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a52d3931f19e64ac15b39df05e66111d935ef04a | wikidoc | Polycystin 1 | Polycystin 1
Polycystin 1 (often abbreviated to PC1) is a protein that in humans is encoded by the PKD1 gene . Mutations of PKD1 are associated with most cases of autosomal dominant polycystic kidney disease, a severe hereditary disorder of the kidneys characterised by the development of renal cysts and severe kidney dysfunction .
# Protein Structure and Function
PC1 is a membrane-bound protein 4303 amino acids in length expressed largely upon the primary cilium, as well as apical membranes, adherens junctions, and desmosomes . It possesses eleven transmembrane domains, a large extracellular N-terminal domain, and a short (~200 amino acid) cytoplasmic C-terminal domain . This intracellular domain contains a coiled-coil domain through which PC1 interacts with polycystin 2 (PC2), a membrane-bound Ca2+-permeable ion channel.
PC1 has been proposed to act as a G protein–coupled receptor . The C-terminal domain may be cleaved in a number of different ways. In one instance, a ~35 kDa portion of the tail has been found to accumulate in the cell nucleus in response to decreased fluid flow in the mouse kidney . In another instance, a 15 kDa fragment may be yielded, interacting with transcriptional activator and co-activator STAT6 and p100, or components of the canonical Wnt signaling pathway in an inhibitory manner .
Evidence suggests that PC1 mediates mechanosensation of fluid flow by the primary cilium in the renal epithelium and of mechanical deformation of articular cartilage .
# Gene
Splice variants encoding different isoforms have been noted for PKD1. The gene is closely linked to six pseudogenes in a known duplicated region on chromosome 16p. | Polycystin 1
Polycystin 1 (often abbreviated to PC1) is a protein that in humans is encoded by the PKD1 gene [1][2]. Mutations of PKD1 are associated with most cases of autosomal dominant polycystic kidney disease, a severe hereditary disorder of the kidneys characterised by the development of renal cysts and severe kidney dysfunction [3].
# Protein Structure and Function
PC1 is a membrane-bound protein 4303 amino acids in length expressed largely upon the primary cilium, as well as apical membranes, adherens junctions, and desmosomes [4]. It possesses eleven transmembrane domains, a large extracellular N-terminal domain, and a short (~200 amino acid) cytoplasmic C-terminal domain [4][5]. This intracellular domain contains a coiled-coil domain through which PC1 interacts with polycystin 2 (PC2), a membrane-bound Ca2+-permeable ion channel.
PC1 has been proposed to act as a G protein–coupled receptor [4][6]. The C-terminal domain may be cleaved in a number of different ways. In one instance, a ~35 kDa portion of the tail has been found to accumulate in the cell nucleus in response to decreased fluid flow in the mouse kidney [7]. In another instance, a 15 kDa fragment may be yielded, interacting with transcriptional activator and co-activator STAT6 and p100, or components of the canonical Wnt signaling pathway in an inhibitory manner [8][9].
Evidence suggests that PC1 mediates mechanosensation of fluid flow by the primary cilium in the renal epithelium and of mechanical deformation of articular cartilage [10].
# Gene
Splice variants encoding different isoforms have been noted for PKD1. The gene is closely linked to six pseudogenes in a known duplicated region on chromosome 16p.[11] | https://www.wikidoc.org/index.php/Polycystin_1 | |
f12b514d471fadc49d2413f774a635296b3064a3 | wikidoc | Polycystin 2 | Polycystin 2
Polycystin-2 is a protein that in humans is encoded by the PKD2 gene.
This gene encodes a member of the polycystin protein family, called TRPP2, previously known as polycystin-2, PC2 or APKD2. TRPP2 contains multiple transmembrane domains, and cytoplasmic N- and C-termini. The protein may be an integral membrane protein involved in cell-cell/matrix interactions. TRPP2 may function in renal tubular development, morphology, and function, and may modulate intracellular calcium homeostasis and other signal transduction pathways. This protein interacts with polycystin 1 (TRPP1) to produce cation-permeable currents. It was discovered by Stefan Somlo at Yale University.
# Clinical significance
Mutations in this gene have been associated with autosomal dominant polycystic kidney disease.
# Interactions
Polycystin 2 has been shown to interact with the proteins TRPC1, PKD1 and TNNI3. | Polycystin 2
Polycystin-2 is a protein that in humans is encoded by the PKD2 gene.[1][2]
This gene encodes a member of the polycystin protein family, called TRPP2, previously known as polycystin-2, PC2 or APKD2. TRPP2 contains multiple transmembrane domains, and cytoplasmic N- and C-termini. The protein may be an integral membrane protein involved in cell-cell/matrix interactions. TRPP2 may function in renal tubular development, morphology, and function, and may modulate intracellular calcium homeostasis and other signal transduction pathways. This protein interacts with polycystin 1 (TRPP1) to produce cation-permeable currents. It was discovered by Stefan Somlo at Yale University.
# Clinical significance
Mutations in this gene have been associated with autosomal dominant polycystic kidney disease.[2]
# Interactions
Polycystin 2 has been shown to interact with the proteins TRPC1,[3] PKD1[3][4] and TNNI3.[5] | https://www.wikidoc.org/index.php/Polycystin_2 | |
133ad545b06c21157a331656df9d90d125d280a3 | wikidoc | Polydisperse | Polydisperse
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
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A collection of objects is called polydisperse or polysized if they have a broad range of size, shape and mass characteristics. A sample of objects that have a uniform size, shape and mass distribution are called monodisperse. In practice, polydisperse collections are common because it is relatively easy to create a polydisperse collection of particles, objects or polymers. Monodisperse collections, on the other hand, are extremely uncommon because the technological challenges that must be overcome in order to produce such collections are often enormous.
- Polydisperse collection.
Polydisperse collection.
Examples:
Polymers: Most will possess a distribution of molecular mass
Particles: Most manufactured particles will possess a wide distribution of size, surface area and mass
Thin-films: Most thin-films will possess a varied distribution of film thickness. | Polydisperse
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
A collection of objects is called polydisperse or polysized if they have a broad range of size, shape and mass characteristics. A sample of objects that have a uniform size, shape and mass distribution are called monodisperse. In practice, polydisperse collections are common because it is relatively easy to create a polydisperse collection of particles, objects or polymers. Monodisperse collections, on the other hand, are extremely uncommon because the technological challenges that must be overcome in order to produce such collections are often enormous.
- Polydisperse collection.
Polydisperse collection.
Examples:
Polymers: Most will possess a distribution of molecular mass
Particles: Most manufactured particles will possess a wide distribution of size, surface area and mass
Thin-films: Most thin-films will possess a varied distribution of film thickness. | https://www.wikidoc.org/index.php/Polydisperse | |
9dd7cbc860864b19b88ab93fba08b26af782cd86 | wikidoc | Polyethylene | Polyethylene
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Polyethylene (IUPAC name polyethene) is a thermoplastic commodity heavily used in consumer products. Over 60 million tons of the material are produced worldwide every year.
# Description
Polyethylene is a polymer consisting of long chains of the monomer ethylene (IUPAC name ethene). The recommended scientific name 'polyethene' is systematically derived from the scientific name of the monomer. In certain circumstances it is useful to use a structure–based nomenclature. In such cases IUPAC recommends poly(methylene). The difference is due to the 'opening up' of the monomer's double bond upon polymerisation.
In the polymer industry the name is sometimes shortened to PE, in a manner similar to that by which other polymers like polypropylene and polystyrene are shortened to PP and PS, respectively. In the United Kingdom the polymer is commonly called polythene, although this is not recognised scientifically.
The ethene molecule (known almost universally by its common name ethylene), C2H4 is CH2=CH2, Two CH2 groups connected by a double bond, thus:
Polyethylene is created through polymerization of ethene. It can be produced through radical polymerization, anionic addition polymerization, ion coordination polymerization or cationic addition polymerization. This is because ethene does not have any substituent groups that influence the stability of the propagation head of the polymer. Each of these methods results in a different type of polyethylene.
# Classification of polyethylenes
Polyethylene is classified into several different categories based mostly on its density and branching. The mechanical properties of PE depend significantly on variables such as the extent and type of branching, the crystal structure, and the molecular weight.
- Ultra high molecular weight polyethylene (UHMWPE)
- Ultra low molecular weight polyethylene (ULMWPE - PE-WAX)
- High molecular weight polyethylene (HMWPE)
- High density polyethylene (HDPE)
- High density cross-linked polyethylene (HDXLPE)
- Cross-linked polyethylene (PEX)
- Medium density polyethylene (MDPE)
- Low density polyethylene (LDPE)
- Linear low density polyethylene (LLDPE)
- Very low density polyethylene (VLDPE)
UHMWPE is polyethylene with a molecular weight numbering in the millions, usually between 3.1 and 5.67 million. The high molecular weight results in less efficient packing of the chains into the crystal structure as evidenced by densities less than high density polyethylene (e.g. 0.930 - 0.935 g/cm3). The high molecular weight results in a very tough material. UHMWPE can be made through any catalyst technology, although Ziegler catalysts are most common. Because of its outstanding toughness, cut, wear and excellent chemical resistance, UHWMPE is used in a wide diversity of applications. These include can and bottle handling machine parts, moving parts on weaving machines, bearings, gears, artificial joints, edge protection on ice rinks, butchers' chopping boards. It competes with Aramid in bulletproof vests as Spectra (or Dyneema) fibers.
HDPE is defined by a density of greater or equal to 0.941 g/cm3. HDPE has a low degree of branching and thus stronger intermolecular forces and tensile strength. HDPE can be produced by chromium/silica catalysts, Ziegler-Natta catalysts or metallocene catalysts. The lack of branching is ensured by an appropriate choice of catalyst (e.g. chromium catalysts or Ziegler-Natta catalysts) and reaction conditions. HDPE is used in products and packaging such as milk jugs, detergent bottles, margarine tubs, garbage containers and water pipes.
HDPE is also widely used in the fireworks community. In tubes of varying length (depending on the size of the ordnance), HDPE is used as a replacement for the supplied cardboard mortar tubes for two primary reasons. One, it is much safer than the supplied cardboard tubes because if a shell were to malfunction and explode inside (flower pot) an HDPE tube, the tube will not shatter. The second reason is that they are reusable allowing designers to create multiple shot mortar racks. Pyrotechnicians discourage the use of PVC tubing in mortar tubes because it tends to shatter, sending shards of plastic at possible spectators, and will not show up in x-rays.
PEX is a medium- to high-density polyethylene containing cross-link bonds introduced into the polymer structure, changing the thermoplast into an elastomer. The high-temperature properties of the polymer are improved, its flow is reduced and its chemical resistance is enhanced. PEX is used in some potable water plumbing systems, as tubes made of the material can be expanded to fit over a metal nipple, and it will slowly return to its original shape, forming a permanent, water-tight connection.
MDPE is defined by a density range of 0.926 - 0.940 g/cm3. MDPE can be produced by chromium/silica catalysts, Ziegler-Natta catalysts or metallocene catalysts.MDPE has good shock and drop resistance properties. It also is less notch sensitive than HDPE, stress cracking resistance is better than HDPE. MDPE is typically used in gas pipes and fittings, sacks, shrink film, packaging film, carrier bags, screw closures.
LLDPE is defined by a density range of 0.915 - 0.925 g/cm3. is a substantially linear polymer, with significant numbers of short branches, commonly made by copolymerization of ethylene with short-chain alpha-olefins (e.g. 1-butene, 1-hexene, and 1-octene). LLDPE has higher tensile strength than LDPE. Exhibits higher impact and puncture resistance than LDPE. Lower thickness (gauge) films can be blown compared to LDPE, with better environmental stress cracking resistance compared to LDPE but is not as easy to process. LLDPE is used in packaging, particularly film for bags and sheets. Lower thickness (gauge) may be used compared to LDPE. Cable covering, toys, lids, buckets and containers, pipe. While other applications are available, LLDPE is used predominantly in film applications due to its toughness, flexibility, and relative transparency.
LDPE is defined by a density range of 0.910 - 0.940 g/cm3. LDPE has a high degree of short and long chain branching, which means that the chains do not pack into the crystal structure as well. It has therefore less strong intermolecular forces as the instantaneous-dipole induced-dipole attraction is less. This results in a lower tensile strength and increased ductility. LDPE is created by free radical polymerization. The high degree of branches with long chains gives molten LDPE unique and desirable flow properties. LDPE is used for both rigid containers and plastic film applications such as plastic bags and film wrap.
VLDPE is defined by a density range of 0.880 - 0.915 g/cm3. is a substantially linear polymer, with high levels of short chain branches, commonly made by copolymerization of ethylene with short-chain alpha-olefins (e.g. 1-butene, 1-hexene, and 1-octene). VLDPE is most commonly produced using metallocene catalysts due to the greater co-monomer incorporation exhibited by these catalysts. VLDPE’s are used for hose and tubing, ice and frozen food bags, food packaging and stretch wrap, as well as impact modifiers when blended with other polymers.
Recently, much research activity has focused on the nature and distribution of long chain branches in polyethylene. In HDPE, a relatively small number of these branches, perhaps 1 in 100 or 1,000 branches per backbone carbon, can significantly affect the rheological properties of the polymer.
# Ethylene copolymers
In addition to copolymerization with alpha-olefins, ethylene can also be copolymerized with a wide range of other monomers and ionic composition that creates ionized free radicals. Common examples include vinyl acetate (resulting product is ethylene-vinyl acetate copolymer, or EVA, widely used in athletic shoe sole foams), and a variety of acrylates (applications include packaging and sporting goods).
# History
Polyethylene was first synthesized by the German chemist Hans von Pechmann, who prepared it by accident in 1898 while heating diazomethane. When his colleagues Eugen Bamberger and Friedrich Tschirner characterized the white, waxy substance he had created, they recognized that it contained long -CH2- chains and termed it polymethylene.
The first industrially practical polyethylene synthesis was discovered (again by accident) in 1933 by Eric Fawcett and Reginald Gibson at the ICI works in Northwich, England. Upon applying extremely high pressure (several hundred atmospheres) to a mixture of ethylene and benzaldehyde, they again produced a white waxy material. Because the reaction had been initiated by trace oxygen contamination in their apparatus, the experiment was at first difficult to reproduce. It was not until 1935 that another ICI chemist, Michael Perrin, developed this accident into a reproducible high-pressure synthesis for polyethylene that became the basis for industrial LDPE production beginning in 1939.
Subsequent landmarks in polyethylene synthesis have revolved around the development of several types of catalyst that promote ethylene polymerization at more mild temperatures and pressures. The first of these was a chromium trioxide based catalyst discovered in 1951 by Robert Banks and J. Paul Hogan at Phillips Petroleum. In 1953, the German chemist Karl Ziegler developed a catalytic system based on titanium halides and organoaluminum compounds that worked at even milder conditions than the Phillips catalyst. The Phillips catalyst is less expensive and easier to work with, however, and both methods are used in industrial practice.
By the end of the 1950s both the Phillips and Ziegler type catalysts were being used for HDPE production. Phillips' initially had difficulties producing a HDPE product of uniform quality, and filled warehouses with off-specification plastic. However, financial ruin was unexpectedly averted in 1957, when the hula hoop, a toy consisting of a circular polyethylene tube, became a fad among youth in the United States.
A third type of catalytic system, one based on metallocenes, was discovered in 1976 in Germany by Walter Kaminsky and Hansjörg Sinn. The Ziegler and metallocene catalyst families have since proven to be very flexible at copolymerizing ethylene with other olefins and have become the basis for the wide range of polyethylene resins available today, including very low density polyethylene , and linear low density polyethylene . Such resins, in the form of fibers like Dyneema, have (as of 2005) begun to replace aramids in many high-strength applications.
Until recently, the metallocenes were the most active single-site catalysts for ethylene polymerisation known - new catalysts are typically compared to zirconocene dichloride. Much effort is currently being exerted on developing new single-site (so-called post-metallocene) catalysts, that may allow greater tuning of the polymer structure than is possible with metallocenes. Recently, work by Fujita at the Mitsui corporation (amongst others) has demonstrated that certain salicylaldimine complexes of Group 4 metals show substantially higher activity than the metallocenes.
# Physical properties
Depending on the crystallinity and molecular weight, a melting point and glass transition may or may not be observable. The temperature at which these occur varies strongly with the type of polyethylene. For common commercial grades of medium-density and high-density polyethylene, the melting point is typically in the range 120-130 °C. The melt point for average commercial low-density polyethylene is typically 105-115 °C. Most LDPE, MDPE, and HDPE grades have excellent chemical resistance and do not dissolve at room temperature because of the crystallinity. Polyethylene (other than cross-linked polyethylene) usually can be dissolved at elevated temperatures in aromatic hydrocarbons, such as toluene or xylene, or chlorinated solvents, such as trichloroethane or trichlorobenzene. | Polyethylene
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Polyethylene (IUPAC name polyethene) is a thermoplastic commodity heavily used in consumer products. Over 60 million tons of the material are produced worldwide every year.
# Description
Polyethylene is a polymer consisting of long chains of the monomer ethylene (IUPAC name ethene). The recommended scientific name 'polyethene' is systematically derived from the scientific name of the monomer.[1][2] In certain circumstances it is useful to use a structure–based nomenclature. In such cases IUPAC recommends poly(methylene).[2] The difference is due to the 'opening up' of the monomer's double bond upon polymerisation.
In the polymer industry the name is sometimes shortened to PE, in a manner similar to that by which other polymers like polypropylene and polystyrene are shortened to PP and PS, respectively. In the United Kingdom the polymer is commonly called polythene, although this is not recognised scientifically.
The ethene molecule (known almost universally by its common name ethylene), C2H4 is CH2=CH2, Two CH2 groups connected by a double bond, thus:
Polyethylene is created through polymerization of ethene. It can be produced through radical polymerization, anionic addition polymerization, ion coordination polymerization or cationic addition polymerization. This is because ethene does not have any substituent groups that influence the stability of the propagation head of the polymer. Each of these methods results in a different type of polyethylene.
# Classification of polyethylenes
Polyethylene is classified into several different categories based mostly on its density and branching. The mechanical properties of PE depend significantly on variables such as the extent and type of branching, the crystal structure, and the molecular weight.
- Ultra high molecular weight polyethylene (UHMWPE)
- Ultra low molecular weight polyethylene (ULMWPE - PE-WAX)
- High molecular weight polyethylene (HMWPE)
- High density polyethylene (HDPE)
- High density cross-linked polyethylene (HDXLPE)
- Cross-linked polyethylene (PEX)
- Medium density polyethylene (MDPE)
- Low density polyethylene (LDPE)
- Linear low density polyethylene (LLDPE)
- Very low density polyethylene (VLDPE)
UHMWPE is polyethylene with a molecular weight numbering in the millions, usually between 3.1 and 5.67 million. The high molecular weight results in less efficient packing of the chains into the crystal structure as evidenced by densities less than high density polyethylene (e.g. 0.930 - 0.935 g/cm3). The high molecular weight results in a very tough material. UHMWPE can be made through any catalyst technology, although Ziegler catalysts are most common. Because of its outstanding toughness, cut, wear and excellent chemical resistance, UHWMPE is used in a wide diversity of applications. These include can and bottle handling machine parts, moving parts on weaving machines, bearings, gears, artificial joints, edge protection on ice rinks, butchers' chopping boards. It competes with Aramid in bulletproof vests as Spectra (or Dyneema) fibers.
HDPE is defined by a density of greater or equal to 0.941 g/cm3. HDPE has a low degree of branching and thus stronger intermolecular forces and tensile strength. HDPE can be produced by chromium/silica catalysts, Ziegler-Natta catalysts or metallocene catalysts. The lack of branching is ensured by an appropriate choice of catalyst (e.g. chromium catalysts or Ziegler-Natta catalysts) and reaction conditions. HDPE is used in products and packaging such as milk jugs, detergent bottles, margarine tubs, garbage containers and water pipes.
HDPE is also widely used in the fireworks community. In tubes of varying length (depending on the size of the ordnance), HDPE is used as a replacement for the supplied cardboard mortar tubes for two primary reasons. One, it is much safer than the supplied cardboard tubes because if a shell were to malfunction and explode inside (flower pot) an HDPE tube, the tube will not shatter. The second reason is that they are reusable allowing designers to create multiple shot mortar racks. Pyrotechnicians discourage the use of PVC tubing in mortar tubes because it tends to shatter, sending shards of plastic at possible spectators, and will not show up in x-rays.
PEX is a medium- to high-density polyethylene containing cross-link bonds introduced into the polymer structure, changing the thermoplast into an elastomer. The high-temperature properties of the polymer are improved, its flow is reduced and its chemical resistance is enhanced. PEX is used in some potable water plumbing systems, as tubes made of the material can be expanded to fit over a metal nipple, and it will slowly return to its original shape, forming a permanent, water-tight connection.
MDPE is defined by a density range of 0.926 - 0.940 g/cm3. MDPE can be produced by chromium/silica catalysts, Ziegler-Natta catalysts or metallocene catalysts.MDPE has good shock and drop resistance properties. It also is less notch sensitive than HDPE, stress cracking resistance is better than HDPE. MDPE is typically used in gas pipes and fittings, sacks, shrink film, packaging film, carrier bags, screw closures.
LLDPE is defined by a density range of 0.915 - 0.925 g/cm3. is a substantially linear polymer, with significant numbers of short branches, commonly made by copolymerization of ethylene with short-chain alpha-olefins (e.g. 1-butene, 1-hexene, and 1-octene). LLDPE has higher tensile strength than LDPE. Exhibits higher impact and puncture resistance than LDPE. Lower thickness (gauge) films can be blown compared to LDPE, with better environmental stress cracking resistance compared to LDPE but is not as easy to process. LLDPE is used in packaging, particularly film for bags and sheets. Lower thickness (gauge) may be used compared to LDPE. Cable covering, toys, lids, buckets and containers, pipe. While other applications are available, LLDPE is used predominantly in film applications due to its toughness, flexibility, and relative transparency.
LDPE is defined by a density range of 0.910 - 0.940 g/cm3. LDPE has a high degree of short and long chain branching, which means that the chains do not pack into the crystal structure as well. It has therefore less strong intermolecular forces as the instantaneous-dipole induced-dipole attraction is less. This results in a lower tensile strength and increased ductility. LDPE is created by free radical polymerization. The high degree of branches with long chains gives molten LDPE unique and desirable flow properties. LDPE is used for both rigid containers and plastic film applications such as plastic bags and film wrap.
VLDPE is defined by a density range of 0.880 - 0.915 g/cm3. is a substantially linear polymer, with high levels of short chain branches, commonly made by copolymerization of ethylene with short-chain alpha-olefins (e.g. 1-butene, 1-hexene, and 1-octene). VLDPE is most commonly produced using metallocene catalysts due to the greater co-monomer incorporation exhibited by these catalysts. VLDPE’s are used for hose and tubing, ice and frozen food bags, food packaging and stretch wrap, as well as impact modifiers when blended with other polymers.
Recently, much research activity has focused on the nature and distribution of long chain branches in polyethylene. In HDPE, a relatively small number of these branches, perhaps 1 in 100 or 1,000 branches per backbone carbon, can significantly affect the rheological properties of the polymer.
# Ethylene copolymers
In addition to copolymerization with alpha-olefins, ethylene can also be copolymerized with a wide range of other monomers and ionic composition that creates ionized free radicals. Common examples include vinyl acetate (resulting product is ethylene-vinyl acetate copolymer, or EVA, widely used in athletic shoe sole foams), and a variety of acrylates (applications include packaging and sporting goods).
# History
Polyethylene was first synthesized by the German chemist Hans von Pechmann, who prepared it by accident in 1898 while heating diazomethane. When his colleagues Eugen Bamberger and Friedrich Tschirner characterized the white, waxy substance he had created, they recognized that it contained long -CH2- chains and termed it polymethylene.
The first industrially practical polyethylene synthesis was discovered (again by accident) in 1933 by Eric Fawcett and Reginald Gibson at the ICI works in Northwich, England.[3] Upon applying extremely high pressure (several hundred atmospheres) to a mixture of ethylene and benzaldehyde, they again produced a white waxy material. Because the reaction had been initiated by trace oxygen contamination in their apparatus, the experiment was at first difficult to reproduce. It was not until 1935 that another ICI chemist, Michael Perrin, developed this accident into a reproducible high-pressure synthesis for polyethylene that became the basis for industrial LDPE production beginning in 1939.
Subsequent landmarks in polyethylene synthesis have revolved around the development of several types of catalyst that promote ethylene polymerization at more mild temperatures and pressures. The first of these was a chromium trioxide based catalyst discovered in 1951 by Robert Banks and J. Paul Hogan at Phillips Petroleum. In 1953, the German chemist Karl Ziegler developed a catalytic system based on titanium halides and organoaluminum compounds that worked at even milder conditions than the Phillips catalyst. The Phillips catalyst is less expensive and easier to work with, however, and both methods are used in industrial practice.
By the end of the 1950s both the Phillips and Ziegler type catalysts were being used for HDPE production. Phillips' initially had difficulties producing a HDPE product of uniform quality, and filled warehouses with off-specification plastic. However, financial ruin was unexpectedly averted in 1957, when the hula hoop, a toy consisting of a circular polyethylene tube, became a fad among youth in the United States.
A third type of catalytic system, one based on metallocenes, was discovered in 1976 in Germany by Walter Kaminsky and Hansjörg Sinn. The Ziegler and metallocene catalyst families have since proven to be very flexible at copolymerizing ethylene with other olefins and have become the basis for the wide range of polyethylene resins available today, including very low density polyethylene , and linear low density polyethylene . Such resins, in the form of fibers like Dyneema, have (as of 2005) begun to replace aramids in many high-strength applications.
Until recently, the metallocenes were the most active single-site catalysts for ethylene polymerisation known - new catalysts are typically compared to zirconocene dichloride. Much effort is currently being exerted on developing new single-site (so-called post-metallocene) catalysts, that may allow greater tuning of the polymer structure than is possible with metallocenes. Recently, work by Fujita at the Mitsui corporation (amongst others) has demonstrated that certain salicylaldimine complexes of Group 4 metals show substantially higher activity than the metallocenes.
# Physical properties
Depending on the crystallinity and molecular weight, a melting point and glass transition may or may not be observable. The temperature at which these occur varies strongly with the type of polyethylene. For common commercial grades of medium-density and high-density polyethylene, the melting point is typically in the range 120-130 °C. The melt point for average commercial low-density polyethylene is typically 105-115 °C. Most LDPE, MDPE, and HDPE grades have excellent chemical resistance and do not dissolve at room temperature because of the crystallinity. Polyethylene (other than cross-linked polyethylene) usually can be dissolved at elevated temperatures in aromatic hydrocarbons, such as toluene or xylene, or chlorinated solvents, such as trichloroethane or trichlorobenzene. | https://www.wikidoc.org/index.php/Polyethene | |
298b09834a3b9d564c0463303bb0165b90a028b9 | wikidoc | Polyomavirus | Polyomavirus
File:Polyomavirus SV40 TEM B82-0338 lores.jpg
- African green monkey polyomavirus
- Baboon polyomavirus 2
- BK polyomavirus
- Bovine polyomavirus
- Budgerigar fledgling disease virus
- Hamster polyomavirus
- JC polyomavirus
- Murine pneumotropic virus
- Murine polyomavirus
- Rabbit kidney vacuolating virus
- Simian virus 12
- Simian virus 40
Polyomavirus is the sole genus of viruses within the family Polyomaviridae. Polyomaviruses are DNA-based (double-stranded DNA,~5000 base pairs,circular genome), small (40-50 nanometers in diameter), and icosahedral in shape, and do not have a lipoprotein envelope. They are potentially oncogenic (tumor-causing); they often persist as latent infections in a host without causing disease, but may produce tumors in a host of a different species, or a host with an ineffective immune system. The name polyoma refers to the viruses' ability to produce multiple (poly-) tumors (-oma).
There are four polyomaviruses found in humans: JC virus, which can infect the respiratory system, kidneys, or brain (sometimes causing the fatal progressive multifocal leukoencephalopathy in the latter case), and BK virus, which produces a mild respiratory infection and can affect the kidneys of immunosuppressed transplant patients. Both viruses are very widespread: approximately 80 percent of the adult population in the United States have antibodies to BK and JC. Two recently discovered polyomaviruses, KI (Karolinska Institute) and WU (Washington University) viruses, are closely related to each other and have been isolated from respiratory secretions.
The Simian vacuolating virus 40 replicates in the kidneys of monkeys without causing disease, but causes sarcomas in hamsters. It is unknown whether it can cause disease in humans, which has caused concern since the virus may have been introduced into the general population in the 1950s through a contaminated polio vaccine.
An avian polyomavirus sometimes referred to as the Budgerigar fledgling disease virus is a frequent cause of death among caged birds.
The genus Polyomavirus used to be one of two genera within the now obsolete family Papovaviridae (the other genus being Papillomavirus which is now assigned to its own family Papillomaviridae). The name Papovaviridae derives from three abbreviations: Pa for Papillomavirus, Po for Polyomavirus, and Va for "vacuolating".
# Replication
Prior to genome replication, the processes of viral attachment, entry and uncoating occur. Cellular receptors for polyomaviruses are currently unknown, however, attachment of polyomaviruses to host cells is mediated by viral protein 1 (VP1). This can be confirmed as anti-VP1 antibodies have been shown to prevent the binding of polyomavirus to host cells.
Polyomavirus virions are subsequently endocytosed and transported directly to the nucleus in endocytic vacuoles where uncoating occurs.
Polyomaviruses replicate in the nucleus of the host. They are able to utilise the host’s machinery because the genomic structure is homologous to that of the mammalian host. Viral replication occurs in two distinct phases; early and late gene expression, separated by genome replication.
Early gene expression is responsible for the synthesis of non-structural proteins. Since Polyomaviruses rely on the host to control both the gene expression, the role of the non-structural proteins is to regulate the cellular mechanisms. Close to the N terminal end of polyomavirus genome are enhancer elements which induce activation and transcription of a molecule known as the T-antigen (see SV40 Large T-antigen). Early mRNA’s, encoding T-antigen are produced by host RNA polymerase II. T-antigen autoregulates early mRNA’s, subsequently leading to elevated levels of T-antigen. At high concentrations of T-antigen, early gene expression is repressed, triggering the late phase of viral infection to begin.
Genome replication acts to separate the early and late phase gene expression. The duplicated viral genome is synthesised and processed as if it were cellular DNA, exploiting the host’s machinery. As the daughter viral DNA are synthesised they associate with cellular nucleosomes to form structures that are often referred to as "minichromosomes". In this manner the DNA is packaged more efficiently.
Late gene expression synthesises the structural proteins, responsible for the viral particle composition. This occurs during and after genome replication. As with the early gene expression products, late gene expression generates an array of proteins as a result of alternative splicing.
Within each viral protein are 'nuclear localization signals' which cause the viral proteins to amass in the nucleus. Assembly of new virus particles consequently occurs within the nucleus of the host cell.
Release of newly synthesized polyomavirus particles exit the infected cell by one of two mechanisms. Firstly and less commonly, they are transported in cytoplasmic vacuoles to the plasma membrane, where budding ocurs. More frequently, they are released when the cell lyses due to the cytotoxicity of virus particles present in the infected cell.
# The Polyoma Middle T-Antigen
The Polyoma Middle T-Antigen is used in animal breast cancer model systems like the PYMT system where it ist coupled to the MMTV promotor. There it functions as an oncogene, while the tissue where the tumor develops is determined by the MMTV promotor. | Polyomavirus
Template:Taxobox begin
Template:Taxobox begin placement virus
File:Polyomavirus SV40 TEM B82-0338 lores.jpg
Template:Taxobox group i entry
Template:Taxobox familia entry
Template:Taxobox genus entry
Template:Taxobox end placement
Template:Taxobox section subdivision
- African green monkey polyomavirus
- Baboon polyomavirus 2
- BK polyomavirus
- Bovine polyomavirus
- Budgerigar fledgling disease virus
- Hamster polyomavirus
- JC polyomavirus
- Murine pneumotropic virus
- Murine polyomavirus
- Rabbit kidney vacuolating virus
- Simian virus 12
- Simian virus 40
Template:Taxobox end
Polyomavirus is the sole genus of viruses within the family Polyomaviridae. Polyomaviruses are DNA-based (double-stranded DNA,~5000 base pairs,circular genome), small (40-50 nanometers in diameter), and icosahedral in shape, and do not have a lipoprotein envelope. They are potentially oncogenic (tumor-causing); they often persist as latent infections in a host without causing disease, but may produce tumors in a host of a different species, or a host with an ineffective immune system. The name polyoma refers to the viruses' ability to produce multiple (poly-) tumors (-oma).
