnal enuresis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include weight gain, bloating symptom, constipation, xerostomia, asthenia, dizziness, headache, somnolence, blurred vision, urinary retention, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Hospitalized patients
- 100 mg orally per day in divided doses; may increase up to a max of 300 mg/day
- Outpatients
- 75 mg orally per day; may increase up to a max of 200 mg/day; usual maintenance dose, 50 to 150 mg/day
- 25 mg orally at bedtime, may increase in 25 mg increments to max dose of 150mg at bedtime
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Imipramine in adult patients
### Non–Guideline-Supported Use
There is limited information about Off-Label Non-Guideline-Supported Use of Imipramine in adult patients
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Children 6 to 12 y
- Initial, 25 mg orally 1 h before bedtime, may increase in 25 mg increments to max dose of 50 mg/d or 2.5 mg/kg/d
- Children over 12 y
- Initial, 25 mg orally 1 h before bedtime, may increase in 25 mg increments to max dose of 75 mg/d or 2.5 mg/kg/d
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Imipramine in pediatric patients
### Non–Guideline-Supported Use
There is limited information about Off-Label Non-Guideline-Supported Use of Imipramine in pediatric patients
# Contraindications
- Concomitant use of monoamine oxidase inhibiting compounds
- Acute recovery period after a myocardial infarction
- Hypersensitivity
# Warnings
- 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.
- 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 imipramine hydrochloride should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
- 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 imipramine hydrochloride is not approved for use in treating bipolar depression.
- A dose of 2.5 mg/kg/day of imipramine hydrochloride should not be exceeded in childhood. ECG changes of unknown significance have been reported in pediatric patients with doses twice this amount.
- Extreme caution should be used when this drug is given to:
- Patients with cardiovascular disease because of the possibility of conduction defects, arrhythmias, congestive heart failure, myocardial infarction, strokes, and tachycardia. These patients require cardiac surveillance at all dosage levels of the drug; patients with increased intraocular pressure, history of urinary retention, or history of narrow-angle glaucoma because of the drug’s anticholinergic properties; hyperthyroid patients or those on thyroid medication because of the possibility of cardiovascular toxicity;patients with a history of seizure disorder because this drug has been shown to lower the seizure threshold; patients receiving guanethidine, clonidine, or similar agents, since imipramine hydrochloride may block the pharmacologic effects of these drugs.
- Patients receiving methylphenidate hydrochloride. Since methylphenidate hydrochloride may inhibit the metabolism of imipramine, downward dosage adjustment of imipramine hydrochloride may be required when given concomitantly with methylphenidate hydrochloride.
- Imipramine may enhance the CNS depressant effects of alcohol. Therefore, it should be borne in mind that the dangers inherent in a suicide attempt or accidental overdosage with the drug may be increased for the patient who uses excessive amounts of alcohol.
- Since imipramine hydrochloride may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned accordingly.
# Adverse Reactions
## Clinical Trials Experience
### Central Nervous System
- Orthostatic hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, ECG changes, precipitation of congestive heart failure, stroke
- Nausea and vomiting, anorexia, epigastric distress, diarrhea; peculiar taste, stomatitis, abdominal cramps, black tongue.
- Skin rash, petechiae, urticaria, itching, photosensitization, edema (general or of face and tongue); drug fever, cross-sensitivity with desipramine.
- Jaundice (simulating obstructive); altered liver function; weight gain or loss; perspiration; flushing; urinary frequency; drowsiness, dizziness, weakness and fatigue; headache; parotid swelling; alopecia; proneness to falling.
## Postmarketing Experience
There is limited information about adverse reactions reported from postmarketing experience of Imipramine.
# Drug Interactions
- 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 interaction 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.
- The plasma concentration of imipramine may increase when the drug is given concomitantly with hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and decrease by concomitant administration with hepatic enzyme inducers (e.g., barbiturates, phenytoin), and adjustment of the dosage of imipramine may therefore be necessary.
- In occasional susceptible patients or in those receiving anticholinergic drugs (including antiparkinsonism agents) in addition, the atropine-like effects may become more pronounced (e.g., paralytic ileus). Close supervision and careful adjustment of dosage is required when imipramine hydrochloride is administered concomitantly with anticholinergic drugs.
- Avoid the use of preparations, such as decongestants and local anesthetics, that contain any sympathomimetic amine (e.g., epinephrine, norepinephrine), since it has been reported that tricyclic antidepressants can potentiate the effects of catecholamines.
- Caution should be exercised when imipramine hydrochloride is used with agents that lower blood pressure. Imipramine hydrochloride may potentiate the effects of CNS depressant drugs.
- Patients should be warned that imipramine hydrochloride may enhance the CNS depressant effects of alcohol.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Animal reproduction studies have yielded inconclusive results (see also Animal Pharmacology& Toxicology)
There have been no well-controlled studies conducted with pregnant women to determine the effect of imipramine hydrochloride on the fetus. However, there have been clinical reports of congenital malformations associated with the use of the drug. Although a causal relationship between these effects and the drug could not be established, the possibility of fetal risk from the maternal ingestion of imipramine hydrochloride cannot be excluded. Therefore, imipramine hydrochloride should be used in women who are or might become pregnant only if the clinical condition clearly justifies potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Imipramine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Imipramine during labor and delivery.
### Nursing Mothers
- Limited data suggest that imipramine hydrochloride is likely to be excreted in human breast milk. As a general rule, a woman taking a drug should not nurse since the possibility exists that the drug may be excreted in breast milk and be harmful to the child.
### Pediatric Use
- Safety and effectiveness in the pediatric population other than pediatric patients with nocturnal enuresis have not been established (see Box Warning and Warnings: Clinical Worsening and Suicide Risk). Anyone considering the use of imipramine hydrochloride in a child or adolescent must balance the potential risks with the clinical need.
- The safety and effectiveness of the drug as temporary adjunctive therapy for nocturnal enuresis in pediatric patients less than 6 years of age has not been established.
- The safety of the drug for long-term, chronic use as adjunctive therapy for nocturnal enuresis in pediatric patients 6 years of age or older has not been established; consideration should be given to instituting a drug-free period following an adequate therapeutic trial with a favorable response.
- A dose of 2.5 mg/kg/day should not be exceeded in childhood. ECG changes of unknown significance have been reported in pediatric patients with doses twice this amount.
### Geriatic Use
- In the literature, there were four well-controlled, randomized, double-blind, parallel group comparison clinical studies done with imipramine in the elderly population. There was a total number of 651 subjects included in these studies. These studies did not provide a comparison to younger subjects. There were no additional adverse experiences identified in the elderly.
- Clinical studies of imipramine in the original application did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Post-marketing clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for the elderly should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. (See also Dosage and Administration:Adolescents and Geriatric Patients.) (See also Precautions: General)
### Gender
There is no FDA guidance on the use of Imipramine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Imipramine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Imipramine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Imipramine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Imipramine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Imipramine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Imipramine Administration in the drug label.
### Monitoring
There is limited information regarding Imipramine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Imipramine and IV administrations.
# Overdosage
- Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic overdose. Therefore, hospital monitoring is required as soon as possible.
- Children have been reported to be more sensitive than adults to an acute overdosage of imipramine hydrochloride. An acute overdose of any amount in infants or young children, especially, must be considered serious and potentially fatal.
- These may vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the interval between drug ingestion and the start of treatment. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity.
Other CNS manifestations may include drowsiness, stupor, ataxia, restlessness, agitation, hyperactive reflexes, muscle rigidity, athetoid and choreiform movements.
Cardiac abnormalities may include tachycardia and signs of congestive failure. Respiratory depression, cyanosis, shock, vomiting, hyperpyrexia, mydriasis, and diaphoresis may also be present.
- Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient.
- Gastrointestinal Decontamination
- All patients suspected of tricyclic overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated.
- Cardiovascular
- A maximal limb-lead QRS duration of ≥0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH>7.60 or a pCO2<20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium, or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide).
- In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic poisoning.
- CNS
- In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center.
- Psychiatric Follow-up
- Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate.
- Pediatric Management
- The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.
# Pharmacology
## Mechanism of Action
- The mechanism of action of imipramine hydrochloride is not definitely known. However, it does not act primarily by stimulation of the central nervous system. The clinical effect is hypothesized as being due to potentiation of adrenergic synapses by blocking uptake of norepinephrine at nerve endings. The mode of action of the drug in controlling childhood enuresis is thought to be apart from its antidepressant effect.
## Structure
- Imipramine hydrochloride, the original tricyclic antidepressant, is a member of the dibenzazepine group of compounds. It is designated 5-[3-(Dimethylamino) propyl]-10, 11-dihydro-5H-dibenz [b,f]-azepine monohydrochloride. Structurally, it may be represented as follows:
- Imipramine hydrochloride USP is a white to off-white, odorless, or practically odorless crystalline powder. It is freely soluble in water and in alcohol, soluble in acetone, and insoluble in ether and in benzene. It melts at 170-174°C.
- Each tablet, for oral administration, contains 10 mg, 25 mg or 50 mg imipramine hydrochloride USP. Inactive ingredients for 10 mg include: corn starch, D & C Yellow #10 Aluminum Lake, FD & C Red #30 Aluminum Lake, hydroxypropyl cellulose, hypromellose, lactose (anhydrous), magnesium stearate, polyethylene glycol, povidone and titanium dioxide; for 25 mg: corn starch, D & C Yellow #10 Aluminum Lake, FD & C Blue #2 Aluminum Lake, FD & C Red #40 Aluminum Lake, hydroxypropyl cellulose, hypromellose, lactose (anhydrous), magnesium stearate, polyethylene glycol, povidone and titanium dioxide; for 50 mg: corn starch, D & C Yellow #10 Aluminum Lake, FD & C Blue #1 Aluminum Lake, FD & C Red #40 Aluminum Lake, hydroxypropyl cellulose, hypromellose, lactose (anhydrous), magnesium stearate, polyethylene glycol, povidone and titanium dioxide.
## Pharmacodynamics
There is limited information information related to the pharmacodynamics of Imipramine.
## Pharmacokinetics
There is limited information information related to the pharmacodynamics of Imipramine.
## Nonclinical Toxicology
There is limited information regarding Imipramine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Imipramine Clinical Studies in the drug label.
# How Supplied
- Imipramine hydrochloride tablets USP for oral administration are available as:
- 10 mg: Round, film-coated, yellow tablets, debossed GG on one side and 41 on the reverse side, and supplied as:
- NDC 0781-1762-31 bottles of 30
- NDC 0781-1762-01 bottles of 100
- NDC 0781-1762-10 bottles of 1000
- 25 mg: Round, film-coated, beige tablets, debossed GG on one side and 47 on the reverse side, and supplied as:
- NDC 0781-1764-31 bottles of 30
- NDC 0781-1764-01 bottles of 100
- NDC 0781-1764-10 bottles of 1000
- NDC 0781-1764-13 unit dose packages of 100
- 50 mg: Round, film-coated, green tablets, debossed GG on one side and 42 on the reverse side, and supplied as:
- NDC 0781-1766-31 bottles of 30
- NDC 0781-1766-01 bottles of 100
- NDC 0781-1766-10 bottles of 1000
- NDC 0781-1766-13 unit dose packages of 100
## Storage
- Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature).
- Dispense in a tight, light-resistant container.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about:
- All risks and benefits of treatment with antidepressant medicines
- All treatment choices for depression or other serious mental illness
- Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
- Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions.
- Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
- Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
- Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.
- Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:
- Thoughts about suicide or dying
- Attempts to commit suicide
- New or worse depression
- New or worse anxiety
- Feeling very agitated or restless
- Panic attacks
- Trouble sleeping (insomnia)
- New or worse irritability
- Acting aggressive, being angry, or violent
- Acting on dangerous impulses
- An extreme increase in activity and talking (mania)
- Other unusual changes in behavior or mood
- Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
- Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
- Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
- Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
- Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.
# Precautions with Alcohol
Alcohol-Imipramine 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 Imipramine Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Imipramine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Imipramine | |
dc24372ca2b95dc95e45eeed9c9a75a5338c846f | wikidoc | Impalement | Impalement
# Overview
Impalement, as a method of execution, is the penetration of a human by an object such as a stake, pole, spear, or hook, often by complete or partial perforation of the torso. It was used particularly in response to "crimes against the state" and regarded across a number of cultures as a very harsh form of capital punishment and recorded in myth and art. Impalement was also used during wartime to suppress rebellion, punish traitors or collaborators, and as a punishment for breaches of military discipline.
Offenses where impalement was occasionally employed include: contempt for the state's responsibility for safe roads and trade routes by committing highway robbery or grave robbery, violating state policies or monopolies, or subverting standards for trade. Offenders have also been impaled for a variety of cultural, sexual and religious reasons.
References to impalement in Babylonia and the Neo-Assyrian Empire are found as early as the 18th century BC. Within the Ottoman Empire, this form of execution continued into the 20th century.
# Methods
## Longitudinal impalement
Impaling an individual along the body length has been documented in several cases, and the merchant Jean de Thevenot provides an eyewitness account of this, from 17th century Egypt, in the case of a man condemned to death for the use of false weights:
They lay the Malefactor upon his Belly, with his Hands tied behind his Back, then they slit up his Fundament with a Razor, and throw into it a handful of Paste that they have in readiness, which immediately stops the Blood. After that they thrust up into his Body a very long Stake as big as a Mans Arm, sharp at the point and tapered, which they grease a little before; when they have driven it in with a Mallet, till it come out at his Breast, or at his Head or Shoulders, they lift him up, and plant this Stake very streight in the Ground, upon which they leave him so exposed for a day. One day I saw a Man upon the Pale, who was Sentenced to continue so for three Hours alive and that he might not die too soon, the Stake was not thrust up far enough to come out at any part of his Body, and they also put a stay or rest upon the Pale, to hinder the weight of his body from making him sink down upon it, or the point of it from piercing him through, which would have presently killed him: In this manner he was left for some Hours, (during which time he spoke) and turning from one side to another, prayed those that passed by to kill him, making a thousand wry Mouths and Faces, because of the pain be suffered when he stirred himself, but after Dinner the Basha sent one to dispatch him; which was easily done, by making the point of the Stake come out at his Breast, and then he was left till next Morning, when he was taken down, because he stunk horridly.
### Survival time
The survival time on the stake is quite variedly reported, from a few seconds or minutes to a few hours or 1 to 3 days. The Dutch overlords at Batavia, present day Jakarta, seem to have been particularly proficient in prolonging the lifetime of the impaled, one witnessing a man surviving 6 days on the stake, another hearing from local surgeons that some could survive 8 or more days. A critical determinant for survival length seems to be precisely how the stake was inserted: If it went into the "interior" parts, vital organs could easily be damaged, leading to a swift death. However, by letting the stake follow the spine, the impalement procedure would not damage the vital organs, and the person could survive for several days.
## Transversal impalement
Alternatively, the impalement could be transversally performed, for example in the frontal-to-dorsal direction, that is, from front (through abdomen, chest or directly through the heart) to back or vice versa
In the Holy Roman Empire (and elsewhere in Central/Eastern Europe), women who killed their newborn could be liable to be placed in an open grave, and have a stake hammered into their heart. A detailed description of an execution in this manner comes from 17th century Košice (then in Hungary, now in eastern Slovakia). A woman was to be executed for infanticide, the executioner had two assistants to help him. First, a grave, some one-and-a-half ell deep was dug. The woman was placed within it, her hands and feet secured by driving nails through them. Then, the executioner placed a small thorn bush upon her face. He then placed and held vertically a wooden stave at her heart, while his assistants piled earth on the woman. Her head, though, was kept free of earth, at the behest of the clerics, because that would have quickened her death process. Once the earth had been piled upon her, the executioner grabbed with a pair of tongs a rod made of iron, which had been made red hot. He positioned the glowing iron rod beside the wooden stave, and as one of his assistants hammered the rod in, the other assistant emptied a trough of earth upon the woman's head. It is said that a scream was heard, and that the earth actually moved upwards for a moment, before all was over.
## Variations
### Gaunching
Joseph Pitton de Tournefort, travelling on botanical research in the Levant 1700–1702, observed both ordinary longitudinal impalement, but also a method called "gaunching", in which the condemned is hoisted up by means of a rope over a bed of sharp metal hooks. He is then released, and depending on how the hooks enter his body, he may survive in impaled condition for a few days.
Forty years earlier than de Tournefort, de Thévenot described much the same process, adding that it was seldom used because it was regarded as too cruel. Some 80 years prior to de Thevenot, in 1579, Hans Jacob Breuning von Buchenbach witnessed a variant of the gaunching ritual. A large iron hook was fixed on the horizontal cross-bar of the gallows and the individual was forced upon this hook, piercing him from the abdomen through his back, so that he hung from it, hands, feet and head downward. On top of the cross bar, the executioner situated himself and performed various torture on the impaled man below him.
### Hooks in the city wall
While gaunching as de Tournefort describes involves the erection of a scaffold, it seems that in the city of Algiers, hooks were embedded in the city walls, and on occasion, people were thrown upon them from the battlements.
Thomas Shaw, who was chaplain for the Levant Company stationed at Algiers during the 1720s, describes the various forms of executions practiced as follows:
"..but the Moors and Arabs are either impaled for the same crime, or else they are hung up by the neck, over the battlements of the city walls, or else they are thrown upon the chingan or hooks that are fixed all over the walls below, where sometimes they break from one hook to another, and hang in the most exquisite torments, thirty or forty hours."
According to one source, these hooks in the wall as an execution method were introduced with the construction of the new city gate in 1573. Before that time, gaunching as described by de Tournefort was in use. As for the actual frequency of throwing persons on hooks in Algiers, Capt. Henry Boyde notes that in his own 20 years of captivity there, he knew of only one case where a Christian slave who had murdered his master had met that fate, and "not above" two or three Moors besides. Taken captive in 1596, the barber-surgeon William Davies relates something of the heights involved when thrown upon hooks (although it is somewhat unclear if this relates specifically to the city of Algiers, or elsewhere in the Barbary States): "Their ganshing is after this manner: he sitteth upon a wall, being five fathoms high, within two fathoms of the top of the wall; right under the place where he sits, is a strong iron hook fastened, being very sharp; then he is thrust off the wall upon this hook, with some part of his body, and there he hangeth, sometimes two or three days, before he dieth." Davies adds that "these deaths are very seldom", but that he had personally witnessed it
### Hanged by the ribs
A slightly variant way of executing people by means of impalement was to force an iron meat hook beneath a person's ribs and hang him up to die slowly. This technique was in 18th century Ottoman-controlled Bosnia called the cengela, but the practice is also attested, for example, in 1770s Dutch Suriname as a punishment meted out to rebellious slaves.
### Bamboo torture
A recurring horror story on many websites and popular media outlets is that Japanese soldiers during World War II inflicted bamboo torture upon prisoners of war. The victim was supposedly tied securely in place above a young bamboo shoot. Over several days, the sharp, fast growing shoot would first puncture, then completely penetrate the victim's body, eventually emerging through the other side. The cast of the TV program MythBusters investigated bamboo torture in a 2008 episode and found that a bamboo shoot can penetrate through several inches of ballistic gelatin in three days. For research purposes, ballistic gelatin is considered comparable to human flesh, and the experiment thus supported the viability of this form of torture, if not its historical use.
# History
## Antiquity
### Mesopotamia and the ancient Near East
The earliest known use of impalement as a form of execution occurred in civilizations of the ancient Near East. For example, the Code of Hammurabi, promulgated about 1772 BC by the Babylonian king Hammurabi specifies impaling for a woman who killed her husband for the sake of another man. In the late Isin/Larsa period, from about the same time, it seems that, in some city states, mere adultery on the wife's part (without murder of her husband mentioned) could be punished by impalement. From the royal archives of the city of Mari (at the Syrian-Iraqi border by the western bank of Euphrates), most of it also roughly contemporary to Hammurabi, it is known that soldiers taken captive in war were on occasion impaled. Roughly contemporary with Babylonia under Hammurabi, king Siwe-Palar-huhpak of Elam, a country lying directly east of Babylonia in present-day Iran, made official edicts in which he threatened the allies of his enemies with impalement, among other terrible fates. For acts of perceived great sacrilege, some individuals, in diverse cultures, have been impaled for their effrontery. For example, roughly 1200 BC, merchants of Ugarit express deep concern to each other that a fellow citizen is to be impaled in the Phoenician town Sidon, due to some "great sin" committed against the patron deity of Sidon.
### Pharaonic Egypt
During Dynasty 19, Merenptah had Libu prisoners of war impaled ("caused to be set upon a stake") to the south of Memphis, following an attempted invasion of Egypt during his Regnal Year 5. The relevant determinative for ḫt ("stake") depicts an individual transfixed though the abdomen. Other Egyptian kings employing impalements include Sobekhotep II, Akhenaten, Seti, and Ramesses IX.
### Neo-Assyrian Empire
Evidence by carvings and statues is found as well, for example from Neo-Assyrian empire (rough dating, 934-609 BCE). The image of the impaled Judeans is a detail from the public commemoration of the Assyrian victory in 701 BC after the Siege of Lachish, under King Sennacherib (r.705-681 BC), who proceeded similarly against the inhabitants of Ekron during the same campaign. From Sennacherib's father Sargon II's time (r.722-705 BC), a relief from his palace at Khorsabad shows the impalement of 14 enemies during an attack on the city of Pazashi. A peculiarity about the "Neo-Assyrian" way of impaling was that the stake was "driven into the body immediately under the ribs", rather than along the full body length. For the Neo-Assyrians, mass executions seem to have been not only designed to instill terror and to enforce obedience, but also, it can seem, as proofs of their might that they took pride in. For example, Neo-Assyrian King Ashurnasirpal II (r.883-859 BC) was evidently proud enough of his bloody work that he committed it to monument and eternal memory as follows:
"I cut off their hands, I burned them with fire, a pile of the living men and of heads over against the city gate I set up, men I impaled on stakes, the city I destroyed and devastated, I turned it into mounds and ruin heaps, the young men and the maidens in the fire I burned"
Paul Kern, in his (1999) "Ancient Siege Warfare" provides some statistics on how different Neo-Assyrian kings from the times of Ashurnasirpal II commemorated their punishments of rebels
Although impalement of rebels and enemies is particularly well-attested from Neo-Assyrian times, the 14th century BC Mitanni king Shattiwaza charges his predecessor, the usurper Shuttarna III for having delivered unto the (Middle) Assyrians several nobles, who had them promptly impaled. Some scholars have said, though, that it is only with king Ashur-bel-kala (r.1074-1056) that we have solid evidence that punishments like flaying and impaling came into use. From the Middle Assyrian period, we have evidence about impalement as a form of punishment relative to other types of perceived crimes as well. The law code discovered and deciphered by Dr. Otto Schroeder contains in its paragraph 51 the following injunction against abortion:
If a woman with her consent brings on a miscarriage, they seize her, and determine her guilt. On a stake they impale her, and do not bury her; and if through the miscarriage she dies, they likewise impale her and do not bury her
### Ambiguous Biblical evidence
Some controversy exist between different Bible translations concerning the actual fate of the 5th century BC Persian minister Haman and his ten sons, whether they were impaled or hanged For example, the English Standard Version, Esther 5:14 opts for hanging, whereas The New International Reader's version opts for impalement.
The Assyriologist Paul Haupt opts for impalement in his 1908 essay "Critical notes on Esther", while Benjamin Shaw has an extended discussion of the topic on the website ligonier.org from 2012.
Other passages in the Bible allude to the practice of impalement, such as II Samuel 21:9, concerning the fate of the sons of Saul.
Although conclusive evidence might be wanting either way for whether Hebrew Law allowed for impalement, or just hanging, the Neo-Assyrian method of impalement as seen in the carvings could, perhaps, equally easily be seen as a form of hanging upon a pole, rather than focusing upon the stake's actual penetration of the body.
### Rome
From John Granger Cook, 2014, - "Stipes is Seneca's term of the object used for impalement. This narrative and his Ep. 14.5 are the only two textually explicit references of impalement in Latin texts..."
## Europe
Within the Holy Roman Empire, in article 131 of the 1532 Constitutio Criminalis Carolina, the following punishment was stated for women found guilty of infanticide. Generally, they should be drowned, but the law code allowed for, in particularly severe cases, that the old punishment could be implemented. That is, the woman would be buried alive, and then a stake would be driven through her heart. Similarly, burial alive, combined with transversal impalement is attested as an early execution method for people found guilty of adultery. For example, from the 1348 statutes of Zwickau, it seems that an adulterous couple could be punished in the following way: They were to be placed on top of each other in a grave, with a layer of thorns between them. Then, a single stake was to be hammered through them. A similar punishment by impalement for a proven male adulterer is mentioned in a 13th-century ordinance for Bohemian mining town Iglau, whereas in a 1340 Vienna statute, the husband of a woman caught in flagrante in adultery could, if he wished to, demand that his wife and her lover be impaled, alternatively demand a monetary restitution. Occasionally, women found guilty of witchcraft have been condemned to be impaled. In 1587 Kiel, 101-year-old Sunde Bohlen was, on being condemned as a witch, buried alive, and afterwards had a stake driven through her heart.
Rapists of virgins and children are also attested to have been buried alive, with a stake driven through them. In one such judicial tradition, the rapist was to be placed in an open grave, and the rape victim was ordered to make the three first strokes on the stake herself; the executioners then finishing the impalement procedure. Serving as an example of the fate of a child molester, in August 1465 in Zurich, Switzerland, Ulrich Moser was condemned to be impaled, for having sexually violated six girls between the ages four and nine. His clothes were taken off, and he was placed on his back. His arms and legs were stretched out, each secured to a pole. Then a stake was driven through his navel down into the ground. Thereafter, people left him to die.
Cases of longitudinal impalement can be found typically in the context of war or as a punishment of robbers, the latter being attested as practice in Central and Eastern Europe.
Individuals perceived of collaborating with the enemy have, on occasion, been impaled. For example, in 1632 during the Thirty Years' War, the German officer Fuchs was impaled on suspicion of defecting to the Swedes, a Swedish corporal was likewise impaled for trying to defect to the Germans. In 1654, under the Ottoman siege of the Venetian garrison at Crete, several peasants were impaled for supplying provisions to the besieged. Likewise in 1685, some Christians were impaled by the Hungarians for having provided supplies to the Turks.
In 1677, a particularly brutal German General Kops leading the forces of Holy Roman Emperor Leopold I designed to keep Hungary dominated by the Germans, rather than to become dominated by the Turks, began impaling and quartering his Hungarian subjects/opponents. An opposing general for the Hungarians, Wesselényi, responded in kind, by flaying alive Imperial troops, and fixing sharp iron hooks in fortress walls, upon which he threw captured Germans to be impaled. Finally, Emperor Leopold I had had enough of the mutual bloodshed, and banished Kops in order to establish a needed cessation of hostilities. After the Treaty of The Hague (1720), Sicily fell under Habsburg rule, but the locals deeply resented the German overlords. One parish priest (who exhorted his parishioners to kill the Germans) is said to have broken into joy when a German soldier arrived at his village, exclaiming it was gone a whole eight days since last he killed a German, and shot the soldier off his horse. The priest was later impaled. In the short-lived 1784 Horea Revolt against the Austrians and Hungarians, the rebels gained hold of two officers they promptly impaled. On their side, the imperial troops got hold of Horea's 13-year-old son, and impaled him. That seems to have merely inflamed the rebel leader's determination, although the revolt was quashed shortly afterwards.
From 1748 and onwards, German regiments organized manhunts on "robbers" in Hungary/Croatia, impaling those caught.
### Execution of Paul Wasansky in 1570
Occasionally, individual murderers were perceived to have been so heinous that standard punishments like beheading or to be broken on the wheel were not regarded as sufficiently commensurate with their crimes, and extended rituals of execution that might include impalement were devised. The case of Pavel Vašanský (Paul Wasansky in German transcript) may serve as an example here.
Paul Wasansky, who in 1570 was executed in Ivančice, in present-day Czech Republic, on account of 124 confessed murders (he was a roaming highwayman), underwent a particularly gruelling execution procedure: First, his limbs were cut off and his nipples were ripped off with glowing pincers. He was then flayed, afterwards impaled and finally roasted alive. The pamphlet, which purports to give Wasansky's verbatim confession, does not record how Wasansky was apprehended, nor what means of torture was used to extract his confessions.
### Dracula
During the 15th century, Vlad III ("Dracula"), Prince of Wallachia, is credited as the first notable figure to prefer this method of execution during the late medieval period, and became so notorious for its liberal employment that among his several nicknames he was known as Vlad the Impaler. After being orphaned, betrayed, forced into exile and pursued by his enemies, he retook control of Wallachia in 1456. He dealt harshly with his enemies, especially those who had betrayed his family in the past, or had profited from the misfortunes of Wallachia. Though a variety of methods was employed, he has been most associated with his use of impalement. The liberal use of capital punishment was eventually extended to Saxon settlers, members of a rival clan, and criminals in his domain, whether they were members of the boyar nobility or peasants, and eventually to any among his subjects that displeased him. Following the multiple campaigns against the invading Ottoman Turks, Vlad would never show mercy to his prisoners of war. After The Night Attack of Vlad Ţepeş in mid-June 1462 failed to assassinate the Ottoman sultan, the road to Târgovişte, the capital of Vlad's principality of Wallachia, eventually became inundated in a "forest" of 20,000 impaled and decaying corpses, and it is reported that Mehmet II's invading army of Turks turned back to Constantinople in 1462 after encountering thousands of impaled corpses along the Danube River. Woodblock prints from the era portray his victims impaled from either the frontal or the dorsal aspect, but not vertically.
soldiers, Polish–Soviet War, 1920 image by Frenchman telling his story to The New York Times, 1920 Sees Bolshevism as Hideous Religion ]]
As an example of how Vlad Țepeș soon became iconic for all horrors unimaginable, the following pamphlet from 1521 pours out putative incidents like this one:
He let children be roasted; those, their mothers were forced to eat. And (he) cut off the breasts of women; those, their husbands were forced to eat. After that, he had them all impaled
## Ottoman Empire
Longitudinal impalement is an execution method often attested within the Ottoman Empire, for a variety of offenses.
### Siege of Constantinople
The Ottoman Empire used impalement during, and before, the last siege of Constantinople in 1453. For example, during the buildup phase to the great siege the year before, in 1452, the sultan declared that all ships sailing up or down through the Bosphorus had to anchor at his fortress there, for inspection. One Venetian captain, Antonio Rizzo, sought to defy the ban, but his ship was hit by a cannonball. He and his crew were picked up from the waters, the crew members to be beheaded (or sawn asunder according to Niccolò Barbaro), whereas Rizzo was impaled. In the early days of the siege in May 1453, contingents of the Ottoman army made mop-up operations at minor fortifications like Therapia and Studium. The surrendered soldiers, some 40 individuals from each place, were impaled.
### Civil crimes
Within the Ottoman Empire, some civil crimes (rather than rebel activity/treasonous behavior), such as highway robbery, might be punished by impalement. For some periods at least, executions for civil crimes were claimed to have been rather rare in the Ottoman Empire. For example, Aubry de La Motraye, lived in the realm for 14 years from 1699 to 1713 and claimed that he hadn't heard of twenty thieves in Constantinople during that time. As for highway robbers, who sure enough had been impaled, Aubry heard of only 6 such cases during his residence there. Staying at Aleppo from 1740–54, Alexander Russell notes that in the 20 years gone by, there were no more than "half a dozen" public executions there. Jean de Thévenot, traveling in the Ottoman Empire and its territories like Egypt in the late 1650s, emphasizes the regional variations in impalement frequency. Of Constantinople and Turkey, de Thévenot writes that impalement was "not much practiced" and "very rarely put in practice." An exception he highlighted was the situation of Christians in Constantinople. If a Christian spoke or acted out against the "Law of Mahomet", or consorted with a Turkish woman, or broke into a mosque, then he might face impalement unless he converted to Islam. In contrast, de Thévenot says that in Egypt impalement was a "very ordinary punishment" against the Arabs there, whereas Turks in Egypt were strangled in prison instead of being publicly executed like the natives. Thus, the actual frequency of impalement within the Ottoman Empire varied greatly, not only from time to time, but also from place to place, and between different population groups in the empire.
Highway robbers were still impaled into the 1830s, but one source says the practice was rare by then. Travelling to Smyrna and Constantinople in 1843, Stephen Massett was told by a man who witnessed the event that "just a few years ago", a dozen or so robbers were impaled at Adrianople. All of them, however, had been strangled prior to impalement. Writing around 1850, the archaeologist Austen Henry Layard mentions that the latest case he was acquainted with happened "about ten years ago" in Baghdad, on four rebel Arab sheikhs.
Impalement of pirates, rather than highway robbers, is also occasionally recorded. In October 1767, for example, Hassan Bey, who had preyed on Turkish ships in the Euxine Sea for a number of years, was captured and impaled, even though he had offered 500.000 ducats for his pardon.
### Klephts and rebels in Greece
During the Ottoman rule of Greece, impalement became an important tool of psychological warfare, intended to put terror into the peasant population. By the 18th century, Greek bandits turned guerrilla insurgents (known as klephts) became an increasing annoyance to the Ottoman government. Captured klephts were often impaled, as were peasants that harbored or aided them. Victims were publicly impaled and placed at highly visible points, and had the intended effect on many villages who not only refused to help the klephts, but would even turn them in to the authorities. The Ottomans engaged in active campaigns to capture these insurgents in 1805 and 1806, and were able to enlist Greek villagers, eager to avoid the stake, in the hunt for their outlaw countrymen.
Impalement was, on occasion, aggravated with being set over a fire, the impaling stake acting as a spit, so that the impaled victim might be roasted alive. Among other severities, Ali Pasha, an Albanian-born Ottoman noble who ruled Ioannina, had rebels, criminals, and even the descendants of those who had wronged him or his family in the past, impaled and roasted alive. For example, Thomas Smart Hughes, visiting Greece and Albania in 1812–13, says the following about his stay in Ioannina:
"Here criminals have been roasted alive over a slow fire, impaled, and skinned alive; others have had their extremities chopped off, and some have been left to perish with the skin of the face stripped over their necks. At first I doubted the truth of these assertions, but they were abundantly confirmed to me by persons of undoubted veracity. Some of the most respectable inhabitants of loannina assured me that they had sometimes conversed with these wretched victims on the very stake, being prevented from yielding to their torturing requests for water by fear of a similar fate themselves. Our own resident, as he was once going into the serai of Litaritza, saw a Greek priest, the leader of a gang of robbers, nailed alive to the outer wall of the palace, in sight of the whole city."
During the Greek War of Independence (1821–1832), Greek revolutionaries or civilians were tortured and executed by impalement. A German witness of the Constantinople massacre (April 1821) narrates the impalement of about 65 Greeks by Turkish mob. Other Greeks had been impaled during the first months of the resurrection in Patras, as it is recorded in the diary of the French consul Hughes Pouqueville and published by his brother François Pouqueville.
Athanasios Diakos, a klepht and later a rebel military commander, was captured after the Battle of Alamana (1821), near Thermopylae, and after refusing to convert to Islam and join the Ottoman army, he was impaled, and died after three days. Diakos became a martyr for a Greek independence and was later honored as a national hero.
One of the worst atrocities committed by the Greeks was the massacre following the Siege of Tripolitsa in October 1821, where several thousands were massacred, many impaled and roasted. Two months earlier, in August 1821, about the same time that some 40 Ionians were impaled by the Turks, Greek insurgents roasted at least as many Turks alive at Hydra William St Clair, in his "That Greece Might Still Be Free" warns against the skewed perception the Greek War of Independence received in Europe, and writes:
The Turkish atrocities against the Greek population were (...) witnessed with horror by many Europeans and soon were reported all over Europe. The initial atrocities in Greece, on the other hand, were seen by very few Europeans. If any were reported they were put down to justifiable hatred arising from extreme provocation, and explained away in the same terms as the occasional atrocities committed by European armies
### Rebels elsewhere in the Ottoman Empire
Impaling perceived rebels was an attested practice in other parts of the empire as well, such as the 1809 quelling of a Bosnian revolt, and during the Serbian Revolution (1804–1835) against the Ottoman Empire, about 200 Serbs were impaled in Belgrade in 1814. Historian James J. Reid, in his Crisis of the Ottoman Empire: Prelude to Collapse 1839–1878 notes several instances of later use, in particular in times of crises, ordered by military commanders(if not, that is, directly ordered by the supreme authority possessed by the Sultan). He notes late instances of impalement during rebellions (rather than cases of robbery) like the Bosnian revolt of 1852, within the 1860s Macedonian times of trouble, during the Cretan insurrection of 1866–69, and during the insurrections in Bosnia and Herzegovina in 1876–77.
### Occurrences in genocides
Allegations of impalement during the Assyrian and Armenian genocides have also been recorded.
Aurora Mardiganian, a survivor of the Armenian genocide of 1915–1923, recalled sixteen young Armenian girls being "crucified" by their Ottoman tormentors. The film "Auction of Souls" (1919), which was based on her book "Ravished Armenia", showed the victims nailed to crosses. However, almost 70 years later Mardiganian revealed that the scene was inaccurate and went on to describe what was actually an impalement:
"The Turks didn't make their crosses like that. The Turks made little pointed crosses. They took the clothes off the girls. They made them bend down, and after raping them, they made them sit on the pointed wood, through the vagina. That's the way they killed - the Turks. Americans have made it a more civilized way. They can't show such terrible things."
A Russian clergyman visiting ravaged Christian villages in northwestern Persia during the Assyrian genocide found the remains of several impaled people. He notes: "The bodies were so firmly fixed, in some instances, that the stakes could not be withdrawn; it was necessary to saw them off and bury the victims as they were."
# References and notes
- ↑ Thévenot (1687) p.259 Other highly detailed accounts on methods are:
1. Extremely detailed description of the execution of Archbishop Serapheim in 1601. Vaporis (2000), p.101-102 2. Jean Coppin's account from 1640s Cairo, very similar to Thévenot's, Raymond (2000), p.240 3. Stavorinus (1798) p. 288–291 4. von Taube (1777) footnote p. 70–71 5. The regrettably highly partisan "Aiolos (2004)", notes on methods partly from Guer, see for example, Guer (1747),p.162 6. d'Arvieux (1755), p. 230–31 7. Recollection 20 years after second-hand narration, Massett (1863), p. 88–89 8. Ivo Andric's novel "The Bridge on the Drina", follows Serapheim execution (1.) closely. Excerpt: The Bridge on the Drina 9. A literary rendition in The Casket, from 1827, Purser (1827), p.337 10. Koller (2004), p. 145–46
- ↑ 2 died during impalement process, Blount (1636), p.52 9 minutes, 1773 case, Hungary: Korabinsky (1786) p.139
- ↑ 1800 assassin of General Kleber a few hours Shepherd (1814)p.255, six hours Hurd (1814),p.308
- ↑ fifteen hours Bond (1856) p. 172–73 24+ hours von Taube (1777), footnote p. 70–71, Hartmann (1799)p. 520, two to three days von Troilo (1676) p.45, Hueber (1693) p.480, Dampier (1729)p.140, "Aiolos (2004)", 'd'Arvieux (1755), p. 230–31, Moryson, Hadfield (2001), p.170-171 two to three days in warm weather, dead by midnight in cold, Mentzel, Allemann (1919), p.102
- ↑ de Pages (1791) p.284
- ↑ Stavorinus (1798)p. 288–291
- ↑ For following the spine: von Taube (1777), footnote p. 70–71, Stavorinus (1798)p. 288–291 Another description, using a 15 cm thick stake, let it pass between the liver and the rib cage, Koller (2004), p.145
- ↑ von Meyer von Knonau (1855)p.176, column 2, Example of thrusting a roasting spit through the stomach on orders of 16th Central Asian ruler Mirza Abu Bakr Dughlat upon his own nephew, Elias, Ross (1898), p.227
- ↑ For extra-cardial chest impalement Döpler (1697) p.371
- ↑ Roch (1687)pp. 350–51
- ↑ A possible case of 16th century dorsal-to-front impalement is given by di Varthema (1863) p. 147 See also wood block print in Wallachia subsection. In addition, the alleged "bamboo torture" seems to presume a dorsal-to-front impalement, see specific sub-section
- ↑ Wagner (1687), p.55 NOTE: The German word "Pfahl" (with the associated verb "zu pfählen") refers to a wooden stake, and is the word used in influential law texts like the 1532 Constitutio Criminalis Carolina, so the reader should not assume that the use of a heated metal rod was the standard procedure. For 1532 law text, see for example, Koch (1824) p.63
- ↑ de Tournefort (1741) p. 98–100 A detailed description of the apparatus and procedure of gaunching can be found in Mundy (1907), p.55-56 and in Moryson, Hadfield (2001), p.170-171
- ↑ Thévenot (1687)p. 68–69. For a fourth description plus drawing, see Schweigger (1613), p.173 Schweigger adds that many times, people are allowed to shorten the gaunched individual's time of misery by cutting his throat or decapitating him. Alexander Russell, from 1740s Aleppo knew of instances of "gaunching", but said those were rare, compared with other types of capital punishment.Russell (1794)p.334
- ↑ Breuning von Buchenbach, Hans Jakob
- ↑ Buchenbach (1612), p.86-87
- ↑ Thomas Shaw
- ↑ Shaw (1757) p. 253–254 Shaw's contemporary John Braithwaite reports impalement and throwing onto hooks for Morocco as well, Braithwaite (1729) p.366 On Morocco and Fez, see also the travel account by Sieur Mouette, who was captive there from 1670-1682, Stevens (1711), p.69
- ↑ Morgan (1729) p.392
- ↑ in one of his acerbic comments and footnotes to translated accounts from Catholic priests' narratives of the redemption of slaves. Examples of other such acerbic notes: Boyde (1736) p.3, p.25, p.35, p.44 (compares French and Algerine slavery), p.45, p.51, p.52
- ↑ Boyde (1736) p.75, footnote
- ↑ Osborne (1745), p.478
- ↑ Koller (2004), p. 146
- ↑ Stedman (1813) p.116
- ↑ As an example of popular promotion of this horror story, see for example:WW2 People's WarJAPANESE TORTURE TECHNIQUES
- ↑ Middle chronology is used here
- ↑ Article 153 in: Harper (1904), The Code of Hammurabi
- ↑ Tetlow (2004) p.34
- ↑ Hamblin (2006), p.208
- ↑ Herrenschmidt, Bottéro (2000), p.84
- ↑ Mayer,ed. (2005), p.141
- ↑ Kitchen, Kenneth (2002). Ramesside inscriptions translated and annotated: Translations. Volume 4: Merenptah and the late Nineteenth Dynasty. Oxford: Blackwell Publishers. p. 1..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Jump up to: 33.0 33.1
- ↑ Ussishkin, Amit (2006), p.346
- ↑ Ekron incident from Sennacherib's own self-glorification, see Callaway (1995), p.169
- ↑ Relief and text in Ephʿal (2009), p. 51–52
- ↑ Relative to later impalement practices, at least
- ↑ Layard (1850) p.374
- ↑ Olmstead(1918), p.66
- ↑ Paul Kern
- ↑ Kern (1999), p. 68–76, Relative to impalement, for example, Ashurnasirpal II is credited with 5 distinct incidents, Shalmaneser III (r.858-824 BC),For a number of examples of impalement of rebels and subjugated people under Neo-Assyrian king Shalmaneser III, see Olmstead (1921), Battle at Sugania p.348,Siege of Til Bashere p.354, Battle of Arzashkun p.360,Battle of Kulisi p.368, Battle of Kinalua p.378 For the last, see also Bryce (2012), p.244 Tiglath-Pileser III (r.745-727), For some specifics on Tiglath-Pileser's policy, see for example, Crouch (2009), p. 39–41 and Ashurbanipal (r.668-627 BC), Ashurbanipal congratulates himself once over having impaled fleeing survivors from towns he has burnt down, Ehrlich (2004), p.5
- ↑ where Ashur-uballit I was king at that time
- ↑ Kuhrt (1995), p.292 and Gadd (1965), p.9
- ↑ Richardson, Laneri (2007), p.197
- ↑ Schroeder (1920), Keilschrifttexte aus Assur verschiedenen Inhalts
- ↑ Jastrow (1921), p. 48–49
- ↑ Haman conspired to have all the Jews in the empire killed, the Book of Esther tells that story, and how Haman's plan was thwarted, and he was given the punishment he had thought to mete out to Mordecai
- ↑ Book of Esther, ESV Bible edition
- ↑ Book of Esther, NIRV Bible edition
- ↑ Haupt (1908), p. 122, 152, 154, 170
- ↑ Shaw (2012), Was Haman Hanged or Impaled?
- ↑ The theologian Adam Clarke was deeply suspicious of whether this passage ought to be regarded as part of the original Biblical text, and wrote:
"(The definition of יקע (YaQ'a) in Strong's: "a prim. primitive root; prop. properly to sever oneself, i.e. (by impl. implication) to be dislocated; fig. to abandon; causat. causatively to impale (and thus allow to drop to pieces by rotting):- be alienated, depart, hang (up), be out of joint. The seven sons of Saul, mentioned here, , are represented as a sacrifice required by God, to make an atonement for the sin of Saul. Till I get farther light on the subject, I am led to conclude that the whole chapter is not now what it would be coming from the pen of an inspired writer; and that this part of the Jewish records has suffered much from rabbinical glosses, alterations, and additions." ),Clarke 1831, Bible ed. p. II 267
- ↑ Crucifixion in the Mediterranean World by John Granger Cook, 2014, published by Mohr Siebeck,ISBN 9783161531248
- ↑ For law text, Koch (1824) p.63
- ↑ Engel, Jacob (2006), p.75 A similar punishment of the couple by impalement for adultery if caught in the act is mentioned in Bavarian sources as well, see His (1928), p.150
- ↑ Schwetschke (1789), col. 692
- ↑ Ehrlich (2005), p.42
- ↑ Fick (1867), p.14
- ↑ Engelmann (1834)p.158
- ↑ Osenbrüggen (1868), p.297
- ↑ Schwab (1827), p.256
- ↑ Gottfried, van Hulsius (1633), p.462
- ↑ Han (1669), p.203
- ↑ Beer (1713), p.127
- ↑ von Loen (1751), p.420-422
- ↑ von Imhoff (1736), p.1051
- ↑ Mannheimer Zeitung (1784), p.638 After the revolt was crushed by early 1785, some 150 rebels are said to have been impaled. Vehse, Demmler (1856), p.318
- ↑ Woltersdorf (1812)p.267
- ↑ Other such "heinous murderers" cases that have impalement as a prominent element include, for example a case from 1504 and another from 1519, both in Wiltenburg (2012), pp.124-125, the execution of the murderer nicknamed Puschpeter in 1575, Bastian (1860), p.105, the execution of the head of the Pappenheimer family in 1600, Muir (1997), p. 110–111, as well as an unnamed murder in Breslau in 1615, having confessed to 96 acts of murder, Roch (1687), p.249
- ↑ Daschitsky (1570), p.12
- ↑ Jump up to: 71.0 71.1 Reid, (2000), p. 440
- ↑ Florescu (1999)
- ↑ Jump up to: 73.0 73.1 Axinte, Dracula: Between myth and reality
- ↑ "er liess kinnder praten die musten ire mütter essen. Und schneyd den frawen den prüst ab den musten ire man essen. Darnach liess er sie all spissen.", Gutknecht (1521), p.7
- ↑ Philippides, Hanak (2011), p.587
- ↑ Runciman (1965), p.67
- ↑ Pears, (2004), p.253
- ↑ de La Mottraye p.188
- ↑ Russell (1794) p.331
- ↑ See de Thévenot(1687), p. 68–69 and p.259
- ↑ Late Ottoman cases in 1830s Balkans, i) Some five case reported 1833, M*r (1833) p. 440–41 columns 2 ii) 1834, Two such corpses, close to the village Paracini in the vicinity of Jagodina, see: Burgess (1835) p.275 iii) Rarity of such cases in the 1830s,Goodrich (1836)p.308 1835, Retaliative cycle Turkish authorities relative Kurdish "robbers", Slade (1837) p.191
- ↑ Stephen Massett
- ↑ Massett (1863), p. 88–89
- ↑ Layard (1871), p.307
- ↑ Ranft (1769), p.345
- ↑ missing
- ↑ "Aiolos (2004)"
- ↑ Dumas (2008), volume 8, chapter 3
- ↑ Hughes (1820) p.454, see also, on roasting incident: Holland (1815) p.194
- ↑ J.W.A.Streit, Constantinopel im Jahr 1821, oder Darstellung der blutigen und höchst schauderhaften Begebenheiten ... Leipzig, 1822, pp. 30, 31, 42-45. Cited by Kyriakos Simopoulos, "How Foreigners saw the Greece of the 1821 Revolution", Athens, 2004 (5th edition), vol. 1, pp. 153, 154, in Greek language.
- ↑ Cited by K. Simopoulos in "How Foreigners saw the Greece of the 1821 Revolution", Athens, 2004 (5th edition), vol. 1, p. 145, footnote 46. In Greek language.
- ↑ Makrygiannis Yannis, Memoirs, p. 27. (In greek language) Yannis Makrygiannis (1797-1864) was a general and politician, hero of the Greek Revolution.
- ↑ Paroulakis (1984)
- ↑ Turkish reprisals on Greek War of independence, i) 2.June 1821, 10 Greeks at Bucharest, Fick (1821) p.254 ii) During the massacre at Crete around 24 June 1821, most are said to have been impaled: Siegman (1821) p.988, column 1 iii) 36 Greek hostages, including 7 bishops at onset of Siege of Tripolitsa Colburn (1821) p.56 iv) In conjunction with the Chios Massacre in 1822, several Chiote merchants were detained and executed at Constantinople, 6 of whom were impaled alive: Hughes (1822)p.169 v) Omer Vrioni organizing in 1821 Greek hunts where civilians were, at least in one instance, impaled on his orders.Waddington (1825) p. 52–54 vi) In early 1822 Cassandreia, some 300 civilians massacred, several reported to have been impaled, Grund (1822) p.4 vii) During the last Siege of Missolonghi, in 1826, the Ottoman besiegers offered opportunity for capitulation for the besieged, while they also sent a message of consequences for refusal by impaling alive a priest, two women and several children in front of the line. The offer of capitulation was declined by the besieged Greeks. Alison(1856), p.206
- ↑ Green (1827)p. 70–72
- ↑ Constable (1821) p.275 57 Turks roasted at Hydra, according to one source. Merry (2004), p.470
- ↑ St Clair (2008) p.25 According to one source, the early spring weeks of 1821 saw the murders of more than 20.000 Turks in Greece. Merry (2004), p.470</
- ↑ 20-50 "daily" brought in, most impaled Urban (1810) p.74
- ↑ Sowards (2009) The Serbian Revolution and the Serbian State
- ↑ Obituary James Reid
- ↑ Reid (2000), p.441
- ↑ Erish (2012) p.212
- ↑ Shahbaz (1918), p.142
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- Vaporis, Nomikos M. (2000). Witnesses for Christ. Crestwood, NY: St Vladimir's Seminary Press. ISBN 9780881411966.
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- Vehse, Karl E.; Demmler, Franz (tr.) (1856). Memoirs of the Court, Aristocracy, and Diplomacy of Austria. 2. London: Longman, Brown, Green, and Longmans.
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- Grund (26 February 1822). Türkish-Griechische Angelegenheiten. Staats und gelehrte zeitung des hamburgischen unpartheyischen correspondenten. 33. Hamburg: Grundschen Erben. p. 4.
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- Hughes, Thomas S. (1822). An Address to the people of England in the CAUSE OF THE GREEKS. The Pamphleteer. 21. London: A.J. Valpy. pp. 167–188.
- Jastrow Jr., Morris (1921). "An Assyrian Law Code". Journal of the American Oriental Society. Baltimore: American Oriental Society. 41: 1–59. doi:10.2307/593702. ISSN 0003-0279.
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Impalement, as a method of execution, is the penetration of a human by an object such as a stake, pole, spear, or hook, often by complete or partial perforation of the torso. It was used particularly in response to "crimes against the state" and regarded across a number of cultures as a very harsh form of capital punishment and recorded in myth and art. Impalement was also used during wartime to suppress rebellion, punish traitors or collaborators, and as a punishment for breaches of military discipline.
Offenses where impalement was occasionally employed include: contempt for the state's responsibility for safe roads and trade routes by committing highway robbery or grave robbery, violating state policies or monopolies, or subverting standards for trade. Offenders have also been impaled for a variety of cultural, sexual and religious reasons.
References to impalement in Babylonia and the Neo-Assyrian Empire are found as early as the 18th century BC. Within the Ottoman Empire, this form of execution continued into the 20th century.
# Methods
## Longitudinal impalement
Impaling an individual along the body length has been documented in several cases, and the merchant Jean de Thevenot provides an eyewitness account of this, from 17th century Egypt, in the case of a man condemned to death for the use of false weights:[1]
They lay the Malefactor upon his Belly, with his Hands tied behind his Back, then they slit up his Fundament with a Razor, and throw into it a handful of Paste that they have in readiness, which immediately stops the Blood. After that they thrust up into his Body a very long Stake as big as a Mans Arm, sharp at the point and tapered, which they grease a little before; when they have driven it in with a Mallet, till it come out at his Breast, or at his Head or Shoulders, they lift him up, and plant this Stake very streight in the Ground, upon which they leave him so exposed for a day. One day I saw a Man upon the Pale, who was Sentenced to continue so for three Hours alive and that he might not die too soon, the Stake was not thrust up far enough to come out at any part of his Body, and they also put a stay or rest upon the Pale, to hinder the weight of his body from making him sink down upon it, or the point of it from piercing him through, which would have presently killed him: In this manner he was left for some Hours, (during which time he spoke) and turning from one side to another, prayed those that passed by to kill him, making a thousand wry Mouths and Faces, because of the pain be suffered when he stirred himself, but after Dinner the Basha sent one to dispatch him; which was easily done, by making the point of the Stake come out at his Breast, and then he was left till next Morning, when he was taken down, because he stunk horridly.
### Survival time
The survival time on the stake is quite variedly reported, from a few seconds or minutes[2] to a few hours[3] or 1 to 3 days.[4] The Dutch overlords at Batavia, present day Jakarta, seem to have been particularly proficient in prolonging the lifetime of the impaled, one witnessing a man surviving 6 days on the stake,[5] another hearing from local surgeons that some could survive 8 or more days.[6] A critical determinant for survival length seems to be precisely how the stake was inserted: If it went into the "interior" parts, vital organs could easily be damaged, leading to a swift death. However, by letting the stake follow the spine, the impalement procedure would not damage the vital organs, and the person could survive for several days.[7]
## Transversal impalement
Alternatively, the impalement could be transversally performed, for example in the frontal-to-dorsal direction, that is, from front (through abdomen,[8] chest[9] or directly through the heart[10]) to back or vice versa[11]
In the Holy Roman Empire (and elsewhere in Central/Eastern Europe), women who killed their newborn could be liable to be placed in an open grave, and have a stake hammered into their heart. A detailed description of an execution in this manner comes from 17th century Košice (then in Hungary, now in eastern Slovakia). A woman was to be executed for infanticide, the executioner had two assistants to help him. First, a grave, some one-and-a-half ell deep was dug. The woman was placed within it, her hands and feet secured by driving nails through them. Then, the executioner placed a small thorn bush upon her face. He then placed and held vertically a wooden stave at her heart, while his assistants piled earth on the woman. Her head, though, was kept free of earth, at the behest of the clerics, because that would have quickened her death process. Once the earth had been piled upon her, the executioner grabbed with a pair of tongs a rod made of iron, which had been made red hot. He positioned the glowing iron rod beside the wooden stave, and as one of his assistants hammered the rod in, the other assistant emptied a trough of earth upon the woman's head. It is said that a scream was heard, and that the earth actually moved upwards for a moment, before all was over.[12]
## Variations
### Gaunching
Joseph Pitton de Tournefort, travelling on botanical research in the Levant 1700–1702, observed both ordinary longitudinal impalement, but also a method called "gaunching", in which the condemned is hoisted up by means of a rope over a bed of sharp metal hooks. He is then released, and depending on how the hooks enter his body, he may survive in impaled condition for a few days.[13]
Forty years earlier than de Tournefort, de Thévenot described much the same process, adding that it was seldom used because it was regarded as too cruel.[14] Some 80 years prior to de Thevenot, in 1579, Hans Jacob Breuning von Buchenbach[15] witnessed a variant of the gaunching ritual. A large iron hook was fixed on the horizontal cross-bar of the gallows and the individual was forced upon this hook, piercing him from the abdomen through his back, so that he hung from it, hands, feet and head downward. On top of the cross bar, the executioner situated himself and performed various torture on the impaled man below him.[16]
### Hooks in the city wall
While gaunching as de Tournefort describes involves the erection of a scaffold, it seems that in the city of Algiers, hooks were embedded in the city walls, and on occasion, people were thrown upon them from the battlements.
Thomas Shaw,[17] who was chaplain for the Levant Company stationed at Algiers during the 1720s, describes the various forms of executions practiced as follows:[18]
"..but the Moors and Arabs are either impaled for the same crime, or else they are hung up by the neck, over the battlements of the city walls, or else they are thrown upon the chingan or hooks that are fixed all over the walls below, where sometimes they break from one hook to another, and hang in the most exquisite torments, thirty or forty hours."
According to one source, these hooks in the wall as an execution method were introduced with the construction of the new city gate in 1573. Before that time, gaunching as described by de Tournefort was in use.[19] As for the actual frequency of throwing persons on hooks in Algiers, Capt. Henry Boyde notes[20] that in his own 20 years of captivity there, he knew of only one case where a Christian slave who had murdered his master had met that fate, and "not above" two or three Moors besides.[21] Taken captive in 1596, the barber-surgeon William Davies relates something of the heights involved when thrown upon hooks (although it is somewhat unclear if this relates specifically to the city of Algiers, or elsewhere in the Barbary States): "Their ganshing is after this manner: he sitteth upon a wall, being five fathoms high, within two fathoms of the top of the wall; right under the place where he sits, is a strong iron hook fastened, being very sharp; then he is thrust off the wall upon this hook, with some part of his body, and there he hangeth, sometimes two or three days, before he dieth." Davies adds that "these deaths are very seldom", but that he had personally witnessed it [22]
### Hanged by the ribs
A slightly variant way of executing people by means of impalement was to force an iron meat hook beneath a person's ribs and hang him up to die slowly. This technique was in 18th century Ottoman-controlled Bosnia called the cengela,[23] but the practice is also attested, for example, in 1770s Dutch Suriname as a punishment meted out to rebellious slaves.[24]
### Bamboo torture
A recurring horror story on many websites and popular media outlets is that Japanese soldiers during World War II inflicted bamboo torture upon prisoners of war. The victim was supposedly tied securely in place above a young bamboo shoot. Over several days, the sharp, fast growing shoot would first puncture, then completely penetrate the victim's body, eventually emerging through the other side.[25] The cast of the TV program MythBusters investigated bamboo torture in a 2008 episode and found that a bamboo shoot can penetrate through several inches of ballistic gelatin in three days. For research purposes, ballistic gelatin is considered comparable to human flesh, and the experiment thus supported the viability of this form of torture, if not its historical use.
# History
## Antiquity
### Mesopotamia and the ancient Near East
The earliest known use of impalement as a form of execution occurred in civilizations of the ancient Near East. For example, the Code of Hammurabi, promulgated about 1772 BC[26] by the Babylonian king Hammurabi specifies impaling for a woman who killed her husband for the sake of another man.[27] In the late Isin/Larsa period, from about the same time, it seems that, in some city states, mere adultery on the wife's part (without murder of her husband mentioned) could be punished by impalement.[28] From the royal archives of the city of Mari (at the Syrian-Iraqi border by the western bank of Euphrates), most of it also roughly contemporary to Hammurabi, it is known that soldiers taken captive in war were on occasion impaled.[29] Roughly contemporary with Babylonia under Hammurabi, king Siwe-Palar-huhpak of Elam, a country lying directly east of Babylonia in present-day Iran, made official edicts in which he threatened the allies of his enemies with impalement, among other terrible fates.[30] For acts of perceived great sacrilege, some individuals, in diverse cultures, have been impaled for their effrontery. For example, roughly 1200 BC, merchants of Ugarit express deep concern to each other that a fellow citizen is to be impaled in the Phoenician town Sidon, due to some "great sin" committed against the patron deity of Sidon.[31]
### Pharaonic Egypt
During Dynasty 19, Merenptah had Libu prisoners of war impaled ("caused to be set upon a stake") to the south of Memphis, following an attempted invasion of Egypt during his Regnal Year 5.[32] The relevant determinative for ḫt ("stake") depicts an individual transfixed though the abdomen.[33] Other Egyptian kings employing impalements include Sobekhotep II, Akhenaten, Seti, and Ramesses IX.[33]
### Neo-Assyrian Empire
Evidence by carvings and statues is found as well, for example from Neo-Assyrian empire (rough dating, 934-609 BCE). The image of the impaled Judeans is a detail from the public commemoration of the Assyrian victory in 701 BC after the Siege of Lachish,[34] under King Sennacherib (r.705-681 BC), who proceeded similarly against the inhabitants of Ekron during the same campaign.[35] From Sennacherib's father Sargon II's time (r.722-705 BC), a relief from his palace at Khorsabad shows the impalement of 14 enemies during an attack on the city of Pazashi.[36] A peculiarity[37] about the "Neo-Assyrian" way of impaling was that the stake was "driven into the body immediately under the ribs",[38] rather than along the full body length. For the Neo-Assyrians, mass executions seem to have been not only designed to instill terror and to enforce obedience, but also, it can seem, as proofs of their might that they took pride in. For example, Neo-Assyrian King Ashurnasirpal II (r.883-859 BC) was evidently proud enough of his bloody work that he committed it to monument and eternal memory as follows:[39]
"I cut off their hands, I burned them with fire, a pile of the living men and of heads over against the city gate I set up, men I impaled on stakes, the city I destroyed and devastated, I turned it into mounds and ruin heaps, the young men and the maidens in the fire I burned"
Paul Kern,[40] in his (1999) "Ancient Siege Warfare" provides some statistics on how different Neo-Assyrian kings from the times of Ashurnasirpal II commemorated their punishments of rebels[41]
Although impalement of rebels and enemies is particularly well-attested from Neo-Assyrian times, the 14th century BC Mitanni king Shattiwaza charges his predecessor, the usurper Shuttarna III for having delivered unto the (Middle) Assyrians[42] several nobles, who had them promptly impaled.[43] Some scholars have said, though, that it is only with king Ashur-bel-kala (r.1074-1056) that we have solid evidence that punishments like flaying and impaling came into use.[44] From the Middle Assyrian period, we have evidence about impalement as a form of punishment relative to other types of perceived crimes as well. The law code discovered and deciphered by Dr. Otto Schroeder[45] contains in its paragraph 51 the following injunction against abortion:[46]
If a woman with her consent brings on a miscarriage, they seize her, and determine her guilt. On a stake they impale her, and do not bury her; and if through the miscarriage she dies, they likewise impale her and do not bury her
### Ambiguous Biblical evidence
Some controversy exist between different Bible translations concerning the actual fate of the 5th century BC Persian minister Haman and his ten sons, whether they were impaled or hanged[47] For example, the English Standard Version, Esther 5:14 opts for hanging,[48] whereas The New International Reader's version opts for impalement.[49]
The Assyriologist Paul Haupt opts for impalement in his 1908 essay "Critical notes on Esther",[50] while Benjamin Shaw has an extended discussion of the topic on the website ligonier.org from 2012.[51]
Other passages in the Bible allude to the practice of impalement, such as II Samuel 21:9, concerning the fate of the sons of Saul.