There are four polyomaviruses found in humans: JC virus, which can infect the respiratory system, kidneys, or brain (sometimes causing the fatal progressive multifocal leukoencephalopathy in the latter case), and BK virus, which produces a mild respiratory infection and can affect the kidneys of immunosuppressed transplant patients. Both viruses are very widespread: approximately 80 percent of the adult population in the United States have antibodies to BK and JC. Two recently discovered polyomaviruses, KI (Karolinska Institute)[1] and WU (Washington University)[2] viruses, are closely related to each other and have been isolated from respiratory secretions.
The Simian vacuolating virus 40 replicates in the kidneys of monkeys without causing disease, but causes sarcomas in hamsters. It is unknown whether it can cause disease in humans, which has caused concern since the virus may have been introduced into the general population in the 1950s through a contaminated polio vaccine.
An avian polyomavirus sometimes referred to as the Budgerigar fledgling disease virus is a frequent cause of death among caged birds.
The genus Polyomavirus used to be one of two genera within the now obsolete family Papovaviridae (the other genus being Papillomavirus which is now assigned to its own family Papillomaviridae). The name Papovaviridae derives from three abbreviations: Pa for Papillomavirus, Po for Polyomavirus, and Va for "vacuolating".
# Replication
Prior to genome replication, the processes of viral attachment, entry and uncoating occur. Cellular receptors for polyomaviruses are currently unknown, however, attachment of polyomaviruses to host cells is mediated by viral protein 1 (VP1). This can be confirmed as anti-VP1 antibodies have been shown to prevent the binding of polyomavirus to host cells.[3]
Polyomavirus virions are subsequently endocytosed and transported directly to the nucleus in endocytic vacuoles where uncoating occurs.
Polyomaviruses replicate in the nucleus of the host. They are able to utilise the host’s machinery because the genomic structure is homologous to that of the mammalian host. Viral replication occurs in two distinct phases; early and late gene expression, separated by genome replication.
Early gene expression is responsible for the synthesis of non-structural proteins. Since Polyomaviruses rely on the host to control both the gene expression, the role of the non-structural proteins is to regulate the cellular mechanisms. Close to the N terminal end of polyomavirus genome are enhancer elements which induce activation and transcription of a molecule known as the T-antigen (see SV40 Large T-antigen). Early mRNA’s, encoding T-antigen are produced by host RNA polymerase II. T-antigen autoregulates early mRNA’s, subsequently leading to elevated levels of T-antigen. At high concentrations of T-antigen, early gene expression is repressed, triggering the late phase of viral infection to begin.
Genome replication acts to separate the early and late phase gene expression. The duplicated viral genome is synthesised and processed as if it were cellular DNA, exploiting the host’s machinery. As the daughter viral DNA are synthesised they associate with cellular nucleosomes to form structures that are often referred to as "minichromosomes". In this manner the DNA is packaged more efficiently.
Late gene expression synthesises the structural proteins, responsible for the viral particle composition. This occurs during and after genome replication. As with the early gene expression products, late gene expression generates an array of proteins as a result of alternative splicing.
Within each viral protein are 'nuclear localization signals' which cause the viral proteins to amass in the nucleus. Assembly of new virus particles consequently occurs within the nucleus of the host cell.
Release of newly synthesized polyomavirus particles exit the infected cell by one of two mechanisms. Firstly and less commonly, they are transported in cytoplasmic vacuoles to the plasma membrane, where budding ocurs. More frequently, they are released when the cell lyses due to the cytotoxicity of virus particles present in the infected cell.
# The Polyoma Middle T-Antigen
The Polyoma Middle T-Antigen is used in animal breast cancer model systems like the PYMT system where it ist coupled to the MMTV promotor. There it functions as an oncogene, while the tissue where the tumor develops is determined by the MMTV promotor.
# External links
- MicrobiologyBytes: Polyomaviruses
## Species
- African green monkey polyomavirus (AGMPyV)
- Baboon polyomavirus 2 (PPyV)
- BK polyomavirus (BKPyV)
- Bovine polyomavirus (BPyV)
- Budgerigar fledgling disease virus (BFPyV)
- Hamster polyomavirus (HaPyV)
- JC polyomavirus (JCPyV)
- Murine pneumotropic virus (MPtV)
- Murine polyomavirus (MPyV)
- Rabbit kidney vacuolating virus (RKV)
- Simian virus 12 (SV-12)
- Simian virus 40 (SV-40, type species)
de:Polyomaviren | https://www.wikidoc.org/index.php/Polyoma_virus | |
f23941b41b6a2347f0a6cc62be36e8d17c2be41d | wikidoc | Polythiazide | Polythiazide
# 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
Polythiazide is a thiazide diuretic that is FDA approved for the treatment of edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy and various forms of renal dysfunction; and hypertension.. Common adverse reactions include cardiac dysrhythmia, hypotension, disorder of glucose regulation, hypercalcemia, hyperuricemia, hypokalemia, hypomagnesemia
hyponatremia, immune hypersensitivity reaction, systemic lupus erythematosus.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Edema=
- Dosing Information
- Usual dosage: 1-4 mg PO qd
- Dosing Information
- Usual dosage: 2-4 mg PO qd
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Polythiazide in adult patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Polythiazide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Polythiazide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Polythiazide in pediatric patients.
# Contraindications
Anuria. Hypersensitivity to this or other sulfonamide derived drugs.
# Warnings
Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.
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.
Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs.
Sensitivity reactions may occur in patients with a history of allergy or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.
All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance; namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Medication such as digitalis may also influence serum electrolytes. Warning signs, irrespective of cause, are: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.
Hypokalemia may develop with thiazides as with any other potent diuretic, especially with brisk diuresis, when severe cirrhosis is present, or during concomitant use of corticosteroids or ACTH.
Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Digitalis therapy may exaggerate metabolic effects of hypokalemia especially with reference to myocardial activity.
Any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.
Insulin requirements in diabetic patients may be increased, decreased, or unchanged. Latent diabetes mellitus may become manifest during thiazide administration.
Thiazide drugs may increase the responsiveness to tubocurarine.
The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.
Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.
If progressive renal impairment becomes evident, as indicated by a rising nonprotein nitrogen or blood urea nitrogen, a careful reappraisal of therapy is necessary with consideration given to withholding or discontinuing diuretic therapy.
Thiazides may decrease serum PBI levels without signs of thyroid disturbance.
# Adverse Reactions
## Clinical Trials Experience
- Gastrointestinal System Reactions
- anorexia
- gastric irritation
- nausea
- vomiting
- cramping
- diarrhea
- constipation
- jaundice (intrahepatic cholestatic jaundice)
- pancreatitis
- Central Nervous System Reactions
- dizziness
- vertigo
- paresthesias
- headache
- xanthopsia
- Hematologic Reactions
- leukopenia
- agranulocytosis
- thrombocytopenia
- aplastic anemia
- Dermatologic—Hypersensitivity Reactions
- purpura
- photosensitivity
- rash
- urticaria
- necrotizing angiitis, vasculitis, cutaneous vasculitis
- Cardiovascular Reaction
- Orthostatic hypotension may occur and may be aggravated by alcohol, barbiturates or narcotics.
- F. Other
- hyperglycemia
- glycosuria
- hyperuricemia
- muscle spasm
- weakness
- restlessness
Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn.
## Postmarketing Experience
There is limited information about the post marketing experience.
# Drug Interactions
There is no FDA guidance on the use of Polythiazide with respect to specific drug interactions.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Thiazides cross the placental barrier and appear in cord blood. The use of thiazides in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult.
Pregnancy Category (AUS):
Thiazides appear in breast milk. If use of the drug is deemed essential, the patient should stop nursing.
### Labor and Delivery
There is no FDA guidance on use of Polythiazide during labor and delivery.
### Nursing Mothers
Thiazides appear in breast milk. If use of the drug is deemed essential, the patient should stop nursing.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
There is no FDA guidance on the use of Polythiazide in geriatric settings.
### Gender
There is no FDA guidance on the use of Polythiazide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Polythiazide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Polythiazide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Polythiazide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Polythiazide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Polythiazide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Therapy should be individualized according to patient response. This therapy should be titrated to gain maximal therapeutic response as well as the minimal dose possible to maintain that therapeutic response. The usual dosage of Renese tablets for diuretic therapy is 1 to 4 mg daily, and for antihypertensive therapy is 2 to 4 mg daily.
### Monitoring
There is limited information about the drug monitoring.
# IV Compatibility
There is limited information about the IV Compatibility.
# Overdosage
There is limited information regarding Polythiazide overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
The mechanism of action results in an interference with the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic potency. The mechanism whereby thiazides function in the control of hypertension is unknown.
## Structure
## Pharmacodynamics
There is no FDA information on the use of Polythiazide with respect to pharmacodynamics.
## Pharmacokinetics
There is no FDA information on the use of Polythiazide with respect to pharmacokinetics.
## Nonclinical Toxicology
There is no FDA information on the use of Polythiazide with respect to nonclinical toxicology.
# Clinical Studies
There is limited information regarding Polythiazide Clinical Studies in the drug label.
# How Supplied
RENESE (polythiazide) Tablets are available as:
1 mg white, scored tablets in bottles of 100 (NDC 0069-3750-66).
2 mg yellow, scored tablets in bottles of 100 (NDC 0069-3760-66).
4 mg white, scored tablets in bottles of 100 (NDC 0069-3770-66).
## Storage
There is limited information regarding Polythiazide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is no FDA guidance on the use of Polythiazide with respect to FDA Provided Patient Information.
# Precautions with Alcohol
Alcohol-Polythiazide 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 Polythiazide Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information about the Look-Alike Drug Names.
# Drug Shortage Status
Drug Shortage
# Price | Polythiazide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Adeel Jamil, M.D. [3]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Polythiazide is a thiazide diuretic that is FDA approved for the treatment of edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy and various forms of renal dysfunction; and hypertension.. Common adverse reactions include cardiac dysrhythmia, hypotension, disorder of glucose regulation, hypercalcemia, hyperuricemia, hypokalemia, hypomagnesemia
hyponatremia, immune hypersensitivity reaction, systemic lupus erythematosus.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Edema=
- Dosing Information
- Usual dosage: 1-4 mg PO qd
- Dosing Information
- Usual dosage: 2-4 mg PO qd
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Polythiazide in adult patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Polythiazide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Polythiazide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Polythiazide in pediatric patients.
# Contraindications
Anuria. Hypersensitivity to this or other sulfonamide derived drugs.
# Warnings
Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.
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.
Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs.
Sensitivity reactions may occur in patients with a history of allergy or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.
All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance; namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Medication such as digitalis may also influence serum electrolytes. Warning signs, irrespective of cause, are: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.
Hypokalemia may develop with thiazides as with any other potent diuretic, especially with brisk diuresis, when severe cirrhosis is present, or during concomitant use of corticosteroids or ACTH.
Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Digitalis therapy may exaggerate metabolic effects of hypokalemia especially with reference to myocardial activity.
Any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.
Insulin requirements in diabetic patients may be increased, decreased, or unchanged. Latent diabetes mellitus may become manifest during thiazide administration.
Thiazide drugs may increase the responsiveness to tubocurarine.
The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.
Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.
If progressive renal impairment becomes evident, as indicated by a rising nonprotein nitrogen or blood urea nitrogen, a careful reappraisal of therapy is necessary with consideration given to withholding or discontinuing diuretic therapy.
Thiazides may decrease serum PBI levels without signs of thyroid disturbance.
# Adverse Reactions
## Clinical Trials Experience
- Gastrointestinal System Reactions
- anorexia
- gastric irritation
- nausea
- vomiting
- cramping
- diarrhea
- constipation
- jaundice (intrahepatic cholestatic jaundice)
- pancreatitis
- Central Nervous System Reactions
- dizziness
- vertigo
- paresthesias
- headache
- xanthopsia
- Hematologic Reactions
- leukopenia
- agranulocytosis
- thrombocytopenia
- aplastic anemia
- Dermatologic—Hypersensitivity Reactions
- purpura
- photosensitivity
- rash
- urticaria
- necrotizing angiitis, vasculitis, cutaneous vasculitis
- Cardiovascular Reaction
- Orthostatic hypotension may occur and may be aggravated by alcohol, barbiturates or narcotics.
- F. Other
- hyperglycemia
- glycosuria
- hyperuricemia
- muscle spasm
- weakness
- restlessness
Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn.
## Postmarketing Experience
There is limited information about the post marketing experience.
# Drug Interactions
There is no FDA guidance on the use of Polythiazide with respect to specific drug interactions.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Thiazides cross the placental barrier and appear in cord blood. The use of thiazides in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult.
Pregnancy Category (AUS):
Thiazides appear in breast milk. If use of the drug is deemed essential, the patient should stop nursing.
### Labor and Delivery
There is no FDA guidance on use of Polythiazide during labor and delivery.
### Nursing Mothers
Thiazides appear in breast milk. If use of the drug is deemed essential, the patient should stop nursing.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
There is no FDA guidance on the use of Polythiazide in geriatric settings.
### Gender
There is no FDA guidance on the use of Polythiazide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Polythiazide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Polythiazide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Polythiazide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Polythiazide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Polythiazide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Therapy should be individualized according to patient response. This therapy should be titrated to gain maximal therapeutic response as well as the minimal dose possible to maintain that therapeutic response. The usual dosage of Renese tablets for diuretic therapy is 1 to 4 mg daily, and for antihypertensive therapy is 2 to 4 mg daily.
### Monitoring
There is limited information about the drug monitoring.
# IV Compatibility
There is limited information about the IV Compatibility.
# Overdosage
There is limited information regarding Polythiazide overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
The mechanism of action results in an interference with the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic potency. The mechanism whereby thiazides function in the control of hypertension is unknown.
## Structure
## Pharmacodynamics
There is no FDA information on the use of Polythiazide with respect to pharmacodynamics.
## Pharmacokinetics
There is no FDA information on the use of Polythiazide with respect to pharmacokinetics.
## Nonclinical Toxicology
There is no FDA information on the use of Polythiazide with respect to nonclinical toxicology.
# Clinical Studies
There is limited information regarding Polythiazide Clinical Studies in the drug label.
# How Supplied
RENESE (polythiazide) Tablets are available as:
1 mg white, scored tablets in bottles of 100 (NDC 0069-3750-66).
2 mg yellow, scored tablets in bottles of 100 (NDC 0069-3760-66).
4 mg white, scored tablets in bottles of 100 (NDC 0069-3770-66).
## Storage
There is limited information regarding Polythiazide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is no FDA guidance on the use of Polythiazide with respect to FDA Provided Patient Information.
# Precautions with Alcohol
Alcohol-Polythiazide 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 Polythiazide Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information about the Look-Alike Drug Names.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Polythiazide | |
cfa5876d03132f146a564dbd50b16067ff349545 | wikidoc | Pomalidomide | Pomalidomide
# 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
Pomalidomide is an antineoplastic agent that is FDA approved for the treatment of multiple myeloma. There is a Black Box Warning for this drug as shown here. Common adverse reactions include peripheral edema, rash, hypercalcemia,constipation, diarrhea, nausea, anemia,neutropenia,thrombocytopenia,dizziness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
Multiple Myeloma
- Pomalidomide is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.
# Dosage
Multiple Myeloma
- Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating Pomalidomide.
- The recommended starting dose of Pomalidomide is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. Pomalidomide may be given in combination with dexamethasone.
- Pomalidomide may be taken with water. Inform patients not to break, chew, or open the capsules. Pomalidomide should be taken without food (at least 2 hours before or 2 hours after a meal).
Dose Adjustments for Toxicities
- For other Grade 3 or 4 toxicities, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion.
- To initiate a new cycle of Pomalidomide the neutrophil count must be at least 500 per mcL and the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue Pomalidomide.
Dose Adjustment for Strong CYP1A2 Inhibitors in the Presence of Strong CYP3A4 and P-gp Inhibitors
- Avoid co-administration of strong inhibitors of CYP1A2. If necessary to co-administer strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp, reduce Pomalidomide dose by 50%. No clinical efficacy or safety data exist.
# DOSAGE FORMS AND STRENGTHS
- Pomalidomide is available in the following capsule strengths:
- 1 mg: Dark blue opaque cap and yellow opaque body, imprinted “POML” on the cap in white ink and “1 mg” on the body in black ink
- 2 mg: Dark blue opaque cap and orange opaque body, imprinted “POML” on the cap and “2 mg” on the body in white ink
- 3 mg: Dark blue opaque cap and green opaque body, imprinted “POML” on the cap and “3 mg” on the body in white ink
- 4 mg: Dark blue opaque cap and blue opaque body, imprinted “POML” on the cap and “4 mg” on the body in white ink
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pomalidomide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pomalidomide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Pomalidomide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pomalidomide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pomalidomide in pediatric patients.
# Contraindications
Pregnancy
Pomalidomide can cause fetal harm when administered to a pregnant female. Pomalidomide is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis. 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.
# Warnings
Embryo-Fetal Toxicity
Pomalidomide is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. Pomalidomide is only available through the Pomalidomide REMS program.
Females of Reproductive Potential
- Females of reproductive potential must avoid pregnancy while taking Pomalidomide and for at least 4 weeks after completing therapy.
- Females must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with Pomalidomide, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of Pomalidomide therapy.
- Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing Pomalidomide therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles, or every 2 weeks in women with irregular menstrual cycles.
Males
- Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking Pomalidomide and for up to 28 days after discontinuing Pomalidomide, even if they have undergone a successful vasectomy. Male patients taking Pomalidomide must not donate sperm.
Blood Donation
- Patients must not donate blood during treatment with Pomalidomide and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to Pomalidomide.
Pomalidomide REMS™ Program
- Because of the embryo-fetal risk, Pomalidomide is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “Pomalidomide REMS.”
- Required components of the Pomalidomide REMS program include the following:
- Prescribers must be certified with the Pomalidomide REMS program by enrolling and complying with the REMS requirements.
- Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements.
- Pharmacies must be certified with the Pomalidomide REMS program, must only dispense to patients who are authorized to receive Pomalidomide and comply with REMS requirements.
Further information about the Pomalidomide REMS program is available at www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436.
Venous Thromboembolism
- Patients receiving Pomalidomide have developed venous thromboembolic events (VTEs) (venous thromboembolism) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors.
Hematologic Toxicity
- Neutropenia was the most frequently reported Grade 3/4 adverse reaction, followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%.
- Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification.
Hypersensitivity Reactions
- Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.
Dizziness and Confusional State
- In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced Grade 3/4 dizziness, and 3% of patients experienced Grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusional state may be a problem and to not take other medications that may cause dizziness or confusional state without adequate medical advice.
Neuropathy
- In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of Grade 3 or higher neuropathy adverse reactions reported.
Risk of Second Primary Malignancies
- Cases of acute myelogenous leukemia have been reported in patients receiving Pomalidomide as an investigational therapy outside of multiple myeloma.
Tumor Lysis Syndrome
- Tumor lysis syndrome (TLS) may occur in patients treated with pomalidomide. Patients at risk for TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions are described in detail in other labeling sections:
- Fetal Risk
- Venous Thromboembolism
- Hematologic Toxicity
- Hypersensitivity Reactions
- Dizziness and Confusional State
- Neuropathy
- Risk of Second Primary Malignancies
- Tumor Lysis Syndrome
Clinical Trials Experience in Multiple Myeloma
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- In Clinical Trial 1, data were evaluated from 219 patients (safety population) who received treatment with Pomalidomide + Low-dose Dexamethasone (Low-dose Dex) (112 patients) or Pomalidomide alone (107 patients). Median number of treatment cycles was 5. Sixty-three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty-seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%.
- TABLES 2, 3, and 4 summarize all treatment-emergent adverse reactions reported for the Pomalidomide + Low-dose Dex and Pomalidomide alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug related and those that reflect the patient’s underlying disease.
Other Adverse Reactions
- Other adverse reactions of Pomalidomide in patients with multiple myeloma, not described above, and considered important:
- Ear and labyrinth disorders: vertigo
- Hepatobiliary disorders: hyperbilirubinemia
- Infections and infestations: Pneumocystis jiroveci pneumonia, respiratory syncytial virus infection, neutropenic sepsis
- Investigations: Alanine aminotransferase increased
- Metabolism and nutritional disorders: hyperkalemia
- Renal and urinary disorders: urinary retention
- Reproductive system and breast disorders: Pelvic pain
- Respiratory, thoracic and mediastinal disorders: Interstitial lung disease
## Postmarketing Experience
- The following adverse drug reactions have been identified from the worldwide post-marketing experience with Pomalidomide: pancytopenia, tumor lysis syndrome.
- 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.
# Drug Interactions
- Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp).
Drugs That May Increase Pomalidomide Plasma Concentrations
- CYP1A2 inhibitors: Pomalidomide exposure is increased when Pomalidomide is co-administered with a strong CYP1A2 inhibitor (fluvoxamine) in the presence of a strong CYP3A4/5 and P-gp inhibitor (ketoconazole). Ketoconazole in the absence of a CYP1A2 inhibitor does not increase pomalidomide exposure. Avoid co-administration of strong CYP1A2 inhibitors (e.g. ciprofloxacin and fluvoxamine). If it is medically necessary to co-administer strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp, Pomalidomide dose should be reduced by 50%.
The effect of a CYP1A2 inhibitor in the absence of a co-administered CYP3A4 and P-gp inhibitor has not been studied. Monitor for toxicities if CYP1A2 inhibitors are to be co-administered in the absence of a co-administered CYP3A4 and P-gp inhibitor, and reduce dose if needed.
Drugs That May Decrease Pomalidomide Plasma Concentrations
- Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.
- CYP1A2 inducers: Co-administration of Pomalidomide with drugs that are CYP1A2 inducers has not been studied and may reduce pomalidomide exposure.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category X
Risk Summary
- Pomalidomide can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. Pomalidomide is a thalidomide analogue.
- Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants.
- Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. 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.
- If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to Pomalidomide to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.
Animal Data
- Pomalidomide was teratogenic in both rats and rabbits in the embryo-fetal developmental studies when administered during the period of organogenesis.
- In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg/kg/day. Malformations or absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central, and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg/day. Other embryo-fetal toxicities included increased resorptions leading to decreased number of viable fetuses.
- In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg/kg/day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg/kg/day. Additional malformations observed at 250 mg/kg/day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs, and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg/kg/day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg/day. Additional embryo-fetal toxicity included increased resorption.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pomalidomide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pomalidomide during labor and delivery.
### Nursing Mothers
- It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from Pomalidomide a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness of Pomalidomide in patients below the age of 18 years have not been established.
### Geriatic Use
- No dosage adjustment is required for Pomalidomide based on age.
- Of the total number of patients in clinical studies of Pomalidomide 41% were aged 65 years and older, while 12% were aged 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients aged greater than or equal to 65 years were more likely to experience pneumonia than patients aged less than or equal to 65 years.
### Gender
Females of Reproductive Potential and Males
- Pomalidomide can cause fetal harm when administered during pregnancy. Females of reproductive potential must avoid pregnancy while taking Pomalidomide and for at least 4 weeks after completing therapy.
Females
- Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously: one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings, or implants), or partner’s vasectomy, and 1 additional effective contraceptive method – male latex or synthetic condom, diaphragm, or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with Pomalidomide during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of Pomalidomide therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed.
- Females of reproductive potential must have 2 negative pregnancy tests before initiating Pomalidomide. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing Pomalidomide Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. Pomalidomide treatment must be discontinued during this evaluation.
Males
- Pomalidomide is present in the semen of males who take Pomalidomide Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking Pomalidomide and for up to 28 days after discontinuing Pomalidomide, even if they have undergone a successful vasectomy. Male patients taking Pomalidomide must not donate sperm.
### Race
There is no FDA guidance on the use of Pomalidomide with respect to specific racial populations.
### Renal Impairment
- Pomalidomide and its metabolites are primarily excreted by the kidneys. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid Pomalidomide in patients with a serum creatinine greater than 3.0 mg/dL.
### Hepatic Impairment
- Pomalidomide is metabolized in the liver. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid Pomalidomide in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pomalidomide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pomalidomide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Pomalidomide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Pomalidomide in the drug label.
# Overdosage
- No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable.
# Pharmacology
## Mechanism of Action
- Pomalidomide, an analogue of thalidomide, is an immunomodulatory agent with antineoplastic activity. In in vitro cellular assays, pomalidomide inhibited proliferation and induced apoptosis of hematopoietic tumor cells. Additionally, pomalidomide inhibited the proliferation of lenalidomide-resistant multiple myeloma cell lines and synergized with dexamethasone in both lenalidomide-sensitive and lenalidomide-resistant cell lines to induce tumor cell apoptosis. Pomalidomide enhanced T cell- and natural killer (NK) cell-mediated immunity and inhibited production of pro-inflammatory cytokines (eg, TNF-α and IL-6) by monocytes. Pomalidomide demonstrated anti-angiogenic activity in a mouse tumor model and in the in vitro umbilical cord model.
## Structure
- Pomalidomide is an immunomodulatory antineoplastic agent. The chemical name is (RS)-4-Amino-2-(2,6-dioxo-piperidin-3-yl)-isoindoline-1,3-dione and it has the following chemical structure:
- The empirical formula for pomalidomide is C13H11N3O4 and the gram molecular weight is 273.24.
- Pomalidomide is a yellow solid powder. It has limited to low solubility into organic solvents and it has low solubility in all pH solutions (about 0.01 mg/mL). Pomalidomide has a chiral carbon atom which exists as a racemic mixture of the R(+) and S(-) enantiomers.
- Pomalidomide is available in 1-mg, 2-mg, 3-mg, and 4-mg capsules for oral administration. Each capsule contains pomalidomide as the active ingredient and the following inactive ingredients: mannitol, pregelatinized starch, and sodium stearyl fumarate. The 1-mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, white ink, and black ink. The 2-mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, FD&C red 3, and white ink. The 3-mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, and white ink. The 4-mg capsule shell contains gelatin, titanium dioxide, FD&C blue 1, FD&C blue 2, and white ink.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Pomalidomide in the drug label.
## Pharmacokinetics
Absorption
- Following administration of single oral doses of Pomalidomide the maximum plasma concentration (Cmax) for pomalidomide occurs at 2 and 3 hours postdose. The systemic exposure (AUC) of pomalidomide increases in an approximately dose proportional manner.
- In patients with multiple myeloma who received Pomalidomide 4 mg daily alone or in combination with dexamethasone, pomalidomide steady-state drug exposure was characterized by AUC(Τ) of 400 ngh/mL and Cmax of 75 ng/mL. Following multiple doses, pomalidomide has an accumulation ratio of 27% to 31%.
Distribution
- Pomalidomide has a mean apparent volume of distribution (Vd/F) between 62 and 138 L at steady state. Pomalidomide is distributed in semen of healthy subjects at a concentration of approximately 67% of plasma level at 4 hours postdose (~Tmax) after 4 days of once-daily dosing at 2 mg. Human plasma protein binding ranges from 12% to 44% and is not concentration dependent. Pomalidomide is a substrate for P-glycoprotein (P-gp).
Metabolism
- Pomalidomide is primarily metabolized in the liver by CYP1A2 and CYP3A4. In vitro, CYP1A2 and CYP3A4 were identified as the primary enzymes involved in the CYP-mediated hydroxylation of pomalidomide, with additional minor contributions from CYP2C19 and CYP2D6.
Elimination
- Pomalidomide is eliminated with a median plasma half-life of approximately 9.5 hours in healthy subjects and approximately 7.5 hours in patients with multiple myeloma. Pomalidomide has a mean total body clearance (CL/F) of 7-10 L/h.
- Following a single oral administration of -pomalidomide (2 mg) to healthy subjects, approximately 73% and 15% of the radioactive dose was eliminated in urine and feces, respectively, with approximately 2% and 8% of the radiolabeled dose eliminated unchanged as pomalidomide in urine and feces.
Drug Interactions
Drugs that Inhibit Pomalidomide Metabolism
- CYP1A2 Inhibitors: The effect of CYP1A2 inhibitors, in the absence of a co-administered CYP3A4 and P-gp inhibitor, is unknown. However, co-administration of fluvoxamine (a strong CYP1A2 inhibitor) in the presence of ketoconazole (a strong CYP3A4 and P-gp inhibitor) to 12 healthy male subjects increased exposure (geometric mean AUCINF) to pomalidomide by 146% compared to pomalidomide administered alone.
- Strong CYP3A4 and P-glycoprotein (P-gp) Inhibitors: Co-administration of ketoconazole (a strong CYP3A4 and P-gp inhibitor) in 16 healthy male subjects resulted in an increased exposure (geometric mean AUCINF) to pomalidomide of 19% compared to pomalidomide administered alone.
Drugs that Induce Pomalidomide Metabolism
- Strong CYP1A2 Inducers: Co-administration of Pomalidomide with drugs that are CYP1A2 inducers has not been studied and may reduce pomalidomide exposure.
- Strong CYP3A4 Inducers: Co-administration of carbamazepine to 16 healthy male subjects decreased exposure (geometric mean AUCINF) to pomalidomide by 21% compared to pomalidomide administered alone.
- Dexamethasone: Co-administration of multiple doses of 4 mg Pomalidomide with 20 mg to 40 mg dexamethasone (a weak to moderate inducer of CYP3A4) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone.
- In Vitro Inhibition of Drug Metabolizing Enzymes and Transporters by Pomalidomide
- Pomalidomide does not inhibit or induce CYP450 enzymes or transporters in vitro.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of 12 monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study.
- Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes, and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day.
- In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males in this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females.
# Clinical Studies
Multiple Myeloma
- Trial 1 was a phase 2, multicenter, randomized open-label study in patients with relapsed multiple myeloma who were refractory to their last myeloma therapy and had received lenalidomide and bortezomib. Patients were considered relapsed if they had achieved at least stable disease for at least 1 cycle of treatment to at least 1 prior regimen and then developed progressive disease. Patients were considered refractory if they experienced disease progression on or within 60 days of their last therapy. A total of 221 patients were randomized to receive Pomalidomide alone or Pomalidomide with Low-dose Dex. In Trial 1, the safety and efficacy of Pomalidomide 4 mg, once daily for 21 of 28 days, until disease progression, were evaluated alone and in combination with Low-dose Dex (40 mg/day given only on Days 1, 8, 15, and 22 of each 28-day cycle for patients aged 75 years or younger, or 20 mg/day given only on Days 1, 8, 15, and 22 of each 28-day cycle for patients aged greater than 75 years). Patients in the Pomalidomide alone arm were allowed to add Low-dose Dex upon disease progression.
- Table 5 summarizes the baseline patient and disease characteristics in Trial 1. The baseline demographics and disease characteristics were balanced and comparable between the study arms.
- Table 6 summarizes the analysis results of overall response rate (ORR) and duration of response (DOR), based on assessments by the Independent Review Adjudication Committee for the treatment arms in Study 1. ORR did not differ based on type of prior anti-myeloma therapy.
# How Supplied
- Dark blue opaque cap and yellow opaque body, imprinted “POML” on the cap in white ink and “1 mg” on the body in black ink
1 mg bottles of 21 (NDC 59572-501-21)
1 mg bottles of 100 (NDC 59572-501-00)
- Dark blue opaque cap and orange opaque body, imprinted “POML” on the cap and “2 mg” on the body in white ink
2 mg bottles of 21 (NDC 59572-502-21)
2 mg bottles of 100 (NDC 59572-502-00)
- Dark blue opaque cap and green opaque body, imprinted “POML” on the cap and “3 mg” on the body in white ink
3 mg bottles of 21 (NDC 59572-503-21)
3 mg bottles of 100 (NDC 59572-503-00)
- Dark blue opaque cap and blue opaque body, imprinted “POML” on the cap and “4 mg” on the body in white ink
4 mg bottles of 21 (NDC 59572-504-21)
4 mg bottles of 100 (NDC 59572-504-00)
## Storage
- Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Embryo-Fetal Toxicity
- Advise females of reproductive potential that they must avoid pregnancy while taking Pomalidomide and for at least 4 weeks after completing therapy.
- Initiate Pomalidomide treatment in females of reproductive potential only following a negative pregnancy test.
- Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use 2 different forms of contraception, including at least 1 highly effective form, simultaneously during Pomalidomide therapy, during therapy interruption, and for 4 weeks after she has completely finished taking Pomalidomide Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch, or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm, and cervical cap.
- Instruct patient to immediately stop taking Pomalidomide and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant.
- Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception.
- Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking Pomalidomide and for up to 28 days after discontinuing Pomalidomide, even if they have undergone a successful vasectomy.
Advise male patients taking Pomalidomide that they must not donate sperm.
- All patients must be instructed to not donate blood while taking Pomalidomide and for 1 month following discontinuation of Pomalidomide.
Pomalidomide REMS Program
- Because of the risk of embryo-fetal toxicity, Pomalidomide is only available through a restricted program called Pomalidomide REMS.
- Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive Pomalidomide In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements.
- Pomalidomide is available only from pharmacies that are certified in Pomalidomide REMS. Provide patients with the telephone number and Web site for information on how to obtain the product.
Venous Thromboembolism
- Inform patients of the potential risk of developing venous thromboembolic events and discuss the need for appropriate prophylactic treatment.
Hematologic Toxicities
- Inform patients on the risks of developing neutropenia, thrombocytopenia, and anemia and the need to report signs and symptoms associated with these events to their healthcare provider for further evaluation.
Hypersensitivity
- Inform patients of the potential for a severe hypersensitivity reaction to Pomalidomide if they have had such a reaction in the past to either THALOMID® or REVLIMID®.
Dizziness and Confusional State
- Inform patients of the potential risk of dizziness and confusional state with the drug, to avoid situations where dizziness or confusional state may be a problem, and not to take other medications that may cause dizziness or confusional state without adequate medical advice.
Neuropathy
- Inform patients of the risk of neuropathy and to report the signs and symptoms associated with these events to their healthcare provider for further evaluation .
Second Primary Malignancies
- Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with Pomalidomide is unknown.
Tumor Lysis Syndrome
Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation.
Dosing Instructions
- Inform patients on how to take Pomalidomide
- Pomalidomide should be taken once daily at about the same time each day.
- Pomalidomide should be taken without food (at least 2 hours before or 2 hours after a meal).
- The capsules should not be opened, broken, or chewed. Pomalidomide should be swallowed whole with water.
- Instruct patients that if they miss a dose of Pomalidomide they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take Pomalidomide at the usual time. Warn patients not to take 2 doses to make up for the one that they missed.
Other Information
Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide.
# Precautions with Alcohol
- Alcohol-Pomalidomide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- POMALYST
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Pomalidomide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Disclaimer
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# Black Box Warning
# Overview
Pomalidomide is an antineoplastic agent that is FDA approved for the treatment of multiple myeloma. There is a Black Box Warning for this drug as shown here. Common adverse reactions include peripheral edema, rash, hypercalcemia,constipation, diarrhea, nausea, anemia,neutropenia,thrombocytopenia,dizziness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
Multiple Myeloma
- Pomalidomide is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.
# Dosage
Multiple Myeloma
- Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating Pomalidomide.
- The recommended starting dose of Pomalidomide is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. Pomalidomide may be given in combination with dexamethasone.
- Pomalidomide may be taken with water. Inform patients not to break, chew, or open the capsules. Pomalidomide should be taken without food (at least 2 hours before or 2 hours after a meal).
Dose Adjustments for Toxicities
- For other Grade 3 or 4 toxicities, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion.
- To initiate a new cycle of Pomalidomide the neutrophil count must be at least 500 per mcL and the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue Pomalidomide.
Dose Adjustment for Strong CYP1A2 Inhibitors in the Presence of Strong CYP3A4 and P-gp Inhibitors
- Avoid co-administration of strong inhibitors of CYP1A2. If necessary to co-administer strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp, reduce Pomalidomide dose by 50%. No clinical efficacy or safety data exist.
# DOSAGE FORMS AND STRENGTHS
- Pomalidomide is available in the following capsule strengths:
- 1 mg: Dark blue opaque cap and yellow opaque body, imprinted “POML” on the cap in white ink and “1 mg” on the body in black ink
- 2 mg: Dark blue opaque cap and orange opaque body, imprinted “POML” on the cap and “2 mg” on the body in white ink
- 3 mg: Dark blue opaque cap and green opaque body, imprinted “POML” on the cap and “3 mg” on the body in white ink
- 4 mg: Dark blue opaque cap and blue opaque body, imprinted “POML” on the cap and “4 mg” on the body in white ink
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pomalidomide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pomalidomide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Pomalidomide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pomalidomide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pomalidomide in pediatric patients.
# Contraindications
Pregnancy
Pomalidomide can cause fetal harm when administered to a pregnant female. Pomalidomide is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis. 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.
# Warnings
Embryo-Fetal Toxicity
Pomalidomide is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. Pomalidomide is only available through the Pomalidomide REMS program.
Females of Reproductive Potential
- Females of reproductive potential must avoid pregnancy while taking Pomalidomide and for at least 4 weeks after completing therapy.
- Females must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with Pomalidomide, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of Pomalidomide therapy.
- Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing Pomalidomide therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles, or every 2 weeks in women with irregular menstrual cycles.
Males
- Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking Pomalidomide and for up to 28 days after discontinuing Pomalidomide, even if they have undergone a successful vasectomy. Male patients taking Pomalidomide must not donate sperm.
Blood Donation
- Patients must not donate blood during treatment with Pomalidomide and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to Pomalidomide.
Pomalidomide REMS™ Program
- Because of the embryo-fetal risk, Pomalidomide is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “Pomalidomide REMS.”
- Required components of the Pomalidomide REMS program include the following:
- Prescribers must be certified with the Pomalidomide REMS program by enrolling and complying with the REMS requirements.
- Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements.
- Pharmacies must be certified with the Pomalidomide REMS program, must only dispense to patients who are authorized to receive Pomalidomide and comply with REMS requirements.
Further information about the Pomalidomide REMS program is available at www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436.
Venous Thromboembolism
- Patients receiving Pomalidomide have developed venous thromboembolic events (VTEs) (venous thromboembolism) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors.
Hematologic Toxicity
- Neutropenia was the most frequently reported Grade 3/4 adverse reaction, followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%.
- Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification.
Hypersensitivity Reactions
- Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.
Dizziness and Confusional State
- In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced Grade 3/4 dizziness, and 3% of patients experienced Grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusional state may be a problem and to not take other medications that may cause dizziness or confusional state without adequate medical advice.
Neuropathy
- In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of Grade 3 or higher neuropathy adverse reactions reported.
Risk of Second Primary Malignancies
- Cases of acute myelogenous leukemia have been reported in patients receiving Pomalidomide as an investigational therapy outside of multiple myeloma.
Tumor Lysis Syndrome
- Tumor lysis syndrome (TLS) may occur in patients treated with pomalidomide. Patients at risk for TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions are described in detail in other labeling sections:
- Fetal Risk
- Venous Thromboembolism
- Hematologic Toxicity
- Hypersensitivity Reactions
- Dizziness and Confusional State
- Neuropathy
- Risk of Second Primary Malignancies
- Tumor Lysis Syndrome
Clinical Trials Experience in Multiple Myeloma
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- In Clinical Trial 1, data were evaluated from 219 patients (safety population) who received treatment with Pomalidomide + Low-dose Dexamethasone (Low-dose Dex) (112 patients) or Pomalidomide alone (107 patients). Median number of treatment cycles was 5. Sixty-three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty-seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%.
- TABLES 2, 3, and 4 summarize all treatment-emergent adverse reactions reported for the Pomalidomide + Low-dose Dex and Pomalidomide alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug related and those that reflect the patient’s underlying disease.
Other Adverse Reactions
- Other adverse reactions of Pomalidomide in patients with multiple myeloma, not described above, and considered important:
- Ear and labyrinth disorders: vertigo
- Hepatobiliary disorders: hyperbilirubinemia
- Infections and infestations: Pneumocystis jiroveci pneumonia, respiratory syncytial virus infection, neutropenic sepsis
- Investigations: Alanine aminotransferase increased
- Metabolism and nutritional disorders: hyperkalemia
- Renal and urinary disorders: urinary retention
- Reproductive system and breast disorders: Pelvic pain
- Respiratory, thoracic and mediastinal disorders: Interstitial lung disease
## Postmarketing Experience
- The following adverse drug reactions have been identified from the worldwide post-marketing experience with Pomalidomide: pancytopenia, tumor lysis syndrome.
- 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.
# Drug Interactions
- Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp).
Drugs That May Increase Pomalidomide Plasma Concentrations
- CYP1A2 inhibitors: Pomalidomide exposure is increased when Pomalidomide is co-administered with a strong CYP1A2 inhibitor (fluvoxamine) in the presence of a strong CYP3A4/5 and P-gp inhibitor (ketoconazole). Ketoconazole in the absence of a CYP1A2 inhibitor does not increase pomalidomide exposure. Avoid co-administration of strong CYP1A2 inhibitors (e.g. ciprofloxacin and fluvoxamine). If it is medically necessary to co-administer strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp, Pomalidomide dose should be reduced by 50%.
The effect of a CYP1A2 inhibitor in the absence of a co-administered CYP3A4 and P-gp inhibitor has not been studied. Monitor for toxicities if CYP1A2 inhibitors are to be co-administered in the absence of a co-administered CYP3A4 and P-gp inhibitor, and reduce dose if needed.
Drugs That May Decrease Pomalidomide Plasma Concentrations
- Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.
- CYP1A2 inducers: Co-administration of Pomalidomide with drugs that are CYP1A2 inducers has not been studied and may reduce pomalidomide exposure.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category X
Risk Summary
- Pomalidomide can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. Pomalidomide is a thalidomide analogue.
- Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants.
- Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. 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.
- If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to Pomalidomide to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.
Animal Data
- Pomalidomide was teratogenic in both rats and rabbits in the embryo-fetal developmental studies when administered during the period of organogenesis.
- In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg/kg/day. Malformations or absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central, and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg/day. Other embryo-fetal toxicities included increased resorptions leading to decreased number of viable fetuses.
- In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg/kg/day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg/kg/day. Additional malformations observed at 250 mg/kg/day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs, and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg/kg/day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg/day. Additional embryo-fetal toxicity included increased resorption.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pomalidomide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pomalidomide during labor and delivery.
### Nursing Mothers
- It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from Pomalidomide a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness of Pomalidomide in patients below the age of 18 years have not been established.
### Geriatic Use
- No dosage adjustment is required for Pomalidomide based on age.
- Of the total number of patients in clinical studies of Pomalidomide 41% were aged 65 years and older, while 12% were aged 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients aged greater than or equal to 65 years were more likely to experience pneumonia than patients aged less than or equal to 65 years.
### Gender
Females of Reproductive Potential and Males
- Pomalidomide can cause fetal harm when administered during pregnancy. Females of reproductive potential must avoid pregnancy while taking Pomalidomide and for at least 4 weeks after completing therapy.
Females
- Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously: one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings, or implants), or partner’s vasectomy, and 1 additional effective contraceptive method – male latex or synthetic condom, diaphragm, or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with Pomalidomide during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of Pomalidomide therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed.
- Females of reproductive potential must have 2 negative pregnancy tests before initiating Pomalidomide. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing Pomalidomide Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. Pomalidomide treatment must be discontinued during this evaluation.
Males
- Pomalidomide is present in the semen of males who take Pomalidomide Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking Pomalidomide and for up to 28 days after discontinuing Pomalidomide, even if they have undergone a successful vasectomy. Male patients taking Pomalidomide must not donate sperm.
### Race
There is no FDA guidance on the use of Pomalidomide with respect to specific racial populations.
### Renal Impairment
- Pomalidomide and its metabolites are primarily excreted by the kidneys. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid Pomalidomide in patients with a serum creatinine greater than 3.0 mg/dL.
### Hepatic Impairment
- Pomalidomide is metabolized in the liver. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid Pomalidomide in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pomalidomide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pomalidomide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Pomalidomide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Pomalidomide in the drug label.
# Overdosage
- No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable.
# Pharmacology
## Mechanism of Action
- Pomalidomide, an analogue of thalidomide, is an immunomodulatory agent with antineoplastic activity. In in vitro cellular assays, pomalidomide inhibited proliferation and induced apoptosis of hematopoietic tumor cells. Additionally, pomalidomide inhibited the proliferation of lenalidomide-resistant multiple myeloma cell lines and synergized with dexamethasone in both lenalidomide-sensitive and lenalidomide-resistant cell lines to induce tumor cell apoptosis. Pomalidomide enhanced T cell- and natural killer (NK) cell-mediated immunity and inhibited production of pro-inflammatory cytokines (eg, TNF-α and IL-6) by monocytes. Pomalidomide demonstrated anti-angiogenic activity in a mouse tumor model and in the in vitro umbilical cord model.
## Structure
- Pomalidomide is an immunomodulatory antineoplastic agent. The chemical name is (RS)-4-Amino-2-(2,6-dioxo-piperidin-3-yl)-isoindoline-1,3-dione and it has the following chemical structure:
- The empirical formula for pomalidomide is C13H11N3O4 and the gram molecular weight is 273.24.
- Pomalidomide is a yellow solid powder. It has limited to low solubility into organic solvents and it has low solubility in all pH solutions (about 0.01 mg/mL). Pomalidomide has a chiral carbon atom which exists as a racemic mixture of the R(+) and S(-) enantiomers.
- Pomalidomide is available in 1-mg, 2-mg, 3-mg, and 4-mg capsules for oral administration. Each capsule contains pomalidomide as the active ingredient and the following inactive ingredients: mannitol, pregelatinized starch, and sodium stearyl fumarate. The 1-mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, white ink, and black ink. The 2-mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, FD&C red 3, and white ink. The 3-mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, and white ink. The 4-mg capsule shell contains gelatin, titanium dioxide, FD&C blue 1, FD&C blue 2, and white ink.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Pomalidomide in the drug label.
## Pharmacokinetics
Absorption
- Following administration of single oral doses of Pomalidomide the maximum plasma concentration (Cmax) for pomalidomide occurs at 2 and 3 hours postdose. The systemic exposure (AUC) of pomalidomide increases in an approximately dose proportional manner.
- In patients with multiple myeloma who received Pomalidomide 4 mg daily alone or in combination with dexamethasone, pomalidomide steady-state drug exposure was characterized by AUC(Τ) of 400 ng•h/mL and Cmax of 75 ng/mL. Following multiple doses, pomalidomide has an accumulation ratio of 27% to 31%.
Distribution
- Pomalidomide has a mean apparent volume of distribution (Vd/F) between 62 and 138 L at steady state. Pomalidomide is distributed in semen of healthy subjects at a concentration of approximately 67% of plasma level at 4 hours postdose (~Tmax) after 4 days of once-daily dosing at 2 mg. Human plasma protein binding ranges from 12% to 44% and is not concentration dependent. Pomalidomide is a substrate for P-glycoprotein (P-gp).
Metabolism
- Pomalidomide is primarily metabolized in the liver by CYP1A2 and CYP3A4. In vitro, CYP1A2 and CYP3A4 were identified as the primary enzymes involved in the CYP-mediated hydroxylation of pomalidomide, with additional minor contributions from CYP2C19 and CYP2D6.
Elimination
- Pomalidomide is eliminated with a median plasma half-life of approximately 9.5 hours in healthy subjects and approximately 7.5 hours in patients with multiple myeloma. Pomalidomide has a mean total body clearance (CL/F) of 7-10 L/h.
- Following a single oral administration of [14C]-pomalidomide (2 mg) to healthy subjects, approximately 73% and 15% of the radioactive dose was eliminated in urine and feces, respectively, with approximately 2% and 8% of the radiolabeled dose eliminated unchanged as pomalidomide in urine and feces.
Drug Interactions
Drugs that Inhibit Pomalidomide Metabolism
- CYP1A2 Inhibitors: The effect of CYP1A2 inhibitors, in the absence of a co-administered CYP3A4 and P-gp inhibitor, is unknown. However, co-administration of fluvoxamine (a strong CYP1A2 inhibitor) in the presence of ketoconazole (a strong CYP3A4 and P-gp inhibitor) to 12 healthy male subjects increased exposure (geometric mean AUCINF) to pomalidomide by 146% compared to pomalidomide administered alone.
- Strong CYP3A4 and P-glycoprotein (P-gp) Inhibitors: Co-administration of ketoconazole (a strong CYP3A4 and P-gp inhibitor) in 16 healthy male subjects resulted in an increased exposure (geometric mean AUCINF) to pomalidomide of 19% compared to pomalidomide administered alone.
Drugs that Induce Pomalidomide Metabolism
- Strong CYP1A2 Inducers: Co-administration of Pomalidomide with drugs that are CYP1A2 inducers has not been studied and may reduce pomalidomide exposure.
- Strong CYP3A4 Inducers: Co-administration of carbamazepine to 16 healthy male subjects decreased exposure (geometric mean AUCINF) to pomalidomide by 21% compared to pomalidomide administered alone.
- Dexamethasone: Co-administration of multiple doses of 4 mg Pomalidomide with 20 mg to 40 mg dexamethasone (a weak to moderate inducer of CYP3A4) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone.
- In Vitro Inhibition of Drug Metabolizing Enzymes and Transporters by Pomalidomide
- Pomalidomide does not inhibit or induce CYP450 enzymes or transporters in vitro.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of 12 monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study.
- Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes, and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day.
- In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males in this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females.
# Clinical Studies
Multiple Myeloma
- Trial 1 was a phase 2, multicenter, randomized open-label study in patients with relapsed multiple myeloma who were refractory to their last myeloma therapy and had received lenalidomide and bortezomib. Patients were considered relapsed if they had achieved at least stable disease for at least 1 cycle of treatment to at least 1 prior regimen and then developed progressive disease. Patients were considered refractory if they experienced disease progression on or within 60 days of their last therapy. A total of 221 patients were randomized to receive Pomalidomide alone or Pomalidomide with Low-dose Dex. In Trial 1, the safety and efficacy of Pomalidomide 4 mg, once daily for 21 of 28 days, until disease progression, were evaluated alone and in combination with Low-dose Dex (40 mg/day given only on Days 1, 8, 15, and 22 of each 28-day cycle for patients aged 75 years or younger, or 20 mg/day given only on Days 1, 8, 15, and 22 of each 28-day cycle for patients aged greater than 75 years). Patients in the Pomalidomide alone arm were allowed to add Low-dose Dex upon disease progression.
- Table 5 summarizes the baseline patient and disease characteristics in Trial 1. The baseline demographics and disease characteristics were balanced and comparable between the study arms.
- Table 6 summarizes the analysis results of overall response rate (ORR) and duration of response (DOR), based on assessments by the Independent Review Adjudication Committee for the treatment arms in Study 1. ORR did not differ based on type of prior anti-myeloma therapy.
# How Supplied
- Dark blue opaque cap and yellow opaque body, imprinted “POML” on the cap in white ink and “1 mg” on the body in black ink
1 mg bottles of 21 (NDC 59572-501-21)
1 mg bottles of 100 (NDC 59572-501-00)
- Dark blue opaque cap and orange opaque body, imprinted “POML” on the cap and “2 mg” on the body in white ink
2 mg bottles of 21 (NDC 59572-502-21)
2 mg bottles of 100 (NDC 59572-502-00)
- Dark blue opaque cap and green opaque body, imprinted “POML” on the cap and “3 mg” on the body in white ink
3 mg bottles of 21 (NDC 59572-503-21)
3 mg bottles of 100 (NDC 59572-503-00)
- Dark blue opaque cap and blue opaque body, imprinted “POML” on the cap and “4 mg” on the body in white ink
4 mg bottles of 21 (NDC 59572-504-21)
4 mg bottles of 100 (NDC 59572-504-00)
## Storage
- Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Embryo-Fetal Toxicity
- Advise females of reproductive potential that they must avoid pregnancy while taking Pomalidomide and for at least 4 weeks after completing therapy.
- Initiate Pomalidomide treatment in females of reproductive potential only following a negative pregnancy test.
- Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use 2 different forms of contraception, including at least 1 highly effective form, simultaneously during Pomalidomide therapy, during therapy interruption, and for 4 weeks after she has completely finished taking Pomalidomide Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch, or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm, and cervical cap.
- Instruct patient to immediately stop taking Pomalidomide and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant.
- Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception.
- Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking Pomalidomide and for up to 28 days after discontinuing Pomalidomide, even if they have undergone a successful vasectomy.
Advise male patients taking Pomalidomide that they must not donate sperm.
- All patients must be instructed to not donate blood while taking Pomalidomide and for 1 month following discontinuation of Pomalidomide.
Pomalidomide REMS Program
- Because of the risk of embryo-fetal toxicity, Pomalidomide is only available through a restricted program called Pomalidomide REMS.
- Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive Pomalidomide In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements.
- Pomalidomide is available only from pharmacies that are certified in Pomalidomide REMS. Provide patients with the telephone number and Web site for information on how to obtain the product.
Venous Thromboembolism
- Inform patients of the potential risk of developing venous thromboembolic events and discuss the need for appropriate prophylactic treatment.
Hematologic Toxicities
- Inform patients on the risks of developing neutropenia, thrombocytopenia, and anemia and the need to report signs and symptoms associated with these events to their healthcare provider for further evaluation.
Hypersensitivity
- Inform patients of the potential for a severe hypersensitivity reaction to Pomalidomide if they have had such a reaction in the past to either THALOMID® or REVLIMID®.
Dizziness and Confusional State
- Inform patients of the potential risk of dizziness and confusional state with the drug, to avoid situations where dizziness or confusional state may be a problem, and not to take other medications that may cause dizziness or confusional state without adequate medical advice.
Neuropathy
- Inform patients of the risk of neuropathy and to report the signs and symptoms associated with these events to their healthcare provider for further evaluation .
Second Primary Malignancies
- Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with Pomalidomide is unknown.
Tumor Lysis Syndrome
Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation.
Dosing Instructions
- Inform patients on how to take Pomalidomide
- Pomalidomide should be taken once daily at about the same time each day.
- Pomalidomide should be taken without food (at least 2 hours before or 2 hours after a meal).
- The capsules should not be opened, broken, or chewed. Pomalidomide should be swallowed whole with water.
- Instruct patients that if they miss a dose of Pomalidomide they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take Pomalidomide at the usual time. Warn patients not to take 2 doses to make up for the one that they missed.
Other Information
Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide.
# Precautions with Alcohol
- Alcohol-Pomalidomide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- POMALYST
# Look-Alike Drug Names
- A® — B®[1]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Pomalidomide | |
c45ff5946e74e8b1950c0b3b0d1c38416dc8a3fa | wikidoc | Posaconazole | Posaconazole
- Content
- Posaconazole injection, delayed-release tablets, and oral suspension are indicated for prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy.
- Noxafil injection is indicated in patients 18 years of age and older.
- Noxafil delayed-release tablets and oral suspension are indicated in patients 13 years of age and older.
- Noxafil oral suspension is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole.
- The prescriber should follow the specific dosing instructions for each formulation.
- Noxafil injection should be administered via a central venous line, including a central venous catheter or peripherally inserted central catheter (PICC), by slow intravenous infusion over approximately 90 minutes. If a central venous catheter is not available, Noxafil injection may be administered through a peripheral venous catheter by slow intravenous infusion over 30 minutes only as a single dose in advance of central venous line placement or to bridge the period during which a central venous line is replaced or is in use for other intravenous treatment. When multiple dosing is required, the infusion should be done via a central venous line. Never give Noxafil injection as an intravenous bolus injection.
- The delayed-release tablet and oral suspension are not to be used interchangeably due to the differences in the dosing of each formulation.
- Noxafil delayed-release tablets must be swallowed whole, and not be divided, crushed, or chewed. Noxafil delayed-release tablets should be taken with food.
- Noxafil oral suspension should be administered with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat a full meal.
- Coadministration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.
- Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections when receiving Noxafil delayed-release tablets or oral suspension.
- Equilibrate the refrigerated vial of posaconazole injection to room temperature.
- Aseptically transfer 16.7 mL of posaconazole solution to an intravenous bag (or bottle) containing approximately 150 mL of 5% dextrose in water or sodium chloride 0.9%. Noxafil injection should only be administered with these diluents. Use of other infusion solutions may result in particulate formation.
- Noxafil injection is a single dose sterile solution without preservatives. Once admixed, the product should be used immediately. If not used immediately, the solution can be stored up to 24 hours refrigerated 2-8°C (36-46°F). This medicinal product is for single use only and any unused solution should be discarded.
- Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit. Once admixed, the solution of Noxafil ranges from colorless to yellow. Variations of color within this range do not affect the quality of the product.
- Intravenous Line Compatibility
- A study was conducted to evaluate physical compatibility of Noxafil injection with injectable drug products and commonly used intravenous diluents during simulated Y-site infusion. Compatibility was determined through visual observations, measurement of particulate matter and turbidity.
- Based on the results of the study, the following drug products and diluents can be infused at the same time through the same intravenous line (or cannula) as Noxafil injection. Co-administered drug products should be prepared in 5% dextrose in water or sodium chloride 0.9%. Co-administration of drug products prepared in other infusion solutions may result in particulate formation.
- Any products or diluents not listed in the table above should not be coadministered through the same intravenous line (or cannula).
- Noxafil injection must be administered through a 0.22 micron polyethersulfone (PES) or polyvinylidene difluoride (PVDF) filter.
- Administer via a central venous line, including a central venous catheter or PICC by slow infusion over approximately 90 minutes. Noxafil injection is not for bolus administration.
- If a central venous catheter is not available, Noxafil injection may be administered through a peripheral venous catheter only as a single dose in advance of central venous line placement or to bridge the period during which a central venous line is replaced or is in use for other treatment. When multiple dosing is required, the infusion should be done via a central venous line. When administered through a peripheral venous catheter, the infusion should be administered over approximately 30 minutes. Note: In clinical trials, multiple peripheral infusions given through the same vein resulted in infusion site reactions
- It is recommended that the spoon is rinsed with water after each administration and before storage.
- Noxafil delayed-release tablets:
- Noxafil delayed-release tablets should be taken with food to enhance the oral absorption of posaconazole and optimize plasma concentrations.
- Noxafil delayed-release tablets should be used only for the prophylaxis indication.
- Noxafil delayed-release tablets generally provide higher plasma drug exposures than Noxafil oral suspension under both fed and fasted conditions, and therefore is the preferred oral formulation for the prophylaxis indication.
- Noxafil oral suspension:
- Each dose of Noxafil oral suspension should be administered during or immediately (i.e., within 20 minutes) following a full meal to enhance the oral absorption of posaconazole and optimize plasma concentrations.
- In patients who cannot eat a full meal and for whom Noxafil delayed-release tablets or Noxafil injection are not options, each dose of Noxafil oral suspension should be administered with a liquid nutritional supplement or an acidic carbonated beverage.
- In patients who cannot eat a full meal or tolerate an oral nutritional supplement or an acidic carbonated beverage and who do not have the option of taking Noxafil delayed-release tablets or Noxafil injection, an alternative antifungal therapy should be considered or patients should be monitored closely for breakthrough fungal infections.
- The pharmacokinetics of Noxafil oral suspension are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment.
- Noxafil injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Noxafil injection. In patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <50 mL/min), receiving the Noxafil injection, accumulation of the intravenous vehicle, Betadex Sulfobutyl Ether Sodium (SBECD), is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Noxafil therapy.
- Aspergillosis, Invasive
- Aspergillosis, Invasive, in severely immunocompromised patients; Prophylaxis
- Candidiasis of the esophagus, Recurrent; Prophylaxis - HIV infection
- Candidiasis of the esophagus - HIV infection
- Fusarium infection
- Mycosis
- Necrotizing pulmonary aspergillosis, chronic, (Or cavitary)
- Noxafil is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents.
- Noxafil is contraindicated with sirolimus. Concomitant administration of Noxafil with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity.
- Noxafil is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of Noxafil with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes.
- Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 (e.g., atorvastatin, lovastatin, and simvastatin) is contraindicated since increased plasma concentration of these drugs can lead to rhabdomyolysis.
- Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism.
- Concomitant administration of Noxafil with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors.
- Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly.
- Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, cases of torsades de pointes have been reported in patients taking posaconazole.
- Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. Multiple, time-matched ECGs collected over a 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18-85 years of age) administered posaconazole oral suspension 400 mg BID with a high-fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline was –5 msec following administration of the recommended clinical dose. A decrease in the QTc(F) interval (–3 msec) was also observed in a small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc(F) interval change from baseline was <0 msec (–8 msec). No healthy subject administered posaconazole had a QTc(F) interval ≥500 msec or an increase ≥60 msec in their QTc(F) interval from baseline.
- Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4 . Rigorous attempts to correct potassium, magnesium, and calcium should be made before starting posaconazole.
- Hepatic reactions (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver function tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption. Cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with posaconazole. These severe hepatic reactions were seen primarily in subjects receiving the posaconazole oral suspension 800 mg daily (400 mg BID or 200 mg QID) in clinical trials.
- Liver function tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver function tests during posaconazole therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to posaconazole.
- Due to the variability in exposure with Noxafil delayed-release tablets and oral suspension, patients with severe renal impairment should be monitored closely for breakthrough fungal infections.
- Noxafil injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Noxafil injection. In patients with moderate or severe renal impairment (eGFR <50 mL/min), receiving the Noxafil injection, accumulation of the intravenous vehicle, SBECD, is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Noxafil therapy.
- Concomitant administration of Noxafil with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects.
- The following serious and otherwise important adverse reactions are reported.
- Hypersensitivity
- Arrhythmias and QT Prolongation
- Hepatic Toxicity
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of Noxafil cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials, the type of adverse reactions reported for posaconazole injection and posaconazole delayed-release tablets were generally similar to that reported in trials of posaconazole oral suspension.
- Multiple doses of posaconazole injection administered via a peripheral venous catheter were associated with thrombophlebitis (60% incidence). Therefore, in subsequent studies, posaconazole injection was administered via central venous catheter.
- The safety of posaconazole injection has been assessed in 268 patients in a clinical trial. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole injection when given as antifungal prophylaxis (Posaconazole Injection Study 1).
- Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 55% male, had a mean age of 51 years (range 18-82 years, 19% of patients were ≥65 years of age), and were 95% white and 8% Hispanic. Ten patients received a single dose of 200 mg posaconazole injection, 21 patients received 200 mg daily dose for a median of 14 days, and 237 patients received 300 mg daily dose for a median of 9 days.
- Table 4 presents treatment-emergent adverse reactions observed in patients treated with posaconazole injection 300 mg daily dose in the posaconazole injection study. Each patient received a loading dose, 300 mg twice on Day 1. Following posaconazole intravenous therapy, patients received posaconazole oral suspension to complete 28 days of total posaconazole therapy.
- The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing with 300 mg once daily were diarrhea (32%), hypokalemia (22%), pyrexia (21%), and nausea (19%). These adverse reactions were consistent with those seen in studies with Noxafil oral suspension.
- The safety of posaconazole delayed-release tablets has been assessed in 230 patients in clinical trials. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole delayed-release tablets when given as antifungal prophylaxis (Delayed-Release Tablet Study 1). Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 62% male, had a mean age of 51 years (range 19-78 years, 17% of patients were ≥65 years of age), and were 93% white and 16% Hispanic. Posaconazole therapy was given for a median duration of 28 days. Twenty patients received 200 mg daily dose and 210 patients received 300 mg daily dose (following twice daily dosing on Day 1 in each cohort).
- Table 5 presents treatment-emergent adverse reactions observed in patients treated with 300 mg daily dose at an incidence of ≥10% in posaconazole delayed-release tablet study.
- The most frequently reported adverse reactions (>25%) with posaconazole delayed-release tablets 300 mg once daily were diarrhea, pyrexia, and nausea.
- The most common adverse reaction leading to discontinuation of posaconazole delayed-release tablets 300 mg once daily was nausea (2%).
- The safety of posaconazole oral suspension has been assessed in 1844 patients. This includes 605 patients in the active-controlled prophylaxis studies, 557 patients in the active-controlled OPC studies, 239 patients in refractory OPC studies, and 443 patients from other indications.
- This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy, neutropenia post-chemotherapy, GVHD post HSCT, and HIV infection, as well as non-neutropenic patients. This patient population was 71% male, had a mean age of 42 years (range 8-84 years, 6% of patients were ≥65 years of age and 1% was 10% in posaconazole prophylaxis studies. Table 7 presents treatment-emergent adverse reactions observed at an incidence of at least 10% in the OPC/rOPC studies.
- Prophylaxis of Aspergillus and Candida
- In the 2 randomized, comparative prophylaxis studies (Oral Suspension Studies 1 and 2), the safety of posaconazole oral suspension 200 mg three times a day was compared to fluconazole 400 mg once daily or itraconazole 200 mg twice a day in severely immunocompromised patients.
- The most frequently reported adverse reactions (>30%) in the prophylaxis clinical trials were fever, diarrhea, and nausea.
- The most common adverse reactions leading to discontinuation of posaconazole in the prophylaxis studies were associated with GI disorders, specifically, nausea (2%), vomiting (2%), and hepatic enzymes increased (2%).
- HIV Infected Subjects with OPC: In 2 randomized comparative studies in OPC, the safety of posaconazole oral suspension at a dose of less than or equal to 400 mg QD in 557 HIV-infected patients was compared to the safety of fluconazole in 262 HIV-infected patients at a dose of 100 mg QD.
- An additional 239 HIV-infected patients with refractory OPC received posaconazole oral suspension in 2 non-comparative trials for refractory OPC (rOPC). Of these subjects, 149 received the 800-mg/day dose and the remainder received the less than or equal to 400-mg QD dose.