Although conclusive evidence might be wanting either way for whether Hebrew Law allowed for impalement, or just hanging, the Neo-Assyrian method of impalement as seen in the carvings could, perhaps, equally easily be seen as a form of hanging upon a pole, rather than focusing upon the stake's actual penetration of the body.
### Rome
From John Granger Cook, 2014, - "Stipes is Seneca's term of the object used for impalement. This narrative and his Ep. 14.5 are the only two textually explicit references of impalement in Latin texts..."
## Europe
Within the Holy Roman Empire, in article 131 of the 1532 Constitutio Criminalis Carolina, the following punishment was stated for women found guilty of infanticide. Generally, they should be drowned, but the law code allowed for, in particularly severe cases, that the old punishment could be implemented. That is, the woman would be buried alive, and then a stake would be driven through her heart.[54] Similarly, burial alive, combined with transversal impalement is attested as an early execution method for people found guilty of adultery. For example, from the 1348 statutes of Zwickau, it seems that an adulterous couple could be punished in the following way: They were to be placed on top of each other in a grave, with a layer of thorns between them. Then, a single stake was to be hammered through them.[55] A similar punishment by impalement for a proven male adulterer is mentioned in a 13th-century ordinance for Bohemian mining town Iglau,[56] whereas in a 1340 Vienna statute, the husband of a woman caught in flagrante in adultery could, if he wished to, demand that his wife and her lover be impaled, alternatively demand a monetary restitution.[57] Occasionally, women found guilty of witchcraft have been condemned to be impaled. In 1587 Kiel, 101-year-old Sunde Bohlen was, on being condemned as a witch, buried alive, and afterwards had a stake driven through her heart.[58]
Rapists of virgins and children are also attested to have been buried alive, with a stake driven through them. In one such judicial tradition, the rapist was to be placed in an open grave, and the rape victim was ordered to make the three first strokes on the stake herself; the executioners then finishing the impalement procedure.[59] Serving as an example of the fate of a child molester, in August 1465 in Zurich, Switzerland, Ulrich Moser was condemned to be impaled, for having sexually violated six girls between the ages four and nine. His clothes were taken off, and he was placed on his back. His arms and legs were stretched out, each secured to a pole. Then a stake was driven through his navel down into the ground. Thereafter, people left him to die.[60]
Cases of longitudinal impalement can be found typically in the context of war or as a punishment of robbers, the latter being attested as practice in Central and Eastern Europe.
Individuals perceived of collaborating with the enemy have, on occasion, been impaled. For example, in 1632 during the Thirty Years' War, the German officer Fuchs was impaled on suspicion of defecting to the Swedes,[61] a Swedish corporal was likewise impaled for trying to defect to the Germans.[62] In 1654, under the Ottoman siege of the Venetian garrison at Crete, several peasants were impaled for supplying provisions to the besieged.[63] Likewise in 1685, some Christians were impaled by the Hungarians for having provided supplies to the Turks.[64]
In 1677, a particularly brutal German General Kops leading the forces of Holy Roman Emperor Leopold I designed to keep Hungary dominated by the Germans, rather than to become dominated by the Turks, began impaling and quartering his Hungarian subjects/opponents. An opposing general for the Hungarians, Wesselényi, responded in kind, by flaying alive Imperial troops, and fixing sharp iron hooks in fortress walls, upon which he threw captured Germans to be impaled. Finally, Emperor Leopold I had had enough of the mutual bloodshed, and banished Kops in order to establish a needed cessation of hostilities.[65] After the Treaty of The Hague (1720), Sicily fell under Habsburg rule, but the locals deeply resented the German overlords. One parish priest (who exhorted his parishioners to kill the Germans) is said to have broken into joy when a German soldier arrived at his village, exclaiming it was gone a whole eight days since last he killed a German, and shot the soldier off his horse. The priest was later impaled.[66] In the short-lived 1784 Horea Revolt against the Austrians and Hungarians, the rebels gained hold of two officers they promptly impaled. On their side, the imperial troops got hold of Horea's 13-year-old son, and impaled him. That seems to have merely inflamed the rebel leader's determination, although the revolt was quashed shortly afterwards.[67]
From 1748 and onwards, German regiments organized manhunts on "robbers" in Hungary/Croatia, impaling those caught.[68]
### Execution of Paul Wasansky in 1570
Occasionally, individual murderers were perceived to have been so heinous that standard punishments like beheading or to be broken on the wheel were not regarded as sufficiently commensurate with their crimes, and extended rituals of execution that might include impalement were devised. The case of Pavel Vašanský (Paul Wasansky in German transcript) may serve as an example here.[69]
Paul Wasansky, who in 1570 was executed in Ivančice, in present-day Czech Republic, on account of 124 confessed murders (he was a roaming highwayman), underwent a particularly gruelling execution procedure: First, his limbs were cut off and his nipples were ripped off with glowing pincers. He was then flayed, afterwards impaled and finally roasted alive.[70] The pamphlet, which purports to give Wasansky's verbatim confession, does not record how Wasansky was apprehended, nor what means of torture was used to extract his confessions.
### Dracula
During the 15th century, Vlad III ("Dracula"), Prince of Wallachia, is credited as the first notable figure to prefer this method of execution during the late medieval period,[71] and became so notorious for its liberal employment that among his several nicknames he was known as Vlad the Impaler.[72] After being orphaned, betrayed, forced into exile and pursued by his enemies, he retook control of Wallachia in 1456. He dealt harshly with his enemies, especially those who had betrayed his family in the past, or had profited from the misfortunes of Wallachia. Though a variety of methods was employed, he has been most associated with his use of impalement. The liberal use of capital punishment was eventually extended to Saxon settlers, members of a rival clan,[73] and criminals in his domain, whether they were members of the boyar nobility or peasants, and eventually to any among his subjects that displeased him. Following the multiple campaigns against the invading Ottoman Turks, Vlad would never show mercy to his prisoners of war. After The Night Attack of Vlad Ţepeş in mid-June 1462 failed to assassinate the Ottoman sultan, the road to Târgovişte, the capital of Vlad's principality of Wallachia, eventually became inundated in a "forest" of 20,000 impaled and decaying corpses, and it is reported that Mehmet II's invading army of Turks turned back to Constantinople in 1462 after encountering thousands of impaled corpses along the Danube River.[73] Woodblock prints from the era portray his victims impaled from either the frontal or the dorsal aspect, but not vertically.
soldiers, Polish–Soviet War, 1920 image by Frenchman telling his story to The New York Times, 1920 Sees Bolshevism as Hideous Religion ]]
As an example of how Vlad Țepeș soon became iconic for all horrors unimaginable, the following pamphlet from 1521 pours out putative incidents like this one:
He let children be roasted; those, their mothers were forced to eat. And (he) cut off the breasts of women; those, their husbands were forced to eat. After that, he had them all impaled
## Ottoman Empire
Longitudinal impalement is an execution method often attested within the Ottoman Empire, for a variety of offenses.
### Siege of Constantinople
The Ottoman Empire used impalement during, and before, the last siege of Constantinople in 1453.[71] For example, during the buildup phase to the great siege the year before, in 1452, the sultan declared that all ships sailing up or down through the Bosphorus had to anchor at his fortress there, for inspection. One Venetian captain, Antonio Rizzo, sought to defy the ban, but his ship was hit by a cannonball. He and his crew were picked up from the waters, the crew members to be beheaded (or sawn asunder according to Niccolò Barbaro[75]), whereas Rizzo was impaled.[76] In the early days of the siege in May 1453, contingents of the Ottoman army made mop-up operations at minor fortifications like Therapia and Studium. The surrendered soldiers, some 40 individuals from each place, were impaled.[77]
### Civil crimes
Within the Ottoman Empire, some civil crimes (rather than rebel activity/treasonous behavior), such as highway robbery, might be punished by impalement. For some periods at least, executions for civil crimes were claimed to have been rather rare in the Ottoman Empire. For example, Aubry de La Motraye, lived in the realm for 14 years from 1699 to 1713 and claimed that he hadn't heard of twenty thieves in Constantinople during that time. As for highway robbers, who sure enough had been impaled, Aubry heard of only 6 such cases during his residence there.[78] Staying at Aleppo from 1740–54, Alexander Russell notes that in the 20 years gone by, there were no more than "half a dozen" public executions there.[79] Jean de Thévenot, traveling in the Ottoman Empire and its territories like Egypt in the late 1650s, emphasizes the regional variations in impalement frequency. Of Constantinople and Turkey, de Thévenot writes that impalement was "not much practiced" and "very rarely put in practice." An exception he highlighted was the situation of Christians in Constantinople. If a Christian spoke or acted out against the "Law of Mahomet", or consorted with a Turkish woman, or broke into a mosque, then he might face impalement unless he converted to Islam. In contrast, de Thévenot says that in Egypt impalement was a "very ordinary punishment" against the Arabs there, whereas Turks in Egypt were strangled in prison instead of being publicly executed like the natives.[80] Thus, the actual frequency of impalement within the Ottoman Empire varied greatly, not only from time to time, but also from place to place, and between different population groups in the empire.
Highway robbers were still impaled into the 1830s, but one source says the practice was rare by then.[81] Travelling to Smyrna and Constantinople in 1843, Stephen Massett[82] was told by a man who witnessed the event that "just a few years ago", a dozen or so robbers were impaled at Adrianople. All of them, however, had been strangled prior to impalement.[83] Writing around 1850, the archaeologist Austen Henry Layard mentions that the latest case he was acquainted with happened "about ten years ago" in Baghdad, on four rebel Arab sheikhs.[84]
Impalement of pirates, rather than highway robbers, is also occasionally recorded. In October 1767, for example, Hassan Bey, who had preyed on Turkish ships in the Euxine Sea for a number of years, was captured and impaled, even though he had offered 500.000 ducats for his pardon.[85]
### Klephts and rebels in Greece
During the Ottoman rule of Greece, impalement became an important tool of psychological warfare, intended to put terror into the peasant population. By the 18th century, Greek bandits turned guerrilla insurgents (known as klephts) became an increasing annoyance to the Ottoman government. Captured klephts were often impaled, as were peasants that harbored or aided them. Victims were publicly impaled and placed at highly visible points, and had the intended effect on many villages who not only refused to help the klephts, but would even turn them in to the authorities. [86]The Ottomans engaged in active campaigns to capture these insurgents in 1805 and 1806, and were able to enlist Greek villagers, eager to avoid the stake, in the hunt for their outlaw countrymen.[87]
Impalement was, on occasion, aggravated with being set over a fire, the impaling stake acting as a spit, so that the impaled victim might be roasted alive.[88] Among other severities, Ali Pasha, an Albanian-born Ottoman noble who ruled Ioannina, had rebels, criminals, and even the descendants of those who had wronged him or his family in the past, impaled and roasted alive. For example, Thomas Smart Hughes, visiting Greece and Albania in 1812–13, says the following about his stay in Ioannina:[89]
"Here criminals have been roasted alive over a slow fire, impaled, and skinned alive; others have had their extremities chopped off, and some have been left to perish with the skin of the face stripped over their necks. At first I doubted the truth of these assertions, but they were abundantly confirmed to me by persons of undoubted veracity. Some of the most respectable inhabitants of loannina assured me that they had sometimes conversed with these wretched victims on the very stake, being prevented from yielding to their torturing requests for water by fear of a similar fate themselves. Our own resident, as he was once going into the serai of Litaritza, saw a Greek priest, the leader of a gang of robbers, nailed alive to the outer wall of the palace, in sight of the whole city."
During the Greek War of Independence (1821–1832), Greek revolutionaries or civilians were tortured and executed by impalement. A German witness of the Constantinople massacre (April 1821) narrates the impalement of about 65 Greeks by Turkish mob.[90] Other Greeks had been impaled during the first months of the resurrection in Patras, as it is recorded in the diary of the French consul Hughes Pouqueville and published by his brother François Pouqueville.[91]
Athanasios Diakos, a klepht and later a rebel military commander, was captured after the Battle of Alamana (1821), near Thermopylae, and after refusing to convert to Islam and join the Ottoman army, he was impaled, and died after three days.[92] Diakos became a martyr for a Greek independence and was later honored as a national hero.[93][94]
One of the worst atrocities committed by the Greeks was the massacre following the Siege of Tripolitsa in October 1821, where several thousands were massacred, many impaled and roasted.[95] Two months earlier, in August 1821, about the same time that some 40 Ionians were impaled by the Turks, Greek insurgents roasted at least as many Turks alive at Hydra[96] William St Clair, in his "That Greece Might Still Be Free" warns against the skewed perception the Greek War of Independence received in Europe, and writes:[97]
The Turkish atrocities against the Greek population were (...) witnessed with horror by many Europeans and soon were reported all over Europe. The initial atrocities in Greece, on the other hand, were seen by very few Europeans. If any were reported they were put down to justifiable hatred arising from extreme provocation, and explained away in the same terms as the occasional atrocities committed by European armies
### Rebels elsewhere in the Ottoman Empire
Impaling perceived rebels was an attested practice in other parts of the empire as well, such as the 1809 quelling of a Bosnian revolt,[98] and during the Serbian Revolution (1804–1835) against the Ottoman Empire, about 200 Serbs were impaled in Belgrade in 1814.[99] Historian James J. Reid,[100] in his Crisis of the Ottoman Empire: Prelude to Collapse 1839–1878 notes several instances of later use, in particular in times of crises, ordered by military commanders(if not, that is, directly ordered by the supreme authority possessed by the Sultan). He notes late instances of impalement during rebellions (rather than cases of robbery) like the Bosnian revolt of 1852, within the 1860s Macedonian times of trouble, during the Cretan insurrection of 1866–69, and during the insurrections in Bosnia and Herzegovina in 1876–77.[101]
### Occurrences in genocides
Allegations of impalement during the Assyrian and Armenian genocides have also been recorded.
Aurora Mardiganian, a survivor of the Armenian genocide of 1915–1923, recalled sixteen young Armenian girls being "crucified" by their Ottoman tormentors. The film "Auction of Souls" (1919), which was based on her book "Ravished Armenia", showed the victims nailed to crosses. However, almost 70 years later Mardiganian revealed that the scene was inaccurate and went on to describe what was actually an impalement:[102]
"The Turks didn't make their crosses like that. The Turks made little pointed crosses. They took the clothes off the girls. They made them bend down, and after raping them, they made them sit on the pointed wood, through the vagina. That's the way they killed - the Turks. Americans have made it a more civilized way. They can't show such terrible things."
A Russian clergyman visiting ravaged Christian villages in northwestern Persia during the Assyrian genocide found the remains of several impaled people. He notes: "The bodies were so firmly fixed, in some instances, that the stakes could not be withdrawn; it was necessary to saw them off and bury the victims as they were."[103]
# References and notes
- ↑ Thévenot (1687) p.259 Other highly detailed accounts on methods are:
1. Extremely detailed description of the execution of Archbishop Serapheim in 1601. Vaporis (2000), p.101-102 2. Jean Coppin's account from 1640s Cairo, very similar to Thévenot's, Raymond (2000), p.240 3. Stavorinus (1798) p. 288–291 4. von Taube (1777) footnote ** p. 70–71 5. The regrettably highly partisan "Aiolos (2004)", notes on methods partly from Guer, see for example, Guer (1747),p.162 6. d'Arvieux (1755), p. 230–31 7. Recollection 20 years after second-hand narration, Massett (1863), p. 88–89 8. Ivo Andric's novel "The Bridge on the Drina", follows Serapheim execution (1.) closely. Excerpt: The Bridge on the Drina 9. A literary rendition in The Casket, from 1827, Purser (1827), p.337 10. Koller (2004), p. 145–46
- ↑ 2 died during impalement process, Blount (1636), p.52 9 minutes, 1773 case, Hungary: Korabinsky (1786) p.139
- ↑ 1800 assassin of General Kleber a few hours Shepherd (1814)p.255, six hours Hurd (1814),p.308
- ↑ fifteen hours Bond (1856) p. 172–73 24+ hours von Taube (1777), footnote ** p. 70–71, Hartmann (1799)p. 520, two to three days von Troilo (1676) p.45, Hueber (1693) p.480, Dampier (1729)p.140, "Aiolos (2004)", 'd'Arvieux (1755), p. 230–31, Moryson, Hadfield (2001), p.170-171 two to three days in warm weather, dead by midnight in cold, Mentzel, Allemann (1919), p.102
- ↑ de Pages (1791) p.284
- ↑ Stavorinus (1798)p. 288–291
- ↑ For following the spine: von Taube (1777), footnote ** p. 70–71, Stavorinus (1798)p. 288–291 Another description, using a 15 cm thick stake, let it pass between the liver and the rib cage, Koller (2004), p.145
- ↑ von Meyer von Knonau (1855)p.176, column 2, Example of thrusting a roasting spit through the stomach on orders of 16th Central Asian ruler Mirza Abu Bakr Dughlat upon his own nephew, Elias, Ross (1898), p.227
- ↑ For extra-cardial chest impalement Döpler (1697) p.371
- ↑ Roch (1687)pp. 350–51
- ↑ A possible case of 16th century dorsal-to-front impalement is given by di Varthema (1863) p. 147 See also wood block print in Wallachia subsection. In addition, the alleged "bamboo torture" seems to presume a dorsal-to-front impalement, see specific sub-section
- ↑ Wagner (1687), p.55 NOTE: The German word "Pfahl" (with the associated verb "zu pfählen") refers to a wooden stake, and is the word used in influential law texts like the 1532 Constitutio Criminalis Carolina, so the reader should not assume that the use of a heated metal rod was the standard procedure. For 1532 law text, see for example, Koch (1824) p.63
- ↑ de Tournefort (1741) p. 98–100 A detailed description of the apparatus and procedure of gaunching can be found in Mundy (1907), p.55-56 and in Moryson, Hadfield (2001), p.170-171
- ↑ Thévenot (1687)p. 68–69. For a fourth description plus drawing, see Schweigger (1613), p.173 Schweigger adds that many times, people are allowed to shorten the gaunched individual's time of misery by cutting his throat or decapitating him. Alexander Russell, from 1740s Aleppo knew of instances of "gaunching", but said those were rare, compared with other types of capital punishment.Russell (1794)p.334
- ↑ Breuning von Buchenbach, Hans Jakob
- ↑ Buchenbach (1612), p.86-87
- ↑ Thomas Shaw
- ↑ Shaw (1757) p. 253–254 Shaw's contemporary John Braithwaite reports impalement and throwing onto hooks for Morocco as well, Braithwaite (1729) p.366 On Morocco and Fez, see also the travel account by Sieur Mouette, who was captive there from 1670-1682, Stevens (1711), p.69
- ↑ Morgan (1729) p.392
- ↑ in one of his acerbic comments and footnotes to translated accounts from Catholic priests' narratives of the redemption of slaves. Examples of other such acerbic notes: Boyde (1736) p.3, p.25, p.35, p.44 (compares French and Algerine slavery), p.45, p.51, p.52
- ↑ Boyde (1736) p.75, footnote
- ↑ Osborne (1745), p.478
- ↑ Koller (2004), p. 146
- ↑ Stedman (1813) p.116
- ↑ As an example of popular promotion of this horror story, see for example:WW2 People's WarJAPANESE TORTURE TECHNIQUES
- ↑ Middle chronology is used here
- ↑ Article 153 in: Harper (1904), The Code of Hammurabi
- ↑ Tetlow (2004) p.34
- ↑ Hamblin (2006), p.208
- ↑ Herrenschmidt, Bottéro (2000), p.84
- ↑ Mayer,ed. (2005), p.141
- ↑ Kitchen, Kenneth (2002). Ramesside inscriptions translated and annotated: Translations. Volume 4: Merenptah and the late Nineteenth Dynasty. Oxford: Blackwell Publishers. p. 1..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Jump up to: 33.0 33.1 http://ifpeakoilwerenoobject.blogspot.co.uk/2012/02/impalements-in-antiquity-2.html
- ↑ Ussishkin, Amit (2006), p.346
- ↑ Ekron incident from Sennacherib's own self-glorification, see Callaway (1995), p.169
- ↑ Relief and text in Ephʿal (2009), p. 51–52
- ↑ Relative to later impalement practices, at least
- ↑ Layard (1850) p.374
- ↑ Olmstead(1918), p.66
- ↑ Paul Kern
- ↑ Kern (1999), p. 68–76, Relative to impalement, for example, Ashurnasirpal II is credited with 5 distinct incidents, Shalmaneser III (r.858-824 BC),For a number of examples of impalement of rebels and subjugated people under Neo-Assyrian king Shalmaneser III, see Olmstead (1921), Battle at Sugania p.348,Siege of Til Bashere p.354, Battle of Arzashkun p.360,Battle of Kulisi p.368, Battle of Kinalua p.378 For the last, see also Bryce (2012), p.244 Tiglath-Pileser III (r.745-727), For some specifics on Tiglath-Pileser's policy, see for example, Crouch (2009), p. 39–41 and Ashurbanipal (r.668-627 BC), Ashurbanipal congratulates himself once over having impaled fleeing survivors from towns he has burnt down, Ehrlich (2004), p.5
- ↑ where Ashur-uballit I was king at that time
- ↑ Kuhrt (1995), p.292 and Gadd (1965), p.9
- ↑ Richardson, Laneri (2007), p.197
- ↑ Schroeder (1920), Keilschrifttexte aus Assur verschiedenen Inhalts
- ↑ Jastrow (1921), p. 48–49
- ↑ Haman conspired to have all the Jews in the empire killed, the Book of Esther tells that story, and how Haman's plan was thwarted, and he was given the punishment he had thought to mete out to Mordecai
- ↑ Book of Esther, ESV Bible edition
- ↑ Book of Esther, NIRV Bible edition
- ↑ Haupt (1908), p. 122, 152, 154, 170
- ↑ Shaw (2012), Was Haman Hanged or Impaled?
- ↑ The theologian Adam Clarke was deeply suspicious of whether this passage ought to be regarded as part of the original Biblical text, and wrote:
"(The definition of יקע (YaQ'a) in Strong's: "a prim. primitive root; prop. properly to sever oneself, i.e. (by impl. implication) to be dislocated; fig. to abandon; causat. causatively to impale (and thus allow to drop to pieces by rotting):- be alienated, depart, hang (up), be out of joint. The seven sons of Saul, mentioned here, [II Samuel 21:9], are represented as a sacrifice required by God, to make an atonement for the sin of Saul. Till I get farther light on the subject, I am led to conclude that the whole chapter is not now what it would be coming from the pen of an inspired writer; and that this part of the Jewish records has suffered much from rabbinical glosses, alterations, and additions." ),Clarke 1831, Bible ed. p. II 267
- ↑ Crucifixion in the Mediterranean World by John Granger Cook, 2014, published by Mohr Siebeck,ISBN 9783161531248
- ↑ For law text, Koch (1824) p.63
- ↑ Engel, Jacob (2006), p.75 A similar punishment of the couple by impalement for adultery if caught in the act is mentioned in Bavarian sources as well, see His (1928), p.150
- ↑ Schwetschke (1789), col. 692
- ↑ Ehrlich (2005), p.42
- ↑ Fick (1867), p.14
- ↑ Engelmann (1834)p.158
- ↑ Osenbrüggen (1868), p.297
- ↑ Schwab (1827), p.256
- ↑ Gottfried, van Hulsius (1633), p.462
- ↑ Han (1669), p.203
- ↑ Beer (1713), p.127
- ↑ von Loen (1751), p.420-422
- ↑ von Imhoff (1736), p.1051
- ↑ Mannheimer Zeitung (1784), p.638 After the revolt was crushed by early 1785, some 150 rebels are said to have been impaled. Vehse, Demmler (1856), p.318
- ↑ Woltersdorf (1812)p.267
- ↑ Other such "heinous murderers" cases that have impalement as a prominent element include, for example a case from 1504 and another from 1519, both in Wiltenburg (2012), pp.124-125, the execution of the murderer nicknamed Puschpeter in 1575, Bastian (1860), p.105, the execution of the head of the Pappenheimer family in 1600, Muir (1997), p. 110–111, as well as an unnamed murder in Breslau in 1615, having confessed to 96 acts of murder, Roch (1687), p.249
- ↑ Daschitsky (1570), p.12
- ↑ Jump up to: 71.0 71.1 Reid, (2000), p. 440
- ↑ Florescu (1999)
- ↑ Jump up to: 73.0 73.1 Axinte, Dracula: Between myth and reality
- ↑ "er liess kinnder praten die musten ire mütter essen. Und schneyd den frawen den prüst ab den musten ire man essen. Darnach liess er sie all spissen.", Gutknecht (1521), p.7
- ↑ Philippides, Hanak (2011), p.587
- ↑ Runciman (1965), p.67
- ↑ Pears, (2004), p.253
- ↑ de La Mottraye p.188
- ↑ Russell (1794) p.331
- ↑ See de Thévenot(1687), p. 68–69 and p.259
- ↑ Late Ottoman cases in 1830s Balkans, i) Some five case reported 1833, M***r (1833) p. 440–41 columns 2 ii) 1834, Two such corpses, close to the village Paracini in the vicinity of Jagodina, see: Burgess (1835) p.275 iii) Rarity of such cases in the 1830s,Goodrich (1836)p.308 1835, Retaliative cycle Turkish authorities relative Kurdish "robbers", Slade (1837) p.191
- ↑ Stephen Massett
- ↑ Massett (1863), p. 88–89
- ↑ Layard (1871), p.307
- ↑ Ranft (1769), p.345
- ↑ missing
- ↑ "Aiolos (2004)"
- ↑ Dumas (2008), volume 8, chapter 3
- ↑ Hughes (1820) p.454, see also, on roasting incident: Holland (1815) p.194
- ↑ J.W.A.Streit, Constantinopel im Jahr 1821, oder Darstellung der blutigen und höchst schauderhaften Begebenheiten ... Leipzig, 1822, pp. 30, 31, 42-45. Cited by Kyriakos Simopoulos, "How Foreigners saw the Greece of the 1821 Revolution", Athens, 2004 (5th edition), vol. 1, pp. 153, 154, in Greek language.
- ↑ Cited by K. Simopoulos in "How Foreigners saw the Greece of the 1821 Revolution", Athens, 2004 (5th edition), vol. 1, p. 145, footnote 46. In Greek language.
- ↑ Makrygiannis Yannis, Memoirs, p. 27. (In greek language) Yannis Makrygiannis (1797-1864) was a general and politician, hero of the Greek Revolution.
- ↑ Paroulakis (1984)
- ↑ Turkish reprisals on Greek War of independence, i) 2.June 1821, 10 Greeks at Bucharest, Fick (1821) p.254 ii) During the massacre at Crete around 24 June 1821, most are said to have been impaled: Siegman (1821) p.988, column 1 iii) 36 Greek hostages, including 7 bishops at onset of Siege of Tripolitsa Colburn (1821) p.56 iv) In conjunction with the Chios Massacre in 1822, several Chiote merchants were detained and executed at Constantinople, 6 of whom were impaled alive: Hughes (1822)p.169 v) Omer Vrioni organizing in 1821 Greek hunts where civilians were, at least in one instance, impaled on his orders.Waddington (1825) p. 52–54 vi) In early 1822 Cassandreia, some 300 civilians massacred, several reported to have been impaled, Grund (1822) p.4 vii) During the last Siege of Missolonghi, in 1826, the Ottoman besiegers offered opportunity for capitulation for the besieged, while they also sent a message of consequences for refusal by impaling alive a priest, two women and several children in front of the line. The offer of capitulation was declined by the besieged Greeks. Alison(1856), p.206
- ↑ Green (1827)p. 70–72
- ↑ Constable (1821) p.275 57 Turks roasted at Hydra, according to one source. Merry (2004), p.470
- ↑ St Clair (2008) p.25 According to one source, the early spring weeks of 1821 saw the murders of more than 20.000 Turks in Greece. Merry (2004), p.470</
- ↑ 20-50 "daily" brought in, most impaled Urban (1810) p.74
- ↑ Sowards (2009) The Serbian Revolution and the Serbian State
- ↑ Obituary James Reid
- ↑ Reid (2000), p.441
- ↑ Erish (2012) p.212
- ↑ Shahbaz (1918), p.142
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- Vaporis, Nomikos M. (2000). Witnesses for Christ. Crestwood, NY: St Vladimir's Seminary Press. ISBN 9780881411966.
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Template:Capital punishment | https://www.wikidoc.org/index.php/Impalement | |
2561e60ffdafdaad6f40507cd80184e6b21246e0 | wikidoc | Inbreeding | Inbreeding
Inbreeding is breeding between close relatives, whether plant or animal. If practiced repeatedly, it often leads to a reduction in genetic diversity, and the increased gene expression of recessive traits, resulting in inbreeding depression. This may result in inbred individuals exhibiting reduced health and fitness and lower levels of fertility.
Livestock breeders often practice inbreeding to "fix" desirable characteristics within a population. However, they must then cull unfit offspring, especially when trying to establish the new and desirable trait in their stock.
In plant breeding, inbred lines are used as stocks for the creation of hybrid lines to make use of the heterosis effect. Inbreeding in plants also occurs naturally in the form of self-pollination.
# Results of inbreeding
Inbreeding may result in a far higher expression of deleterious recessive genes within a population than would normally be expected. As a result, first-generation inbred individuals are more likely to show physical and health defects, including:
- reduced fertility both in litter size and sperm viability
- increased genetic disorders
- fluctuating facial asymmetry
- lower birth rate
- higher infant mortality
- slower growth rate
- smaller adult size
- loss of immune system function.
Natural selection works to remove individuals who acquire the above types of traits from the gene pool. Therefore, many more individuals in the first generation of inbreeding will never live to reproduce. Over time, with isolation such as a population bottleneck caused by purposeful (assortative) breeding or natural environmental stresses, the deleterious inherited traits are culled.
The cheetah once was reduced by disease, habitat restriction, overhunting of prey, competition from other predators (primarily lions, competition from human land use, etc.) to a very small number of individuals. All cheetahs now come from this very small gene pool. Should a virus appear that none of the cheetahs have resistance to, extinction is always a possibility. Currently, the threatening virus is feline infectious peritonitis, which has a disease rate in domestic cats from 1%-5%; in the cheetah population it is ranging between 50% to 60%. The cheetah is also known, in spite of its small gene pool, for few genetic illnesses.
Island species are often very inbred, as their isolation from the larger group on a mainland allows for natural selection to work upon their population. This type of isolation may result in the formation of race or even speciation, as the inbreeding first removes many deleterious genes, and allows expression of genes that allow a population to adapt to an ecosystem. As the adaptation becomes more pronounced the new species or race radiates from its entrance into the new space, or dies out if it cannot adapt and, most importantly reproduce.
The reduced genetic diversity that results from inbreeding may mean a species may not be able to adapt to changes in environmental conditions. Each individual will have similar immune systems, as immune systems are genetically based. Where a species becomes endangered, the population may fall below a minimum whereby the forced interbreeding between the remaining animals will result in extinction.
In the South American sea lion, there was concern that recent population crashes would reduce genetic diversity. Historical analysis indicated that a population expansion from just two matrilineal lines were responsible for most individuals within the population. Even so, the diversity within the lines allowed for great variation in the gene pool that may inoculate the South American sea lion from extinction.
Natural breedings include inbreeding by necessity, and most animals only migrate when necessary. In many cases, the closest living mate is a mother, sister, grandmother, father, grandfather... In all cases the environment presents stresses to select or remove those individuals who cannot survive because of illness from the population.
In lions, prides are often followed by related males in bachelor groups. When the dominant male is killed or driven off by one of these bachelors, a father may be replaced with his son. There is no mechanism for preventing inbreeding or to ensure outcrossing. In the prides, most lionesses are related to one another. If there is more than one dominant male, the group of alpha males are usually related. Two lines then are being "line bred". Also, in some populations such as the Crater lions, it is known that a population bottleneck has occurred. Far greater genetic heterozygosity than what was expected was found. In fact, predators are known for low genetic variance, along with most of the top portion of the tropic levels of an ecosystem. Additionally, the alpha males of two neighboring prides can potentially be from the same litter; one brother may come to acquire leadership over another's pride, and subsequently mate with his 'nieces' or cousins. However, killing another male's cubs, upon the takeover, allows for the new selected gene complement of the incoming alpha male to prevail over the previous male. There are genetic assays being scheduled for lions to determine their genetic diversity. The preliminary studies show results inconsistent with the outcrossing paradigm based on individual environments of the studied groups.
There was an assumption that wild populations do not inbreed; this is not what is observed some cases in the wild. However, in species such as horses, animals in wild or feral conditions often drive off the young of both genders, thought to be a mechanism by which the species instinctively avoids some of the genetic consequences of inbreeding.
# Inbreeding in domestic animals
Breeding in domestic animals is assortative breeding primarily (see selective breeding). Without the sorting of individuals by trait, a breed could not be established, nor could poor genetic material be removed.
Inbreeding is used by breeders of domestic animals to fix desirable genetic traits within a population or to attempt to remove deleterious traits by allowing them to manifest phenotypically from the genotypes. Inbreeding is defined as the use of close relations for breeding such as mother to son, father to daughter, brother to sister. Breeders must cull unfit breeding suppressed individuals and/or individuals who demonstrate either homozygosity or heterozygosity for genetic based diseases. The issue of casual breeders who inbreed irresponsibly is discussed in the following quote on cattle...
Meanwhile, milk production per cow per lactation increased from 17,444 lbs to 25,013 lbs from 1978 to 1998 for the Holstein breed. Mean breeding values for milk of Holstein cows increased by 4,829 lbs during this period (#gtrend). High producing cows are increasingly difficult to breed and are subject to higher health costs than cows of lower genetic merit for production (Cassell, 2001).
Intensive selection for higher yield has increased relationships among animals within breed and increased the rate of casual inbreeding.
Many of the traits that affect profitability in crosses of modern dairy breeds have not been studied in designed experiments. Indeed, all crossbreeding research involving North American breeds and strains is very dated (McAllister, 2001) if it exists at all.
Linebreeding, a specific form of inbreeding, is accomplished through breedings of cousins, aunt to nephew, half brother to half sister. This was used to isolate breeds within the companion and livestock industry. For instance an animal with a desirable colour is bred back within the lines with identified selection traits whether it be milk production or adherence to breed standard of appearance or behavior. Breeders must then cull unfit individuals, and in some cases the breeders will then outbreed to increase the level of genetic diversity. Again casual breeding is problematical as it is without the requisite culling of individuals who are either maladaptive, not to breed standard or carriers of poor genetic material that must be removed from a healthy breeding program.
Outcrossing is where two unrelated individuals have been crossed to produce progeny. In outcrossing, unless there is verifiable genetic information, one may find that all individuals are distantly related to an ancient progenitor. If the trait carries throughout a population, all individuals can have this trait. This is called the founder's effect. In the well established breeds, that are commonly bred,a large gene pool is present. For example, in 2004, over 18,000 Persian cats were registered. A possibility exists for a complete outcross, if no barriers exist between the individuals to breed. However it is not always the case, and a form of distant linebreeding occurs. Again it is up to the assortative breeder to know what sort of traits both positive and negative exist within the diversity of one breeding. This diversity of genetic expression, within even close relatives, increases the variability and diversity of viable stock.
The two dog sites above also point out that in the registered dog population, the onset of large numbers of casual breeders has cooresponded with an increase in the number of genetic illnesses of dogs by not understanding how, why and which traits are inherited. The dog sites indicate that the largest percentage of dog breeders in the US are casual breeders. Therefore the investment in a papered animal,with an expected short term profit, motivates some to ignore the practice of culling. Casual breeders in companion animals often ignore breeding restrictions within their contracts with source companion animal breeders. The casual breeders breed the very culls that a genetics based breeder has released as a pet. The casual breeder also was cited in the quotes above on cattle raising.
Inbreeding is also deliberately induced in laboratory mice in order to guarantee a consistent and uniform animal model for experimental purposes.
# Inbreeding in humans
The taboo of incest has been discussed by many social scientists. Anthropologists attest that it exists in most cultures. As inbreeding within the first generation often produces expression of recessive traits, the prohibition has been discussed as a possible functional response to the requirement of culling those born deformed, or with undesirable traits. The eugenicists used breeding techniques to promulgate their ideas of human perfection and "illness" on all humans. Some anthropologists like Charles Davenport advocated the traditional forms of assortative breeding to form "better" human stock. Geneticists and other medical professionals have studied the effects of inbreeding in humans, noting considerable medical consequences even in the first generation.
## Royalty and nobility
The royal and noble families of Europe have close blood ties which are strengthened by royal intermarriage; the most discussed instances of interbreeding relate to European monarchies. Examples abound in every royal family; in particular, the ruling dynasties of Spain and Portugal were in the past very inbred. Several Habsburgs, Bourbons and Wittelsbachs married aunts, uncles, nieces and nephews. Even in the British royal family, which is very moderate in comparison, there has scarcely been a monarch in 300 years who has not married a (near or distant) relative. Indeed, Queen Elizabeth II and her husband Prince Philip, Duke of Edinburgh are second cousins once removed, both being descended from King Christian IX of Denmark. They are also third cousins as great-great-grandchildren of Queen Victoria of the United Kingdom. European monarchies did avoid brother-sister marriages, though Jean V of Armagnac was an exception.
It is not necessarily the case that there was a greater amount of inbreeding within royalty than there is in the population as a whole: it may simply be better documented. Among genetic populations that are isolated, opportunities for exogamy are reduced. Isolation may be geographical, leading to inbreeding among peasants in remote mountain valleys. Or isolation may be social, induced by the lack of appropriate partners, such as Protestant princesses for Protestant royal heirs. Since the late Middle Ages, it is the urban middle class that has had the widest opportunity for outbreeding.
There were at times serious long-term health and political consequences to multi-generational interbreeding in royal families between persons who were closely related. Most notable was Charles II of Spain, who had multiple, severe disabilities largely linked to inbreeding. Not only was he developmentally disabled and could not chew his food properly, he also could not produce children, thus leading to the collapse of his bloodline and the War of the Spanish Succession.
Other examples of royal family intermarriage include:
- Some Egyptian Pharaohs and Peruvian Sapa Incas married their sisters; in both cases we find a special combination between endogamy and polygamy. Normally the son of the old ruler and the ruler's oldest (half-)sister became the new ruler.
- The Inca had an unwritten rule that the new ruler must be a son of the Inca and his wife and sister. He then had to marry his sister (not half-sister), which ultimately led to the catastrophic Huascars reign, culminating in a civil war and then fall of the empire.
- Cleopatra VII and Ptolemy XIII, married and named co-rulers of ancient Egypt following their father's death, were brother and sister. Not only this, but all rulers of the Ptolemaic dynasty from Ptolemy II on engaged in inbreeding among brothers and sisters, so as to keep the Ptolemaic blood "pure".
- The House of Habsburg inmarried particularly often. Famous in this case is the Habsburger (Unter) Lippe (Habsburg jaw/Habsburg lip/"Austrian lip"), typical for many Habsburg relatives over a period of six centuries. The condition progressed through the generations to the point that last of the Spanish Habsburgs, Charles II of Spain, could not properly chew his food. (See mandibular prognathism.)
- Charles V, Holy Roman Emperor, King of Spain and Infanta Isabella of Portugal were first cousins.
- John, Crown Prince of Portugal and Joan of Habsburg were double first cousins.
- Mary, Queen of Scots and Henry Stuart, Lord Darnley were half first cousins, and 3rd cousins once removed.
- King Louis XIV of France and Infanta Maria Theresa of Spain were double first cousins.
- King William III and Queen Mary II of England were first cousins.
- King George I of Great Britain and Princess Sophia Dorothea of Celle were paternal first cousins.
- King Philip V of Spain and Princess Maria Luisa of Savoy were double second cousins.
- King Gustav III of Sweden and Princess Sophia Magdalena of Denmark were second cousins.
- King Christian VII of Denmark and Princess Caroline Matilda of Great Britain were first cousins
- King George IV of the United Kingdom and Princess Caroline of Brunswick were first cousins.
- William I, German Emperor and Princess Augusta of Saxe-Weimar were second cousins.
- Queen Victoria of the United Kingdom and Prince Albert of Saxe-Coburg and Gotha were first cousins.
- Emperor Franz Joseph I of Austria and Princess Elisabeth of Bavaria were first cousins.
- King George V of the United Kingdom and Princess Mary of Teck were second cousins once removed.
- Prince Gustav Adolf, Duke of Västerbotten and Princess Sibylla of Saxe-Coburg and Gotha, parents of the present King Carl XVI Gustaf of Sweden, were second cousins.
- Prince Nicola Pignatelli (1648–1730) and Princess Giovanna Pignatelli (1666–1723) were half great-granduncle and half great-grandniece, representing a peculiar alliance between two relatives. Nicola was a son of Giulio Pignatelli, Prince of Noia (1587-1658) through his third wife and Giovanna a great-great-granddaughter through his first marriage.
- A similar alliance was the marriage between Princess Sophie of Sweden and Grand Duke Leopold of Baden, half-brother of her maternal grandfather.
Intermarriage in European royal families is no longer practiced as often as in the past. This is likely due to changes in the importance of marriage as a method of forming political alliances through kinship ties between nobility, as well as an awareness of modern medical science. These ties were often sealed only upon the birth of progeny within the arranged marriage. Marriage was seen as a union of lines of nobility, not of a contract between individuals as it is seen today. More marry for "love", best illustrated by the second marriage of Prince Charles of the United Kingdom. During the tumult of the removal, sometimes by revolution, of most lines of nobility from state government, it became less important to marry for the good of the respective monarchies and the states they governed. | Inbreeding
Template:Cleanup
Inbreeding is breeding between close relatives, whether plant or animal. If practiced repeatedly, it often leads to a reduction in genetic diversity, and the increased gene expression of recessive traits, resulting in inbreeding depression. This may result in inbred individuals exhibiting reduced health and fitness and lower levels of fertility.
Livestock breeders often practice inbreeding to "fix" desirable characteristics within a population. However, they must then cull unfit offspring, especially when trying to establish the new and desirable trait in their stock.
In plant breeding, inbred lines are used as stocks for the creation of hybrid lines to make use of the heterosis effect. Inbreeding in plants also occurs naturally in the form of self-pollination.
# Results of inbreeding
Inbreeding may result in a far higher expression of deleterious recessive genes within a population than would normally be expected. As a result, first-generation inbred individuals are more likely to show physical and health defects, including:
- reduced fertility both in litter size and sperm viability
- increased genetic disorders
- fluctuating facial asymmetry
- lower birth rate
- higher infant mortality
- slower growth rate
- smaller adult size
- loss of immune system function.
Natural selection works to remove individuals who acquire the above types of traits from the gene pool. Therefore, many more individuals in the first generation of inbreeding will never live to reproduce. Over time, with isolation such as a population bottleneck caused by purposeful (assortative) breeding or natural environmental stresses, the deleterious inherited traits are culled.
The cheetah once was reduced by disease, habitat restriction, overhunting of prey, competition from other predators (primarily lions, competition from human land use, etc.) to a very small number of individuals.[1][2] All cheetahs now come from this very small gene pool. Should a virus appear that none of the cheetahs have resistance to, extinction is always a possibility. Currently, the threatening virus is feline infectious peritonitis, which has a disease rate in domestic cats from 1%-5%; in the cheetah population it is ranging between 50% to 60%. The cheetah is also known, in spite of its small gene pool, for few genetic illnesses.
Island species are often very inbred, as their isolation from the larger group on a mainland allows for natural selection to work upon their population. This type of isolation may result in the formation of race or even speciation, as the inbreeding first removes many deleterious genes, and allows expression of genes that allow a population to adapt to an ecosystem. As the adaptation becomes more pronounced the new species or race radiates from its entrance into the new space, or dies out if it cannot adapt and, most importantly reproduce.[3]
The reduced genetic diversity that results from inbreeding may mean a species may not be able to adapt to changes in environmental conditions. Each individual will have similar immune systems, as immune systems are genetically based. Where a species becomes endangered, the population may fall below a minimum whereby the forced interbreeding between the remaining animals will result in extinction.
In the South American sea lion, there was concern that recent population crashes would reduce genetic diversity. Historical analysis indicated that a population expansion from just two matrilineal lines were responsible for most individuals within the population. Even so, the diversity within the lines allowed for great variation in the gene pool that may inoculate the South American sea lion from extinction.[4]
Natural breedings include inbreeding by necessity, and most animals only migrate when necessary. In many cases, the closest living mate is a mother, sister, grandmother, father, grandfather... In all cases the environment presents stresses to select or remove those individuals who cannot survive because of illness from the population.
In lions, prides are often followed by related males in bachelor groups. When the dominant male is killed or driven off by one of these bachelors, a father may be replaced with his son. There is no mechanism for preventing inbreeding or to ensure outcrossing. In the prides, most lionesses are related to one another. If there is more than one dominant male, the group of alpha males are usually related. Two lines then are being "line bred". Also, in some populations such as the Crater lions, it is known that a population bottleneck has occurred. Far greater genetic heterozygosity than what was expected was found.[5] In fact, predators are known for low genetic variance, along with most of the top portion of the tropic levels of an ecosystem.[6] Additionally, the alpha males of two neighboring prides can potentially be from the same litter; one brother may come to acquire leadership over another's pride, and subsequently mate with his 'nieces' or cousins. However, killing another male's cubs, upon the takeover, allows for the new selected gene complement of the incoming alpha male to prevail over the previous male. There are genetic assays being scheduled for lions to determine their genetic diversity. The preliminary studies show results inconsistent with the outcrossing paradigm based on individual environments of the studied groups.[7]
There was an assumption that wild populations do not inbreed; this is not what is observed some cases in the wild. However, in species such as horses, animals in wild or feral conditions often drive off the young of both genders, thought to be a mechanism by which the species instinctively avoids some of the genetic consequences of inbreeding.[8]
# Inbreeding in domestic animals
Breeding in domestic animals is assortative breeding primarily (see selective breeding). Without the sorting of individuals by trait, a breed could not be established, nor could poor genetic material be removed.
Inbreeding is used by breeders of domestic animals to fix desirable genetic traits within a population or to attempt to remove deleterious traits by allowing them to manifest phenotypically from the genotypes. Inbreeding is defined as the use of close relations for breeding such as mother to son, father to daughter, brother to sister. Breeders must cull unfit breeding suppressed individuals and/or individuals who demonstrate either homozygosity or heterozygosity for genetic based diseases.[9] The issue of casual breeders who inbreed irresponsibly is discussed in the following quote on cattle...
Meanwhile, milk production per cow per lactation increased from 17,444 lbs to 25,013 lbs from 1978 to 1998 for the Holstein breed. Mean breeding values for milk of Holstein cows increased by 4,829 lbs during this period (http://aipl.arsusda.gov/main/data.html#gtrend). High producing cows are increasingly difficult to breed and are subject to higher health costs than cows of lower genetic merit for production (Cassell, 2001).
Intensive selection for higher yield has increased relationships among animals within breed and increased the rate of casual inbreeding.
Many of the traits that affect profitability in crosses of modern dairy breeds have not been studied in designed experiments. Indeed, all crossbreeding research involving North American breeds and strains is very dated (McAllister, 2001) if it exists at all.
[10]
Linebreeding, a specific form of inbreeding, is accomplished through breedings of cousins, aunt to nephew, half brother to half sister. This was used to isolate breeds within the companion and livestock industry. For instance an animal with a desirable colour is bred back within the lines with identified selection traits whether it be milk production or adherence to breed standard of appearance or behavior. Breeders must then cull unfit individuals, and in some cases the breeders will then outbreed to increase the level of genetic diversity. Again casual breeding is problematical as it is without the requisite culling of individuals who are either maladaptive, not to breed standard or carriers of poor genetic material that must be removed from a healthy breeding program. [11]
Outcrossing is where two unrelated individuals have been crossed to produce progeny. In outcrossing, unless there is verifiable genetic information, one may find that all individuals are distantly related to an ancient progenitor. If the trait carries throughout a population, all individuals can have this trait. This is called the founder's effect. In the well established breeds, that are commonly bred,a large gene pool is present. For example, in 2004, over 18,000 Persian cats were registered.[12] A possibility exists for a complete outcross, if no barriers exist between the individuals to breed. However it is not always the case, and a form of distant linebreeding occurs. Again it is up to the assortative breeder to know what sort of traits both positive and negative exist within the diversity of one breeding. This diversity of genetic expression, within even close relatives, increases the variability and diversity of viable stock. [13]
The two dog sites above also point out that in the registered dog population, the onset of large numbers of casual breeders has cooresponded with an increase in the number of genetic illnesses of dogs by not understanding how, why and which traits are inherited. The dog sites indicate that the largest percentage of dog breeders in the US are casual breeders. Therefore the investment in a papered animal,with an expected short term profit, motivates some to ignore the practice of culling. Casual breeders in companion animals often ignore breeding restrictions within their contracts with source companion animal breeders. The casual breeders breed the very culls that a genetics based breeder has released as a pet. The casual breeder also was cited in the quotes above on cattle raising.
Inbreeding is also deliberately induced in laboratory mice in order to guarantee a consistent and uniform animal model for experimental purposes.
# Inbreeding in humans
The taboo of incest has been discussed by many social scientists. Anthropologists attest that it exists in most cultures. As inbreeding within the first generation often produces expression of recessive traits, the prohibition has been discussed as a possible functional response to the requirement of culling those born deformed, or with undesirable traits.[citation needed] The eugenicists used breeding techniques to promulgate their ideas of human perfection and "illness" on all humans.[citation needed] Some anthropologists like Charles Davenport advocated the traditional forms of assortative breeding to form "better" human stock.[citation needed] Geneticists and other medical professionals have studied the effects of inbreeding in humans, noting considerable medical consequences even in the first generation.[14]
## Royalty and nobility
The royal and noble families of Europe have close blood ties which are strengthened by royal intermarriage; the most discussed instances of interbreeding relate to European monarchies. Examples abound in every royal family; in particular, the ruling dynasties of Spain and Portugal were in the past very inbred. Several Habsburgs, Bourbons and Wittelsbachs married aunts, uncles, nieces and nephews. Even in the British royal family, which is very moderate in comparison, there has scarcely been a monarch in 300 years who has not married a (near or distant) relative. Indeed, Queen Elizabeth II and her husband Prince Philip, Duke of Edinburgh are second cousins once removed, both being descended from King Christian IX of Denmark. They are also third cousins as great-great-grandchildren of Queen Victoria of the United Kingdom. European monarchies did avoid brother-sister marriages, though Jean V of Armagnac was an exception.
It is not necessarily the case that there was a greater amount of inbreeding within royalty than there is in the population as a whole: it may simply be better documented. Among genetic populations that are isolated, opportunities for exogamy are reduced. Isolation may be geographical, leading to inbreeding among peasants in remote mountain valleys. Or isolation may be social, induced by the lack of appropriate partners, such as Protestant princesses for Protestant royal heirs. Since the late Middle Ages, it is the urban middle class that has had the widest opportunity for outbreeding.
There were at times serious long-term health and political consequences to multi-generational interbreeding in royal families between persons who were closely related.[16] Most notable was Charles II of Spain, who had multiple, severe disabilities largely linked to inbreeding.[17] Not only was he developmentally disabled and could not chew his food properly, he also could not produce children,[18] thus leading to the collapse of his bloodline and the War of the Spanish Succession.[19]
Other examples of royal family intermarriage include:
- Some Egyptian Pharaohs and Peruvian Sapa Incas married their sisters; in both cases we find a special combination between endogamy and polygamy. Normally the son of the old ruler and the ruler's oldest (half-)sister became the new ruler.
- The Inca had an unwritten rule that the new ruler must be a son of the Inca and his wife and sister. He then had to marry his sister (not half-sister), which ultimately led to the catastrophic Huascars reign, culminating in a civil war and then fall of the empire.
- Cleopatra VII and Ptolemy XIII, married and named co-rulers of ancient Egypt following their father's death, were brother and sister. Not only this, but all rulers of the Ptolemaic dynasty from Ptolemy II on engaged in inbreeding among brothers and sisters, so as to keep the Ptolemaic blood "pure".
- The House of Habsburg inmarried particularly often. Famous in this case is the Habsburger (Unter) Lippe (Habsburg jaw/Habsburg lip/"Austrian lip"), typical for many Habsburg relatives over a period of six centuries.[20] The condition progressed through the generations to the point that last of the Spanish Habsburgs, Charles II of Spain, could not properly chew his food.[21] (See mandibular prognathism.)
- Charles V, Holy Roman Emperor, King of Spain and Infanta Isabella of Portugal were first cousins.
- John, Crown Prince of Portugal and Joan of Habsburg were double first cousins.
- Mary, Queen of Scots and Henry Stuart, Lord Darnley were half first cousins, and 3rd cousins once removed.
- King Louis XIV of France and Infanta Maria Theresa of Spain were double first cousins.
- King William III and Queen Mary II of England were first cousins.
- King George I of Great Britain and Princess Sophia Dorothea of Celle were paternal first cousins.
- King Philip V of Spain and Princess Maria Luisa of Savoy were double second cousins.
- King Gustav III of Sweden and Princess Sophia Magdalena of Denmark were second cousins.
- King Christian VII of Denmark and Princess Caroline Matilda of Great Britain were first cousins
- King George IV of the United Kingdom and Princess Caroline of Brunswick were first cousins.
- William I, German Emperor and Princess Augusta of Saxe-Weimar were second cousins.
- Queen Victoria of the United Kingdom and Prince Albert of Saxe-Coburg and Gotha were first cousins.
- Emperor Franz Joseph I of Austria and Princess Elisabeth of Bavaria were first cousins.
- King George V of the United Kingdom and Princess Mary of Teck were second cousins once removed.
- Prince Gustav Adolf, Duke of Västerbotten and Princess Sibylla of Saxe-Coburg and Gotha, parents of the present King Carl XVI Gustaf of Sweden, were second cousins.
- Prince Nicola Pignatelli (1648–1730) and Princess Giovanna Pignatelli (1666–1723) were half great-granduncle and half great-grandniece, representing a peculiar alliance between two relatives. Nicola was a son of Giulio Pignatelli, Prince of Noia (1587-1658) through his third wife and Giovanna a great-great-granddaughter through his first marriage.
- A similar alliance was the marriage between Princess Sophie of Sweden and Grand Duke Leopold of Baden, half-brother of her maternal grandfather.
Intermarriage in European royal families is no longer practiced as often as in the past. This is likely due to changes in the importance of marriage as a method of forming political alliances through kinship ties between nobility, as well as an awareness of modern medical science. These ties were often sealed only upon the birth of progeny within the arranged marriage. Marriage was seen as a union of lines of nobility, not of a contract between individuals as it is seen today. More marry for "love", best illustrated by the second marriage of Prince Charles of the United Kingdom. During the tumult of the removal, sometimes by revolution, of most lines of nobility from state government, it became less important to marry for the good of the respective monarchies and the states they governed. | https://www.wikidoc.org/index.php/Inbred | |
5102d12ff436ea5ac83c95cf9d183fb57e99cd04 | wikidoc | Penetrance | Penetrance
# Overview
Penetrance is a term used in genetics that describes the extent to which the properties controlled by a gene, its phenotype, will be expressed. For example Huntingtons disease has 95% penetrance whereby 5% of those with the dominant allele for Huntingtons don't acquire the disease and 95% do. Penetrance is the percentage of individuals with a specific genotype which possess an associated phenotype. For example, if 50% of the individuals carrying the "blue" gene are blue, the "blue" gene has 50% penetrance.
If a gene is highly penetrant, the trait it produces will always or almost always be apparent in an individual carrying the gene. A gene with low penetrance will only sometimes produce the symptom or trait with which it has been associated at a detectable level. In the case of low penetrance it is difficult to distinguish environmental from genetic factors.
Common examples used to show degrees of penetrance are often highly penetrant. There are several reasons for this:
- Highly penetrant genes, and highly heritable symptoms, are easier to demonstrate – if the gene is present, the phenotype is expressed (recessivity, dominance, and co-dominance are fairly simple additions to this principle);
- Genes which are highly penetrant are more easily noticed by geneticists, and genes for symptoms which are highly heritable are more easily inferred to exist, and then more easily tracked down.
However, relatively few of the genes in the genome show high penetrance. Traits such as height or intelligence are modified by multiple genes as well as by environmental factors. Distribution of polygenic traits often falls along a bell curve.
The penetrance of some diseases is age-related. An example is multiple endocrine neoplasia 1 (MEN 1), a disorder characterized by parathyroid hyperplasia and pancreatic islet-cell and pituitary adenomas. It is due to a mutation in the menin gene on chromosome 11q13. In one study the age-related penetrance of MEN1 was 7 percent by age 10 years and nearly 100 percent by age 60 years. | Penetrance
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Penetrance is a term used in genetics that describes the extent to which the properties controlled by a gene, its phenotype, will be expressed. For example Huntingtons disease has 95% penetrance whereby 5% of those with the dominant allele for Huntingtons don't acquire the disease and 95% do. Penetrance is the percentage of individuals with a specific genotype which possess an associated phenotype. For example, if 50% of the individuals carrying the "blue" gene are blue, the "blue" gene has 50% penetrance.
If a gene is highly penetrant, the trait it produces will always or almost always be apparent in an individual carrying the gene. A gene with low penetrance will only sometimes produce the symptom or trait with which it has been associated at a detectable level. In the case of low penetrance it is difficult to distinguish environmental from genetic factors.
Common examples used to show degrees of penetrance are often highly penetrant. There are several reasons for this:
- Highly penetrant genes, and highly heritable symptoms, are easier to demonstrate – if the gene is present, the phenotype is expressed (recessivity, dominance, and co-dominance are fairly simple additions to this principle);
- Genes which are highly penetrant are more easily noticed by geneticists, and genes for symptoms which are highly heritable are more easily inferred to exist, and then more easily tracked down.
However, relatively few of the genes in the genome show high penetrance. Traits such as height or intelligence are modified by multiple genes as well as by environmental factors. Distribution of polygenic traits often falls along a bell curve.
The penetrance of some diseases is age-related. An example is multiple endocrine neoplasia 1 (MEN 1), a disorder characterized by parathyroid hyperplasia and pancreatic islet-cell and pituitary adenomas. It is due to a mutation in the menin gene on chromosome 11q13. In one study the age-related penetrance of MEN1 was 7 percent by age 10 years and nearly 100 percent by age 60 years. | https://www.wikidoc.org/index.php/Incomplete_penetrance | |
57369202565d981b4ba51672ba9cf332329c2484 | wikidoc | Indapamide | Indapamide
# Disclaimer
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# Overview
Indapamide is a thiazide-like diuretic that is FDA approved for the {{{indicationType}}} of hypertension and salt and fluid retention associated with congestive heart failure. Common adverse reactions include hypokalemia, cramp, asthenia, dizziness, headache, lethargy, numbness, fatigue, and malaise.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The adult starting indapamide dose for hypertension is 1.25 mg as a single daily dose taken in the morning.
- If the response to 1.25 mg is not satisfactory after four weeks, the daily dose may be increased to 2.5 mg taken once daily.
- If the response to 2.5 mg is not satisfactory after four weeks, the daily dose may be increased to 5 mg taken once daily, but adding another antihypertensive should be considered.
- Dosing Information
- The adult starting indapamide dose for edema of congestive heart failure is 2.5 mg as a single daily dose taken in the morning.
- If the response to 2.5 mg is not satisfactory after one week, the daily dose may be increased to 5 mg taken once daily.
- If the antihypertensive response to indapamide is insufficient, indapamide may be combined with other antihypertensive drugs, with careful monitoring of blood pressure. It is recommended that the usual dose of other agents be reduced by 50% during initial combination therapy. As the blood pressure response becomes evident, further dosage adjustments may be necessary.
- In general, doses of 5 mg and larger have not appeared to provide additional effects on blood pressure or heart failure, but are associated with a greater degree of hypokalemia. There is minimal clinical trial experience in patients with doses greater than 5 mg once a day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Indapamide in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 2.5 mg/d
- Dosing Information
- 2.5 mg/d
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness of indapamide 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 Indapamide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Indapamide in pediatric patients.
# Contraindications
- Anuria
- Hypersensitivity to indapamide or to other sulfonamide-derived drugs
# Warnings
- Severe cases of hyponatremia, accompanied by hypokalemia, have been reported with recommended doses of indapamide. This occurred primarily in elderly females. This appears to be dose-related. Also, a large case-controlled pharmacoepidemiology study indicates that there is an increased risk of hyponatremia with indapamide 2.5 mg and 5 mg doses. Hyponatremia considered possibly clinically significant (< 125 mEq/L) has not been observed in clinical trials with the 1.25 mg dosage. Thus, patients should be started at the 1.25 mg dose and maintained at the lowest possible dose.
- Hypokalemia occurs commonly with diuretics, and electrolyte monitoring is essential, particularly in patients who would be at increased risk from hypokalemia, such as those with cardiac arrhythmias or who are receiving concomitant cardiac glycosides.
- In general, diuretics should not be given concomitantly with lithium because they reduce its renal clearance and add a high risk of lithium toxicity. Read prescribing information for lithium preparations before use of such concomitant therapy.
### Precautions
- Hypokalemia, Hyponatremia, And Other Fluid And Electrolyte Imbalances
- Periodic determinations of serum electrolytes should be performed at appropriate intervals. In addition, patients should be observed for clinical signs of fluid or electrolyte imbalance, such as hyponatremia, hypochloremic alkalosis, or hypokalemia. Warning signs include dry mouth, thirst, weakness, fatigue, lethargy, drowsiness, restlessness, muscle pains or cramps, hypotension, oliguria, tachycardia, and gastrointestinal disturbance. Electrolyte determinations are particularly important in patients who are vomiting excessively or receiving parenteral fluids, in patients subject to electrolyte imbalance (including those with heart failure, kidney disease, and cirrhosis), and in patients on a salt-restricted diet.