- In the OPC/rOPC studies, the most common adverse reactions were fever, diarrhea, nausea, headache, vomiting, and coughing.
- The most common adverse reactions that led to treatment discontinuation of posaconazole in the Controlled OPC Pool included respiratory impairment (1%) and pneumonia (1%). In the refractory OPC pool, the most common adverse reactions that led to treatment discontinuation of posaconazole were AIDS (7%) and respiratory impairment (3%).
- Adverse reactions were reported more frequently in the pool of patients with refractory OPC. Among these highly immunocompromised patients with advanced HIV disease, serious adverse reactions (SARs) were reported in 55% (132/239). The most commonly reported SARs were fever (13%) and neutropenia (10%).
- Less Common Adverse Reactions
- Clinically significant adverse reactions reported during clinical trials in prophylaxis, OPC/rOPC or other trials with posaconazole which occurred in less than 5% of patients are listed below:
- Blood and lymphatic system disorders
- Hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, neutropenia aggravated
- Endocrine disorders
- Adrenal insufficiency
- Nervous system disorders
- Paresthesia
- Immune system disorders
- Allergic reaction
- Cardiac disorders
- Torsades de pointes
- Vascular disorders
- Pulmonary embolism
- Liver and Biliary System Disorders
- Bilirubinemia, hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice, AST Increased, ALT Increased
- Metabolic and Nutritional Disorders
- Hypokalemia
Platelet, Bleeding, and Clotting Disorders: thrombocytopenia
Renal & Urinary System Disorders: renal failure acute
Clinical Laboratory Values: In healthy volunteers and patients, elevation of liver function test values did not appear to be associated with higher plasma concentrations of posaconazole.
- For the prophylaxis studies, the number of patients with changes in liver function tests from Common Toxicity Criteria (CTC) Grade 0, 1, or 2 at baseline to Grade 3 or 4 during the study is presented in Table 8.
- Posaconazole is also a strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole.
- The following information was derived from data with posaconazole oral suspension or early tablet formulation. All drug interactions with posaconazole oral suspension, except for those that affect the absorption of posaconazole (via gastric pH and motility) are considered relevant to posaconazole injection as well.
- Sirolimus
- Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity. Therefore, posaconazole is contraindicated with sirolimus.
- Tacrolimus
- Posaconazole has been shown to significantly increase the Cmax and AUC of tacrolimus. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly.
- Cyclosporine
- Posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly.
- Concomitant administration of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes. Therefore, posaconazole is contraindicated with these drugs.
- Concomitant administration of posaconazole with simvastatin increases the simvastatin plasma concentrations by approximately 10-fold. Therefore, posaconazole is contraindicated with HMG-CoA reductase inhibitors primarily metabolized through CYP3A4.
- Most of the ergot alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. Therefore, posaconazole is contraindicated with ergot alkaloids.
- Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant use of posaconazole and other benzodiazepines metabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. Patients must be monitored closely for adverse effects associated with high plasma concentrations of benzodiazepines metabolized by CYP3A4 and benzodiazepine receptor antagonists must be available to reverse these effects.
- Efavirenz
- Efavirenz induces UDP-glucuronidase and significantly decreases posaconazole plasma concentrations. It is recommended to avoid concomitant use of efavirenz with posaconazole unless the benefit outweighs the risks.
- Ritonavir and Atazanavir
- Ritonavir and atazanavir are metabolized by CYP3A4 and posaconazole increases plasma concentrations of these drugs. Frequent monitoring of adverse effects and toxicity of ritonavir and atazanavir should be performed during coadministration with posaconazole.
- Fosamprenavir
- Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended.
- Rifabutin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Rifabutin is also metabolized by CYP3A4. Therefore, coadministration of rifabutin with posaconazole increases rifabutin plasma concentrations. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections as well as frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) are recommended.
- Phenytoin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Phenytoin is also metabolized by CYP3A4. Therefore, coadministration of phenytoin with posaconazole increases phenytoin plasma concentrations. Concomitant use of posaconazole and phenytoin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended and frequent monitoring of phenytoin concentrations should be performed while coadministered with posaconazole and dose reduction of phenytoin should be considered.
- Posaconazole Delayed-Release Tablet
- No clinically relevant effects on the pharmacokinetics of posaconazole were observed when posaconazole delayed-release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors. No dosage adjustment of posaconazole delayed-release tablets is required when posaconazole delayed-release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors.
- Posaconazole Oral Suspension
- Cimetidine (an H2-receptor antagonist) and esomeprazole (a proton pump inhibitor) when given with posaconazole oral suspension results in decreased posaconazole plasma concentrations. It is recommended to avoid concomitant use of cimetidine and esomeprazole with posaconazole oral suspension unless the benefit outweighs the risks. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended.
- No clinically relevant effects were observed when posaconazole oral suspension is concomitantly used with antacids and H2-receptor antagonists other than cimetidine. No dosage adjustment of posaconazole oral suspension is required when posaconazole oral suspension is concomitantly used with antacids and H2-receptor antagonists other than cimetidine.
- Most of the vinca alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma concentrations of vinca alkaloids (e.g., vincristine and vinblastine) which may lead to neurotoxicity. Therefore, it is recommended that dose adjustment of the vinca alkaloid be considered.
- Posaconazole may increase the plasma concentrations of calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, diltiazem, nifedipine, nicardipine, felodipine). Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is recommended during coadministration. Dose reduction of calcium channel blockers may be needed.
- Increased plasma concentrations of digoxin have been reported in patients receiving digoxin and posaconazole. Therefore, monitoring of digoxin plasma concentrations is recommended during coadministration.
- Posaconazole Delayed-Release Tablet
- Concomitant administration of metoclopramide with posaconazole delayed-release tablets did not affect the pharmacokinetics of posaconazole. No dosage adjustment of posaconazole delayed-release tablets is required when given concomitantly with metoclopramide.
- Posaconazole Oral Suspension
- Metoclopramide, when given with posaconazole oral suspension, decreases posaconazole plasma concentrations. If metoclopramide is concomitantly administered with posaconazole oral suspension, it is recommended to closely monitor for breakthrough fungal infections.
- Loperamide does not affect posaconazole plasma concentrations after posaconazole oral suspension administration. No dosage adjustment of posaconazole is required when loperamide and posaconazole are used concomitantly.
- Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when posaconazole and glipizide are concomitantly used.
- Posaconazole has been shown to cause skeletal malformations (cranial malformations and missing ribs) in rats when given in doses ≥27 mg/kg (≥1.4 times the 400-mg BID oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400-mg BID oral suspension regimen. No malformations were seen in rabbits at doses up to 80 mg/kg. In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg, 2.9 or 5.2 times the exposure achieved with the 400-mg BID oral suspension regimen, caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Posaconazole in women who are pregnant.
- The safety and effectiveness of posaconazole oral suspension and posaconazole delayed-release tablets have been established in the age groups 13 to 17 years of age. Use of posaconazole in these age groups is supported by evidence from adequate and well-controlled studies of posaconazole in adults. The safety and effectiveness of posaconazole in pediatric patients below the age of 13 years have not been established.
- A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times a day) of posaconazole oral suspension for prophylaxis of invasive fungal infections. The safety profile in these patients <18 years of age appears similar to the safety profile observed in adults. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state average posaconazole concentration (Cavg) was similar between these patients and adults (≥18 years of age).
- A total of 16 patients 8 to 17 years of age were treated with 800 mg/day (400 mg twice a day or 200 mg four times a day) of posaconazole oral suspension in a study for another indication. Based on pharmacokinetic data in 12 of these pediatric patients, the mean steady-state average posaconazole concentration (Cavg) was similar between these patients and adults (≥18 years of age).
- In the prophylaxis studies, the mean steady-state posaconazole average concentration (Cavg) was similar among ten adolescents (13 to 17 years of age) and adults (≥18 years of age). This is consistent with pharmacokinetic data from another study in which mean steady-state posaconazole Cavg from 12 adolescent patients (8 to 17 years of age) was similar to that in the adults (≥18 years of age).
- Of the 230 patients treated with posaconazole delayed-release tablets, 38 (17%) were greater than 65 years of age. The pharmacokinetics of posaconazole delayed-release tablets are comparable in young and elderly subjects. No overall differences in safety were observed between the geriatric patients and younger patients; therefore, no dosage adjustment is recommended for geriatric patients.
- Of the 605 patients randomized to posaconazole oral suspension in the prophylaxis clinical trials, 63 (10%) were ≥65 years of age. In addition, 48 patients treated with greater than or equal to 800-mg/day posaconazole in another indication were ≥65 years of age. No overall differences in safety were observed between the geriatric patients and younger patients.
- The pharmacokinetics of posaconazole oral suspension are comparable in young and elderly subjects (≥65 years of age); therefore no adjustment in the dosage of Noxafil oral suspension is necessary in geriatric patients.
- No overall differences in the pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out.
- Similar recommendations apply to posaconazole delayed-release tablets; however, a specific study has not been conducted with the delayed-release tablets.
- Noxafil injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Noxafil injection. In patients with moderate or severe renal impairment (eGFR <50 mL/min), receiving the Noxafil injection, accumulation of the intravenous vehicle, SBECD, is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Noxafil therapy.
- Compared to subjects with normal hepatic function, the mean Cmax was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, or severe hepatic impairment, respectively. The mean apparent oral clearance (CL/F) was reduced by 18%, 36%, and 28% in subjects with mild, moderate, or severe hepatic impairment, respectively, compared to subjects with normal hepatic function. The elimination half-life (t½) was 27 hours, 39 hours, 27 hours, and 43 hours in subjects with normal hepatic function and mild, moderate, or severe hepatic impairment, respectively.
- It is recommended that no dose adjustment of Noxafil is needed in patients with mild to severe hepatic impairment (Child-Pugh Class A, B, or C). Similar recommendations apply to posaconazole delayed-release tablets; however, a specific study has not been conducted with the delayed-release tablets.
- Similar recommendations apply to posaconazole injection; however, a specific study has not been conducted with the posaconazole injection.
- Intravenous
- Noxafil increases concentrations of cyclosporine or tacrolimus; reduce dose of cyclosporine and tacrolimus and monitor concentrations frequently
- Elevations in LFTs may occur. Discontinuation should be considered in patients who develop abnormal LFTs or monitor LFTs during treatment.
- Patients who develop abnormal liver function tests during posaconazole therapy should be monitored for the development of more severe hepatic injury.
- Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Noxafil therapy.
- During the clinical trials, some patients received posaconazole oral suspension up to 1600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg BID posaconazole oral suspension for 3 days. No related adverse reactions were noted by the investigator.
- Posaconazole is not removed by hemodialysis.
- Posaconazole is designated chemically as 4-methoxy]phenyl]-1-piperazinyl]phenyl]-2--2,4-dihydro-3H-1,2,4-triazol-3-one with an empirical formula of C37H42F2N8O4 and a molecular weight of 700.8. The chemical structure is:
- Posaconazole is a white powder with a low aqueous solubility.
- Noxafil injection is available as a clear colorless to yellow, sterile liquid essentially free of foreign matter. Each vial contains 300 mg of posaconazole and the following inactive ingredients: 6.68 g Betadex Sulfobutyl Ether Sodium (SBECD), 0.003 g edetate disodium, hydrochloric acid and sodium hydroxide to adjust the pH to 2.6, and water for injection.
- Noxafil delayed-release tablet is a yellow, coated, oblong tablet containing 100 mg of posaconazole. Each delayed-release tablet contains the inactive ingredients: hypromellose acetate succinate, microcrystalline cellulose, hydroxypropylcellulose, silicon dioxide, croscarmellose sodium, magnesium stearate, and Opadry® II Yellow (consists of the following ingredients: polyvinyl alcohol partially hydrolyzed, Macrogol/PEG 3350, titanium dioxide, talc, and iron oxide yellow).
- Noxafil oral suspension is a white, cherry-flavored immediate-release suspension containing 40 mg of posaconazole per mL and the following inactive ingredients: polysorbate 80, simethicone, sodium benzoate, sodium citrate dihydrate, citric acid monohydrate, glycerin, xanthan gum, liquid glucose, titanium dioxide, artificial cherry flavor, and purified water.
- In clinical studies of neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) or hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD), a wide range of plasma exposures to posaconazole was noted following administration of Noxafil oral suspension. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 10). A lower Cavg may be associated with an increased risk of treatment failure, defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections.
- Posaconazole injection exhibits dose proportional pharmacokinetics after single doses between 200 and 300 mg in healthy volunteers and patients. The mean pharmacokinetic parameters after single doses with posaconazole injection in healthy volunteers and patients are shown in Table 11.
- Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with posaconazole 200 mg QD; therefore, no dose adjustments are required for these coadministered drugs when coadministered with posaconazole 200 mg QD.
- Following administration of Noxafil oral suspension, posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is a minor elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug).
- Posaconazole injection is eliminated with a mean terminal half-life (t½) of 27 hours and a total body clearance (CL) of 7.3 L/h.
- Posaconazole delayed-release tablet is eliminated with a mean half-life (t½) ranging between 26 to 31 hours.
- Posaconazole oral suspension is eliminated with a mean half-life (t½) of 35 hours (range: 20-66 hours).
- Mechanism of Action
- Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. This may be responsible for the antifungal activity of posaconazole.
- Activity in vitro
- Posaconazole has in vitro activity against Aspergillus fumigatus and Candida albicans, including Candida albicans isolates from patients refractory to itraconazole or fluconazole or both drugs. However, correlation between the results of susceptibility tests and clinical outcome has not been established. Posaconazole interpretive criteria (breakpoints) have not been established for any fungus.
- Drug Resistance
- Clinical isolates of Candida albicans and Candida glabrata with decreased susceptibility to posaconazole were observed in oral swish samples taken during prophylaxis with posaconazole and fluconazole, suggesting a potential for development of resistance. These isolates also showed reduced susceptibility to other azoles, suggesting cross-resistance between azoles. The clinical significance of this finding is not known.
- No drug-related neoplasms were recorded in rats or mice treated with posaconazole for 2 years at doses higher than the clinical dose. In a 2-year carcinogenicity study, rats were given posaconazole orally at doses up to 20 mg/kg (females), or 30 mg/kg (males). These doses are equivalent to 3.9- or 3.5-times the exposure achieved with a 400-mg BID oral suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered a high-fat meal (400-mg BID oral suspension regimen). In the mouse study, mice were treated at oral doses up to 60 mg/kg/day or 4.8-times the exposure achieved with a 400-mg BID oral suspension regimen.
- Posaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), a chromosome aberration study in human peripheral blood lymphocytes, a Chinese hamster ovary cell mutagenicity study, and a mouse bone marrow micronucleus study.
- Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 × the 400-mg BID oral suspension regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 × the 400-mg BID oral suspension regimen).
- In a nonclinical study using intravenous administration of posaconazole in very young dogs (dosed from 2 to 8 weeks of age), an increase in the incidence of brain ventricle enlargement was observed in treated animals as compared with concurrent control animals. No difference in the incidence of brain ventricle enlargement between control and treated animals was observed following the subsequent 5-month treatment-free period. There were no neurologic, behavioral or developmental abnormalities in the dogs with this finding, and a similar brain finding was not seen with oral posaconazole administration to juvenile dogs (4 days to 9 months of age).
- The clinical significance of this finding is unknown; therefore, the use of posaconazole injection to patients under 18 years of age is not recommended.
- Two randomized, controlled studies were conducted using posaconazole as prophylaxis for the prevention of invasive fungal infections (IFIs) among patients at high risk due to severely compromised immune systems.
- The first study (Oral Suspension Study 1) was a randomized, double-blind trial that compared posaconazole oral suspension (200 mg three times a day) with fluconazole capsules (400 mg once daily) as prophylaxis against invasive fungal infections in allogeneic hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD). Efficacy of prophylaxis was evaluated using a composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (patients may have met more than one of these criteria). This assessed all patients while on study therapy plus 7 days and at 16 weeks post-randomization. The mean duration of therapy was comparable between the 2 treatment groups (80 days, posaconazole; 77 days, fluconazole). Table 22 contains the results from Oral Suspension Study 1.]
- The second study (Oral Suspension Study 2) was a randomized, open-label study that compared posaconazole oral suspension (200 mg 3 times a day) with fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice a day) as prophylaxis against IFIs in neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS. As in Oral Suspension Study 1, efficacy of prophylaxis was evaluated using a composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (Patients might have met more than one of these criteria). This study assessed patients while on treatment plus 7 days and 100 days postrandomization. The mean duration of therapy was comparable between the 2 treatment groups (29 days, posaconazole; 25 days, fluconazole or itraconazole). Table 23 contains the results from Oral Suspension Study 2.
- In summary, 2 clinical studies of prophylaxis were conducted with the posaconazole oral suspension. As seen in the accompanying tables (Tables 22 and 23), clinical failure represented a composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Oral Suspension Study 1 (Table 22), the clinical failure rate of posaconazole (33%) was similar to fluconazole (37%), (95% CI for the difference posaconazole–comparator -11.5% to 3.7%) while in Oral Suspension Study 2 (Table 23) clinical failure was lower for patients treated with posaconazole (27%) when compared to patients treated with fluconazole or itraconazole (42%), (95% CI for the difference posaconazole–comparator -22.9% to -7.8%).
- All-cause mortality was similar at 16 weeks for both treatment arms in Oral Suspension Study 1 ; all-cause mortality was lower at 100 days for posaconazole-treated patients in Oral Suspension Study 2 . Both studies demonstrated substantially fewer breakthrough infections caused by Aspergillus species in patients receiving posaconazole prophylaxis when compared to patients receiving fluconazole or itraconazole.
- Posaconazole Oral Suspension Study 3 was a randomized, controlled, evaluator-blinded study in HIV-infected patients with oropharyngeal candidiasis. Patients were treated with posaconazole or fluconazole oral suspension (both posaconazole and fluconazole were given as follows: 100 mg twice a day for 1 day followed by 100 mg once a day for 13 days).
- Clinical and mycological outcomes were assessed after 14 days of treatment and at 4 weeks after the end of treatment. Patients who received at least 1 dose of study medication and had a positive oral swish culture of Candida species at baseline were included in the analyses (see TABLE 24). The majority of the subjects had C. albicans as the baseline pathogen.
- Clinical success at Day 14 (complete or partial resolution of all ulcers and/or plaques and symptoms) and clinical relapse rates (recurrence of signs or symptoms after initial cure or improvement) 4 weeks after the end of treatment were similar between the treatment arms (see TABLE 24).
- Mycologic eradication rates (absence of colony forming units in quantitative culture at the end of therapy, Day 14), as well as mycologic relapse rates (4 weeks after the end of treatment) were also similar between the treatment arms
- Mycologic response rates, using a criterion for success as a posttreatment quantitative culture with ≤20 colony forming units (CFU/mL) were also similar between the two groups (posaconazole 68.0%, fluconazole 68.1%). The clinical significance of this finding is unknown.
- Posaconazole Oral Suspension Study 4 was a noncomparative study of posaconazole oral suspension in HIV-infected subjects with OPC that was refractory to treatment with fluconazole or itraconazole. An episode of OPC was considered refractory if there was failure to improve or worsening of OPC after a standard course of therapy with fluconazole greater than or equal to 100 mg/day for at least 10 consecutive days or itraconazole 200 mg/day for at least 10 consecutive days and treatment with either fluconazole or itraconazole had not been discontinued for more than 14 days prior to treatment with posaconazole. Of the 199 subjects enrolled in this study, 89 subjects met these strict criteria for refractory infection.
- Forty-five subjects with refractory OPC were treated with posaconazole oral suspension 400 mg BID for 3 days, followed by 400 mg QD for 25 days with an option for further treatment during a 3-month maintenance period. Following a dosing amendment, a further 44 subjects were treated with posaconazole 400 mg BID for 28 days. The efficacy of posaconazole was assessed by the clinical success (cure or improvement) rate after 4 weeks of treatment. The clinical success rate was 74.2% (66/89). The clinical success rates for both the original and the amended dosing regimens were similar (73.3% and 75.0%, respectively).
- Noxafil injection is available in Type I glass vials closed with bromobutyl rubber stopper and aluminum seal (NDC 0085-4331-01) containing 300 mg per 16.7 mL of solution (18 mg of posaconazole per mL). Store refrigerated at 2-8°C (36-46°F).
- Noxafil 100 mg delayed-release tablets; yellow, coated, oblong, debossed with "100" on one side. Bottles with child-resistant closures of 60 delayed-release tablets (NDC 0085-4324-02). Store at 20-25°C (68-77°F), excursions permitted to 15-30°C (59-86°F) .
- Noxafil oral suspension is available in 4-ounce (123 mL) amber glass bottles with child-resistant closures (NDC 0085-1328-01) containing 105 mL of suspension (40 mg of posaconazole per mL).
- Advise patients to take Noxafil delayed-release tablets with food.
- Physicians should instruct their patients that if they miss a dose, they should take it as soon as they remember. If they do not remember until it is within 12 hours of the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose.
- Advise patients to take each dose of Noxafil oral suspension during or immediately (i.e., within 20 minutes) following a full meal. In patients who cannot eat a full meal, each dose of Noxafil oral suspension should be administered with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in order to enhance absorption.
- Patients should be advised to inform their physician immediately if they:
develop severe diarrhea or vomiting.
- Patients are currently taking drugs that are known to prolong the QTc interval and are metabolized through CYP3A4.
- Are currently taking a cyclosporine or tacrolimus, or they notice swelling in an arm or leg or shortness of breath.
- Are taking other drugs or before they begin taking other drugs as certain drugs can decrease or increase the plasma concentrations of posaconazole.
- Patients should be advised to inform their physician immediately if they
- notice a change in heart rate or heart rhythm, or have a heart condition or circulatory disease. Posaconazole can be administered with caution to patients with potentially proarrhythmic conditions.
- are pregnant, plan to become pregnant, or are nursing.
- have liver disease or develop itching, nausea or vomiting, their eyes or skin turn yellow, they feel more tired than usual or feel like they have the flu.
- have ever had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole, or voriconazole.
- ↑ Jump up to: 1.0 1.1 Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA; et al. (2008). "Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America". Clin Infect Dis. 46 (3): 327–60. doi:10.1086/525258. PMID 18177225 PMID: 18177225 Check |pmid= value (help).CS1 maint: Explicit use of et al. (link) 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}
- ↑ Jump up to: 2.0 2.1 Pappas PG, Kauffman CA, Andes D, Benjamin DK, Calandra TF, Edwards JE; et al. (2009). "Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America". Clin Infect Dis. 48 (5): 503–35. doi:10.1086/596757. PMID 19191635 PMID: 19191635 Check |pmid= value (help).CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Raad II, Graybill JR, Bustamante AB, Cornely OA, Gaona-Flores V, Afif C; et al. (2006). "Safety of long-term oral posaconazole use in the treatment of refractory invasive fungal infections". Clin Infect Dis. 42 (12): 1726–34. doi:10.1086/504328. PMID 16705579 PMID: 16705579 Check |pmid= value (help).CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ "NOXAFIL- posaconazole suspension". | Posaconazole
- Content
- Posaconazole injection, delayed-release tablets, and oral suspension are indicated for prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy.
- Noxafil injection is indicated in patients 18 years of age and older.
- Noxafil delayed-release tablets and oral suspension are indicated in patients 13 years of age and older.
- Noxafil oral suspension is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole.
- The prescriber should follow the specific dosing instructions for each formulation.
- Noxafil injection should be administered via a central venous line, including a central venous catheter or peripherally inserted central catheter (PICC), by slow intravenous infusion over approximately 90 minutes. If a central venous catheter is not available, Noxafil injection may be administered through a peripheral venous catheter by slow intravenous infusion over 30 minutes only as a single dose in advance of central venous line placement or to bridge the period during which a central venous line is replaced or is in use for other intravenous treatment. When multiple dosing is required, the infusion should be done via a central venous line. Never give Noxafil injection as an intravenous bolus injection.
- The delayed-release tablet and oral suspension are not to be used interchangeably due to the differences in the dosing of each formulation.
- Noxafil delayed-release tablets must be swallowed whole, and not be divided, crushed, or chewed. Noxafil delayed-release tablets should be taken with food.
- Noxafil oral suspension should be administered with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat a full meal.
- Coadministration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.
- Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections when receiving Noxafil delayed-release tablets or oral suspension.
- Equilibrate the refrigerated vial of posaconazole injection to room temperature.
- Aseptically transfer 16.7 mL of posaconazole solution to an intravenous bag (or bottle) containing approximately 150 mL of 5% dextrose in water or sodium chloride 0.9%. Noxafil injection should only be administered with these diluents. Use of other infusion solutions may result in particulate formation.
- Noxafil injection is a single dose sterile solution without preservatives. Once admixed, the product should be used immediately. If not used immediately, the solution can be stored up to 24 hours refrigerated 2-8°C (36-46°F). This medicinal product is for single use only and any unused solution should be discarded.
- Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit. Once admixed, the solution of Noxafil ranges from colorless to yellow. Variations of color within this range do not affect the quality of the product.
- Intravenous Line Compatibility
- A study was conducted to evaluate physical compatibility of Noxafil injection with injectable drug products and commonly used intravenous diluents during simulated Y-site infusion. Compatibility was determined through visual observations, measurement of particulate matter and turbidity.
- Based on the results of the study, the following drug products and diluents can be infused at the same time through the same intravenous line (or cannula) as Noxafil injection. Co-administered drug products should be prepared in 5% dextrose in water or sodium chloride 0.9%. Co-administration of drug products prepared in other infusion solutions may result in particulate formation.
- Any products or diluents not listed in the table above should not be coadministered through the same intravenous line (or cannula).
- Noxafil injection must be administered through a 0.22 micron polyethersulfone (PES) or polyvinylidene difluoride (PVDF) filter.
- Administer via a central venous line, including a central venous catheter or PICC by slow infusion over approximately 90 minutes. Noxafil injection is not for bolus administration.
- If a central venous catheter is not available, Noxafil injection may be administered through a peripheral venous catheter only as a single dose in advance of central venous line placement or to bridge the period during which a central venous line is replaced or is in use for other treatment. When multiple dosing is required, the infusion should be done via a central venous line. When administered through a peripheral venous catheter, the infusion should be administered over approximately 30 minutes. Note: In clinical trials, multiple peripheral infusions given through the same vein resulted in infusion site reactions
- It is recommended that the spoon is rinsed with water after each administration and before storage.
- Noxafil delayed-release tablets:
- Noxafil delayed-release tablets should be taken with food to enhance the oral absorption of posaconazole and optimize plasma concentrations.
- Noxafil delayed-release tablets should be used only for the prophylaxis indication.
- Noxafil delayed-release tablets generally provide higher plasma drug exposures than Noxafil oral suspension under both fed and fasted conditions, and therefore is the preferred oral formulation for the prophylaxis indication.
- Noxafil oral suspension:
- Each dose of Noxafil oral suspension should be administered during or immediately (i.e., within 20 minutes) following a full meal to enhance the oral absorption of posaconazole and optimize plasma concentrations.
- In patients who cannot eat a full meal and for whom Noxafil delayed-release tablets or Noxafil injection are not options, each dose of Noxafil oral suspension should be administered with a liquid nutritional supplement or an acidic carbonated beverage.
- In patients who cannot eat a full meal or tolerate an oral nutritional supplement or an acidic carbonated beverage and who do not have the option of taking Noxafil delayed-release tablets or Noxafil injection, an alternative antifungal therapy should be considered or patients should be monitored closely for breakthrough fungal infections.
- The pharmacokinetics of Noxafil oral suspension are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment.
- Noxafil injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Noxafil injection. In patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <50 mL/min), receiving the Noxafil injection, accumulation of the intravenous vehicle, Betadex Sulfobutyl Ether Sodium (SBECD), is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Noxafil therapy.
- Aspergillosis, Invasive[1]
- Aspergillosis, Invasive, in severely immunocompromised patients; Prophylaxis
- Candidiasis of the esophagus, Recurrent; Prophylaxis - HIV infection
- Candidiasis of the esophagus - HIV infection
- Fusarium infection[3]
- Mycosis
- Necrotizing pulmonary aspergillosis, chronic, (Or cavitary)[2]
- Noxafil is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents.
- Noxafil is contraindicated with sirolimus. Concomitant administration of Noxafil with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity.
- Noxafil is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of Noxafil with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes.
- Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 (e.g., atorvastatin, lovastatin, and simvastatin) is contraindicated since increased plasma concentration of these drugs can lead to rhabdomyolysis.
- Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism.
- Concomitant administration of Noxafil with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors.
- Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly.
- Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, cases of torsades de pointes have been reported in patients taking posaconazole.
- Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. Multiple, time-matched ECGs collected over a 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18-85 years of age) administered posaconazole oral suspension 400 mg BID with a high-fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline was –5 msec following administration of the recommended clinical dose. A decrease in the QTc(F) interval (–3 msec) was also observed in a small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc(F) interval change from baseline was <0 msec (–8 msec). No healthy subject administered posaconazole had a QTc(F) interval ≥500 msec or an increase ≥60 msec in their QTc(F) interval from baseline.
- Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4 [see CONTRAINDICATIONS (4.3) and DRUG INTERACTIONS (7.2)]. Rigorous attempts to correct potassium, magnesium, and calcium should be made before starting posaconazole.
- Hepatic reactions (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver function tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption. Cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with posaconazole. These severe hepatic reactions were seen primarily in subjects receiving the posaconazole oral suspension 800 mg daily (400 mg BID or 200 mg QID) in clinical trials.
- Liver function tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver function tests during posaconazole therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to posaconazole.
- Due to the variability in exposure with Noxafil delayed-release tablets and oral suspension, patients with severe renal impairment should be monitored closely for breakthrough fungal infections.
- Noxafil injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Noxafil injection. In patients with moderate or severe renal impairment (eGFR <50 mL/min), receiving the Noxafil injection, accumulation of the intravenous vehicle, SBECD, is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Noxafil therapy.
- Concomitant administration of Noxafil with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects.
- The following serious and otherwise important adverse reactions are reported.
- Hypersensitivity
- Arrhythmias and QT Prolongation
- Hepatic Toxicity
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of Noxafil cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials, the type of adverse reactions reported for posaconazole injection and posaconazole delayed-release tablets were generally similar to that reported in trials of posaconazole oral suspension.
- Multiple doses of posaconazole injection administered via a peripheral venous catheter were associated with thrombophlebitis (60% incidence). Therefore, in subsequent studies, posaconazole injection was administered via central venous catheter.
- The safety of posaconazole injection has been assessed in 268 patients in a clinical trial. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole injection when given as antifungal prophylaxis (Posaconazole Injection Study 1).
- Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 55% male, had a mean age of 51 years (range 18-82 years, 19% of patients were ≥65 years of age), and were 95% white and 8% Hispanic. Ten patients received a single dose of 200 mg posaconazole injection, 21 patients received 200 mg daily dose for a median of 14 days, and 237 patients received 300 mg daily dose for a median of 9 days.
- Table 4 presents treatment-emergent adverse reactions observed in patients treated with posaconazole injection 300 mg daily dose in the posaconazole injection study. Each patient received a loading dose, 300 mg twice on Day 1. Following posaconazole intravenous therapy, patients received posaconazole oral suspension to complete 28 days of total posaconazole therapy.
- The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing with 300 mg once daily were diarrhea (32%), hypokalemia (22%), pyrexia (21%), and nausea (19%). These adverse reactions were consistent with those seen in studies with Noxafil oral suspension.
- The safety of posaconazole delayed-release tablets has been assessed in 230 patients in clinical trials. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole delayed-release tablets when given as antifungal prophylaxis (Delayed-Release Tablet Study 1). Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 62% male, had a mean age of 51 years (range 19-78 years, 17% of patients were ≥65 years of age), and were 93% white and 16% Hispanic. Posaconazole therapy was given for a median duration of 28 days. Twenty patients received 200 mg daily dose and 210 patients received 300 mg daily dose (following twice daily dosing on Day 1 in each cohort).
- Table 5 presents treatment-emergent adverse reactions observed in patients treated with 300 mg daily dose at an incidence of ≥10% in posaconazole delayed-release tablet study.
- The most frequently reported adverse reactions (>25%) with posaconazole delayed-release tablets 300 mg once daily were diarrhea, pyrexia, and nausea.
- The most common adverse reaction leading to discontinuation of posaconazole delayed-release tablets 300 mg once daily was nausea (2%).
- The safety of posaconazole oral suspension has been assessed in 1844 patients. This includes 605 patients in the active-controlled prophylaxis studies, 557 patients in the active-controlled OPC studies, 239 patients in refractory OPC studies, and 443 patients from other indications.
- This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy, neutropenia post-chemotherapy, GVHD post HSCT, and HIV infection, as well as non-neutropenic patients. This patient population was 71% male, had a mean age of 42 years (range 8-84 years, 6% of patients were ≥65 years of age and 1% was <18 years of age), and were 64% white, 16% Hispanic, and 36% non-white (including 14% black). Posaconazole therapy was given to 171 patients for ≥6 months, with 58 patients receiving posaconazole therapy for ≥12 months. Table 6 presents treatment-emergent adverse reactions observed at an incidence of >10% in posaconazole prophylaxis studies. Table 7 presents treatment-emergent adverse reactions observed at an incidence of at least 10% in the OPC/rOPC studies.
- Prophylaxis of Aspergillus and Candida
- In the 2 randomized, comparative prophylaxis studies (Oral Suspension Studies 1 and 2), the safety of posaconazole oral suspension 200 mg three times a day was compared to fluconazole 400 mg once daily or itraconazole 200 mg twice a day in severely immunocompromised patients.
- The most frequently reported adverse reactions (>30%) in the prophylaxis clinical trials were fever, diarrhea, and nausea.
- The most common adverse reactions leading to discontinuation of posaconazole in the prophylaxis studies were associated with GI disorders, specifically, nausea (2%), vomiting (2%), and hepatic enzymes increased (2%).
- HIV Infected Subjects with OPC: In 2 randomized comparative studies in OPC, the safety of posaconazole oral suspension at a dose of less than or equal to 400 mg QD in 557 HIV-infected patients was compared to the safety of fluconazole in 262 HIV-infected patients at a dose of 100 mg QD.
- An additional 239 HIV-infected patients with refractory OPC received posaconazole oral suspension in 2 non-comparative trials for refractory OPC (rOPC). Of these subjects, 149 received the 800-mg/day dose and the remainder received the less than or equal to 400-mg QD dose.
- In the OPC/rOPC studies, the most common adverse reactions were fever, diarrhea, nausea, headache, vomiting, and coughing.
- The most common adverse reactions that led to treatment discontinuation of posaconazole in the Controlled OPC Pool included respiratory impairment (1%) and pneumonia (1%). In the refractory OPC pool, the most common adverse reactions that led to treatment discontinuation of posaconazole were AIDS (7%) and respiratory impairment (3%).
- Adverse reactions were reported more frequently in the pool of patients with refractory OPC. Among these highly immunocompromised patients with advanced HIV disease, serious adverse reactions (SARs) were reported in 55% (132/239). The most commonly reported SARs were fever (13%) and neutropenia (10%).
- Less Common Adverse Reactions
- Clinically significant adverse reactions reported during clinical trials in prophylaxis, OPC/rOPC or other trials with posaconazole which occurred in less than 5% of patients are listed below:
- Blood and lymphatic system disorders
- Hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, neutropenia aggravated
- Endocrine disorders
- Adrenal insufficiency
- Nervous system disorders
- Paresthesia
- Immune system disorders
- Allergic reaction
- Cardiac disorders
- Torsades de pointes
- Vascular disorders
- Pulmonary embolism
- Liver and Biliary System Disorders
- Bilirubinemia, hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice, AST Increased, ALT Increased
- Metabolic and Nutritional Disorders
- Hypokalemia
Platelet, Bleeding, and Clotting Disorders: thrombocytopenia
Renal & Urinary System Disorders: renal failure acute
Clinical Laboratory Values: In healthy volunteers and patients, elevation of liver function test values did not appear to be associated with higher plasma concentrations of posaconazole.
- For the prophylaxis studies, the number of patients with changes in liver function tests from Common Toxicity Criteria (CTC) Grade 0, 1, or 2 at baseline to Grade 3 or 4 during the study is presented in Table 8.
- Posaconazole is also a strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole.
- The following information was derived from data with posaconazole oral suspension or early tablet formulation. All drug interactions with posaconazole oral suspension, except for those that affect the absorption of posaconazole (via gastric pH and motility) are considered relevant to posaconazole injection as well.
- Sirolimus
- Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity. Therefore, posaconazole is contraindicated with sirolimus.
- Tacrolimus
- Posaconazole has been shown to significantly increase the Cmax and AUC of tacrolimus. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly.
- Cyclosporine
- Posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly.
- Concomitant administration of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes. Therefore, posaconazole is contraindicated with these drugs.
- Concomitant administration of posaconazole with simvastatin increases the simvastatin plasma concentrations by approximately 10-fold. Therefore, posaconazole is contraindicated with HMG-CoA reductase inhibitors primarily metabolized through CYP3A4.
- Most of the ergot alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. Therefore, posaconazole is contraindicated with ergot alkaloids.
- Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant use of posaconazole and other benzodiazepines metabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. Patients must be monitored closely for adverse effects associated with high plasma concentrations of benzodiazepines metabolized by CYP3A4 and benzodiazepine receptor antagonists must be available to reverse these effects.
- Efavirenz
- Efavirenz induces UDP-glucuronidase and significantly decreases posaconazole plasma concentrations. It is recommended to avoid concomitant use of efavirenz with posaconazole unless the benefit outweighs the risks.
- Ritonavir and Atazanavir
- Ritonavir and atazanavir are metabolized by CYP3A4 and posaconazole increases plasma concentrations of these drugs. Frequent monitoring of adverse effects and toxicity of ritonavir and atazanavir should be performed during coadministration with posaconazole.
- Fosamprenavir
- Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended.
- Rifabutin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Rifabutin is also metabolized by CYP3A4. Therefore, coadministration of rifabutin with posaconazole increases rifabutin plasma concentrations. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections as well as frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) are recommended.
- Phenytoin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Phenytoin is also metabolized by CYP3A4. Therefore, coadministration of phenytoin with posaconazole increases phenytoin plasma concentrations. Concomitant use of posaconazole and phenytoin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended and frequent monitoring of phenytoin concentrations should be performed while coadministered with posaconazole and dose reduction of phenytoin should be considered.
- Posaconazole Delayed-Release Tablet
- No clinically relevant effects on the pharmacokinetics of posaconazole were observed when posaconazole delayed-release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors. No dosage adjustment of posaconazole delayed-release tablets is required when posaconazole delayed-release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors.
- Posaconazole Oral Suspension
- Cimetidine (an H2-receptor antagonist) and esomeprazole (a proton pump inhibitor) when given with posaconazole oral suspension results in decreased posaconazole plasma concentrations. It is recommended to avoid concomitant use of cimetidine and esomeprazole with posaconazole oral suspension unless the benefit outweighs the risks. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended.
- No clinically relevant effects were observed when posaconazole oral suspension is concomitantly used with antacids and H2-receptor antagonists other than cimetidine. No dosage adjustment of posaconazole oral suspension is required when posaconazole oral suspension is concomitantly used with antacids and H2-receptor antagonists other than cimetidine.
- Most of the vinca alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma concentrations of vinca alkaloids (e.g., vincristine and vinblastine) which may lead to neurotoxicity. Therefore, it is recommended that dose adjustment of the vinca alkaloid be considered.
- Posaconazole may increase the plasma concentrations of calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, diltiazem, nifedipine, nicardipine, felodipine). Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is recommended during coadministration. Dose reduction of calcium channel blockers may be needed.
- Increased plasma concentrations of digoxin have been reported in patients receiving digoxin and posaconazole. Therefore, monitoring of digoxin plasma concentrations is recommended during coadministration.
- Posaconazole Delayed-Release Tablet
- Concomitant administration of metoclopramide with posaconazole delayed-release tablets did not affect the pharmacokinetics of posaconazole. No dosage adjustment of posaconazole delayed-release tablets is required when given concomitantly with metoclopramide.
- Posaconazole Oral Suspension
- Metoclopramide, when given with posaconazole oral suspension, decreases posaconazole plasma concentrations. If metoclopramide is concomitantly administered with posaconazole oral suspension, it is recommended to closely monitor for breakthrough fungal infections.
- Loperamide does not affect posaconazole plasma concentrations after posaconazole oral suspension administration. No dosage adjustment of posaconazole is required when loperamide and posaconazole are used concomitantly.
- Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when posaconazole and glipizide are concomitantly used.
- Posaconazole has been shown to cause skeletal malformations (cranial malformations and missing ribs) in rats when given in doses ≥27 mg/kg (≥1.4 times the 400-mg BID oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400-mg BID oral suspension regimen. No malformations were seen in rabbits at doses up to 80 mg/kg. In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg, 2.9 or 5.2 times the exposure achieved with the 400-mg BID oral suspension regimen, caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Posaconazole in women who are pregnant.
- The safety and effectiveness of posaconazole oral suspension and posaconazole delayed-release tablets have been established in the age groups 13 to 17 years of age. Use of posaconazole in these age groups is supported by evidence from adequate and well-controlled studies of posaconazole in adults. The safety and effectiveness of posaconazole in pediatric patients below the age of 13 years have not been established.
- A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times a day) of posaconazole oral suspension for prophylaxis of invasive fungal infections. The safety profile in these patients <18 years of age appears similar to the safety profile observed in adults. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state average posaconazole concentration (Cavg) was similar between these patients and adults (≥18 years of age).
- A total of 16 patients 8 to 17 years of age were treated with 800 mg/day (400 mg twice a day or 200 mg four times a day) of posaconazole oral suspension in a study for another indication. Based on pharmacokinetic data in 12 of these pediatric patients, the mean steady-state average posaconazole concentration (Cavg) was similar between these patients and adults (≥18 years of age).
- In the prophylaxis studies, the mean steady-state posaconazole average concentration (Cavg) was similar among ten adolescents (13 to 17 years of age) and adults (≥18 years of age). This is consistent with pharmacokinetic data from another study in which mean steady-state posaconazole Cavg from 12 adolescent patients (8 to 17 years of age) was similar to that in the adults (≥18 years of age).
- Of the 230 patients treated with posaconazole delayed-release tablets, 38 (17%) were greater than 65 years of age. The pharmacokinetics of posaconazole delayed-release tablets are comparable in young and elderly subjects. No overall differences in safety were observed between the geriatric patients and younger patients; therefore, no dosage adjustment is recommended for geriatric patients.
- Of the 605 patients randomized to posaconazole oral suspension in the prophylaxis clinical trials, 63 (10%) were ≥65 years of age. In addition, 48 patients treated with greater than or equal to 800-mg/day posaconazole in another indication were ≥65 years of age. No overall differences in safety were observed between the geriatric patients and younger patients.
- The pharmacokinetics of posaconazole oral suspension are comparable in young and elderly subjects (≥65 years of age); therefore no adjustment in the dosage of Noxafil oral suspension is necessary in geriatric patients.
- No overall differences in the pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out.
- Similar recommendations apply to posaconazole delayed-release tablets; however, a specific study has not been conducted with the delayed-release tablets.
- Noxafil injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Noxafil injection. In patients with moderate or severe renal impairment (eGFR <50 mL/min), receiving the Noxafil injection, accumulation of the intravenous vehicle, SBECD, is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Noxafil therapy.
- Compared to subjects with normal hepatic function, the mean Cmax was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, or severe hepatic impairment, respectively. The mean apparent oral clearance (CL/F) was reduced by 18%, 36%, and 28% in subjects with mild, moderate, or severe hepatic impairment, respectively, compared to subjects with normal hepatic function. The elimination half-life (t½) was 27 hours, 39 hours, 27 hours, and 43 hours in subjects with normal hepatic function and mild, moderate, or severe hepatic impairment, respectively.
- It is recommended that no dose adjustment of Noxafil is needed in patients with mild to severe hepatic impairment (Child-Pugh Class A, B, or C). Similar recommendations apply to posaconazole delayed-release tablets; however, a specific study has not been conducted with the delayed-release tablets.
- Similar recommendations apply to posaconazole injection; however, a specific study has not been conducted with the posaconazole injection.
- Intravenous
- Noxafil increases concentrations of cyclosporine or tacrolimus; reduce dose of cyclosporine and tacrolimus and monitor concentrations frequently
- Elevations in LFTs may occur. Discontinuation should be considered in patients who develop abnormal LFTs or monitor LFTs during treatment.
- Patients who develop abnormal liver function tests during posaconazole therapy should be monitored for the development of more severe hepatic injury.
- Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Noxafil therapy.
- During the clinical trials, some patients received posaconazole oral suspension up to 1600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg BID posaconazole oral suspension for 3 days. No related adverse reactions were noted by the investigator.
- Posaconazole is not removed by hemodialysis.
- Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3R,5R)-5- (2,4-difluorophenyl)tetrahydro-5- (1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with an empirical formula of C37H42F2N8O4 and a molecular weight of 700.8. The chemical structure is:
- Posaconazole is a white powder with a low aqueous solubility.
- Noxafil injection is available as a clear colorless to yellow, sterile liquid essentially free of foreign matter. Each vial contains 300 mg of posaconazole and the following inactive ingredients: 6.68 g Betadex Sulfobutyl Ether Sodium (SBECD), 0.003 g edetate disodium, hydrochloric acid and sodium hydroxide to adjust the pH to 2.6, and water for injection.
- Noxafil delayed-release tablet is a yellow, coated, oblong tablet containing 100 mg of posaconazole. Each delayed-release tablet contains the inactive ingredients: hypromellose acetate succinate, microcrystalline cellulose, hydroxypropylcellulose, silicon dioxide, croscarmellose sodium, magnesium stearate, and Opadry® II Yellow (consists of the following ingredients: polyvinyl alcohol partially hydrolyzed, Macrogol/PEG 3350, titanium dioxide, talc, and iron oxide yellow).
- Noxafil oral suspension is a white, cherry-flavored immediate-release suspension containing 40 mg of posaconazole per mL and the following inactive ingredients: polysorbate 80, simethicone, sodium benzoate, sodium citrate dihydrate, citric acid monohydrate, glycerin, xanthan gum, liquid glucose, titanium dioxide, artificial cherry flavor, and purified water.
- In clinical studies of neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) or hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD), a wide range of plasma exposures to posaconazole was noted following administration of Noxafil oral suspension. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 10). A lower Cavg may be associated with an increased risk of treatment failure, defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections.
- Posaconazole injection exhibits dose proportional pharmacokinetics after single doses between 200 and 300 mg in healthy volunteers and patients. The mean pharmacokinetic parameters after single doses with posaconazole injection in healthy volunteers and patients are shown in Table 11.
- Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with posaconazole 200 mg QD; therefore, no dose adjustments are required for these coadministered drugs when coadministered with posaconazole 200 mg QD.
- Following administration of Noxafil oral suspension, posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is a minor elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug).
- Posaconazole injection is eliminated with a mean terminal half-life (t½) of 27 hours and a total body clearance (CL) of 7.3 L/h.
- Posaconazole delayed-release tablet is eliminated with a mean half-life (t½) ranging between 26 to 31 hours.
- Posaconazole oral suspension is eliminated with a mean half-life (t½) of 35 hours (range: 20-66 hours).
- Mechanism of Action
- Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. This may be responsible for the antifungal activity of posaconazole.
- Activity in vitro
- Posaconazole has in vitro activity against Aspergillus fumigatus and Candida albicans, including Candida albicans isolates from patients refractory to itraconazole or fluconazole or both drugs. However, correlation between the results of susceptibility tests and clinical outcome has not been established. Posaconazole interpretive criteria (breakpoints) have not been established for any fungus.
- Drug Resistance
- Clinical isolates of Candida albicans and Candida glabrata with decreased susceptibility to posaconazole were observed in oral swish samples taken during prophylaxis with posaconazole and fluconazole, suggesting a potential for development of resistance. These isolates also showed reduced susceptibility to other azoles, suggesting cross-resistance between azoles. The clinical significance of this finding is not known.
- No drug-related neoplasms were recorded in rats or mice treated with posaconazole for 2 years at doses higher than the clinical dose. In a 2-year carcinogenicity study, rats were given posaconazole orally at doses up to 20 mg/kg (females), or 30 mg/kg (males). These doses are equivalent to 3.9- or 3.5-times the exposure achieved with a 400-mg BID oral suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered a high-fat meal (400-mg BID oral suspension regimen). In the mouse study, mice were treated at oral doses up to 60 mg/kg/day or 4.8-times the exposure achieved with a 400-mg BID oral suspension regimen.
- Posaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), a chromosome aberration study in human peripheral blood lymphocytes, a Chinese hamster ovary cell mutagenicity study, and a mouse bone marrow micronucleus study.
- Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 × the 400-mg BID oral suspension regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 × the 400-mg BID oral suspension regimen).
- In a nonclinical study using intravenous administration of posaconazole in very young dogs (dosed from 2 to 8 weeks of age), an increase in the incidence of brain ventricle enlargement was observed in treated animals as compared with concurrent control animals. No difference in the incidence of brain ventricle enlargement between control and treated animals was observed following the subsequent 5-month treatment-free period. There were no neurologic, behavioral or developmental abnormalities in the dogs with this finding, and a similar brain finding was not seen with oral posaconazole administration to juvenile dogs (4 days to 9 months of age).
- The clinical significance of this finding is unknown; therefore, the use of posaconazole injection to patients under 18 years of age is not recommended.
- Two randomized, controlled studies were conducted using posaconazole as prophylaxis for the prevention of invasive fungal infections (IFIs) among patients at high risk due to severely compromised immune systems.
- The first study (Oral Suspension Study 1) was a randomized, double-blind trial that compared posaconazole oral suspension (200 mg three times a day) with fluconazole capsules (400 mg once daily) as prophylaxis against invasive fungal infections in allogeneic hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD). Efficacy of prophylaxis was evaluated using a composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (patients may have met more than one of these criteria). This assessed all patients while on study therapy plus 7 days and at 16 weeks post-randomization. The mean duration of therapy was comparable between the 2 treatment groups (80 days, posaconazole; 77 days, fluconazole). Table 22 contains the results from Oral Suspension Study 1.[File:Posaconazole01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
- The second study (Oral Suspension Study 2) was a randomized, open-label study that compared posaconazole oral suspension (200 mg 3 times a day) with fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice a day) as prophylaxis against IFIs in neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS. As in Oral Suspension Study 1, efficacy of prophylaxis was evaluated using a composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (Patients might have met more than one of these criteria). This study assessed patients while on treatment plus 7 days and 100 days postrandomization. The mean duration of therapy was comparable between the 2 treatment groups (29 days, posaconazole; 25 days, fluconazole or itraconazole). Table 23 contains the results from Oral Suspension Study 2.
- In summary, 2 clinical studies of prophylaxis were conducted with the posaconazole oral suspension. As seen in the accompanying tables (Tables 22 and 23), clinical failure represented a composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Oral Suspension Study 1 (Table 22), the clinical failure rate of posaconazole (33%) was similar to fluconazole (37%), (95% CI for the difference posaconazole–comparator -11.5% to 3.7%) while in Oral Suspension Study 2 (Table 23) clinical failure was lower for patients treated with posaconazole (27%) when compared to patients treated with fluconazole or itraconazole (42%), (95% CI for the difference posaconazole–comparator -22.9% to -7.8%).
- All-cause mortality was similar at 16 weeks for both treatment arms in Oral Suspension Study 1 [POS 58/301 (19%) vs. FLU 59/299 (20%)]; all-cause mortality was lower at 100 days for posaconazole-treated patients in Oral Suspension Study 2 [POS 44/304 (14%) vs. FLU/ITZ 64/298 (21%)]. Both studies demonstrated substantially fewer breakthrough infections caused by Aspergillus species in patients receiving posaconazole prophylaxis when compared to patients receiving fluconazole or itraconazole.
- Posaconazole Oral Suspension Study 3 was a randomized, controlled, evaluator-blinded study in HIV-infected patients with oropharyngeal candidiasis. Patients were treated with posaconazole or fluconazole oral suspension (both posaconazole and fluconazole were given as follows: 100 mg twice a day for 1 day followed by 100 mg once a day for 13 days).
- Clinical and mycological outcomes were assessed after 14 days of treatment and at 4 weeks after the end of treatment. Patients who received at least 1 dose of study medication and had a positive oral swish culture of Candida species at baseline were included in the analyses (see TABLE 24). The majority of the subjects had C. albicans as the baseline pathogen.
- Clinical success at Day 14 (complete or partial resolution of all ulcers and/or plaques and symptoms) and clinical relapse rates (recurrence of signs or symptoms after initial cure or improvement) 4 weeks after the end of treatment were similar between the treatment arms (see TABLE 24).
- Mycologic eradication rates (absence of colony forming units in quantitative culture at the end of therapy, Day 14), as well as mycologic relapse rates (4 weeks after the end of treatment) were also similar between the treatment arms
- Mycologic response rates, using a criterion for success as a posttreatment quantitative culture with ≤20 colony forming units (CFU/mL) were also similar between the two groups (posaconazole 68.0%, fluconazole 68.1%). The clinical significance of this finding is unknown.
- Posaconazole Oral Suspension Study 4 was a noncomparative study of posaconazole oral suspension in HIV-infected subjects with OPC that was refractory to treatment with fluconazole or itraconazole. An episode of OPC was considered refractory if there was failure to improve or worsening of OPC after a standard course of therapy with fluconazole greater than or equal to 100 mg/day for at least 10 consecutive days or itraconazole 200 mg/day for at least 10 consecutive days and treatment with either fluconazole or itraconazole had not been discontinued for more than 14 days prior to treatment with posaconazole. Of the 199 subjects enrolled in this study, 89 subjects met these strict criteria for refractory infection.
- Forty-five subjects with refractory OPC were treated with posaconazole oral suspension 400 mg BID for 3 days, followed by 400 mg QD for 25 days with an option for further treatment during a 3-month maintenance period. Following a dosing amendment, a further 44 subjects were treated with posaconazole 400 mg BID for 28 days. The efficacy of posaconazole was assessed by the clinical success (cure or improvement) rate after 4 weeks of treatment. The clinical success rate was 74.2% (66/89). The clinical success rates for both the original and the amended dosing regimens were similar (73.3% and 75.0%, respectively).
- Noxafil injection is available in Type I glass vials closed with bromobutyl rubber stopper and aluminum seal (NDC 0085-4331-01) containing 300 mg per 16.7 mL of solution (18 mg of posaconazole per mL). Store refrigerated at 2-8°C (36-46°F).
- Noxafil 100 mg delayed-release tablets; yellow, coated, oblong, debossed with "100" on one side. Bottles with child-resistant closures of 60 delayed-release tablets (NDC 0085-4324-02). Store at 20-25°C (68-77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
- Noxafil oral suspension is available in 4-ounce (123 mL) amber glass bottles with child-resistant closures (NDC 0085-1328-01) containing 105 mL of suspension (40 mg of posaconazole per mL).
- Advise patients to take Noxafil delayed-release tablets with food.
- Physicians should instruct their patients that if they miss a dose, they should take it as soon as they remember. If they do not remember until it is within 12 hours of the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose.
- Advise patients to take each dose of Noxafil oral suspension during or immediately (i.e., within 20 minutes) following a full meal. In patients who cannot eat a full meal, each dose of Noxafil oral suspension should be administered with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in order to enhance absorption.
- Patients should be advised to inform their physician immediately if they:
develop severe diarrhea or vomiting.
- Patients are currently taking drugs that are known to prolong the QTc interval and are metabolized through CYP3A4.
- Are currently taking a cyclosporine or tacrolimus, or they notice swelling in an arm or leg or shortness of breath.
- Are taking other drugs or before they begin taking other drugs as certain drugs can decrease or increase the plasma concentrations of posaconazole.
- Patients should be advised to inform their physician immediately if they
- notice a change in heart rate or heart rhythm, or have a heart condition or circulatory disease. Posaconazole can be administered with caution to patients with potentially proarrhythmic conditions.
- are pregnant, plan to become pregnant, or are nursing.
- have liver disease or develop itching, nausea or vomiting, their eyes or skin turn yellow, they feel more tired than usual or feel like they have the flu.
- have ever had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole, or voriconazole.
- ↑ Jump up to: 1.0 1.1 Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA; et al. (2008). "Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America". Clin Infect Dis. 46 (3): 327–60. doi:10.1086/525258. PMID 18177225 PMID: 18177225 Check |pmid= value (help).CS1 maint: Explicit use of et al. (link) 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}
- ↑ Jump up to: 2.0 2.1 Pappas PG, Kauffman CA, Andes D, Benjamin DK, Calandra TF, Edwards JE; et al. (2009). "Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America". Clin Infect Dis. 48 (5): 503–35. doi:10.1086/596757. PMID 19191635 PMID: 19191635 Check |pmid= value (help).CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Raad II, Graybill JR, Bustamante AB, Cornely OA, Gaona-Flores V, Afif C; et al. (2006). "Safety of long-term oral posaconazole use in the treatment of refractory invasive fungal infections". Clin Infect Dis. 42 (12): 1726–34. doi:10.1086/504328. PMID 16705579 PMID: 16705579 Check |pmid= value (help).CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ "NOXAFIL- posaconazole suspension". | https://www.wikidoc.org/index.php/Posaconazole | |
cd041786de86b304b0167dbf493221c8e824d787 | wikidoc | Postprandial | Postprandial
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Postprandial means after eating/ after a meal. This term is often used in the context of blood sugar (or blood glucose) levels, which are normally measured 2 hours after eating. However this is not the only context on which this term is used.
- Postprandial hyperglycemia = high blood sugar which happens after eating
- Postprandial dip = mild decrease in blood sugar after eating a big meal
- Postprandial hypotension: a drastic decline in blood pressure which happens after eating | Postprandial
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Postprandial means after eating/ after a meal.[1] This term is often used in the context of blood sugar (or blood glucose) levels, which are normally measured 2 hours after eating. However this is not the only context on which this term is used.
- Postprandial hyperglycemia = high blood sugar which happens after eating
- Postprandial dip = mild decrease in blood sugar after eating a big meal
- Postprandial hypotension: a drastic decline in blood pressure which happens after eating [2] | https://www.wikidoc.org/index.php/Postprandial | |
d9b7d58dc764589fc3a3308bd6dab834d202a088 | wikidoc | Pound (mass) | Pound (mass)
The pound or pound-mass (abbreviation: lb, or sometimes in the United States: #) is a unit of mass used in the imperial, United States customary and other systems of measurement. A number of different definitions have been used, the most common today being the international avoirdupois pound of exactly 453.59237 grams.
The word pound comes from the Latin word pendere, meaning "to weigh". The Latin word libra means "scales, balances" and it also describes a Roman unit of mass similar to a pound. This is the origin of the abbreviation "lb" for the pound.
# Definitions
Historically, in different parts of the world, at different points in time, and for different applications, the pound (or its translation) has referred to broadly similar but not identical standards of mass or weight.
## English pounds
A number of different definitions of the pound have been used in England. Amongst these are the avoirdupois pound and the obsolete Troy, tower, merchant's and London pounds.
There is a historical link between the pound as a unit of mass and the pound as a unit of currency. Originally the pound sterling was equivalent to the value a Tower pound of silver (worth about £79 or about $158 US today). In 1528, the standard was changed to the Troy pound (worth about £84 or $168 today).
### Avoirdupois pound
The avoirdupois pound was invented by London merchants in 1303. Originally it was based on independent standards measured to be about 7,002 troy grains.
During the reign of Henry VIII of England, the avoirdupois pound was redefined as 7,000 troy grains. Since then, the grain has often been considered as a part of the avoirdupois system.
In the United Kingdom, the avoirdupois pound was defined as a unit of mass by the Weights and Measures Act of 1878, but having a different value (in relation to the kilogram) than it does now, of approximately 0.453592338 kg, which would make the kilogram approximately equal to 2.20462278 pounds. (This was a measured quantity, with the independently maintained artifact still serving as the official standard for this pound.) This old value is sometimes called the imperial pound, and this definition and terminology are obsolete unless referring to the slightly-different 1878 definition.
In the United States, the (avoirdupois) pound as a unit of mass has been officially defined in terms of the kilogram since 1893. In 1893, the relationship was specified to be 2.20462 pounds per kilogram. In 1894, the relationship was specified to be 2.20462234 pounds per kilogram. This change followed a determination of the British pound. The current international pound differs from the United States 1894 pound by approximately one part in 10 million.
In 1958 the United States and countries of the Commonwealth of Nations agreed upon common definitions for the pound and the yard. The international avoirdupois pound was defined as exactly 453.59237 grams.
In the United Kingdom, the use of the international pound was implemented in the Weights and Measures Act 1963.
An avoirdupois pound is equal to 16 avoirdupois ounces and to exactly 7,000 grains. The conversion factor between the kilogram and the international pound was therefore chosen to be divisible by 7, and an (international) grain is thus equal to exactly 64.79891 milligrams.
### Troy pound
The troy pound takes its name from the French market town of Troyes in France where English merchants traded at least as early as the time of Charlemagne (early ninth century). The system of Troy weights was used in England by apothecaries and jewellers.
A troy pound is equal to 12 troy ounces and to 5,760 grains. Today, the grain is common to the avoirdupois and troy systems of units of mass making an international troy pound equal to 373.241721 grams.
The troy pound is no longer in general use. In Canada, Australia, the United Kingdom, and other places the troy pound is no longer a legal unit for trade. In the United Kingdom, the use of the troy pound was abolished on 6 January 1879. The troy ounce is still used for measurements of precious metals such as gold, silver, and platinum, and sometimes gems such as opals.
Most measurements of the mass of precious metals using pounds refer to troy pounds, even though it is not always explicitly stated that this is the case. Some notable exceptions are:
- Encyclopædia Britannica which uses either avoirdupois pounds or troy ounces, likely never both in the same article, and
- the mass of Tutankhamun's sarcophagus lid. This is 110 kilograms. It is often stated to have been 242 or 243 (avoirdupois) pounds but sometimes, much less commonly, it is stated as 296 (troy) pounds.
### Tower pound
The tower pound was based on the wheat grain unlike all the other English measures, where the grain was based on the barley grain.
### Merchants' pound
The merchants' pound (mercantile pound, libra mercantoria or commercial pound) was equal to 9,600 wheat grains (15 tower ounces or 6,750 grains). It was used in England until the 14th century for most goods (other than money, spices and electuaries).
### London pound
A London pound was equal to 7,200 troy grains (16 tower ounces or, equivalently, 15 troy ounces).
### Wool pound
The wool pound was equal to 6,992 grains. It was a unit of mass used to measure the quantity of wool.
## Roman libra
The libra (Latin for "pound") is an ancient Roman unit of mass that was equivalent to approximately 327 grams. It was divided into 12 uncia, or ounces. The libra is the origin of the abbreviation for pound, lb.
## French livre
Since the Middle Ages various pounds have been used in France. The word pound translates to livre in French, a word which continues to be used today to refer to a metric pound.
The livre esterlin was equivalent to about 367.1 (Expression error: Missing operand for *. ) and was used between the late ninth and the mid-fourteenth centuries.
The livre poids de marc or livre de Paris was equivalent to about 489.5 grams (7,555 gr) and was used between the 1350s and the late 18th century.. It was introduced by the government of John II.
The livre métrique was set equal to the kilogram by the decree of 13 Brumaire an IX between 1800 and 1812. This was a form of official metric pound.
The livre usuelle was set equal to 500 grams, by the decree of 28 March 1812. It was abolished as a unit of mass effective 1 January 1840 by a decree of 4 July 1837.
## Russian funt
The Russian pound (Фунт, funt) is an obsolete Russian unit of measurement of mass. It is equal to 409.5124 g.
## Jersey pound
A Jersey pound is an obsolete unit of mass used on the island of Jersey from the 14th century to the 19th century. It was equivalent to about 7,561 grains. It may have been derived from the French livre poids de marc.
## Trone pound
The trone pound is one of a number of obsolete Scottish units of measurement. It was equivalent to between 21 to 28 avoirdupois ounces.
## Metric pounds
In many countries upon the introduction of a metric system, the pound (or its translation) became an informal term for half of a kilogram or 500 grams, often following an official redefinition of an existing unit during the 19th century. The Dutch pond is an exception. It was officially redefined as 1 kilogram, with an ounce of 100 grams. If the pound is used in the Netherlands today it is likely to refer to 500 grams; the former definition is no longer used. However, the 100-gram ounce remains in limited use. In daily life pond is exclusively used for amounts of 500-grams, as is ons for 100 grams.
In German the term is Pfund, in French livre, in Dutch pond, in Spanish and Portuguese libra, and in Italian libbra.
Hundreds of older pounds were replaced in this way. Examples of the older pounds are one of around 459 to 460 grams in Spain, Portugal, and Latin America; one of 498.1 grams in Norway; and several different ones in what is now Germany.
Although the use of the pound as an informal term persists in these countries to a varying degree, scales and measuring devices are denominated only in grams and kilograms. A pound of product must be determined by weighing the product in grams. The use of the term pound is usually forbidden for official use in trade.
# Use in commerce
In the United States of America the United States Department of Commerce, the Technology Administration, and the National Institute of Standards and Technology (NIST) have defined the use of mass and weight in the exchange of goods under the Uniform Laws and Regulations in the areas of legal metrology and engine fuel quality in NIST Handbook 130.