- The risk of hypokalemia secondary to diuresis and natriuresis is increased when larger doses are used, when the diuresis is brisk, when severe cirrhosis is present and during concomitant use of corticosteroids or ACTH. Interference with adequate oral intake of electrolytes will also contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis, such as increased ventricular irritability.
- Dilutional hyponatremia may occur in edematous patients; the appropriate treatment is restriction of water rather than administration of salt, except in rare instances when the hyponatremia is life threatening. However, in actual salt depletion, appropriate replacement is the treatment of choice. Any chloride deficit that may occur during treatment is generally mild and usually does not require specific treatment except in extraordinary circumstances as in liver or renal disease. Thiazide-like diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.
- Hyperuricemia and Gout
- Serum concentrations of uric acid increased by an average of 0.69 mg/100 mL in patients treated with indapamide 1.25 mg, and by an average of 1 mg/100 mL in patients treated with indapamide 2.5 mg and 5 mg, and frank gout may be precipitated in certain patients receiving indapamide. Serum concentrations of uric acid should, therefore, be monitored periodically during treatment.
- Renal Impairment
- Indapamide, like the thiazides, should be used with caution in patients with severe renal disease, as reduced plasma volume may exacerbate or precipitate azotemia. If progressive renal impairment is observed in a patient receiving indapamide, withholding or discontinuing diuretic therapy should be considered. Renal function tests should be performed periodically during treatment with indapamide.
- Impaired Hepatic Function
- Indapamide, like the thiazides, should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
- Glucose Tolerance
- Latent diabetes may become manifest and insulin requirements in diabetic patients may be altered during thiazide administration. A mean increase in glucose of 6.47 mg/dL was observed in patients treated with indapamide 1.25 mg, which was not considered clinically significant in these trials. Serum concentrations of glucose should be monitored routinely during treatment with indapamide.
- Calcium Excretion
- Calcium excretion is decreased by diuretics pharmacologically related to indapamide. After six to eight weeks of indapamide 1.25 mg treatment and in long-term studies of hypertensive patients with higher doses of indapamide, however, serum concentrations of calcium increased only slightly with indapamide. Prolonged treatment with drugs pharmacologically related to indapamide may in rare instances be associated with hypercalcemia and hypophosphatemia secondary to physiologic changes in the parathyroid gland; however, the common complications of hyperparathyroidism, such as renal lithiasis, bone resorption, and peptic ulcer, have not been seen. Treatment should be discontinued before tests for parathyroid function are performed. Like the thiazides, indapamide may decrease serum PBI levels without signs of thyroid disturbance.
- Interaction With Systemic Lupus Erythematosus
- Thiazides have exacerbated or activated systemic lupus erythematosus and this possibility should be considered with indapamide as well.
- Post-Sympathectomy Patient
- The antihypertensive effect of the drug may be enhanced in the post-sympathectomized patient.
# Adverse Reactions
## Clinical Trials Experience
- Most adverse effects have been mild and transient.
- The Clinical Adverse Reactions listed in Table 1 represent data from Phase II/III placebo-controlled studies (306 patients given indapamide 1.25 mg). The clinical adverse reactions listed in Table 2 represent data from Phase II placebo-controlled studies and long-term controlled clinical trials (426 patients given indapamide 2.5 mg or 5 mg). The reactions are arranged into two groups: 1) a cumulative incidence equal to or greater than 5%; 2) a cumulative incidence less than 5%. Reactions are counted regardless of relation to drug.
- All other clinical adverse reactions occurred at an incidence of < 1%.
- Approximately 4% of patients given indapamide 1.25 mg compared to 5% of the patients given placebo discontinued treatment in the trials of up to eight weeks because of adverse reactions.
- In controlled clinical trials of six to eight weeks in duration, 20% of patients receiving indapamide 1.25 mg, 61% of patients receiving indapamide 5 mg, and 80% of patients receiving indapamide 10 mg had at least one potassium value below 3.4 mEq/L. In the indapamide 1.25 mg group, about 40% of those patients who reported hypokalemia as a laboratory adverse event returned to normal serum potassium values without intervention. Hypokalemia with concomitant clinical signs or symptoms occurred in 2% of patients receiving indapamide 1.25 mg.
- Because most of these data are from long-term studies (up to 40 weeks of treatment), it is probable that many of the adverse experiences reported are due to causes other than the drug. Approximately 10% of patients given indapamide discontinued treatment in long-term trials because of reactions either related or unrelated to the drug.
- Hypokalemia with concomitant clinical signs or symptoms occurred in 3% of patients receiving indapamide 2.5 mg q.d. and 7% of patients receiving indapamide 5 mg q.d. In long-term controlled clinical trials comparing the hypokalemic effects of daily doses of indapamide and hydrochlorothiazide, however, 47% of patients receiving indapamide 2.5 mg, 72% of patients receiving indapamide 5 mg, and 44% of patients receiving hydrochlorothiazide 50 mg had at least one potassium value (out of a total of 11 taken during the study) below 3.5 mEq/L. In the indapamide 2.5 mg group, over 50% of those patients returned to normal serum potassium values without intervention.
- In clinical trials of six to eight weeks, the mean changes in selected values were as shown in the tables below.
- No patients receiving indapamide 1.25 mg experienced hyponatremia considered possibly clinically significant (<125 mEq/L).
- Indapamide had no adverse effects on lipids.
- The following reactions have been reported with clinical usage of indapamide: jaundice (intrahepatic cholestatic jaundice), hepatitis, pancreatitis, and abnormal liver function tests. These reactions were reversible with discontinuance of the drug.
- Also reported are erythema multiforme, Stevens-Johnson syndrome, bullous eruptions, purpura, photosensitivity, fever, pneumonitis, anaphylactic reactions, agranulocytosis, leukopenia, thrombocytopenia and aplastic anemia. Other adverse reactions reported with antihypertensive/diuretics are necrotizing angiitis, respiratory distress, sialadenitis, and xanthopsia.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Indapamide in the drug label.
# Drug Interactions
- Other Antihypertensives
- Indapamide may add to or potentiate the action of other antihypertensive drugs. In limited controlled trials that compared the effect of indapamide combined with other antihypertensive drugs with the effect of the other drugs administered alone, there was no notable change in the nature or frequency of adverse reactions associated with the combined therapy.
- Norepinephrine
- Indapamide, like the thiazides, may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Reproduction studies have been performed in rats, mice and rabbits at doses up to 6,250 times the therapeutic human dose and have revealed no evidence of impaired fertility or harm to the fetus due to indapamide. Postnatal development in rats and mice was unaffected by pre-treatment of parent animals during gestation. There are, however, no adequate and well-controlled studies in pregnant women. Moreover, diuretics are known to cross the placental barrier and appear in cord blood. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. There may be hazards associated with this use such as fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult.
- Usage in Pregnancy
- The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developed toxemia.
- Edema during pregnancy may arise from pathological causes or from the physiologic and mechanical consequences of pregnancy. Indapamide is indicated in pregnancy when edema is due to pathologic causes, just as it is in the absence of pregnancy. Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. There is hypervolemia during normal pregnancy which is not harmful to either the fetus or the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Indapamide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Indapamide during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because most drugs are excreted in human milk, if use of this drug is deemed essential, the patient should stop nursing.
### Pediatric Use
- Safety and effectiveness of indapamide in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of indapamide 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.
- Severe cases of hyponatremia, accompanied by hypokalemia have been reported with recommended doses of indapamide in elderly females.
### Gender
There is no FDA guidance on the use of Indapamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Indapamide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Indapamide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Indapamide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Indapamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Indapamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Serum concentrations of electrolytes, glucose, and uric acid should be monitored periodically during treatment.
- If the antihypertensive response to indapamide is insufficient, indapamide may be combined with other antihypertensive drugs, with careful monitoring of blood pressure.
# IV Compatibility
There is limited information regarding IV Compatibility of Indapamide in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Symptoms of overdosage include nausea, vomiting, weakness, gastrointestinal disorders and disturbances of electrolyte balance. In severe instances, hypotension and depressed respiration may be observed.
### Management
- Support of respiration and cardiac circulation should be instituted. There is no specific antidote. An evacuation of the stomach is recommended by emesis and gastric lavage after which the electrolyte and fluid balance should be evaluated carefully.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Indapamide in the drug label.
# Pharmacology
## Mechanism of Action
- Indapamide is the first of a new class of antihypertensive/diuretics, the indolines.
## Structure
- Indapamide is an oral antihypertensive/diuretic. Its molecule contains both a polar sulfamoyl chlorobenzamide moiety and a lipid-soluble methylindoline moiety. It differs chemically from the thiazides in that it does not possess the thiazide ring system and contains only one sulfonamide group. The chemical name of indapamide is 4-Chloro- N-(2-methyl-1-indolinyl)-3-Sulfamoylbenzamide, and its molecular weight is 365.84. The compound is a weak acid, pKa=8.8, and is soluble in aqueous solutions of strong bases. It is a white to yellow-white crystalline (tetragonal) powder, and has the following structural formula:
- Each tablet, for oral administration, contains 1.25 mg or 2.5 mg of indapamide. In addition, each tablet contains the following inactive ingredients: corn starch, hypromellose, lactose monohydrate, magnesium stearate, maltodextrin, microcrystalline cellulose, polydextrose, polyethylene glycol, talc, titanium dioxide, triacetin. The 1.25 mg tablet also contains FD&C yellow #6 aluminum lake (sunset yellow lake).
## Pharmacodynamics
- The oral administration of 2.5 mg (two 1.25 mg tablets) of indapamide to male subjects produced peak concentrations of approximately 115 ng/mL of the drug in blood within two hours. The oral administration of 5 mg (two 2.5 mg tablets) of indapamide to healthy male subjects produced peak concentrations of approximately 260 ng/mL of the drug in the blood within two hours.
- In a parallel design double-blind, placebo controlled trial in hypertension, daily doses of indapamide between 1.25 mg and 10 mg produced dose-related antihypertensive effects. Doses of 5 and 10 mg were not distinguishable from each other although each was differentiated from placebo and 1.25 mg indapamide. At daily doses of 1.25 mg, 5 mg and 10 mg, a mean decrease of serum potassium of 0.28, 0.61 and 0.76 mEq/L, respectively, was observed and uric acid increased by about 0.69 mg/100 mL.
- In other parallel design, dose-ranging clinical trials in hypertension and edema, daily doses of indapamide between 0.5 and 5 mg produced dose-related effects. Generally, doses of 2.5 and 5 mg were not distinguishable from each other although each was differentiated from placebo and from 0.5 or 1 mg indapamide. At daily doses of 2.5 and 5 mg a mean decrease of serum potassium of 0.5 and 0.6 mEq/Liter, respectively, was observed and uric acid increased by about 1 mg/100 mL.
- At these doses, the effects of indapamide on blood pressure and edema are approximately equal to those obtained with conventional doses of other antihypertensive/diuretics.
- In hypertensive patients, daily doses of 1.25, 2.5 and 5 mg of indapamide have no appreciable cardiac inotropic or chronotropic effect. The drug decreases peripheral resistance, with little or no effect on cardiac output, rate or rhythm. Chronic administration of indapamide to hypertensive patients has little or no effect on glomerular filtration rate or renal plasma flow.
- Indapamide had an antihypertensive effect in patients with varying degrees of renal impairment, although in general, diuretic effects declined as renal function decreased.
- In a small number of controlled studies, indapamide taken with other antihypertensive drugs such as hydralazine, propranolol, guanethidine and methyldopa, appeared to have the additive effect typical of thiazide-type diuretics.
## Pharmacokinetics
- A minimum of 70% of a single oral dose is eliminated by the kidneys and an additional 23% by the gastrointestinal tract, probably including the biliary route. The half-life of indapamide in whole blood is approximately 14 hours.
- Indapamide is preferentially and reversibly taken up by the erythrocytes in the peripheral blood. The whole blood/plasma ratio is approximately 6:1 at the time of peak concentration and decreases to 3.5:1 at eight hours. From 71 to 79% of the indapamide in plasma is reversibly bound to plasma proteins.
- Indapamide is an extensively metabolized drug, with only about 7% of the total dose administered, recovered in the urine as unchanged drug during the first 48 hours after administration. The urinary elimination of 14C-labeled indapamide and metabolites is biphasic with a terminal half-life of excretion of total radioactivity of 26 hours.
## Nonclinical Toxicology
- Both mouse and rat lifetime carcinogenicity studies were conducted. There was no significant difference in the incidence of tumors between the indapamide-treated animals and the control groups.
# Clinical Studies
There is limited information regarding Clinical Studies of Indapamide in the drug label.
# How Supplied
- Indapamide Tablets, USP are available as follows:
- Keep tightly closed.
- Store at controlled room temperature 20° to 25°C (68° to 77°F) . Avoid excessive heat.
- Dispense in a tight, light-resistant container as defined in the USP.
## Storage
There is limited information regarding Indapamide 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 Indapamide in the drug label.
# Precautions with Alcohol
- Alcohol-Indapamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Lozol®
# Look-Alike Drug Names
- N/A
# Drug Shortage Status
# Price | Indapamide
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
Indapamide is a thiazide-like diuretic that is FDA approved for the {{{indicationType}}} of hypertension and salt and fluid retention associated with congestive heart failure. Common adverse reactions include hypokalemia, cramp, asthenia, dizziness, headache, lethargy, numbness, fatigue, and malaise.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The adult starting indapamide dose for hypertension is 1.25 mg as a single daily dose taken in the morning.
- If the response to 1.25 mg is not satisfactory after four weeks, the daily dose may be increased to 2.5 mg taken once daily.
- If the response to 2.5 mg is not satisfactory after four weeks, the daily dose may be increased to 5 mg taken once daily, but adding another antihypertensive should be considered.
- Dosing Information
- The adult starting indapamide dose for edema of congestive heart failure is 2.5 mg as a single daily dose taken in the morning.
- If the response to 2.5 mg is not satisfactory after one week, the daily dose may be increased to 5 mg taken once daily.
- If the antihypertensive response to indapamide is insufficient, indapamide may be combined with other antihypertensive drugs, with careful monitoring of blood pressure. It is recommended that the usual dose of other agents be reduced by 50% during initial combination therapy. As the blood pressure response becomes evident, further dosage adjustments may be necessary.
- In general, doses of 5 mg and larger have not appeared to provide additional effects on blood pressure or heart failure, but are associated with a greater degree of hypokalemia. There is minimal clinical trial experience in patients with doses greater than 5 mg once a day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Indapamide in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 2.5 mg/d[1][2]
- Dosing Information
- 2.5 mg/d[3]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness of indapamide 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 Indapamide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Indapamide in pediatric patients.
# Contraindications
- Anuria
- Hypersensitivity to indapamide or to other sulfonamide-derived drugs
# Warnings
- Severe cases of hyponatremia, accompanied by hypokalemia, have been reported with recommended doses of indapamide. This occurred primarily in elderly females. This appears to be dose-related. Also, a large case-controlled pharmacoepidemiology study indicates that there is an increased risk of hyponatremia with indapamide 2.5 mg and 5 mg doses. Hyponatremia considered possibly clinically significant (< 125 mEq/L) has not been observed in clinical trials with the 1.25 mg dosage. Thus, patients should be started at the 1.25 mg dose and maintained at the lowest possible dose.
- Hypokalemia occurs commonly with diuretics, and electrolyte monitoring is essential, particularly in patients who would be at increased risk from hypokalemia, such as those with cardiac arrhythmias or who are receiving concomitant cardiac glycosides.
- In general, diuretics should not be given concomitantly with lithium because they reduce its renal clearance and add a high risk of lithium toxicity. Read prescribing information for lithium preparations before use of such concomitant therapy.
### Precautions
- Hypokalemia, Hyponatremia, And Other Fluid And Electrolyte Imbalances
- Periodic determinations of serum electrolytes should be performed at appropriate intervals. In addition, patients should be observed for clinical signs of fluid or electrolyte imbalance, such as hyponatremia, hypochloremic alkalosis, or hypokalemia. Warning signs include dry mouth, thirst, weakness, fatigue, lethargy, drowsiness, restlessness, muscle pains or cramps, hypotension, oliguria, tachycardia, and gastrointestinal disturbance. Electrolyte determinations are particularly important in patients who are vomiting excessively or receiving parenteral fluids, in patients subject to electrolyte imbalance (including those with heart failure, kidney disease, and cirrhosis), and in patients on a salt-restricted diet.
- The risk of hypokalemia secondary to diuresis and natriuresis is increased when larger doses are used, when the diuresis is brisk, when severe cirrhosis is present and during concomitant use of corticosteroids or ACTH. Interference with adequate oral intake of electrolytes will also contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis, such as increased ventricular irritability.
- Dilutional hyponatremia may occur in edematous patients; the appropriate treatment is restriction of water rather than administration of salt, except in rare instances when the hyponatremia is life threatening. However, in actual salt depletion, appropriate replacement is the treatment of choice. Any chloride deficit that may occur during treatment is generally mild and usually does not require specific treatment except in extraordinary circumstances as in liver or renal disease. Thiazide-like diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.
- Hyperuricemia and Gout
- Serum concentrations of uric acid increased by an average of 0.69 mg/100 mL in patients treated with indapamide 1.25 mg, and by an average of 1 mg/100 mL in patients treated with indapamide 2.5 mg and 5 mg, and frank gout may be precipitated in certain patients receiving indapamide. Serum concentrations of uric acid should, therefore, be monitored periodically during treatment.
- Renal Impairment
- Indapamide, like the thiazides, should be used with caution in patients with severe renal disease, as reduced plasma volume may exacerbate or precipitate azotemia. If progressive renal impairment is observed in a patient receiving indapamide, withholding or discontinuing diuretic therapy should be considered. Renal function tests should be performed periodically during treatment with indapamide.
- Impaired Hepatic Function
- Indapamide, like the thiazides, should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
- Glucose Tolerance
- Latent diabetes may become manifest and insulin requirements in diabetic patients may be altered during thiazide administration. A mean increase in glucose of 6.47 mg/dL was observed in patients treated with indapamide 1.25 mg, which was not considered clinically significant in these trials. Serum concentrations of glucose should be monitored routinely during treatment with indapamide.
- Calcium Excretion
- Calcium excretion is decreased by diuretics pharmacologically related to indapamide. After six to eight weeks of indapamide 1.25 mg treatment and in long-term studies of hypertensive patients with higher doses of indapamide, however, serum concentrations of calcium increased only slightly with indapamide. Prolonged treatment with drugs pharmacologically related to indapamide may in rare instances be associated with hypercalcemia and hypophosphatemia secondary to physiologic changes in the parathyroid gland; however, the common complications of hyperparathyroidism, such as renal lithiasis, bone resorption, and peptic ulcer, have not been seen. Treatment should be discontinued before tests for parathyroid function are performed. Like the thiazides, indapamide may decrease serum PBI levels without signs of thyroid disturbance.
- Interaction With Systemic Lupus Erythematosus
- Thiazides have exacerbated or activated systemic lupus erythematosus and this possibility should be considered with indapamide as well.
- Post-Sympathectomy Patient
- The antihypertensive effect of the drug may be enhanced in the post-sympathectomized patient.
# Adverse Reactions
## Clinical Trials Experience
- Most adverse effects have been mild and transient.
- The Clinical Adverse Reactions listed in Table 1 represent data from Phase II/III placebo-controlled studies (306 patients given indapamide 1.25 mg). The clinical adverse reactions listed in Table 2 represent data from Phase II placebo-controlled studies and long-term controlled clinical trials (426 patients given indapamide 2.5 mg or 5 mg). The reactions are arranged into two groups: 1) a cumulative incidence equal to or greater than 5%; 2) a cumulative incidence less than 5%. Reactions are counted regardless of relation to drug.
- All other clinical adverse reactions occurred at an incidence of < 1%.
- Approximately 4% of patients given indapamide 1.25 mg compared to 5% of the patients given placebo discontinued treatment in the trials of up to eight weeks because of adverse reactions.
- In controlled clinical trials of six to eight weeks in duration, 20% of patients receiving indapamide 1.25 mg, 61% of patients receiving indapamide 5 mg, and 80% of patients receiving indapamide 10 mg had at least one potassium value below 3.4 mEq/L. In the indapamide 1.25 mg group, about 40% of those patients who reported hypokalemia as a laboratory adverse event returned to normal serum potassium values without intervention. Hypokalemia with concomitant clinical signs or symptoms occurred in 2% of patients receiving indapamide 1.25 mg.
- Because most of these data are from long-term studies (up to 40 weeks of treatment), it is probable that many of the adverse experiences reported are due to causes other than the drug. Approximately 10% of patients given indapamide discontinued treatment in long-term trials because of reactions either related or unrelated to the drug.
- Hypokalemia with concomitant clinical signs or symptoms occurred in 3% of patients receiving indapamide 2.5 mg q.d. and 7% of patients receiving indapamide 5 mg q.d. In long-term controlled clinical trials comparing the hypokalemic effects of daily doses of indapamide and hydrochlorothiazide, however, 47% of patients receiving indapamide 2.5 mg, 72% of patients receiving indapamide 5 mg, and 44% of patients receiving hydrochlorothiazide 50 mg had at least one potassium value (out of a total of 11 taken during the study) below 3.5 mEq/L. In the indapamide 2.5 mg group, over 50% of those patients returned to normal serum potassium values without intervention.
- In clinical trials of six to eight weeks, the mean changes in selected values were as shown in the tables below.
- No patients receiving indapamide 1.25 mg experienced hyponatremia considered possibly clinically significant (<125 mEq/L).
- Indapamide had no adverse effects on lipids.
- The following reactions have been reported with clinical usage of indapamide: jaundice (intrahepatic cholestatic jaundice), hepatitis, pancreatitis, and abnormal liver function tests. These reactions were reversible with discontinuance of the drug.
- Also reported are erythema multiforme, Stevens-Johnson syndrome, bullous eruptions, purpura, photosensitivity, fever, pneumonitis, anaphylactic reactions, agranulocytosis, leukopenia, thrombocytopenia and aplastic anemia. Other adverse reactions reported with antihypertensive/diuretics are necrotizing angiitis, respiratory distress, sialadenitis, and xanthopsia.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Indapamide in the drug label.
# Drug Interactions
- Other Antihypertensives
- Indapamide may add to or potentiate the action of other antihypertensive drugs. In limited controlled trials that compared the effect of indapamide combined with other antihypertensive drugs with the effect of the other drugs administered alone, there was no notable change in the nature or frequency of adverse reactions associated with the combined therapy.
- Norepinephrine
- Indapamide, like the thiazides, may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Reproduction studies have been performed in rats, mice and rabbits at doses up to 6,250 times the therapeutic human dose and have revealed no evidence of impaired fertility or harm to the fetus due to indapamide. Postnatal development in rats and mice was unaffected by pre-treatment of parent animals during gestation. There are, however, no adequate and well-controlled studies in pregnant women. Moreover, diuretics are known to cross the placental barrier and appear in cord blood. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. There may be hazards associated with this use such as fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult.
- Usage in Pregnancy
- The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developed toxemia.
- Edema during pregnancy may arise from pathological causes or from the physiologic and mechanical consequences of pregnancy. Indapamide is indicated in pregnancy when edema is due to pathologic causes, just as it is in the absence of pregnancy. Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. There is hypervolemia during normal pregnancy which is not harmful to either the fetus or the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Indapamide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Indapamide during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because most drugs are excreted in human milk, if use of this drug is deemed essential, the patient should stop nursing.
### Pediatric Use
- Safety and effectiveness of indapamide in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of indapamide 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.
- Severe cases of hyponatremia, accompanied by hypokalemia have been reported with recommended doses of indapamide in elderly females.
### Gender
There is no FDA guidance on the use of Indapamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Indapamide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Indapamide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Indapamide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Indapamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Indapamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Serum concentrations of electrolytes, glucose, and uric acid should be monitored periodically during treatment.
- If the antihypertensive response to indapamide is insufficient, indapamide may be combined with other antihypertensive drugs, with careful monitoring of blood pressure.
# IV Compatibility
There is limited information regarding IV Compatibility of Indapamide in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Symptoms of overdosage include nausea, vomiting, weakness, gastrointestinal disorders and disturbances of electrolyte balance. In severe instances, hypotension and depressed respiration may be observed.
### Management
- Support of respiration and cardiac circulation should be instituted. There is no specific antidote. An evacuation of the stomach is recommended by emesis and gastric lavage after which the electrolyte and fluid balance should be evaluated carefully.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Indapamide in the drug label.
# Pharmacology
## Mechanism of Action
- Indapamide is the first of a new class of antihypertensive/diuretics, the indolines.
## Structure
- Indapamide is an oral antihypertensive/diuretic. Its molecule contains both a polar sulfamoyl chlorobenzamide moiety and a lipid-soluble methylindoline moiety. It differs chemically from the thiazides in that it does not possess the thiazide ring system and contains only one sulfonamide group. The chemical name of indapamide is 4-Chloro- N-(2-methyl-1-indolinyl)-3-Sulfamoylbenzamide, and its molecular weight is 365.84. The compound is a weak acid, pKa=8.8, and is soluble in aqueous solutions of strong bases. It is a white to yellow-white crystalline (tetragonal) powder, and has the following structural formula:
- Each tablet, for oral administration, contains 1.25 mg or 2.5 mg of indapamide. In addition, each tablet contains the following inactive ingredients: corn starch, hypromellose, lactose monohydrate, magnesium stearate, maltodextrin, microcrystalline cellulose, polydextrose, polyethylene glycol, talc, titanium dioxide, triacetin. The 1.25 mg tablet also contains FD&C yellow #6 aluminum lake (sunset yellow lake).
## Pharmacodynamics
- The oral administration of 2.5 mg (two 1.25 mg tablets) of indapamide to male subjects produced peak concentrations of approximately 115 ng/mL of the drug in blood within two hours. The oral administration of 5 mg (two 2.5 mg tablets) of indapamide to healthy male subjects produced peak concentrations of approximately 260 ng/mL of the drug in the blood within two hours.
- In a parallel design double-blind, placebo controlled trial in hypertension, daily doses of indapamide between 1.25 mg and 10 mg produced dose-related antihypertensive effects. Doses of 5 and 10 mg were not distinguishable from each other although each was differentiated from placebo and 1.25 mg indapamide. At daily doses of 1.25 mg, 5 mg and 10 mg, a mean decrease of serum potassium of 0.28, 0.61 and 0.76 mEq/L, respectively, was observed and uric acid increased by about 0.69 mg/100 mL.
- In other parallel design, dose-ranging clinical trials in hypertension and edema, daily doses of indapamide between 0.5 and 5 mg produced dose-related effects. Generally, doses of 2.5 and 5 mg were not distinguishable from each other although each was differentiated from placebo and from 0.5 or 1 mg indapamide. At daily doses of 2.5 and 5 mg a mean decrease of serum potassium of 0.5 and 0.6 mEq/Liter, respectively, was observed and uric acid increased by about 1 mg/100 mL.
- At these doses, the effects of indapamide on blood pressure and edema are approximately equal to those obtained with conventional doses of other antihypertensive/diuretics.
- In hypertensive patients, daily doses of 1.25, 2.5 and 5 mg of indapamide have no appreciable cardiac inotropic or chronotropic effect. The drug decreases peripheral resistance, with little or no effect on cardiac output, rate or rhythm. Chronic administration of indapamide to hypertensive patients has little or no effect on glomerular filtration rate or renal plasma flow.
- Indapamide had an antihypertensive effect in patients with varying degrees of renal impairment, although in general, diuretic effects declined as renal function decreased.
- In a small number of controlled studies, indapamide taken with other antihypertensive drugs such as hydralazine, propranolol, guanethidine and methyldopa, appeared to have the additive effect typical of thiazide-type diuretics.
## Pharmacokinetics
- A minimum of 70% of a single oral dose is eliminated by the kidneys and an additional 23% by the gastrointestinal tract, probably including the biliary route. The half-life of indapamide in whole blood is approximately 14 hours.
- Indapamide is preferentially and reversibly taken up by the erythrocytes in the peripheral blood. The whole blood/plasma ratio is approximately 6:1 at the time of peak concentration and decreases to 3.5:1 at eight hours. From 71 to 79% of the indapamide in plasma is reversibly bound to plasma proteins.
- Indapamide is an extensively metabolized drug, with only about 7% of the total dose administered, recovered in the urine as unchanged drug during the first 48 hours after administration. The urinary elimination of 14C-labeled indapamide and metabolites is biphasic with a terminal half-life of excretion of total radioactivity of 26 hours.
## Nonclinical Toxicology
- Both mouse and rat lifetime carcinogenicity studies were conducted. There was no significant difference in the incidence of tumors between the indapamide-treated animals and the control groups.
# Clinical Studies
There is limited information regarding Clinical Studies of Indapamide in the drug label.
# How Supplied
- Indapamide Tablets, USP are available as follows:
- Keep tightly closed.
- Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. Avoid excessive heat.
- Dispense in a tight, light-resistant container as defined in the USP.
## Storage
There is limited information regarding Indapamide 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 Indapamide in the drug label.
# Precautions with Alcohol
- Alcohol-Indapamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Lozol®[4]
# Look-Alike Drug Names
- N/A[5]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Indapamide | |
b2c3928e1985ea5e41b2e33f0443e92e57ea3b4c | wikidoc | Index case | Index case
# Overview
The index case or primary case is the initial patient in the population of an epidemiological investigation,
-r more generally, the first case of a condition or syndrome (not necessarily contagious) to be described in the medical literature, whether or not the patient is thought to be the first person affected.
An index case will sometimes achieve the status of a "classic" case in the literature, as did Phineas Gage.
The index case may indicate the source of the disease, the possible spread, and which reservoir holds the disease in between outbreaks. The index case is the first patient that indicates the existence of an outbreak. Earlier cases may be found and are labeled primary, secondary, tertiary, etc. "Patient Zero" was used to refer to the index case in the spread of HIV in North America.
In genetics, the index case is the case of the original patient (propositus or proband) that stimulates investigation of other members of the family to discover a possible genetic factor.
# Gaëtan Dugas Case ("Patient Zero")
In the early years of the AIDS epidemic, a “patient zero” transmission scenario was compiled by Dr. William Darrow and colleagues at the U.S. Centers for Disease Control and Prevention (CDC). This epidemiological study showed how “patient zero” had infected multiple partners with HIV, and they, in turn, transmitted it to others and rapidly spread the virus to locations all over the world (Auerbach et al., 1984). The CDC identified Gaëtan Dugas as a carrier of the virus from Africa to the United States and spreading it to other men he encountered gay bathhouses.
Journalist Randy Shilts subsequently wrote about Patient Zero, based on Darrow's findings, in his 1987 book And the Band Played On, which identified Patient Zero as Gaëtan Dugas. Dugas was a flight attendant who was sexually promiscuous in several North American cities, according to Shilts' book. He was vilified for several years as a "mass spreader" of HIV, and seen as the original source of the HIV epidemic among homosexual men. Four years later, Darrow repudiated the study's methodology and how Shilts had represented its conclusions.
A 2007 study published in the Proceedings of the National Academy of Sciences of the USA by Michael Worobey and Dr. Arthur Pitchenik claimed that, based on the results of genetic analysis, current North American strains of HIV probably moved from Africa to Haiti and then entered the United States around 1969, probably through a single immigrant. However, a Robert Rayford died in St. Louis, Missouri, of complications from AIDS in 1969, and most likely became infected in 1966, so there were prior carriers of HIV strains in North America.
The phrase "patient zero" is now used in the media to refer to the index case for infectious disease outbreaks, as well as for computer virus outbreaks, and, more broadly, as the source of ideas or actions that have far-reaching consequences.
# Other Index Patients
- Mary Mallon was an index case of a typhoid outbreak. An apparently healthy carrier, she infected 47 people while working as a cook. She eventually was quarantined to prevent her from spreading the disease to others.
- The first recorded victim of the Ebola virus was a 44-year-old schoolteacher named Mabalo Lokela, who died 8 September 1976, 14 days after symptom onset.
- 64-year-old Liu Jianlun, a Guangdong doctor, transmitted SARS during a stay in the Hong Kong Metropole Hotel in 2003.
- A baby in the Lewis House at 40 Broad Street is considered the index patient in the 1854 cholera outbreak in the Soho neighborhood of London. (The Ghost Map, Steven Johnson, 2005.)
- Édgar Enrique Hernández may be patient zero of the 2009 swine flu outbreak. He recovered, and a bronze statue has been erected in his honor. Maria Adela Gutierrez, who contracted the virus about the same time as Hernández, became the first officially confirmed fatality.
# See Also
- Proband
- Mayinga N'Seka | Index case
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
The index case or primary case is the initial patient in the population of an epidemiological investigation,[1][2]
or more generally, the first case of a condition or syndrome (not necessarily contagious) to be described in the medical literature, whether or not the patient is thought to be the first person affected.[citation needed]
An index case will sometimes achieve the status of a "classic" case in the literature, as did Phineas Gage.
The index case may indicate the source of the disease, the possible spread, and which reservoir holds the disease in between outbreaks. The index case is the first patient that indicates the existence of an outbreak. Earlier cases may be found and are labeled primary, secondary, tertiary, etc.[3] "Patient Zero" was used to refer to the index case in the spread of HIV in North America.[4]
In genetics, the index case is the case of the original patient (propositus or proband) that stimulates investigation of other members of the family to discover a possible genetic factor.[5]
# Gaëtan Dugas Case ("Patient Zero")
In the early years of the AIDS epidemic, a “patient zero” transmission scenario was compiled by Dr. William Darrow and colleagues at the U.S. Centers for Disease Control and Prevention (CDC).[6] This epidemiological study showed how “patient zero” had infected multiple partners with HIV, and they, in turn, transmitted it to others and rapidly spread the virus to locations all over the world (Auerbach et al., 1984). The CDC identified Gaëtan Dugas as a carrier of the virus from Africa to the United States and spreading it to other men he encountered gay bathhouses.[7]
Journalist Randy Shilts subsequently wrote about Patient Zero, based on Darrow's findings,[6] in his 1987 book And the Band Played On, which identified Patient Zero as Gaëtan Dugas.[8] Dugas was a flight attendant who was sexually promiscuous in several North American cities, according to Shilts' book. He was vilified for several years as a "mass spreader" of HIV, and seen as the original source of the HIV epidemic among homosexual men.[6] Four years later, Darrow repudiated the study's methodology and how Shilts had represented its conclusions.[6]
A 2007 study published in the Proceedings of the National Academy of Sciences of the USA by Michael Worobey and Dr. Arthur Pitchenik claimed that, based on the results of genetic analysis, current North American strains of HIV probably moved from Africa to Haiti and then entered the United States around 1969,[9] probably through a single immigrant. However, a Robert Rayford died in St. Louis, Missouri, of complications from AIDS in 1969, and most likely became infected in 1966, so there were prior carriers of HIV strains in North America.
The phrase "patient zero" is now used in the media to refer to the index case for infectious disease outbreaks, as well as for computer virus outbreaks, and, more broadly, as the source of ideas or actions that have far-reaching consequences.[10][11][12][13][14]
# Other Index Patients
- Mary Mallon was an index case of a typhoid outbreak. An apparently healthy carrier, she infected 47 people while working as a cook. She eventually was quarantined to prevent her from spreading the disease to others.[15]
- The first recorded victim of the Ebola virus was a 44-year-old schoolteacher named Mabalo Lokela, who died 8 September 1976, 14 days after symptom onset.[16]
- 64-year-old Liu Jianlun, a Guangdong doctor, transmitted SARS during a stay in the Hong Kong Metropole Hotel in 2003.[17][18]
- A baby in the Lewis House at 40 Broad Street is considered the index patient in the 1854 cholera outbreak in the Soho neighborhood of London. (The Ghost Map, Steven Johnson, 2005.)[19]
- Édgar Enrique Hernández may be patient zero of the 2009 swine flu outbreak.[20] He recovered, and a bronze statue has been erected in his honor.[21] Maria Adela Gutierrez, who contracted the virus about the same time as Hernández, became the first officially confirmed fatality.
# See Also
- Proband
- Mayinga N'Seka | https://www.wikidoc.org/index.php/Index_Case | |
f4c7416933b633f9c5e090c431f75a3ef52efa15 | wikidoc | Induration | Induration
Induration (in'doo rā'shən, -dyoo-), a noun, means, in terms of pathology, (a) hardening of an area of the body as a reaction to inflammation, hyperemia, or neoplastic infiltration, or (b) an area or part of the body that has undergone such a reaction. Most often this term is used to describe dermatologic findings.
# Examples of usage
"Both erythema and induration appear to be adequate indices of tuberculin sensitivity."
"The erythema had spread to 20 cm, and the central induration had spread to 9 cm."
# Footnotes
- ↑ Random House Webster's Unabridged Dictionary. Random House, Inc. 2001. Page 975. ISBN 037572026.
- ↑ Kimura, et al. "Comparison of erythema and induration as results of tuberculin tests." Int J Tuberc Lung Dis. 2005;9(8):853-7. PMID 16104630.
- ↑ Race, et al. "Painful nodule with induration and spreading erythema." Baylor University Medical Center Proceedings. 2005;18(4):401–404. | Induration
Template:SignSymptom infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Induration (in'doo rā'shən, -dyoo-), a noun, means, in terms of pathology, (a) hardening of an area of the body as a reaction to inflammation, hyperemia, or neoplastic infiltration, or (b) an area or part of the body that has undergone such a reaction.[1] Most often this term is used to describe dermatologic findings.
# Examples of usage
"Both erythema and induration appear to be adequate indices of tuberculin sensitivity."[2]
"The erythema had spread to 20 cm, and the central induration had spread to 9 cm."[3]
# Footnotes
- ↑ Random House Webster's Unabridged Dictionary. Random House, Inc. 2001. Page 975. ISBN 037572026.
- ↑ Kimura, et al. "Comparison of erythema and induration as results of tuberculin tests." Int J Tuberc Lung Dis. 2005;9(8):853-7. PMID 16104630.
- ↑ Race, et al. "Painful nodule with induration and spreading erythema." Baylor University Medical Center Proceedings. 2005;18(4):401–404.
# External links
- Hear pronunciation at Merriam-Webster online...
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Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Induration | |
3a8b0a9aa784bb6e3a385433cfb36b4f73248e49 | wikidoc | Infarction | Infarction
# Overview
An infarction is the process resulting in a macroscopic area of necrotic tissue in some organ caused by loss of adequate blood supply. Supplying arteries may be blocked from within by some obstruction (e.g. a blood clot or fatty cholesterol deposit), or may be mechanically compressed or ruptured by trauma.
Infarction is commonly associated with atherosclerosis, where an atherosclerotic plaque ruptures, a thrombus forms on the surface occluding the blood flow and occasionally forming an embolus that occludes other blood vessels downstream. Infarction can also involve mechanical blockage of the blood supply, such as when part of the gut herniates or twists.
Infarctions are divided into two types according the amount of hemorrhaging present:
- White infarctions (anemic infarcts) affect solid organs such as the heart, spleen, and kidneys. The occlusion is most often composed of platelets, and the organ becomes white, or pale.
- Red infarctions (hemorrhagic infarcts), generally affecting the lungs. The occlusion consists more of red blood cells and fibrin strands.
Diseases commonly associated with infarctions include:
- Myocardial infarction (heart attack)
- Pulmonary embolism ("lung attack")
- Cerebrovascular accident (stroke – 80% are due to infarction)
- Peripheral artery occlusive disease (the most severe form of which is gangrene)
- Antiphospholipid syndrome
- Sepsis
- Giant-cell arteritis (GCA)
- Hernia
- Volvulus
cs:Infarkt
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it:Infarto
hu:Infarktus
no:Infarkt
sq:Infarkti
sv:Infarkt
ur:احتِشاء | Infarction
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
An infarction is the process resulting in a macroscopic area of necrotic tissue in some organ caused by loss of adequate blood supply. Supplying arteries may be blocked from within by some obstruction (e.g. a blood clot or fatty cholesterol deposit), or may be mechanically compressed or ruptured by trauma.
Infarction is commonly associated with atherosclerosis, where an atherosclerotic plaque ruptures, a thrombus forms on the surface occluding the blood flow and occasionally forming an embolus that occludes other blood vessels downstream. Infarction can also involve mechanical blockage of the blood supply, such as when part of the gut herniates or twists.
Infarctions are divided into two types according the amount of hemorrhaging present:
- White infarctions (anemic infarcts) affect solid organs such as the heart, spleen, and kidneys. The occlusion is most often composed of platelets, and the organ becomes white, or pale.
- Red infarctions (hemorrhagic infarcts), generally affecting the lungs. The occlusion consists more of red blood cells and fibrin strands.
Diseases commonly associated with infarctions include:
- Myocardial infarction (heart attack)
- Pulmonary embolism ("lung attack")
- Cerebrovascular accident (stroke – 80% are due to infarction)
- Peripheral artery occlusive disease (the most severe form of which is gangrene)
- Antiphospholipid syndrome
- Sepsis
- Giant-cell arteritis (GCA)
- Hernia
- Volvulus
cs:Infarkt
de:Infarkt
et:Infarkt
it:Infarto
hu:Infarktus
no:Infarkt
sq:Infarkti
sv:Infarkt
ur:احتِشاء
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Infarct | |
423df37c5fe882b4d707f110733e4ee85a7d1d2f | wikidoc | Infliximab | Infliximab
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# Black Box Warning
# Overview
Infliximab is a tumor necrosis factor blocker that is FDA approved for the treatment of crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash, abdominal pain, nausea, headache, pharyngitis, respiratory tract infection, fatigue, fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing information
- The recommended dose of infliximab is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of adults with moderately to severely active Crohn's disease or fistulizing Crohn's disease. For adult patients who respond and then lose their response, consideration may be given to treatment with 10 mg/kg. Patients who do not respond by Week 14 are unlikely to respond with continued dosing and consideration should be given to discontinue infliximab in these patients.
- Dosing information
- The recommended dose of infliximab is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of adult patients with moderately to severely active ulcerative colitis.
- Dosing Information
- The recommended dose of infliximab is 3 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 3 mg/kg every 8 weeks thereafter for the treatment of moderately to severely active rheumatoid arthritis. infliximab should be given in combination with methotrexate. For patients who have an incomplete response, consideration may be given to adjusting the dose up to 10 mg/kg or treating as often as every 4 weeks bearing in mind that risk of serious infections is increased at higher doses.
- Dosing Information
- The recommended dose of infliximab is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 6 weeks thereafter for the treatment of active ankylosing spondylitis.
- Dosing Information
- The recommended dose of infliximab is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of psoriatic arthritis. infliximab can be used with or without methotrexate.
- Dosing Information
- The recommended dose of infliximab is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of chronic severe (i.e., extensive and/or disabling) plaque psoriasis.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Infliximab in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 3-5 mg/kg, at weeks 0, 2, and 6, followed by infusions administered every 6-8 weeks.
- Dosing Information
- Administer IV infusions of 5 mg/kg until disease is controlled.
- Dosing Information
- Administer IV infusions of 1 to 10 mg/kg.
- Dosing Information
- Administer IV infusions of 3 mg/kg at weeks 0, 2, 6, followed by IV infusions every 8 weeks.
- Dosing Information
- Administer IV infusions of 3-5 mg/kg every 4-8 weeks.
- Dosing Information
- Administer IV infusion of 3-6 mg/kg, initially every 2, 4, and 6 weeks, followed by every 4-8 weeks according to treatment response.
- Dosing Information
- Administer IV infusions of 5 mg/kg on the first, fourteenth, and forty-second day, followed by infusions every 8 weeks.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- The recommended dose of infliximab for pediatric patients 6 years and older with moderately to severely active Crohn's disease is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks.
- Dosing information
- The recommended dose of infliximab for pediatric patients 6 years and older with moderately to severely active ulcerative colitis is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Infliximab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Infliximab in pediatric patients.
# Contraindications
- Moderate to severe heart failure.
- Hypersensitivity reaction to infliximab or to inactive components of the product or to any murine proteins.
# Warnings
### Serious Infections
- Patients treated with infliximab are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.
- Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, or parasitic organisms including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF-blockers. Patients have frequently presented with disseminated rather than localized disease.
- Treatment with infliximab should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants such as corticosteroids or methrotexate may be at greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients:
- With chronic or recurrent infection.
- Who have been exposed to tuberculosis.
- With a history of an opportunistic infection.
- Who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis.
- With underlying conditions that may predispose them to infection.
- Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving infliximab, including patients who have previously received treatment for latent or active tuberculosis. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating infliximab and periodically during therapy.
- Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating infliximab, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG).
- Anti-tuberculosis therapy should also be considered prior to initiation of infliximab in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
- Tuberculosis should be strongly considered in patients who develop a new infection during infliximab treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.
- Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with infliximab, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with infliximab.
- Infliximab should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with infliximab should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated.
For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy.
### Malignancies
Malignancies, some fatal, have been reported among children, adolescents and young adults who received treatment with TNF-blocking agents (initiation of therapy ≤ 18 years of age), including infliximab. Approximately half of these cases were lymphomas, including Hodgkin's lymphoma and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (range 1 to 84 months) after the first dose of TNF blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports.
- In the controlled portions of clinical trials of all the TNF-blocking agents, more cases of lymphoma have been observed among patients receiving a TNF blocker compared with control patients. In the controlled and open-label portions of infliximab clinical trials, 5 patients developed lymphomas among 5707 patients treated with infliximab (median duration of follow-up 1.0 years) vs. 0 lymphomas in 1600 control patients (median duration of follow-up 0.4 years). In rheumatoid arthritis patients, 2 lymphomas were observed for a rate of 0.08 cases per 100 patient-years of follow-up, which is approximately three-fold higher than expected in the general population. In the combined clinical trial population for rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 5 lymphomas were observed for a rate of 0.10 cases per 100 patient-years of follow-up, which is approximately four-fold higher than expected in the general population. Patients with Crohn's disease, rheumatoid arthritis or plaque psoriasis, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF blocker therapy, patients with rheumatoid arthritis may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.
- Hepatosplenic T-cell lymphoma (HSTCL)
- Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including infliximab. These cases have had a very aggressive disease course and have been fatal. All reported infliximab cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males. All of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with infliximab at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to infliximab or infliximab in combination with these other immunosuppressants. When treating patients with inflammatory bowel disease, particularly in adolescents and young adults, consideration of whether to use infliximab alone or in combination with other immunosuppressants should take into account a possibility that there is a higher risk of HSTCL with combination therapy versus an observed increased risk of immunogenicity and hypersensitivity reactions with infliximab monotherapy from the clinical trial data.
Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including infliximab. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.
- In the controlled portions of clinical trials of some TNF-blocking agents including infliximab, more malignancies (excluding lymphoma and nonmelanoma skin cancer ) have been observed in patients receiving those TNF-blockers compared with control patients. During the controlled portions of infliximab trials in patients with moderately to severely active rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 14 patients were diagnosed with malignancies (excluding lymphoma and NMSC) among 4019 infliximab-treated patients vs. 1 among 1597 control patients (at a rate of 0.52/100 patient-years among infliximab-treated patients vs. a rate of 0.11/100 patient-years among control patients), with median duration of follow-up 0.5 years for infliximab-treated patients and 0.4 years for control patients. Of these, the most common malignancies were breast cancer, colorectal cancer, and melanoma. The rate of malignancies among infliximab-treated patients was similar to that expected in the general population whereas the rate in control patients was lower than expected.
- In a clinical trial exploring the use of infliximab in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, the majority of lung or head and neck origin, were reported in infliximab-treated patients compared with control patients. All patients had a history of heavy smoking. Prescribers should exercise caution when considering the use of infliximab in patients with moderate to severe COPD.
- Psoriasis patients should be monitored for nonmelanoma skin cancers (NMSCs), particularly those patients who have had prior prolonged phototherapy treatment. In the maintenance portion of clinical trials for infliximab, NMSCs were more common in patients with previous phototherapy.
- The potential role of TNF-blocking therapy in the development of malignancies is not known. Rates in clinical trials for infliximab cannot be compared to rates in clinical trials of other TNF-blockers and may not predict rates observed in a broader patient population. Caution should be exercised in considering infliximab treatment in patients with a history of malignancy or in continuing treatment in patients who develop malignancy while receiving infliximab.
### Hepatitis B Virus Reactivation
- Use of TNF blockers, including infliximab, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients should be tested for HBV infection before initiating TNF blocker therapy, including infliximab. For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. Patients who are carriers of HBV and require treatment with TNF blockers should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, TNF blockers should be stopped and antiviral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF blocker therapy in this situation and monitor patients closely.
- Severe hepatic reactions, including acute liver failure, jaundice, hepatitis and cholestasis, have been reported rarely in postmarketing data in patients receiving infliximab. Autoimmune hepatitis has been diagnosed in some of these cases. Severe hepatic reactions occurred between 2 weeks to more than 1 year after initiation of infliximab; elevations in hepatic aminotransferase levels were not noted prior to discovery of the liver injury in many of these cases. Some of these cases were fatal or necessitated liver transplantation. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (e.g., ≥5 times the upper limit of normal) develop, infliximab should be discontinued, and a thorough investigation of the abnormality should be undertaken. In clinical trials, mild or moderate elevations of ALT and AST have been observed in patients receiving infliximab without progression to severe hepatic injury.
- Infliximab has been associated with adverse outcomes in patients with heart failure, and should be used in patients with heart failure only after consideration of other treatment options. The results of a randomized study evaluating the use of infliximab in patients with heart failure (NYHA Functional Class III/IV) suggested higher mortality in patients who received 10 mg/kg infliximab, and higher rates of cardiovascular adverse events at doses of 5 mg/kg and 10 mg/kg. There have been post-marketing reports of worsening heart failure, with and without identifiable precipitating factors, in patients taking infliximab. There have also been rare post-marketing reports of new onset heart failure, including heart failure in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age. If a decision is made to administer infliximab to patients with heart failure, they should be closely monitored during therapy, and infliximab should be discontinued if new or worsening symptoms of heart failure appear.
- Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia, some with a fatal outcome, have been reported in patients receiving infliximab. The causal relationship to infliximab therapy remains unclear. Although no high-risk group(s) has been identified, caution should be exercised in patients being treated with infliximab who have ongoing or a history of significant hematologic abnormalities. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever) while on infliximab. Discontinuation of infliximab therapy should be considered in patients who develop significant hematologic abnormalities.
- Infliximab has been associated with hypersensitivity reactions that vary in their time of onset and required hospitalization in some cases. Most hypersensitivity reactions, which include urticaria, dyspnea, and/or hypotension, have occurred during or within 2 hours of infliximab infusion.
- However, in some cases, serum sickness-like reactions have been observed in patients after initial infliximab therapy (i.e., as early as after the second dose), and when infliximab therapy was reinstituted following an extended period without infliximab treatment. Symptoms associated with these reactions include fever, rash, headache, sore throat, myalgias, polyarthralgias, hand and facial edema and/or dysphagia. These reactions were associated with a marked increase in antibodies to infliximab, loss of detectable serum concentrations of infliximab, and possible loss of drug efficacy.
- Infliximab should be discontinued for severe hypersensitivity reactions. Medications for the treatment of hypersensitivity reactions (e.g., acetaminophen, antihistamines, corticosteroids and/or epinephrine) should be available for immediate use in the event of a reaction.
- In rheumatoid arthritis, Crohn's disease and psoriasis clinical trials, re-administration of infliximab after a period of no treatment resulted in a higher incidence of infusion reactions relative to regular maintenance treatment. In general, the benefit-risk of re-administration of infliximab after a period of no-treatment, especially as a re-induction regimen given at weeks 0, 2 and 6, should be carefully considered. In the case where infliximab maintenance therapy for psoriasis is interrupted, infliximab should be reinitiated as a single dose followed by maintenance therapy.
- Infliximab and other agents that inhibit TNF have been associated in rare cases with CNS manifestation of systemic vasculitis, seizure and new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of infliximab in patients with these neurologic disorders and should consider discontinuation of infliximab if these disorders develop.
- Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another TNFα-blocking agent, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse reactions seen with the combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNFα-blocking agents. Therefore, the combination of infliximab and anakinra is not recommended.
- In clinical studies, concurrent administration of TNF-blocking agents and abatacept have been associated with an increased risk of infections including serious infections compared with TNF-blocking agents alone, without increased clinical benefit. Therefore, the combination of infliximab and abatacept is not recommended.
- There is insufficient information regarding the concomitant use of infliximab with other biological therapeutics used to treat the same conditions as infliximab. The concomitant use of infliximab with these biologics is not recommended because of the possibility of an increased risk of infection.
- Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.
- Treatment with infliximab may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with infliximab, treatment should be discontinued.
- In patients receiving anti-TNF therapy, limited data are available on the response to vaccination with live vaccines or on the secondary transmission of infection by live vaccines. Use of live vaccines could result in clinical infections, including disseminated infections. It is recommended that live vaccines not be given concurrently with infliximab. Caution is advised in the administration of live vaccines to infants born to female patients treated with infliximab during pregnancy since infliximab is known to cross the placenta and has been detected up to 6 months in the serum of infants born to female patients treated with infliximab during pregnancy.
- Other uses of therapeutic infectious agents such as live attenuated bacteria (e.g., BCG bladder instillation for the treatment of cancer) could result in clinical infections, including disseminated infections. It is recommended that therapeutic infectious agents not be given concurrently with infliximab.
- It is recommended that all pediatric patients be brought up to date with all vaccinations prior to initiating infliximab therapy. The interval between vaccination and initiation of infliximab therapy should be in accordance with current vaccination guidelines.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not predict the rates observed in broader patient populations in clinical practice.
### Adverse Reactions in Adults
- The data described herein reflect exposure to infliximab in 4779 adult patients (1304 patients with rheumatoid arthritis, 1106 patients with Crohn's disease, 202 with ankylosing spondylitis, 293 with psoriatic arthritis, 484 with ulcerative colitis, 1373 with plaque psoriasis, and 17 patients with other conditions), including 2625 patients exposed beyond 30 weeks and 374 exposed beyond 1 year. One of the most-common reasons for discontinuation of treatment was infusion-related reactions (e.g., dyspnea, flushing, headache and rash).
- An infusion reaction was defined in clinical trials as any adverse event occurring during an infusion or within 1 hour after an infusion. In phase 3 clinical studies, 18% of infliximab-treated patients experienced an infusion reaction compared to 5% of placebo-treated patients. Of infliximab-treated patients who had an infusion reaction during the induction period, 27% experienced an infusion reaction during the maintenance period. Of patients who did not have an infusion reaction during the induction period, 9% experienced an infusion reaction during the maintenance period.
- Among all infliximab infusions, 3% were accompanied by nonspecific symptoms such as fever or chills, 1% were accompanied by cardiopulmonary reactions (primarily chest pain, hypotension, hypertension or dyspnea), and <1% were accompanied by pruritus, urticaria, or the combined symptoms of pruritus/urticaria and cardiopulmonary reactions. Serious infusion reactions occurred in <1% of patients and included anaphylaxis, convulsions, erythematous rash and hypotension. Approximately 3% of patients discontinued infliximab because of infusion reactions, and all patients recovered with treatment and/or discontinuation of the infusion. infliximab infusions beyond the initial infusion were not associated with a higher incidence of reactions. The infusion reaction rates remained stable in psoriasis through 1 year in psoriasis Study I. In psoriasis Study II, the rates were variable over time and somewhat higher following the final infusion than after the initial infusion. Across the 3 psoriasis studies, the percent of total infusions resulting in infusion reactions (i.e., an adverse event occurring within 1 hour) was 7% in the 3 mg/kg group, 4% in the 5 mg/kg group, and 1% in the placebo group.
- Patients who became positive for antibodies to infliximab were more likely (approximately two- to three-fold) to have an infusion reaction than were those who were negative. Use of concomitant immunosuppressant agents appeared to reduce the frequency of both antibodies to infliximab and infusion reactions.
- In a clinical trial of patients with moderate to severe psoriasis designed to assess the efficacy of long-term maintenance therapy versus re-treatment with an induction regimen of infliximab following disease flare, 4% (8/219) of patients in the re-treatment therapy arm experienced serious infusion reactions versus < 1% (1/222) in the maintenance therapy arm. Patients enrolled in this trial did not receive any concomitant immunosuppressant therapy. In this study, the majority of serious infusion reactions occurred during the second infusion at Week 2. Symptoms included, but were not limited to, dyspnea, urticaria, facial edema, and hypotension. In all cases, infliximab treatment was discontinued and/or other treatment instituted with complete resolution of signs and symptoms.
In psoriasis studies, approximately 1% of infliximab-treated patients experienced a possible delayed hypersensitivity reaction, generally reported as serum sickness or a combination of arthralgia and/or myalgia with fever and/or rash. These reactions generally occurred within 2 weeks after repeat infusion.
- In infliximab clinical studies, treated infections were reported in 36% of infliximab-treated patients (average of 51 weeks of follow-up) and in 25% of placebo-treated patients (average of 37 weeks of follow-up). The infections most frequently reported were respiratory tract infections (including sinusitis, pharyngitis, and bronchitis) and urinary tract infections. Among infliximab-treated patients, serious infections included pneumonia, cellulitis, abscess, skin ulceration, sepsis, and bacterial infection. In clinical trials, 7 opportunistic infections were reported; 2 cases each of coccidioidomycosis (1 case was fatal) and histoplasmosis (1 case was fatal), and 1 case each of pneumocystosis, nocardiosis and cytomegalovirus. Tuberculosis was reported in 14 patients, 4 of whom died due to miliary tuberculosis. Other cases of tuberculosis, including disseminated tuberculosis, also have been reported post-marketing. Most of these cases of tuberculosis occurred within the first 2 months after initiation of therapy with infliximab and may reflect recrudescence of latent disease. In the 1-year placebo-controlled studies RA I and RA II, 5.3% of patients receiving infliximab every 8 weeks with MTX developed serious infections as compared to 3.4% of placebo patients receiving MTX. Of 924 patients receiving infliximab, 1.7% developed pneumonia and 0.4% developed TB, when compared to 0.3% and 0.0% in the placebo arm respectively. In a shorter (22-week) placebo-controlled study of 1082 RA patients randomized to receive placebo, 3 mg/kg or 10 mg/kg infliximab infusions at 0, 2, and 6 weeks, followed by every 8 weeks with MTX, serious infections were more frequent in the 10 mg/kg infliximab group (5.3%) than the 3 mg/kg or placebo groups (1.7% in both). During the 54-week Crohn's II Study, 15% of patients with fistulizing Crohn's disease developed a new fistula-related abscess.
- In infliximab clinical studies in patients with ulcerative colitis, infections treated with antimicrobials were reported in 27% of infliximab-treated patients (average of 41 weeks of follow-up) and in 18% of placebo-treated patients (average 32 weeks of follow-up). The types of infections, including serious infections, reported in patients with ulcerative colitis were similar to those reported in other clinical studies.
- The onset of serious infections may be preceded by constitutional symptoms such as fever, chills, weight loss, and fatigue. The majority of serious infections, however, may also be preceded by signs or symptoms localized to the site of the infection.
- Approximately half of infliximab-treated patients in clinical trials who were antinuclear antibody (ANA) negative at baseline developed a positive ANA during the trial compared with approximately one-fifth of placebo-treated patients. Anti-dsDNA antibodies were newly detected in approximately one-fifth of infliximab-treated patients compared with 0% of placebo-treated patients. Reports of lupus and lupus-like syndromes, however, remain uncommon.
- In controlled trials, more infliximab-treated patients developed malignancies than placebo-treated patients.
- In a randomized controlled clinical trial exploring the use of infliximab in patients with moderate to severe COPD who were either current smokers or ex-smokers, 157 patients were treated with infliximab at doses similar to those used in rheumatoid arthritis and Crohn's disease. Of these infliximab-treated patients, 9 developed a malignancy, including 1 lymphoma, for a rate of 7.67 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% CI 3.51 – 14.56). There was 1 reported malignancy among 77 control patients for a rate of 1.63 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% CI 0.04 – 9.10). The majority of the malignancies developed in the lung or head and neck.
- In a randomized study evaluating infliximab in moderate to severe heart failure (NYHA Class III/IV; left ventricular ejection fraction ≤35%), 150 patients were randomized to receive treatment with 3 infusions of infliximab 10 mg/kg, 5 mg/kg, or placebo, at 0, 2, and 6 weeks. Higher incidences of mortality and hospitalization due to worsening heart failure were observed in patients receiving the 10 mg/kg infliximab dose. At 1 year, 8 patients in the 10 mg/kg infliximab group had died compared with 4 deaths each in the 5 mg/kg infliximab and the placebo groups. There were trends toward increased dyspnea, hypotension, angina, and dizziness in both the 10 mg/kg and 5 mg/kg infliximab treatment groups, versus placebo. infliximab has not been studied in patients with mild heart failure (NYHA Class I/II).
- Treatment with infliximab can be associated with the development of antibodies to infliximab. The assay used to measure anti-infliximab antibodies in patient samples is subject to interference by serum infliximab, possibly resulting in an underestimation of the rate of patient antibody formation. The incidence of antibodies to infliximab in patients given a 3-dose induction regimen followed by maintenance dosing was approximately 10% as assessed through 1 to 2 years of infliximab treatment. A higher incidence of antibodies to infliximab was observed in Crohn's disease patients receiving infliximab after drug-free intervals >16 weeks. In a study of psoriatic arthritis in which 191 patients received 5 mg/kg with or without MTX, antibodies to infliximab occurred in 15% of patients. The majority of antibody-positive patients had low titers. Patients who were antibody-positive were more likely to have higher rates of clearance, reduced efficacy and to experience an infusion reaction than were patients who were antibody negative. Antibody development was lower among rheumatoid arthritis and Crohn's disease patients receiving immunosuppressant therapies such as 6-MP/AZA or MTX.
- In the psoriasis Study II, which included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 36% of patients treated with 5 mg/kg every 8 weeks for 1 year, and in 51% of patients treated with 3 mg/kg every 8 weeks for 1 year. In the psoriasis Study III, which also included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 20% of patients treated with 5 mg/kg induction (weeks 0, 2 and 6), and in 27% of patients treated with 3 mg/kg induction. Despite the increase in antibody formation, the infusion reaction rates in Studies I and II in patients treated with 5 mg/kg induction followed by every 8 week maintenance for 1 year and in Study III in patients treated with 5 mg/kg induction (14.1%–23.0%) and serious infusion reaction rates (<1%) were similar to those observed in other study populations. The clinical significance of apparent increased immunogenicity on efficacy and infusion reactions in psoriasis patients as compared to patients with other diseases treated with infliximab over the long term is not known.
- The data reflect the percentage of patients whose test results were positive for antibodies to infliximab in an ELISA assay, and they are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to infliximab with the incidence of antibodies to other products may be misleading.
Severe liver injury, including acute liver failure and autoimmune hepatitis, has been reported rarely in patients receiving infliximab. Reactivation of hepatitis B virus has occurred in patients receiving TNF-blocking agents, including infliximab, who are chronic carriers of this virus.
In clinical trials in rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, plaque psoriasis, and psoriatic arthritis, elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving infliximab than in controls the table below, both when infliximab was given as monotherapy and when it was used in combination with other immunosuppressive agents. In general, patients who developed ALT and AST elevations were asymptomatic, and the abnormalities decreased or resolved with either continuation or discontinuation of infliximab, or modification of concomitant medications.
- During the placebo-controlled portion across the 3 clinical trials up to week 16, the proportion of patients who experienced at least 1 serious adverse reaction (SAE; defined as resulting in death, life threatening, requires hospitalization, or persistent or significant disability/incapacity) was 0.5% in the 3 mg/kg infliximab group, 1.9% in the placebo group, and 1.6% in the 5 mg/kg infliximab group.
- Among patients in the 2 Phase 3 studies, 12.4% of patients receiving infliximab 5 mg/kg every 8 weeks through 1 year of maintenance treatment experienced at least 1 SAE in Study I. In Study II, 4.1% and 4.7% of patients receiving infliximab 3 mg/kg and 5 mg/kg every 8 weeks, respectively, through 1 year of maintenance treatment experienced at least 1 SAE.
- One death due to bacterial sepsis occurred 25 days after the second infusion of 5 mg/kg infliximab. Serious infections included sepsis, and abscesses. In Study I, 2.7% of patients receiving infliximab 5 mg/kg every 8 weeks through 1 year of maintenance treatment experienced at least 1 serious infection. In Study II, 1.0% and 1.3% of patients receiving infliximab 3 mg/kg and 5 mg/kg, respectively, through 1 year of treatment experienced at least 1 serious infection. The most common serious infection (requiring hospitalization) was abscess (skin, throat, and peri-rectal) reported by 5 (0.7%) patients in the 5 mg/kg infliximab group. Two active cases of tuberculosis were reported: 6 weeks and 34 weeks after starting infliximab.
- In the placebo-controlled portion of the psoriasis studies, 7 of 1123 patients who received infliximab at any dose were diagnosed with at least one NMSC compared to 0 of 334 patients who received placebo.
- In the psoriasis studies, 1% (15/1373) of patients experienced serum sickness or a combination of arthralgia and/or myalgia with fever, and/or rash, usually early in the treatment course. Of these patients, 6 required hospitalization due to fever, severe myalgia, arthralgia, swollen joints, and immobility.
- Safety data are available from 4779 infliximab-treated adult patients, including 1304 with rheumatoid arthritis, 1106 with Crohn's disease, 484 with ulcerative colitis, 202 with ankylosing spondylitis, 293 with psoriatic arthritis, 1373 with plaque psoriasis and 17 with other conditions. Adverse reactions reported in ≥5% of all patients with rheumatoid arthritis receiving 4 or more infusions are in Table 2. The types and frequencies of adverse reactions observed were similar in infliximab-treated rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis and Crohn's disease patients except for abdominal pain, which occurred in 26% of infliximab-treated patients with Crohn's disease. In the Crohn's disease studies, there were insufficient numbers and duration of follow-up for patients who never received infliximab to provide meaningful comparisons.
The most common serious adverse reactions observed in clinical trials were infections . Other serious, medically relevant adverse reactions ≥0.2% or clinically significant adverse reactions by body system were as follows:
- Body as a whole: Allergic reaction, edema
- Blood: Pancytopenia
- Cardiovascular: Hypotension
- Gastrointestinal: Constipation, intestinal obstruction
- Central and Peripheral Nervous: Dizziness
- Heart Rate and Rhythm: Bradycardia
- Liver and Biliary: Hepatitis
- Metabolic and Nutritional: Dehydration
- Platelet, Bleeding and Clotting: Thrombocytopenia
- Neoplasms: Lymphoma
- Red Blood Cell: Anemia, hemolytic anemia
- Resistance Mechanism: Cellulitis, sepsis, serum sickness, sarcoidosis
- Respiratory: Lower respiratory tract infection (including pneumonia), pleurisy, pulmonary edema
- Skin and Appendages: Increased sweating
- Vascular (Extracardiac): Thrombophlebitis
- White Cell and Reticuloendothelial: Leukopenia, lymphadenopathy
### Adverse Reactions in Pediatric Patients
- There were some differences in the adverse reactions observed in the pediatric patients receiving infliximab compared to those observed in adults with Crohn's disease. These differences are discussed in the following paragraphs.
- The following adverse reactions were reported more commonly in 103 randomized pediatric Crohn's disease patients administered 5 mg/kg infliximab through 54 weeks than in 385 adult Crohn's disease patients receiving a similar treatment regimen: anemia (11%), leukopenia (9%), flushing (9%), viral infection (8%), neutropenia (7%), bone fracture (7%), bacterial infection (6%), and respiratory tract allergic reaction (6%).
- Infections were reported in 56% of randomized pediatric patients in Study Peds Crohn's and in 50% of adult patients in Study Crohn's I. In Study Peds Crohn's, infections were reported more frequently for patients who received every 8-week as opposed to every 12-week infusions (74% and 38%, respectively), while serious infections were reported for 3 patients in the every 8-week and 4 patients in the every 12-week maintenance treatment group. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was abscess. Pneumonia was reported for 3 patients, (2 in the every 8-week and 1 in the every 12-week maintenance treatment groups). Herpes zoster was reported for 2 patients in the every 8-week maintenance treatment group.
- In Study Peds Crohn's, 18% of randomized patients experienced 1 or more infusion reactions, with no notable difference between treatment groups. Of the 112 patients in Study Peds Crohn's, there were no serious infusion reactions, and 2 patients had non-serious anaphylactoid reactions.
- In Study Peds Crohn's, in which all patients received stable doses of 6-MP, AZA, or MTX, excluding inconclusive samples, 3 of 24 patients had antibodies to infliximab. Although 105 patients were tested for antibodies to infliximab, 81 patients were classified as inconclusive because they could not be ruled as negative due to assay interference by the presence of infliximab in the sample.
- Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 18% of pediatric patients in Crohn's disease clinical trials; 4% had ALT elevations ≥3 × ULN, and 1% had elevations ≥5 × ULN. (Median follow-up was 53 weeks.)
- Overall, the adverse reactions reported in the pediatric ulcerative colitis trial and adult ulcerative colitis (Study UC I and Study UC II) studies were generally consistent. In a pediatric UC trial, the most common adverse reactions were upper respiratory tract infection, pharyngitis, abdominal pain, fever, and headache.
- Infections were reported in 31 (52%) of 60 treated patients in the pediatric UC trial and 22 (37%) required oral or parenteral antimicrobial treatment. The proportion of patients with infections in the pediatric UC trial was similar to that in the pediatric Crohn's disease study (Study Peds Crohn's) but higher than the proportion in the adults' ulcerative colitis studies (Study UC I and Study UC II). The overall incidence of infections in the pediatric UC trial was 13/22 (59%) in the every 8 week maintenance treatment group. Upper respiratory tract infection (7/60 ) and pharyngitis (5/60 ) were the most frequently reported respiratory system infections. Serious infections were reported in 12% (7/60) of all treated patients.
- In the pediatric UC trial, excluding inconclusive samples, 4 of 19 patients had antibodies to infliximab. Although 52 patients were tested, 33 patients were classified as inconclusive because they could not be ruled as negative due to assay interference by the presence of infliximab in the sample.
- Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 17% (10/60) of pediatric patients in the pediatric UC trial; 7% (4/60) had ALT elevations ≥3 × ULN, and 2% (1/60) had elevations ≥5 × ULN (median follow-up was 49 weeks).
- Overall, 8 of 60 (13%) treated patients experienced one or more infusion reactions, including 4 of 22 (18%) patients in the every 8-week treatment maintenance group. No serious infusion reactions were reported.
- In the pediatric UC trial, 45 patients were in the 12 to 17 year age group and 15 in the 6 to 11 year age group. The numbers of patients in each subgroup are too small to make any definitive conclusions about the effect of age on safety events. There were higher proportions of patients with serious adverse events (40% vs. 18%) and discontinuation due to adverse events (40% vs. 16%) in the younger age group than in the older age group. While the proportion of patients with infections was also higher in the younger age group (60% vs. 49%), for serious infections, the proportions were similar in the two age groups (13% in the 6 to 11 year age group vs. 11% in the 12 to 17 year age group). Overall proportions of adverse reactions, including infusion reactions, were similar between the 6 to 11 and 12 to 17 year age groups (13%).
## Postmarketing Experience
Adverse reactions have been reported during post approval use of infliximab in adult and pediatric patients. 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 infliximab exposure.
The following adverse reactions, some with fatal outcome, have been reported during post-approval use of infliximab: neutropenia, interstitial lung disease (including pulmonary fibrosis/interstitial pneumonitis and very rare rapidly progressive disease), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pericardial effusion, systemic and cutaneous vasculitis, erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, peripheral demyelinating disorders (such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy), new onset and worsening psoriasis (all subtypes including pustular, primarily palmoplantar), transverse myelitis, and neuropathies (additional neurologic reactions have also been observed), acute liver failure, jaundice, hepatitis, and cholestasis, serious infections and malignancies, including melanoma and Merkel cell carcinoma.
- In post-marketing experience, cases of anaphylactic reactions, including laryngeal/pharyngeal edema and severe bronchospasm, and seizure have been associated with infliximab administration.
- Cases of myocardial ischemia and myocardial infarction and transient visual loss have also been rarely reported in association with infliximab during or within 2 hours of infusion.
- The following serious adverse reactions have been reported in the post-marketing experience in children: infections (some fatal) including opportunistic infections and tuberculosis, infusion reactions, and hypersensitivity reactions.
- Serious adverse reactions in the post-marketing experience with infliximab in the pediatric population have also included malignancies, including hepatosplenic T-cell lymphomas, transient hepatic enzyme abnormalities, lupus-like syndromes, and the development of autoantibodies.
# Drug Interactions
- An increased risk of serious infections was seen in clinical studies of other TNFα-blocking agents used in combination with anakinra or abatacept, with no added clinical benefit. Because of the nature of the adverse reactions seen with these combinations with TNF-blocker therapy, similar toxicities may also result from the combination of anakinra or abatacept with other TNFα-blocking agents. Therefore, the combination of infliximibe and anakinra or abatacept is not recommended.
- The use of tocilizumab in combination with biological DMARDs such as TNF antagonists, including infliximibe, should be avoided because of the possibility of increased immunosuppression and increased risk of infection.
- The combination of infliximibe with other biological therapeutics used to treat the same conditions as infliximibe is not recommended.
- Specific drug interaction studies, including interactions with MTX, have not been conducted. The majority of patients in rheumatoid arthritis or Crohn's disease clinical studies received one or more concomitant medications. In rheumatoid arthritis, concomitant medications besides MTX were nonsteroidal anti-inflammatory agents (NSAIDs), folic acid, corticosteroids and/or narcotics. Concomitant Crohn's disease medications were antibiotics, antivirals, corticosteroids, 6-MP/AZA and aminosalicylates. In psoriatic arthritis clinical trials, concomitant medications included MTX in approximately half of the patients as well as NSAIDs, folic acid and corticosteroids. Concomitant MTX use may decrease the incidence of anti-infliximab antibody production and increase infliximab concentrations.
- Patients with Crohn's disease who received immunosuppressants tended to experience fewer infusion reactions compared to patients on no immunosuppressants . Serum infliximab concentrations appeared to be unaffected by baseline use of medications for the treatment of Crohn's disease including corticosteroids, antibiotics (metronidazole or ciprofloxacin) and aminosalicylates.
- The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, IL-1, IL-6, IL-10, IFN) during chronic inflammation. Therefore, it is expected that for a molecule that antagonizes cytokine activity, such as infliximab, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of infliximibe in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.
- It is recommended that live vaccines not be given concurrently with infliximibe.
- It is recommended that therapeutic infectious agents not be given concurrently with infliximibe.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- It is not known whether infliximab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Infliximab should be given to a pregnant woman only if clearly needed. Because infliximab does not cross-react with TNFα in species other than humans and chimpanzees, animal reproduction studies have not been conducted with infliximab. No evidence of maternal toxicity, embryotoxicity or teratogenicity was observed in a developmental toxicity study conducted in mice using an analogous antibody that selectively inhibits the functional activity of mouse TNFα. Doses of 10 to 15 mg/kg in pharmacodynamic animal models with the anti-TNF analogous antibody produced maximal pharmacologic effectiveness. Doses up to 40 mg/kg were shown to produce no adverse effects in animal reproduction studies.
- As with other IgG antibodies, infliximab crosses the placenta and has been detected up to 6 months in the serum of infants born to female patients treated with infliximab during pregnancy. Consequently, these infants may be at increased risk of infection, and caution is advised in the administration of live vaccines to these infants
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Infliximab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Infliximab during labor and delivery.
### Nursing Mothers
- It is not known whether infliximab is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from infliximab, women should not breast-feed their infants while taking infliximab. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
The safety and effectiveness of infliximibe have been established in pediatric patients 6 to 17 years of age for induction and maintenance treatment of Crohn's disease or ulcerative colitis. However, infliximibe has not been studied in children with Crohn's disease or ulcerative colitis <6 years of age.
- Infliximibe is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy.
- Infliximibe has been studied only in combination with conventional immunosuppressive therapy in pediatric Crohn's disease. The longer term (greater than 1 year) safety and effectiveness of infliximibe in pediatric Crohn's disease patients have not been established in clinical trials.
- The safety and effectiveness of infliximibe for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients aged 6 years and older with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy are supported by evidence from adequate and well-controlled studies of infliximibe in adults. Additional safety and pharmacokinetic data were collected in 60 pediatric patients aged 6 years and older. The effectiveness of infliximibe in inducing and maintaining mucosal healing could not be established. Although 41 patients had a Mayo endoscopy subscore of 0 or 1 at the Week 8 endoscopy, the induction phase was open-label and lacked a control group. Only 9 patients had an optional endoscopy at Week 54.
- In the pediatric UC trial, approximately half of the patients were on concomitant immunomodulators (AZA, 6-MP, MTX) at study start. Due to the risk of HSTCL, a careful risk-benefit assessment should be made when infliximibe is used in combination with other immunosuppressants.
- The longer term (greater than 1 year) safety and effectiveness of infliximibe in pediatric ulcerative colitis patients have not been established in clinical trials.
- The safety and efficacy of infliximibe in patients with juvenile rheumatoid arthritis (JRA) were evaluated in a multicenter, randomized, placebo-controlled, double-blind study for 14 weeks, followed by a double-blind, all-active treatment extension, for a maximum of 44 weeks. Patients with active JRA between the ages of 4 and 17 years who had been treated with MTX for at least 3 months were enrolled. Concurrent use of folic acid, oral corticosteroids (≤0.2 mg/kg/day of prednisone or equivalent), NSAIDs, and/or disease modifying antirheumatic drugs (DMARDs) was permitted.
- Doses of 3 mg/kg infliximibe or placebo were administered intravenously at Weeks 0, 2 and 6. Patients randomized to placebo crossed-over to receive 6 mg/kg infliximibe E at Weeks 14, 16, and 20, and then every 8 weeks through Week 44. Patients who completed the study continued to receive open-label treatment with infliximibe for up to 2 years in a companion extension study.
- The study failed to establish the efficacy of infliximibe in the treatment of JRA. Key observations in the study included a high placebo response rate and a higher rate of immunogenicity than what has been observed in adults. Additionally, a higher rate of clearance of infliximab was observed than had been observed in adults.
- A total of 60 patients with JRA were treated with doses of 3 mg/kg and 57 patients were treated with doses of 6 mg/kg. The proportion of patients with infusion reactions who received 3 mg/kg infliximibe was 35% (21/60) over 52 weeks compared with 18% (10/57) in patients who received 6 mg/kg over 38 weeks. The most common infusion reactions reported were vomiting, fever, headache, and hypotension. In the 3 mg/kg infliximibe group, 4 patients had a serious infusion reaction and 3 patients reported a possible anaphylactic reaction (2 of which were among the serious infusion reactions). In the 6 mg/kg infliximibe group, 2 patients had a serious infusion reaction, 1 of whom had a possible anaphylactic reaction. Two of the 6 patients who experienced serious infusion reactions received infliximibe by rapid infusion (duration of less than 2 hours). Antibodies to infliximab developed in 38% (20/53) of patients who received 3 mg/kg infliximibe compared with 12% (6/49) of patients who received 6 mg/kg.
- A total of 68% (41/60) of patients who received 3 mg/kg infliximibe in combination with MTX experienced an infection over 52 weeks compared with 65% (37/57) of patients who received 6 mg/kg infliximibe in combination with MTX over 38 weeks. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was pneumonia. Other notable infections included primary varicella infection in 1 patient and herpes zoster in 1 patient.
### Geriatic Use
In rheumatoid arthritis and plaque psoriasis clinical trials, no overall differences were observed in effectiveness or safety in 181 patients with rheumatoid arthritis and 75 patients with plaque psoriasis, aged 65 or older who received infliximibe , compared to younger patients - although the incidence of serious adverse reactions in patients aged 65 or older was higher in both infliximibe and control groups compared to younger patients. In Crohn's disease, ulcerative colitis, ankylosing spondylitis and psoriatic arthritis studies, there were insufficient numbers of patients aged 65 and over to determine whether they respond differently from patients aged 18 to 65. There is a greater incidence of infections in the elderly population in general. The incidence of serious infections in infliximibe-treated patients 65 years and older was greater than in those under 65 years of age; therefore caution should be used in treating the elderl
### Gender
There is no FDA guidance on the use of Infliximab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Infliximab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Infliximab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Infliximab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Infliximab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Infliximab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
- Infliximab is intended for use under the guidance and supervision of a physician. The reconstituted infusion solution should be prepared by a trained medical professional using aseptic technique by the following procedure:
- Calculate the dose, total volume of reconstituted infliximab solution required and the number of infliximab vials needed. Each infliximab vial contains 100 mg of the infliximab antibody.
- Reconstitute each infliximab vial with 10 mL of Sterile Water for Injection, USP, using a syringe equipped with a 21-gauge or smaller needle as follows: Remove the flip-top from the vial and wipe the top with an alcohol swab. Insert the syringe needle into the vial through the center of the rubber stopper and direct the stream of Sterile Water for Injection, USP, to the glass wall of the vial. Gently swirl the solution by rotating the vial to dissolve the lyophilized powder. Avoid prolonged or vigorous agitation. Do not shake. Foaming of the solution on reconstitution is not unusual. Allow the reconstituted solution to stand for 5 minutes. The solution should be colorless to light yellow and opalescent, and the solution may develop a few translucent particles as infliximab is a protein. Do not use if the lyophilized cake has not fully dissolved or if opaque particles, discoloration, or other foreign particles are present.
- Dilute the total volume of the reconstituted infliximab solution dose to 250 mL with sterile 0.9% Sodium Chloride Injection, USP, by withdrawing a volume equal to the volume of reconstituted infliximab from the 0.9% Sodium Chloride Injection, USP, 250 mL bottle or bag. Slowly add the total volume of reconstituted infliximab solution to the 250 mL infusion bottle or bag. Gently mix. The resulting infusion concentration should range between 0.4 mg/mL and 4 mg/mL.
- The infliximab infusion should begin within 3 hours of reconstitution and dilution. The infusion must be administered over a period of not less than 2 hours and must use an infusion set with an in-line, sterile, non-pyrogenic, low-protein-binding filter (pore size of 1.2 µm or less). The vials do not contain antibacterial preservatives. Therefore, any unused portion of the infusion solution should not be stored for reuse.
- No physical biochemical compatibility studies have been conducted to evaluate the co-administration of infliximab with other agents. infliximab should not be infused concomitantly in the same intravenous line with other agents.
- Parenteral drug products should be inspected visually before and after reconstitution for particulate matter and discoloration prior to administration, whenever solution and container permit. If visibly opaque particles, discoloration or other foreign particulates are observed, the solution should not be used.
### Monitoring
Prior to initiating infliximab and periodically during therapy, patients should be evaluated for active tuberculosis and tested for latent infection.
# IV Compatibility
No physical biochemical compatibility studies have been conducted to evaluate the co-administration of infliximab with other agents. infliximab should not be infused concomitantly in the same intravenous line with other agents.
# Overdosage
Single doses up to 20 mg/kg have been administered without any direct toxic effect. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.
# Pharmacology
## Mechanism of Action
Infliximab neutralizes the biological activity of TNFα by binding with high affinity to the soluble and transmembrane forms of TNFα and inhibits binding of TNFα with its receptors. Infliximab does not neutralize TNFβ (lymphotoxin-α), a related cytokine that utilizes the same receptors as TNFα. Biological activities attributed to TNFα include: induction of pro-inflammatory cytokines such as interleukins (IL) 1 and 6, enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes, activation of neutrophil and eosinophil functional activity, induction of acute phase reactants and other liver proteins, as well as tissue degrading enzymes produced by synoviocytes and/or chondrocytes. Cells expressing transmembrane TNFα bound by infliximab can be lysed in vitro or in vivo. Infliximab inhibits the functional activity of TNFα in a wide variety of in vitro bioassays utilizing human fibroblasts, endothelial cells, neutrophils, B and T- lymphocytes and epithelial cells. The relationship of these biological response markers to the mechanism(s) by which infliximab exerts its clinical effects is unknown. Anti-TNFα antibodies reduce disease activity in the cotton-top tamarin colitis model, and decrease synovitis and joint erosions in a murine model of collagen-induced arthritis. Infliximab prevents disease in transgenic mice that develop polyarthritis as a result of constitutive expression of human TNFα, and when administered after disease onset, allows eroded joints to heal.
## Structure
Infliximab, the active ingredient in infliximab, is a chimeric IgG1κ monoclonal antibody (composed of human constant and murine variable regions) specific for human tumor necrosis factor-alpha (TNFα). It has a molecular weight of approximately 149.1 kilodaltons. Infliximab is produced by a recombinant cell line cultured by continuous perfusion and is purified by a series of steps that includes measures to inactivate and remove viruses.
Infliximab is supplied as a sterile, white, lyophilized powder for intravenous infusion. Following reconstitution with 10 mL of Sterile Water for Injection, USP, the resulting pH is approximately 7.2. Each single-use vial contains 100 mg infliximab, 500 mg sucrose, 0.5 mg polysorbate 80, 2.2 mg monobasic sodium phosphate, monohydrate, and 6.1 mg dibasic sodium phosphate, dihydrate. No preservatives are present.
## Pharmacodynamics
Elevated concentrations of TNFα have been found in involved tissues and fluids of patients with rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis. In rheumatoid arthritis, treatment with infliximab reduced infiltration of inflammatory cells into inflamed areas of the joint as well as expression of molecules mediating cellular adhesion , chemoattraction and tissue degradation . In Crohn's disease, treatment with infliximab reduced infiltration of inflammatory cells and TNFα production in inflamed areas of the intestine, and reduced the proportion of mononuclear cells from the lamina propria able to express TNFα and interferon. After treatment with infliximab, patients with rheumatoid arthritis or Crohn's disease exhibited decreased levels of serum IL-6 and C-reactive protein (CRP) compared to baseline. Peripheral blood lymphocytes from infliximab-treated patients showed no significant decrease in number or in proliferative responses to in vitro mitogenic stimulation when compared to cells from untreated patients. In psoriatic arthritis, treatment with infliximab resulted in a reduction in the number of T-cells and blood vessels in the synovium and psoriatic skin lesions as well as a reduction of macrophages in the synovium. In plaque psoriasis, infliximab treatment may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which infliximab exerts its clinical effects is unknown.
## Pharmacokinetics
In adults, single intravenous (IV) infusions of 3 mg/kg to 20 mg/kg showed a linear relationship between the dose administered and the maximum serum concentration. The volume of distribution at steady state was independent of dose and indicated that infliximab was distributed primarily within the vascular compartment. Pharmacokinetic results for single doses of 3 mg/kg to 10 mg/kg in rheumatoid arthritis, 5 mg/kg in Crohn's disease, and 3 mg/kg to 5 mg/kg in plaque psoriasis indicate that the median terminal half-life of infliximab is 7.7 to 9.5 days.
Following an initial dose of infliximab, repeated infusions at 2 and 6 weeks resulted in predictable concentration-time profiles following each treatment. No systemic accumulation of infliximab occurred upon continued repeated treatment with 3 mg/kg or 10 mg/kg at 4- or 8-week intervals. Development of antibodies to infliximab increased infliximab clearance. At 8 weeks after a maintenance dose of 3 to 10 mg/kg of infliximab, median infliximab serum concentrations ranged from approximately 0.5 to 6 mcg/mL; however, infliximab concentrations were not detectable (<0.1 mcg/mL) in patients who became positive for antibodies to infliximab. No major differences in clearance or volume of distribution were observed in patient subgroups defined by age, weight, or gender. It is not known if there are differences in clearance or volume of distribution in patients with marked impairment of hepatic or renal function.
Infliximab pharmacokinetic characteristics (including peak and trough concentrations and terminal half-life) were similar in pediatric (aged 6 to 17 years) and adult patients with Crohn's disease or ulcerative colitis following the administration of 5 mg/kg infliximab.
Population pharmacokinetic analysis showed that in children with juvenile rheumatoid arthritis (JRA) with a body weight of up to 35 kg receiving 6 mg/kg infliximab and children with JRA with body weight greater than 35 kg up to adult body weight receiving 3mg/kg infliximab, the steady state area under the concentration curve (AUCss) was similar to that observed in adults receiving 3 mg/kg of infliximab.
## Nonclinical Toxicology
The significance of the results of nonclinical studies for human risk is unknown. A repeat dose toxicity study was conducted with mice given cV1q anti-mouse TNFα to evaluate tumorigenicity. CV1q is an analogous antibody that inhibits the function of TNFα in mice. Animals were assigned to 1 of 3 dose groups: control, 10 mg/kg or 40 mg/kg cV1q given weekly for 6 months. The weekly doses of 10 mg/kg and 40 mg/kg are 2 and 8 times, respectively, the human dose of 5 mg/kg for Crohn's disease. Results indicated that cV1q did not cause tumorigenicity in mice. No clastogenic or mutagenic effects of infliximab were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively. Chromosomal aberrations were not observed in an assay performed using human lymphocytes. It is not known whether infliximab can impair fertility in humans. No impairment of fertility was observed in a fertility and general reproduction toxicity study with the analogous mouse antibody used in the 6-month chronic toxicity study.
# Clinical Studies
### Crohn's Disease
The safety and efficacy of single and multiple doses of infliximab were assessed in 2 randomized, double-blind, placebo-controlled clinical studies in 653 patients with moderate to severely active Crohn's disease with an inadequate response to prior conventional therapies. Concomitant stable doses of aminosalicylates, corticosteroids and/or immunomodulatory agents were permitted and 92% of patients continued to receive at least one of these medications.
In the single-dose trial of 108 patients, 16% (4/25) of placebo patients achieved a clinical response (decrease in CDAI ≥70 points) at Week 4 vs. 81% (22/27) of patients receiving 5 mg/kg infliximab (p<0.001, two-sided, Fisher's Exact test). Additionally, 4% (1/25) of placebo patients and 48% (13/27) of patients receiving 5 mg/kg infliximab achieved clinical remission (CDAI<150) at Week 4.
In a multidose trial (ACCENT I ), 545 patients received 5 mg/kg at Week 0 and were then randomized to one of three treatment groups; the placebo maintenance group received placebo at Weeks 2 and 6, and then every 8 weeks; the 5 mg/kg maintenance group received 5 mg/kg at Weeks 2 and 6, and then every 8 weeks; and the 10 mg/kg maintenance group received 5 mg/kg at Weeks 2 and 6, and then 10 mg/kg every 8 weeks. Patients in response at Week 2 were randomized and analyzed separately from those not in response at Week 2. Corticosteroid taper was permitted after Week 6.
At Week 2, 57% (311/545) of patients were in clinical response. At Week 30, a significantly greater proportion of these patients in the 5 mg/kg and 10 mg/kg maintenance groups achieved clinical remission compared to patients in the placebo maintenance group (Table 3).
Additionally, a significantly greater proportion of patients in the 5 mg/kg and 10 mg/kg infliximab maintenance groups were in clinical remission and were able to discontinue corticosteroid use compared to patients in the placebo maintenance group at Week 54 (Table 3).
Patients in the infliximab maintenance groups (5 mg/kg and 10 mg/kg) had a longer time to loss of response than patients in the placebo maintenance group (Figure 1). At Weeks 30 and 54, significant improvement from baseline was seen among the 5 mg/kg and 10 mg/kg infliximab-treated groups compared to the placebo group in the disease-specific inflammatory bowel disease questionnaire (IBDQ), particularly the bowel and systemic components, and in the physical component summary score of the general health-related quality of life questionnaire SF-36.
In a subset of 78 patients who had mucosal ulceration at baseline and who participated in an endoscopic substudy, 13 of 43 patients in the infliximab maintenance group had endoscopic evidence of mucosal healing compared to 1 of 28 patients in the placebo group at Week 10. Of the infliximab-treated patients showing mucosal healing at Week 10, 9 of 12 patients also showed mucosal healing at Week 54.
Patients who achieved a response and subsequently lost response were eligible to receive infliximab on an episodic basis at a dose that was 5 mg/kg higher than the dose to which they were randomized. The majority of such patients responded to the higher dose. Among patients who were not in response at Week 2, 59% (92/157) of infliximab maintenance patients responded by Week 14 compared to 51% (39/77) of placebo maintenance patients. Among patients who did not respond by Week 14, additional therapy did not result in significantly more responses.
The safety and efficacy of infliximab were assessed in 2 randomized, double-blind, placebo-controlled studies in patients with fistulizing Crohn's disease with fistula(s) that were of at least 3 months duration. Concurrent use of stable doses of corticosteroids, 5-aminosalicylates, antibiotics, MTX, 6-mercaptopurine (6-MP) and/or azathioprine (AZA) was permitted.
In the first trial, 94 patients received 3 doses of either placebo or infliximab at Weeks 0, 2 and 6. Fistula response (≥50% reduction in number of enterocutaneous fistulas draining upon gentle compression on at least 2 consecutive visits without an increase in medication or surgery for Crohn's disease) was seen in 68% (21/31) of patients in the 5 mg/kg infliximab group (P=0.002) and 56% (18/32) of patients in the 10 mg/kg infliximab group (P=0.021) vs. 26% (8/31) of patients in the placebo arm. The median time to onset of response and median duration of response in infliximab-treated patients was 2 and 12 weeks, respectively. Closure of all fistulas was achieved in 52% of infliximab-treated patients compared with 13% of placebo-treated patients (P<0.001).
In the second trial (ACCENT II ), patients who were enrolled had to have at least 1 draining enterocutaneous (perianal, abdominal) fistula. All patients received 5 mg/kg infliximab at Weeks 0, 2 and 6. Patients were randomized to placebo or 5 mg/kg infliximab maintenance at Week 14. Patients received maintenance doses at Week 14 and then every 8 weeks through Week 46. Patients who were in fistula response (fistula response was defined the same as in the first trial) at both Weeks 10 and 14 were randomized separately from those not in response. The primary endpoint was time from randomization to loss of response among those patients who were in fistula response.
Among the randomized patients (273 of the 296 initially enrolled), 87% had perianal fistulas and 14% had abdominal fistulas. Eight percent also had rectovaginal fistulas. Greater than 90% of the patients had received previous immunosuppressive and antibiotic therapy.
At Week 14, 65% (177/273) of patients were in fistula response. Patients randomized to infliximab maintenance had a longer time to loss of fistula response compared to the placebo maintenance group (Figure 2). At Week 54, 38% (33/87) of infliximab-treated patients had no draining fistulas compared with 22% (20/90) of placebo-treated patients (P=0.02). Compared to placebo maintenance, patients on infliximab maintenance had a trend toward fewer hospitalizations.
Patients who achieved a fistula response and subsequently lost response were eligible to receive infliximab maintenance therapy at a dose that was 5 mg/kg higher than the dose to which they were randomized. Of the placebo maintenance patients, 66% (25/38) responded to 5 mg/kg infliximab, and 57% (12/21) of infliximab maintenance patients responded to 10 mg/kg.
Patients who had not achieved a response by Week 14 were unlikely to respond to additional doses of infliximab.
Similar proportions of patients in either group developed new fistulas (17% overall) and similar numbers developed abscesses (15% overall).
### Pediatric Crohn's Disease
The safety and efficacy of infliximab were assessed in a randomized, open-label study (Study Peds Crohn's) in 112 pediatric patients aged 6 to 17 years old with moderately to severely active Crohn's disease and an inadequate response to conventional therapies. The median age was 13 years and the median Pediatric Crohn's Disease Activity Index (PCDAI) was 40 (on a scale of 0 to 100). All patients were required to be on a stable dose of 6-MP, AZA, or MTX; 35% were also receiving corticosteroids at baseline.
All patients received induction dosing of 5 mg/kg infliximab at Weeks 0, 2, and 6. At Week 10, 103 patients were randomized to a maintenance regimen of 5 mg/kg infliximab given either every 8 weeks or every 12 weeks.
At Week 10, 88% of patients were in clinical response (defined as a decrease from baseline in the PCDAI score of ≥15 points and total PCDAI score of ≤30 points), and 59% were in clinical remission (defined as PCDAI score of ≤10 points).
The proportion of pediatric patients achieving clinical response at Week 10 compared favorably with the proportion of adults achieving a clinical response in Study Crohn's I. The study definition of clinical response in Study Peds Crohn's was based on the PCDAI score, whereas the CDAI score was used in the adult Study Crohn's I.
At both Week 30 and Week 54, the proportion of patients in clinical response was greater in the every 8-week treatment group than in the every 12-week treatment group (73% vs. 47% at Week 30, and 64% vs. 33% at Week 54). At both Week 30 and Week 54, the proportion of patients in clinical remission was also greater in the every 8-week treatment group than in the every 12-week treatment group (60% vs. 35% at Week 30, and 56% vs. 24% at Week 54), table below.
For patients in Study Peds Crohn's receiving corticosteroids at baseline, the proportion of patients able to discontinue corticosteroids while in remission at Week 30 was 46% for the every 8-week maintenance group and 33% for the every 12-week maintenance group. At Week 54, the proportion of patients able to discontinue corticosteroids while in remission was 46% for the every 8-week maintenance group and 17% for the every 12-week maintenance group.
### Ulcerative Colitis
The safety and efficacy of infliximab were assessed in 2 randomized, double-blind, placebo-controlled clinical studies in 728 patients with moderately to severely active ulcerative colitis (UC) (Mayo score5 6 to 12 , Endoscopy subscore ≥2) with an inadequate response to conventional oral therapies (Studies UC I and UC II). Concomitant treatment with stable doses of aminosalicylates, corticosteroids and/or immunomodulatory agents was permitted. Corticosteroid taper was permitted after Week 8. Patients were randomized at week 0 to receive either placebo, 5 mg/kg infliximab or 10 mg/kg infliximab at Weeks 0, 2, 6, and every 8 weeks thereafter through Week 46 in Study UC I, and at Weeks 0, 2, 6, and every 8 weeks thereafter through Week 22 in Study UC II. In Study UC II, patients were allowed to continue blinded therapy to Week 46 at the investigator's discretion.
Patients in Study UC I had failed to respond or were intolerant to oral corticosteroids, 6-MP, or AZA. Patients in Study UC II had failed to respond or were intolerant to the above treatments and/or aminosalicylates. Similar proportions of patients in Studies UC I and UC II were receiving corticosteroids (61% and 51%, respectively), 6-MP/AZA (49% and 43%) and aminosalicylates (70% and 75%) at baseline. More patients in Study UC II than UC I were taking solely aminosalicylates for UC (26% vs. 11%, respectively). Clinical response was defined as a decrease from baseline in the Mayo score by ≥30% and ≥3 points, accompanied by a decrease in the rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1.
In both Study UC I and Study UC II, greater percentages of patients in both infliximab groups achieved clinical response, clinical remission and mucosal healing than in the placebo group. Each of these effects was maintained through the end of each trial (Week 54 in Study UC I, and Week 30 in Study UC II). In addition, a greater proportion of patients in infliximab groups demonstrated sustained response and sustained remission than in the placebo groups (table below).
Of patients on corticosteroids at baseline, greater proportions of patients in the infliximab treatment groups were in clinical remission and able to discontinue corticosteroids at Week 30 compared with the patients in the placebo treatment groups (22% in infliximab treatment groups vs. 10% in placebo group in Study UC I; 23% in infliximab treatment groups vs. 3% in placebo group in Study UC II). In Study UC I, this effect was maintained through Week 54 (21% in infliximab treatment groups vs. 9% in placebo group). The infliximab-associated response was generally similar in the 5 mg/kg and 10 mg/kg dose groups.
The improvement with infliximab was consistent across all Mayo subscores through Week 54 (Study UC I shown in Table 6; Study UC II through Week 30 was similar).
### Pediatric Ulcerative Colitis
The safety and effectiveness of infliximab for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients aged 6 years and older with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy are supported by evidence from adequate and well-controlled studies of infliximab in adults. Additional safety and pharmacokinetic data were collected in an open-label pediatric UC trial in 60 pediatric patients aged 6 through 17 years (median age 14.5 years) with moderately to severely active ulcerative colitis (Mayo score of 6 to 12; Endoscopic subscore ≥ 2) and an inadequate response to conventional therapies. At baseline, the median Mayo score was 8, 53% of patients were receiving immunomodulator therapy (6-MP/AZA/MTX), and 62% of patients were receiving corticosteroids (median dose 0.5 mg/kg/day in prednisone equivalents). Discontinuation of immunomodulators and corticosteroid taper were permitted after Week 0.
All patients received induction dosing of 5 mg/kg infliximab at Weeks 0, 2, and 6. Patients who did not respond to infliximab at Week 8 received no further infliximab and returned for safety follow-up. At Week 8, 45 patients were randomized to a maintenance regimen of 5 mg/kg infliximab given either every 8 weeks through Week 46 or every 12 weeks through Week 42. Patients were allowed to change to a higher dose and/or more frequent administration schedule if they experienced loss of response.
Clinical response at Week 8 was defined as a decrease from baseline in the Mayo score by ≥ 30% and ≥ 3 points, including a decrease in the rectal bleeding subscore by ≥ 1 points or achievement of a rectal bleeding subscore of 0 or 1.
Clinical remission at Week 8 was measured by the Mayo score, defined as a Mayo score of ≤2 points with no individual subscore >1. Clinical remission was also assessed at Week 8 and Week 54 using the Pediatric Ulcerative Colitis Activity Index (PUCAI)6 score and was defined by a PUCAI score of <10 points.
Endoscopies were performed at baseline and at Week 8. A Mayo endoscopy subscore of 0 indicated normal or inactive disease and a subscore of 1 indicated mild disease (erythema, decreased vascular pattern, or mild friability).
Of the 60 patients treated, 44 were in clinical response at Week 8. Of 32 patients taking concomitant immunomodulators at baseline, 23 achieved clinical response at Week 8, compared to 21 of 28 of those not taking concomitant immunomodulators at baseline. At Week 8, 24 of 60 patients were in clinical remission as measured by the Mayo score and 17 of 51 patients were in remission as measured by the PUCAI score.
At Week 54, 8 of 21 patients in the every 8-week maintenance group and 4 of 22 patients in the every 12-week maintenance group achieved remission as measured by the PUCAI score.
During maintenance phase, 23 of 45 randomized patients (9 in the every 8-week group and 14 in the every 12-week group) required an increase in their dose and/or increase in frequency of infliximab administration due to loss of response. Nine of the 23 patients who required a change in dose had achieved remission at Week 54. Seven of those patients received the 10 mg/kg every 8-week dosing.
### Rheumatoid Arthritis
The safety and efficacy of infliximab were assessed in 2 multicenter, randomized, double-blind, pivotal trials: ATTRACT (Study RA I) and ASPIRE (Study RA II). Concurrent use of stable doses of folic acid, oral corticosteroids (≤10 mg/day) and/or non-steroidal anti-inflammatory drugs (NSAIDs) was permitted.
Study RA I was a placebo-controlled study of 428 patients with active rheumatoid arthritis despite treatment with MTX. Patients enrolled had a median age of 54 years, median disease duration of 8.4 years, median swollen and tender joint count of 20 and 31 respectively, and were on a median dose of 15 mg/wk of MTX. Patients received either placebo + MTX or one of 4 doses/schedules of infliximab + MTX: 3 mg/kg or 10 mg/kg of infliximab by IV infusion at Weeks 0, 2 and 6 followed by additional infusions every 4 or 8 weeks in combination with MTX.
Study RA II was a placebo-controlled study of 3 active treatment arms in 1004 MTX naive patients of 3 or fewer years' duration active rheumatoid arthritis. Patients enrolled had a median age of 51 years with a median disease duration of 0.6 years, median swollen and tender joint count of 19 and 31, respectively, and >80% of patients had baseline joint erosions. At randomization, all patients received MTX (optimized to 20 mg/wk by Week 8) and either placebo, 3 mg/kg or 6 mg/kg infliximab at Weeks 0, 2, and 6 and every 8 weeks thereafter.
Data on use of infliximab without concurrent MTX are limited.
In Study RA I, all doses/schedules of infliximab + MTX resulted in improvement in signs and symptoms as measured by the American College of Rheumatology response criteria (ACR 20) with a higher percentage of patients achieving an ACR 20, 50 and 70 compared to placebo + MTX (Table 7). This improvement was observed at Week 2 and maintained through Week 102. Greater effects on each component of the ACR 20 were observed in all patients treated with infliximab + MTX compared to placebo + MTX (Table 8). More patients treated with infliximab reached a major clinical response than placebo-treated patients (Table 7).
In Study RA II, after 54 weeks of treatment, both doses of infliximab + MTX resulted in statistically significantly greater response in signs and symptoms compared to MTX alone as measured by the proportion of patients achieving ACR 20, 50 and 70 responses (Table 7). More patients treated with infliximab reached a major clinical response than placebo-treated patients (Table 7).
Structural damage in both hands and feet was assessed radiographically at Week 54 by the change from baseline in the van der Heijde-modified Sharp (vdH-S) score, a composite score of structural damage that measures the number and size of joint erosions and the degree of joint space narrowing in hands/wrists and feet.3
In Study RA I, approximately 80% of patients had paired X-ray data at 54 weeks and approximately 70% at 102 weeks. The inhibition of progression of structural damage was observed at 54 weeks (Table 9) and maintained through 102 weeks.
In Study RA II, >90% of patients had at least 2 evaluable X-rays. Inhibition of progression of structural damage was observed at Weeks 30 and 54 (Table 9) in the infliximab + MTX groups compared to MTX alone. Patients treated with infliximab + MTX demonstrated less progression of structural damage compared to MTX alone, whether baseline acute-phase reactants (ESR and CRP) were normal or elevated: patients with elevated baseline acute-phase reactants treated with MTX alone demonstrated a mean progression in vdH-S score of 4.2 units compared to patients treated with infliximab + MTX who demonstrated 0.5 units of progression; patients with normal baseline acute phase reactants treated with MTX alone demonstrated a mean progression in vdH-S score of 1.8 units compared to infliximab + MTX who demonstrated 0.2 units of progression. Of patients receiving infliximab + MTX, 59% had no progression (vdH-S score ≤ 0 unit) of structural damage compared to 45% of patients receiving MTX alone. In a subset of patients who began the study without erosions, infliximab + MTX maintained an erosion-free state at 1 year in a greater proportion of patients than MTX alone, 79% (77/98) vs. 58% (23/40), respectively (P<0.01). Fewer patients in the infliximab + MTX groups (47%) developed erosions in uninvolved joints compared to MTX alone (59%).
Physical function and disability were assessed using the Health Assessment Questionnaire (HAQ-DI) and the general health-related quality of life questionnaire SF-36.
In Study RA I, all doses/schedules of infliximab + MTX showed significantly greater improvement from baseline in HAQ-DI and SF-36 physical component summary score averaged over time through Week 54 compared to placebo + MTX, and no worsening in the SF-36 mental component summary score. The median (interquartile range) improvement from baseline to Week 54 in HAQ-DI was 0.1 (-0.1, 0.5) for the placebo + MTX group and 0.4 (0.1, 0.9) for infliximab + MTX (p<0.001). Both HAQ-DI and SF-36 effects were maintained through Week 102. Approximately 80% of patients in all doses/schedules of infliximab + MTX remained in the trial through 102 weeks.
In Study RA II, both infliximab treatment groups showed greater improvement in HAQ-DI from baseline averaged over time through Week 54 compared to MTX alone; 0.7 for infliximab + MTX vs. 0.6 for MTX alone (P≤0.001). No worsening in the SF-36 mental component summary score was observed.
### Ankylosing Spondylitis
The safety and efficacy of infliximab were assessed in a randomized, multicenter, double-blind, placebo-controlled study in 279 patients with active ankylosing spondylitis. Patients were between 18 and 74 years of age, and had ankylosing spondylitis as defined by the modified New York criteria for Ankylosing Spondylitis.4 Patients were to have had active disease as evidenced by both a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score >4 (possible range 0–10) and spinal pain >4 (on a Visual Analog Scale of 0–10). Patients with complete ankylosis of the spine were excluded from study participation, and the use of Disease Modifying Anti-Rheumatic Drugs (DMARDs) and systemic corticosteroids were prohibited. Doses of infliximab 5 mg/kg or placebo were administered intravenously at Weeks 0, 2, 6, 12 and 18.
At 24 weeks, improvement in the signs and symptoms of ankylosing spondylitis, as measured by the proportion of patients achieving a 20% improvement in ASAS response criteria (ASAS 20), was seen in 60% of patients in the infliximab-treated group vs. 18% of patients in the placebo group (p<0.001). Improvement was observed at Week 2 and maintained through Week 24 (Figure 3 and Table 10).
At 24 weeks, the proportions of patients achieving a 50% and a 70% improvement in the signs and symptoms of ankylosing spondylitis, as measured by ASAS response criteria (ASAS 50 and ASAS 70, respectively), were 44% and 28%, respectively, for patients receiving infliximab, compared to 9% and 4%, respectively, for patients receiving placebo (P<0.001, infliximab vs. placebo). A low level of disease activity (defined as a value <20 in each of the 4 ASAS response parameters) was achieved in 22% of infliximab-treated patients vs. 1% in placebo-treated patients (P<0.001).
The median improvement from baseline in the general health-related quality-of-life questionnaire SF-36 physical component summary score at Week 24 was 10.2 for the infliximab group vs. 0.8 for the placebo group (P<0.001). There was no change in the SF-36 mental component summary score in either the infliximab group or the placebo group.
Results of this study were similar to those seen in a multicenter double-blind, placebo-controlled study of 70 patients with ankylosing spondylitis.
### Psoriatic Arthritis
Safety and efficacy of infliximab were assessed in a multicenter, double-blind, placebo-controlled study in 200 adult patients with active psoriatic arthritis despite DMARD or NSAID therapy (≥5 swollen joints and ≥5 tender joints) with 1 or more of the following subtypes: arthritis involving DIP joints (n=49), arthritis mutilans (n=3), asymmetric peripheral arthritis (n=40), polyarticular arthritis (n=100), and spondylitis with peripheral arthritis (n=8). Patients also had plaque psoriasis with a qualifying target lesion ≥2 cm in diameter. Forty-six percent of patients continued on stable doses of methotrexate (≤25 mg/week). During the 24-week double-blind phase, patients received either 5 mg/kg infliximab or placebo at Weeks 0, 2, 6, 14, and 22 (100 patients in each group). At Week 16, placebo patients with <10% improvement from baseline in both swollen and tender joint counts were switched to infliximab induction (early escape). At Week 24, all placebo-treated patients crossed over to infliximab induction. Dosing continued for all patients through Week 46.
Treatment with infliximab resulted in improvement in signs and symptoms, as assessed by the ACR criteria, with 58% of infliximab-treated patients achieving ACR 20 at Week 14, compared with 11% of placebo-treated patients (P< 0.001). The response was similar regardless of concomitant use of methotrexate. Improvement was observed as early as Week 2. At 6 months, the ACR 20/50/70 responses were achieved by 54%, 41%, and 27%, respectively, of patients receiving infliximab compared to 16%, 4%, and 2%, respectively, of patients receiving placebo. Similar responses were seen in patients with each of the subtypes of psoriatic arthritis, although few patients were enrolled with the arthritis mutilans and spondylitis with peripheral arthritis subtypes.
Compared to placebo, treatment with infliximab resulted in improvements in the components of the ACR response criteria, as well as in dactylitis and enthesopathy (Table 11). The clinical response was maintained through Week 54. Similar ACR responses were observed in an earlier randomized, placebo-controlled study of 104 psoriatic arthritis patients, and the responses were maintained through 98 weeks in an open-label extension phase.
Improvement in Psoriasis Area and Severity Index (PASI) in psoriatic arthritis patients with baseline body surface area (BSA) ≥3% (n=87 placebo, n=83 infliximab) was achieved at Week 14, regardless of concomitant methotrexate use, with 64% of infliximab-treated patients achieving at least 75% improvement from baseline vs. 2% of placebo-treated patients; improvement was observed in some patients as early as Week 2. At 6 months, the PASI 75 and PASI 90 responses were achieved by 60% and 39%, respectively, of patients receiving infliximab compared to 1% and 0%, respectively, of patients receiving placebo. The PASI response was generally maintained through Week 54.
Structural damage in both hands and feet was assessed radiographically by the change from baseline in the van der Heijde-Sharp (vdH-S) score, modified by the addition of hand DIP joints. The total modified vdH-S score is a composite score of structural damage that measures the number and size of joint erosions and the degree of joint space narrowing (JSN) in the hands and feet. At Week 24, infliximab-treated patients had less radiographic progression than placebo-treated patients (mean change of -0.70 vs. 0.82, P<0.001). infliximab-treated patients also had less progression in their erosion scores (-0.56 vs 0.51) and JSN scores (-0.14 vs 0.31). The patients in the infliximab group demonstrated continued inhibition of structural damage at Week 54. Most patients showed little or no change in the vdH-S score during this 12-month study (median change of 0 in both patients who initially received infliximab or placebo). More patients in the placebo group (12%) had readily apparent radiographic progression compared with the infliximab group (3%).
Physical function status was assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. infliximab-treated patients demonstrated significant improvement in physical function as assessed by HAQ-DI (median percent improvement in HAQ-DI score from baseline to Week 14 and 24 of 43% for infliximab-treated patients vs 0% for placebo-treated patients).
During the placebo-controlled portion of the trial (24 weeks), 54% of infliximab-treated patients achieved a clinically meaningful improvement in HAQ-DI (≥0.3 unit decrease) compared to 22% of placebo-treated patients. infliximab-treated patients also demonstrated greater improvement in the SF-36 physical and mental component summary scores than placebo-treated patients. The responses were maintained for up to 2 years in an open-label extension study.
The safety and efficacy of infliximab were assessed in 3 randomized, double-blind, placebo-controlled studies in patients 18 years of age and older with chronic, stable plaque psoriasis involving ≥10% BSA, a minimum PASI score of 12, and who were candidates for systemic therapy or phototherapy. Patients with guttate, pustular, or erythrodermic psoriasis were excluded from these studies. No concomitant anti-psoriatic therapies were allowed during the study, with the exception of low-potency topical corticosteroids on the face and groin after Week 10 of study initiation.
Study I (EXPRESS) evaluated 378 patients who received placebo or infliximab at a dose of 5 mg/kg at Weeks 0, 2, and 6 (induction therapy), followed by maintenance therapy every 8 weeks. At Week 24, the placebo group crossed over to infliximab induction therapy (5 mg/kg), followed by maintenance therapy every 8 weeks. Patients originally randomized to infliximab continued to receive infliximab 5 mg/kg every 8 weeks through Week 46. Across all treatment groups, the median baseline PASI score was 21 and the baseline Static Physician Global Assessment (sPGA) score ranged from moderate (52% of patients) to marked (36%) to severe (2%). In addition, 75% of patients had a BSA >20%. Seventy-one percent of patients previously received systemic therapy, and 82% received phototherapy.
Study II (EXPRESS II) evaluated 835 patients who received placebo or infliximab at doses of 3 mg/kg or 5 mg/kg at Weeks 0, 2, and 6 (induction therapy). At Week 14, within each infliximab dose group, patients were randomized to either scheduled (every 8 weeks) or as needed (PRN) maintenance treatment through Week 46. At Week 16, the placebo group crossed over to infliximab induction therapy (5 mg/kg), followed by maintenance therapy every 8 weeks. Across all treatment groups, the median baseline PASI score was 18, and 63% of patients had a BSA >20%. Fifty-five percent of patients previously received systemic therapy, and 64% received a phototherapy.
Study III (SPIRIT) evaluated 249 patients who had previously received either psoralen plus ultraviolet A treatment (PUVA) or other systemic therapy for their psoriasis. These patients were randomized to receive either placebo or infliximab at doses of 3 mg/kg or 5 mg/kg at Weeks 0, 2, and 6. At Week 26, patients with a sPGA score of moderate or worse (greater than or equal to 3 on a scale of 0 to 5) received an additional dose of the randomized treatment. Across all treatment groups, the median baseline PASI score was 19, and the baseline sPGA score ranged from moderate (62% of patients) to marked (22%) to severe (3%). In addition, 75% of patients had a BSA >20%. Of the enrolled patients, 114 (46%) received the Week 26 additional dose.
In Studies I, II and III, the primary endpoint was the proportion of patients who achieved a reduction in score of at least 75% from baseline at Week 10 by the PASI (PASI 75). In Study I and Study III, another evaluated outcome included the proportion of patients who achieved a score of "cleared" or "minimal" by the sPGA. The sPGA is a 6-category scale ranging from "5 = severe" to "0 = cleared" indicating the physician's overall assessment of the psoriasis severity focusing on induration, erythema, and scaling. Treatment success, defined as "cleared" or "minimal," consisted of none or minimal elevation in plaque, up to faint red coloration in erythema, and none or minimal fine scale over <5% of the plaque.
Study II also evaluated the proportion of patients who achieved a score of "clear" or "excellent" by the relative Physician's Global Assessment (rPGA). The rPGA is a 6-category scale ranging from "6 = worse" to "1 = clear" that was assessed relative to baseline. Overall lesions were graded with consideration to the percent of body involvement as well as overall induration, scaling, and erythema. Treatment success, defined as "clear" or "excellent," consisted of some residual pinkness or pigmentation to marked improvement (nearly normal skin texture; some erythema may be present). The results of these studies are presented in Table 12.
In Study I, in the subgroup of patients with more extensive psoriasis who had previously received phototherapy, 85% of patients on 5 mg/kg infliximab achieved a PASI 75 at Week 10 compared with 4% of patients on placebo.
In Study II, in the subgroup of patients with more extensive psoriasis who had previously received phototherapy, 72% and 77% of patients on 3 mg/kg and 5 mg/kg infliximab achieved a PASI 75 at Week 10 respectively compared with 1% on placebo. In Study II, among patients with more extensive psoriasis who had failed or were intolerant to phototherapy, 70% and 78% of patients on 3 mg/kg and 5 mg/kg infliximab achieved a PASI 75 at Week 10 respectively, compared with 2% on placebo.
Maintenance of response was studied in a subset of 292 and 297 infliximab-treated patients in the 3 mg/kg and 5 mg/kg groups; respectively, in Study II. Stratified by PASI response at Week 10 and investigational site, patients in the active treatment groups were re-randomized to either a scheduled or as needed maintenance (PRN) therapy, beginning on Week 14.
The groups that received a maintenance dose every 8 weeks appear to have a greater percentage of patients maintaining a PASI 75 through week 50 as compared to patients who received the as-needed or PRN doses, and the best response was maintained with the 5 mg/kg every 8-week dose. These results are shown in Figure 4. At Week 46, when infliximab serum concentrations were at trough level, in the every 8-week dose group, 54% of patients in the 5 mg/kg group compared to 36% in the 3 mg/kg group achieved PASI 75. The lower percentage of PASI 75 responders in the 3 mg/kg every 8-week dose group compared to the 5 mg/kg group was associated with a lower percentage of patients with detectable trough serum infliximab levels. This may be related in part to higher antibody rates. In addition, in a subset of patients who had achieved a response at Week 10, maintenance of response appears to be greater in patients who received infliximab every 8 weeks at the 5 mg/kg dose. Regardless of whether the maintenance doses are PRN or every 8 weeks, there is a decline in response in a subpopulation of patients in each group over time. The results of Study I through Week 50 in the 5 mg/kg every 8 weeks maintenance dose group were similar to the results from Study II.
Efficacy and safety of infliximab treatment beyond 50 weeks have not been evaluated in patients with plaque psoriasis.
# How Supplied
Each infliximab 20 mL vial is individually packaged in a carton. Infliximab is supplied in an accumulator carton containing 10 vials.
- NDC 57894-030-01 100 mg vial
- Each single dose vial contains 100 mg of infliximab for final reconstitution volume of 10 mL.
## Storage
- Infliximab must be refrigerated at 2ºC to 8ºC (36ºF to 46ºF).
- Do not use infliximab beyond the expiration date (Exp) located on the carton and the vial. This product contains no preservative.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients or their caregivers should be advised of the potential benefits and risks of infliximab. Physicians should instruct their patients to read the Medication Guide before starting infliximab therapy and to reread it each time they receive an infusion. It is important that the patient's overall health be assessed at each treatment visit and that any questions resulting from the patient's or their caregiver's reading of the Medication Guide be discussed.
- Immunosuppression: Inform patients that infliximab may lower the ability of their immune system to fight infections. Instruct patients of the importance of contacting their doctors if they develop any symptoms of an infection, including tuberculosis and reactivation of hepatitis B virus infections. Patients should be counseled about the risk of lymphoma and other malignancies while receiving infliximab.
- Other Medical Conditions: Advise patients to report any signs of new or worsening medical conditions such as heart disease, neurological disease, or autoimmune disorders. Advise patients to report any symptoms of a cytopenia such as bruising, bleeding or persistent fever.
# Precautions with Alcohol
Alcohol-Infliximab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Remicade
# Look-Alike Drug Names
- Infliximab - Rituximab
# Drug Shortage Status
Drug Shortage
# Price | Infliximab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2]
# Disclaimer
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# Black Box Warning
# Overview
Infliximab is a tumor necrosis factor blocker that is FDA approved for the treatment of crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash, abdominal pain, nausea, headache, pharyngitis, respiratory tract infection, fatigue, fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing information
- The recommended dose of infliximab is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of adults with moderately to severely active Crohn's disease or fistulizing Crohn's disease. For adult patients who respond and then lose their response, consideration may be given to treatment with 10 mg/kg. Patients who do not respond by Week 14 are unlikely to respond with continued dosing and consideration should be given to discontinue infliximab in these patients.
- Dosing information
- The recommended dose of infliximab is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of adult patients with moderately to severely active ulcerative colitis.
- Dosing Information
- The recommended dose of infliximab is 3 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 3 mg/kg every 8 weeks thereafter for the treatment of moderately to severely active rheumatoid arthritis. infliximab should be given in combination with methotrexate. For patients who have an incomplete response, consideration may be given to adjusting the dose up to 10 mg/kg or treating as often as every 4 weeks bearing in mind that risk of serious infections is increased at higher doses.
- Dosing Information
- The recommended dose of infliximab is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 6 weeks thereafter for the treatment of active ankylosing spondylitis.
- Dosing Information
- The recommended dose of infliximab is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of psoriatic arthritis. infliximab can be used with or without methotrexate.
- Dosing Information
- The recommended dose of infliximab is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of chronic severe (i.e., extensive and/or disabling) plaque psoriasis.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Infliximab in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 3-5 mg/kg, at weeks 0, 2, and 6, followed by infusions administered every 6-8 weeks.[1][2]
- Dosing Information
- Administer IV infusions of 5 mg/kg until disease is controlled.[3]
- Dosing Information
- Administer IV infusions of 1 to 10 mg/kg.[4]
- Dosing Information
- Administer IV infusions of 3 mg/kg at weeks 0, 2, 6, followed by IV infusions every 8 weeks.[5]
- Dosing Information
- Administer IV infusions of 3-5 mg/kg every 4-8 weeks.[6]
- Dosing Information
- Administer IV infusion of 3-6 mg/kg, initially every 2, 4, and 6 weeks, followed by every 4-8 weeks according to treatment response.[7]
- Dosing Information
- Administer IV infusions of 5 mg/kg on the first, fourteenth, and forty-second day, followed by infusions every 8 weeks.[8]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- The recommended dose of infliximab for pediatric patients 6 years and older with moderately to severely active Crohn's disease is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks.
- Dosing information
- The recommended dose of infliximab for pediatric patients 6 years and older with moderately to severely active ulcerative colitis is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Infliximab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Infliximab in pediatric patients.
# Contraindications
- Moderate to severe heart failure.
- Hypersensitivity reaction to infliximab or to inactive components of the product or to any murine proteins.
# Warnings
### Serious Infections
- Patients treated with infliximab are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.
- Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, or parasitic organisms including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis,[] legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF-blockers. Patients have frequently presented with disseminated rather than localized disease.
- Treatment with infliximab should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants such as corticosteroids or methrotexate may be at greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients:
- With chronic or recurrent infection.
- Who have been exposed to tuberculosis.
- With a history of an opportunistic infection.
- Who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis.
- With underlying conditions that may predispose them to infection.
- Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving infliximab, including patients who have previously received treatment for latent or active tuberculosis. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating infliximab and periodically during therapy.
- Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating infliximab, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG).
- Anti-tuberculosis therapy should also be considered prior to initiation of infliximab in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
- Tuberculosis should be strongly considered in patients who develop a new infection during infliximab treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.
- Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with infliximab, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with infliximab.
- Infliximab should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with infliximab should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated.
For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy.
### Malignancies
Malignancies, some fatal, have been reported among children, adolescents and young adults who received treatment with TNF-blocking agents (initiation of therapy ≤ 18 years of age), including infliximab. Approximately half of these cases were lymphomas, including Hodgkin's lymphoma and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (range 1 to 84 months) after the first dose of TNF blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports.