NIST Handbook 130 states:
U.S. federal law, which supersedes this handbook, also defines weight, particularly Net Weight, in terms of the avoirdupois pound or mass pound. From 21CFR101 Part 101.105 - Declaration of net quantity of contents when exempt:
See also 21CFR201 Part 201.51 - "Declaration of net quantity of contents" for general labeling and prescription labeling requirements.
From paragraph "a" above, although the avoirdupois pound is a measure of mass, in commerce it is used with the term "Net Weight", because "there is a firmly established general consumer usage and trade custom of declaring the contents of a liquid by weight, or a solid..." | Pound (mass)
Template:Wiktionarypar
The pound or pound-mass (abbreviation: lb, or sometimes in the United States: #) is a unit of mass used in the imperial, United States customary and other systems of measurement. A number of different definitions have been used, the most common today being the international avoirdupois pound of exactly 453.59237 grams.
The word pound comes from the Latin word pendere, meaning "to weigh".[citation needed] The Latin word libra means "scales, balances" and it also describes a Roman unit of mass similar to a pound.[citation needed] This is the origin of the abbreviation "lb" for the pound.[citation needed]
# Definitions
Historically, in different parts of the world, at different points in time, and for different applications, the pound (or its translation) has referred to broadly similar but not identical standards of mass or weight.
## English pounds
A number of different definitions of the pound have been used in England. Amongst these are the avoirdupois pound and the obsolete Troy, tower, merchant's and London pounds.[1]
There is a historical link between the pound as a unit of mass and the pound as a unit of currency. Originally the pound sterling was equivalent to the value a Tower pound of silver (worth about £79 or about $158 US[2] today). In 1528, the standard was changed to the Troy pound (worth about £84 or $168 today).
Template:English pounds
Template:Seealso
### Avoirdupois pound
The avoirdupois pound was invented by London merchants in 1303. Originally it was based on independent standards measured to be about 7,002 troy grains.
During the reign of Henry VIII of England, the avoirdupois pound was redefined as 7,000 troy grains. Since then, the grain has often been considered as a part of the avoirdupois system.
In the United Kingdom, the avoirdupois pound was defined as a unit of mass by the Weights and Measures Act of 1878, but having a different value (in relation to the kilogram) than it does now, of approximately 0.453592338 kg, which would make the kilogram approximately equal to 2.20462278 pounds. (This was a measured quantity, with the independently maintained artifact still serving as the official standard for this pound.) This old value is sometimes called the imperial pound, and this definition and terminology are obsolete unless referring to the slightly-different 1878 definition.
In the United States, the (avoirdupois) pound as a unit of mass has been officially defined in terms of the kilogram since 1893. In 1893, the relationship was specified to be 2.20462 pounds per kilogram. In 1894, the relationship was specified to be 2.20462234 pounds per kilogram. This change followed a determination of the British pound. The current international pound differs from the United States 1894 pound by approximately one part in 10 million.[3]
In 1958 the United States and countries of the Commonwealth of Nations agreed upon common definitions for the pound and the yard. The international avoirdupois pound was defined as exactly 453.59237 grams.
In the United Kingdom, the use of the international pound was implemented in the Weights and Measures Act 1963.[4]
Template:"
An avoirdupois pound is equal to 16 avoirdupois ounces and to exactly 7,000 grains. The conversion factor between the kilogram and the international pound was therefore chosen to be divisible by 7, and an (international) grain is thus equal to exactly 64.79891 milligrams.
### Troy pound
The troy pound takes its name from the French market town of Troyes in France where English merchants traded at least as early as the time of Charlemagne (early ninth century). The system of Troy weights was used in England by apothecaries and jewellers.
A troy pound is equal to 12 troy ounces and to 5,760 grains. Today, the grain is common to the avoirdupois and troy systems of units of mass making an international troy pound equal to 373.241721 grams.
The troy pound is no longer in general use. In Canada, Australia, the United Kingdom, and other places the troy pound is no longer a legal unit for trade. In the United Kingdom, the use of the troy pound was abolished on 6 January 1879. The troy ounce is still used for measurements of precious metals such as gold, silver, and platinum, and sometimes gems such as opals.
Most measurements of the mass of precious metals using pounds refer to troy pounds, even though it is not always explicitly stated that this is the case. Some notable exceptions are:
- Encyclopædia Britannica which uses either avoirdupois pounds or troy ounces, likely never both in the same article, and
- the mass of Tutankhamun's sarcophagus lid. This is 110 kilograms. It is often stated to have been 242 or 243 (avoirdupois) pounds but sometimes, much less commonly, it is stated as 296 (troy) pounds.
### Tower pound
The tower pound was based on the wheat grain unlike all the other English measures, where the grain was based on the barley grain.
### Merchants' pound
The merchants' pound (mercantile pound, libra mercantoria or commercial pound) was equal to 9,600 wheat grains (15 tower ounces or 6,750 grains). It was used in England until the 14th century for most goods (other than money, spices and electuaries).[5]
### London pound
A London pound was equal to 7,200 troy grains (16 tower ounces or, equivalently, 15 troy ounces).
### Wool pound
The wool pound was equal to 6,992 grains. It was a unit of mass used to measure the quantity of wool.[6]
## Roman libra
The libra (Latin for "pound") is an ancient Roman unit of mass that was equivalent to approximately 327 grams. It was divided into 12 uncia, or ounces. The libra is the origin of the abbreviation for pound, lb.
## French livre
Since the Middle Ages various pounds have been used in France. The word pound translates to livre in French, a word which continues to be used today to refer to a metric pound.
The livre esterlin was equivalent to about 367.1 (Expression error: Missing operand for *. ) and was used between the late ninth and the mid-fourteenth centuries.[7]
The livre poids de marc or livre de Paris was equivalent to about 489.5 grams (7,555 gr) and was used between the 1350s and the late 18th century.[7]. It was introduced by the government of John II.
The livre métrique was set equal to the kilogram by the decree of 13 Brumaire an IX between 1800 and 1812. This was a form of official metric pound.[7]
The livre usuelle was set equal to 500 grams, by the decree of 28 March 1812. It was abolished as a unit of mass effective 1 January 1840 by a decree of 4 July 1837.[7]
Template:Seealso
## Russian funt
The Russian pound (Фунт, funt) is an obsolete Russian unit of measurement of mass. It is equal to 409.5124 g.
## Jersey pound
A Jersey pound is an obsolete unit of mass used on the island of Jersey from the 14th century to the 19th century. It was equivalent to about 7,561 grains. It may have been derived from the French livre poids de marc.[8]
## Trone pound
The trone pound is one of a number of obsolete Scottish units of measurement. It was equivalent to between 21 to 28 avoirdupois ounces.
## Metric pounds
In many countries upon the introduction of a metric system, the pound (or its translation) became an informal term for half of a kilogram or 500 grams, often following an official redefinition of an existing unit during the 19th century. The Dutch pond is an exception. It was officially redefined as 1 kilogram, with an ounce of 100 grams. If the pound is used in the Netherlands today it is likely to refer to 500 grams; the former definition is no longer used. However, the 100-gram ounce remains in limited use. In daily life pond is exclusively used for amounts of 500-grams, as is ons for 100 grams.
In German the term is Pfund, in French livre, in Dutch pond, in Spanish and Portuguese libra, and in Italian libbra.
Hundreds of older pounds were replaced in this way. Examples of the older pounds are one of around 459 to 460 grams in Spain, Portugal, and Latin America; one of 498.1 grams in Norway; and several different ones in what is now Germany.
Although the use of the pound as an informal term persists in these countries to a varying degree, scales and measuring devices are denominated only in grams and kilograms. A pound of product must be determined by weighing the product in grams. The use of the term pound is usually forbidden for official use in trade.
# Use in commerce
In the United States of America the United States Department of Commerce, the Technology Administration, and the National Institute of Standards and Technology (NIST) have defined the use of mass and weight in the exchange of goods under the Uniform Laws and Regulations in the areas of legal metrology and engine fuel quality in NIST Handbook 130.
NIST Handbook 130 states:
U.S. federal law, which supersedes this handbook, also defines weight, particularly Net Weight, in terms of the avoirdupois pound or mass pound. From 21CFR101 Part 101.105 - Declaration of net quantity of contents when exempt:
See also 21CFR201 Part 201.51 - "Declaration of net quantity of contents" for general labeling and prescription labeling requirements.
From paragraph "a" above, although the avoirdupois pound is a measure of mass, in commerce it is used with the term "Net Weight", because "there is a firmly established general consumer usage and trade custom of declaring the contents of a liquid by weight, or a solid..." | https://www.wikidoc.org/index.php/Pound_(mass) | |
d75a2b823061f41945d322174c568ad249f239a2 | wikidoc | Praziquantel | Praziquantel
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# Overview
Praziquantel is an anthelmintic, antiparasitic agent that is FDA approved for the treatment of clonorchiasis, infection by opisthorchis viverrini, schistosomiasis. Common adverse reactions include cardiac dysrhythmia, rash, urticaria, abdominal pain, defecation urgency, diarrhea, hemorrhagic diarrhea, nausea, vomiting, dizziness, headache, acute CNS inflammatory disease, seizure, somnolence, fever, malaise.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended dose for clonorchiasis or opisthorchiasis is 25 milligrams/kilogram/day 3 times a day as a 1-day treatment. The interval between doses should be not less than 4 and not more than 6 hours. The tablets should be taken with meals and washed down with water.
- Dosing Information
- The recommended dose for clonorchiasis or opisthorchiasis is 25 milligrams/kilogram 3 times a day as a 1-day treatment. The interval between doses should be not less than 4 and not more than 6 hours. The tablets should be taken with meals and washed down with water.
- Dosing Information
- The recommended adult dose for Schistosoma hematobium, Schistosoma japonicum, Schistosoma mansoni, and Schistosoma mekongi is praziquantel 20 milligrams/kilogram 3 times a day as a 1-day treatment. The interval between the individual doses should not be less than 4 and not more than 6 hours.
- Praziquantel tablets should be swallowed whole (unchewed) and washed down with water during meals. If the tablets or parts of the tablets are kept in the mouth, a bitter taste (which can promote gagging or vomiting) may be experienced.
- Although single dose therapy is effective, the administration of larger doses has been reported in some studies to be associated with a higher incidence of adverse effects than seen with repeated smaller doses.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Praziquantel in adult patients.
### Non–Guideline-Supported Use
- Infection by Paragonimus
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Clonorchiasis
- Dosing Information
- Safety of praziquantel in children under 4 years of age has not been established.
- The recommended dose for clonorchiasis or opisthorchiasis is 25 milligrams/kilogram 3 times a day as a 1-day treatment. The interval between the individual doses should not be less than 4 hours and not more than 6 hours.
- Praziquantel tablets should be swallowed whole (unchewed) and washed down with water during meals. If the tablets or parts of the tablets are kept in the mouth, a bitter taste (which can promote gagging or vomiting) may be experienced.
- Dosing Information
- Safety of praziquantel in children under 4 years of age has not been established.
- The recommended dose for clonorchiasis or opisthorchiasis is 25 milligrams/kilogram 3 times a day as a 1-day treatment. The interval between the individual doses should not be less than 4 hours and not more than 6 hours.
- Praziquantel tablets should be swallowed whole (unchewed) and washed down with water during meals. If the tablets or parts of the tablets are kept in the mouth, a bitter taste (which can promote gagging or vomiting) may be experienced.
### Schistosomiasis
- Dosing Information
- Safety of praziquantel in children under 4 years of age has not been established.
- The recommended dose for Schistosoma infections in children 4 years of age or older is praziquantel 20 milligrams/kilogram 3 times a day as a 1-day treatment. The interval between the individual doses should not be less than 4 hours and not more than 6 hours.
- Praziquantel tablets should be swallowed whole (unchewed) and washed down with water during meals. If the tablets or parts of the tablets are kept in the mouth, a bitter taste (which can promote gagging or vomiting) may be experienced.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Praziquantel in pediatric patients.
### Non–Guideline-Supported Use
- Hymenolepiasis
# Contraindications
- BILTRICIDE is contraindicated in patients who previously have shown hypersensitivity to the drug or any of the excipients. Since parasite destruction within the eye may cause irreversible lesions, ocular cysticercosis must not be treated with this compound.
- Concomitant administration with strong Cytochrome P450 (P450) inducers, such as rifampin, is contraindicated since therapeutically effective blood levels of praziquantel may not be achieved (see PRECAUTIONS/Drug Interactions). In patients receiving rifampin who need immediate treatment for schistosomiasis, alternative agents for schistosomiasis should be considered. However, if treatment with praziquantel is necessary, rifampin should be discontinued 4 weeks before administration of praziquantel. Treatment with rifampin can then be restarted one day after completion of praziquantel treatment.
# Warnings
- Therapeutically effective levels of BILTRICIDE may not be achieved when administered concomitantly with strong P450 inducers, such as rifampin.
### Precautions
General
- Approximately 80% of a dose of praziquantel is excreted in the kidneys, almost exclusively (>99%) in the form of metabolites. Excretion might be delayed in patients with impaired renal function, but accumulation of unchanged drug would not be expected. Therefore, dose adjustment for renal impairment is not considered necessary. Nephrotoxic effects of praziquantel or its metabolites are not known.
- Caution should be exercised in the administration of the usual recommended dose of praziquantel to hepatosplenic schistosomiasis patients with moderate to severe liver impairment (Child-Pugh class B and C). Reduced metabolism of praziquantel by the liver in these patients may lead to considerably higher and longer lasting plasma concentrations of unmetabolized praziquantel.
- Minimal increases in liver enzymes have been reported in some patients.
- Patients suffering from cardiac irregularities should be monitored during treatment.
- As BILTRICIDE can exacerbate central nervous system pathology due to schistosomiasis, as a general rule this drug should not be administered to individuals reporting a history of epilepsy and/or other signs of potential central nervous systems involvement such as subcutaneous nodules suggestive of cysticercosis.
- When schistosomiasis or fluke infection is found to be associated with cerebral cysticercosis it is advised to hospitalize the patient for the duration of treatment.
# Adverse Reactions
## Clinical Trials Experience
- In general BILTRICIDE is very well tolerated. Side effects are usually mild and transient and do not require treatment. The following side effects were observed generally in order of severity: malaise, headache, dizziness, abdominal discomfort with or without nausea, rise in temperature and, rarely, urticaria. Such symptoms can, however, also result from the infection itself. Such side effects may be more frequent and/or serious in patients with a heavy worm burden.
## Postmarketing Experience
- Additional adverse events reported from worldwide post marketing experience and from publications with praziquantel include: abdominal pain, allergic reaction (generalized hypersensitivity) including polyserositis, anorexia, arrhythmia (including bradycardia, ectopic rhythms, ventricular fibrillation, AV blocks), asthenia, bloody diarrhea, convulsion, eosinophilia, myalgia, pruritis, somnolence, vertigo and vomiting.
# Drug Interactions
- Concomitant administration of rifampin, a strong P450 inducer, with praziquantel is contraindicated and must be avoided (see CONTRAINDICATIONS). In a crossover study with a 2-week washout period, 10 healthy subjects ingested a single 40 mg/kg dose of praziquantel following pre-treatment with oral rifampin (600 mg daily for 5 days). Plasma praziquantel concentrations were undetectable in 7 out of 10 subjects. When a single 40 mg/kg dose of praziquantel was administered to these healthy subjects two weeks after discontinuation of rifampin, the mean praziquantel AUC and Cmax were 23% and 35% lower, respectively, than when praziquantel was given alone. In patients receiving rifampin, for example, as part of a combination regimen for the treatment of tuberculosis, alternative agents for schistosomiasis should be considered. However, if treatment with praziquantel is necessary, treatment with rifampin should be discontinued 4 weeks before administration of praziquantel. Treatment with rifampin can then be restarted one day after completion of praziquantel treatment.
- Concomitant administration of other drugs that increase the activity of drug metabolizing liver enzymes (P450 inducers), for example, antiepileptic drugs (phenytoin, phenobarbital and carbamazepine), and dexamethasone, may also reduce plasma levels of praziquantel. Concomitant administration of drugs that decrease the activity of drug metabolizing liver enzymes (P 450 inhibitors), for example, cimetidine, ketoconazole, itraconazole, erythromycin may increase plasma levels of praziquantel.
- Chloroquine, when taken simultaneously, may lead to lower concentrations of praziquantel in blood. The mechanism of this drug-drug interaction is unclear.
- Grapefruit juice was reported to produce a 1.6-fold increase in the Cmax and a 1.9-fold increase in the AUC of praziquantel. However, the effect of this exposure increase on the therapeutic effect and safety of praziquantel has not been systematically evaluated.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Pregnancy Category B
- Reproduction studies have been performed in rats and rabbits at doses up to 40 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to praziquantel. There are, however, no adequate and well-controlled studies in pregnant women. An increase of the abortion rate was found in rats at three times the single human therapeutic dose. While animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Praziquantel in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Praziquantel during labor and delivery.
### Nursing Mothers
- Praziquantel appeared in the milk of nursing women at a concentration of about 1/4 that of maternal serum although it is not known, whether a pharmacological effect is likely to occur in children. Women should not nurse on the day of BILTRICIDE treatment and during the subsequent 72 hours.
### Pediatric Use
- Safety in children under 4 years of age has not been established.
### Geriatic Use
- Clinical studies of praziquantel did not include a sufficient number of subjects ages 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, but greater sensitivity of some older patients cannot be ruled out.
- This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, the risk of toxic reactions to this drug may be greater in these patients.
### Gender
- There is no FDA guidance on the use of Praziquantel with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Praziquantel with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Praziquantel in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Praziquantel in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Praziquantel in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Praziquantel in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- The dosage recommended for the treatment of schistosomiasis is: 20 mg/kg bodyweight three times a day as a one day treatment, at intervals of not less than 4 hours and not more than 6 hours. The recommended dose for clonorchiasis and opisthorchiasis is: 25 mg/kg bodyweight three times a day as a one day treatment, at intervals of not less than 4 hours and not more than 6 hours. The tablets should be washed down unchewed with water during meals. Keeping the tablets or segments thereof in the mouth can reveal a bitter taste which can promote gagging or vomiting.
### Monitoring
- There is limited information regarding Monitoring of Praziquantel in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Praziquantel in the drug label.
# Overdosage
- In rats and mice the acute LD50 was about 2,500 mg/kg. No data are available in humans. In the event of overdose a fast-acting laxative should be given.
# Pharmacology
## Mechanism of Action
- Praziquantel induces a rapid contraction of schistosomes by a specific effect on the permeability of the cell membrane. The drug further causes vacuolization and disintegration of the schistosome tegument.
## Structure
- BILTRICIDE® (praziquantel) is a trematodicide provided in tablet form for the oral treatment of schistosome infections and infections due to liver fluke.
- BILTRICIDE (praziquantel) is 2-(cyclohexylcarbonyl)-1,2,3,6,7, 11b-hexahydro-4H-pyrazino isoquinolin-4-one with the molecular formula; C19H24N2O2. The structural formula is as follows:
- Praziquantel is a white to nearly white crystalline powder of bitter taste. The compound is stable under normal conditions and melts at 136-140°C with decomposition. The active substance is hygroscopic. Praziquantel is easily soluble in chloroform and dimethylsulfoxide, soluble in ethanol and very slightly soluble in water.
- BILTRICIDE tablets contain 600 mg of praziquantel. Inactive ingredients: corn starch, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, polyethylene glycol, titanium dioxide and hypromellose.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Praziquantel in the drug label.
## Pharmacokinetics
- After oral administration BILTRICIDE is rapidly absorbed (80%), subjected to a first pass effect, metabolized and eliminated by the kidneys. Maximal serum concentration is achieved 1-3 hours after dosing. The half-life of praziquantel in serum is 0.8-1.5 hours.
Special Populations
- The pharmacokinetics of praziquantel were studied in 40 patients with Schistosoma mansoni infections with varying degrees of hepatic dysfunction (See table1). In patients with schistosomiasis, the pharmacokinetic parameters did not differ significantly between those with normal hepatic function (Group 1) and those with mild (Child-Pugh class A) hepatic impairment. However, in patients with moderate-to-severe hepatic dysfunction (Child-Pugh class B and C), praziquantel half-life, Cmax, and AUC increased progressively with the degree of hepatic impairment. In Child-Pugh class B, the increases in mean half-life, Cmax, and AUC relative to Group 1 were 1.58-fold, 1.76-fold, and 3.55-fold, respectively. The corresponding increases in Child-Pugh class C patients were 2.82-fold, 4.29-fold, and 15-fold for half-life, Cmax, and AUC.
## Nonclinical Toxicology
Mutagenesis, Carcinogenesis
- Mutagenic effects in Salmonella tests found by one laboratory have not been confirmed in the same tested strain by other laboratories. Long term carcinogenicity studies in rats and golden hamsters did not reveal any carcinogenic effect.
# Clinical Studies
- There is limited information regarding Clinical Studies of Praziquantel in the drug label.
# How Supplied
- BILTRICIDE is supplied as a 600 mg white to orange tinged, film-coated, oblong tablet with three scores. The tablet is coded with “BAYER” on one side and “LG” on the reverse side. When broken, each of the four segments contains 150 mg of active ingredient so that the dosage can be easily adjusted to the patient’s bodyweight.
- Segments are broken off by pressing the score (notch) with thumbnails. If 1/4 of a tablet is required, this is best achieved by breaking the segment from the outer end.
- BILTRICIDE is available in bottles of 6 tablets.
## Storage
There is limited information regarding Praziquantel Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information for Patients
- Patients should be warned not to drive a car and not to operate machinery on the day of BILTRICIDE treatment and the following day.
# Precautions with Alcohol
- Alcohol-Praziquantel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Biltricide
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Praziquantel
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]
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# Overview
Praziquantel is an anthelmintic, antiparasitic agent that is FDA approved for the treatment of clonorchiasis, infection by opisthorchis viverrini, schistosomiasis. Common adverse reactions include cardiac dysrhythmia, rash, urticaria, abdominal pain, defecation urgency, diarrhea, hemorrhagic diarrhea, nausea, vomiting, dizziness, headache, acute CNS inflammatory disease, seizure, somnolence, fever, malaise.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended dose for clonorchiasis or opisthorchiasis is 25 milligrams/kilogram/day 3 times a day as a 1-day treatment. The interval between doses should be not less than 4 and not more than 6 hours. The tablets should be taken with meals and washed down with water.
- Dosing Information
- The recommended dose for clonorchiasis or opisthorchiasis is 25 milligrams/kilogram 3 times a day as a 1-day treatment. The interval between doses should be not less than 4 and not more than 6 hours. The tablets should be taken with meals and washed down with water.
- Dosing Information
- The recommended adult dose for Schistosoma hematobium, Schistosoma japonicum, Schistosoma mansoni, and Schistosoma mekongi is praziquantel 20 milligrams/kilogram 3 times a day as a 1-day treatment. The interval between the individual doses should not be less than 4 and not more than 6 hours.
- Praziquantel tablets should be swallowed whole (unchewed) and washed down with water during meals. If the tablets or parts of the tablets are kept in the mouth, a bitter taste (which can promote gagging or vomiting) may be experienced.
- Although single dose therapy is effective, the administration of larger doses has been reported in some studies to be associated with a higher incidence of adverse effects than seen with repeated smaller doses.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Praziquantel in adult patients.
### Non–Guideline-Supported Use
- Infection by Paragonimus
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Clonorchiasis
- Dosing Information
- Safety of praziquantel in children under 4 years of age has not been established.
- The recommended dose for clonorchiasis or opisthorchiasis is 25 milligrams/kilogram 3 times a day as a 1-day treatment. The interval between the individual doses should not be less than 4 hours and not more than 6 hours.
- Praziquantel tablets should be swallowed whole (unchewed) and washed down with water during meals. If the tablets or parts of the tablets are kept in the mouth, a bitter taste (which can promote gagging or vomiting) may be experienced.
- Dosing Information
- Safety of praziquantel in children under 4 years of age has not been established.
- The recommended dose for clonorchiasis or opisthorchiasis is 25 milligrams/kilogram 3 times a day as a 1-day treatment. The interval between the individual doses should not be less than 4 hours and not more than 6 hours.
- Praziquantel tablets should be swallowed whole (unchewed) and washed down with water during meals. If the tablets or parts of the tablets are kept in the mouth, a bitter taste (which can promote gagging or vomiting) may be experienced.
### Schistosomiasis
- Dosing Information
- Safety of praziquantel in children under 4 years of age has not been established.
- The recommended dose for Schistosoma infections in children 4 years of age or older is praziquantel 20 milligrams/kilogram 3 times a day as a 1-day treatment. The interval between the individual doses should not be less than 4 hours and not more than 6 hours.
- Praziquantel tablets should be swallowed whole (unchewed) and washed down with water during meals. If the tablets or parts of the tablets are kept in the mouth, a bitter taste (which can promote gagging or vomiting) may be experienced.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Praziquantel in pediatric patients.
### Non–Guideline-Supported Use
- Hymenolepiasis
# Contraindications
- BILTRICIDE is contraindicated in patients who previously have shown hypersensitivity to the drug or any of the excipients. Since parasite destruction within the eye may cause irreversible lesions, ocular cysticercosis must not be treated with this compound.
- Concomitant administration with strong Cytochrome P450 (P450) inducers, such as rifampin, is contraindicated since therapeutically effective blood levels of praziquantel may not be achieved (see PRECAUTIONS/Drug Interactions). In patients receiving rifampin who need immediate treatment for schistosomiasis, alternative agents for schistosomiasis should be considered. However, if treatment with praziquantel is necessary, rifampin should be discontinued 4 weeks before administration of praziquantel. Treatment with rifampin can then be restarted one day after completion of praziquantel treatment.
# Warnings
- Therapeutically effective levels of BILTRICIDE may not be achieved when administered concomitantly with strong P450 inducers, such as rifampin.
### Precautions
General
- Approximately 80% of a dose of praziquantel is excreted in the kidneys, almost exclusively (>99%) in the form of metabolites. Excretion might be delayed in patients with impaired renal function, but accumulation of unchanged drug would not be expected. Therefore, dose adjustment for renal impairment is not considered necessary. Nephrotoxic effects of praziquantel or its metabolites are not known.
- Caution should be exercised in the administration of the usual recommended dose of praziquantel to hepatosplenic schistosomiasis patients with moderate to severe liver impairment (Child-Pugh class B and C). Reduced metabolism of praziquantel by the liver in these patients may lead to considerably higher and longer lasting plasma concentrations of unmetabolized praziquantel.
- Minimal increases in liver enzymes have been reported in some patients.
- Patients suffering from cardiac irregularities should be monitored during treatment.
- As BILTRICIDE can exacerbate central nervous system pathology due to schistosomiasis, as a general rule this drug should not be administered to individuals reporting a history of epilepsy and/or other signs of potential central nervous systems involvement such as subcutaneous nodules suggestive of cysticercosis.
- When schistosomiasis or fluke infection is found to be associated with cerebral cysticercosis it is advised to hospitalize the patient for the duration of treatment.
# Adverse Reactions
## Clinical Trials Experience
- In general BILTRICIDE is very well tolerated. Side effects are usually mild and transient and do not require treatment. The following side effects were observed generally in order of severity: malaise, headache, dizziness, abdominal discomfort with or without nausea, rise in temperature and, rarely, urticaria. Such symptoms can, however, also result from the infection itself. Such side effects may be more frequent and/or serious in patients with a heavy worm burden.
## Postmarketing Experience
- Additional adverse events reported from worldwide post marketing experience and from publications with praziquantel include: abdominal pain, allergic reaction (generalized hypersensitivity) including polyserositis, anorexia, arrhythmia (including bradycardia, ectopic rhythms, ventricular fibrillation, AV blocks), asthenia, bloody diarrhea, convulsion, eosinophilia, myalgia, pruritis, somnolence, vertigo and vomiting.
# Drug Interactions
- Concomitant administration of rifampin, a strong P450 inducer, with praziquantel is contraindicated and must be avoided (see CONTRAINDICATIONS). In a crossover study with a 2-week washout period, 10 healthy subjects ingested a single 40 mg/kg dose of praziquantel following pre-treatment with oral rifampin (600 mg daily for 5 days). Plasma praziquantel concentrations were undetectable in 7 out of 10 subjects. When a single 40 mg/kg dose of praziquantel was administered to these healthy subjects two weeks after discontinuation of rifampin, the mean praziquantel AUC and Cmax were 23% and 35% lower, respectively, than when praziquantel was given alone. In patients receiving rifampin, for example, as part of a combination regimen for the treatment of tuberculosis, alternative agents for schistosomiasis should be considered. However, if treatment with praziquantel is necessary, treatment with rifampin should be discontinued 4 weeks before administration of praziquantel. Treatment with rifampin can then be restarted one day after completion of praziquantel treatment.
- Concomitant administration of other drugs that increase the activity of drug metabolizing liver enzymes (P450 inducers), for example, antiepileptic drugs (phenytoin, phenobarbital and carbamazepine), and dexamethasone, may also reduce plasma levels of praziquantel. Concomitant administration of drugs that decrease the activity of drug metabolizing liver enzymes (P 450 inhibitors), for example, cimetidine, ketoconazole, itraconazole, erythromycin may increase plasma levels of praziquantel.
- Chloroquine, when taken simultaneously, may lead to lower concentrations of praziquantel in blood. The mechanism of this drug-drug interaction is unclear.
- Grapefruit juice was reported to produce a 1.6-fold increase in the Cmax and a 1.9-fold increase in the AUC of praziquantel. However, the effect of this exposure increase on the therapeutic effect and safety of praziquantel has not been systematically evaluated.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Pregnancy Category B
- Reproduction studies have been performed in rats and rabbits at doses up to 40 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to praziquantel. There are, however, no adequate and well-controlled studies in pregnant women. An increase of the abortion rate was found in rats at three times the single human therapeutic dose. While animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Praziquantel in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Praziquantel during labor and delivery.
### Nursing Mothers
- Praziquantel appeared in the milk of nursing women at a concentration of about 1/4 that of maternal serum although it is not known, whether a pharmacological effect is likely to occur in children. Women should not nurse on the day of BILTRICIDE treatment and during the subsequent 72 hours.
### Pediatric Use
- Safety in children under 4 years of age has not been established.
### Geriatic Use
- Clinical studies of praziquantel did not include a sufficient number of subjects ages 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, but greater sensitivity of some older patients cannot be ruled out.
- This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, the risk of toxic reactions to this drug may be greater in these patients.
### Gender
- There is no FDA guidance on the use of Praziquantel with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Praziquantel with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Praziquantel in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Praziquantel in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Praziquantel in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Praziquantel in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- The dosage recommended for the treatment of schistosomiasis is: 20 mg/kg bodyweight three times a day as a one day treatment, at intervals of not less than 4 hours and not more than 6 hours. The recommended dose for clonorchiasis and opisthorchiasis is: 25 mg/kg bodyweight three times a day as a one day treatment, at intervals of not less than 4 hours and not more than 6 hours. The tablets should be washed down unchewed with water during meals. Keeping the tablets or segments thereof in the mouth can reveal a bitter taste which can promote gagging or vomiting.
### Monitoring
- There is limited information regarding Monitoring of Praziquantel in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Praziquantel in the drug label.
# Overdosage
- In rats and mice the acute LD50 was about 2,500 mg/kg. No data are available in humans. In the event of overdose a fast-acting laxative should be given.
# Pharmacology
## Mechanism of Action
- Praziquantel induces a rapid contraction of schistosomes by a specific effect on the permeability of the cell membrane. The drug further causes vacuolization and disintegration of the schistosome tegument.
## Structure
- BILTRICIDE® (praziquantel) is a trematodicide provided in tablet form for the oral treatment of schistosome infections and infections due to liver fluke.
- BILTRICIDE (praziquantel) is 2-(cyclohexylcarbonyl)-1,2,3,6,7, 11b-hexahydro-4H-pyrazino [2, 1-a] isoquinolin-4-one with the molecular formula; C19H24N2O2. The structural formula is as follows:
- Praziquantel is a white to nearly white crystalline powder of bitter taste. The compound is stable under normal conditions and melts at 136-140°C with decomposition. The active substance is hygroscopic. Praziquantel is easily soluble in chloroform and dimethylsulfoxide, soluble in ethanol and very slightly soluble in water.
- BILTRICIDE tablets contain 600 mg of praziquantel. Inactive ingredients: corn starch, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, polyethylene glycol, titanium dioxide and hypromellose.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Praziquantel in the drug label.
## Pharmacokinetics
- After oral administration BILTRICIDE is rapidly absorbed (80%), subjected to a first pass effect, metabolized and eliminated by the kidneys. Maximal serum concentration is achieved 1-3 hours after dosing. The half-life of praziquantel in serum is 0.8-1.5 hours.