- In the controlled portions of clinical trials of all the TNF-blocking agents, more cases of lymphoma have been observed among patients receiving a TNF blocker compared with control patients. In the controlled and open-label portions of infliximab clinical trials, 5 patients developed lymphomas among 5707 patients treated with infliximab (median duration of follow-up 1.0 years) vs. 0 lymphomas in 1600 control patients (median duration of follow-up 0.4 years). In rheumatoid arthritis patients, 2 lymphomas were observed for a rate of 0.08 cases per 100 patient-years of follow-up, which is approximately three-fold higher than expected in the general population. In the combined clinical trial population for rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 5 lymphomas were observed for a rate of 0.10 cases per 100 patient-years of follow-up, which is approximately four-fold higher than expected in the general population. Patients with Crohn's disease, rheumatoid arthritis or plaque psoriasis, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF blocker therapy, patients with rheumatoid arthritis may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.
- Hepatosplenic T-cell lymphoma (HSTCL)
- Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including infliximab. These cases have had a very aggressive disease course and have been fatal. All reported infliximab cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males. All of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with infliximab at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to infliximab or infliximab in combination with these other immunosuppressants. When treating patients with inflammatory bowel disease, particularly in adolescents and young adults, consideration of whether to use infliximab alone or in combination with other immunosuppressants should take into account a possibility that there is a higher risk of HSTCL with combination therapy versus an observed increased risk of immunogenicity and hypersensitivity reactions with infliximab monotherapy from the clinical trial data.
Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including infliximab. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.
- In the controlled portions of clinical trials of some TNF-blocking agents including infliximab, more malignancies (excluding lymphoma and nonmelanoma skin cancer [NMSC]) have been observed in patients receiving those TNF-blockers compared with control patients. During the controlled portions of infliximab trials in patients with moderately to severely active rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 14 patients were diagnosed with malignancies (excluding lymphoma and NMSC) among 4019 infliximab-treated patients vs. 1 among 1597 control patients (at a rate of 0.52/100 patient-years among infliximab-treated patients vs. a rate of 0.11/100 patient-years among control patients), with median duration of follow-up 0.5 years for infliximab-treated patients and 0.4 years for control patients. Of these, the most common malignancies were breast cancer, colorectal cancer, and melanoma. The rate of malignancies among infliximab-treated patients was similar to that expected in the general population whereas the rate in control patients was lower than expected.
- In a clinical trial exploring the use of infliximab in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, the majority of lung or head and neck origin, were reported in infliximab-treated patients compared with control patients. All patients had a history of heavy smoking. Prescribers should exercise caution when considering the use of infliximab in patients with moderate to severe COPD.
- Psoriasis patients should be monitored for nonmelanoma skin cancers (NMSCs), particularly those patients who have had prior prolonged phototherapy treatment. In the maintenance portion of clinical trials for infliximab, NMSCs were more common in patients with previous phototherapy.
- The potential role of TNF-blocking therapy in the development of malignancies is not known. Rates in clinical trials for infliximab cannot be compared to rates in clinical trials of other TNF-blockers and may not predict rates observed in a broader patient population. Caution should be exercised in considering infliximab treatment in patients with a history of malignancy or in continuing treatment in patients who develop malignancy while receiving infliximab.
### Hepatitis B Virus Reactivation
- Use of TNF blockers, including infliximab, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients should be tested for HBV infection before initiating TNF blocker therapy, including infliximab. For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. Patients who are carriers of HBV and require treatment with TNF blockers should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, TNF blockers should be stopped and antiviral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF blocker therapy in this situation and monitor patients closely.
- Severe hepatic reactions, including acute liver failure, jaundice, hepatitis and cholestasis, have been reported rarely in postmarketing data in patients receiving infliximab. Autoimmune hepatitis has been diagnosed in some of these cases. Severe hepatic reactions occurred between 2 weeks to more than 1 year after initiation of infliximab; elevations in hepatic aminotransferase levels were not noted prior to discovery of the liver injury in many of these cases. Some of these cases were fatal or necessitated liver transplantation. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (e.g., ≥5 times the upper limit of normal) develop, infliximab should be discontinued, and a thorough investigation of the abnormality should be undertaken. In clinical trials, mild or moderate elevations of ALT and AST have been observed in patients receiving infliximab without progression to severe hepatic injury.
- Infliximab has been associated with adverse outcomes in patients with heart failure, and should be used in patients with heart failure only after consideration of other treatment options. The results of a randomized study evaluating the use of infliximab in patients with heart failure (NYHA Functional Class III/IV) suggested higher mortality in patients who received 10 mg/kg infliximab, and higher rates of cardiovascular adverse events at doses of 5 mg/kg and 10 mg/kg. There have been post-marketing reports of worsening heart failure, with and without identifiable precipitating factors, in patients taking infliximab. There have also been rare post-marketing reports of new onset heart failure, including heart failure in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age. If a decision is made to administer infliximab to patients with heart failure, they should be closely monitored during therapy, and infliximab should be discontinued if new or worsening symptoms of heart failure appear.
- Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia, some with a fatal outcome, have been reported in patients receiving infliximab. The causal relationship to infliximab therapy remains unclear. Although no high-risk group(s) has been identified, caution should be exercised in patients being treated with infliximab who have ongoing or a history of significant hematologic abnormalities. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever) while on infliximab. Discontinuation of infliximab therapy should be considered in patients who develop significant hematologic abnormalities.
- Infliximab has been associated with hypersensitivity reactions that vary in their time of onset and required hospitalization in some cases. Most hypersensitivity reactions, which include urticaria, dyspnea, and/or hypotension, have occurred during or within 2 hours of infliximab infusion.
- However, in some cases, serum sickness-like reactions have been observed in patients after initial infliximab therapy (i.e., as early as after the second dose), and when infliximab therapy was reinstituted following an extended period without infliximab treatment. Symptoms associated with these reactions include fever, rash, headache, sore throat, myalgias, polyarthralgias, hand and facial edema and/or dysphagia. These reactions were associated with a marked increase in antibodies to infliximab, loss of detectable serum concentrations of infliximab, and possible loss of drug efficacy.
- Infliximab should be discontinued for severe hypersensitivity reactions. Medications for the treatment of hypersensitivity reactions (e.g., acetaminophen, antihistamines, corticosteroids and/or epinephrine) should be available for immediate use in the event of a reaction.
- In rheumatoid arthritis, Crohn's disease and psoriasis clinical trials, re-administration of infliximab after a period of no treatment resulted in a higher incidence of infusion reactions relative to regular maintenance treatment. In general, the benefit-risk of re-administration of infliximab after a period of no-treatment, especially as a re-induction regimen given at weeks 0, 2 and 6, should be carefully considered. In the case where infliximab maintenance therapy for psoriasis is interrupted, infliximab should be reinitiated as a single dose followed by maintenance therapy.
- Infliximab and other agents that inhibit TNF have been associated in rare cases with CNS manifestation of systemic vasculitis, seizure and new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of infliximab in patients with these neurologic disorders and should consider discontinuation of infliximab if these disorders develop.
- Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another TNFα-blocking agent, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse reactions seen with the combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNFα-blocking agents. Therefore, the combination of infliximab and anakinra is not recommended.
- In clinical studies, concurrent administration of TNF-blocking agents and abatacept have been associated with an increased risk of infections including serious infections compared with TNF-blocking agents alone, without increased clinical benefit. Therefore, the combination of infliximab and abatacept is not recommended.
- There is insufficient information regarding the concomitant use of infliximab with other biological therapeutics used to treat the same conditions as infliximab. The concomitant use of infliximab with these biologics is not recommended because of the possibility of an increased risk of infection.
- Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.
- Treatment with infliximab may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with infliximab, treatment should be discontinued.
- In patients receiving anti-TNF therapy, limited data are available on the response to vaccination with live vaccines or on the secondary transmission of infection by live vaccines. Use of live vaccines could result in clinical infections, including disseminated infections. It is recommended that live vaccines not be given concurrently with infliximab. Caution is advised in the administration of live vaccines to infants born to female patients treated with infliximab during pregnancy since infliximab is known to cross the placenta and has been detected up to 6 months in the serum of infants born to female patients treated with infliximab during pregnancy.
- Other uses of therapeutic infectious agents such as live attenuated bacteria (e.g., BCG bladder instillation for the treatment of cancer) could result in clinical infections, including disseminated infections. It is recommended that therapeutic infectious agents not be given concurrently with infliximab.
- It is recommended that all pediatric patients be brought up to date with all vaccinations prior to initiating infliximab therapy. The interval between vaccination and initiation of infliximab therapy should be in accordance with current vaccination guidelines.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not predict the rates observed in broader patient populations in clinical practice.
### Adverse Reactions in Adults
- The data described herein reflect exposure to infliximab in 4779 adult patients (1304 patients with rheumatoid arthritis, 1106 patients with Crohn's disease, 202 with ankylosing spondylitis, 293 with psoriatic arthritis, 484 with ulcerative colitis, 1373 with plaque psoriasis, and 17 patients with other conditions), including 2625 patients exposed beyond 30 weeks and 374 exposed beyond 1 year. One of the most-common reasons for discontinuation of treatment was infusion-related reactions (e.g., dyspnea, flushing, headache and rash).
-
- An infusion reaction was defined in clinical trials as any adverse event occurring during an infusion or within 1 hour after an infusion. In phase 3 clinical studies, 18% of infliximab-treated patients experienced an infusion reaction compared to 5% of placebo-treated patients. Of infliximab-treated patients who had an infusion reaction during the induction period, 27% experienced an infusion reaction during the maintenance period. Of patients who did not have an infusion reaction during the induction period, 9% experienced an infusion reaction during the maintenance period.
- Among all infliximab infusions, 3% were accompanied by nonspecific symptoms such as fever or chills, 1% were accompanied by cardiopulmonary reactions (primarily chest pain, hypotension, hypertension or dyspnea), and <1% were accompanied by pruritus, urticaria, or the combined symptoms of pruritus/urticaria and cardiopulmonary reactions. Serious infusion reactions occurred in <1% of patients and included anaphylaxis, convulsions, erythematous rash and hypotension. Approximately 3% of patients discontinued infliximab because of infusion reactions, and all patients recovered with treatment and/or discontinuation of the infusion. infliximab infusions beyond the initial infusion were not associated with a higher incidence of reactions. The infusion reaction rates remained stable in psoriasis through 1 year in psoriasis Study I. In psoriasis Study II, the rates were variable over time and somewhat higher following the final infusion than after the initial infusion. Across the 3 psoriasis studies, the percent of total infusions resulting in infusion reactions (i.e., an adverse event occurring within 1 hour) was 7% in the 3 mg/kg group, 4% in the 5 mg/kg group, and 1% in the placebo group.
- Patients who became positive for antibodies to infliximab were more likely (approximately two- to three-fold) to have an infusion reaction than were those who were negative. Use of concomitant immunosuppressant agents appeared to reduce the frequency of both antibodies to infliximab and infusion reactions.
- In a clinical trial of patients with moderate to severe psoriasis designed to assess the efficacy of long-term maintenance therapy versus re-treatment with an induction regimen of infliximab following disease flare, 4% (8/219) of patients in the re-treatment therapy arm experienced serious infusion reactions versus < 1% (1/222) in the maintenance therapy arm. Patients enrolled in this trial did not receive any concomitant immunosuppressant therapy. In this study, the majority of serious infusion reactions occurred during the second infusion at Week 2. Symptoms included, but were not limited to, dyspnea, urticaria, facial edema, and hypotension. In all cases, infliximab treatment was discontinued and/or other treatment instituted with complete resolution of signs and symptoms.
In psoriasis studies, approximately 1% of infliximab-treated patients experienced a possible delayed hypersensitivity reaction, generally reported as serum sickness or a combination of arthralgia and/or myalgia with fever and/or rash. These reactions generally occurred within 2 weeks after repeat infusion.
- In infliximab clinical studies, treated infections were reported in 36% of infliximab-treated patients (average of 51 weeks of follow-up) and in 25% of placebo-treated patients (average of 37 weeks of follow-up). The infections most frequently reported were respiratory tract infections (including sinusitis, pharyngitis, and bronchitis) and urinary tract infections. Among infliximab-treated patients, serious infections included pneumonia, cellulitis, abscess, skin ulceration, sepsis, and bacterial infection. In clinical trials, 7 opportunistic infections were reported; 2 cases each of coccidioidomycosis (1 case was fatal) and histoplasmosis (1 case was fatal), and 1 case each of pneumocystosis, nocardiosis and cytomegalovirus. Tuberculosis was reported in 14 patients, 4 of whom died due to miliary tuberculosis. Other cases of tuberculosis, including disseminated tuberculosis, also have been reported post-marketing. Most of these cases of tuberculosis occurred within the first 2 months after initiation of therapy with infliximab and may reflect recrudescence of latent disease. In the 1-year placebo-controlled studies RA I and RA II, 5.3% of patients receiving infliximab every 8 weeks with MTX developed serious infections as compared to 3.4% of placebo patients receiving MTX. Of 924 patients receiving infliximab, 1.7% developed pneumonia and 0.4% developed TB, when compared to 0.3% and 0.0% in the placebo arm respectively. In a shorter (22-week) placebo-controlled study of 1082 RA patients randomized to receive placebo, 3 mg/kg or 10 mg/kg infliximab infusions at 0, 2, and 6 weeks, followed by every 8 weeks with MTX, serious infections were more frequent in the 10 mg/kg infliximab group (5.3%) than the 3 mg/kg or placebo groups (1.7% in both). During the 54-week Crohn's II Study, 15% of patients with fistulizing Crohn's disease developed a new fistula-related abscess.
- In infliximab clinical studies in patients with ulcerative colitis, infections treated with antimicrobials were reported in 27% of infliximab-treated patients (average of 41 weeks of follow-up) and in 18% of placebo-treated patients (average 32 weeks of follow-up). The types of infections, including serious infections, reported in patients with ulcerative colitis were similar to those reported in other clinical studies.
- The onset of serious infections may be preceded by constitutional symptoms such as fever, chills, weight loss, and fatigue. The majority of serious infections, however, may also be preceded by signs or symptoms localized to the site of the infection.
- Approximately half of infliximab-treated patients in clinical trials who were antinuclear antibody (ANA) negative at baseline developed a positive ANA during the trial compared with approximately one-fifth of placebo-treated patients. Anti-dsDNA antibodies were newly detected in approximately one-fifth of infliximab-treated patients compared with 0% of placebo-treated patients. Reports of lupus and lupus-like syndromes, however, remain uncommon.
- In controlled trials, more infliximab-treated patients developed malignancies than placebo-treated patients.
- In a randomized controlled clinical trial exploring the use of infliximab in patients with moderate to severe COPD who were either current smokers or ex-smokers, 157 patients were treated with infliximab at doses similar to those used in rheumatoid arthritis and Crohn's disease. Of these infliximab-treated patients, 9 developed a malignancy, including 1 lymphoma, for a rate of 7.67 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% CI 3.51 – 14.56). There was 1 reported malignancy among 77 control patients for a rate of 1.63 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% CI 0.04 – 9.10). The majority of the malignancies developed in the lung or head and neck.
- In a randomized study evaluating infliximab in moderate to severe heart failure (NYHA Class III/IV; left ventricular ejection fraction ≤35%), 150 patients were randomized to receive treatment with 3 infusions of infliximab 10 mg/kg, 5 mg/kg, or placebo, at 0, 2, and 6 weeks. Higher incidences of mortality and hospitalization due to worsening heart failure were observed in patients receiving the 10 mg/kg infliximab dose. At 1 year, 8 patients in the 10 mg/kg infliximab group had died compared with 4 deaths each in the 5 mg/kg infliximab and the placebo groups. There were trends toward increased dyspnea, hypotension, angina, and dizziness in both the 10 mg/kg and 5 mg/kg infliximab treatment groups, versus placebo. infliximab has not been studied in patients with mild heart failure (NYHA Class I/II).
- Treatment with infliximab can be associated with the development of antibodies to infliximab. The assay used to measure anti-infliximab antibodies in patient samples is subject to interference by serum infliximab, possibly resulting in an underestimation of the rate of patient antibody formation. The incidence of antibodies to infliximab in patients given a 3-dose induction regimen followed by maintenance dosing was approximately 10% as assessed through 1 to 2 years of infliximab treatment. A higher incidence of antibodies to infliximab was observed in Crohn's disease patients receiving infliximab after drug-free intervals >16 weeks. In a study of psoriatic arthritis in which 191 patients received 5 mg/kg with or without MTX, antibodies to infliximab occurred in 15% of patients. The majority of antibody-positive patients had low titers. Patients who were antibody-positive were more likely to have higher rates of clearance, reduced efficacy and to experience an infusion reaction than were patients who were antibody negative. Antibody development was lower among rheumatoid arthritis and Crohn's disease patients receiving immunosuppressant therapies such as 6-MP/AZA or MTX.
- In the psoriasis Study II, which included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 36% of patients treated with 5 mg/kg every 8 weeks for 1 year, and in 51% of patients treated with 3 mg/kg every 8 weeks for 1 year. In the psoriasis Study III, which also included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 20% of patients treated with 5 mg/kg induction (weeks 0, 2 and 6), and in 27% of patients treated with 3 mg/kg induction. Despite the increase in antibody formation, the infusion reaction rates in Studies I and II in patients treated with 5 mg/kg induction followed by every 8 week maintenance for 1 year and in Study III in patients treated with 5 mg/kg induction (14.1%–23.0%) and serious infusion reaction rates (<1%) were similar to those observed in other study populations. The clinical significance of apparent increased immunogenicity on efficacy and infusion reactions in psoriasis patients as compared to patients with other diseases treated with infliximab over the long term is not known.
- The data reflect the percentage of patients whose test results were positive for antibodies to infliximab in an ELISA assay, and they are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to infliximab with the incidence of antibodies to other products may be misleading.
Severe liver injury, including acute liver failure and autoimmune hepatitis, has been reported rarely in patients receiving infliximab. Reactivation of hepatitis B virus has occurred in patients receiving TNF-blocking agents, including infliximab, who are chronic carriers of this virus.
In clinical trials in rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, plaque psoriasis, and psoriatic arthritis, elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving infliximab than in controls the table below, both when infliximab was given as monotherapy and when it was used in combination with other immunosuppressive agents. In general, patients who developed ALT and AST elevations were asymptomatic, and the abnormalities decreased or resolved with either continuation or discontinuation of infliximab, or modification of concomitant medications.
- During the placebo-controlled portion across the 3 clinical trials up to week 16, the proportion of patients who experienced at least 1 serious adverse reaction (SAE; defined as resulting in death, life threatening, requires hospitalization, or persistent or significant disability/incapacity) was 0.5% in the 3 mg/kg infliximab group, 1.9% in the placebo group, and 1.6% in the 5 mg/kg infliximab group.
- Among patients in the 2 Phase 3 studies, 12.4% of patients receiving infliximab 5 mg/kg every 8 weeks through 1 year of maintenance treatment experienced at least 1 SAE in Study I. In Study II, 4.1% and 4.7% of patients receiving infliximab 3 mg/kg and 5 mg/kg every 8 weeks, respectively, through 1 year of maintenance treatment experienced at least 1 SAE.
- One death due to bacterial sepsis occurred 25 days after the second infusion of 5 mg/kg infliximab. Serious infections included sepsis, and abscesses. In Study I, 2.7% of patients receiving infliximab 5 mg/kg every 8 weeks through 1 year of maintenance treatment experienced at least 1 serious infection. In Study II, 1.0% and 1.3% of patients receiving infliximab 3 mg/kg and 5 mg/kg, respectively, through 1 year of treatment experienced at least 1 serious infection. The most common serious infection (requiring hospitalization) was abscess (skin, throat, and peri-rectal) reported by 5 (0.7%) patients in the 5 mg/kg infliximab group. Two active cases of tuberculosis were reported: 6 weeks and 34 weeks after starting infliximab.
- In the placebo-controlled portion of the psoriasis studies, 7 of 1123 patients who received infliximab at any dose were diagnosed with at least one NMSC compared to 0 of 334 patients who received placebo.
- In the psoriasis studies, 1% (15/1373) of patients experienced serum sickness or a combination of arthralgia and/or myalgia with fever, and/or rash, usually early in the treatment course. Of these patients, 6 required hospitalization due to fever, severe myalgia, arthralgia, swollen joints, and immobility.
- Safety data are available from 4779 infliximab-treated adult patients, including 1304 with rheumatoid arthritis, 1106 with Crohn's disease, 484 with ulcerative colitis, 202 with ankylosing spondylitis, 293 with psoriatic arthritis, 1373 with plaque psoriasis and 17 with other conditions. Adverse reactions reported in ≥5% of all patients with rheumatoid arthritis receiving 4 or more infusions are in Table 2. The types and frequencies of adverse reactions observed were similar in infliximab-treated rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis and Crohn's disease patients except for abdominal pain, which occurred in 26% of infliximab-treated patients with Crohn's disease. In the Crohn's disease studies, there were insufficient numbers and duration of follow-up for patients who never received infliximab to provide meaningful comparisons.
The most common serious adverse reactions observed in clinical trials were infections [see Adverse Reactions (6.1)]. Other serious, medically relevant adverse reactions ≥0.2% or clinically significant adverse reactions by body system were as follows:
- Body as a whole: Allergic reaction, edema
- Blood: Pancytopenia
- Cardiovascular: Hypotension
- Gastrointestinal: Constipation, intestinal obstruction
- Central and Peripheral Nervous: Dizziness
- Heart Rate and Rhythm: Bradycardia
- Liver and Biliary: Hepatitis
- Metabolic and Nutritional: Dehydration
- Platelet, Bleeding and Clotting: Thrombocytopenia
- Neoplasms: Lymphoma
- Red Blood Cell: Anemia, hemolytic anemia
- Resistance Mechanism: Cellulitis, sepsis, serum sickness, sarcoidosis
- Respiratory: Lower respiratory tract infection (including pneumonia), pleurisy, pulmonary edema
- Skin and Appendages: Increased sweating
- Vascular (Extracardiac): Thrombophlebitis
- White Cell and Reticuloendothelial: Leukopenia, lymphadenopathy
### Adverse Reactions in Pediatric Patients
- There were some differences in the adverse reactions observed in the pediatric patients receiving infliximab compared to those observed in adults with Crohn's disease. These differences are discussed in the following paragraphs.
- The following adverse reactions were reported more commonly in 103 randomized pediatric Crohn's disease patients administered 5 mg/kg infliximab through 54 weeks than in 385 adult Crohn's disease patients receiving a similar treatment regimen: anemia (11%), leukopenia (9%), flushing (9%), viral infection (8%), neutropenia (7%), bone fracture (7%), bacterial infection (6%), and respiratory tract allergic reaction (6%).
- Infections were reported in 56% of randomized pediatric patients in Study Peds Crohn's and in 50% of adult patients in Study Crohn's I. In Study Peds Crohn's, infections were reported more frequently for patients who received every 8-week as opposed to every 12-week infusions (74% and 38%, respectively), while serious infections were reported for 3 patients in the every 8-week and 4 patients in the every 12-week maintenance treatment group. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was abscess. Pneumonia was reported for 3 patients, (2 in the every 8-week and 1 in the every 12-week maintenance treatment groups). Herpes zoster was reported for 2 patients in the every 8-week maintenance treatment group.
- In Study Peds Crohn's, 18% of randomized patients experienced 1 or more infusion reactions, with no notable difference between treatment groups. Of the 112 patients in Study Peds Crohn's, there were no serious infusion reactions, and 2 patients had non-serious anaphylactoid reactions.
- In Study Peds Crohn's, in which all patients received stable doses of 6-MP, AZA, or MTX, excluding inconclusive samples, 3 of 24 patients had antibodies to infliximab. Although 105 patients were tested for antibodies to infliximab, 81 patients were classified as inconclusive because they could not be ruled as negative due to assay interference by the presence of infliximab in the sample.
- Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 18% of pediatric patients in Crohn's disease clinical trials; 4% had ALT elevations ≥3 × ULN, and 1% had elevations ≥5 × ULN. (Median follow-up was 53 weeks.)
- Overall, the adverse reactions reported in the pediatric ulcerative colitis trial and adult ulcerative colitis (Study UC I and Study UC II) studies were generally consistent. In a pediatric UC trial, the most common adverse reactions were upper respiratory tract infection, pharyngitis, abdominal pain, fever, and headache.
- Infections were reported in 31 (52%) of 60 treated patients in the pediatric UC trial and 22 (37%) required oral or parenteral antimicrobial treatment. The proportion of patients with infections in the pediatric UC trial was similar to that in the pediatric Crohn's disease study (Study Peds Crohn's) but higher than the proportion in the adults' ulcerative colitis studies (Study UC I and Study UC II). The overall incidence of infections in the pediatric UC trial was 13/22 (59%) in the every 8 week maintenance treatment group. Upper respiratory tract infection (7/60 [12%]) and pharyngitis (5/60 [8%]) were the most frequently reported respiratory system infections. Serious infections were reported in 12% (7/60) of all treated patients.
- In the pediatric UC trial, excluding inconclusive samples, 4 of 19 patients had antibodies to infliximab. Although 52 patients were tested, 33 patients were classified as inconclusive because they could not be ruled as negative due to assay interference by the presence of infliximab in the sample.
- Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 17% (10/60) of pediatric patients in the pediatric UC trial; 7% (4/60) had ALT elevations ≥3 × ULN, and 2% (1/60) had elevations ≥5 × ULN (median follow-up was 49 weeks).
- Overall, 8 of 60 (13%) treated patients experienced one or more infusion reactions, including 4 of 22 (18%) patients in the every 8-week treatment maintenance group. No serious infusion reactions were reported.
- In the pediatric UC trial, 45 patients were in the 12 to 17 year age group and 15 in the 6 to 11 year age group. The numbers of patients in each subgroup are too small to make any definitive conclusions about the effect of age on safety events. There were higher proportions of patients with serious adverse events (40% vs. 18%) and discontinuation due to adverse events (40% vs. 16%) in the younger age group than in the older age group. While the proportion of patients with infections was also higher in the younger age group (60% vs. 49%), for serious infections, the proportions were similar in the two age groups (13% in the 6 to 11 year age group vs. 11% in the 12 to 17 year age group). Overall proportions of adverse reactions, including infusion reactions, were similar between the 6 to 11 and 12 to 17 year age groups (13%).
## Postmarketing Experience
Adverse reactions have been reported during post approval use of infliximab in adult and pediatric patients. 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 infliximab exposure.
The following adverse reactions, some with fatal outcome, have been reported during post-approval use of infliximab: neutropenia, interstitial lung disease (including pulmonary fibrosis/interstitial pneumonitis and very rare rapidly progressive disease), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pericardial effusion, systemic and cutaneous vasculitis, erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, peripheral demyelinating disorders (such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy), new onset and worsening psoriasis (all subtypes including pustular, primarily palmoplantar), transverse myelitis, and neuropathies (additional neurologic reactions have also been observed), acute liver failure, jaundice, hepatitis, and cholestasis, serious infections and malignancies, including melanoma and Merkel cell carcinoma.
- In post-marketing experience, cases of anaphylactic reactions, including laryngeal/pharyngeal edema and severe bronchospasm, and seizure have been associated with infliximab administration.
- Cases of myocardial ischemia and myocardial infarction and transient visual loss have also been rarely reported in association with infliximab during or within 2 hours of infusion.
- The following serious adverse reactions have been reported in the post-marketing experience in children: infections (some fatal) including opportunistic infections and tuberculosis, infusion reactions, and hypersensitivity reactions.
- Serious adverse reactions in the post-marketing experience with infliximab in the pediatric population have also included malignancies, including hepatosplenic T-cell lymphomas, transient hepatic enzyme abnormalities, lupus-like syndromes, and the development of autoantibodies.
# Drug Interactions
- An increased risk of serious infections was seen in clinical studies of other TNFα-blocking agents used in combination with anakinra or abatacept, with no added clinical benefit. Because of the nature of the adverse reactions seen with these combinations with TNF-blocker therapy, similar toxicities may also result from the combination of anakinra or abatacept with other TNFα-blocking agents. Therefore, the combination of infliximibe and anakinra or abatacept is not recommended.
- The use of tocilizumab in combination with biological DMARDs such as TNF antagonists, including infliximibe, should be avoided because of the possibility of increased immunosuppression and increased risk of infection.
- The combination of infliximibe with other biological therapeutics used to treat the same conditions as infliximibe is not recommended.
- Specific drug interaction studies, including interactions with MTX, have not been conducted. The majority of patients in rheumatoid arthritis or Crohn's disease clinical studies received one or more concomitant medications. In rheumatoid arthritis, concomitant medications besides MTX were nonsteroidal anti-inflammatory agents (NSAIDs), folic acid, corticosteroids and/or narcotics. Concomitant Crohn's disease medications were antibiotics, antivirals, corticosteroids, 6-MP/AZA and aminosalicylates. In psoriatic arthritis clinical trials, concomitant medications included MTX in approximately half of the patients as well as NSAIDs, folic acid and corticosteroids. Concomitant MTX use may decrease the incidence of anti-infliximab antibody production and increase infliximab concentrations.
- Patients with Crohn's disease who received immunosuppressants tended to experience fewer infusion reactions compared to patients on no immunosuppressants [see Adverse Reactions (6.1)]. Serum infliximab concentrations appeared to be unaffected by baseline use of medications for the treatment of Crohn's disease including corticosteroids, antibiotics (metronidazole or ciprofloxacin) and aminosalicylates.
- The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, IL-1, IL-6, IL-10, IFN) during chronic inflammation. Therefore, it is expected that for a molecule that antagonizes cytokine activity, such as infliximab, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of infliximibe in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.
- It is recommended that live vaccines not be given concurrently with infliximibe.
- It is recommended that therapeutic infectious agents not be given concurrently with infliximibe.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- It is not known whether infliximab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Infliximab should be given to a pregnant woman only if clearly needed. Because infliximab does not cross-react with TNFα in species other than humans and chimpanzees, animal reproduction studies have not been conducted with infliximab. No evidence of maternal toxicity, embryotoxicity or teratogenicity was observed in a developmental toxicity study conducted in mice using an analogous antibody that selectively inhibits the functional activity of mouse TNFα. Doses of 10 to 15 mg/kg in pharmacodynamic animal models with the anti-TNF analogous antibody produced maximal pharmacologic effectiveness. Doses up to 40 mg/kg were shown to produce no adverse effects in animal reproduction studies.
- As with other IgG antibodies, infliximab crosses the placenta and has been detected up to 6 months in the serum of infants born to female patients treated with infliximab during pregnancy. Consequently, these infants may be at increased risk of infection, and caution is advised in the administration of live vaccines to these infants
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Infliximab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Infliximab during labor and delivery.
### Nursing Mothers
- It is not known whether infliximab is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from infliximab, women should not breast-feed their infants while taking infliximab. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
The safety and effectiveness of infliximibe have been established in pediatric patients 6 to 17 years of age for induction and maintenance treatment of Crohn's disease or ulcerative colitis. However, infliximibe has not been studied in children with Crohn's disease or ulcerative colitis <6 years of age.
- Infliximibe is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy.
- Infliximibe has been studied only in combination with conventional immunosuppressive therapy in pediatric Crohn's disease. The longer term (greater than 1 year) safety and effectiveness of infliximibe in pediatric Crohn's disease patients have not been established in clinical trials.
- The safety and effectiveness of infliximibe for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients aged 6 years and older with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy are supported by evidence from adequate and well-controlled studies of infliximibe in adults. Additional safety and pharmacokinetic data were collected in 60 pediatric patients aged 6 years and older. The effectiveness of infliximibe in inducing and maintaining mucosal healing could not be established. Although 41 patients had a Mayo endoscopy subscore of 0 or 1 at the Week 8 endoscopy, the induction phase was open-label and lacked a control group. Only 9 patients had an optional endoscopy at Week 54.
- In the pediatric UC trial, approximately half of the patients were on concomitant immunomodulators (AZA, 6-MP, MTX) at study start. Due to the risk of HSTCL, a careful risk-benefit assessment should be made when infliximibe is used in combination with other immunosuppressants.
- The longer term (greater than 1 year) safety and effectiveness of infliximibe in pediatric ulcerative colitis patients have not been established in clinical trials.
- The safety and efficacy of infliximibe in patients with juvenile rheumatoid arthritis (JRA) were evaluated in a multicenter, randomized, placebo-controlled, double-blind study for 14 weeks, followed by a double-blind, all-active treatment extension, for a maximum of 44 weeks. Patients with active JRA between the ages of 4 and 17 years who had been treated with MTX for at least 3 months were enrolled. Concurrent use of folic acid, oral corticosteroids (≤0.2 mg/kg/day of prednisone or equivalent), NSAIDs, and/or disease modifying antirheumatic drugs (DMARDs) was permitted.
- Doses of 3 mg/kg infliximibe or placebo were administered intravenously at Weeks 0, 2 and 6. Patients randomized to placebo crossed-over to receive 6 mg/kg infliximibe E at Weeks 14, 16, and 20, and then every 8 weeks through Week 44. Patients who completed the study continued to receive open-label treatment with infliximibe for up to 2 years in a companion extension study.
- The study failed to establish the efficacy of infliximibe in the treatment of JRA. Key observations in the study included a high placebo response rate and a higher rate of immunogenicity than what has been observed in adults. Additionally, a higher rate of clearance of infliximab was observed than had been observed in adults.
- A total of 60 patients with JRA were treated with doses of 3 mg/kg and 57 patients were treated with doses of 6 mg/kg. The proportion of patients with infusion reactions who received 3 mg/kg infliximibe was 35% (21/60) over 52 weeks compared with 18% (10/57) in patients who received 6 mg/kg over 38 weeks. The most common infusion reactions reported were vomiting, fever, headache, and hypotension. In the 3 mg/kg infliximibe group, 4 patients had a serious infusion reaction and 3 patients reported a possible anaphylactic reaction (2 of which were among the serious infusion reactions). In the 6 mg/kg infliximibe group, 2 patients had a serious infusion reaction, 1 of whom had a possible anaphylactic reaction. Two of the 6 patients who experienced serious infusion reactions received infliximibe by rapid infusion (duration of less than 2 hours). Antibodies to infliximab developed in 38% (20/53) of patients who received 3 mg/kg infliximibe compared with 12% (6/49) of patients who received 6 mg/kg.
- A total of 68% (41/60) of patients who received 3 mg/kg infliximibe in combination with MTX experienced an infection over 52 weeks compared with 65% (37/57) of patients who received 6 mg/kg infliximibe in combination with MTX over 38 weeks. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was pneumonia. Other notable infections included primary varicella infection in 1 patient and herpes zoster in 1 patient.
### Geriatic Use
In rheumatoid arthritis and plaque psoriasis clinical trials, no overall differences were observed in effectiveness or safety in 181 patients with rheumatoid arthritis and 75 patients with plaque psoriasis, aged 65 or older who received infliximibe , compared to younger patients - although the incidence of serious adverse reactions in patients aged 65 or older was higher in both infliximibe and control groups compared to younger patients. In Crohn's disease, ulcerative colitis, ankylosing spondylitis and psoriatic arthritis studies, there were insufficient numbers of patients aged 65 and over to determine whether they respond differently from patients aged 18 to 65. There is a greater incidence of infections in the elderly population in general. The incidence of serious infections in infliximibe-treated patients 65 years and older was greater than in those under 65 years of age; therefore caution should be used in treating the elderl
### Gender
There is no FDA guidance on the use of Infliximab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Infliximab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Infliximab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Infliximab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Infliximab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Infliximab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
- Infliximab is intended for use under the guidance and supervision of a physician. The reconstituted infusion solution should be prepared by a trained medical professional using aseptic technique by the following procedure:
- Calculate the dose, total volume of reconstituted infliximab solution required and the number of infliximab vials needed. Each infliximab vial contains 100 mg of the infliximab antibody.
- Reconstitute each infliximab vial with 10 mL of Sterile Water for Injection, USP, using a syringe equipped with a 21-gauge or smaller needle as follows: Remove the flip-top from the vial and wipe the top with an alcohol swab. Insert the syringe needle into the vial through the center of the rubber stopper and direct the stream of Sterile Water for Injection, USP, to the glass wall of the vial. Gently swirl the solution by rotating the vial to dissolve the lyophilized powder. Avoid prolonged or vigorous agitation. Do not shake. Foaming of the solution on reconstitution is not unusual. Allow the reconstituted solution to stand for 5 minutes. The solution should be colorless to light yellow and opalescent, and the solution may develop a few translucent particles as infliximab is a protein. Do not use if the lyophilized cake has not fully dissolved or if opaque particles, discoloration, or other foreign particles are present.
- Dilute the total volume of the reconstituted infliximab solution dose to 250 mL with sterile 0.9% Sodium Chloride Injection, USP, by withdrawing a volume equal to the volume of reconstituted infliximab from the 0.9% Sodium Chloride Injection, USP, 250 mL bottle or bag. Slowly add the total volume of reconstituted infliximab solution to the 250 mL infusion bottle or bag. Gently mix. The resulting infusion concentration should range between 0.4 mg/mL and 4 mg/mL.
- The infliximab infusion should begin within 3 hours of reconstitution and dilution. The infusion must be administered over a period of not less than 2 hours and must use an infusion set with an in-line, sterile, non-pyrogenic, low-protein-binding filter (pore size of 1.2 µm or less). The vials do not contain antibacterial preservatives. Therefore, any unused portion of the infusion solution should not be stored for reuse.
- No physical biochemical compatibility studies have been conducted to evaluate the co-administration of infliximab with other agents. infliximab should not be infused concomitantly in the same intravenous line with other agents.
- Parenteral drug products should be inspected visually before and after reconstitution for particulate matter and discoloration prior to administration, whenever solution and container permit. If visibly opaque particles, discoloration or other foreign particulates are observed, the solution should not be used.
### Monitoring
Prior to initiating infliximab and periodically during therapy, patients should be evaluated for active tuberculosis and tested for latent infection.
# IV Compatibility
No physical biochemical compatibility studies have been conducted to evaluate the co-administration of infliximab with other agents. infliximab should not be infused concomitantly in the same intravenous line with other agents.
# Overdosage
Single doses up to 20 mg/kg have been administered without any direct toxic effect. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.
# Pharmacology
## Mechanism of Action
Infliximab neutralizes the biological activity of TNFα by binding with high affinity to the soluble and transmembrane forms of TNFα and inhibits binding of TNFα with its receptors. Infliximab does not neutralize TNFβ (lymphotoxin-α), a related cytokine that utilizes the same receptors as TNFα. Biological activities attributed to TNFα include: induction of pro-inflammatory cytokines such as interleukins (IL) 1 and 6, enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes, activation of neutrophil and eosinophil functional activity, induction of acute phase reactants and other liver proteins, as well as tissue degrading enzymes produced by synoviocytes and/or chondrocytes. Cells expressing transmembrane TNFα bound by infliximab can be lysed in vitro or in vivo. Infliximab inhibits the functional activity of TNFα in a wide variety of in vitro bioassays utilizing human fibroblasts, endothelial cells, neutrophils, B and T- lymphocytes and epithelial cells. The relationship of these biological response markers to the mechanism(s) by which infliximab exerts its clinical effects is unknown. Anti-TNFα antibodies reduce disease activity in the cotton-top tamarin colitis model, and decrease synovitis and joint erosions in a murine model of collagen-induced arthritis. Infliximab prevents disease in transgenic mice that develop polyarthritis as a result of constitutive expression of human TNFα, and when administered after disease onset, allows eroded joints to heal.
## Structure
Infliximab, the active ingredient in infliximab, is a chimeric IgG1κ monoclonal antibody (composed of human constant and murine variable regions) specific for human tumor necrosis factor-alpha (TNFα). It has a molecular weight of approximately 149.1 kilodaltons. Infliximab is produced by a recombinant cell line cultured by continuous perfusion and is purified by a series of steps that includes measures to inactivate and remove viruses.
Infliximab is supplied as a sterile, white, lyophilized powder for intravenous infusion. Following reconstitution with 10 mL of Sterile Water for Injection, USP, the resulting pH is approximately 7.2. Each single-use vial contains 100 mg infliximab, 500 mg sucrose, 0.5 mg polysorbate 80, 2.2 mg monobasic sodium phosphate, monohydrate, and 6.1 mg dibasic sodium phosphate, dihydrate. No preservatives are present.
## Pharmacodynamics
Elevated concentrations of TNFα have been found in involved tissues and fluids of patients with rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis. In rheumatoid arthritis, treatment with infliximab reduced infiltration of inflammatory cells into inflamed areas of the joint as well as expression of molecules mediating cellular adhesion [E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)], chemoattraction [IL-8 and monocyte chemotactic protein (MCP-1)] and tissue degradation [matrix metalloproteinase (MMP) 1 and 3]. In Crohn's disease, treatment with infliximab reduced infiltration of inflammatory cells and TNFα production in inflamed areas of the intestine, and reduced the proportion of mononuclear cells from the lamina propria able to express TNFα and interferon. After treatment with infliximab, patients with rheumatoid arthritis or Crohn's disease exhibited decreased levels of serum IL-6 and C-reactive protein (CRP) compared to baseline. Peripheral blood lymphocytes from infliximab-treated patients showed no significant decrease in number or in proliferative responses to in vitro mitogenic stimulation when compared to cells from untreated patients. In psoriatic arthritis, treatment with infliximab resulted in a reduction in the number of T-cells and blood vessels in the synovium and psoriatic skin lesions as well as a reduction of macrophages in the synovium. In plaque psoriasis, infliximab treatment may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which infliximab exerts its clinical effects is unknown.
## Pharmacokinetics
In adults, single intravenous (IV) infusions of 3 mg/kg to 20 mg/kg showed a linear relationship between the dose administered and the maximum serum concentration. The volume of distribution at steady state was independent of dose and indicated that infliximab was distributed primarily within the vascular compartment. Pharmacokinetic results for single doses of 3 mg/kg to 10 mg/kg in rheumatoid arthritis, 5 mg/kg in Crohn's disease, and 3 mg/kg to 5 mg/kg in plaque psoriasis indicate that the median terminal half-life of infliximab is 7.7 to 9.5 days.
Following an initial dose of infliximab, repeated infusions at 2 and 6 weeks resulted in predictable concentration-time profiles following each treatment. No systemic accumulation of infliximab occurred upon continued repeated treatment with 3 mg/kg or 10 mg/kg at 4- or 8-week intervals. Development of antibodies to infliximab increased infliximab clearance. At 8 weeks after a maintenance dose of 3 to 10 mg/kg of infliximab, median infliximab serum concentrations ranged from approximately 0.5 to 6 mcg/mL; however, infliximab concentrations were not detectable (<0.1 mcg/mL) in patients who became positive for antibodies to infliximab. No major differences in clearance or volume of distribution were observed in patient subgroups defined by age, weight, or gender. It is not known if there are differences in clearance or volume of distribution in patients with marked impairment of hepatic or renal function.
Infliximab pharmacokinetic characteristics (including peak and trough concentrations and terminal half-life) were similar in pediatric (aged 6 to 17 years) and adult patients with Crohn's disease or ulcerative colitis following the administration of 5 mg/kg infliximab.
Population pharmacokinetic analysis showed that in children with juvenile rheumatoid arthritis (JRA) with a body weight of up to 35 kg receiving 6 mg/kg infliximab and children with JRA with body weight greater than 35 kg up to adult body weight receiving 3mg/kg infliximab, the steady state area under the concentration curve (AUCss) was similar to that observed in adults receiving 3 mg/kg of infliximab.
## Nonclinical Toxicology
The significance of the results of nonclinical studies for human risk is unknown. A repeat dose toxicity study was conducted with mice given cV1q anti-mouse TNFα to evaluate tumorigenicity. CV1q is an analogous antibody that inhibits the function of TNFα in mice. Animals were assigned to 1 of 3 dose groups: control, 10 mg/kg or 40 mg/kg cV1q given weekly for 6 months. The weekly doses of 10 mg/kg and 40 mg/kg are 2 and 8 times, respectively, the human dose of 5 mg/kg for Crohn's disease. Results indicated that cV1q did not cause tumorigenicity in mice. No clastogenic or mutagenic effects of infliximab were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively. Chromosomal aberrations were not observed in an assay performed using human lymphocytes. It is not known whether infliximab can impair fertility in humans. No impairment of fertility was observed in a fertility and general reproduction toxicity study with the analogous mouse antibody used in the 6-month chronic toxicity study.
# Clinical Studies
### Crohn's Disease
The safety and efficacy of single and multiple doses of infliximab were assessed in 2 randomized, double-blind, placebo-controlled clinical studies in 653 patients with moderate to severely active Crohn's disease [Crohn's Disease Activity Index (CDAI) ≥220 and ≤400] with an inadequate response to prior conventional therapies. Concomitant stable doses of aminosalicylates, corticosteroids and/or immunomodulatory agents were permitted and 92% of patients continued to receive at least one of these medications.
In the single-dose trial of 108 patients, 16% (4/25) of placebo patients achieved a clinical response (decrease in CDAI ≥70 points) at Week 4 vs. 81% (22/27) of patients receiving 5 mg/kg infliximab (p<0.001, two-sided, Fisher's Exact test). Additionally, 4% (1/25) of placebo patients and 48% (13/27) of patients receiving 5 mg/kg infliximab achieved clinical remission (CDAI<150) at Week 4.
In a multidose trial (ACCENT I [Study Crohn's I]), 545 patients received 5 mg/kg at Week 0 and were then randomized to one of three treatment groups; the placebo maintenance group received placebo at Weeks 2 and 6, and then every 8 weeks; the 5 mg/kg maintenance group received 5 mg/kg at Weeks 2 and 6, and then every 8 weeks; and the 10 mg/kg maintenance group received 5 mg/kg at Weeks 2 and 6, and then 10 mg/kg every 8 weeks. Patients in response at Week 2 were randomized and analyzed separately from those not in response at Week 2. Corticosteroid taper was permitted after Week 6.
At Week 2, 57% (311/545) of patients were in clinical response. At Week 30, a significantly greater proportion of these patients in the 5 mg/kg and 10 mg/kg maintenance groups achieved clinical remission compared to patients in the placebo maintenance group (Table 3).
Additionally, a significantly greater proportion of patients in the 5 mg/kg and 10 mg/kg infliximab maintenance groups were in clinical remission and were able to discontinue corticosteroid use compared to patients in the placebo maintenance group at Week 54 (Table 3).
Patients in the infliximab maintenance groups (5 mg/kg and 10 mg/kg) had a longer time to loss of response than patients in the placebo maintenance group (Figure 1). At Weeks 30 and 54, significant improvement from baseline was seen among the 5 mg/kg and 10 mg/kg infliximab-treated groups compared to the placebo group in the disease-specific inflammatory bowel disease questionnaire (IBDQ), particularly the bowel and systemic components, and in the physical component summary score of the general health-related quality of life questionnaire SF-36.
In a subset of 78 patients who had mucosal ulceration at baseline and who participated in an endoscopic substudy, 13 of 43 patients in the infliximab maintenance group had endoscopic evidence of mucosal healing compared to 1 of 28 patients in the placebo group at Week 10. Of the infliximab-treated patients showing mucosal healing at Week 10, 9 of 12 patients also showed mucosal healing at Week 54.
Patients who achieved a response and subsequently lost response were eligible to receive infliximab on an episodic basis at a dose that was 5 mg/kg higher than the dose to which they were randomized. The majority of such patients responded to the higher dose. Among patients who were not in response at Week 2, 59% (92/157) of infliximab maintenance patients responded by Week 14 compared to 51% (39/77) of placebo maintenance patients. Among patients who did not respond by Week 14, additional therapy did not result in significantly more responses.
The safety and efficacy of infliximab were assessed in 2 randomized, double-blind, placebo-controlled studies in patients with fistulizing Crohn's disease with fistula(s) that were of at least 3 months duration. Concurrent use of stable doses of corticosteroids, 5-aminosalicylates, antibiotics, MTX, 6-mercaptopurine (6-MP) and/or azathioprine (AZA) was permitted.
In the first trial, 94 patients received 3 doses of either placebo or infliximab at Weeks 0, 2 and 6. Fistula response (≥50% reduction in number of enterocutaneous fistulas draining upon gentle compression on at least 2 consecutive visits without an increase in medication or surgery for Crohn's disease) was seen in 68% (21/31) of patients in the 5 mg/kg infliximab group (P=0.002) and 56% (18/32) of patients in the 10 mg/kg infliximab group (P=0.021) vs. 26% (8/31) of patients in the placebo arm. The median time to onset of response and median duration of response in infliximab-treated patients was 2 and 12 weeks, respectively. Closure of all fistulas was achieved in 52% of infliximab-treated patients compared with 13% of placebo-treated patients (P<0.001).
In the second trial (ACCENT II [Study Crohn's II]), patients who were enrolled had to have at least 1 draining enterocutaneous (perianal, abdominal) fistula. All patients received 5 mg/kg infliximab at Weeks 0, 2 and 6. Patients were randomized to placebo or 5 mg/kg infliximab maintenance at Week 14. Patients received maintenance doses at Week 14 and then every 8 weeks through Week 46. Patients who were in fistula response (fistula response was defined the same as in the first trial) at both Weeks 10 and 14 were randomized separately from those not in response. The primary endpoint was time from randomization to loss of response among those patients who were in fistula response.
Among the randomized patients (273 of the 296 initially enrolled), 87% had perianal fistulas and 14% had abdominal fistulas. Eight percent also had rectovaginal fistulas. Greater than 90% of the patients had received previous immunosuppressive and antibiotic therapy.
At Week 14, 65% (177/273) of patients were in fistula response. Patients randomized to infliximab maintenance had a longer time to loss of fistula response compared to the placebo maintenance group (Figure 2). At Week 54, 38% (33/87) of infliximab-treated patients had no draining fistulas compared with 22% (20/90) of placebo-treated patients (P=0.02). Compared to placebo maintenance, patients on infliximab maintenance had a trend toward fewer hospitalizations.
Patients who achieved a fistula response and subsequently lost response were eligible to receive infliximab maintenance therapy at a dose that was 5 mg/kg higher than the dose to which they were randomized. Of the placebo maintenance patients, 66% (25/38) responded to 5 mg/kg infliximab, and 57% (12/21) of infliximab maintenance patients responded to 10 mg/kg.
Patients who had not achieved a response by Week 14 were unlikely to respond to additional doses of infliximab.
Similar proportions of patients in either group developed new fistulas (17% overall) and similar numbers developed abscesses (15% overall).
### Pediatric Crohn's Disease
The safety and efficacy of infliximab were assessed in a randomized, open-label study (Study Peds Crohn's) in 112 pediatric patients aged 6 to 17 years old with moderately to severely active Crohn's disease and an inadequate response to conventional therapies. The median age was 13 years and the median Pediatric Crohn's Disease Activity Index (PCDAI) was 40 (on a scale of 0 to 100). All patients were required to be on a stable dose of 6-MP, AZA, or MTX; 35% were also receiving corticosteroids at baseline.
All patients received induction dosing of 5 mg/kg infliximab at Weeks 0, 2, and 6. At Week 10, 103 patients were randomized to a maintenance regimen of 5 mg/kg infliximab given either every 8 weeks or every 12 weeks.
At Week 10, 88% of patients were in clinical response (defined as a decrease from baseline in the PCDAI score of ≥15 points and total PCDAI score of ≤30 points), and 59% were in clinical remission (defined as PCDAI score of ≤10 points).
The proportion of pediatric patients achieving clinical response at Week 10 compared favorably with the proportion of adults achieving a clinical response in Study Crohn's I. The study definition of clinical response in Study Peds Crohn's was based on the PCDAI score, whereas the CDAI score was used in the adult Study Crohn's I.
At both Week 30 and Week 54, the proportion of patients in clinical response was greater in the every 8-week treatment group than in the every 12-week treatment group (73% vs. 47% at Week 30, and 64% vs. 33% at Week 54). At both Week 30 and Week 54, the proportion of patients in clinical remission was also greater in the every 8-week treatment group than in the every 12-week treatment group (60% vs. 35% at Week 30, and 56% vs. 24% at Week 54), table below.
For patients in Study Peds Crohn's receiving corticosteroids at baseline, the proportion of patients able to discontinue corticosteroids while in remission at Week 30 was 46% for the every 8-week maintenance group and 33% for the every 12-week maintenance group. At Week 54, the proportion of patients able to discontinue corticosteroids while in remission was 46% for the every 8-week maintenance group and 17% for the every 12-week maintenance group.
### Ulcerative Colitis
The safety and efficacy of infliximab were assessed in 2 randomized, double-blind, placebo-controlled clinical studies in 728 patients with moderately to severely active ulcerative colitis (UC) (Mayo score5 6 to 12 [of possible range 0 to 12], Endoscopy subscore ≥2) with an inadequate response to conventional oral therapies (Studies UC I and UC II). Concomitant treatment with stable doses of aminosalicylates, corticosteroids and/or immunomodulatory agents was permitted. Corticosteroid taper was permitted after Week 8. Patients were randomized at week 0 to receive either placebo, 5 mg/kg infliximab or 10 mg/kg infliximab at Weeks 0, 2, 6, and every 8 weeks thereafter through Week 46 in Study UC I, and at Weeks 0, 2, 6, and every 8 weeks thereafter through Week 22 in Study UC II. In Study UC II, patients were allowed to continue blinded therapy to Week 46 at the investigator's discretion.
Patients in Study UC I had failed to respond or were intolerant to oral corticosteroids, 6-MP, or AZA. Patients in Study UC II had failed to respond or were intolerant to the above treatments and/or aminosalicylates. Similar proportions of patients in Studies UC I and UC II were receiving corticosteroids (61% and 51%, respectively), 6-MP/AZA (49% and 43%) and aminosalicylates (70% and 75%) at baseline. More patients in Study UC II than UC I were taking solely aminosalicylates for UC (26% vs. 11%, respectively). Clinical response was defined as a decrease from baseline in the Mayo score by ≥30% and ≥3 points, accompanied by a decrease in the rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1.
In both Study UC I and Study UC II, greater percentages of patients in both infliximab groups achieved clinical response, clinical remission and mucosal healing than in the placebo group. Each of these effects was maintained through the end of each trial (Week 54 in Study UC I, and Week 30 in Study UC II). In addition, a greater proportion of patients in infliximab groups demonstrated sustained response and sustained remission than in the placebo groups (table below).
Of patients on corticosteroids at baseline, greater proportions of patients in the infliximab treatment groups were in clinical remission and able to discontinue corticosteroids at Week 30 compared with the patients in the placebo treatment groups (22% in infliximab treatment groups vs. 10% in placebo group in Study UC I; 23% in infliximab treatment groups vs. 3% in placebo group in Study UC II). In Study UC I, this effect was maintained through Week 54 (21% in infliximab treatment groups vs. 9% in placebo group). The infliximab-associated response was generally similar in the 5 mg/kg and 10 mg/kg dose groups.
The improvement with infliximab was consistent across all Mayo subscores through Week 54 (Study UC I shown in Table 6; Study UC II through Week 30 was similar).
### Pediatric Ulcerative Colitis
The safety and effectiveness of infliximab for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients aged 6 years and older with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy are supported by evidence from adequate and well-controlled studies of infliximab in adults. Additional safety and pharmacokinetic data were collected in an open-label pediatric UC trial in 60 pediatric patients aged 6 through 17 years (median age 14.5 years) with moderately to severely active ulcerative colitis (Mayo score of 6 to 12; Endoscopic subscore ≥ 2) and an inadequate response to conventional therapies. At baseline, the median Mayo score was 8, 53% of patients were receiving immunomodulator therapy (6-MP/AZA/MTX), and 62% of patients were receiving corticosteroids (median dose 0.5 mg/kg/day in prednisone equivalents). Discontinuation of immunomodulators and corticosteroid taper were permitted after Week 0.
All patients received induction dosing of 5 mg/kg infliximab at Weeks 0, 2, and 6. Patients who did not respond to infliximab at Week 8 received no further infliximab and returned for safety follow-up. At Week 8, 45 patients were randomized to a maintenance regimen of 5 mg/kg infliximab given either every 8 weeks through Week 46 or every 12 weeks through Week 42. Patients were allowed to change to a higher dose and/or more frequent administration schedule if they experienced loss of response.
Clinical response at Week 8 was defined as a decrease from baseline in the Mayo score by ≥ 30% and ≥ 3 points, including a decrease in the rectal bleeding subscore by ≥ 1 points or achievement of a rectal bleeding subscore of 0 or 1.
Clinical remission at Week 8 was measured by the Mayo score, defined as a Mayo score of ≤2 points with no individual subscore >1. Clinical remission was also assessed at Week 8 and Week 54 using the Pediatric Ulcerative Colitis Activity Index (PUCAI)6 score and was defined by a PUCAI score of <10 points.
Endoscopies were performed at baseline and at Week 8. A Mayo endoscopy subscore of 0 indicated normal or inactive disease and a subscore of 1 indicated mild disease (erythema, decreased vascular pattern, or mild friability).
Of the 60 patients treated, 44 were in clinical response at Week 8. Of 32 patients taking concomitant immunomodulators at baseline, 23 achieved clinical response at Week 8, compared to 21 of 28 of those not taking concomitant immunomodulators at baseline. At Week 8, 24 of 60 patients were in clinical remission as measured by the Mayo score and 17 of 51 patients were in remission as measured by the PUCAI score.
At Week 54, 8 of 21 patients in the every 8-week maintenance group and 4 of 22 patients in the every 12-week maintenance group achieved remission as measured by the PUCAI score.
During maintenance phase, 23 of 45 randomized patients (9 in the every 8-week group and 14 in the every 12-week group) required an increase in their dose and/or increase in frequency of infliximab administration due to loss of response. Nine of the 23 patients who required a change in dose had achieved remission at Week 54. Seven of those patients received the 10 mg/kg every 8-week dosing.
### Rheumatoid Arthritis
The safety and efficacy of infliximab were assessed in 2 multicenter, randomized, double-blind, pivotal trials: ATTRACT (Study RA I) and ASPIRE (Study RA II). Concurrent use of stable doses of folic acid, oral corticosteroids (≤10 mg/day) and/or non-steroidal anti-inflammatory drugs (NSAIDs) was permitted.
Study RA I was a placebo-controlled study of 428 patients with active rheumatoid arthritis despite treatment with MTX. Patients enrolled had a median age of 54 years, median disease duration of 8.4 years, median swollen and tender joint count of 20 and 31 respectively, and were on a median dose of 15 mg/wk of MTX. Patients received either placebo + MTX or one of 4 doses/schedules of infliximab + MTX: 3 mg/kg or 10 mg/kg of infliximab by IV infusion at Weeks 0, 2 and 6 followed by additional infusions every 4 or 8 weeks in combination with MTX.
Study RA II was a placebo-controlled study of 3 active treatment arms in 1004 MTX naive patients of 3 or fewer years' duration active rheumatoid arthritis. Patients enrolled had a median age of 51 years with a median disease duration of 0.6 years, median swollen and tender joint count of 19 and 31, respectively, and >80% of patients had baseline joint erosions. At randomization, all patients received MTX (optimized to 20 mg/wk by Week 8) and either placebo, 3 mg/kg or 6 mg/kg infliximab at Weeks 0, 2, and 6 and every 8 weeks thereafter.
Data on use of infliximab without concurrent MTX are limited.
In Study RA I, all doses/schedules of infliximab + MTX resulted in improvement in signs and symptoms as measured by the American College of Rheumatology response criteria (ACR 20) with a higher percentage of patients achieving an ACR 20, 50 and 70 compared to placebo + MTX (Table 7). This improvement was observed at Week 2 and maintained through Week 102. Greater effects on each component of the ACR 20 were observed in all patients treated with infliximab + MTX compared to placebo + MTX (Table 8). More patients treated with infliximab reached a major clinical response than placebo-treated patients (Table 7).
In Study RA II, after 54 weeks of treatment, both doses of infliximab + MTX resulted in statistically significantly greater response in signs and symptoms compared to MTX alone as measured by the proportion of patients achieving ACR 20, 50 and 70 responses (Table 7). More patients treated with infliximab reached a major clinical response than placebo-treated patients (Table 7).
Structural damage in both hands and feet was assessed radiographically at Week 54 by the change from baseline in the van der Heijde-modified Sharp (vdH-S) score, a composite score of structural damage that measures the number and size of joint erosions and the degree of joint space narrowing in hands/wrists and feet.3
In Study RA I, approximately 80% of patients had paired X-ray data at 54 weeks and approximately 70% at 102 weeks. The inhibition of progression of structural damage was observed at 54 weeks (Table 9) and maintained through 102 weeks.
In Study RA II, >90% of patients had at least 2 evaluable X-rays. Inhibition of progression of structural damage was observed at Weeks 30 and 54 (Table 9) in the infliximab + MTX groups compared to MTX alone. Patients treated with infliximab + MTX demonstrated less progression of structural damage compared to MTX alone, whether baseline acute-phase reactants (ESR and CRP) were normal or elevated: patients with elevated baseline acute-phase reactants treated with MTX alone demonstrated a mean progression in vdH-S score of 4.2 units compared to patients treated with infliximab + MTX who demonstrated 0.5 units of progression; patients with normal baseline acute phase reactants treated with MTX alone demonstrated a mean progression in vdH-S score of 1.8 units compared to infliximab + MTX who demonstrated 0.2 units of progression. Of patients receiving infliximab + MTX, 59% had no progression (vdH-S score ≤ 0 unit) of structural damage compared to 45% of patients receiving MTX alone. In a subset of patients who began the study without erosions, infliximab + MTX maintained an erosion-free state at 1 year in a greater proportion of patients than MTX alone, 79% (77/98) vs. 58% (23/40), respectively (P<0.01). Fewer patients in the infliximab + MTX groups (47%) developed erosions in uninvolved joints compared to MTX alone (59%).
Physical function and disability were assessed using the Health Assessment Questionnaire (HAQ-DI) and the general health-related quality of life questionnaire SF-36.
In Study RA I, all doses/schedules of infliximab + MTX showed significantly greater improvement from baseline in HAQ-DI and SF-36 physical component summary score averaged over time through Week 54 compared to placebo + MTX, and no worsening in the SF-36 mental component summary score. The median (interquartile range) improvement from baseline to Week 54 in HAQ-DI was 0.1 (-0.1, 0.5) for the placebo + MTX group and 0.4 (0.1, 0.9) for infliximab + MTX (p<0.001). Both HAQ-DI and SF-36 effects were maintained through Week 102. Approximately 80% of patients in all doses/schedules of infliximab + MTX remained in the trial through 102 weeks.
In Study RA II, both infliximab treatment groups showed greater improvement in HAQ-DI from baseline averaged over time through Week 54 compared to MTX alone; 0.7 for infliximab + MTX vs. 0.6 for MTX alone (P≤0.001). No worsening in the SF-36 mental component summary score was observed.
### Ankylosing Spondylitis
The safety and efficacy of infliximab were assessed in a randomized, multicenter, double-blind, placebo-controlled study in 279 patients with active ankylosing spondylitis. Patients were between 18 and 74 years of age, and had ankylosing spondylitis as defined by the modified New York criteria for Ankylosing Spondylitis.4 Patients were to have had active disease as evidenced by both a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score >4 (possible range 0–10) and spinal pain >4 (on a Visual Analog Scale [VAS] of 0–10). Patients with complete ankylosis of the spine were excluded from study participation, and the use of Disease Modifying Anti-Rheumatic Drugs (DMARDs) and systemic corticosteroids were prohibited. Doses of infliximab 5 mg/kg or placebo were administered intravenously at Weeks 0, 2, 6, 12 and 18.
At 24 weeks, improvement in the signs and symptoms of ankylosing spondylitis, as measured by the proportion of patients achieving a 20% improvement in ASAS response criteria (ASAS 20), was seen in 60% of patients in the infliximab-treated group vs. 18% of patients in the placebo group (p<0.001). Improvement was observed at Week 2 and maintained through Week 24 (Figure 3 and Table 10).
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At 24 weeks, the proportions of patients achieving a 50% and a 70% improvement in the signs and symptoms of ankylosing spondylitis, as measured by ASAS response criteria (ASAS 50 and ASAS 70, respectively), were 44% and 28%, respectively, for patients receiving infliximab, compared to 9% and 4%, respectively, for patients receiving placebo (P<0.001, infliximab vs. placebo). A low level of disease activity (defined as a value <20 [on a scale of 0–100 mm] in each of the 4 ASAS response parameters) was achieved in 22% of infliximab-treated patients vs. 1% in placebo-treated patients (P<0.001).
The median improvement from baseline in the general health-related quality-of-life questionnaire SF-36 physical component summary score at Week 24 was 10.2 for the infliximab group vs. 0.8 for the placebo group (P<0.001). There was no change in the SF-36 mental component summary score in either the infliximab group or the placebo group.
Results of this study were similar to those seen in a multicenter double-blind, placebo-controlled study of 70 patients with ankylosing spondylitis.
### Psoriatic Arthritis
Safety and efficacy of infliximab were assessed in a multicenter, double-blind, placebo-controlled study in 200 adult patients with active psoriatic arthritis despite DMARD or NSAID therapy (≥5 swollen joints and ≥5 tender joints) with 1 or more of the following subtypes: arthritis involving DIP joints (n=49), arthritis mutilans (n=3), asymmetric peripheral arthritis (n=40), polyarticular arthritis (n=100), and spondylitis with peripheral arthritis (n=8). Patients also had plaque psoriasis with a qualifying target lesion ≥2 cm in diameter. Forty-six percent of patients continued on stable doses of methotrexate (≤25 mg/week). During the 24-week double-blind phase, patients received either 5 mg/kg infliximab or placebo at Weeks 0, 2, 6, 14, and 22 (100 patients in each group). At Week 16, placebo patients with <10% improvement from baseline in both swollen and tender joint counts were switched to infliximab induction (early escape). At Week 24, all placebo-treated patients crossed over to infliximab induction. Dosing continued for all patients through Week 46.
Treatment with infliximab resulted in improvement in signs and symptoms, as assessed by the ACR criteria, with 58% of infliximab-treated patients achieving ACR 20 at Week 14, compared with 11% of placebo-treated patients (P< 0.001). The response was similar regardless of concomitant use of methotrexate. Improvement was observed as early as Week 2. At 6 months, the ACR 20/50/70 responses were achieved by 54%, 41%, and 27%, respectively, of patients receiving infliximab compared to 16%, 4%, and 2%, respectively, of patients receiving placebo. Similar responses were seen in patients with each of the subtypes of psoriatic arthritis, although few patients were enrolled with the arthritis mutilans and spondylitis with peripheral arthritis subtypes.
Compared to placebo, treatment with infliximab resulted in improvements in the components of the ACR response criteria, as well as in dactylitis and enthesopathy (Table 11). The clinical response was maintained through Week 54. Similar ACR responses were observed in an earlier randomized, placebo-controlled study of 104 psoriatic arthritis patients, and the responses were maintained through 98 weeks in an open-label extension phase.
Improvement in Psoriasis Area and Severity Index (PASI) in psoriatic arthritis patients with baseline body surface area (BSA) ≥3% (n=87 placebo, n=83 infliximab) was achieved at Week 14, regardless of concomitant methotrexate use, with 64% of infliximab-treated patients achieving at least 75% improvement from baseline vs. 2% of placebo-treated patients; improvement was observed in some patients as early as Week 2. At 6 months, the PASI 75 and PASI 90 responses were achieved by 60% and 39%, respectively, of patients receiving infliximab compared to 1% and 0%, respectively, of patients receiving placebo. The PASI response was generally maintained through Week 54.
Structural damage in both hands and feet was assessed radiographically by the change from baseline in the van der Heijde-Sharp (vdH-S) score, modified by the addition of hand DIP joints. The total modified vdH-S score is a composite score of structural damage that measures the number and size of joint erosions and the degree of joint space narrowing (JSN) in the hands and feet. At Week 24, infliximab-treated patients had less radiographic progression than placebo-treated patients (mean change of -0.70 vs. 0.82, P<0.001). infliximab-treated patients also had less progression in their erosion scores (-0.56 vs 0.51) and JSN scores (-0.14 vs 0.31). The patients in the infliximab group demonstrated continued inhibition of structural damage at Week 54. Most patients showed little or no change in the vdH-S score during this 12-month study (median change of 0 in both patients who initially received infliximab or placebo). More patients in the placebo group (12%) had readily apparent radiographic progression compared with the infliximab group (3%).
Physical function status was assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. infliximab-treated patients demonstrated significant improvement in physical function as assessed by HAQ-DI (median percent improvement in HAQ-DI score from baseline to Week 14 and 24 of 43% for infliximab-treated patients vs 0% for placebo-treated patients).
During the placebo-controlled portion of the trial (24 weeks), 54% of infliximab-treated patients achieved a clinically meaningful improvement in HAQ-DI (≥0.3 unit decrease) compared to 22% of placebo-treated patients. infliximab-treated patients also demonstrated greater improvement in the SF-36 physical and mental component summary scores than placebo-treated patients. The responses were maintained for up to 2 years in an open-label extension study.
The safety and efficacy of infliximab were assessed in 3 randomized, double-blind, placebo-controlled studies in patients 18 years of age and older with chronic, stable plaque psoriasis involving ≥10% BSA, a minimum PASI score of 12, and who were candidates for systemic therapy or phototherapy. Patients with guttate, pustular, or erythrodermic psoriasis were excluded from these studies. No concomitant anti-psoriatic therapies were allowed during the study, with the exception of low-potency topical corticosteroids on the face and groin after Week 10 of study initiation.
Study I (EXPRESS) evaluated 378 patients who received placebo or infliximab at a dose of 5 mg/kg at Weeks 0, 2, and 6 (induction therapy), followed by maintenance therapy every 8 weeks. At Week 24, the placebo group crossed over to infliximab induction therapy (5 mg/kg), followed by maintenance therapy every 8 weeks. Patients originally randomized to infliximab continued to receive infliximab 5 mg/kg every 8 weeks through Week 46. Across all treatment groups, the median baseline PASI score was 21 and the baseline Static Physician Global Assessment (sPGA) score ranged from moderate (52% of patients) to marked (36%) to severe (2%). In addition, 75% of patients had a BSA >20%. Seventy-one percent of patients previously received systemic therapy, and 82% received phototherapy.
Study II (EXPRESS II) evaluated 835 patients who received placebo or infliximab at doses of 3 mg/kg or 5 mg/kg at Weeks 0, 2, and 6 (induction therapy). At Week 14, within each infliximab dose group, patients were randomized to either scheduled (every 8 weeks) or as needed (PRN) maintenance treatment through Week 46. At Week 16, the placebo group crossed over to infliximab induction therapy (5 mg/kg), followed by maintenance therapy every 8 weeks. Across all treatment groups, the median baseline PASI score was 18, and 63% of patients had a BSA >20%. Fifty-five percent of patients previously received systemic therapy, and 64% received a phototherapy.
Study III (SPIRIT) evaluated 249 patients who had previously received either psoralen plus ultraviolet A treatment (PUVA) or other systemic therapy for their psoriasis. These patients were randomized to receive either placebo or infliximab at doses of 3 mg/kg or 5 mg/kg at Weeks 0, 2, and 6. At Week 26, patients with a sPGA score of moderate or worse (greater than or equal to 3 on a scale of 0 to 5) received an additional dose of the randomized treatment. Across all treatment groups, the median baseline PASI score was 19, and the baseline sPGA score ranged from moderate (62% of patients) to marked (22%) to severe (3%). In addition, 75% of patients had a BSA >20%. Of the enrolled patients, 114 (46%) received the Week 26 additional dose.
In Studies I, II and III, the primary endpoint was the proportion of patients who achieved a reduction in score of at least 75% from baseline at Week 10 by the PASI (PASI 75). In Study I and Study III, another evaluated outcome included the proportion of patients who achieved a score of "cleared" or "minimal" by the sPGA. The sPGA is a 6-category scale ranging from "5 = severe" to "0 = cleared" indicating the physician's overall assessment of the psoriasis severity focusing on induration, erythema, and scaling. Treatment success, defined as "cleared" or "minimal," consisted of none or minimal elevation in plaque, up to faint red coloration in erythema, and none or minimal fine scale over <5% of the plaque.
Study II also evaluated the proportion of patients who achieved a score of "clear" or "excellent" by the relative Physician's Global Assessment (rPGA). The rPGA is a 6-category scale ranging from "6 = worse" to "1 = clear" that was assessed relative to baseline. Overall lesions were graded with consideration to the percent of body involvement as well as overall induration, scaling, and erythema. Treatment success, defined as "clear" or "excellent," consisted of some residual pinkness or pigmentation to marked improvement (nearly normal skin texture; some erythema may be present). The results of these studies are presented in Table 12.
In Study I, in the subgroup of patients with more extensive psoriasis who had previously received phototherapy, 85% of patients on 5 mg/kg infliximab achieved a PASI 75 at Week 10 compared with 4% of patients on placebo.
In Study II, in the subgroup of patients with more extensive psoriasis who had previously received phototherapy, 72% and 77% of patients on 3 mg/kg and 5 mg/kg infliximab achieved a PASI 75 at Week 10 respectively compared with 1% on placebo. In Study II, among patients with more extensive psoriasis who had failed or were intolerant to phototherapy, 70% and 78% of patients on 3 mg/kg and 5 mg/kg infliximab achieved a PASI 75 at Week 10 respectively, compared with 2% on placebo.
Maintenance of response was studied in a subset of 292 and 297 infliximab-treated patients in the 3 mg/kg and 5 mg/kg groups; respectively, in Study II. Stratified by PASI response at Week 10 and investigational site, patients in the active treatment groups were re-randomized to either a scheduled or as needed maintenance (PRN) therapy, beginning on Week 14.
The groups that received a maintenance dose every 8 weeks appear to have a greater percentage of patients maintaining a PASI 75 through week 50 as compared to patients who received the as-needed or PRN doses, and the best response was maintained with the 5 mg/kg every 8-week dose. These results are shown in Figure 4. At Week 46, when infliximab serum concentrations were at trough level, in the every 8-week dose group, 54% of patients in the 5 mg/kg group compared to 36% in the 3 mg/kg group achieved PASI 75. The lower percentage of PASI 75 responders in the 3 mg/kg every 8-week dose group compared to the 5 mg/kg group was associated with a lower percentage of patients with detectable trough serum infliximab levels. This may be related in part to higher antibody rates. In addition, in a subset of patients who had achieved a response at Week 10, maintenance of response appears to be greater in patients who received infliximab every 8 weeks at the 5 mg/kg dose. Regardless of whether the maintenance doses are PRN or every 8 weeks, there is a decline in response in a subpopulation of patients in each group over time. The results of Study I through Week 50 in the 5 mg/kg every 8 weeks maintenance dose group were similar to the results from Study II.
Efficacy and safety of infliximab treatment beyond 50 weeks have not been evaluated in patients with plaque psoriasis.
# How Supplied
Each infliximab 20 mL vial is individually packaged in a carton. Infliximab is supplied in an accumulator carton containing 10 vials.
- NDC 57894-030-01 100 mg vial
- Each single dose vial contains 100 mg of infliximab for final reconstitution volume of 10 mL.
## Storage
- Infliximab must be refrigerated at 2ºC to 8ºC (36ºF to 46ºF).
- Do not use infliximab beyond the expiration date (Exp) located on the carton and the vial. This product contains no preservative.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients or their caregivers should be advised of the potential benefits and risks of infliximab. Physicians should instruct their patients to read the Medication Guide before starting infliximab therapy and to reread it each time they receive an infusion. It is important that the patient's overall health be assessed at each treatment visit and that any questions resulting from the patient's or their caregiver's reading of the Medication Guide be discussed.
- Immunosuppression: Inform patients that infliximab may lower the ability of their immune system to fight infections. Instruct patients of the importance of contacting their doctors if they develop any symptoms of an infection, including tuberculosis and reactivation of hepatitis B virus infections. Patients should be counseled about the risk of lymphoma and other malignancies while receiving infliximab.
- Other Medical Conditions: Advise patients to report any signs of new or worsening medical conditions such as heart disease, neurological disease, or autoimmune disorders. Advise patients to report any symptoms of a cytopenia such as bruising, bleeding or persistent fever.
# Precautions with Alcohol
Alcohol-Infliximab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Remicade
# Look-Alike Drug Names
- Infliximab - Rituximab
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Infliximab | |
fd2d47dd26b97b90c090ac0e6c2f821f3505a959 | wikidoc | Vital heat | Vital heat
Vital heat, also called innate or natural heat, or calidum innatum, is a term that has generally referred to the heat produced within the body, usually the heat produced by the heart and the circulatory system.
According to Ancient Greek physicians, vital heat was produced by the heart, maintained by the pneuma (spirit or soul), and circulated throughout the body by blood vessels, which were thought to be intact tubes using blood to transmit heat. Aristotle supported this argument by showing that when the heart is made cold compared to other organs, the individual dies. He believed that the heat produced in the heart caused blood to react in a similar way to boiling, expanding out through the blood vessels with every beat. This extreme heat, according to him, can lead to a self-consuming flame if it is not cooled by air from the lungs.
Galen wrote in On the Usefulness of the Parts of the Body (170): "The heart is, as it were, the hearthstone and source of the innate heat by which the animal is governed." In the 11th century, Avicenna agreed with this notion, stating that the heart produced breath, the "vital power or innate heat" within the body, in his Canon of Medicine.
Later, the term innate heat was attributed to friction caused by the motion of blood through arteries, as evidenced by the Cyclopaedia (1728): | Vital heat
Template:WikiDoc Cardiology News
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
Vital heat, also called innate or natural heat, or calidum innatum, is a term that has generally referred to the heat produced within the body, usually the heat produced by the heart and the circulatory system.
According to Ancient Greek physicians, vital heat was produced by the heart, maintained by the pneuma (spirit or soul), and circulated throughout the body by blood vessels, which were thought to be intact tubes using blood to transmit heat. Aristotle supported this argument by showing that when the heart is made cold compared to other organs, the individual dies. He believed that the heat produced in the heart caused blood to react in a similar way to boiling, expanding out through the blood vessels with every beat. This extreme heat, according to him, can lead to a self-consuming flame if it is not cooled by air from the lungs.[1]
Galen wrote in On the Usefulness of the Parts of the Body (170): "The heart is, as it were, the hearthstone and source of the innate heat by which the animal is governed." In the 11th century, Avicenna agreed with this notion, stating that the heart produced breath, the "vital power or innate heat" within the body, in his Canon of Medicine.[2]
Later, the term innate heat was attributed to friction caused by the motion of blood through arteries, as evidenced by the Cyclopaedia (1728): | https://www.wikidoc.org/index.php/Innate_heat | |
0fd8047251b0aa7b591de6ef78963d9b550beaa4 | wikidoc | Tinzaparin | Tinzaparin
# 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
Tinzaparin is a low molecular weight heparin that is FDA approved for the treatment of acute symptomatic deep vein thrombosis with or without pulmonary embolism. There is a Black Box Warning for this drug as shown here. Common adverse reactions include bleeding, erythema, increase liver function tests, neurologic pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Deep Venous Thrombosis
- Dosage Information
- 175 anti-Xa IU/kg SC once daily for at least 6 days (INR at least 2.0 for two consecutive days)
- Warfarin therapy should be initiated within 1-3 days of tinzaparin initiation.
- (100 anti-Xa IU equals 1 mg tinzaparin sodium.)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
### Prophylaxis in Deep Venous Thrombosis
- Developed by: ACCP
- Class of Recommendation: Class IIa
- Strength of Evidence: Category B
- Dosing Information/Recommendation
- 3500 anti-Xa IU once daily SC for 5 to 10 days
### Pulmonary thromboembolism
- Developed by: ACCP
- Class of Recommendation: Class I
- Strength of Evidence: Category B
- Dosing Information/Recommendation
- 175 anti-Xa IU/kg SC once daily (until INR is 2.0 for two consecutive days)
- co-administered with oral anticoagulation
### Non–Guideline-Supported Use
### Hemodialysis
- Dosage Information
- 3500 anti-Xa IU once daily SC
### Venous thromboembolism
- Dosage Information
- 175 anti-Xa IU/kg SC once daily
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Tinzaparin 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 Tinzaparin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tinzaparin in pediatric patients.
# Contraindications
- Tinzaparin is contraindicated in patients with active major bleeding, in patients with (or history of) heparin-induced thrombocytopenia, or in patients with hypersensitivity to tinzaparin sodium.
- Patients with known hypersensitivity to heparin, sulfites, benzyl alcohol, or pork products should not be treated with tinzaparin.
# Warnings
- Tinzaparin is not intended for intramuscular or intravenous administration.
- Tinzaparin cannot be used interchangeably (unit for unit) with heparin or other low molecular weight heparins as they differ in manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units, and dosage. Each of these medications has its own instructions for use.
- Tinzaparin should not be used in patients with a history of heparin-induced thrombocytopenia.
### Increased Risk for Death in Elderly Patients with Renal Insufficiency
- Tinzaparin may increase the risk for death, compared to UFH, when administered to elderly patients with renal insufficiency.
- A clinical study compared tinzaparin (175 IU/kg once daily; N = 269) and UFH (N = 268) in the initial treatment of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in elderly patients with renal insufficiency (i.e., patients aged 70 years or older with estimated creatinine clearance of ≤ 30 mL/min or patients aged 75 years or older with estimated creatinine clearance of ≤ 60 mL/min).
- Oral anticoagulants were co-administered beginning on Days 1-3 and study treatment was continued for at least five days until the international normalized ratio (INR) was between 2-3 on two successive days; oral anticoagulants were then continued alone and patients were followed until 90 days after the start of treatment.
- Overall mortality rates were 6.3% in patients treated with UFH and 11.5% in patients treated with tinzaparin. Consider the use of alternatives to tinzaparin in elderly patients with renal insufficiency.
### Hemorrhage
- Tinzaparin, like other anticoagulants, should be used with extreme caution in conditions with increased risk of hemorrhage, such as bacterial endocarditis; severe uncontrolled hypertension; congenital or acquired bleeding disorders including hepatic failure and amyloidosis; active ulcerative and angiodysplastic gastrointestinal disease; hemorrhagic stroke; shortly after brain, spinal or ophthalmological surgery, or in patients treated concomitantly with platelet inhibitors.
- Bleeding can occur in any tissue or organ of the body during therapy with tinzaparin. Hemorrhage in some cases has been reported to result in death or permanent disability.
- A hemorrhagic event should be seriously considered in the presence of an unexplained fall in hematocrit, hemoglobin, or blood pressure.
- If severe hemorrhage occurs, tinzaparin should be discontinued.
- Spinal or epidural hematomas can occur with the associated use of low molecular weight heparins or heparinoids and spinal/epidural anesthesia or spinal puncture which can result in long-term or permanent paralysis. The risk of these events is higher with the use of post-operative indwelling epidural catheters or with the concomitant use of additional drugs affecting hemostasis such as NSAIDs.
### Thrombocytopenia
- Thrombocytopenia can occur with the administration of tinzaparin.
- In clinical studies, thrombocytopenia (platelet count <100,000/mm3 if baseline value ≥150,000/mm3, ≥50% decline if baseline <150,000/mm3) was identified in 1% of patients given tinzaparin; severe thrombocytopenia (platelet count less than 50,000/mm3) occurred in 0.13%.
- Thrombocytopenia of any degree should be monitored closely.
- If the platelet count falls below 100,000/mm3, tinzaparin should be discontinued. Cases of thrombocytopenia with disseminated thrombosis also have been observed in clinical practice with heparins, and low molecular weight heparins, including tinzaparin sodium. Some of these cases were complicated by organ infarction with secondary organ dysfunction or limb ischemia, and have resulted in death.
### Hypersensitivity
- Tinzaparin contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening asthmatic episodes in certain susceptible people.
- The overall prevalence of sulfite sensitivity in the general population is unknown, but is probably low.
- Sulfite sensitivity is more frequent in asthmatic people than in non-asthmatic people.
### Priapism
- Priapism has been reported from post-marketing surveillance as a rare occurrence. In some cases surgical intervention was required.
### Miscellaneous
- Tinzaparin multiple dose vial contains benzyl alcohol as a preservative.
- The administration of medications containing benzyl alcohol as a preservative to premature neonates has been associated with a fatal “Gasping Syndrome."
- Because benzyl alcohol may cross the placenta, tinzaparin preserved with benzyl alcohol should be used with caution in pregnant women only if clearly needed
# Adverse Reactions
## Clinical Trials Experience
### Bleeding
Bleeding is the most common adverse event associated with tinzaparin; however, the incidence of major bleeding is low. In clinical trials, the definition of major bleeding included bleeding accompanied by ≥2 gram/dL decrease in hemoglobin, requiring transfusion of 2 or more units of blood products, or bleeding which was intracranial, retroperitoneal, or into a major prosthetic joint. The data are provided in Table 4.
Fatal or nonfatal hemorrhage from any tissue or organ can occur. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding. Hemorrhagic complications may present as, but are not limited to, paralysis; paresthesia; headache, chest, abdomen, joint, muscle or other pain; dizziness; shortness of breath, difficult breathing or swallowing; swelling; weakness; hypotension, shock, or coma. Therefore, the possibility of hemorrhage should be considered in evaluating the condition of any anticoagulated patient with complaints which do not indicate an obvious diagnosis.
### Thrombocytopenia
In clinical studies thrombocytopenia was identified in 1% of patients treated with tinzaparin. Severe thrombocytopenia (platelet count <50,000/mm3) occurred in 0.13%.
### Elevations of Serum Aminotransferases
Asymptomatic increases in aspartate (AST ) and/or alanine (ALT ) aminotransferase levels greater than 3 times the upper limit of normal of the laboratory reference range have been reported in up to 8.8% and 13% for AST and ALT, respectively, of patients receiving tinzaparin sodium for the treatment of DVT. Similar increases in aminotransferase levels have also been observed in patients and healthy volunteers treated with heparin and other low molecular weight heparins. Such elevations are reversible and are rarely associated with increases in bilirubin.
### Local Reactions
Mild local irritation, pain, hematoma, and ecchymosis may follow SC injection of tinzaparin. Injection site hematoma has been reported in approximately 16% of patients treated with tinzaparin.
### Hypersensitivity
Anaphylactic/anaphylactoid reactions may occur in association with tinzaparin use.
### Adverse Events
Adverse events with tinzaparin or heparin reported at a frequency of ≥1% in clinical trials with patients undergoing treatment for proximal DVT with or without PE, are provided in Table 5.
### Other Adverse Events in Completed or Ongoing Trials
Other adverse events reported at a frequency of ≥1% in 4,000 patients who received tinzaparin in completed or ongoing clinical trials are listed by body system:
- Body as a Whole: injection site hematoma, reaction unclassified.
- Cardiovascular: hypotension, hypertension, tachycardia, angina pectoris.
- Central and Peripheral Nervous System: dizziness.
- Gastrointestinal: flatulence, gastrointestinal disorder (not otherwise specified), dyspepsia.
- Platelet, Bleeding and Clotting Disorders: hematoma, thrombocytopenia.
- Psychiatric: insomnia, confusion.
- Red Blood Cell Disorders: anemia.
- Resistance Mechanism Disorders: healing impaired, infection.
- Respiratory System: pneumonia, respiratory disorder.
- Dermatology: rash erythematous, pruritus, bullous eruption, skin disorder.
- Urinary System: urinary retention, dysuria.
- Vascular (Extracardiac) Disorders: thrombophlebitis.
## Postmarketing Experience
# Drug Interactions
- Because of increased risk of bleeding, tinzaparin should be used with caution in patients receiving oral anticoagulants, platelet inhibitors (e.g., salicylates, dipyridamole, sulfinpyrazone, dextran, NSAIDs including ketorolac tromethamine, ticlopidine, and clopidogrel), and thrombolytics.
- If coadministration is essential, close clinical and laboratory monitoring of these patients is advised
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. The fetal risk summary below describes the potential of tinzaparin to increase the risk of developmental abnormalities above background risk.
Tinzaparin is not predicted to increase the risk of developmental abnormalities. Tinzaparin does not cross the placenta, based on human and animal studies, and shows no evidence of teratogenic effects or fetotoxicity.
Pregnancy alone confers an increased risk for thromboembolism that is even higher for women with preexisting thromboembolic disease, certain high risk pregnancy conditions, and a history of complications during a previous pregnancy.
All patients receiving anticoagulants such as tinzaparin, including pregnant women, are at risk for bleeding. Pregnant women receiving tinzaparin should be carefully monitored for evidence of bleeding or excessive anticoagulation. Hemorrhage can occur at any site and may lead to death of mother and/or fetus. Pregnant women should be apprised of the potential hazard to the fetus and the mother if tinzaparin is administered during pregnancy. Consideration for use of a shorter acting agent should be specifically addressed as delivery approaches.
Fifty-four women pregnant or planning to become pregnant with conditions requiring anticoagulation received tinzaparin in an open-label, prospective, pregnancy dose finding study. Patients received 50 to 175 IU/kg/day, with dosing starting as early as prior to conception or as late as 32 weeks gestation. Duration of exposure ranged from 3 to 463 days (median 159 days). From 55 pregnancies, there were 50 live births, 3 first trimester miscarriages, and 2 intrauterine deaths at 17 and 30 weeks. Approximately 6% of pregnancies were complicated by fetal distress.
Approximately 10% of pregnant women receiving tinzaparin experienced significant vaginal bleeding. A cause and effect relationship for the above observations has not been established.
Teratogenicity studies have been performed in rats at SC doses up to 1800 IU/kg/day (about 2 times the maximum recommended human dose based on body surface area) and in rabbits at SC doses up to 1900 IU/kg/day (about 4 times the maximum recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to tinzaparin sodium. 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. tinzaparin does not cross the placenta.
Cases of "Gasping Syndrome" have occurred in premature infants when large amounts of benzyl alcohol have been administered (99 - 404 mg/kg/day). The 2 mL vial of tinzaparin contains 20 mg of benzyl alcohol (10 mg of benzyl alcohol per mL). If tinzaparin is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of potential hazards to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tinzaparin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tinzaparin during labor and delivery.
### Nursing Mothers
In studies where tinzaparin sodium was administered subcutaneously to lactating rats, very low levels of tinzaparin sodium were found in breast milk. It is not known whether tinzaparin sodium is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tinzaparin is administered to nursing women.
### Pediatric Use
Safety and effectiveness of tinzaparin sodium in pediatric patients have not been established.
### Geriatic Use
tinzaparin may increase the risk for death, compared to UFH, when administered to elderly patients with renal insufficiency. In the clinical studies for the treatment of DVT described in the clinical studies section, 58% of patients were 65 or older and 29% were 75 and over. In these studies, no significant overall differences in safety or effectiveness were observed between these subjects and younger subjects.
### Gender
There is no FDA guidance on the use of Tinzaparin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tinzaparin with respect to specific racial populations.
### Renal Impairment
In patients being treated with tinzaparin sodium (175 IU/kg) for DVT, a population pharmacokinetic (PK) analysis determined that tinzaparin sodium clearance based on anti-Xa activity was related to creatinine clearance calculated by the Cockroft Gault equation. In this PK analysis, a reduction in tinzaparin sodium clearance in moderate (30-50 mL/min) and severe (80 mL/min).
In a study of 12 chronic renal failure patients undergoing hemodialysis, anti-Xa clearance was reduced 28%, consistent with estimates from the population PK analyses. In another study of 6 patients undergoing hemodialysis, the half-life of anti-Xa activity following a single IV dose of 75 IU/kg of tinzaparin sodium on an off-dialysis day was prolonged relative to that for healthy volunteers (5.2 versus 1.6 hours).
Tinzaparin may increase the risk for death, compared to unfractionated heparin (UFH), when administered to elderly patients with renal insufficiency.
### Hepatic Impairment
No prospective studies have assessed tinzaparin sodium pharmacokinetics or pharmacodynamics in hepatically-impaired patients. However, the hepatic route is not a major route of elimination of low molecular weight heparins.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tinzaparin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tinzaparin in patients who are immunocompromised.
### Obesity
Based on the results of a prospective clinical study and the population PK analyses, weight-based dosing is appropriate for heavy/obese patients. Tinzaparin sodium PK parameters based on anti-Xa activity are independent of body weight and body mass index (BMI) when tinzaparin sodium is dosed on a weight basis at 175 IU/kg or 75 IU/kg. In a prospective study of heavy/obese subjects (101 to 165 kg; BMI 26‑61 kg/m2), anti-Xa activity time profiles were similar to those in normal-weight volunteer studies. Data at the 175 IU/kg dose are shown in Figure 2. Clinical trial experience is limited in patients with a BMI >40 kg/m2.
# Administration and Monitoring
### Administration
Tinzaparin is a clear, colorless to slightly yellow solution, and as with other parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Tinzaparin is administered by SC injection. It must not be administered by intramuscular or intravenous injection.
### Subcutaneous Injection Technique
Patients should be lying down (supine) or sitting and tinzaparin administered by deep SC injection. Administration should be alternated between the left and right anterolateral and left and right posterolateral abdominal wall. The injection site should be varied daily. The whole length of the needle should be introduced into a skin fold held between the thumb and forefinger; the skin fold should be held throughout the injection. To minimize bruising, do not rub the injection site after completion of the injection.
### Monitoring
Periodic complete blood counts including platelet count and hematocrit or hemoglobin, and stool tests for occult blood are recommended during treatment with tinzaparin. When administered at the recommended doses, routine anticoagulation tests such as prothrombin time (PT) and activated partial thromboplastin time (aPTT) are relatively insensitive measures of tinzaparin activity and, therefore, are unsuitable for monitoring.
# IV Compatibility
There is limited information regarding the compatibility of Tinzaparin and IV administrations.
# Overdosage
Accidental overdosage of tinzaparin may lead to bleeding complications. Nosebleeds, blood in urine or tarry stools may be noted as the first signs of bleeding. Easy bruising or petechial hemorrhages may precede frank bleeding. In case of minor bleeding, the patient should be monitored for signs of more severe bleeding.
Of patients known to have received an overdose of tinzaparin sodium in clinical trials, defined as one or more doses >200 IU/kg for the treatment of DVT or >100 IU/kg for the prevention of DVT, approximately 16% experienced a bleeding complication.
Of spontaneous reports of probable overdosing with tinzaparin sodium, approximately 81% were accompanied by bleeding, usually hematoma. Most patients who have bleeding complications while receiving tinzaparin can be controlled by discontinuing tinzaparin, applying pressure to the site, if possible, and replacing volume and hemostatic blood elements (e.g., red blood cells, fresh frozen plasma, platelets) as required. In the event that this is ineffective, protamine sulfate can be administered.
In cases of serious bleeding or large overdose, protamine sulfate (1% solution) can be given by slow IV infusion at a dose of 1 mg protamine for every 100 anti-Xa IU of tinzaparin given. A second infusion of 0.5 mg protamine sulfate per 100 anti-Xa IU of tinzaparin may be administered if the aPTT measured 2 to 4 hours after the first infusion remains prolonged. Even with the additional dose of protamine, the aPTT may remain more prolonged than would usually be found following administration of protamine to reverse unfractionated heparin. Protamine does not completely neutralize tinzaparin sodium anti-Xa activity (maximum about 60%).
Particular care should be taken to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions have been reported with protamine sulfate, it should be given only when resuscitation facilities are readily available. For additional information consult the labeling of Protamine Sulfate Injection, USP, products.
Single SC doses of tinzaparin sodium at 22,000 and 7,700 IU/kg (about 10 and 7 times the maximum recommended human dose, respectively, based upon body surface area) were lethal to mice and rats, respectively. Symptoms of acute toxicity included hematoma formation and bleeding at the injection site, anemia, decreased motor activity, unsteady gait, piloerection, and ptosis.
# Pharmacology
There is limited information regarding Tinzaparin Pharmacology in the drug label.
## Mechanism of Action
Tinzaparin sodium is a low molecular weight heparin with antithrombotic properties. Tinzaparin sodium inhibits reactions that lead to the clotting of blood including the formation of fibrin clots, both in vitro and in vivo. It acts as a potent co-inhibitor of several activated coagulation factors, especially Factor Xa and IIa (thrombin). The primary inhibitory activity is mediated through the plasma protease inhibitor, antithrombin.
Bleeding time is usually unaffected by tinzaparin sodium. Activated partial thromboplastin time (aPTT) is prolonged by therapeutic doses of tinzaparin sodium used in the treatment of deep vein thrombosis (DVT). Prothrombin time (PT) may be slightly prolonged with tinzaparin sodium treatment but usually remains within the normal range. Neither aPTT nor PT can be used for therapeutic monitoring of tinzaparin sodium.
Neither unfractionated heparin nor tinzaparin sodium have intrinsic fibrinolytic activity; therefore, they do not lyse existing clots. Tinzaparin sodium induces release of tissue factor pathway inhibitor, which may contribute to the antithrombotic effect. Heparin is also known to have a variety of actions that are independent of its anticoagulant effects. These include interactions with endothelial cell growth factors, inhibition of smooth muscle cell proliferation, activation of lipoprotein lipase, suppression of aldosterone secretion, and induction of platelet aggregation.
## Structure
Tinzaparin sodium is the sodium salt of a low molecular weight heparin obtained by controlled enzymatic depolymerization of heparin from porcine intestinal mucosa using heparinase from Flavobacterium heparinum. The majority of the components have a 2-O-sulpho-4-enepyranosuronic acid structure at the non-reducing end and a 2-N,6-O-disulpho-D-glucosamine structure at the reducing end of the chain.
Potency is determined by means of a biological assay and interpreted by the first International Low Molecular Weight Heparin Standard as units of anti-factor Xa (anti-Xa) activity per milligram. The mean tinzaparin sodium anti-factor Xa activity is approximately 100 IU per milligram. The average molecular weight ranges between 5,500 and 7,500 daltons. The molecular weight distribution is:
## Pharmacodynamics
Anti-Xa and anti-IIa activities are the primary biomarkers for assessing tinzaparin sodium exposure because plasma concentrations of low molecular weight heparins cannot be measured directly. Because of analytical assay limitations, anti-Xa activity is the more widely used biomarker. The measurements of anti-Xa and anti-IIa activities in plasma serve as surrogates for the concentrations of molecules which contain the high-affinity binding site for antithrombin (anti-Xa and anti-IIa activities). Monitoring patients based on anti-Xa activity is generally not advised.
Studies with tinzaparin sodium in healthy volunteers and patients have been conducted with both fixed- and weight-adjusted dose administration. Recommended therapy with tinzaparin sodium is based on weight-adjusted dosing
## Pharmacokinetics
### Absorption
Plasma levels of anti-Xa activity increase in the first 2 to 3 hours following SC injection of tinzaparin sodium and reach a maximum within 4 to 5 hours. Maximum concentrations (Cmax) of 0.25 and 0.87 IU/mL are achieved following a single SC fixed dose of 4,500 IU (approximately 64.3 IU/kg) and weight-adjusted dose of 175 IU/kg of tinzaparin sodium, respectively. Based on the extent of absorption (AUC0‑∞), a comparison of 4,500 IU and 12,250 IU single doses indicates that increases in anti-Xa activity are greater than dose proportional relative to the increase in dose. Following a single SC injection of tinzaparin sodium, the mean anti-Xa to anti-IIa activity ratio, based on the area under the anti-Xa and anti-IIa time profiles, is 2.8 and is higher than that of unfractionated heparin (approximately 1.2). The absolute bioavailability (following 4,500 IU SC and intravenous administrations) is 86.7% based on anti-Xa activity.
### Distribution
The volume of distribution of tinzaparin sodium ranges from 3.1 L to 5.0 L. These values are similar in magnitude to blood volume, suggesting that the distribution of anti-Xa activity is limited to the central compartment.
### Metabolism
Low molecular weight heparins are partially metabolized by desulphation and depolymerization.
### Elimination
In healthy volunteers, the elimination half-life following SC administration of 4,500 IU or 175 IU/kg tinzaparin sodium is approximately 3-4 hours based on anti-Xa activity. Clearance following IV administration of 4,500 IU tinzaparin sodium is approximately 1.7 L/hr. The primary route of elimination is renal. Anti-Xa activity did not accumulate with once daily dosing of 175 IU/kg for five days in healthy volunteers.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies in animals have been performed to evaluate the carcinogenic potential of tinzaparin sodium. Tinzaparin sodium displayed no genotoxic potential in an in vitro bacterial cell mutation assay (AMES test), in vitro Chinese hamster ovary cell forward gene mutation test, in vitro human lymphocyte chromosomal aberration assay, and in vivo mouse micronucleus assay. Tinzaparin sodium at SC doses up to 1800 IU/kg/day in rats (about 2 times the maximum recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance.
# Clinical Studies
### Treatment of Acute Deep Vein Thrombosis (DVT) With or Without Pulmonary Embolism (PE)
In a randomized, multicenter, double-blind trial tinzaparin (tinzaparin sodium injection) was compared to unfractionated heparin in 435 hospitalized patients with symptomatic, proximal DVT. Six percent of the enrolled patients had symptomatic pulmonary embolism confirmed by segmental or greater lung scan defect. The study patients ranged in age from 19 to 92 years (mean 61 ± 17 years), 55% were male, 88% were white and 8% black. Patients received either tinzaparin SC once daily according to body weight (175 IU/kg) and a placebo IV bolus followed by continuous placebo IV infusion, or unfractionated heparin as an initial IV bolus dose (5,000 IU) followed by continuous IV infusion of unfractionated heparin with the rate adjusted according to the aPTT (1.5 to 2.5 times control value) and a once daily SC placebo injection. Treatment continued for approximately 6 days, and both treatment groups also received oral warfarin sodium starting on Day 2 which continued to Day 90 with doses titrated to a target INR of 2.0 to 3.0.
The 90-day cumulative thromboembolic (TE) rate with tinzaparin was not significantly different than the rate with unfractionated heparin. The data are provided in Table 3.
Mortality with tinzaparin was 4.6% (10 patients) and with heparin 9.6% (21 patients). The 95% confidence interval (CI) for the mortality difference was 0.16%, 9.76%.
In a multicenter, open-label, randomized clinical trial tinzaparin was compared to unfractionated heparin as initial treatment for hospitalized patients with symptomatic PE not requiring thrombolytic therapy, embolectomy, or vena cava interruption. Patients were excluded if they carried an unusually high risk for thromboembolic and/or bleeding events or other complications. Of the 608 patients treated, 422 had documented DVT. Prior to determination of study eligibility and randomization, patients were allowed to receive unfractionated heparin; 78% of the patients received unfractionated heparin at therapeutic doses for up to 24 hours, and an additional 4% received heparin at therapeutic doses for greater than 24 hours. After randomization, tinzaparin was administered SC once daily, 175 IU/kg body weight; heparin as an initial IV bolus (50 IU/kg) followed by continuous IV infusion with the rate adjusted according to the aPTT (2 to 3 times control value). For both groups, treatment continued for approximately 8 days. All patients also received oral anticoagulant treatment starting in the first 3 days which continued to Day 90.
Thromboembolic events were infrequent for both treatment groups. No difference was observed between the two treatment groups for incidence of recurrence of thromboembolic events.
# How Supplied
tinzaparin is available in a multiple dose 2 mL vial in the following packages:
- Box of 1: 2 mL vial (20,000 anti-Xa IU per mL); NDC 50222-342-08
- Box of 10: 2 mL vials (20,000 anti-Xa IU per mL); NDC 50222-342-53
## Storage
Store at 25° C (77° F); excursions permitted to 15°-30° C (59°-86° F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of tinzaparin in the drug label.
# Precautions with Alcohol
Alcohol-Tinzaparin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Innohep®
# Look-Alike Drug Names
There is limited information regarding Tinzaparin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Tinzaparin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]
# Disclaimer
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# Black Box Warning
# Overview
Tinzaparin is a low molecular weight heparin that is FDA approved for the treatment of acute symptomatic deep vein thrombosis with or without pulmonary embolism. There is a Black Box Warning for this drug as shown here. Common adverse reactions include bleeding, erythema, increase liver function tests, neurologic pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Deep Venous Thrombosis
- Dosage Information
- 175 anti-Xa IU/kg SC once daily for at least 6 days (INR at least 2.0 for two consecutive days)
- Warfarin therapy should be initiated within 1-3 days of tinzaparin initiation.
- (100 anti-Xa IU equals 1 mg tinzaparin sodium.)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
### Prophylaxis in Deep Venous Thrombosis
- Developed by: ACCP
- Class of Recommendation: Class IIa
- Strength of Evidence: Category B
- Dosing Information/Recommendation
- 3500 anti-Xa IU once daily SC for 5 to 10 days[1]
### Pulmonary thromboembolism
- Developed by: ACCP
- Class of Recommendation: Class I
- Strength of Evidence: Category B
- Dosing Information/Recommendation[2]
- 175 anti-Xa IU/kg SC once daily (until INR is 2.0 for two consecutive days)
- co-administered with oral anticoagulation
### Non–Guideline-Supported Use
### Hemodialysis
- Dosage Information
- 3500 anti-Xa IU once daily SC[3]
### Venous thromboembolism
- Dosage Information
- 175 anti-Xa IU/kg SC once daily[4]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Tinzaparin 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 Tinzaparin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tinzaparin in pediatric patients.
# Contraindications
- Tinzaparin is contraindicated in patients with active major bleeding, in patients with (or history of) heparin-induced thrombocytopenia, or in patients with hypersensitivity to tinzaparin sodium.
- Patients with known hypersensitivity to heparin, sulfites, benzyl alcohol, or pork products should not be treated with tinzaparin.
# Warnings
- Tinzaparin is not intended for intramuscular or intravenous administration.
- Tinzaparin cannot be used interchangeably (unit for unit) with heparin or other low molecular weight heparins as they differ in manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units, and dosage. Each of these medications has its own instructions for use.
- Tinzaparin should not be used in patients with a history of heparin-induced thrombocytopenia.
### Increased Risk for Death in Elderly Patients with Renal Insufficiency
- Tinzaparin may increase the risk for death, compared to UFH, when administered to elderly patients with renal insufficiency.
- A clinical study compared tinzaparin (175 IU/kg once daily; N = 269) and UFH (N = 268) in the initial treatment of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in elderly patients with renal insufficiency (i.e., patients aged 70 years or older with estimated creatinine clearance of ≤ 30 mL/min or patients aged 75 years or older with estimated creatinine clearance of ≤ 60 mL/min).
- Oral anticoagulants were co-administered beginning on Days 1-3 and study treatment was continued for at least five days until the international normalized ratio (INR) was between 2-3 on two successive days; oral anticoagulants were then continued alone and patients were followed until 90 days after the start of treatment.
- Overall mortality rates were 6.3% in patients treated with UFH and 11.5% in patients treated with tinzaparin. Consider the use of alternatives to tinzaparin in elderly patients with renal insufficiency.
### Hemorrhage
- Tinzaparin, like other anticoagulants, should be used with extreme caution in conditions with increased risk of hemorrhage, such as bacterial endocarditis; severe uncontrolled hypertension; congenital or acquired bleeding disorders including hepatic failure and amyloidosis; active ulcerative and angiodysplastic gastrointestinal disease; hemorrhagic stroke; shortly after brain, spinal or ophthalmological surgery, or in patients treated concomitantly with platelet inhibitors.
- Bleeding can occur in any tissue or organ of the body during therapy with tinzaparin. Hemorrhage in some cases has been reported to result in death or permanent disability.
- A hemorrhagic event should be seriously considered in the presence of an unexplained fall in hematocrit, hemoglobin, or blood pressure.
- If severe hemorrhage occurs, tinzaparin should be discontinued.
- Spinal or epidural hematomas can occur with the associated use of low molecular weight heparins or heparinoids and spinal/epidural anesthesia or spinal puncture which can result in long-term or permanent paralysis. The risk of these events is higher with the use of post-operative indwelling epidural catheters or with the concomitant use of additional drugs affecting hemostasis such as NSAIDs.
### Thrombocytopenia
- Thrombocytopenia can occur with the administration of tinzaparin.
- In clinical studies, thrombocytopenia (platelet count <100,000/mm3 if baseline value ≥150,000/mm3, ≥50% decline if baseline <150,000/mm3) was identified in 1% of patients given tinzaparin; severe thrombocytopenia (platelet count less than 50,000/mm3) occurred in 0.13%.
- Thrombocytopenia of any degree should be monitored closely.
- If the platelet count falls below 100,000/mm3, tinzaparin should be discontinued. Cases of thrombocytopenia with disseminated thrombosis also have been observed in clinical practice with heparins, and low molecular weight heparins, including tinzaparin sodium. Some of these cases were complicated by organ infarction with secondary organ dysfunction or limb ischemia, and have resulted in death.
### Hypersensitivity
- Tinzaparin contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening asthmatic episodes in certain susceptible people.
- The overall prevalence of sulfite sensitivity in the general population is unknown, but is probably low.
- Sulfite sensitivity is more frequent in asthmatic people than in non-asthmatic people.
### Priapism
- Priapism has been reported from post-marketing surveillance as a rare occurrence. In some cases surgical intervention was required.
### Miscellaneous
- Tinzaparin multiple dose vial contains benzyl alcohol as a preservative.
- The administration of medications containing benzyl alcohol as a preservative to premature neonates has been associated with a fatal “Gasping Syndrome."
- Because benzyl alcohol may cross the placenta, tinzaparin preserved with benzyl alcohol should be used with caution in pregnant women only if clearly needed
# Adverse Reactions
## Clinical Trials Experience
### Bleeding
Bleeding is the most common adverse event associated with tinzaparin; however, the incidence of major bleeding is low. In clinical trials, the definition of major bleeding included bleeding accompanied by ≥2 gram/dL decrease in hemoglobin, requiring transfusion of 2 or more units of blood products, or bleeding which was intracranial, retroperitoneal, or into a major prosthetic joint. The data are provided in Table 4.
Fatal or nonfatal hemorrhage from any tissue or organ can occur. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding. Hemorrhagic complications may present as, but are not limited to, paralysis; paresthesia; headache, chest, abdomen, joint, muscle or other pain; dizziness; shortness of breath, difficult breathing or swallowing; swelling; weakness; hypotension, shock, or coma. Therefore, the possibility of hemorrhage should be considered in evaluating the condition of any anticoagulated patient with complaints which do not indicate an obvious diagnosis.
### Thrombocytopenia
In clinical studies thrombocytopenia was identified in 1% of patients treated with tinzaparin. Severe thrombocytopenia (platelet count <50,000/mm3) occurred in 0.13%.
### Elevations of Serum Aminotransferases
Asymptomatic increases in aspartate (AST [SGOT]) and/or alanine (ALT [SGPT]) aminotransferase levels greater than 3 times the upper limit of normal of the laboratory reference range have been reported in up to 8.8% and 13% for AST and ALT, respectively, of patients receiving tinzaparin sodium for the treatment of DVT. Similar increases in aminotransferase levels have also been observed in patients and healthy volunteers treated with heparin and other low molecular weight heparins. Such elevations are reversible and are rarely associated with increases in bilirubin.
### Local Reactions
Mild local irritation, pain, hematoma, and ecchymosis may follow SC injection of tinzaparin. Injection site hematoma has been reported in approximately 16% of patients treated with tinzaparin.
### Hypersensitivity
Anaphylactic/anaphylactoid reactions may occur in association with tinzaparin use.
### Adverse Events
Adverse events with tinzaparin or heparin reported at a frequency of ≥1% in clinical trials with patients undergoing treatment for proximal DVT with or without PE, are provided in Table 5.
### Other Adverse Events in Completed or Ongoing Trials
Other adverse events reported at a frequency of ≥1% in 4,000 patients who received tinzaparin in completed or ongoing clinical trials are listed by body system:
- Body as a Whole: injection site hematoma, reaction unclassified.
- Cardiovascular: hypotension, hypertension, tachycardia, angina pectoris.
- Central and Peripheral Nervous System: dizziness.
- Gastrointestinal: flatulence, gastrointestinal disorder (not otherwise specified), dyspepsia.
- Platelet, Bleeding and Clotting Disorders: hematoma, thrombocytopenia.
- Psychiatric: insomnia, confusion.
- Red Blood Cell Disorders: anemia.
- Resistance Mechanism Disorders: healing impaired, infection.
- Respiratory System: pneumonia, respiratory disorder.
- Dermatology: rash erythematous, pruritus, bullous eruption, skin disorder.
- Urinary System: urinary retention, dysuria.
- Vascular (Extracardiac) Disorders: thrombophlebitis.
## Postmarketing Experience
# Drug Interactions
- Because of increased risk of bleeding, tinzaparin should be used with caution in patients receiving oral anticoagulants, platelet inhibitors (e.g., salicylates, dipyridamole, sulfinpyrazone, dextran, NSAIDs including ketorolac tromethamine, ticlopidine, and clopidogrel), and thrombolytics.
- If coadministration is essential, close clinical and laboratory monitoring of these patients is advised
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. The fetal risk summary below describes the potential of tinzaparin to increase the risk of developmental abnormalities above background risk.
Tinzaparin is not predicted to increase the risk of developmental abnormalities. Tinzaparin does not cross the placenta, based on human and animal studies, and shows no evidence of teratogenic effects or fetotoxicity.
Pregnancy alone confers an increased risk for thromboembolism that is even higher for women with preexisting thromboembolic disease, certain high risk pregnancy conditions, and a history of complications during a previous pregnancy.
All patients receiving anticoagulants such as tinzaparin, including pregnant women, are at risk for bleeding. Pregnant women receiving tinzaparin should be carefully monitored for evidence of bleeding or excessive anticoagulation. Hemorrhage can occur at any site and may lead to death of mother and/or fetus. Pregnant women should be apprised of the potential hazard to the fetus and the mother if tinzaparin is administered during pregnancy. Consideration for use of a shorter acting agent should be specifically addressed as delivery approaches.
Fifty-four women pregnant or planning to become pregnant with conditions requiring anticoagulation received tinzaparin in an open-label, prospective, pregnancy dose finding study. Patients received 50 to 175 IU/kg/day, with dosing starting as early as prior to conception or as late as 32 weeks gestation. Duration of exposure ranged from 3 to 463 days (median 159 days). From 55 pregnancies, there were 50 live births, 3 first trimester miscarriages, and 2 intrauterine deaths at 17 and 30 weeks. Approximately 6% of pregnancies were complicated by fetal distress.
Approximately 10% of pregnant women receiving tinzaparin experienced significant vaginal bleeding. A cause and effect relationship for the above observations has not been established.
Teratogenicity studies have been performed in rats at SC doses up to 1800 IU/kg/day (about 2 times the maximum recommended human dose based on body surface area) and in rabbits at SC doses up to 1900 IU/kg/day (about 4 times the maximum recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to tinzaparin sodium. 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. tinzaparin does not cross the placenta.
Cases of "Gasping Syndrome" have occurred in premature infants when large amounts of benzyl alcohol have been administered (99 - 404 mg/kg/day). The 2 mL vial of tinzaparin contains 20 mg of benzyl alcohol (10 mg of benzyl alcohol per mL). If tinzaparin is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of potential hazards to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tinzaparin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tinzaparin during labor and delivery.
### Nursing Mothers
In studies where tinzaparin sodium was administered subcutaneously to lactating rats, very low levels of tinzaparin sodium were found in breast milk. It is not known whether tinzaparin sodium is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tinzaparin is administered to nursing women.
### Pediatric Use
Safety and effectiveness of tinzaparin sodium in pediatric patients have not been established.
### Geriatic Use
tinzaparin may increase the risk for death, compared to UFH, when administered to elderly patients with renal insufficiency. In the clinical studies for the treatment of DVT described in the clinical studies section, 58% of patients were 65 or older and 29% were 75 and over. In these studies, no significant overall differences in safety or effectiveness were observed between these subjects and younger subjects.
### Gender
There is no FDA guidance on the use of Tinzaparin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tinzaparin with respect to specific racial populations.
### Renal Impairment
In patients being treated with tinzaparin sodium (175 IU/kg) for DVT, a population pharmacokinetic (PK) analysis determined that tinzaparin sodium clearance based on anti-Xa activity was related to creatinine clearance calculated by the Cockroft Gault equation. In this PK analysis, a reduction in tinzaparin sodium clearance in moderate (30-50 mL/min) and severe (<30 mL/min) renal impairment was observed. Patients with severe renal impairment exhibited a 24% reduction in tinzaparin sodium clearance relative to patients with normal renal function (>80 mL/min).
In a study of 12 chronic renal failure patients undergoing hemodialysis, anti-Xa clearance was reduced 28%, consistent with estimates from the population PK analyses. In another study of 6 patients undergoing hemodialysis, the half-life of anti-Xa activity following a single IV dose of 75 IU/kg of tinzaparin sodium on an off-dialysis day was prolonged relative to that for healthy volunteers (5.2 versus 1.6 hours).
Tinzaparin may increase the risk for death, compared to unfractionated heparin (UFH), when administered to elderly patients with renal insufficiency.
### Hepatic Impairment
No prospective studies have assessed tinzaparin sodium pharmacokinetics or pharmacodynamics in hepatically-impaired patients. However, the hepatic route is not a major route of elimination of low molecular weight heparins.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tinzaparin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tinzaparin in patients who are immunocompromised.
### Obesity
Based on the results of a prospective clinical study and the population PK analyses, weight-based dosing is appropriate for heavy/obese patients. Tinzaparin sodium PK parameters based on anti-Xa activity are independent of body weight and body mass index (BMI) when tinzaparin sodium is dosed on a weight basis at 175 IU/kg or 75 IU/kg. In a prospective study of heavy/obese subjects (101 to 165 kg; BMI 26‑61 kg/m2), anti-Xa activity time profiles were similar to those in normal-weight volunteer studies. Data at the 175 IU/kg dose are shown in Figure 2. Clinical trial experience is limited in patients with a BMI >40 kg/m2.
# Administration and Monitoring
### Administration
Tinzaparin is a clear, colorless to slightly yellow solution, and as with other parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Tinzaparin is administered by SC injection. It must not be administered by intramuscular or intravenous injection.
### Subcutaneous Injection Technique
Patients should be lying down (supine) or sitting and tinzaparin administered by deep SC injection. Administration should be alternated between the left and right anterolateral and left and right posterolateral abdominal wall. The injection site should be varied daily. The whole length of the needle should be introduced into a skin fold held between the thumb and forefinger; the skin fold should be held throughout the injection. To minimize bruising, do not rub the injection site after completion of the injection.
### Monitoring
Periodic complete blood counts including platelet count and hematocrit or hemoglobin, and stool tests for occult blood are recommended during treatment with tinzaparin. When administered at the recommended doses, routine anticoagulation tests such as prothrombin time (PT) and activated partial thromboplastin time (aPTT) are relatively insensitive measures of tinzaparin activity and, therefore, are unsuitable for monitoring.
# IV Compatibility
There is limited information regarding the compatibility of Tinzaparin and IV administrations.
# Overdosage
Accidental overdosage of tinzaparin may lead to bleeding complications. Nosebleeds, blood in urine or tarry stools may be noted as the first signs of bleeding. Easy bruising or petechial hemorrhages may precede frank bleeding. In case of minor bleeding, the patient should be monitored for signs of more severe bleeding.
Of patients known to have received an overdose of tinzaparin sodium in clinical trials, defined as one or more doses >200 IU/kg for the treatment of DVT or >100 IU/kg for the prevention of DVT, approximately 16% experienced a bleeding complication.
Of spontaneous reports of probable overdosing with tinzaparin sodium, approximately 81% were accompanied by bleeding, usually hematoma. Most patients who have bleeding complications while receiving tinzaparin can be controlled by discontinuing tinzaparin, applying pressure to the site, if possible, and replacing volume and hemostatic blood elements (e.g., red blood cells, fresh frozen plasma, platelets) as required. In the event that this is ineffective, protamine sulfate can be administered.
In cases of serious bleeding or large overdose, protamine sulfate (1% solution) can be given by slow IV infusion at a dose of 1 mg protamine for every 100 anti-Xa IU of tinzaparin given. A second infusion of 0.5 mg protamine sulfate per 100 anti-Xa IU of tinzaparin may be administered if the aPTT measured 2 to 4 hours after the first infusion remains prolonged. Even with the additional dose of protamine, the aPTT may remain more prolonged than would usually be found following administration of protamine to reverse unfractionated heparin. Protamine does not completely neutralize tinzaparin sodium anti-Xa activity (maximum about 60%).
Particular care should be taken to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions have been reported with protamine sulfate, it should be given only when resuscitation facilities are readily available. For additional information consult the labeling of Protamine Sulfate Injection, USP, products.
Single SC doses of tinzaparin sodium at 22,000 and 7,700 IU/kg (about 10 and 7 times the maximum recommended human dose, respectively, based upon body surface area) were lethal to mice and rats, respectively. Symptoms of acute toxicity included hematoma formation and bleeding at the injection site, anemia, decreased motor activity, unsteady gait, piloerection, and ptosis.
# Pharmacology
There is limited information regarding Tinzaparin Pharmacology in the drug label.
## Mechanism of Action
Tinzaparin sodium is a low molecular weight heparin with antithrombotic properties. Tinzaparin sodium inhibits reactions that lead to the clotting of blood including the formation of fibrin clots, both in vitro and in vivo. It acts as a potent co-inhibitor of several activated coagulation factors, especially Factor Xa and IIa (thrombin). The primary inhibitory activity is mediated through the plasma protease inhibitor, antithrombin.
Bleeding time is usually unaffected by tinzaparin sodium. Activated partial thromboplastin time (aPTT) is prolonged by therapeutic doses of tinzaparin sodium used in the treatment of deep vein thrombosis (DVT). Prothrombin time (PT) may be slightly prolonged with tinzaparin sodium treatment but usually remains within the normal range. Neither aPTT nor PT can be used for therapeutic monitoring of tinzaparin sodium.
Neither unfractionated heparin nor tinzaparin sodium have intrinsic fibrinolytic activity; therefore, they do not lyse existing clots. Tinzaparin sodium induces release of tissue factor pathway inhibitor, which may contribute to the antithrombotic effect. Heparin is also known to have a variety of actions that are independent of its anticoagulant effects. These include interactions with endothelial cell growth factors, inhibition of smooth muscle cell proliferation, activation of lipoprotein lipase, suppression of aldosterone secretion, and induction of platelet aggregation.
## Structure
Tinzaparin sodium is the sodium salt of a low molecular weight heparin obtained by controlled enzymatic depolymerization of heparin from porcine intestinal mucosa using heparinase from Flavobacterium heparinum. The majority of the components have a 2-O-sulpho-4-enepyranosuronic acid structure at the non-reducing end and a 2-N,6-O-disulpho-D-glucosamine structure at the reducing end of the chain.
Potency is determined by means of a biological assay and interpreted by the first International Low Molecular Weight Heparin Standard as units of anti-factor Xa (anti-Xa) activity per milligram. The mean tinzaparin sodium anti-factor Xa activity is approximately 100 IU per milligram. The average molecular weight ranges between 5,500 and 7,500 daltons. The molecular weight distribution is:
## Pharmacodynamics
Anti-Xa and anti-IIa activities are the primary biomarkers for assessing tinzaparin sodium exposure because plasma concentrations of low molecular weight heparins cannot be measured directly. Because of analytical assay limitations, anti-Xa activity is the more widely used biomarker. The measurements of anti-Xa and anti-IIa activities in plasma serve as surrogates for the concentrations of molecules which contain the high-affinity binding site for antithrombin (anti-Xa and anti-IIa activities). Monitoring patients based on anti-Xa activity is generally not advised.
Studies with tinzaparin sodium in healthy volunteers and patients have been conducted with both fixed- and weight-adjusted dose administration. Recommended therapy with tinzaparin sodium is based on weight-adjusted dosing
## Pharmacokinetics
### Absorption
Plasma levels of anti-Xa activity increase in the first 2 to 3 hours following SC injection of tinzaparin sodium and reach a maximum within 4 to 5 hours. Maximum concentrations (Cmax) of 0.25 and 0.87 IU/mL are achieved following a single SC fixed dose of 4,500 IU (approximately 64.3 IU/kg) and weight-adjusted dose of 175 IU/kg of tinzaparin sodium, respectively. Based on the extent of absorption (AUC0‑∞), a comparison of 4,500 IU and 12,250 IU single doses indicates that increases in anti-Xa activity are greater than dose proportional relative to the increase in dose. Following a single SC injection of tinzaparin sodium, the mean anti-Xa to anti-IIa activity ratio, based on the area under the anti-Xa and anti-IIa time profiles, is 2.8 and is higher than that of unfractionated heparin (approximately 1.2). The absolute bioavailability (following 4,500 IU SC and intravenous [IV] administrations) is 86.7% based on anti-Xa activity.
### Distribution
The volume of distribution of tinzaparin sodium ranges from 3.1 L to 5.0 L. These values are similar in magnitude to blood volume, suggesting that the distribution of anti-Xa activity is limited to the central compartment.
### Metabolism
Low molecular weight heparins are partially metabolized by desulphation and depolymerization.