Special Populations
- The pharmacokinetics of praziquantel were studied in 40 patients with Schistosoma mansoni infections with varying degrees of hepatic dysfunction (See table1). In patients with schistosomiasis, the pharmacokinetic parameters did not differ significantly between those with normal hepatic function (Group 1) and those with mild (Child-Pugh class A) hepatic impairment. However, in patients with moderate-to-severe hepatic dysfunction (Child-Pugh class B and C), praziquantel half-life, Cmax, and AUC increased progressively with the degree of hepatic impairment. In Child-Pugh class B, the increases in mean half-life, Cmax, and AUC relative to Group 1 were 1.58-fold, 1.76-fold, and 3.55-fold, respectively. The corresponding increases in Child-Pugh class C patients were 2.82-fold, 4.29-fold, and 15-fold for half-life, Cmax, and AUC.
## Nonclinical Toxicology
Mutagenesis, Carcinogenesis
- Mutagenic effects in Salmonella tests found by one laboratory have not been confirmed in the same tested strain by other laboratories. Long term carcinogenicity studies in rats and golden hamsters did not reveal any carcinogenic effect.
# Clinical Studies
- There is limited information regarding Clinical Studies of Praziquantel in the drug label.
# How Supplied
- BILTRICIDE is supplied as a 600 mg white to orange tinged, film-coated, oblong tablet with three scores. The tablet is coded with “BAYER” on one side and “LG” on the reverse side. When broken, each of the four segments contains 150 mg of active ingredient so that the dosage can be easily adjusted to the patient’s bodyweight.
- Segments are broken off by pressing the score (notch) with thumbnails. If 1/4 of a tablet is required, this is best achieved by breaking the segment from the outer end.
- BILTRICIDE is available in bottles of 6 tablets.
## Storage
There is limited information regarding Praziquantel Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information for Patients
- Patients should be warned not to drive a car and not to operate machinery on the day of BILTRICIDE treatment and the following day.
# Precautions with Alcohol
- Alcohol-Praziquantel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Biltricide
# Look-Alike Drug Names
- A® — B®[1]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Praziquantel | |
e1dd38d50fd31d2c302d6c7e469109451fd57d1f | wikidoc | Presbyphagia | Presbyphagia
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# Presbyphagia vs. Dysphagia
Although age-related changes place older adults at risk for dysphagia, an older adult’s swallow is not necessarily an impaired swallow. Presbyphagia refers to characteristic changes in the swallowing mechanism of otherwise healthy older adults. Clinicians are becoming more aware of the need to distinguish among dysphagia, presbyphagia (an old yet healthy swallow) and other related diagnoses in order to avoid over diagnosing and over treating dysphagia. Older adults are more vulnerable and with the increased threat of acute illnesses, medications and any number of age-related conditions, they can cross the line from having a healthy older swallow to being dysphagic.
Work focused primarily on the anatomy and physiology of the oropharyngeal swallowing mechanism indicates a progression of change that may put the older population at increased risk for dysphagia. Such changes combined with naturally diminished functional reserve, the resilient ability to adapt to physiological stress, make the older population more susceptible to dysphagia.
# Age-Associated Changes in Swallowing
## Age-Associated Changes in Oropharyngeal Swallowing
A major characteristic of older healthy swallowing is that it occurs more slowly. The longer duration is found to occur largely before the more automatic pharyngeal phase of the swallow is initiated. In those over age 65, the initiation of laryngeal and pharyngeal events, including laryngeal vestibule closure, are delayed significantly longer than in adults younger than 45 years of age. Although the specific neural underpinning is not confirmed it might be hypothesized that oral events become “uncoupled” from the pharyngeal response, which includes airway protection. Thus, in older healthy adults it is not uncommon for the bolus to be adjacent to an open airway by pooling or pocketing in the pharyngeal recesses, for more time than in younger adults.
Whereas older adults demonstrate a delay in the onset of specific pharyngeal events, such as opening of the upper esophageal sphincter (UES) to permit bolus passage from the pharynx into the esophagus, an equally critical finding is that the range of UES opening is diminished. A scintigraphic study revealed increased pharyngeal residue with age, possibly related to the limited UES opening. Again, these findings indicate exposure of an open airway to material retained in the pharynx, increasing the risk for aspiration in older individuals.
Aspiration (defined as entry of material into the airway thus passing below the vocal folds) and airway penetration (defined as entry of material into the laryngeal vestibule but not below the level of the vocal folds) (Figure 2) are believed to be the most significant adverse clinical outcomes of misdirected bolus flow. In older adults, penetration of the bolus into the airway occurs more often and to a deeper and more severe level than in younger adults. When the swallowing mechanism is functionally altered or perturbed in older people, such as with the placement of a nasogastric tube, airway penetration can be even more pronounced. A study examining this issue found that liquid penetrated the airway significantly more frequently when a nasogastric tube was in place in men and women older than 70 years. That study and additional evidence indicates that under stressful conditions or system perturbations, older individuals are less able to compensate due to the age-related reduction in reserve capacity (add Pendergast reference) and are more at risk to experience airway penetration or aspiration.
## Age-related Change in Lingual Pressure Generation
The tongue is the primary propulsive agent for pumping food through the mouth, into the pharynx while bypassing the airway and through to the esophagus. Recent findings clearly reveal that an age-related change in lingual pressures is another contributing factor to presbyphagia. Healthy older individuals demonstrate significantly reduced isometric (i.e., static) tongue pressures compared with younger counterparts. In contrast, maximal tongue pressures generated during swallowing (i.e., dynamic) remain normal in magnitude. because, fortunately, swallowing is a submaximal pressure-demanding activity. In general, swallowing is considered a submaximal pressure task such that peak tongue pressures used in swallowing are lower than those generated isometrically. Although older individuals manage to achieve pressures necessary to affect a successful swallow, despite a reduction in overall maximum tongue strength, they achieve these pressures more slowly than young swallowers. It has been suggested that the slowness that characterizes senescent swallowing may reflect the increased time necessary to recruit sufficient motor units to generate pressures necessary to operate an effective, safe swallow. | Presbyphagia
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
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# Presbyphagia vs. Dysphagia
Although age-related changes place older adults at risk for dysphagia, an older adult’s swallow is not necessarily an impaired swallow. Presbyphagia refers to characteristic changes in the swallowing mechanism of otherwise healthy older adults.[1] Clinicians are becoming more aware of the need to distinguish among dysphagia, presbyphagia (an old yet healthy swallow) and other related diagnoses in order to avoid over diagnosing and over treating dysphagia. Older adults are more vulnerable and with the increased threat of acute illnesses, medications and any number of age-related conditions, they can cross the line from having a healthy older swallow to being dysphagic.
Work focused primarily on the anatomy and physiology of the oropharyngeal swallowing mechanism indicates a progression of change that may put the older population at increased risk for dysphagia.[1][2][3][4][5][6][7] Such changes combined with naturally diminished functional reserve, the resilient ability to adapt to physiological stress, make the older population more susceptible to dysphagia.
# Age-Associated Changes in Swallowing
## Age-Associated Changes in Oropharyngeal Swallowing
A major characteristic of older healthy swallowing is that it occurs more slowly.[1][2][3][4] The longer duration is found to occur largely before the more automatic pharyngeal phase of the swallow is initiated. In those over age 65, the initiation of laryngeal and pharyngeal events, including laryngeal vestibule closure, are delayed significantly longer than in adults younger than 45 years of age.[2] Although the specific neural underpinning is not confirmed it might be hypothesized that oral events become “uncoupled” from the pharyngeal response, which includes airway protection. Thus, in older healthy adults it is not uncommon for the bolus to be adjacent to an open airway by pooling or pocketing in the pharyngeal recesses, for more time than in younger adults.
Whereas older adults demonstrate a delay in the onset of specific pharyngeal events, such as opening of the upper esophageal sphincter (UES) to permit bolus passage from the pharynx into the esophagus, an equally critical finding is that the range of UES opening is diminished. A scintigraphic study revealed increased pharyngeal residue with age, possibly related to the limited UES opening.[4] Again, these findings indicate exposure of an open airway to material retained in the pharynx, increasing the risk for aspiration in older individuals.
Aspiration (defined as entry of material into the airway [trachea] thus passing below the vocal folds) and airway penetration (defined as entry of material into the laryngeal vestibule but not below the level of the vocal folds) (Figure 2) are believed to be the most significant adverse clinical outcomes of misdirected bolus flow. In older adults, penetration of the bolus into the airway occurs more often and to a deeper and more severe level than in younger adults.[5] When the swallowing mechanism is functionally altered or perturbed in older people, such as with the placement of a nasogastric tube, airway penetration can be even more pronounced. A study examining this issue found that liquid penetrated the airway significantly more frequently when a nasogastric tube was in place in men and women older than 70 years.[1] That study and additional evidence indicates that under stressful conditions or system perturbations, older individuals are less able to compensate due to the age-related reduction in reserve capacity (add Pendergast reference) and are more at risk to experience airway penetration or aspiration.
## Age-related Change in Lingual Pressure Generation
The tongue is the primary propulsive agent for pumping food through the mouth, into the pharynx while bypassing the airway and through to the esophagus. Recent findings clearly reveal that an age-related change in lingual pressures is another contributing factor to presbyphagia. Healthy older individuals demonstrate significantly reduced isometric (i.e., static) tongue pressures compared with younger counterparts. In contrast, maximal tongue pressures generated during swallowing (i.e., dynamic) remain normal in magnitude.[6][7] because, fortunately, swallowing is a submaximal pressure-demanding activity. In general, swallowing is considered a submaximal pressure task such that peak tongue pressures used in swallowing are lower than those generated isometrically. Although older individuals manage to achieve pressures necessary to affect a successful swallow, despite a reduction in overall maximum tongue strength, they achieve these pressures more slowly than young swallowers. It has been suggested that the slowness that characterizes senescent swallowing may reflect the increased time necessary to recruit sufficient motor units to generate pressures necessary to operate an effective, safe swallow. | https://www.wikidoc.org/index.php/Presbyphagia | |
d5c8de0d2cdf46eddb7b1c69785f13c282cdd0cc | wikidoc | Preventorium | Preventorium
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A preventorium was an institution or building for patients infected with tuberculosis who did not yet have an active form of the disease. Popular in the early 20th century, preventoria were designed to isolate these patients from uninfected individuals as well as patients who showed outward symptoms. Philanthropist Nathan Straus opened the first preventorium in Lakewood, New Jersey in 1909. | Preventorium
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A preventorium was an institution or building for patients infected with tuberculosis who did not yet have an active form of the disease. Popular in the early 20th century, preventoria were designed to isolate these patients from uninfected individuals as well as patients who showed outward symptoms. Philanthropist Nathan Straus opened the first preventorium in Lakewood, New Jersey in 1909[2]. | https://www.wikidoc.org/index.php/Preventorium | |
92dec37f141fe972bed98cf7767e4d6b60350188 | wikidoc | Primary FRCA | Primary FRCA
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The Primary FRCA is more fully called the Primary Examination of the Diploma of Fellowship of the Royal College of Anaesthetists.
Trainee anaesthetists in the United Kingdom are required to pass this examination before applying for Higher Specialist Training (a Specialist Registrar post) in Anaesthesia. (In addition to the FRCA, trainees require a minimum of 21 months' Anaesthesia training and 3 months' Intensive Care training before they would be considered for a Specialist Registrar post in Anaesthesia. There may also be additional requirements, at the discretion of each individual Deanery). With the introduction of MMC in August 2007, the Primary FRCA will become a requirement for application to Specialist Training Year 3, known generally as ST3.
The Primary FRCA examination syllabus covers:
- Anatomy
- Physiology
- Clinical Anaesthesia
- Pharmacology
- Physics
- Anaesthetic Equipment
- Clinical Measurement
- Pathology
- Practical Anaesthetic Skills
- Resuscitation
- Statistics
The examination takes the form of a Multiple Choice Question paper and, for candidates successful in this, an Objective Structured Clinical Examination (OSCE) and Viva Voce (oral) examination. Successful Candidates are informed the same day, after the OSCE and Viva exams.
The examination is held three times a year, with the MCQ being held in regional centres around the UK (e.g. London, Manchester, and Glasgow) and the OSCE/Viva being held at Churchill House, the College headquarters in London. Only those candidates who clearly pass the MCQ are invited to participate in the OSCE/Viva. Those who fail the MCQ are deemed to have failed the entire examination.
The examination has the same marking scheme (2+, 2, 1+, 1) as the Final FRCA. | Primary FRCA
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The Primary FRCA is more fully called the Primary Examination of the Diploma of Fellowship of the Royal College of Anaesthetists.
Trainee anaesthetists in the United Kingdom are required to pass this examination before applying for Higher Specialist Training (a Specialist Registrar post) in Anaesthesia. (In addition to the FRCA, trainees require a minimum of 21 months' Anaesthesia training and 3 months' Intensive Care training before they would be considered for a Specialist Registrar post in Anaesthesia. There may also be additional requirements, at the discretion of each individual Deanery). With the introduction of MMC in August 2007, the Primary FRCA will become a requirement for application to Specialist Training Year 3, known generally as ST3.
The Primary FRCA examination syllabus covers:
- Anatomy
- Physiology
- Clinical Anaesthesia
- Pharmacology
- Physics
- Anaesthetic Equipment
- Clinical Measurement
- Pathology
- Practical Anaesthetic Skills
- Resuscitation
- Statistics
The examination takes the form of a Multiple Choice Question paper and, for candidates successful in this, an Objective Structured Clinical Examination (OSCE) and Viva Voce (oral) examination. Successful Candidates are informed the same day, after the OSCE and Viva exams.
The examination is held three times a year, with the MCQ being held in regional centres around the UK (e.g. London, Manchester, and Glasgow) and the OSCE/Viva being held at Churchill House, the College headquarters in London. Only those candidates who clearly pass the MCQ are invited to participate in the OSCE/Viva. Those who fail the MCQ are deemed to have failed the entire examination.
The examination has the same marking scheme (2+, 2, 1+, 1) as the Final FRCA. | https://www.wikidoc.org/index.php/Primary_FRCA | |
86ef0a4eb48c596f950c143dc234871e1aa485d5 | wikidoc | Primary care | Primary care
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Primary care is a term used for the activity of a health care provider who acts as a first point of consultation for all patients. Generally, primary care physicians, nurse practitioners and physician assistants are based in the community, as opposed to the hospital. Alternative names for the field are "general practice" and "family medicine", although the terms are not synonymous.
General practitioners in the United Kingdom are physicians who have completed four to five years of post-medical school training including three to four years based in hospitals and one year attached to a training general practitioner in the community.
Primary care physicians usually include family practice, internal medicine, pediatrics, and at times OB/GYN physicians. It is important to note, however, that the last three of the above specialties are not technically general medicine specialties. These specialties are primary care, but NOT general medicine.
# Continuity of care
The importance of continuity of care has been studied in a systematic review.
Continuity of care is also important for after hospitalizations and emergency department visits (see hospital readmission). Follow-up visits after emergency department visits may also be important.
## Frequency of visits
Physicians vary widely in their setting revisit intervals.
Shorter revisit intervals is associated with better care of hypertension Aand may be associated with better care of diabetes.
# Limitations
## Time
There is insufficient time in primary care to address
- Executing preventive care
- Seeking reimbursement for preventive care
## Financing
Medicare has created G-codes to support billing for the increasing burden of non-face-to-work to help patients. Examples include:
- CPT codes 99358 and 99359 (Prolonged service without direct patient contact)
- CPT codes 99415 and 99416 (Prolonged clinical staff services)
- CPT code 99417 (Prolonged office/outpatient E/M services with or without direct patient contact).
- HCPCS add-on code G2212 (Prolonged office/outpatient E/M services)
Primary care practices underuse these codes.
# Interventions to improve primary care
Interventions to improve primary care via replacement (clinic-based or home-based) or augmentation have been studied.
# Consoliding and integrating small practices to larger systems
Primary card practices are shifting to being part of larger systems. | Primary care
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Primary care is a term used for the activity of a health care provider who acts as a first point of consultation for all patients. Generally, primary care physicians, nurse practitioners and physician assistants are based in the community, as opposed to the hospital. Alternative names for the field are "general practice" and "family medicine", although the terms are not synonymous.
General practitioners in the United Kingdom are physicians who have completed four to five years of post-medical school training including three to four years based in hospitals and one year attached to a training general practitioner in the community.
Primary care physicians usually include family practice, internal medicine, pediatrics, and at times OB/GYN physicians. It is important to note, however, that the last three of the above specialties are not technically general medicine specialties. These specialties are primary care, but NOT general medicine.
# Continuity of care
The importance of continuity of care has been studied in a systematic review[1].
Continuity of care is also important for after hospitalizations and emergency department visits (see hospital readmission). Follow-up visits after emergency department visits may also be important[2].
## Frequency of visits
Physicians vary widely in their setting revisit intervals[3].
Shorter revisit intervals is associated with better care of hypertension[4][5] Aand may be associated with better care of diabetes[6].
# Limitations
## Time
There is insufficient time in primary care to address
- Executing preventive care[7]
- Seeking reimbursement for preventive care[8]
## Financing
Medicare has created G-codes to support billing for the increasing burden of non-face-to-work to help patients. Examples include:
- CPT codes 99358 and 99359 (Prolonged service without direct patient contact)
- CPT codes 99415 and 99416 (Prolonged clinical staff services)
- CPT code 99417 (Prolonged office/outpatient E/M services with or without direct patient contact).
- HCPCS add-on code G2212 (Prolonged office/outpatient E/M services)[9][10]
Primary care practices underuse these codes[8].
# Interventions to improve primary care
Interventions to improve primary care via replacement (clinic-based or home-based) or augmentation have been studied[11].
# Consoliding and integrating small practices to larger systems
Primary card practices are shifting to being part of larger systems[12][13]. | https://www.wikidoc.org/index.php/Primary_care | |
fe46e8e740fca028d23693e2a6a518465490778a | wikidoc | Primary gain | Primary gain
# Background
The reporting of symptoms by a patient may have significant psychological motivators. Psychologists sometimes categorize these motivators into primary or secondary gain.
Primary gain is internally good; motivationally. For example, a patient might feel guilty about being unable to perform some task. If he has a medical condition justifying his inability, he might not feel so bad. Primary gain can be a component of any disease, but is most dramatically demonstrated in Conversion Disorder (a psychiatric disorder in which stressors manifest themselves as physical symptoms without organic causes - such as a person who becomes blindly inactive after seeing a murder). The "gain" may not be particularly evident to an outside observer.
Secondary gain can also be a component of any disease, but is an external motivator. If a patient's disease allows him/her to miss work, gains him/her sympathy, or avoids a jail sentence, these would be examples of secondary gain. These may, but need not be, recognized by the patient. If he/she is deliberately exaggerating symptoms for personal gain, then he/she is malingering. However, secondary gain may simply be an unconscious psychological component of symptoms and other personalities.
A less well studied process is tertiary gain: the extent to which the patient's symptoms may become more pronounced to subconsciously please health care providers.
Source: DSM-IV-TR | Primary gain
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
The reporting of symptoms by a patient may have significant psychological motivators. Psychologists sometimes categorize these motivators into primary or secondary gain.
Primary gain is internally good; motivationally. For example, a patient might feel guilty about being unable to perform some task. If he has a medical condition justifying his inability, he might not feel so bad. Primary gain can be a component of any disease, but is most dramatically demonstrated in Conversion Disorder (a psychiatric disorder in which stressors manifest themselves as physical symptoms without organic causes - such as a person who becomes blindly inactive after seeing a murder). The "gain" may not be particularly evident to an outside observer.
Secondary gain can also be a component of any disease, but is an external motivator. If a patient's disease allows him/her to miss work, gains him/her sympathy, or avoids a jail sentence, these would be examples of secondary gain. These may, but need not be, recognized by the patient. If he/she is deliberately exaggerating symptoms for personal gain, then he/she is malingering. However, secondary gain may simply be an unconscious psychological component of symptoms and other personalities.
A less well studied process is tertiary gain: the extent to which the patient's symptoms may become more pronounced to subconsciously please health care providers.
Source: DSM-IV-TR
Template:Mental-health-stub | https://www.wikidoc.org/index.php/Primary_gain | |
37f32d6e7baaf1ab58a14662a5311e95a03d901e | wikidoc | Trimethoprim | Trimethoprim
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# Overview
Trimethoprim is a folic acid antagonist that is FDA approved for the treatment of uncomplicated urinary tract infection. Common adverse reactions include pruritus and rash.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Uncomplicated urinary tract infectious disease
- Dosage: 100 mg of trimethoprim every 12 hours or 200 mg of trimethoprim every 24 hours, each for 10 days.
- Caused by Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter species, and coagulase-negative Staphylococcus species, including S. saprophyticus.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trimethoprim in adult patients.
### Non–Guideline-Supported Use
- Bacterial infection of eye
- HIV infection - Pneumocystis pneumonia
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Trimethoprim 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 Trimethoprim in pediatric patients.
### Non–Guideline-Supported Use
- Bacterial infection of eye
# Contraindications
Trimethoprim is contraindicated in individuals hypersensitive to trimethoprim and in those with documented megaloblastic anemia due to folate deficiency.
# Warnings
- Serious hypersensitivity reactions have been reported rarely in patients on trimethoprim therapy. Trimethoprim has been reported rarely to interfere with hematopoiesis, especially when administered in large doses and/or for prolonged periods.
- The presence of clinical signs such as sore throat, fever, pallor, or purpura may be early indications of serious blood disorders.
- Complete blood counts should be obtained if any of these signs are noted in a patient receiving trimethoprim and the drug discontinued if a significant reduction in the count of any formed blood element is found.
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including trimethoprim tablets, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antiobiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
# Adverse Reactions
## Clinical Trials Experience
The adverse effects encountered most often with trimethoprim were rash and pruritus.
### Dermatologic
- Rash, pruritus, and phototoxic skin eruptions. At the recommended dosage regimens of 100 mg b.i.d. or 200 mg q.d., each for 10 days, the incidence of rash is 2.9% to 6.7%. In clinical studies which employed high doses of trimethoprim, an elevated incidence of rash was noted. These rashes were maculopapular, morbilliform, pruritic, and generally mild to moderate, appearing 7 to 14 days after the initiation of therapy.
### Hypersensitivity
- Rare reports of exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell Syndrome), and anaphylaxis have been received.
### Gastrointestinal
- Epigastric distress, nausea, vomiting, and glossitis. Elevation of serum transaminase and bilirubin has been noted, but the significance of this finding is unknown. Cholestatic jaundice has been rarely reported.
### Hematologic
- Thrombocytopenia, leukopenia, neutropenia, megaloblastic anemia, and methemoglobinemia.
### Metabolic
- Hyperkalemia, hyponatremia.
### Neurologic
- Aseptic meningitis has been rarely reported.
### Miscellaneous
- Fever, and increases in BUN and serum creatinine levels.
## Postmarketing Experience
There is limited information regarding Trimethoprim Postmarketing Experience in the drug label.
# Drug Interactions
Trimethoprim may inhibit the hepatic metabolism of phenytoin. Trimethoprim, given at a common clinical dosage, increased the phenytoin half-life by 51% and decreased the phenytoin metabolic clearance rate by 30%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Trimethoprim has been shown to be teratogenic in the rat when given in doses 40 times the human dose. In some rabbit studies, the overall increase in fetal loss (dead and resorbed and malformed conceptuses) was associated with doses six times the human therapeutic dose.
While there are no large, well-controlled studies on the use of trimethoprim in pregnant women, Brumfitt and Pursell,3 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or trimethoprim in combination with sulfamethoxazole. The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving trimethoprim and sulfamethoxazole. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester. In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received trimethoprim and sulfamethoxazole at the time of conception or shortly thereafter.
Because trimethoprim may interfere with folic acid metabolism, trimethoprim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
### Nonteratogenic Effects
The oral administration of trimethoprim to rats at a dose of 70 mg/kg/day commencing with the last third of gestation and continuing through parturition and lactation caused no deleterious effects on gestation or pup growth and survival.
Pregnancy Category (AUS): B3
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trimethoprim in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Trimethoprim during labor and delivery.
### Nursing Mothers
Trimethoprim is excreted in human milk. Because trimethoprim may interfere with folic acid metabolism, caution should be exercised when trimethoprim is administered to a nursing woman.
### Pediatric Use
Safety and effectiveness in pediatric patients below the age of 2 months have not been established. The effectiveness of trimethoprim as a single agent has not been established in pediatric patients under 12 years of age.
### Geriatic Use
Clinical studies of trimethoprim tablets 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 response 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.
Case reports of hyperkalemia in elderly patients receiving trimethoprim-sulfamethoxazole have been published.6 Trimethoprim is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor potassium concentrations and to monitor renal function by calculating creatinine clearance.
### Gender
There is no FDA guidance on the use of Trimethoprim with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Trimethoprim with respect to specific racial populations.
### Renal Impairment
The use of trimethoprim in patients with a creatinine clearance of less than 15 mL/min is not recommended. For patients with a creatinine clearance of 15 to 30 mL/min, the dose should be 50 mg every 12 hours.
### Hepatic Impairment
There is no FDA guidance on the use of Trimethoprim in patients with hepatic impairment.
### Females of Reproductive Potential and Males
No adverse effects on fertility or general reproductive performance were observed in rats given trimethoprim in oral dosages as high as 70 mg/kg/day for males and 14 mg/kg/day for females.
### Immunocompromised Patients
There is no FDA guidance one the use of Trimethoprim in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Trimethoprim Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Trimethoprim and IV administrations.
# Overdosage
### Acute
Signs of acute overdosage with trimethoprim may appear following ingestion of 1 gram or more of the drug and include nausea, vomiting, dizziness, headaches, mental depression, confusion, and bone marrow depression.
Treatment consists of gastric lavage and general supportive measures. Acidification of the urine will increase renal elimination of trimethoprim. Peritoneal dialysis is not effective and hemodialysis is only moderately effective in eliminating the drug.
### Chronic
Use of trimethoprim at high doses and/or for extended periods of time may cause bone marrow depression manifested as thrombocytopenia, leukopenia, and/or megaloblastic anemia. If signs of bone marrow depression occur, trimethoprim should be discontinued and the patient should be given leucovorin; 5 to 15 mg leucovorin daily has been recommended by some investigators.
# Pharmacology
## Mechanism of Action
Bacteriostatic lipophilic weak base structurally related to pyrimethamine, binds to and reversibly inhibits the bacterial enzyme dihydrofolate reductase, selectively blocking conversion of dihydrofolic acid to its functional form, tetrahydrofolic acid. This depletes folate, an essential cofactor in the biosynthesis of nucleic acids, resulting in interference with bacterial nucleic acid and protein production.
## Structure
Trimethoprim is 5--2,4-pyrimidinediamine. It is a white to light yellow, odorless, bitter compound with a molecular weight of 290.32 and the molecular formula C14H18N4O3. The structural formula is:
## Pharmacodynamics
There is limited information regarding Trimethoprim Pharmacodynamics in the drug label.
## Pharmacokinetics
Trimethoprim is rapidly absorbed following oral administration. It exists in the blood as unbound, protein-bound, and metabolized forms. Ten to twenty percent of trimethoprim is metabolized, primarily in the liver; the remainder is excreted unchanged in the urine. The principal metabolites of trimethoprim are the 1- and 3-oxides and the 3'- and 4'-hydroxy derivatives. The free form is considered to be the therapeutically active form. Approximately 44% of trimethoprim is bound to plasma proteins.
Mean peak serum concentrations of approximately 1.0 mcg/mL occur 1 to 4 hours after oral administration of a single 100 mg dose. A single 200 mg dose will result in serum levels approximately twice as high. The half-life of trimethoprim ranges from 8 to 10 hours. However, patients with severely impaired renal function exhibit an increase in the half-life of trimethoprim, which requires either dosage regimen adjustment or not using the drug in such patients. During a 13 week study of trimethoprim administered at a daily dosage of 200 mg (50 mg q.i.d.), the mean minimum steady-state concentration of the drug was 1.1 mcg/mL. Steady-state concentrations were achieved within 2 to 3 days of chronic administration and were maintained throughout the experimental period.
Excretion of trimethoprim is primarily by the kidneys through glomerular filtration and tubular secretion. Urine concentrations of trimethoprim are considerably higher than are the concentrations in the blood. After a single oral dose of 100 mg, urine concentrations of trimethoprim ranged from 30 to 160 mcg/mL during the 0 to 4 hour period and declined to approximately 18 to 91 mcg/mL during the 8 to 24 hour period. A 200 mg single oral dose will result in trimethoprim urine levels approximately twice as high. After oral administration, 50% to 60% of trimethoprim is excreted in the urine within 24 hours, approximately 80% of this being unmetabolized trimethoprim.
Since normal vaginal and fecal flora are the source of most pathogens causing urinary tract infections, it is relevant to consider the distribution of trimethoprim into these sites. Concentrations of trimethoprim in vaginal secretions are consistently greater than those found simultaneously in the serum, being typically 1.6 times the concentrations of simultaneously obtained serum samples. Sufficient trimethoprim is excreted in the feces to markedly reduce or eliminate trimethoprim-susceptible organisms from the fecal flora.
Trimethoprim also passes the placental barrier and is excreted in human milk.
## Nonclinical Toxicology
### Carcinogenesis
Long-term studies in animals to evaluate carcinogenic potential have not been conducted with trimethoprim.
### Mutagenesis
Trimethoprim was demonstrated to be nonmutagenic in the Ames assay. In studies at two laboratories, no chromosomal damage was detected in cultured Chinese hamster ovary cells at concentrations approximately 500 times human plasma levels; at concentrations approximately 1000 times human plasma levels in these same cells, a low level of chromosomal damage was induced at one of the laboratories. No chromosomal abnormalities were observed in cultured human leukocytes at concentrations of trimethoprim up to 20 times human steady-state plasma levels. No chromosomal effects were detected in peripheral lymphocytes of human subjects receiving 320 mg of trimethoprim in combination with up to 1600 mg of sulfamethoxazole per day for as long as 112 weeks.
# Clinical Studies
There is limited information regarding Trimethoprim Clinical Studies in the drug label.
# How Supplied
- Trimethoprim tablets 100 mg in bottles of 100.
- Trimethoprim tablets 200 mg in bottles of 100.
## Storage
Store at 20° to 25°C (68° to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be counseled that antibacterial drugs including trimethoprim tablets, USP should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When trimethoprim tablets, USP are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by trimethoprim tablets, USP or other antibacterial drugs in the future.
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with and without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
# Precautions with Alcohol
Alcohol-Trimethoprim interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Proloprim
- Trimpex
# Look-Alike Drug Names
There is limited information regarding Trimethoprim Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Trimethoprim
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Trimethoprim is a folic acid antagonist that is FDA approved for the treatment of uncomplicated urinary tract infection. Common adverse reactions include pruritus and rash.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Uncomplicated urinary tract infectious disease
- Dosage: 100 mg of trimethoprim every 12 hours or 200 mg of trimethoprim every 24 hours, each for 10 days.
- Caused by Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter species, and coagulase-negative Staphylococcus species, including S. saprophyticus.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trimethoprim in adult patients.
### Non–Guideline-Supported Use
- Bacterial infection of eye
- HIV infection - Pneumocystis pneumonia
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Trimethoprim 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 Trimethoprim in pediatric patients.
### Non–Guideline-Supported Use
- Bacterial infection of eye
# Contraindications
Trimethoprim is contraindicated in individuals hypersensitive to trimethoprim and in those with documented megaloblastic anemia due to folate deficiency.
# Warnings
- Serious hypersensitivity reactions have been reported rarely in patients on trimethoprim therapy. Trimethoprim has been reported rarely to interfere with hematopoiesis, especially when administered in large doses and/or for prolonged periods.
- The presence of clinical signs such as sore throat, fever, pallor, or purpura may be early indications of serious blood disorders.
- Complete blood counts should be obtained if any of these signs are noted in a patient receiving trimethoprim and the drug discontinued if a significant reduction in the count of any formed blood element is found.
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including trimethoprim tablets, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antiobiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
# Adverse Reactions
## Clinical Trials Experience
The adverse effects encountered most often with trimethoprim were rash and pruritus.
### Dermatologic
- Rash, pruritus, and phototoxic skin eruptions. At the recommended dosage regimens of 100 mg b.i.d. or 200 mg q.d., each for 10 days, the incidence of rash is 2.9% to 6.7%. In clinical studies which employed high doses of trimethoprim, an elevated incidence of rash was noted. These rashes were maculopapular, morbilliform, pruritic, and generally mild to moderate, appearing 7 to 14 days after the initiation of therapy.
### Hypersensitivity
- Rare reports of exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell Syndrome), and anaphylaxis have been received.
### Gastrointestinal
- Epigastric distress, nausea, vomiting, and glossitis. Elevation of serum transaminase and bilirubin has been noted, but the significance of this finding is unknown. Cholestatic jaundice has been rarely reported.
### Hematologic
- Thrombocytopenia, leukopenia, neutropenia, megaloblastic anemia, and methemoglobinemia.