### Elimination
In healthy volunteers, the elimination half-life following SC administration of 4,500 IU or 175 IU/kg tinzaparin sodium is approximately 3-4 hours based on anti-Xa activity. Clearance following IV administration of 4,500 IU tinzaparin sodium is approximately 1.7 L/hr. The primary route of elimination is renal. Anti-Xa activity did not accumulate with once daily dosing of 175 IU/kg for five days in healthy volunteers.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies in animals have been performed to evaluate the carcinogenic potential of tinzaparin sodium. Tinzaparin sodium displayed no genotoxic potential in an in vitro bacterial cell mutation assay (AMES test), in vitro Chinese hamster ovary cell forward gene mutation test, in vitro human lymphocyte chromosomal aberration assay, and in vivo mouse micronucleus assay. Tinzaparin sodium at SC doses up to 1800 IU/kg/day in rats (about 2 times the maximum recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance.
# Clinical Studies
### Treatment of Acute Deep Vein Thrombosis (DVT) With or Without Pulmonary Embolism (PE)
In a randomized, multicenter, double-blind trial tinzaparin (tinzaparin sodium injection) was compared to unfractionated heparin in 435 hospitalized patients with symptomatic, proximal DVT. Six percent of the enrolled patients had symptomatic pulmonary embolism confirmed by segmental or greater lung scan defect. The study patients ranged in age from 19 to 92 years (mean 61 ± 17 years), 55% were male, 88% were white and 8% black. Patients received either tinzaparin SC once daily according to body weight (175 IU/kg) and a placebo IV bolus followed by continuous placebo IV infusion, or unfractionated heparin as an initial IV bolus dose (5,000 IU) followed by continuous IV infusion of unfractionated heparin with the rate adjusted according to the aPTT (1.5 to 2.5 times control value) and a once daily SC placebo injection. Treatment continued for approximately 6 days, and both treatment groups also received oral warfarin sodium starting on Day 2 which continued to Day 90 with doses titrated to a target INR of 2.0 to 3.0.
The 90-day cumulative thromboembolic (TE) rate [recurrent DVT or PE] with tinzaparin was not significantly different than the rate with unfractionated heparin. The data are provided in Table 3.
Mortality with tinzaparin was 4.6% (10 patients) and with heparin 9.6% (21 patients). The 95% confidence interval (CI) for the mortality difference was 0.16%, 9.76%.
In a multicenter, open-label, randomized clinical trial tinzaparin was compared to unfractionated heparin as initial treatment for hospitalized patients with symptomatic PE not requiring thrombolytic therapy, embolectomy, or vena cava interruption. Patients were excluded if they carried an unusually high risk for thromboembolic and/or bleeding events or other complications. Of the 608 patients treated, 422 had documented DVT. Prior to determination of study eligibility and randomization, patients were allowed to receive unfractionated heparin; 78% of the patients received unfractionated heparin at therapeutic doses for up to 24 hours, and an additional 4% received heparin at therapeutic doses for greater than 24 hours. After randomization, tinzaparin was administered SC once daily, 175 IU/kg body weight; heparin as an initial IV bolus (50 IU/kg) followed by continuous IV infusion with the rate adjusted according to the aPTT (2 to 3 times control value). For both groups, treatment continued for approximately 8 days. All patients also received oral anticoagulant treatment starting in the first 3 days which continued to Day 90.
Thromboembolic events were infrequent for both treatment groups. No difference was observed between the two treatment groups for incidence of recurrence of thromboembolic events.
# How Supplied
tinzaparin is available in a multiple dose 2 mL vial in the following packages:
- Box of 1: 2 mL vial (20,000 anti-Xa IU per mL); NDC 50222-342-08
- Box of 10: 2 mL vials (20,000 anti-Xa IU per mL); NDC 50222-342-53
## Storage
Store at 25° C (77° F); excursions permitted to 15°-30° C (59°-86° F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of tinzaparin in the drug label.
# Precautions with Alcohol
Alcohol-Tinzaparin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Innohep®
# Look-Alike Drug Names
There is limited information regarding Tinzaparin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Innohep | |
a5bbea92db5f96093c9b6b7a7b2b7f2999e2409c | wikidoc | Innovation | Innovation
In organizational psychology, Innovation is defined as "Introduction of changes which are new to the organization...".
"Innovative performance can be improved by both acquiring knowledge from outside sources and employing external paths to commercialize knowledge resources developed internally".
- Internal - adopting and adapting. Various issues affect knowledge sharing within an organization.
- External (inbound) - incorporating external information
# Measurement
Scales to measure:
- Team Climate Inventory (TCI) has five scales: vision, participative safety, support for innovation, task orientation, interaction frequency
- Hurley has five dimensions: Innovativeness, Participative Decision-Making, Power Sharing, Support and Collaboration, Learning and Development
- Sisodiya developed a scale based on responses by managers
External - incorporating external information
- My organization actively seeks out external sources of knowledge and technology (e.g., published research, regional and national meetings, professional societies, external colleagues) when developing new ideas
# Promoton of innovation
Greenhalgh has described a spectrum of management roles in the diffusion of innovation:
- Let it happen, based on emergence in complexity science
- Help it happen
- Make it happen
Static hierarchies of staff positions may reduce knowledge sharing.
Stress at work can paradoxically increase innovation.
Recommendations to promote knowledge sharing are available
Stress at work may increase creativity.
## Growth mindsets
Growth mindsets in both employees and management may be important.
## Employee characteristics
### Idea elaboration
Regarding idea elaboration, "inside-out network sequencing—that is, mobilizing input and support from inner-circle ties before outer-circle ones—yields an innovation performance advantage".
### Conscientiousness
Conscientiousness, "propensity to plan and coordinate with others ", increased the effectiveness of proactivity
## Leadership approaches
### Complexity leadership; enabling leadership
### Humble leadership
### Hubristic leadership
# Barriers to innovation
The "not invented here syndrome" likely stymies innovation. | Innovation
In organizational psychology, Innovation is defined as "Introduction of changes which are new to the organization..."[1].
"Innovative performance can be improved by both acquiring knowledge from outside sources and employing external paths to commercialize knowledge resources developed internally"[2].
- Internal - adopting and adapting. Various issues affect knowledge sharing within an organization[3][4][5].
- External (inbound) - incorporating external information
# Measurement
Scales to measure:
- Team Climate Inventory (TCI) has five scales: vision, participative safety, support for innovation, task orientation, interaction frequency[6]
- Hurley has five dimensions: Innovativeness, Participative Decision-Making, Power Sharing, Support and Collaboration, Learning and Development[7]
- Sisodiya developed a scale based on responses by managers[8]
External - incorporating external information
- My organization actively seeks out external sources of knowledge and technology (e.g., published research, regional and national meetings, professional societies, external colleagues) when developing new ideas[2]
# Promoton of innovation
Greenhalgh has described a spectrum of management roles in the diffusion of innovation[9]:
- Let it happen, based on emergence in complexity science
- Help it happen
- Make it happen
Static hierarchies of staff positions may reduce knowledge sharing[10].
Stress at work can paradoxically increase innovation[11].
Recommendations to promote knowledge sharing are available[5]
Stress at work may increase creativity.
## Growth mindsets
Growth mindsets in both employees and management may be important.
## Employee characteristics
### Idea elaboration
Regarding idea elaboration, "inside-out network sequencing—that is, mobilizing input and support from inner-circle ties before outer-circle ones—yields an innovation performance advantage"[12].
### Conscientiousness
Conscientiousness, "propensity to plan and coordinate with others ", increased the effectiveness of proactivity[13]
## Leadership approaches
### Complexity leadership; enabling leadership
### Humble leadership
### Hubristic leadership
# Barriers to innovation
The "not invented here syndrome" likely stymies innovation[14]. | https://www.wikidoc.org/index.php/Innovation | |
cadf6eb02d7eeccea9a2c614946b34749c465615 | wikidoc | Solubility | Solubility
Solubility is a characteristic physical property referring to the ability for a given substance, the solute, to dissolve in a solvent. It is measured in terms of the maximum amount of solute dissolved in a solvent at equilibrium. The resulting solution is called a saturated solution. Certain liquids are soluble in all proportions with a given solvent, such as ethanol in water. This property is known as miscibility. Also, the equilibrium solubility can be exceeded under various conditions to give a so-called supersaturated solution, which is metastable.
In a solution, the solvent is often a liquid, which can be a pure substance or a mixture. The species that dissolves (the solute) can be a gas, another liquid, or a solid. Solubilities range widely, from infinitely soluble such as ethanol in water, to poorly soluble, such as silver chloride in water. The term insoluble is often applied to poorly soluble compounds, though strictly speaking there are very few cases where there is absolutely no material dissolved.
# Molecular view
Solubility occurs under dynamic equilibrium. This means that solubility should be viewed as a result of two simultaneous and opposing processes: dissolution and precipitation. The solubility equilibrium occurs when the two processes proceed at the same rate.
The solubility equilibrium is relatively straightforward for covalent substances such as ethanol. When ethanol dissolves in water, the ethanol molecules remain intact but form new hydrogen bonds with the water. However, when an ionic compound such as sodium chloride (NaCl) dissolves in water, the sodium chloride lattice dissociates into separate ions which are solvated (wrapped) with a coating of water molecules. Nonetheless, NaCl is said to dissolve in water, because evaporation of the solvent returns crystalline NaCl.
Sometimes the term "dissolving" is applied to an irreversible chemical reaction, as with iron in nitric acid, but in such a case the thermodynamic concept of solubility does not apply.
When it dissolves, a solute may form several species in the solution. For example, water above the crystals of ferrous hydroxide, Fe(OH)2, will, at equilibrium, contain Fe2+, Fe(OH)+, Fe(OH)2, Fe(OH)3- and possibly other complexes. Therefore, the solubility of ferrous hydroxide depends on pH. In general, solubility in the solvent phase can be given only for a specific solute which is thermodynamically stable, and the value of the solubility will include all the species in the solution (in the example above, all the iron-containing complexes).
# Factors affecting solubility
Solubility is defined for specific phases. For example, the solubility of aragonite and calcite in water are expected to be different, even though both are the same chemical substance (calcium carbonate).
The solubility of one substance dissolving in another is determined by the balance of intermolecular forces between the solvent and solute and the entropy change that accompanies the solvation. Factors such as temperature and pressure will alter this balance, thus changing the solubility.
Solubility may also strongly depend on the presence of other species dissolved in the solvent, for example, complex-forming anions (ligands) in liquids. Solubility will also depend on the excess (or deficiency) of a common ion (common-ion effect) in the solution. To a lesser extent, solubility will depend on the ionic strength of liquid solutions. The last two effects can be quantified using the equation for solubility equilibrium.
There is also a number of less common factors which may affect solubility. Solubility may depend on the crystal (or droplet) size of the solute phase (typically, solubility will increase with the decreasing crystal size for crystals much smaller than 1 μm). For highly defective crystals, solubility may increase with the increasing degree of disorder. The last two effects, although of great practical importance, are not true solubility effects because true solubility occurs at equilbrium, which requires a perfect monocrystal. For substances dissolving in an electrochemical reaction, solubility is expected to depend on the potential of the solute phase.
## Temperature
The solubility of a given solute in a given solvent typically depends on temperature. For around 95% of solid solutes, the solubility increases with temperature, in the temperature range from about ambient to 100 °C. In liquid water at high temperatures, (e.g., that approaching the critical temperature), the solubility of ionic solutes tends to decrease due to the change of properties and structure of liquid water (lower dielectric constant, less of a polar solvent).
Gaseous solutes exhibit more complex behavior with temperature. As the temperature is raised gases usually become less soluble in water, but more soluble in organic solvents.
The chart shows solubility curves for some typical inorganic salts (all solids). Many salts behave like barium nitrate and disodium hydrogen arsenate, and show a large increase in solubility with temperature. Some solutes (e.g. NaCl in water) exhibit solubility which is fairly independent of temperature. A few, such as cerium(III) sulfate, become less soluble in water as temperature increases. This is sometimes referred to as "retrograte" or "inverse" solubility. Occasionally, a more complex pattern is observed, as with sodium sulfate, where the less soluble decahydrate crystal loses water of crystallization at 32 °C to form a more soluble anhydrous phase.
Organic compounds nearly always become soluble as the temperature is raised, in most solvents. The technique of recrystallization, used for purification of solids, depends on this differences in solubility in hot and cold solvent. There are a few exceptions, such as certain cyclodextrins.
## Pressure
For condensed phases (solids and liquids), the pressure dependence of solubility is typically weak and usually neglected in practice. Assuming an ideal solution, the dependence can be quantified as:
where Ni is the mole fraction of the ith component in the solution, P is the pressure, the index T refers to constant temperature, Vi,aq is the partial molar volume of the ith component in the solution, Vi,cr is the partial molar volume of the ith component in the dissolving solid, and R is the universal gas constant.
Henry's law states that the solubility of a gas in a liquid is directly proportional to the partial pressure of that gas above the liquid, which may be written as:
where k is a temperature-dependent constant (for example, 769.2 Latm/mol for dioxygen (O2) in water at 298 K), p is the partial pressure (atm), and c is the concentration of the dissolved gas in the liquid (mol/L).
## Polarity
A popular aphorism used for predicting solubility is "Like dissolves like" This indicates that a solute will dissolve best in a solvent that has a similar polarity to itself. This is a rather simplistic view, since it ignores many solvent-solute interactions, but it is a useful rule-of-thumb. For example, a very polar (hydrophilic) solute such as urea is highly soluble in highly polar water, less soluble in fairly polar methanol, and practically insoluble in non-polar solvents such as benzene. In contrast, a non-polar or lipophilic solute such as naphthalene is insoluble in water, fairly soluble in methanol, and highly soluble in non-polar benzene.
Liquid solubilities also generally follow this rule. Lipophilic plant oils, such as olive oil and palm oil, dissolve in non-polar gasoline (petrol), but polar liquids like water will not mix with gasoline.
Synthetic chemists often use the different solubilities of compounds to separate and purify compounds from reaction mixtures.
# Rate of dissolution
Dissolution is not always an instantaneous process. It is fast when salt and sugar dissolve in water but much slower for a tablet of aspirin or a large crystal of hydrated copper(II) sulfate. The speed at which a solid dissolves may depend on its crystalline properties (crystalline vs amorphous, crystal size) and the presence of polymorphism. This is important in many practical systems, for example in designing methods for controlled drug delivery. Critically, the dissolution rate depends on the presence of mixing and other factors that determine the degree of undersaturation in the liquid solvent film immediately adjacent to the solid solute crystal. In some cases, solubility equilibria can take a long time to establish (hours, days, months, or many years; depending on the nature of the solute and other factors). In practise, it means that the amount of solute in a solution is not always determined by its thermodynamic solubility, but may depend on kinetics of dissolution (or precipitation).
The rate of dissolution and solubility should not be confused--they are different concepts (kinetic and thermodynamic, respectively).
# Quantification of solubility
Solubility is commonly expressed as a concentration, either mass concentration (g of solute per kg of solvent, g per 100 mL (dL) of solvent), molarity, molality, mole fraction or other similar descriptions of concentration. The maximum equilibrium amount of solute that can dissolve per amount of solvent is the solubility of that solute in that solvent under the specified conditions. The advantage of expressing solubility in this manner is its simplicity, while the disadvantage is that it can strongly depend on the presence of other species in the solvent (for example, the common ion effect).
Solubility constants are used to describe saturated solutions of ionic compounds of relatively low solubility (see solubility equilibrium). The solubility constant is a special case of an equilibrium constant. It describes the balance between dissolved ions from the salt and undissolved salt. The solubility constant is also "applicable" (i.e. useful) to precipitation, the reverse of the dissolving reaction. As with other equilibrium constants, temperature can affect the numerical value of solubility constant. The solubility constant is more complicated than solubility. However, the value of this constant is generally independent of the presence of other species in the solvent.
Henry's law is used to quantify the solubility of gases in liquids as a function of the gas's partial pressure. It is a special case of a solubility equilibrium.
The Flory-Huggins solution theory is a theoretical model describing the solubility of polymers. The Hansen Solubility Parameters and the Hildebrand solubility parameters are empirical methods for the prediction of solubility. it is also possible to predict solubility from other physical constants such as the enthalpy of fusion.
The partition coefficient (Log P) is a measure of differential solubility of a compound in a hydrophobic solvent (octanol) and a hydrophilic solvent (water). The logarithm of these two values enables compounds to be ranked in terms of hydrophilicity (or hydrophobicity).
# Applications
Solubility is of fundamental importance in a large number of scientific disciplines and practical applications, the most obvious ones being in chemical engineering, material science, geology, and environmental science.
Solubility is often said to be one of the "characteristic properties of a substance". This means that solubility is commonly used to describe the substance, to shed light on the nature of the substance, to help to distinguish it from other substances, and to guide with an application of the substance. For example, indigo is described as "insoluble in water, alcohol, or ether but soluble in chloroform, nitrobenzene, or concentrated sulfuric acid".
For example, solubility of a substance is useful when separating mixtures. For example, a mixture of salt (sodium chloride) and silica may be separated by dissolving the salt in water, and filtering off the undissolved silica. The synthesis of chemical compounds, by the milligram in a laboratory, or by the ton in industry, both make use of the relative solubilities of the desired product, as well as unreacted starting materials, byproducts, and side products to achieve separation.
Another example of this would be the synthesis of benzoic acid from phenylmagnesium bromide and dry ice. Benzoic acid is more soluble in an organic solvent such as dichloromethane or diethyl ether, and when shaken with this organic solvent in an separatory funnel, will preferentially dissolve in the organic layer. The other reaction products, i.e. the magnesium bromide will remain in the aqueous layer, clearly showing that separation based on solubility is achieved. (On a practical note, the benzoic acid obtained after evaporating the organic solvent should ideally be purified by recrystallizing from hot water.)
# Solubility of ionic compounds in water
Ionic compounds (salts) dissolve in water because of the attraction between positive and negative charges. For example, the salt's positive ions (i.e. Ag+) attract the partially-negative oxygens in H2O. Likewise, the salt's negative ions (i.e. Cl-) attract the partially-positive hydrogens in in H2O. Note: oxygen is partially-negative because it is more electronegative than hydrogen, and vice-versa (see:chemical polarity).
However, there is a limit to how much salt can be dissolved in a given volume of water (1 liter, for example). This amount is given by the solubility product (Ksp). This value depends on both the type of salt (AgCl vs. NaI, for example) and the temperature of the water.
To calculate how much AgCl can dissolve in 1 liter of water, some algebra is required. First,
Next, realize that = since there is always one Ag+ ion for every Cl- ion. Using this fact,
The result: 1 liter of water can dissolve 1.34 × 10-5 moles of AgCl(s) at room temperature. Compared with other types of salts, AgCl is not very soluble in water. In contrast, household table salt (NaCl) has a higher Ksp and is, therefore, more soluble.
# Solubility of organic compounds
The principle outlined above under polarity, that like dissolves like, is the usual guide to solubility with organic systems. For example, petroleum jelly will dissolve in gasoline; both of which are lipophilic. This is because petroleum jelly consists of long carbon chains, as does the gasoline. It will not, on the other hand, dissolve in alcohol or water, since the polarity of these solvents is too high. Sugar will not dissolve in gasoline, since sugar is too polar in comparison with gasoline. A mixture of gasoline and sugar can therefore be separated by filtration, or extraction with water.
# Solid solubility
This term is often used in the field of metallurgy to refer to the extent that an alloying element will dissolve into the base metal without forming a separate phase. The solubility line (or curve) is the line (or lines) on a phase diagram which give the limits of solute addition. That is, the lines show the maximum amount of a component that can be added to another component and still be in solid solution. In microelectronic fabrication, solid solubility refers to the maximum concentration of impurities one can place into the substrate.
# Incongruent dissolution
Many substances dissolve congruently, i.e., the composition of the solid and the dissolved solute stoichiometrically match. However, some substances may dissolve incongruently, whereby the composition of the solute in solution does not match that of the solid. This is accompanied by alteration of the "primary solid" and possibly formation of a secondary solid phase. However, generally, some primary solid also remains and a complex solubility equilibrium establishes. For example, dissolution of albite may result in formation of gibbsite.
In this case, the solubility of albite is expected to depend on the solid-to-solvent ratio. This kind of solubility is of great importance in geology, where it results in formation of metamorphic rocks. | Solubility
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
Solubility is a characteristic physical property referring to the ability for a given substance, the solute, to dissolve in a solvent.[1] It is measured in terms of the maximum amount of solute dissolved in a solvent at equilibrium. The resulting solution is called a saturated solution. Certain liquids are soluble in all proportions with a given solvent, such as ethanol in water. This property is known as miscibility.[2] Also, the equilibrium solubility can be exceeded under various conditions to give a so-called supersaturated solution, which is metastable.[3]
In a solution, the solvent is often a liquid, which can be a pure substance or a mixture.[4] The species that dissolves (the solute) can be a gas, another liquid, or a solid. Solubilities range widely, from infinitely soluble such as ethanol in water, to poorly soluble, such as silver chloride in water. The term insoluble is often applied to poorly soluble compounds, though strictly speaking there are very few cases where there is absolutely no material dissolved.
# Molecular view
Solubility occurs under dynamic equilibrium. This means that solubility should be viewed as a result of two simultaneous and opposing processes: dissolution and precipitation. The solubility equilibrium occurs when the two processes proceed at the same rate.
The solubility equilibrium is relatively straightforward for covalent substances such as ethanol. When ethanol dissolves in water, the ethanol molecules remain intact but form new hydrogen bonds with the water. However, when an ionic compound such as sodium chloride (NaCl) dissolves in water, the sodium chloride lattice dissociates into separate ions which are solvated (wrapped) with a coating of water molecules. Nonetheless, NaCl is said to dissolve in water, because evaporation of the solvent returns crystalline NaCl.
Sometimes the term "dissolving" is applied to an irreversible chemical reaction, as with iron in nitric acid, but in such a case the thermodynamic concept of solubility does not apply.
When it dissolves, a solute may form several species in the solution. For example, water above the crystals of ferrous hydroxide, Fe(OH)2, will, at equilibrium, contain Fe2+, Fe(OH)+, Fe(OH)2, Fe(OH)3- and possibly other complexes. Therefore, the solubility of ferrous hydroxide depends on pH. In general, solubility in the solvent phase can be given only for a specific solute which is thermodynamically stable, and the value of the solubility will include all the species in the solution (in the example above, all the iron-containing complexes).
# Factors affecting solubility
Solubility is defined for specific phases. For example, the solubility of aragonite and calcite in water are expected to be different, even though both are the same chemical substance (calcium carbonate).
The solubility of one substance dissolving in another is determined by the balance of intermolecular forces between the solvent and solute and the entropy change that accompanies the solvation. Factors such as temperature and pressure will alter this balance, thus changing the solubility.
Solubility may also strongly depend on the presence of other species dissolved in the solvent, for example, complex-forming anions (ligands) in liquids. Solubility will also depend on the excess (or deficiency) of a common ion (common-ion effect) in the solution. To a lesser extent, solubility will depend on the ionic strength of liquid solutions. The last two effects can be quantified using the equation for solubility equilibrium.
There is also a number of less common factors which may affect solubility. Solubility may depend on the crystal (or droplet) size of the solute phase (typically, solubility will increase with the decreasing crystal size for crystals much smaller than 1 μm). For highly defective crystals, solubility may increase with the increasing degree of disorder. The last two effects, although of great practical importance, are not true solubility effects because true solubility occurs at equilbrium, which requires a perfect monocrystal. For substances dissolving in an electrochemical reaction, solubility is expected to depend on the potential of the solute phase.
## Temperature
The solubility of a given solute in a given solvent typically depends on temperature. For around 95% of solid solutes, the solubility increases with temperature,[5] in the temperature range from about ambient to 100 °C. In liquid water at high temperatures, (e.g., that approaching the critical temperature), the solubility of ionic solutes tends to decrease due to the change of properties and structure of liquid water (lower dielectric constant, less of a polar solvent).
Gaseous solutes exhibit more complex behavior with temperature. As the temperature is raised gases usually become less soluble in water, but more soluble in organic solvents.[5]
The chart shows solubility curves for some typical inorganic salts (all solids).[6] Many salts behave like barium nitrate and disodium hydrogen arsenate, and show a large increase in solubility with temperature. Some solutes (e.g. NaCl in water) exhibit solubility which is fairly independent of temperature. A few, such as cerium(III) sulfate, become less soluble in water as temperature increases. This is sometimes referred to as "retrograte" or "inverse" solubility. Occasionally, a more complex pattern is observed, as with sodium sulfate, where the less soluble decahydrate crystal loses water of crystallization at 32 °C to form a more soluble anhydrous phase.
Organic compounds nearly always become soluble as the temperature is raised, in most solvents. The technique of recrystallization, used for purification of solids, depends on this differences in solubility in hot and cold solvent. There are a few exceptions, such as certain cyclodextrins.[7]
## Pressure
For condensed phases (solids and liquids), the pressure dependence of solubility is typically weak and usually neglected in practice. Assuming an ideal solution, the dependence can be quantified as:
where Ni is the mole fraction of the ith component in the solution, P is the pressure, the index T refers to constant temperature, Vi,aq is the partial molar volume of the ith component in the solution, Vi,cr is the partial molar volume of the ith component in the dissolving solid, and R is the universal gas constant[8].
Henry's law states that the solubility of a gas in a liquid is directly proportional to the partial pressure of that gas above the liquid, which may be written as:
where k is a temperature-dependent constant (for example, 769.2 L•atm/mol for dioxygen (O2) in water at 298 K), p is the partial pressure (atm), and c is the concentration of the dissolved gas in the liquid (mol/L).
## Polarity
A popular aphorism used for predicting solubility is "Like dissolves like"[9] This indicates that a solute will dissolve best in a solvent that has a similar polarity to itself. This is a rather simplistic view, since it ignores many solvent-solute interactions, but it is a useful rule-of-thumb. For example, a very polar (hydrophilic) solute such as urea is highly soluble in highly polar water, less soluble in fairly polar methanol, and practically insoluble in non-polar solvents such as benzene. In contrast, a non-polar or lipophilic solute such as naphthalene is insoluble in water, fairly soluble in methanol, and highly soluble in non-polar benzene.[10]
Liquid solubilities also generally follow this rule. Lipophilic plant oils, such as olive oil and palm oil, dissolve in non-polar gasoline (petrol), but polar liquids like water will not mix with gasoline.
Synthetic chemists often use the different solubilities of compounds to separate and purify compounds from reaction mixtures.
# Rate of dissolution
Dissolution is not always an instantaneous process. It is fast when salt and sugar dissolve in water but much slower for a tablet of aspirin or a large crystal of hydrated copper(II) sulfate. The speed at which a solid dissolves may depend on its crystalline properties (crystalline vs amorphous, crystal size) and the presence of polymorphism. This is important in many practical systems, for example in designing methods for controlled drug delivery. Critically, the dissolution rate depends on the presence of mixing and other factors that determine the degree of undersaturation in the liquid solvent film immediately adjacent to the solid solute crystal. In some cases, solubility equilibria can take a long time to establish (hours, days, months, or many years; depending on the nature of the solute and other factors). In practise, it means that the amount of solute in a solution is not always determined by its thermodynamic solubility, but may depend on kinetics of dissolution (or precipitation).
The rate of dissolution and solubility should not be confused--they are different concepts (kinetic and thermodynamic, respectively).
# Quantification of solubility
Solubility is commonly expressed as a concentration, either mass concentration (g of solute per kg of solvent, g per 100 mL (dL) of solvent), molarity, molality, mole fraction or other similar descriptions of concentration. The maximum equilibrium amount of solute that can dissolve per amount of solvent is the solubility of that solute in that solvent under the specified conditions. The advantage of expressing solubility in this manner is its simplicity, while the disadvantage is that it can strongly depend on the presence of other species in the solvent (for example, the common ion effect).
Solubility constants are used to describe saturated solutions of ionic compounds of relatively low solubility (see solubility equilibrium). The solubility constant is a special case of an equilibrium constant. It describes the balance between dissolved ions from the salt and undissolved salt. The solubility constant is also "applicable" (i.e. useful) to precipitation, the reverse of the dissolving reaction. As with other equilibrium constants, temperature can affect the numerical value of solubility constant. The solubility constant is more complicated than solubility. However, the value of this constant is generally independent of the presence of other species in the solvent.
Henry's law is used to quantify the solubility of gases in liquids as a function of the gas's partial pressure. It is a special case of a solubility equilibrium.
The Flory-Huggins solution theory is a theoretical model describing the solubility of polymers. The Hansen Solubility Parameters and the Hildebrand solubility parameters are empirical methods for the prediction of solubility. it is also possible to predict solubility from other physical constants such as the enthalpy of fusion.
The partition coefficient (Log P) is a measure of differential solubility of a compound in a hydrophobic solvent (octanol) and a hydrophilic solvent (water). The logarithm of these two values enables compounds to be ranked in terms of hydrophilicity (or hydrophobicity).
# Applications
Solubility is of fundamental importance in a large number of scientific disciplines and practical applications, the most obvious ones being in chemical engineering, material science, geology, and environmental science.
Solubility is often said to be one of the "characteristic properties of a substance". This means that solubility is commonly used to describe the substance, to shed light on the nature of the substance, to help to distinguish it from other substances, and to guide with an application of the substance. For example, indigo is described as "insoluble in water, alcohol, or ether but soluble in chloroform, nitrobenzene, or concentrated sulfuric acid".
For example, solubility of a substance is useful when separating mixtures. For example, a mixture of salt (sodium chloride) and silica may be separated by dissolving the salt in water, and filtering off the undissolved silica. The synthesis of chemical compounds, by the milligram in a laboratory, or by the ton in industry, both make use of the relative solubilities of the desired product, as well as unreacted starting materials, byproducts, and side products to achieve separation.
Another example of this would be the synthesis of benzoic acid from phenylmagnesium bromide and dry ice. Benzoic acid is more soluble in an organic solvent such as dichloromethane or diethyl ether, and when shaken with this organic solvent in an separatory funnel, will preferentially dissolve in the organic layer. The other reaction products, i.e. the magnesium bromide will remain in the aqueous layer, clearly showing that separation based on solubility is achieved. (On a practical note, the benzoic acid obtained after evaporating the organic solvent should ideally be purified by recrystallizing from hot water.)
# Solubility of ionic compounds in water
Ionic compounds (salts) dissolve in water because of the attraction between positive and negative charges. For example, the salt's positive ions (i.e. Ag+) attract the partially-negative oxygens in H2O. Likewise, the salt's negative ions (i.e. Cl-) attract the partially-positive hydrogens in in H2O. Note: oxygen is partially-negative because it is more electronegative than hydrogen, and vice-versa (see:chemical polarity).
However, there is a limit to how much salt can be dissolved in a given volume of water (1 liter, for example). This amount is given by the solubility product (Ksp). This value depends on both the type of salt (AgCl vs. NaI, for example) and the temperature of the water.
To calculate how much AgCl can dissolve in 1 liter of water, some algebra is required. First,
Next, realize that [Ag+] = [Cl-] since there is always one Ag+ ion for every Cl- ion. Using this fact,
The result: 1 liter of water can dissolve 1.34 × 10-5 moles of AgCl(s) at room temperature. Compared with other types of salts, AgCl is not very soluble in water. In contrast, household table salt (NaCl) has a higher Ksp and is, therefore, more soluble.
# Solubility of organic compounds
The principle outlined above under polarity, that like dissolves like, is the usual guide to solubility with organic systems. For example, petroleum jelly will dissolve in gasoline; both of which are lipophilic. This is because petroleum jelly consists of long carbon chains, as does the gasoline. It will not, on the other hand, dissolve in alcohol or water, since the polarity of these solvents is too high. Sugar will not dissolve in gasoline, since sugar is too polar in comparison with gasoline. A mixture of gasoline and sugar can therefore be separated by filtration, or extraction with water.
# Solid solubility
This term is often used in the field of metallurgy to refer to the extent that an alloying element will dissolve into the base metal without forming a separate phase. The solubility line (or curve) is the line (or lines) on a phase diagram which give the limits of solute addition. That is, the lines show the maximum amount of a component that can be added to another component and still be in solid solution. In microelectronic fabrication, solid solubility refers to the maximum concentration of impurities one can place into the substrate.
# Incongruent dissolution
Many substances dissolve congruently, i.e., the composition of the solid and the dissolved solute stoichiometrically match. However, some substances may dissolve incongruently, whereby the composition of the solute in solution does not match that of the solid. This is accompanied by alteration of the "primary solid" and possibly formation of a secondary solid phase. However, generally, some primary solid also remains and a complex solubility equilibrium establishes. For example, dissolution of albite may result in formation of gibbsite.[11]
In this case, the solubility of albite is expected to depend on the solid-to-solvent ratio. This kind of solubility is of great importance in geology, where it results in formation of metamorphic rocks. | https://www.wikidoc.org/index.php/Insoluble | |
5371dbaa0151a55a48fdc1e61d5578ac4eaa1bba | wikidoc | Intelectin | Intelectin
Intelectins are lectins (carbohydrate-binding proteins) expressed in humans and other chordates. Humans express two types of intelectins encoded by ITLN1 and ITLN2 genes respectively. Several intelectins bind microbe-specific carbohydrate residues. Therefore, intelectins have been proposed to function as immune lectins. Even though intelectins contain fibrinogen-like domain found in the ficolins family of immune lectins, there is significant structural divergence. Thus, intelectins may not function through the same lectin-complement pathway. Most intelectins are still poorly characterized and they may have diverse biological roles. Human intelectin-1 (hIntL-1) has also been shown to bind lactoferrin, but the functional consequence has yet to be elucidated. Additionally, hIntL-1 is a major component of asthmatic mucus and may be involved in insulin physiology as well.
# Diversity
The first intelectin was discovered in Xenopus laevis oocyte and is named XL35 or XCGL-1. X. laevis oocyte also contains a closely related XCGL-2. In addition, X. laevis embryos secrete Xenopus embryonic epidermal lectin into the environmental water, presumably to bind microbes. XSL-1 and XSL-2 are also expressed in X. laevis serum when stimulated with lipopolysaccharide. Two additional intestinal intelectins are discovered in X. laevis
Human has two intelectins: hIntL-1 (omentin) and hIntL-2. Mouse also has two intelectins: mIntL-1 and mIntL-2.
# Immune system
Several lines of evidence suggest that intelectins recognize microbes and may function as an innate immune defense protein. Tunicate intelectin is an opsonin for phagocytosis by hemocyte. Amphioxus intelectin has been shown to agglutinate bacteria. In zebrafish and rainbow trout, intelectin expression is stimulated upon microbial exposure. Mammals such as sheep and mice also upregulate intelectin expression upon parasitic infection. Increase in intelectin expression upon microbial exposure support the hypothesis that intelectins play a role in the immune system.
# Structure
Although intelectins require calcium ion for function, the sequences bear no resemblance to C-type lectins. In addition, merely around 50 amino acids (the fibronogen-like domain) align with any known protein, specifically the ficolin family. The first structural details of an intelectin comes from the crystal structure of selenomethionine-labeled XEEL carbohydrate-recognition domain (Se-Met XEEL-CRD) solved by Se-SAD. XEEL-CRD was expressed and Se-Met-labeled in High Five insect cells using a recombinant baculovirus. The fibrinogen-like fold is conserved despite amino acid sequence divergence. However, extensive insertions are present in intelectin compared to ficolins, thus making intelectin a distinct lectin structural class. The Se-Met XEEL-CRD structure then enables the structure solution by molecular replacement of D-glycerol 1-phosphate (GroP)-bound XEEL-CRD, apo-human intelectin-1 (hIntL-1), and galactofuranose-bound hIntL-1.
Each polypeptide chain of XEEL and hIntL-1 contains three bound calcium ions: two in the structural calcium site and one in the ligand binding site. The amino acid residues in the structural calcium site are conserved among intelectins, thus it is likely that most, if not all, intelectins have two structural calcium ions.
In the ligand binding site of XEEL and hIntL-1, the exocyclic vicinal diol of the carbohydrate ligand directly coordinates to the calcium ion. There are large variations in the ligand binding site residues among intelectin homologs suggesting that the intelectin family may have broad ligand specificities and biological functions. As there is no intelectin numbering conventions in different organisms, one should not assume functional homology based on the intelectin number. For example, hIntL-1 has glutamic acid residues in the ligand binding site to coordinate a calcium ion, while zebrafish intelectin-1 are devoided of these acidic residues. Zebrafish intelectin-2 ligand binding site residues are similar to those present in hIntL-1.
- Xenopus embryonic epidermal lectin (XEEL) ligand binding site with bound D-glycerol 1-phosphate. The calcium ion is shown as a green sphere and the ordered water molecules are shown as red spheres.
Xenopus embryonic epidermal lectin (XEEL) ligand binding site with bound D-glycerol 1-phosphate. The calcium ion is shown as a green sphere and the ordered water molecules are shown as red spheres.
- Human intelectin-1 (hIntL-1) ligand binding site with bound allyl-beta-D-galactofuranose. The calcium ion is shown as a green sphere and the ordered water molecules are shown as red spheres.
Human intelectin-1 (hIntL-1) ligand binding site with bound allyl-beta-D-galactofuranose. The calcium ion is shown as a green sphere and the ordered water molecules are shown as red spheres.
# Oligomeric state
hIntL-1 is a disulfide-linked trimer as shown by non-reducing SDS-PAGE and X-ray crystallography. Despite lacking the intermolecular disulfide bonds, XEEL-CRD is trimeric in solution. The N-terminal peptide of the full length XEEL is responsible for dimerizing the trimeric XEEL-CRD into a disulfide-linked hexameric full-length XEEL. Therefore, the N-termini of intelectins are often responsible for forming disulfide-linked oligomer. In intelectin homologs where the N-terminal cysteines are absent, the CRD itself may still capable of forming non-covalent oligomer in solution.
- Disulfide-linked trimeric human intelectin-1.
Disulfide-linked trimeric human intelectin-1.
- Trimeric Xenopus embryonic epidermal lectin carbohydrate-recognition domain (XEEL-CRD). Extensive biophysical investigations conclusively indicate that XEEL-CRD is trimeric in solution despite lacking the intermolecular disulfide bonds found in hIntL-1.
Trimeric Xenopus embryonic epidermal lectin carbohydrate-recognition domain (XEEL-CRD). Extensive biophysical investigations conclusively indicate that XEEL-CRD is trimeric in solution despite lacking the intermolecular disulfide bonds found in hIntL-1. | Intelectin
Intelectins are lectins (carbohydrate-binding proteins) expressed in humans and other chordates. Humans express two types of intelectins encoded by ITLN1 and ITLN2 genes respectively.[1][2] Several intelectins bind microbe-specific carbohydrate residues. Therefore, intelectins have been proposed to function as immune lectins.[3][4] Even though intelectins contain fibrinogen-like domain found in the ficolins family of immune lectins, there is significant structural divergence.[5] Thus, intelectins may not function through the same lectin-complement pathway. Most intelectins are still poorly characterized and they may have diverse biological roles. Human intelectin-1 (hIntL-1) has also been shown to bind lactoferrin,[6] but the functional consequence has yet to be elucidated. Additionally, hIntL-1 is a major component of asthmatic mucus[7] and may be involved in insulin physiology as well.[8]
# Diversity
The first intelectin was discovered in Xenopus laevis oocyte and is named XL35 or XCGL-1.[9][10][11] X. laevis oocyte also contains a closely related XCGL-2.[12] In addition, X. laevis embryos secrete Xenopus embryonic epidermal lectin into the environmental water, presumably to bind microbes.[13][14] XSL-1 and XSL-2 are also expressed in X. laevis serum when stimulated with lipopolysaccharide.[15] Two additional intestinal intelectins are discovered in X. laevis[16]
Human has two intelectins: hIntL-1 (omentin) and hIntL-2.[17] Mouse also has two intelectins: mIntL-1 and mIntL-2.[18]
# Immune system
Several lines of evidence suggest that intelectins recognize microbes and may function as an innate immune defense protein. Tunicate intelectin is an opsonin for phagocytosis by hemocyte.[19] Amphioxus intelectin has been shown to agglutinate bacteria.[20][21] In zebrafish and rainbow trout, intelectin expression is stimulated upon microbial exposure.[22][23][24] Mammals such as sheep and mice also upregulate intelectin expression upon parasitic infection.[25][26] Increase in intelectin expression upon microbial exposure support the hypothesis that intelectins play a role in the immune system.
# Structure
Although intelectins require calcium ion for function, the sequences bear no resemblance to C-type lectins.[3] In addition, merely around 50 amino acids (the fibronogen-like domain) align with any known protein, specifically the ficolin family.[2] The first structural details of an intelectin comes from the crystal structure of selenomethionine-labeled XEEL carbohydrate-recognition domain (Se-Met XEEL-CRD) solved by Se-SAD.[5] XEEL-CRD was expressed and Se-Met-labeled in High Five insect cells using a recombinant baculovirus. The fibrinogen-like fold is conserved despite amino acid sequence divergence. However, extensive insertions are present in intelectin compared to ficolins, thus making intelectin a distinct lectin structural class.[5] The Se-Met XEEL-CRD structure then enables the structure solution by molecular replacement of D-glycerol 1-phosphate (GroP)-bound XEEL-CRD,[5] apo-human intelectin-1 (hIntL-1),[4] and galactofuranose-bound hIntL-1.[4]
Each polypeptide chain of XEEL and hIntL-1 contains three bound calcium ions: two in the structural calcium site and one in the ligand binding site.[4][5] The amino acid residues in the structural calcium site are conserved among intelectins, thus it is likely that most, if not all, intelectins have two structural calcium ions.[5]
In the ligand binding site of XEEL and hIntL-1, the exocyclic vicinal diol of the carbohydrate ligand directly coordinates to the calcium ion.[4][5] There are large variations in the ligand binding site residues among intelectin homologs suggesting that the intelectin family may have broad ligand specificities and biological functions.[5] As there is no intelectin numbering conventions in different organisms, one should not assume functional homology based on the intelectin number. For example, hIntL-1 has glutamic acid residues in the ligand binding site to coordinate a calcium ion, while zebrafish intelectin-1 are devoided of these acidic residues.[5] Zebrafish intelectin-2 ligand binding site residues are similar to those present in hIntL-1.
- Xenopus embryonic epidermal lectin (XEEL) ligand binding site with bound D-glycerol 1-phosphate. The calcium ion is shown as a green sphere and the ordered water molecules are shown as red spheres.[5]
Xenopus embryonic epidermal lectin (XEEL) ligand binding site with bound D-glycerol 1-phosphate. The calcium ion is shown as a green sphere and the ordered water molecules are shown as red spheres.[5]
- Human intelectin-1 (hIntL-1) ligand binding site with bound allyl-beta-D-galactofuranose. The calcium ion is shown as a green sphere and the ordered water molecules are shown as red spheres.[4]
Human intelectin-1 (hIntL-1) ligand binding site with bound allyl-beta-D-galactofuranose. The calcium ion is shown as a green sphere and the ordered water molecules are shown as red spheres.[4]
# Oligomeric state
hIntL-1 is a disulfide-linked trimer as shown by non-reducing SDS-PAGE[3] and X-ray crystallography.[4] Despite lacking the intermolecular disulfide bonds, XEEL-CRD is trimeric in solution.[5] The N-terminal peptide of the full length XEEL is responsible for dimerizing the trimeric XEEL-CRD into a disulfide-linked hexameric full-length XEEL.[5] Therefore, the N-termini of intelectins are often responsible for forming disulfide-linked oligomer. In intelectin homologs where the N-terminal cysteines are absent, the CRD itself may still capable of forming non-covalent oligomer in solution.
- Disulfide-linked trimeric human intelectin-1.[4]
Disulfide-linked trimeric human intelectin-1.[4]
- Trimeric Xenopus embryonic epidermal lectin carbohydrate-recognition domain (XEEL-CRD). Extensive biophysical investigations conclusively indicate that XEEL-CRD is trimeric in solution despite lacking the intermolecular disulfide bonds found in hIntL-1.[5]
Trimeric Xenopus embryonic epidermal lectin carbohydrate-recognition domain (XEEL-CRD). Extensive biophysical investigations conclusively indicate that XEEL-CRD is trimeric in solution despite lacking the intermolecular disulfide bonds found in hIntL-1.[5] | https://www.wikidoc.org/index.php/Intelectin | |
3e275a8f9d5b6291cbb6d0a61994a9fef07053a5 | wikidoc | Internexin | Internexin
Internexin, alpha-internexin, is a Class IV intermediate filament approximately 66 KDa. The protein was originally purified from rat optic nerve and spinal cord. The protein copurifies with other neurofilament subunits, as it was originally discovered, however in some mature neurons it can be the only neurofilament expressed. The protein is present in developing neuroblasts and in the Central Nervous System of adults. The protein is a major component of the intermediate filament network in small interneurons and cerebellar granule cells, where it is present in the parallel fibers.
# Structure
Alpha-internexin has a homologous central rod domain of approximately 310 amino acid residues that form a highly conserved alpha helical region. The central rod domain is responsible for coiled-coil structure and is flanked by an amino terminal head region and a carboxy terminal tail. This rod domain is also involved in the 10 nm filament assembly structure. The head and tail regions contain segments that are highly homologous to the NF-M’s structure. The head region is highly basic and contains many serine and threonine polymers while the tail region has distinct sequence motifs like a glutamate rich region. The alpha domain is composed of heptad repeats of hydrophobic residues that aid the formation of a coiled coil structure. The structure of Alpha-internexin is highly conserved between rats, mice and humans.
Alpha-internexin can form homopolymers, unlike the heteropolymer the neurofilaments form. This formation suggests that α-internexin and the three neurofilaments form separate filament systems. Not only can alpha-internexin form homopolymers but it form a network of extended filaments in the absence of other intermediate filament proteins and efficiently co-assemble with any type IV or type III subunit, in vitro. In Ching et al., a model of the intermediate filaments assembly is proposed. This model includes the following steps:
- Step 1: in the first step of IF assembly two parallel, unstaggered intermediate filament polypeptides chains form a dimer via their a-helical rod domains; these dimers can be either homodimers or heterodimers.
- Step 2: the dimers may associate laterally to form antiparallel, unstaggered tetramers or antiparallel, staggered tetramers.
- Step 3: the dimers may also associate longitudinally with a short head-to-tail overlap of the a-helical rod domains.
- Step 4: these lateral and longitudinal associations lead to the formation of protofibrils (octamers) and ultimately 10 nm intermediate filaments.
The close connection between the neurofilament triplet proteins and α-internexin is quite obvious. α-internexin is functionally interdependent with the neurofilament triplet proteins. If one genetically deletes NF-M and/or NF-H in mice, the transport and presence, in the axons of the Central Nervous System, of α-internexin will be drastically reduced. Not only are they functionally similar, the turnover rates are also similar among the four proteins.
# Function and expression
It is expressed in early development in the neuroblast along with α-internexin and peripherin. As development continues into neurons the neurofilament triplet proteins (NF-L: neurofilament low molecular mass, NF-M: neurofilament medium molecular mass, and NF-H: neurofilament high molecular mass) are expressed in increasing molecular mass order as α-internexin expression decreases. In the neuroblast phase of development α-internexin is found in the neural tube and neural crest derived neuroblasts.
In adult cells, α-internexin is expressed abundantly in the central nervous system, in the cytoplasm of neurons, along with the neurofilament triplet proteins. They are expressed in a relatively fixed stoichiometric ratio to neurofilaments.
Alpha-internexin is a brain and central nervous system filament that is involved in neuronal development and has been suggested to play a role in axonal outgrowth. Gefiltin and xefiltin, homologs of α-internexin in zebrafish and Xenopus laevis, respectively, are highly expressed during retinal growth and optic axon regeneration and therefore have aided the speculation that α-internexin and axonal outgrowth may be connected. With this speculation, studies have been performed to develop a stronger bridge between the two. Through knockout studies using mice, the inhibition of α-internexin had no visible effect on development of the nervous system which suggests that axonal outgrowth is unaffected by α-internexin, however, the knockout study failed to rule out subtle differences that the protein may have caused. Not only has α-internexin been linked to axonal outgrowth but it may regulate axonal stability or diameter through changes in filaments and their subunit composition. Also, internexin could be involved in the maintenance or the formation of dendritic spines. There have been many implications as to the function of α-internexin, but no concrete evidence currently exists to fully support or negate these speculations.
# Disease associations
α-internexin has also been implicated in several degenerative diseases such as Amyotrophic lateral sclerosis, dementia with Lewy bodies, Parkinson’s Disease, neuropathies, tropical spastic paraparesis and HTLV-1 associated myelopathy. In HTLV-1 myelopathy, Tax, transactivator expressed by HTLV-1, interacts with α-internexin in cell culture resulting in dramatic reduction in Tax transcactivation and intermediate filament formation. | Internexin
Internexin, alpha-internexin, is a Class IV intermediate filament approximately 66 KDa. The protein was originally purified from rat optic nerve and spinal cord.[1] The protein copurifies with other neurofilament subunits, as it was originally discovered, however in some mature neurons it can be the only neurofilament expressed. The protein is present in developing neuroblasts and in the Central Nervous System of adults. The protein is a major component of the intermediate filament network in small interneurons and cerebellar granule cells, where it is present in the parallel fibers.
# Structure
Alpha-internexin has a homologous central rod domain of approximately 310 amino acid residues that form a highly conserved alpha helical region. The central rod domain is responsible for coiled-coil structure and is flanked by an amino terminal head region and a carboxy terminal tail.[2] This rod domain is also involved in the 10 nm filament assembly structure. The head and tail regions contain segments that are highly homologous to the NF-M’s structure.[1] The head region is highly basic and contains many serine and threonine polymers while the tail region has distinct sequence motifs like a glutamate rich region.[3] The alpha domain is composed of heptad repeats of hydrophobic residues that aid the formation of a coiled coil structure.[3] The structure of Alpha-internexin is highly conserved between rats, mice and humans.[1]
Alpha-internexin can form homopolymers, unlike the heteropolymer the neurofilaments form. This formation suggests that α-internexin and the three neurofilaments form separate filament systems.[4] Not only can alpha-internexin form homopolymers but it form a network of extended filaments in the absence of other intermediate filament proteins and efficiently co-assemble with any type IV or type III subunit, in vitro.[1] In Ching et al., a model of the intermediate filaments assembly is proposed. This model includes the following steps:
- Step 1: in the first step of IF assembly two parallel, unstaggered intermediate filament polypeptides chains form a dimer via their a-helical rod domains; these dimers can be either homodimers or heterodimers.
- Step 2: the dimers may associate laterally to form antiparallel, unstaggered tetramers or antiparallel, staggered tetramers.
- Step 3: the dimers may also associate longitudinally with a short head-to-tail overlap of the a-helical rod domains.
- Step 4: these lateral and longitudinal associations lead to the formation of protofibrils (octamers) and ultimately 10 nm intermediate filaments.[5]
The close connection between the neurofilament triplet proteins and α-internexin is quite obvious. α-internexin is functionally interdependent with the neurofilament triplet proteins.[4] If one genetically deletes NF-M and/or NF-H in mice, the transport and presence, in the axons of the Central Nervous System, of α-internexin will be drastically reduced. Not only are they functionally similar, the turnover rates are also similar among the four proteins.[4]
# Function and expression
It is expressed in early development in the neuroblast along with α-internexin and peripherin. As development continues into neurons the neurofilament triplet proteins (NF-L: neurofilament low molecular mass, NF-M: neurofilament medium molecular mass, and NF-H: neurofilament high molecular mass) are expressed in increasing molecular mass order as α-internexin expression decreases.[3] In the neuroblast phase of development α-internexin is found in the neural tube and neural crest derived neuroblasts.
In adult cells, α-internexin is expressed abundantly in the central nervous system, in the cytoplasm of neurons, along with the neurofilament triplet proteins. They are expressed in a relatively fixed stoichiometric ratio to neurofilaments.[4]
Alpha-internexin is a brain and central nervous system filament that is involved in neuronal development and has been suggested to play a role in axonal outgrowth. Gefiltin and xefiltin, homologs of α-internexin in zebrafish and Xenopus laevis, respectively, are highly expressed during retinal growth and optic axon regeneration and therefore have aided the speculation that α-internexin and axonal outgrowth may be connected.[1] With this speculation, studies have been performed to develop a stronger bridge between the two. Through knockout studies using mice, the inhibition of α-internexin had no visible effect on development of the nervous system which suggests that axonal outgrowth is unaffected by α-internexin, however, the knockout study failed to rule out subtle differences that the protein may have caused.[4] Not only has α-internexin been linked to axonal outgrowth but it may regulate axonal stability or diameter through changes in filaments and their subunit composition.[1] Also, internexin could be involved in the maintenance or the formation of dendritic spines.[4] There have been many implications as to the function of α-internexin, but no concrete evidence currently exists to fully support or negate these speculations.
# Disease associations
α-internexin has also been implicated in several degenerative diseases such as Amyotrophic lateral sclerosis, dementia with Lewy bodies, Parkinson’s Disease, neuropathies, tropical spastic paraparesis and HTLV-1 associated myelopathy. In HTLV-1 myelopathy, Tax, transactivator expressed by HTLV-1, interacts with α-internexin in cell culture resulting in dramatic reduction in Tax transcactivation and intermediate filament formation. | https://www.wikidoc.org/index.php/Internexin | |
a5012aa8f40b9f7a00698c32f377e01ede327512 | wikidoc | Interplast | Interplast
Interplast is the first international humanitarian organization to provide free reconstructive surgery in developing countries, primarily to children with cleft lip and palate and burn scar contractures.
Interplast was founded in 1969 by plastic surgeon Donald Laub, and as of 2007, has treated more than 64,000 children worldwide. The first patient was a 13-year-old boy who had come to Stanford University Medical Center from his home in Mexicali, Mexico to receive surgery to repair his cleft lip and palate. Soon after, Laub and other surgeons began organizing regular trips to a charity hospital in Mexicali to treat children with disabling deformities.
Over time, Interplast began organizing surgical volunteer trips to other parts of Latin America, and eventually to Asia and Africa as well. As medical infrastructures improved throughout the developing world, Interplast shifted its focus towards educating and empowering doctors in developing countries by providing surgical outreach directors with the resources (money, education, supplies, etc) to offer high-quality care in their own communities.
Interplast was the subject of "A Story of Healing," winner of the 1997 Academy Award for Documentary Short Subject. In 2007, "A Story of Healing" became the first Academy Award-winning film to be released under a Creative Commons license. | Interplast
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Interplast is the first international humanitarian organization to provide free reconstructive surgery in developing countries, primarily to children with cleft lip and palate and burn scar contractures.
Interplast was founded in 1969 by plastic surgeon Donald Laub, and as of 2007, has treated more than 64,000 children worldwide. The first patient was a 13-year-old boy who had come to Stanford University Medical Center from his home in Mexicali, Mexico to receive surgery to repair his cleft lip and palate. Soon after, Laub and other surgeons began organizing regular trips to a charity hospital in Mexicali to treat children with disabling deformities.
Over time, Interplast began organizing surgical volunteer trips to other parts of Latin America, and eventually to Asia and Africa as well. As medical infrastructures improved throughout the developing world, Interplast shifted its focus towards educating and empowering doctors in developing countries by providing surgical outreach directors with the resources (money, education, supplies, etc) to offer high-quality care in their own communities.
Interplast was the subject of "A Story of Healing," winner of the 1997 Academy Award for Documentary Short Subject. In 2007, "A Story of Healing" became the first Academy Award-winning film to be released under a Creative Commons license.
# External links
- Interplast
- Interplast blog: showcases Interplast volunteer surgical trips and visiting educator workshops throughout Africa, Asia and Latin America.
- Watch "A Story of Healing," including epilogue
- Interplast Grand Rounds, Interplast's Web-based collaboration tool
- A Story of Healing at The Internet Movie Database
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Interplast | |
d02883fd0e6bfaea591c0f1d065589f3cc33187a | wikidoc | Peritoneum | Peritoneum
# Overview
In higher vertebrates, the peritoneum is the serous membrane that forms the lining of the abdominal cavity — it covers most of the intra-abdominal organs. It is composed of a layer of mesothelium supported by a thin layer of connective tissue.
The peritoneum both supports the abdominal organs and serves as a conduit for their blood and lymph vessels and nerves.
# Structure
## Layers
The abdominal cavity (the space bounded by the vertebrae, abdominal muscles, diaphragm and pelvic floor) should not be confused with the intraperitoneal space (located within the abdominal cavity, but wrapped in peritoneum). For example, a kidney is inside the abdominal cavity, but is retroperitoneal.
Although they ultimately form one continuous sheet, two types or layers of peritoneum and a potential space between them are referenced:
- The outer layer, called the parietal peritoneum, is attached to the abdominal wall.
- The inner layer, the visceral peritoneum, is wrapped around the internal organs that are located inside the intraperitoneal cavity.
- The potential space between these two layers is the peritoneal cavity; it is filled with a small amount (about 50 ml) of slippery serous fluid that allows the two layers to slide freely over each other.
- The term mesentery is often used to refer to a double layer of visceral peritoneum. There are often blood vessels, nerves, and other structures between these layers. It should be noted that the space between these two layers is technically outside of the peritoneal sac, and thus not in the peritoneal cavity.
## Subdivisions
There are two main regions of the peritoneum, connected by the epiploic foramen:
- the greater sac (or general cavity of the abdomen), represented in red in the diagrams above.
- the lesser sac (or omental bursa), represented in blue. The lesser sac is divided into two "omenta":
The lesser omentum (or gastrohepatic) is attached to the lesser curvature of the stomach and the liver.
The greater omentum (or gastrocolic) hangs from the greater curve of the stomach and loops down in front of the intestines before curving back upwards to attach to the transverse colon. In effect it is draped in front of the intestines like an apron and may serve as an insulating or protective layer.
- The lesser omentum (or gastrohepatic) is attached to the lesser curvature of the stomach and the liver.
- The greater omentum (or gastrocolic) hangs from the greater curve of the stomach and loops down in front of the intestines before curving back upwards to attach to the transverse colon. In effect it is draped in front of the intestines like an apron and may serve as an insulating or protective layer.
The mesentery is the part of the peritoneum through which most abdominal organs are attached to the abdominal wall and supplied with blood and lymph vessels and nerves.
Structures include:
In addition, in the pelvic cavity there are several structures that are usually named not for the peritoneum, but for the areas defined by the peritoneal folds:
# Development
The peritoneum develops ultimately from the mesoderm of the trilaminar embryo. As the mesoderm differentiates, one region known as the lateral plate mesoderm splits to form two layers separated by an intraembryonic coelom. These two layers develop later into the visceral and parietal layers found in all serous cavities, including the peritoneum.
As an embryo develops, the various abdominal organs grow into the abdominal cavity from structures in the abdominal wall. In this process they become enveloped in a layer of peritoneum. The growing organs "take their blood vessels with them" from the abdominal wall, and these blood vessels become covered by peritoneum, forming a mesentery.
# Clinical aspects
## Pathology
- Pneumoperitoneum is the presence of gas within the peritoneal cavity, as may occur when a perforation forms in the stomach or intestines, and heralds a perilous situation.
- Peritonitis refers to inflammation of the peritoneal lining or cavity, as may occur with either a perforation or by spread of infection through the wall of one of the abdominal organs. This too is a serious condition, and often requires emergency surgery.
- Ascites is an accumulation of excess fluid within the peritoneal cavity.
## Peritoneal dialysis
In one form of dialysis, the peritoneal dialysis, a glucose solution is run through a tube into the peritoneal cavity. The fluid is left there for a prescribed amount of time to absorb waste products, and then removed through the tube. The reason for this effect is the high number of arteries and veins in the peritoneal cavity. Through the mechanism of diffusion, waste products are removed from the blood.
# Classification of abdominal structures
The structures in the abdomen are classified as intraperitoneal, retroperitoneal or infraperitoneal depending on whether they are covered with visceral peritoneum and have a mesentery or not.
Structures that are intraperitoneal are generally mobile, while those that are retroperitoneal are relatively fixed in their location.
Some structures, such as the kidneys, are "primarily retroperitoneal", while others such as the majority of the duodenum, are "secondarily retroperitoneal", meaning that structure developed intraperitoneally but lost its mesentery and thus became retroperitoneal.
# Etymology
Peritoneum is derived from Greek. Peri- means around, while -ton- refers to stretching. Thus, peritoneum means stretched around or stretched over.
# Additional images
- Bladder
- Median sagittal section of pelvis, showing arrangement of fasciæ.
- Horizontal disposition of the peritoneum in the lower part of the abdomen.
- Sagittal section through posterior abdominal wall, showing the relations of the capsule of the kidney.
- Topography of thoracic and abdominal viscera. | Peritoneum
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Template:Infobox Anatomy
In higher vertebrates, the peritoneum is the serous membrane that forms the lining of the abdominal cavity — it covers most of the intra-abdominal organs. It is composed of a layer of mesothelium supported by a thin layer of connective tissue.
The peritoneum both supports the abdominal organs and serves as a conduit for their blood and lymph vessels and nerves.
# Structure
## Layers
The abdominal cavity (the space bounded by the vertebrae, abdominal muscles, diaphragm and pelvic floor) should not be confused with the intraperitoneal space (located within the abdominal cavity, but wrapped in peritoneum). For example, a kidney is inside the abdominal cavity, but is retroperitoneal.
Although they ultimately form one continuous sheet, two types or layers of peritoneum and a potential space between them are referenced:
- The outer layer, called the parietal peritoneum, is attached to the abdominal wall.
- The inner layer, the visceral peritoneum, is wrapped around the internal organs that are located inside the intraperitoneal cavity.
- The potential space between these two layers is the peritoneal cavity; it is filled with a small amount (about 50 ml) of slippery serous fluid that allows the two layers to slide freely over each other.
- The term mesentery is often used to refer to a double layer of visceral peritoneum. There are often blood vessels, nerves, and other structures between these layers. It should be noted that the space between these two layers is technically outside of the peritoneal sac, and thus not in the peritoneal cavity.
## Subdivisions
There are two main regions of the peritoneum, connected by the epiploic foramen:
- the greater sac (or general cavity of the abdomen), represented in red in the diagrams above.
- the lesser sac (or omental bursa), represented in blue. The lesser sac is divided into two "omenta":
The lesser omentum (or gastrohepatic) is attached to the lesser curvature of the stomach and the liver.
The greater omentum (or gastrocolic) hangs from the greater curve of the stomach and loops down in front of the intestines before curving back upwards to attach to the transverse colon. In effect it is draped in front of the intestines like an apron and may serve as an insulating or protective layer.
- The lesser omentum (or gastrohepatic) is attached to the lesser curvature of the stomach and the liver.
- The greater omentum (or gastrocolic) hangs from the greater curve of the stomach and loops down in front of the intestines before curving back upwards to attach to the transverse colon. In effect it is draped in front of the intestines like an apron and may serve as an insulating or protective layer.
The mesentery is the part of the peritoneum through which most abdominal organs are attached to the abdominal wall and supplied with blood and lymph vessels and nerves.
Structures include:
In addition, in the pelvic cavity there are several structures that are usually named not for the peritoneum, but for the areas defined by the peritoneal folds:
# Development
The peritoneum develops ultimately from the mesoderm of the trilaminar embryo. As the mesoderm differentiates, one region known as the lateral plate mesoderm splits to form two layers separated by an intraembryonic coelom. These two layers develop later into the visceral and parietal layers found in all serous cavities, including the peritoneum.
As an embryo develops, the various abdominal organs grow into the abdominal cavity from structures in the abdominal wall. In this process they become enveloped in a layer of peritoneum. The growing organs "take their blood vessels with them" from the abdominal wall, and these blood vessels become covered by peritoneum, forming a mesentery.
# Clinical aspects
## Pathology
- Pneumoperitoneum is the presence of gas within the peritoneal cavity, as may occur when a perforation forms in the stomach or intestines, and heralds a perilous situation.
- Peritonitis refers to inflammation of the peritoneal lining or cavity, as may occur with either a perforation or by spread of infection through the wall of one of the abdominal organs. This too is a serious condition, and often requires emergency surgery.
- Ascites is an accumulation of excess fluid within the peritoneal cavity.
## Peritoneal dialysis
In one form of dialysis, the peritoneal dialysis, a glucose solution is run through a tube into the peritoneal cavity. The fluid is left there for a prescribed amount of time to absorb waste products, and then removed through the tube. The reason for this effect is the high number of arteries and veins in the peritoneal cavity. Through the mechanism of diffusion, waste products are removed from the blood.
# Classification of abdominal structures
The structures in the abdomen are classified as intraperitoneal, retroperitoneal or infraperitoneal depending on whether they are covered with visceral peritoneum and have a mesentery or not.
Structures that are intraperitoneal are generally mobile, while those that are retroperitoneal are relatively fixed in their location.
Some structures, such as the kidneys, are "primarily retroperitoneal", while others such as the majority of the duodenum, are "secondarily retroperitoneal", meaning that structure developed intraperitoneally but lost its mesentery and thus became retroperitoneal.
# Etymology
Peritoneum is derived from Greek. Peri- means around, while -ton- refers to stretching. Thus, peritoneum means stretched around or stretched over.
# Additional images
- Bladder
- Median sagittal section of pelvis, showing arrangement of fasciæ.
- Horizontal disposition of the peritoneum in the lower part of the abdomen.
- Sagittal section through posterior abdominal wall, showing the relations of the capsule of the kidney.
- Topography of thoracic and abdominal viscera. | https://www.wikidoc.org/index.php/Intraperitoneal | |
3ba63a7a05a110739b47581f9378e54a7ebee146 | wikidoc | Stillbirth | Stillbirth
Synonyms and keywords: Intrauterine death
# Overview
A stillbirth, meaning "quiet birth" occurs when a fetus which has died in the uterus or during labour or delivery exits a woman's body. The term is often used in distinction to live birth or miscarriage. Most stillbirths occur in full term pregnancies.
Some sources reserve the term "stillbirth" for a fetus which has died after reaching mid-second trimester to full term gestational age. For example, in the United Kingdom, "stillbirth" is used to describe an infant delivered without life after 24 weeks gestation. The sources that use this definition tend to use the term "miscarriage" if the death occurs earlier in development. In contrast, other sources use the term "stillbirth" regardless of the stage of fetal development.
# Human Stillbirth
## Causes
The causes of a large percentage of human stillbirths remain unknown, even in cases where extensive testing and autopsy have been performed. The term used to describe these is sudden antenatal death syndrome or SADS. In cases where the cause is known, some possibilities of the cause of death are:
- Bacterial infection
- Birth defects
- Chromosomal aberrations
- Growth retardation
- Intrahepatic Cholestasis of Pregnancy
- Maternal diabetes or high blood pressure
- Maternal consumption of nicotine, alcohol, recreational drugs (excluding cannabis,) or pharmaceutical drugs contraindicated in pregnancy
- Postdate pregnancy
- Placental abruption
- Physical trauma
- Radiation poisoning
- Rh disease
- Umbilical cord accidents
## Prenatal diagnosis
A decrease or cessation of fetal activity may be an indication of fetal distress or death, though it is not entirely uncommon for a healthy fetus to exhibit such changes, particularly near the end of a pregnancy when there is considerably little space in the uterus for the fetus to move about. Still, medical examination, including a nonstress test, is recommended in the event of any change in the strength or frequency of fetal movement, especially a complete cease; most midwives and obstetricians recommend the use of a kick chart to assist in detecting any changes. Fetal distress or death can be confirmed or ruled out via fetoscopy/doptone, ultrasound, and/or electronic fetal monitoring. If the fetus is alive but inactive, extra attention will be given to the placenta and umbilical cord during ultrasound examination to ensure that there is no compromise of oxygen and nutrient delivery.
## Prenatal maternal treatment
An in utero fetal death does not present an immediate health risk to the woman and labour will usually begin spontaneously after two weeks, so the woman may choose to wait and deliver vaginally. After two weeks, the woman is at risk of developing blood clotting problems, and induction is recommended at this point. In many cases, the woman will find the idea of carrying a dead fetus emotionally traumatizing and will elect to be induced. Cesarean delivery is not recommended unless complications develop during vaginal birth.
## Prevalence
Stillbirth is a relatively common, but often random, occurrence. The mean stillbirth rate in the United States is approximately 1 in 115 births, which is roughly 26,000 stillbirths each year, or on an average one every 20 minutes. In Australia, England, Wales, and Northern Ireland, the rate is approximately 1 in every 200 births, in Scotland 1 in 167. (From The National Statistical Office and other sources.)
In developing countries, where medical care can be of low quality or unavailable, the stillbirth rate is much higher.
# Legal Definitions of Stillbirth
## Australia
In Australia any stillborn fetus weighing more than 400 grams, or more than 20 weeks in gestation, must have its birth registered. Should the parents of a stillborn child have children later that live, when registering the newer children's birth they must add SB beside the name of the stillborn child.
## Canada
Beginning in 1959, "the definition of a stillbirth was revised to conform, in substance, to the definition of fetal death recommended by the World Health Organization." The definition of "fetal death" promulgated by the World Health Organization in 1950 is as follows:
## United Kingdom
Throughout the United Kingdom, stillbirths must be registered by law. The Stillbirth Definition Act (1992) states: "any ‘child’ expelled or issued forth from its mother after the 24th week of pregnancy that did not breathe or show any other signs of life should be registered as a stillbirth." In England and Wales, this must be done within 42 days and a Stillbirth Certificate is issued to the parent(s). In Scotland, this must be done within 21 days.
## United States
In the United States, there is no standard definition of the term 'stillbirth'.
The Centers for Disease Control and Prevention collects statistical information on "live births, fetal deaths, and induced termination of pregnancy" from 57 reporting areas in the United States. Each reporting area has different guidelines and definitions for what is being reported; many do not use the term "stillbirth" at all. The federal guidelines suggests that fetal death and stillbirth can be interchangeable terms. The CDC definition of "fetal death" is based on the definition promulgated by the World Health Organization in 1950 (see section above on Canada).
The federal guidelines recommend reporting those fetal deaths whose birth weight is over 350g, or those over 19 weeks gestation. Forty-one areas use a definition very similar to the federal definition, thirteen areas use a shortened definition of fetal death, and three areas have no formal definition of fetal death. Only 11 areas specifically use the term 'stillbirth' , often synonymously with fetal death, however they are split between whether stillbirths are "irrespective of the duration of pregnancy", or whether some age or weight constraint is applied. | Stillbirth
For patient information, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Intrauterine death
# Overview
A stillbirth, meaning "quiet birth" occurs when a fetus which has died in the uterus or during labour or delivery exits a woman's body. The term is often used in distinction to live birth or miscarriage. Most stillbirths occur in full term pregnancies.
Some sources reserve the term "stillbirth" for a fetus which has died after reaching mid-second trimester to full term gestational age. For example, in the United Kingdom, "stillbirth" is used to describe an infant delivered without life after 24 weeks gestation. The sources that use this definition tend to use the term "miscarriage" if the death occurs earlier in development. In contrast, other sources use the term "stillbirth" regardless of the stage of fetal development.
# Human Stillbirth
## Causes
The causes of a large percentage of human stillbirths remain unknown, even in cases where extensive testing and autopsy have been performed. The term used to describe these is sudden antenatal death syndrome or SADS. In cases where the cause is known, some possibilities of the cause of death are:
- Bacterial infection
- Birth defects
- Chromosomal aberrations
- Growth retardation
- Intrahepatic Cholestasis of Pregnancy
- Maternal diabetes or high blood pressure
- Maternal consumption of nicotine, alcohol, recreational drugs (excluding cannabis,[1]) or pharmaceutical drugs contraindicated in pregnancy
- Postdate pregnancy
- Placental abruption
- Physical trauma
- Radiation poisoning
- Rh disease
- Umbilical cord accidents
## Prenatal diagnosis
A decrease or cessation of fetal activity may be an indication of fetal distress or death, though it is not entirely uncommon for a healthy fetus to exhibit such changes, particularly near the end of a pregnancy when there is considerably little space in the uterus for the fetus to move about. Still, medical examination, including a nonstress test, is recommended in the event of any change in the strength or frequency of fetal movement, especially a complete cease; most midwives and obstetricians recommend the use of a kick chart to assist in detecting any changes. Fetal distress or death can be confirmed or ruled out via fetoscopy/doptone, ultrasound, and/or electronic fetal monitoring. If the fetus is alive but inactive, extra attention will be given to the placenta and umbilical cord during ultrasound examination to ensure that there is no compromise of oxygen and nutrient delivery.
## Prenatal maternal treatment
An in utero fetal death does not present an immediate health risk to the woman and labour will usually begin spontaneously after two weeks, so the woman may choose to wait and deliver vaginally. After two weeks, the woman is at risk of developing blood clotting problems, and induction is recommended at this point. In many cases, the woman will find the idea of carrying a dead fetus emotionally traumatizing and will elect to be induced. Cesarean delivery is not recommended unless complications develop during vaginal birth.
## Prevalence
Stillbirth is a relatively common, but often random, occurrence. The mean stillbirth rate in the United States is approximately 1 in 115 births, which is roughly 26,000 stillbirths each year, or on an average one every 20 minutes. In Australia,[2] England, Wales, and Northern Ireland, the rate is approximately 1 in every 200 births, in Scotland 1 in 167. (From The National Statistical Office and other sources.)
In developing countries, where medical care can be of low quality or unavailable, the stillbirth rate is much higher.
# Legal Definitions of Stillbirth
## Australia
In Australia any stillborn fetus weighing more than 400 grams, or more than 20 weeks in gestation, must have its birth registered. Should the parents of a stillborn child have children later that live, when registering the newer children's birth they must add SB beside the name of the stillborn child.
## Canada
Beginning in 1959, "the definition of a stillbirth was revised to conform, in substance, to the definition of fetal death recommended by the World Health Organization." [3] The definition of "fetal death" promulgated by the World Health Organization in 1950 is as follows:
## United Kingdom
Throughout the United Kingdom, stillbirths must be registered by law. The Stillbirth Definition Act (1992) states: "any ‘child’ expelled or issued forth from its mother after the 24th week of pregnancy that did not breathe or show any other signs of life should be registered as a stillbirth."[5] In England and Wales, this must be done within 42 days and a Stillbirth Certificate is issued to the parent(s).[6] In Scotland, this must be done within 21 days.[7]
## United States
In the United States, there is no standard definition of the term 'stillbirth'.[4]
The Centers for Disease Control and Prevention collects statistical information on "live births, fetal deaths, and induced termination of pregnancy" from 57 reporting areas in the United States. Each reporting area has different guidelines and definitions for what is being reported; many do not use the term "stillbirth" at all. The federal guidelines suggests that fetal death and stillbirth can be interchangeable terms. The CDC definition of "fetal death" is based on the definition promulgated by the World Health Organization in 1950 (see section above on Canada).
The federal guidelines recommend reporting those fetal deaths whose birth weight is over 350g, or those over 19 weeks gestation. Forty-one areas use a definition very similar to the federal definition, thirteen areas use a shortened definition of fetal death, and three areas have no formal definition of fetal death. Only 11 areas specifically use the term 'stillbirth' , often synonymously with fetal death, however they are split between whether stillbirths are "irrespective of the duration of pregnancy", or whether some age or weight constraint is applied. | https://www.wikidoc.org/index.php/Intrauterine_death | |
0dd43ac0c230b5fed7ced516e46156541770fdc7 | wikidoc | Invaginate | Invaginate
Invagination means to fold inward or to sheath. In biology, this can refer to a number of processes.
- Invagination is the morphogenetic processes by which an embryo takes form, and is the initial step of gastrulation, the massive reorganization of the embryo from a simple spherical ball of cells, the blastula, into a multi-layered organism, with differentiated germ layers: endoderm, mesoderm, and ectoderm. More localized invaginations also occur later in embryonic development, to form coelom, etc.
- Invagination is the formation of a cleavage furrow during cytokinesis in animal cells.
- The inner membrane of a mitochondrion invaginates to form cristae, thus providing a much greater surface area to accommodate the protein complexes and other participants that produce ATP.
- Invagination occurs during endocytosis and exocytosis when a vesicle forms within the cell and the membrane closes around it.
In the humanities:
- Used to explain a special kind of meta narrative. Used by Rosalyn Krauss and Jacques Derrida (The Law of Genre,” Glyph 7 (1980).
de:Invagination | Invaginate
Invagination means to fold inward or to sheath. In biology, this can refer to a number of processes.
- Invagination is the morphogenetic processes by which an embryo takes form, and is the initial step of gastrulation, the massive reorganization of the embryo from a simple spherical ball of cells, the blastula, into a multi-layered organism, with differentiated germ layers: endoderm, mesoderm, and ectoderm. More localized invaginations also occur later in embryonic development, to form coelom, etc.
- Invagination is the formation of a cleavage furrow during cytokinesis in animal cells.
- The inner membrane of a mitochondrion invaginates to form cristae, thus providing a much greater surface area to accommodate the protein complexes and other participants that produce ATP.
- Invagination occurs during endocytosis and exocytosis when a vesicle forms within the cell and the membrane closes around it.
In the humanities:
- Used to explain a special kind of meta narrative. Used by Rosalyn Krauss and Jacques Derrida (The Law of Genre,” Glyph 7 (1980).
de:Invagination
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Invaginate | |
6343f7b66e0e2b4041b9d6ee9c4d688aa4245b84 | wikidoc | Invisalign | Invisalign
Invisalign is a series of clear, removable teeth aligners that both orthodontists and dentists use as an alternative to traditional metal dental braces. As of April 2008, more than 730,000 patients have completed or are currently in treatment.
Invisalign is designed, manufactured, and marketed by Santa Clara, California-based medical-device company Align Technology, Inc. Align says that over 35,790 doctors are trained to provide Invisalign treatment in the U.S., with 48,130 doctors worldwide.
# Advantages and disadvantages
## Advantages
The most obvious advantage of the treatment is cosmetic: the aligners are completely transparent, therefore far more difficult to detect than traditional wire and bracket braces. This makes the method particularly popular among adults who want to straighten their teeth without the look of traditional metal braces, which are commonly worn by children and adolescents. In addition, the aligners are marketed as being more comfortable than braces. Due to the removable nature of the device, food can be consumed without the encumbrance of metallic braces.
Clinically, aligners avoid many of the side effects of traditional fixed appliances, for example the effects on the gums and supporting tissues. Fixed appliances are known to cause the roots of teeth to shorten for most patients, and demineralisation or tooth decay occurs in up to 50% of patients because they cannot be removed for eating and cleaning, and because they prevent accurate x-rays from being taken. Patients "graduate" to a new set of aligners in their treatment series approximately every two weeks. The aligners give less force per week and less pain than do fixed appliances (traditional metal braces). Fixed appliances are adjusted approximately every six weeks and apply greater forces.
Aligners should be removed to eat, drink, to clean the teeth, or to have them checked by the clinician. (It is acceptable to wear aligners while drinking water.) Computerized treatment planning is compulsory as part of the Invisalign protocol. As with other forms of orthodontic treatments that incorporate a computerized plan, this allows the prospective patient to review the projected smile design, learn how long the treatment is likely to take, compare different plans, and make a more educated decision about whether or not to use Invisalign.
Invisalign treatments have been claimed to be quicker than traditional orthodontics. A large-scale study of 408 patients with traditional appliances in Indiana took an average of 35.92 months with a maximum of 96 months, while Invisalign takes between 12–18 months. In a much smaller study Invisalign was shown to be faster and achieve straighter teeth than alternatives but relapsed to ultimately get similar results to the traditional appliances examined. The study was considered by the authors, however, to be too small for many conclusions to be statistically significant. Furthermore, this general concept that Invisalign is faster has been challenged by the Invisalign review which points out that there are other brace appliance systems that take half the time, for example by incorporating surgery or temporary implants that insert into the patient's bone, to accelerate the procedure.
## Disadvantages
The product also has potential disadvantages: the very fact that the aligners are removable means they are not continually correcting the teeth. Unlike traditional fixed braces, they are largely dependent on a patient's habits and their consistency in wearing the aligners. The success of the Invisalign aligners is based on a patient's commitment to wear the aligners for a minimum of 20–22 hours per day, only removing them when they are eating, drinking, or brushing their teeth.
The system is also somewhat expensive, as conceded by the Align company, and can be more expensive than traditional wire and bracket systems.
The aligners must be removed for eating. They and the teeth should be cleaned before re-inserting afterwards. This can be troublesome for people who are constantly snacking and may mean the patient has to clean their teeth up to six times daily.
Because the aligners are removed for eating, they can become lost. Because the aligners must be removed for eating and re-inserted, problems occur in patients who forget to do these things. Invsialign treatment will not be successful in patients who forget to remove the inserts, who forget to re-insert them, or who lose them.
By their very nature, Invisalign aligner trays are not as proficient as fixed braces at moving teeth in the vertical dimension. Certain teeth are also slightly problematic for Invisalign aligners to rotate. Some lower premolars with their rounded shape can be difficult for the aligners to grasp and apply a rotational force to.
Unlike traditional braces, if a patient grinds or clenches his or her teeth during the day or while sleeping, the aligners can become damaged. In practice, however, this problem is very rare and a new aligner can be ordered. Also, similar to traditional metal braces, aligners may cause a slight lisp at the beginning of treatment. This usually disappears as the patient becomes used to the treatment.
The aligners are constructed of implantable grade polyurethane, and the Align company has acknowledged that, though extremely rare, there may be cases of allergic and toxic sensitivity reactions to Invisalign. Minor symptoms such as sore throat, cough, and nausea have been reported. In more serious cases, the FDA has received reports of systemic swelling or throat pain that has extended to the upper chest and wind passages requiring emergency medical treatment and discontinuation of the Invisalign treatment. While the Invisalign company provides no information except the MSDS (material safety data sheet) directly to patients or orthodontists, working through the patient's orthodontist Invisalign will make the aligners with several different materials to attempt to reduce toxic or allergic sensitivity.
Should the treatment go off track, or patients fail to keep the aligners in for the required length of time, then the next aligner in the series will not fit, and a new set of impressions and aligners will be necessary, adding to the cost.
## Scientific studies
In a systematic review of the literature, is published in the Journal of the American Dental Association in 2005, Drs. Manual Lagravere and Carlos Flores-Mir were unable to draw strong conclusions about the effectiveness of the Invisalign system. They pointed to the need for randomized clinical trials. Since this paper, more studies about the clinical effectiveness have been published; for example in the UK, Dr Paul Humber has analyzed 100 back-to-back Invisalign cases. In the USA, Akhlaghi and colleagues compared treatment with the invisalign system with treatment with conventional braces and concluded that "conventional fixed appliances achieved better results in the treatment of Class I mild crowding malocclusions". In a comparison of outcomes between the two approaches, Kuncio et al. reported that the Invisalign group displayed greater relapse saying "the mean alignment of the Invisalign group was superior to the Braces group before and after the retention phase, but these differences were not statistically significant. Therefore, even though the Invisalign cases relapsed more, they appear to have the same, if not better, overall alignment scores." In a larger study Djeu and colleagues had similar findings to Akhlaghi above and concluded that "Invisalign was especially deficient in its ability to correct large anteroposterior discrepancies and occlusal contacts". They felt that "The strengths of Invisalign were its ability to close spaces and correct anterior rotations and marginal ridge heights." They added "Invisalign patients finished 4 months sooner than those with fixed appliances on average."
# Pricing
The treatment price is often the same as or more than traditional braces. Treatment price is set by the dentist or orthodontist, although the cost of treatment varies considerably by doctor. Doctor fees are usually determined by complexity and length of treatment. In the U.S., treatments range in price from $3,500 to $7,000, depending on geographic location. For example, in northwest Ohio, the case of a patient with a mild overbite and several teeth that needed to be turned cost $5,580.00 in 2008 (for a 13-month treatment). Braces would have cost $4,500.00 (if the express treatment were available, it would have been $4,300). It is important to remember that costs vary from case to case.
In Europe, the treatment price ranges from €3,000 to €5,700, depending on case complexity and length. Medical insurance is not as common in Europe, and cosmetic treatments are generally not covered by the state-supported universal health-care systems, so the braces are usually paid for entirely by the patients. Financing is frequently available.
# Treatment
An orthodontist begins by taking dental impressions, x-rays and photographs of the patient's teeth and sending them to Align Technology. The impressions are put through a CT scan from which a computer creates a three-dimensional model. Technicians then individualize the teeth in the computer model and move them to their final position as prescribed by the orthodontist. Custom software then simulates the movement of the teeth in stages. The orthodontist reviews the simulation online using Align Technology's ClinCheck via a web browser and approves or modifies the treatment. Once approved, a plastic resin aligner is manufactured for each stage of the computer simulation and shipped to the orthodontist.
'Attachments' are sometimes bonded to teeth that need to be "rotated" or moved more than other teeth. Patients can expect as many as thirteen attachments. They are tooth-colored and made of a glass-like substance.
'Reproximation' is a process by which the contacts between teeth are filed down to allow for a better fit. This may also be a part of treatment.
Average treatment time is about one year, again depending on the complexity of the treatment. Simple treatments (minor crowding, minor spacing) may be as short as twenty weeks—this is known as the "Invisalign Express" program. Although the aligners are removable, they must be worn at least 20 to 22 hours per day to avoid delaying the treatment process. If they are not worn consistently, treatment time will increase.
After the regular aligner or braces treatment is complete, retainers composed of a similar plastic material are usually required to be worn, at least at night.
Like other orthodontic systems, the patient has some flexibility. The final position of the teeth is not completely determined by the last aligner. If the patient wants to change the end position because the actual position is not optimal, new aligners are ordered, which are usually included in the originally quoted cost, called a 'Refinement.' | Invisalign
Editor in Chief: Berna Zorkun DMD [1]
Invisalign is a series of clear, removable teeth aligners that both orthodontists and dentists use as an alternative to traditional metal dental braces. As of April 2008, more than 730,000 patients have completed or are currently in treatment.[1]
Invisalign is designed, manufactured, and marketed by Santa Clara, California-based medical-device company Align Technology, Inc. Align says that over 35,790 doctors are trained to provide Invisalign treatment in the U.S., with 48,130 doctors worldwide.
# Advantages and disadvantages
## Advantages
The most obvious advantage of the treatment is cosmetic: the aligners are completely transparent, therefore far more difficult to detect than traditional wire and bracket braces. This makes the method particularly popular among adults who want to straighten their teeth without the look of traditional metal braces, which are commonly worn by children and adolescents. In addition, the aligners are marketed as being more comfortable than braces.[2] Due to the removable nature of the device, food can be consumed without the encumbrance of metallic braces.
Clinically, aligners avoid many of the side effects of traditional fixed appliances,[3] for example the effects on the gums and supporting tissues.[4] Fixed appliances are known to cause the roots of teeth to shorten for most patients,[5] and demineralisation or tooth decay occurs in up to 50% of patients[6] because they cannot be removed for eating and cleaning, and because they prevent accurate x-rays from being taken. Patients "graduate" to a new set of aligners in their treatment series approximately every two weeks. The aligners give less force per week and less pain than do fixed appliances (traditional metal braces). Fixed appliances are adjusted approximately every six weeks and apply greater forces.[7]
Aligners should be removed to eat, drink, to clean the teeth, or to have them checked by the clinician. (It is acceptable to wear aligners while drinking water.) Computerized treatment planning is compulsory as part of the Invisalign protocol. As with other forms of orthodontic treatments that incorporate a computerized plan, this allows the prospective patient to review the projected smile design, learn how long the treatment is likely to take, compare different plans, and make a more educated decision about whether or not to use Invisalign.
Invisalign treatments have been claimed to be quicker than traditional orthodontics. A large-scale study of 408 patients with traditional appliances in Indiana took an average of 35.92 months with a maximum of 96 months,[8] while Invisalign takes between 12–18 months.[3][9] In a much smaller study[10] Invisalign was shown to be faster and achieve straighter teeth than alternatives but relapsed to ultimately get similar results to the traditional appliances examined. The study was considered by the authors, however, to be too small for many conclusions to be statistically significant. Furthermore, this general concept that Invisalign is faster has been challenged by the Invisalign review which points out that there are other brace appliance systems that take half the time, for example by incorporating surgery or temporary implants that insert into the patient's bone, to accelerate the procedure.[11]
## Disadvantages
The product also has potential disadvantages: the very fact that the aligners are removable means they are not continually correcting the teeth. Unlike traditional fixed braces, they are largely dependent on a patient's habits and their consistency in wearing the aligners. The success of the Invisalign aligners is based on a patient's commitment to wear the aligners for a minimum of 20–22 hours per day, only removing them when they are eating, drinking, or brushing their teeth.
The system is also somewhat expensive, as conceded by the Align company,[12] and can be more expensive than traditional wire and bracket systems.
The aligners must be removed for eating. They and the teeth should be cleaned before re-inserting afterwards. This can be troublesome for people who are constantly snacking and may mean the patient has to clean their teeth up to six times daily.
Because the aligners are removed for eating, they can become lost. Because the aligners must be removed for eating and re-inserted, problems occur in patients who forget to do these things. Invsialign treatment will not be successful in patients who forget to remove the inserts, who forget to re-insert them, or who lose them.
By their very nature, Invisalign aligner trays are not as proficient as fixed braces at moving teeth in the vertical dimension. Certain teeth are also slightly problematic for Invisalign aligners to rotate. Some lower premolars with their rounded shape can be difficult for the aligners to grasp and apply a rotational force to.
Unlike traditional braces, if a patient grinds or clenches his or her teeth during the day or while sleeping, the aligners can become damaged. In practice, however, this problem is very rare and a new aligner can be ordered. Also, similar to traditional metal braces, aligners may cause a slight lisp at the beginning of treatment. This usually disappears as the patient becomes used to the treatment.
The aligners are constructed of implantable grade polyurethane, and the Align company has acknowledged that, though extremely rare, there may be cases of allergic and toxic sensitivity reactions to Invisalign.[12] Minor symptoms such as sore throat, cough, and nausea have been reported. In more serious cases, the FDA has received reports of systemic swelling or throat pain that has extended to the upper chest and wind passages requiring emergency medical treatment and discontinuation of the Invisalign treatment. While the Invisalign company provides no information except the MSDS (material safety data sheet) directly to patients or orthodontists, working through the patient's orthodontist Invisalign will make the aligners with several different materials to attempt to reduce toxic or allergic sensitivity.
Should the treatment go off track, or patients fail to keep the aligners in for the required length of time, then the next aligner in the series will not fit, and a new set of impressions and aligners will be necessary, adding to the cost.[9]
## Scientific studies
In a systematic review of the literature, is published in the Journal of the American Dental Association in 2005,[13] Drs. Manual Lagravere and Carlos Flores-Mir were unable to draw strong conclusions about the effectiveness of the Invisalign system. They pointed to the need for randomized clinical trials.[13] Since this paper, more studies about the clinical effectiveness have been published; for example in the UK, Dr Paul Humber has analyzed 100 back-to-back Invisalign cases.[3] In the USA, Akhlaghi and colleagues compared treatment with the invisalign system with treatment with conventional braces and concluded that "conventional fixed appliances achieved better results in the treatment of Class I mild crowding malocclusions".[14] In a comparison of outcomes between the two approaches, Kuncio et al.[10] reported that the Invisalign group displayed greater relapse saying "the mean alignment of the Invisalign group was superior to the Braces group before and after the retention phase, but these differences were not statistically significant. Therefore, even though the Invisalign cases relapsed more, they appear to have the same, if not better, overall alignment scores." In a larger study[15] Djeu and colleagues had similar findings to Akhlaghi above and concluded that "Invisalign was especially deficient in its ability to correct large anteroposterior discrepancies and occlusal contacts". They felt that "The strengths of Invisalign were its ability to close spaces and correct anterior rotations and marginal ridge heights." They added "Invisalign patients finished 4 months sooner than those with fixed appliances on average."
# Pricing
The treatment price is often the same as or more than traditional braces. Treatment price is set by the dentist or orthodontist, although the cost of treatment varies considerably by doctor. Doctor fees are usually determined by complexity and length of treatment. In the U.S., treatments range in price from $3,500 to $7,000, depending on geographic location. For example, in northwest Ohio, the case of a patient with a mild overbite and several teeth that needed to be turned cost $5,580.00 in 2008 (for a 13-month treatment). Braces would have cost $4,500.00 (if the express treatment were available, it would have been $4,300). It is important to remember that costs vary from case to case.
In Europe, the treatment price ranges from €3,000 to €5,700, depending on case complexity and length. Medical insurance is not as common in Europe, and cosmetic treatments are generally not covered by the state-supported universal health-care systems, so the braces are usually paid for entirely by the patients. Financing is frequently available.
# Treatment
An orthodontist begins by taking dental impressions, x-rays and photographs of the patient's teeth and sending them to Align Technology. The impressions are put through a CT scan from which a computer creates a three-dimensional model. Technicians then individualize the teeth in the computer model and move them to their final position as prescribed by the orthodontist. Custom software then simulates the movement of the teeth in stages. The orthodontist reviews the simulation online using Align Technology's ClinCheck via a web browser and approves or modifies the treatment. Once approved, a plastic resin aligner is manufactured for each stage of the computer simulation and shipped to the orthodontist.[16]
'Attachments' are sometimes bonded to teeth that need to be "rotated" or moved more than other teeth. Patients can expect as many as thirteen attachments. They are tooth-colored and made of a glass-like substance.
'Reproximation' is a process by which the contacts between teeth are filed down to allow for a better fit. This may also be a part of treatment.
Average treatment time is about one year[3], again depending on the complexity of the treatment. Simple treatments (minor crowding, minor spacing) may be as short as twenty weeks—this is known as the "Invisalign Express" program. Although the aligners are removable, they must be worn at least 20 to 22 hours per day to avoid delaying the treatment process. If they are not worn consistently, treatment time will increase.
After the regular aligner or braces treatment is complete, retainers composed of a similar plastic material are usually required to be worn, at least at night.
Like other orthodontic systems, the patient has some flexibility. The final position of the teeth is not completely determined by the last aligner. If the patient wants to change the end position because the actual position is not optimal, new aligners are ordered, which are usually included in the originally quoted cost, called a 'Refinement.' | https://www.wikidoc.org/index.php/Invisalign | |
51737c83b5e42f1e672520b3eba2fd6dc003964d | wikidoc | Involucrin | Involucrin
Involucrin is a protein component of human skin and in humans is encoded by the IVL gene. In binding the protein loricrin, involucrin contributes to the formation of a cell envelope that protects corneocytes in the skin.
# Gene
This gene is mapped to 1q21, among calpactin I light chain, trichohyalin, profillaggrin, loricrin, and calcyclin.
# Function
Involucrin is a highly reactive, soluble, transglutaminase substrate protein present in keratinocytes of epidermis and other stratified squamous epithelia. It first appears in the cell cytosol, but ultimately becomes cross-linked to membrane proteins by transglutaminase thus helping in the formation of an insoluble envelope beneath the plasma membrane functioning as a glutamyl donor during assembly of the cornified envelope.
Involucrin is synthesised in the stratum spinosum and cross linked in the stratum granulosum by the transglutaminase enzyme that makes it highly stable. Thus it provides structural support to the cell, thereby allowing the cell to resist invasion by micro-organisms.
Apigenin, a plant-derived flavanoid that has significant promise as a skin cancer chemopreventive agent, has been found to regulate normal human keratinocyte differentiation by suppressing involucrin, and this is associated with reduced cell proliferation without apoptosis.
# Clinical significance
As one of the precursor proteins of the cornified cell envelope, involucrin is markedly increased in inflammatory skin diseases such as psoriasis
Lamellar ichthyosis involves a decrease in expression of involucrin. This decrease could contribute to the altered desquamation process seen in the disease, since the clinical improvement associated with retinoid treatment is accompanied by increased expression of involucrin.
# Structure
Involucrin consists of a conserved N-terminal region of about 75 amino acid residues followed by two extremely variable length segments that contain glutamine-rich tandem repeats. The glutamine residues in the tandem repeats are the substrate for the transglutaminase in the cross-linking reaction. The total size of the protein varies from 285 residues (in dog) to 835 residues (in orangutan). | Involucrin
Involucrin is a protein component of human skin and in humans is encoded by the IVL gene.[1][2] In binding the protein loricrin, involucrin contributes to the formation of a cell envelope that protects corneocytes in the skin.
# Gene
This gene is mapped to 1q21, among calpactin I light chain, trichohyalin, profillaggrin, loricrin, and calcyclin.[2]
# Function
Involucrin is a highly reactive, soluble, transglutaminase substrate protein present in keratinocytes of epidermis and other stratified squamous epithelia.[3][4] It first appears in the cell cytosol, but ultimately becomes cross-linked to membrane proteins by transglutaminase thus helping in the formation of an insoluble envelope beneath the plasma membrane functioning as a glutamyl donor during assembly of the cornified envelope.[5]
Involucrin is synthesised in the stratum spinosum and cross linked in the stratum granulosum by the transglutaminase enzyme that makes it highly stable. Thus it provides structural support to the cell, thereby allowing the cell to resist invasion by micro-organisms.[citation needed]
Apigenin, a plant-derived flavanoid that has significant promise as a skin cancer chemopreventive agent, has been found to regulate normal human keratinocyte differentiation by suppressing involucrin, and this is associated with reduced cell proliferation without apoptosis.[6]
# Clinical significance
As one of the precursor proteins of the cornified cell envelope, involucrin is markedly increased in inflammatory skin diseases such as psoriasis[7]
Lamellar ichthyosis involves a decrease in expression of involucrin. This decrease could contribute to the altered desquamation process seen in the disease, since the clinical improvement associated with retinoid treatment is accompanied by increased expression of involucrin.[8]
# Structure
Involucrin consists of a conserved N-terminal region of about 75 amino acid residues followed by two extremely variable length segments that contain glutamine-rich tandem repeats. The glutamine residues in the tandem repeats are the substrate for the transglutaminase in the cross-linking reaction. The total size of the protein varies from 285 residues (in dog) to 835 residues (in orangutan).[citation needed] | https://www.wikidoc.org/index.php/Involucrin | |
07c53e9d79077559cd97e8c38faea8b5efe0bbf2 | wikidoc | Iodic acid | Iodic acid
Iodic acid, HIO3, can be obtained as a white solid. It is an isolable compound, unlike chloric acid or bromic acid.
# Preparation
Iodic acid can be produced by oxidizing I2 with chlorine in an aqueous solution
# Properties
Iodic acid is a relatively strong acid with a pKa of 0.75. It is strongly oxidizing in acidic solution, less so in basic solution.
# Uses
Iodic acid is used as a standard strong acid in analytical chemistry. It may be used to standardize solutions of both weak and strong bases, with methyl red or methyl orange as the indicator. | Iodic acid
Iodic acid, HIO3, can be obtained as a white solid. It is an isolable compound, unlike chloric acid or bromic acid.
# Preparation
Iodic acid can be produced by oxidizing I2 with chlorine in an aqueous solution
# Properties
Iodic acid is a relatively strong acid with a pKa of 0.75. It is strongly oxidizing in acidic solution, less so in basic solution.
# Uses
Iodic acid is used as a standard strong acid in analytical chemistry. It may be used to standardize solutions of both weak and strong bases, with methyl red or methyl orange as the indicator.
# External links
Template:Inorganic-compound-stub
cs:Kyselina jodičná
de:Iodsäure
it:Acido iodico
fi:Jodihappo
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Iodic_acid | |
11326225c2a36b5743e63e8b1a8a7051f69d5de1 | wikidoc | Iodine-123 | Iodine-123
Iodine-123 is a radioactive isotope of iodine often used in whole-body nuclear scanning. Its half-life is 13.13 hours; the decay emits gamma radiation.
# Medical application
Typically iodine-123 is injected or prescribed by pill; the patient is later imaged by a nuclear camera. Areas where the radioactive iodine (called radio-iodine) concentrates will show up on the nuclear camera.
Iodine-123 is most commonly used to detect cancers of the thyroid, as this is the organ most receptive to forms of iodine. Once the thyroid has absorbed the radio-iodine, any cancer present will have a differing uptake of radio-iodine than the natural, surrounding tissue. This difference can be analyzed by a doctor to determine whether there exists a possibility for thyroid cancer. A tissue biopsy may also be performed to further determine whether it is cancerous or not, and whether it is malignant or benign. | Iodine-123
Iodine-123 is a radioactive isotope of iodine often used in whole-body nuclear scanning. Its half-life is 13.13 hours; the decay emits gamma radiation.
# Medical application
Typically iodine-123 is injected or prescribed by pill; the patient is later imaged by a nuclear camera. Areas where the radioactive iodine (called radio-iodine) concentrates will show up on the nuclear camera.
Iodine-123 is most commonly used to detect cancers of the thyroid, as this is the organ most receptive to forms of iodine. Once the thyroid has absorbed the radio-iodine, any cancer present will have a differing uptake of radio-iodine than the natural, surrounding tissue. This difference can be analyzed by a doctor to determine whether there exists a possibility for thyroid cancer. A tissue biopsy may also be performed to further determine whether it is cancerous or not, and whether it is malignant or benign.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Iodine-123 | |
9e05ddb3d9591c76138c6208d6d96200bd1122af | wikidoc | Iodine-124 | Iodine-124
Iodine-124 or 124I is an isotope of iodine. This isotope is not stable and therefore is radioactive, also called a radioisotope. It has a half-life of 4.18 days. Modes of Decay: 74.4% electron capture, 25.6% positron emission. 124I decays to 124Te.
# Uses
Iodine-124 is used in medicine as a radiotracer in the body. It can be chemically bonded to a pharmaceutical and injected into the body. Positron Emission Tomography or PET is used to visualize the isotope in the body. Visualization is possible in PET because of the positron release by the iodine nucleus.
# Preparation
Iodine-124 can be made by numereous nuclear reactions via a cyclotron. The most common starting material used is 124Te. | Iodine-124
Iodine-124 or 124I is an isotope of iodine. This isotope is not stable and therefore is radioactive, also called a radioisotope. It has a half-life of 4.18 days. Modes of Decay: 74.4% electron capture, 25.6% positron emission. 124I decays to 124Te.
# Uses
Iodine-124 is used in medicine as a radiotracer in the body. It can be chemically bonded to a pharmaceutical and injected into the body. Positron Emission Tomography or PET is used to visualize the isotope in the body. Visualization is possible in PET because of the positron release by the iodine nucleus.
# Preparation
Iodine-124 can be made by numereous nuclear reactions via a cyclotron. The most common starting material used is 124Te. | https://www.wikidoc.org/index.php/Iodine-124 | |
ad09cea031db22cfbc412592e1f7363ed4d46d4d | wikidoc | Iodine-129 | Iodine-129
Iodine-129 (129I) is a radioisotope of iodine. It decays with a half-life of 15.7 million years with low-energy beta and gamma emissions, decaying to 129Xe.
129I has the longest halflife of any fission product, and is one of only 7 long-lived fission products. Its yield of 0.6576% per fission is about 10% as great as the yield of Tc-99, Zr-93, or Cs-135, but much larger than the yield of Pd-107, Se-79, or Sn-126.
Larger proportions of heavier iodine isotopes like 131I are produced, but because these all have short half-lives, iodine in cooled spent nuclear fuel consists of about 5/6 129I and 1/6 the only stable iodine isotope 127I.
Because 129I is long-lived and relatively difficult to immobilize in the environment, has a modest but sufficient neutron absorption cross section, and is relatively undiluted by other isotopes of the same element, 129I and 99Tc are the leading candidates among fission products for disposal by nuclear transmutation by re-irradiation with neutrons. (Actinide wastes, which are not fission products, are good candidates for disposal by fission in a fast reactor, accelerator-driven subcritical reactor, or fusion-fission reactor.) | Iodine-129
Template:Long-lived fission products
Iodine-129 (129I) is a radioisotope of iodine. It decays with a half-life of 15.7 million years with low-energy beta and gamma emissions, decaying to 129Xe.
129I has the longest halflife of any fission product, and is one of only 7 long-lived fission products. Its yield of 0.6576% per fission is about 10% as great as the yield of Tc-99, Zr-93, or Cs-135, but much larger than the yield of Pd-107, Se-79, or Sn-126.
Larger proportions of heavier iodine isotopes like 131I are produced, but because these all have short half-lives, iodine in cooled spent nuclear fuel consists of about 5/6 129I and 1/6 the only stable iodine isotope 127I.
Because 129I is long-lived and relatively difficult to immobilize in the environment, has a modest but sufficient neutron absorption cross section, and is relatively undiluted by other isotopes of the same element, 129I and 99Tc are the leading candidates among fission products for disposal by nuclear transmutation by re-irradiation with neutrons. (Actinide wastes, which are not fission products, are good candidates for disposal by fission in a fast reactor, accelerator-driven subcritical reactor, or fusion-fission reactor.) | https://www.wikidoc.org/index.php/Iodine-129 | |
2ce3d8dc284deb67ca9731bbb3b52253c27d0512 | wikidoc | Iodine-131 | Iodine-131
Iodine-131 (131I), also called radioiodine, is a radioisotope of iodine.
131I decays with a half-life of 8.0197 days with beta and gamma emissions. This nuclide of iodine atom has 78 neutrons in nucleus, the stable nuclide 127I has 74 neutrons. On decaying, 131I transforms into 131Xe:
{^{131}_{53}I} \rightarrow \beta + {^{131}_{54}Xe}
131I is a fission product with a yield of 2.8336%, and was released in nuclear weapons tests and the Chernobyl accident. However, the short half-life means it is not present in cooled spent nuclear fuel, unlike iodine-129.
It is used in nuclear medicine both diagnostically and therapeutically. Examples of its use in radiation therapy include the treatment of thyrotoxicosis and thyroid cancer. Diagnostic tests exploit the mechanism of absorption of iodine by the normal cells of the thyroid gland. As an example iodine-131 is one of the radioactive isotopes of iodine that can be used to test how well the thyroid gland is functioning.
131I is also used as a radioactive label for radiopharmaceuticals that can be used for imaging and therapy e.g. 131I-metaiodobenzylguanidine (131I-MIBG) for imaging and treating phaeochromocytoma and neuroblastoma.
If 131I is present in high levels in the environment from radioactive fallout, it is absorbed by the body and may cause damage to the thyroid. This can be mitigated by taking iodine supplements, raising the total amount of iodine in the body and therefore reducing uptake and retention in tissues and lowering the relative proportion of radioactive iodine. Such supplements were distributed to the population living nearest to the Chernobyl nuclear power plant after the disaster.
Patients receiving radioiodine treatment are warned not to have sexual intercourse for one month (or shorter, depending on dose given), and women are told not to become pregnant for six months afterwards. These guidelines vary from hospital to hospital and will depend also on the dose of radiation given. One also advises not to hug or hold children when the radiation is still high, and a one or two metre distance to others may be recommended.
Many airports now have radiation detectors in order to detect the smuggling of radioactive materials that may be used in nuclear weapons manufacture. Patients should be warned that if they choose to travel by air, they may set off radiation detectors at airports up to 12 weeks after their treatment with 131I. A physician's letter does not exempt one from interrogation by airport security personnel, because these letters are easily forged. For security reasons, there is no information available in the public domain on which airports use radiation detectors. | Iodine-131
Template:Infobox isotope
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Iodine-131 (131I), also called radioiodine, is a radioisotope of iodine.
131I decays with a half-life of 8.0197 days with beta and gamma emissions. This nuclide of iodine atom has 78 neutrons in nucleus, the stable nuclide 127I has 74 neutrons. On decaying, 131I transforms into 131Xe:
<math> {^{131}_{53}I} \rightarrow \beta + {^{131}_{54}Xe} </math>
131I is a fission product with a yield of 2.8336%, and was released in nuclear weapons tests and the Chernobyl accident. However, the short half-life means it is not present in cooled spent nuclear fuel, unlike iodine-129.
It is used in nuclear medicine both diagnostically and therapeutically. Examples of its use in radiation therapy include the treatment of thyrotoxicosis and thyroid cancer. Diagnostic tests exploit the mechanism of absorption of iodine by the normal cells of the thyroid gland. As an example iodine-131 is one of the radioactive isotopes of iodine that can be used to test how well the thyroid gland is functioning.
131I is also used as a radioactive label for radiopharmaceuticals that can be used for imaging and therapy e.g. 131I-metaiodobenzylguanidine (131I-MIBG) for imaging and treating phaeochromocytoma and neuroblastoma.
If 131I is present in high levels in the environment from radioactive fallout, it is absorbed by the body and may cause damage to the thyroid. This can be mitigated by taking iodine supplements, raising the total amount of iodine in the body and therefore reducing uptake and retention in tissues and lowering the relative proportion of radioactive iodine. Such supplements were distributed to the population living nearest to the Chernobyl nuclear power plant after the disaster.
Patients receiving radioiodine treatment are warned not to have sexual intercourse for one month (or shorter, depending on dose given), and women are told not to become pregnant for six months afterwards. These guidelines vary from hospital to hospital and will depend also on the dose of radiation given. One also advises not to hug or hold children when the radiation is still high, and a one or two metre distance to others may be recommended.
Many airports now have radiation detectors in order to detect the smuggling of radioactive materials that may be used in nuclear weapons manufacture. Patients should be warned that if they choose to travel by air, they may set off radiation detectors at airports up to 12 weeks after their treatment with 131I. A physician's letter does not exempt one from interrogation by airport security personnel, because these letters are easily forged. For security reasons, there is no information available in the public domain on which airports use radiation detectors.
# External links
- ANL factsheet
- RadiologyInfo - The radiology information resource for patients: Radioiodine (I -131) Therapy
- Case Studies in Environmental Medicine: Radiation Exposure from Iodine 131
- Sensitivity of Personal Homeland Security Radiation Detectors to Medical Radionuclides and Implications for Counseling of Nuclear Medicine Patients
- NLM Hazardous Substances Databank – Iodine, Radioactive
Template:Isotope
de:Radioiodtherapie
Template:Jb1
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Iodine-131 | |
fdcf7888011c2662cfa8e8157ba00a35ec7a4bfe | wikidoc | Ion source | Ion source
An ion source is an electro-magnetic device that is used to create charged particles. These are used primarily within mass spectrometers or particle accelerators.
# Mass spectrometry
In mass spectrometry, an ion source is a piece of equipment used to ionize analyte molecules and, if necessary, free them from the solid or liquid phase. Once the analyte ions are free to move electric fields will direct them into the mass analyzer.
There are several types of ion sources:
- Electron ionization (EI)
- Chemical ionization (CI)
- Ion attached ionization (IA) for fragmentation free ionization
- Fast atom bombardment (FAB)
- Field desorption (FD)
- Matrix-assisted laser desorption/ionization (MALDI)
- Atmospheric pressure chemical ionization (APCI)
- Atmospheric pressure photoionization (APPI)
- Electrospray ionization (ESI)
- Desorption electrospray ionization (DESI)
- Glow discharge (GD)
- Inductively coupled plasma (ICP)
- Microwave induced plasma (MIP)
- Thermospray ionization (TS)
- Direct analysis in real time (DART)
# In particle accelerators
In particle accelerators an ion source creates a particle beam at the beginning of the machine, the Source. The technology to create ion sources for particle accelerators depends strongly on the type of particle that needs to be generated: electrons, protons, H- ion or a heavy ion.
Electrons are generated with an electron gun, and there are many varieties of these.
Protons are generated with a plasma-based device, like a duoplasmatron or a magnetron.
H- ions are generated with a magnetron or a Penning source. A magnetron consists of a central cylindrical cathode surrounded by an anode. The discharge voltage is typically greater than 150 V and the current drain is around 40 A. A magnetic field of about 0.2 tesla is parallel to the cathode axis. Hydrogen gas is introduced by a pulsed gas valve. Caesium is often used to lower the work function of the cathode, enhancing the amount of ions that are produced.
For a Penning source, a strong magnetic field parallel to the electric field of the sheath guides electrons and ions on cyclotron spirals from cathode to cathode. Fast H-minus ions are generated at the cathodes as in the magnetron. They are slowed down due to the charge exchange reaction as they migrate to the plasma aperture. This makes for a beam of ions that is colder than the ions obtained from a magnetron.
Heavy ions are generated with an electron cyclotron resonance ion source. The use of electron cyclotron resonance (ECR) ion sources for the production of intense beams of highly charged ions has immensely grown over the last decade. ECR ion sources are used as injectors into linear accelerators, Van-de-Graaff generators or cyclotrons in nuclear and elementary particle physics. In atomic and surface physics ECR ion sources deliver intense beams of highly charged ions for collision experiments or for the investigation of surfaces. For the highest charge states, however, Electron beam ion sources (EBIS) are needed. They can generate even bare ions of mid-heavy elements. The Electron beam ion trap (EBIT), based on the same principle, can produce up to bare uranium ions and can be used as an ion source as well.
# Theory of Operation
Gas flows through the ion source between the anode and the cathode. A positive voltage is applied to the anode. This voltage, combined with the high magnetic field between the tips of the internal and external cathodes allow a plasma to start. Ions from the plasma are repelled by the anode electric field. This creates an ion beam.
# Ion Source Applications
- Surface cleaning and pretreatment for large area deposition
- Thin-film deposition
- Deposition of Thick Diamond-like carbon (DLC) Films
- Surface roughening of polymers for improved adhesion and/or biocompatibility | Ion source
An ion source is an electro-magnetic device that is used to create charged particles. These are used primarily within mass spectrometers or particle accelerators.
# Mass spectrometry
Template:Expand
In mass spectrometry, an ion source is a piece of equipment used to ionize analyte molecules and, if necessary, free them from the solid or liquid phase. Once the analyte ions are free to move electric fields will direct them into the mass analyzer.
There are several types of ion sources:
- Electron ionization (EI)
- Chemical ionization (CI)
- Ion attached ionization (IA) for fragmentation free ionization
- Fast atom bombardment (FAB)
- Field desorption (FD)
- Matrix-assisted laser desorption/ionization (MALDI)
- Atmospheric pressure chemical ionization (APCI)
- Atmospheric pressure photoionization (APPI)
- Electrospray ionization (ESI)
- Desorption electrospray ionization (DESI)
- Glow discharge (GD)
- Inductively coupled plasma (ICP)
- Microwave induced plasma (MIP)
- Thermospray ionization (TS)
- Direct analysis in real time (DART)
# In particle accelerators
In particle accelerators an ion source creates a particle beam at the beginning of the machine, the Source. The technology to create ion sources for particle accelerators depends strongly on the type of particle that needs to be generated: electrons, protons, H- ion or a heavy ion.
Electrons are generated with an electron gun, and there are many varieties of these.
Protons are generated with a plasma-based device, like a duoplasmatron or a magnetron.
H- ions are generated with a magnetron or a Penning source. A magnetron consists of a central cylindrical cathode surrounded by an anode. The discharge voltage is typically greater than 150 V and the current drain is around 40 A. A magnetic field of about 0.2 tesla is parallel to the cathode axis. Hydrogen gas is introduced by a pulsed gas valve. Caesium is often used to lower the work function of the cathode, enhancing the amount of ions that are produced.
For a Penning source, a strong magnetic field parallel to the electric field of the sheath guides electrons and ions on cyclotron spirals from cathode to cathode. Fast H-minus ions are generated at the cathodes as in the magnetron. They are slowed down due to the charge exchange reaction as they migrate to the plasma aperture. This makes for a beam of ions that is colder than the ions obtained from a magnetron.
Heavy ions are generated with an electron cyclotron resonance ion source. The use of electron cyclotron resonance (ECR) ion sources for the production of intense beams of highly charged ions has immensely grown over the last decade. ECR ion sources are used as injectors into linear accelerators, Van-de-Graaff generators or cyclotrons in nuclear and elementary particle physics. In atomic and surface physics ECR ion sources deliver intense beams of highly charged ions for collision experiments or for the investigation of surfaces. For the highest charge states, however, Electron beam ion sources (EBIS) are needed. They can generate even bare ions of mid-heavy elements. The Electron beam ion trap (EBIT), based on the same principle, can produce up to bare uranium ions and can be used as an ion source as well.
# Theory of Operation
Gas flows through the ion source between the anode and the cathode. A positive voltage is applied to the anode. This voltage, combined with the high magnetic field between the tips of the internal and external cathodes allow a plasma to start. Ions from the plasma are repelled by the anode electric field. This creates an ion beam.[1]
# Ion Source Applications
- Surface cleaning and pretreatment for large area deposition
- Thin-film deposition
- Deposition of Thick Diamond-like carbon (DLC) Films
- Surface roughening of polymers for improved adhesion and/or biocompatibility[2] | https://www.wikidoc.org/index.php/Ion_source | |
de0c7e01cda159327cdc53ada4caaaec5cdb719b | wikidoc | Ionization | Ionization
Ionization is the physical process of converting an atom or molecule into an ion by adding or removing charged particles such as electrons or other ions. This process works slightly differently depending on whether an ion with a positive or a negative electric charge is being produced. A positive electric charge is produced when an electron bond to an atom or molecule absorbs enough energy from an external source to escape from the electric potential barrier that originally confined it, where the amount of energy required is called the ionization potential. A negative electric charge is produced when a free electron collides with an atom and is subsequently caught inside the electric potential barrier, releasing any excess energy.
Ionization can generally be broken down into two types: sequential ionization and non-sequential ionization. In classical physics, only sequential ionization can take place and therefore refer to the Classical ionization section for more information. Non-sequential ionization violates several laws of classical physics and thus will be discussed in more detail in the Quantum ionization section.
# Classical ionization
Applying only classical physics and the Bohr model of the atom makes both atomic and molecular ionization entirely deterministic, that is every problem will always have a definite and computable answer. According to classical physics it is absolutely necessary that the energy of the electron exceeds the energy difference of the potential barrier it is trying to pass. Conceptually this idea should make sense: the same way a person can not jump over a one meter wall without jumping at least one meter off the ground, an electron can not get over a 13.6 eV potential barrier without at least 13.6 eV of energy.
## Applying to positive ionization
According to these two principles, the energy required to release an electron is strictly greater than or equal to the potential difference between the current bound atomic or molecular orbital and the highest possible orbital. If the energy absorbed exceeds this potential, then the electron is emitted as a free electron. Otherwise, the electron briefly enters an excited state until the energy absorbed is radiated out and the electron re-enters the lowest available state.
## Applying to negative ionization
Due to the shape of the potential barrier, according to these principles a free electron must have an energy greater than or equal to that of the potential barrier in order to make it over. If it has enough energy to do so, it will be bound to the lowest available energy state, and the remaining energy will be radiated away. If the electron does not have enough energy to surpass the potential barrier, then it is forced away by the electrostatic force, described by Coulombs Law, associated with the electric potential barrier.
## Sequential ionization
Sequential ionization is basically a description of how the ionization of an atom or molecule takes place. More specifically, it means that an ion with a +2 charge can only be created from an ion with a +1 charge or a +3 charge. That is, the numerical charge of an atom or molecule must change sequentially, always moving from one number to an adjacent, or sequential number.
# Quantum ionization
In quantum mechanics ionization can still happen classically where the electron has enough energy to make it over the potential barrier, but there is the additional possibility of tunnel ionization.
## Tunnel ionization
Tunnel ionization is ionization due to quantum tunneling. In classical ionization an electron must have enough energy to make it over the potential barrier, but quantum tunneling allows the electron simply to go through the potential barrier instead of going all the way over it because of the wave nature of the electron. The probability of an electron tunneling through the barrier drops off exponentially with the width of the potential barrier. Therefore, an electron with a higher energy can make it further up the potential barrier, leaving a much thinner barrier to tunnel through and thus a greater chance to do so.
## Non-sequential ionization
When the fact that the electric field of light is an alternating electric field is combined with tunnel ionization, the phenomenon of non-sequential ionization emerges. An electron that tunnels out from an atom or molecule may be sent right back in by the alternating field, at which point it can either recombine with the atom or molecule and release any excess energy, or it also has the chance to further ionize the atom or molecule through high energy collisions. This additional ionization is referred to as non-sequential ionization for two reasons: one, there is no order to how the second electron is removed, and two, an atom or molecule with a +2 charge can be created straight from an atom or molecule with a neutral charge, so the integer charges are not sequential. Non-sequential ionization is often studied at lower laser-field intensities, since most ionization events are sequential when the ionization rate is high. | Ionization
Ionization is the physical process of converting an atom or molecule into an ion by adding or removing charged particles such as electrons or other ions. This process works slightly differently depending on whether an ion with a positive or a negative electric charge is being produced. A positive electric charge is produced when an electron bond to an atom or molecule absorbs enough energy from an external source to escape from the electric potential barrier that originally confined it, where the amount of energy required is called the ionization potential. A negative electric charge is produced when a free electron collides with an atom and is subsequently caught inside the electric potential barrier, releasing any excess energy.
Ionization can generally be broken down into two types: sequential ionization and non-sequential ionization. In classical physics, only sequential ionization can take place and therefore refer to the Classical ionization section for more information. Non-sequential ionization violates several laws of classical physics and thus will be discussed in more detail in the Quantum ionization section.
# Classical ionization
Applying only classical physics and the Bohr model of the atom makes both atomic and molecular ionization entirely deterministic, that is every problem will always have a definite and computable answer. According to classical physics it is absolutely necessary that the energy of the electron exceeds the energy difference of the potential barrier it is trying to pass. Conceptually this idea should make sense: the same way a person can not jump over a one meter wall without jumping at least one meter off the ground, an electron can not get over a 13.6 eV potential barrier without at least 13.6 eV of energy.
## Applying to positive ionization
According to these two principles, the energy required to release an electron is strictly greater than or equal to the potential difference between the current bound atomic or molecular orbital and the highest possible orbital. If the energy absorbed exceeds this potential, then the electron is emitted as a free electron. Otherwise, the electron briefly enters an excited state until the energy absorbed is radiated out and the electron re-enters the lowest available state.
## Applying to negative ionization
Due to the shape of the potential barrier, according to these principles a free electron must have an energy greater than or equal to that of the potential barrier in order to make it over. If it has enough energy to do so, it will be bound to the lowest available energy state, and the remaining energy will be radiated away. If the electron does not have enough energy to surpass the potential barrier, then it is forced away by the electrostatic force, described by Coulombs Law, associated with the electric potential barrier.
## Sequential ionization
Sequential ionization is basically a description of how the ionization of an atom or molecule takes place. More specifically, it means that an ion with a +2 charge can only be created from an ion with a +1 charge or a +3 charge. That is, the numerical charge of an atom or molecule must change sequentially, always moving from one number to an adjacent, or sequential number.
# Quantum ionization
In quantum mechanics ionization can still happen classically where the electron has enough energy to make it over the potential barrier, but there is the additional possibility of tunnel ionization.
## Tunnel ionization
Tunnel ionization is ionization due to quantum tunneling. In classical ionization an electron must have enough energy to make it over the potential barrier, but quantum tunneling allows the electron simply to go through the potential barrier instead of going all the way over it because of the wave nature of the electron. The probability of an electron tunneling through the barrier drops off exponentially with the width of the potential barrier. Therefore, an electron with a higher energy can make it further up the potential barrier, leaving a much thinner barrier to tunnel through and thus a greater chance to do so.
## Non-sequential ionization
When the fact that the electric field of light is an alternating electric field is combined with tunnel ionization, the phenomenon of non-sequential ionization emerges. An electron that tunnels out from an atom or molecule may be sent right back in by the alternating field, at which point it can either recombine with the atom or molecule and release any excess energy, or it also has the chance to further ionize the atom or molecule through high energy collisions. This additional ionization is referred to as non-sequential ionization for two reasons: one, there is no order to how the second electron is removed, and two, an atom or molecule with a +2 charge can be created straight from an atom or molecule with a neutral charge, so the integer charges are not sequential. Non-sequential ionization is often studied at lower laser-field intensities, since most ionization events are sequential when the ionization rate is high. | https://www.wikidoc.org/index.php/Ionization | |
08ca5891abc60186256ff781f1f68f8df74f6e30 | wikidoc | Ipidacrine | Ipidacrine
# Overview
Ipidacrine (Neiromidin) is a novel substance synthesized by the National Research Center for Biologically Active Compounds in the Russian Federation. This compound contains the structure of 4-aminopyridine and is structurally very similar to tacrine.
Ipidacrine is a reversible acetylcholinesterase inhibitor used in memory disorders of different origins.
Ipidacrine directly stimulates impulse transmission in the CNS and neuromuscular synapses by blocking membrane potassium channels. Neiromidin enhances not only choline, but also adrenaline, serotonin, histamine and oxytocin effects on smooth muscle. | Ipidacrine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Ipidacrine (Neiromidin) is a novel substance synthesized by the National Research Center for Biologically Active Compounds in the Russian Federation. This compound contains the structure of 4-aminopyridine and is structurally very similar to tacrine.[1]
Ipidacrine is a reversible acetylcholinesterase inhibitor used in memory disorders of different origins.[2][3][4]
Ipidacrine directly stimulates impulse transmission in the CNS and neuromuscular synapses by blocking membrane potassium channels. Neiromidin enhances not only choline, but also adrenaline, serotonin, histamine and oxytocin effects on smooth muscle.[5] | https://www.wikidoc.org/index.php/Ipidacrine |
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