### Metabolic
- Hyperkalemia, hyponatremia.
### Neurologic
- Aseptic meningitis has been rarely reported.
### Miscellaneous
- Fever, and increases in BUN and serum creatinine levels.
## Postmarketing Experience
There is limited information regarding Trimethoprim Postmarketing Experience in the drug label.
# Drug Interactions
Trimethoprim may inhibit the hepatic metabolism of phenytoin. Trimethoprim, given at a common clinical dosage, increased the phenytoin half-life by 51% and decreased the phenytoin metabolic clearance rate by 30%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Trimethoprim has been shown to be teratogenic in the rat when given in doses 40 times the human dose. In some rabbit studies, the overall increase in fetal loss (dead and resorbed and malformed conceptuses) was associated with doses six times the human therapeutic dose.
While there are no large, well-controlled studies on the use of trimethoprim in pregnant women, Brumfitt and Pursell,3 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or trimethoprim in combination with sulfamethoxazole. The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving trimethoprim and sulfamethoxazole. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester. In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received trimethoprim and sulfamethoxazole at the time of conception or shortly thereafter.
Because trimethoprim may interfere with folic acid metabolism, trimethoprim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
### Nonteratogenic Effects
The oral administration of trimethoprim to rats at a dose of 70 mg/kg/day commencing with the last third of gestation and continuing through parturition and lactation caused no deleterious effects on gestation or pup growth and survival.
Pregnancy Category (AUS): B3
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trimethoprim in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Trimethoprim during labor and delivery.
### Nursing Mothers
Trimethoprim is excreted in human milk. Because trimethoprim may interfere with folic acid metabolism, caution should be exercised when trimethoprim is administered to a nursing woman.
### Pediatric Use
Safety and effectiveness in pediatric patients below the age of 2 months have not been established. The effectiveness of trimethoprim as a single agent has not been established in pediatric patients under 12 years of age.
### Geriatic Use
Clinical studies of trimethoprim tablets 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 response 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.
Case reports of hyperkalemia in elderly patients receiving trimethoprim-sulfamethoxazole have been published.6 Trimethoprim is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor potassium concentrations and to monitor renal function by calculating creatinine clearance.
### Gender
There is no FDA guidance on the use of Trimethoprim with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Trimethoprim with respect to specific racial populations.
### Renal Impairment
The use of trimethoprim in patients with a creatinine clearance of less than 15 mL/min is not recommended. For patients with a creatinine clearance of 15 to 30 mL/min, the dose should be 50 mg every 12 hours.
### Hepatic Impairment
There is no FDA guidance on the use of Trimethoprim in patients with hepatic impairment.
### Females of Reproductive Potential and Males
No adverse effects on fertility or general reproductive performance were observed in rats given trimethoprim in oral dosages as high as 70 mg/kg/day for males and 14 mg/kg/day for females.
### Immunocompromised Patients
There is no FDA guidance one the use of Trimethoprim in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Trimethoprim Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Trimethoprim and IV administrations.
# Overdosage
### Acute
Signs of acute overdosage with trimethoprim may appear following ingestion of 1 gram or more of the drug and include nausea, vomiting, dizziness, headaches, mental depression, confusion, and bone marrow depression.
Treatment consists of gastric lavage and general supportive measures. Acidification of the urine will increase renal elimination of trimethoprim. Peritoneal dialysis is not effective and hemodialysis is only moderately effective in eliminating the drug.
### Chronic
Use of trimethoprim at high doses and/or for extended periods of time may cause bone marrow depression manifested as thrombocytopenia, leukopenia, and/or megaloblastic anemia. If signs of bone marrow depression occur, trimethoprim should be discontinued and the patient should be given leucovorin; 5 to 15 mg leucovorin daily has been recommended by some investigators.
# Pharmacology
## Mechanism of Action
Bacteriostatic lipophilic weak base structurally related to pyrimethamine, binds to and reversibly inhibits the bacterial enzyme dihydrofolate reductase, selectively blocking conversion of dihydrofolic acid to its functional form, tetrahydrofolic acid. This depletes folate, an essential cofactor in the biosynthesis of nucleic acids, resulting in interference with bacterial nucleic acid and protein production.
## Structure
Trimethoprim is 5-[(3,4,5-trimethoxyphenyl)methyl]-2,4-pyrimidinediamine. It is a white to light yellow, odorless, bitter compound with a molecular weight of 290.32 and the molecular formula C14H18N4O3. The structural formula is:
## Pharmacodynamics
There is limited information regarding Trimethoprim Pharmacodynamics in the drug label.
## Pharmacokinetics
Trimethoprim is rapidly absorbed following oral administration. It exists in the blood as unbound, protein-bound, and metabolized forms. Ten to twenty percent of trimethoprim is metabolized, primarily in the liver; the remainder is excreted unchanged in the urine. The principal metabolites of trimethoprim are the 1- and 3-oxides and the 3'- and 4'-hydroxy derivatives. The free form is considered to be the therapeutically active form. Approximately 44% of trimethoprim is bound to plasma proteins.
Mean peak serum concentrations of approximately 1.0 mcg/mL occur 1 to 4 hours after oral administration of a single 100 mg dose. A single 200 mg dose will result in serum levels approximately twice as high. The half-life of trimethoprim ranges from 8 to 10 hours. However, patients with severely impaired renal function exhibit an increase in the half-life of trimethoprim, which requires either dosage regimen adjustment or not using the drug in such patients. During a 13 week study of trimethoprim administered at a daily dosage of 200 mg (50 mg q.i.d.), the mean minimum steady-state concentration of the drug was 1.1 mcg/mL. Steady-state concentrations were achieved within 2 to 3 days of chronic administration and were maintained throughout the experimental period.
Excretion of trimethoprim is primarily by the kidneys through glomerular filtration and tubular secretion. Urine concentrations of trimethoprim are considerably higher than are the concentrations in the blood. After a single oral dose of 100 mg, urine concentrations of trimethoprim ranged from 30 to 160 mcg/mL during the 0 to 4 hour period and declined to approximately 18 to 91 mcg/mL during the 8 to 24 hour period. A 200 mg single oral dose will result in trimethoprim urine levels approximately twice as high. After oral administration, 50% to 60% of trimethoprim is excreted in the urine within 24 hours, approximately 80% of this being unmetabolized trimethoprim.
Since normal vaginal and fecal flora are the source of most pathogens causing urinary tract infections, it is relevant to consider the distribution of trimethoprim into these sites. Concentrations of trimethoprim in vaginal secretions are consistently greater than those found simultaneously in the serum, being typically 1.6 times the concentrations of simultaneously obtained serum samples. Sufficient trimethoprim is excreted in the feces to markedly reduce or eliminate trimethoprim-susceptible organisms from the fecal flora.
Trimethoprim also passes the placental barrier and is excreted in human milk.
## Nonclinical Toxicology
### Carcinogenesis
Long-term studies in animals to evaluate carcinogenic potential have not been conducted with trimethoprim.
### Mutagenesis
Trimethoprim was demonstrated to be nonmutagenic in the Ames assay. In studies at two laboratories, no chromosomal damage was detected in cultured Chinese hamster ovary cells at concentrations approximately 500 times human plasma levels; at concentrations approximately 1000 times human plasma levels in these same cells, a low level of chromosomal damage was induced at one of the laboratories. No chromosomal abnormalities were observed in cultured human leukocytes at concentrations of trimethoprim up to 20 times human steady-state plasma levels. No chromosomal effects were detected in peripheral lymphocytes of human subjects receiving 320 mg of trimethoprim in combination with up to 1600 mg of sulfamethoxazole per day for as long as 112 weeks.
# Clinical Studies
There is limited information regarding Trimethoprim Clinical Studies in the drug label.
# How Supplied
- Trimethoprim tablets 100 mg in bottles of 100.
- Trimethoprim tablets 200 mg in bottles of 100.
## Storage
Store at 20° to 25°C (68° to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be counseled that antibacterial drugs including trimethoprim tablets, USP should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When trimethoprim tablets, USP are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by trimethoprim tablets, USP or other antibacterial drugs in the future.
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with and without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
# Precautions with Alcohol
Alcohol-Trimethoprim interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Proloprim [1]
- Trimpex
# Look-Alike Drug Names
There is limited information regarding Trimethoprim Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Primsol | |
b748b6c256468b61554df6b31fd149e35faaf459 | wikidoc | Priory Group | Priory Group
The Priory Group is an independent provider of mental health care facilities in the United Kingdom. They also provide Schools, some for Asperger's Syndrome (and High-Functioning Autism) pupils. The chief executive is Chai Patel.
They operate at nearly fifty different sites but they are best known for their alcohol and drug treatment centres.
The company runs four types of facility; acute psychiatric hospitals, secure psychiatric units, rehab hospitals and special schools. It was founded in the early 1980s with the purchase of The Priory in London by an American healthcare company.
In 2002, the group was sold for £288 million. The company was sold again in July 2005 for £875 million, netting the five company directors over £50 million.
# Controversy
The healthcare group appeared in the media spotlight in 2005 following allegations of poor care at its homes. Dr Patel was represented at the General Medical Council hearing by the brother of one of the company's leading consultants. A consultant who had previously been brought before the General Medical Council to answer claims of sexual misconduct with a patient, but he was later cleared.
Further controversy surrounds the company due to the action of some of its high profile consultants. Dr Rowan, founder of the group's eating disorder treatment regime is accused of taking cash gifts from a patient and getting her to change her £1.5 million will in his favour. | Priory Group
The Priory Group is an independent provider of mental health care facilities in the United Kingdom. They also provide Schools, some for Asperger's Syndrome (and High-Functioning Autism) pupils. The chief executive is Chai Patel.
They operate at nearly fifty different sites but they are best known for their alcohol and drug treatment centres.
The company runs four types of facility; acute psychiatric hospitals, secure psychiatric units, rehab hospitals and special schools. It was founded in the early 1980s with the purchase of The Priory in London by an American healthcare company.
In 2002, the group was sold for £288 million.[1] The company was sold again in July 2005 for £875 million, netting the five company directors over £50 million.[2]
# Controversy
The healthcare group appeared in the media spotlight in 2005 following allegations of poor care at its homes.[3] Dr Patel was represented at the General Medical Council hearing by the brother of one of the company's leading consultants. A consultant who had previously been brought before the General Medical Council to answer claims of sexual misconduct with a patient, but he was later cleared[4].
Further controversy surrounds the company due to the action of some of its high profile consultants. Dr Rowan, founder of the group's eating disorder treatment regime is accused of taking cash gifts from a patient and getting her to change her £1.5 million will in his favour.[5] | https://www.wikidoc.org/index.php/Priory_Group | |
fb5277ccdbd51e7a35d03a0372b641d1e9e1759c | wikidoc | Proamanullin | Proamanullin
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Promanullin is a cyclic nonribosomal peptide. It is an amatoxin, all of which are found in several members of the Amanita genus of mushrooms.
# Toxicology
Like other amatoxins, proamanullin is an inhibitor of RNA polymerase II. Promanullin has a specific attraction to the enzyme RNA polymerase II. Upon ingestion, it binds to the RNA polymerase II enzyme, effectively causing cytolysis of hepatocytes (liver cells). | Proamanullin
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Promanullin is a cyclic nonribosomal peptide. It is an amatoxin, all of which are found in several members of the Amanita genus of mushrooms.
# Toxicology
Like other amatoxins, proamanullin is an inhibitor of RNA polymerase II. Promanullin has a specific attraction to the enzyme RNA polymerase II. Upon ingestion, it binds to the RNA polymerase II enzyme, effectively causing cytolysis of hepatocytes (liver cells).[1] | https://www.wikidoc.org/index.php/Proamanullin | |
cd4beb568a6737e963fbe90bbb63f0e5685e1858 | wikidoc | Probit model | Probit model
In statistics, a probit model is a popular specification of a generalized linear model. In particular, it is used for Binomial regression using the probit link function. A probit regression is the application of this model to a given dataset. Probit models were introduced by Chester Ittner Bliss in 1935, and a fast method of solving the models was introduced by Ronald Fisher in an appendix to the same article. Because the response is a series of binomial results, the likelihood is often assumed to follow the binomial distribution. Let Y be a binary outcome variable, and let X be a vector of regressors. The probit model assumes that
where Φ is the cumulative distribution function of the standard normal distribution. The parameters β are typically estimated by maximum likelihood.
While easily motivated without it, the probit model can be generated by a simple latent variable model. Suppose that
where \varepsilon | x \sim \mathcal{N}(0,1) , and suppose that Y is an indicator for whether the latent variable Y^- is positive:
0&\text{otherwise}\end{array}\right.
Then it is easy to show that | Probit model
In statistics, a probit model is a popular specification of a generalized linear model. In particular, it is used for Binomial regression using the probit link function. A probit regression is the application of this model to a given dataset. Probit models were introduced by Chester Ittner Bliss in 1935, and a fast method of solving the models was introduced by Ronald Fisher in an appendix to the same article. Because the response is a series of binomial results, the likelihood is often assumed to follow the binomial distribution. Let Y be a binary outcome variable, and let X be a vector of regressors. The probit model assumes that
where Φ is the cumulative distribution function of the standard normal distribution. The parameters β are typically estimated by maximum likelihood.
While easily motivated without it, the probit model can be generated by a simple latent variable model. Suppose that
where <math> \varepsilon | x \sim \mathcal{N}(0,1) </math>, and suppose that <math> Y </math> is an indicator for whether the latent variable <math> Y^* </math> is positive:
0&\text{otherwise}\end{array}\right. </math>
Then it is easy to show that | https://www.wikidoc.org/index.php/Probit_model | |
e5a971171dbf5b67de151770e617a720878bb7ed | wikidoc | Procainamide | Procainamide
# 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
Procainamide is an antiarrhythmic that is FDA approved for the {{{indicationType}}} of ventricular arrhythmias, such as sustained ventricular tachycardia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension and dysrhythmia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Procainamide is useful for arrhythmias which require immediate suppression and for maintenance of arrhythmia control. Intravenous therapy allows most rapid control of serious arrhythmias, including those following myocardial infarction; it should be carried out in circumstances where close observation and monitoring of the patient are possible, such as in hospital or emergency facilities. Intramuscular administration is less apt to produce temporary high plasma levels but therapeutic plasma levels are not obtained as rapidly as with intravenous administration. Oral procainamide dosage forms are preferable for less urgent arrhythmias as well as for long-term maintenance after initial parenteral PA therapy.
- Intramuscular administration may be used as an alternative to the oral route for patients with less threatening arrhythmias but who are nauseated or vomiting, who are ordered to receive nothing by mouth preoperatively, or who may have malabsorptive problems. An initial daily dose of 50 mg per kg body weight may be estimated. This amount should be divided into fractional doses of one-eighth to one-quarter to be injected intramuscularly every three to six hours until oral therapy is possible. If more than three injections are given, the physician may wish to assess patient factors such as age and renal function, clinical response and, if available, blood levels of PA and NAPA in adjusting further doses for that individual. For treatment of arrhythmias associated with anesthesia or surgical operation, the suggested dose is 100 to 500 mg by intramuscular injection.
- Intravenous administration of Procainamide should be done cautiously to avoid a possible hypotensive response. Initial arrhythmia control, under ECG monitoring, may usually be accomplished safely within a half-hour by either of the two methods which follows:
- Direct injection into a vein or into tubing of an established infusion line should be done slowly at a rate not to exceed 50 mg per minute. It is advisable to dilute either the 100 mg/mL or the 500 mg/mL concentrations of procainamide hydrochloride prior to intravenous injection to facilitate control of dosage rate. Doses of 100 mg may be administered every 5 minutes at this rate until the arrhythmia is suppressed or until 500 mg has been administered, after which it is advisable to wait 10 minutes or longer to allow for more distribution into tissues before resuming.
- Alternatively, a loading infusion containing 20 mg of Procainamide Hydrochloride per mL (1 g diluted to 50 mL with 5% Dextrose Injection, USP) may be administered at a constant rate of 1 mL per minute for 25 to 30 minutes to deliver 500 to 600 mg of PA. Some effects may be seen after infusion of the first 100 or 200 mg; it is unusual to require more than 600 mg to achieve satisfactory antiarrhythmic effects.
- The maximum advisable dosage to be given either by repeated bolus injections or such loading infusion is 1 g.
- To maintain therapeutic levels, a more dilute intravenous infusion at a concentration of 2 mg/mL is convenient (1000 mg procainamide HCl in 500 mL of 5% Dextrose Injection, USP), and may be administered at 1 to 3 mL/minute. If daily total fluid intake must be limited, a 4 mg/mL concentration (1 g of Procainamide Hydrochloride Injection in 250 mL of 5% Dextrose Injection, USP) administered at 0.5 to 1.5 mL/minute will deliver an equivalent 2 to 6 mg per minute. The amount needed in a given patient to maintain the therapeutic level should be assessed principally from the clinical response, and will depend upon the patient’s weight and age, renal elimination, hepatic acetylation rate, and cardiac status, but should be adjusted for each patient based upon close observation. A maintenance infusion rate of 50 mcg/min/kg body weight to a person with a normal renal PA elimination half-time of three hours may be expected to produce a plasma level of approximately 6.5 mcg/mL.
- Since the principal route for elimination of PA and NAPA is renal excretion, reduced excretion will prolong the half-life of elimination and lower the dose rate needed to maintain therapeutic levels. Advancing age reduces the renal excretion of PA and NAPA independently of reductions in creatinine clearance; compared to normal young adults, there is approximately 25 percent reduction at age 50 and 50 percent at age 75.
- Intravenous therapy should be terminated if persistent conduction disturbances or hypotension develop. As soon as the patient’s basic cardiac rhythm appears to be stabilized, oral antiarrhythmic maintenance therapy is preferable, if indicated and possible. A period of about three to four hours (one half-time for renal elimination, ordinarily) should elapse after the last intravenous dose before administering the first dose of Procainamide Hydrochloride tablets or capsules.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: ACC/AHA
- Class of Recommendation: Class IIa
- Strength of Evidence: Level B
- For patients who are stable with likely VT, IV antiarrhythmic drugs or elective cardioversion is the preferred treatment strategy. Procainamide can be administered at a rate of 20 to 50 mg/min until the arrhythmia is suppressed, hypotension ensues, QRS duration increases >50%, or the maximum dose of 17 mg/kg is given. Maintenance infusion is 1 to 4 mg/min. Procainamide should be avoided in patients with prolonged QT and congestive heart failure.
- Developed by: ACC/AHA
- Class of Recommendation: Class I
- Strength of Evidence: Level B
- In patients with pre-excited AF and rapid ventricular response who are hemodynamically stable, IV procainamide (1 g over 30 minutes, followed by an infusion of 2 mg/minute over 1 hour) may be used to slow ventricular rate and convert to sinus rhythm.
### Non–Guideline-Supported Use
- Procainamide is effective for the treatment and prophylaxis of ventricular arrhythmias associated with acute myocardial infarction.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Procainamide in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- A loading dose of 3 mg/kg over 20 minutes, a continuous infusion was initiated at a rate of 20 mcg/kg/min and increased, in 10 mcg/kg increments every 30 min, to 40 to 120 mcg/kg/min, until the heart rate decreased below 180 beats/min.
- A higher loading dose of 10 mg/kg over 20 min, a continuous infusion was initiated at 20 mcg/kg/min and increased, in 10 mcg/kg increments every 10 to 15 min, to 40 to 120 mcg/kg/min, until the heart rate decreased below 180 beats/min.
# Contraindications
- Complete Heart Block
- Procainamide should not be administered to patients with complete heart block because of its effects in suppressing nodal or ventricular pacemakers and the hazard of asystole. It may be difficult to recognize complete heart block in patients with ventricular tachycardia, but if significant slowing of ventricular rate occurs during PA treatment without evidence of A-V conduction appearing, PA should be stopped. In cases of second degree A-V block or various types of hemiblock, PA should be avoided or discontinued because of the possibility of increased severity of block, unless the ventricular rate is controlled by an electrical pacemaker.
- Idiosyncratic Hypersensitivity
- In patients sensitive to procaine or other ester-type local anesthetics, cross sensitivity to PA is unlikely. However, it should be borne in mind, and PA should not be used if it produces acute allergic dermatitis, asthma, or anaphylactic symptoms.
- Lupus Erythematosus
- An established diagnosis of systemic lupus erythematosus is a contraindication to PA therapy, since aggravation of symptoms is highly likely.
- Torsades de Pointes
- In the unusual ventricular arrhythmia called “les torsades de pointes” (twistings of the points), characterized by alternation of one or more ventricular premature beats in the directions of the QRS complexes on ECG in persons with prolonged Q-T and often enhanced U waves, Group 1A antiarrhythmic drugs are contraindicated. Administration of PA in such cases may aggravate this special type of ventricular extrasystole or tachycardia instead of suppressing it.
# Warnings
- Digitalis Intoxication
- Caution should be exercised in the use of procainamide in arrhythmias associated with digitalis intoxication. Procainamide can suppress digitalis-induced arrhythmias; however, if there is concomitant marked disturbance of atrioventricular conduction, additional depression of conduction and ventricular asystole or fibrillation may result. Therefore, use of procainamide should be considered only if discontinuation of digitalis, and therapy with potassium, lidocaine, or phenytoin are ineffective.
- First Degree Heart Block
- Caution should be exercised also if the patient exhibits or develops first degree heart block while taking PA, and dosage reduction is advised in such cases. If the block persists despite dosage reduction, continuation of PA administration must be evaluated on the basis of current benefit versus risk of increased heart block.
- Predigitalization for Atrial Flutter or Fibrillation
- Patients with atrial flutter or fibrillation should be cardioverted or digitalized prior to PA administration to avoid enhancement of A-V conduction which may result in ventricular rate acceleration beyond tolerable limits. Adequate digitalization reduces but does not eliminate the possibility of sudden increase in ventricular rate as the atrial rate is slowed by PA in these arrhythmias.
- Congestive Heart Failure
- For patients in congestive heart failure, and those with acute ischemic heart disease or cardiomyopathy, caution should be used in PA therapy, since even slight depression of myocardial contractility may further reduce cardiac output of the damaged heart.
- Concurrent Other Antiarrhythmic Agents
- Concurrent use of PA with other Group 1A antiarrhythmic agents such as quinidine or disopyramide may produce enhanced prolongation of conduction or depression of contractility and hypotension, especially in patients with cardiac decompensation. Such use should be reserved for patients with serious arrhythmias unresponsive to a single drug and employed only if close observation is possible.
- Renal Insufficiency
- Renal insufficiency may lead to accumulation of high plasma levels from conventional doses of PA, with effects similar to those of overdosage, unless dosage is adjusted for the individual patient.
- Myasthenia Gravis
- Patients with myasthenia gravis may show worsening of symptoms from PA due to its procaine-like effect on diminishing acetylcholine release at skeletal muscle motor nerve endings, so that PA administration may be hazardous without optimal adjustment of anticholinesterase medications and other precautions.
- Sulfite Sensitivity
- Procainamide Hydrochloride Injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
### Precautions
- Blood-Pressure and ECG Monitoring
- Blood pressure should be monitored with the patient supine during parenteral, especially intravenous, administration of PA. There is a possibility that relatively high although transient plasma levels of PA may be attained and cause hypotension before the PA can be distributed from the plasma volume to its full apparent volume of distribution which is approximately 50 times greater. Therefore, caution should be exercised to avoid overly rapid administration of PA. If the blood pressure falls 15 mm Hg or more, PA administration should be temporarily discontinued. Electrocardiographic (ECG) monitoring is advisable as well, both for observation of the progress and response of the arrhythmia under treatment, and for early detection of any tendency to excessive widening of the QRS complex, prolongation of the P-R interval, or any signs of heart block. Parenteral therapy with PA should be limited to use in hospitals in which monitoring and intensive supportive care are available, or to emergency situations in which equivalent observation and treatment can be provided.
- General
- Immediately after initiation of PA therapy, patients should be closely observed for possible hypersensitivity reactions. In conversion of atrial fibrillation to normal sinus rhythm by any means, dislodgement of mural thrombi may lead to embolization, which should be kept in mind.
- After achieving and maintaining therapeutic plasma concentrations and satisfactory electrocardiographic and clinical responses, continued frequent periodic monitoring of vital signs and electrocardiograms is advised. If evidence of QRS widening of more than 25 percent or marked prolongation of the Q-T interval occurs, concern for overdosage is appropriate, and interruption of the PA infusion is advisable if a 50 percent increase occurs. Elevated serum creatinine or urea nitrogen, reduced creatinine clearance or history of renal insufficiency, as well as use in older patients (over age 50), provide grounds to anticipate that less than the usual dosage or infusion rate may suffice, since the urinary elimination of PA and NAPA may be reduced, leading to gradual accumulation beyond normally-predicted amounts. If facilities are available for measurement of plasma PA and NAPA, or acetylation capability, individual dose adjustment for optimal therapeutic levels may be easier, but close observation of clinical effectiveness is the most important criterion.
- Laboratory Tests
- Laboratory tests such as complete blood count (CBC), electrocardiogram and serum creatinine or urea nitrogen may be indicated depending on the clinical situation, and periodic rechecking of the CBC and ANA may be helpful in early detection of untoward reactions.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Procainamide in the drug label.
## Postmarketing Experience
A lupus erythematosus-like syndrome of arthralgia, pleural or abdominal pain, and sometimes arthritis, pleural effusion, pericarditis, fever, chills, myalgia, and possibly related hematologic or skin lesions is fairly common after prolonged PA administration, perhaps more often in patients who are slow acetylators. While some series have reported less than 1 in 500, others have reported the syndrome in up to 30 percent of patients on long term oral PA therapy. If discontinuation of PA does not reverse the lupoid symptoms, corticosteroid treatment may be effective.
Hypotension and serious disturbances of cardiorhythm such as ventricular asystole or fibrillation are more common with intravenous administration of PA than with intramuscular administration. Because PA is a peripheral vasodilator in concentrations higher than the usual therapeutic range, transient high plasma levels which may occur especially during intravenous administration may produce temporary but at times severe lowering of blood pressure.
Anorexia, nausea, vomiting, abdominal pain, diarrhea or bitter taste may occur in 3 to 4 percent of patients taking oral procainamide.
Neutropenia, thrombocytopenia, or hemolytic anemia may rarely be encountered. Agranulocytosis has occurred after repeated use of PA, and deaths have been reported.
Dizziness or giddiness, weakness, mental depression and psychosis with hallucinations have been reported.
Angioneurotic edema, urticaria, pruritus, flushing, and maculopapular rash have also occurred.
Elevations of transaminase with and without elevations of alkaline phosphatase and bilirubin have been reported. Some patients have had clinical symptoms (e.g., malaise, right upper quadrant pain). Deaths from liver failure have been reported.
# Drug Interactions
- If other antiarrhythmic drugs are being used, additive effects on the heart may occur with PA administration, and dosage reduction may be necessary.
- Anticholinergic drugs administered concurrently with PA may produce additive antivagal effects on A-V nodal conduction, although this is not as well documented for PA as for quinidine.
- Patients taking PA who require neuromuscular blocking agents such as succinylcholine may require less than usual doses of the latter, due to PA effects on reducing acetylcholine release.
- Drug/Laboratory Test Interactions
- Suprapharmacologic concentrations of lidocaine and meprobamate may inhibit fluorescence of PA and NAPA, and propranolol shows a native fluorescence close to the PA/NAPA peak wavelengths, so that tests which depend on fluorescence measurement may be affected.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Animal reproduction studies have not been conducted with PA. It also is not known whether PA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PA should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Procainamide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Procainamide during labor and delivery.
### Nursing Mothers
- Both PA and NAPA are excreted in human milk, absorbed by the nursing infant. Because of the potential for serious adverse reactions in nursing infants, a decision to discontinue nursing or the drug should be made, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
There is no FDA guidance on the use of Procainamide with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Procainamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Procainamide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Procainamide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Procainamide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Procainamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Procainamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
- Intramuscular
### Monitoring
- Blood-Pressure and ECG Monitoring
- Blood pressure should be monitored with the patient supine during parenteral, especially intravenous, administration of PA. There is a possibility that relatively high although transient plasma levels of PA may be attained and cause hypotension before the PA can be distributed from the plasma volume to its full apparent volume of distribution which is approximately 50 times greater. Therefore, caution should be exercised to avoid overly rapid administration of PA. If the blood pressure falls 15 mm Hg or more, PA administration should be temporarily discontinued. Electrocardiographic (ECG) monitoring is advisable as well, both for observation of the progress and response of the arrhythmia under treatment, and for early detection of any tendency to excessive widening of the QRS complex, prolongation of the P-R interval, or any signs of heart block. Parenteral therapy with PA should be limited to use in hospitals in which monitoring and intensive supportive care are available, or to emergency situations in which equivalent observation and treatment can be provided.
# IV Compatibility
There is limited information regarding IV Compatibility of Procainamide in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Progressive widening of the QRS complex, prolonged Q-T and P-R intervals, lowering of the R and T waves, as well as increasing A-V block, may be seen with doses which are excessive for a given patient. Increased ventricular extrasystoles, or even ventricular tachycardia or fibrillation may occur. After intravenous administration but seldom after oral therapy, transient high plasma levels of PA may induce hypotension, affecting systolic more than diastolic pressures, especially in hypertensive patients. Such high levels may also produce central nervous depression, tremor, and even respiratory depression.
- Plasma levels above 10 mcg/mL are increasingly associated with toxic findings, which are seen occasionally in the 10 to 12 mcg/mL range, more often in the 12 to 15 mcg/mL range, and commonly in patients with plasma levels greater than 15 mcg/mL.
### Management
- Treatment of overdosage or toxic manifestations includes general supportive measures, close observation, monitoring of vital signs and possibly intravenous pressor agents and mechanical cardiorespiratory support. If available, PA and NAPA plasma levels may be helpful in assessing the potential degree of toxicity and response to therapy. Both PA and NAPA are removed from the circulation by hemodialysis but not peritoneal dialysis. No specific antidote for PA is known.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Procainamide in the drug label.
# Pharmacology
## Mechanism of Action
- Procainamide (PA) increases the effective refractory period of the atria, and to a lesser extent the bundle of His-Purkinje system and ventricles of the heart. It reduces impulse conduction velocity in the atria, His-Purkinje fibers, and ventricular muscle, but has variable effects on the atrioventricular (A-V) node, a direct slowing action and a weaker vagolytic effect which may speed A-V conduction slightly. Myocardial excitability is reduced in the atria, Purkinje fibers, papillary muscles, and ventricles by an increase in the threshold for excitation, combined with inhibition of ectopic pacemaker activity by retardation of the slow phase of diastolic depolarization, thus decreasing automaticity especially in ectopic sites. Contractility of the undamaged heart is usually not affected by therapeutic concentrations, although slight reduction of cardiac output may occur, and may be significant in the presence of myocardial damage. Therapeutic levels of PA may exert vagolytic effects and produce slight acceleration of heart rate, while high or toxic concentrations may prolong A-V conduction time or induce A-V block, or even cause abnormal automaticity and spontaneous firing by unknown mechanisms.
- The electrocardiogram may reflect these effects by showing slight sinus tachycardia (due to the anticholinergic action) and widened QRS complexes and, less regularly, prolonged Q-T and P-R intervals (due to longer systole and slower conduction), as well as some decrease in QRS and T wave amplitude. These direct effects of PA on electrical activity, conduction, responsiveness, excitability and automaticity are characteristic of a Group 1A antiarrhythmic agent, the prototype for which is quinidine; PA effects are very similar. However, PA has weaker vagal blocking action than does quinidine, does not induce alpha-adrenergic blockade, and is less depressing to cardiac contractility.
- Following intramuscular injection, procainamide is rapidly absorbed into the bloodstream, and plasma levels peak in 15 to 60 minutes, considerably faster than orally administered procainamide hydrochloride tablets or capsules which produce peak plasma levels in 90 to 120 minutes. Intravenous administration of Procainamide Hydrochloride Injection can produce therapeutic procainamide levels within minutes after infusion is started. About 15 to 20 percent of PA is reversibly bound to plasma proteins, and considerable amounts are more slowly and reversibly bound to tissues of the heart, liver, lung, and kidney. The apparent volume of distribution eventually reaches about 2 liters per kilogram body weight with a half-time of approximately five minutes. While PA has been shown in the dog to cross the blood-brain barrier, it did not concentrate in the brain at levels higher than in plasma. It is not known if PA crosses the placenta. Plasma esterases are far less active in hydrolysis of PA than of procaine. The half-time for elimination of PA is three to four hours in patients with normal renal function, but reduced creatinine clearance and advancing age each prolong the half-time of elimination of PA.
## Structure
- Procainamide Hydrochloride Injection, USP is a sterile, nonpyrogenic solution of procainamide hydrochloride in water for injection. Each milliliter of the 2 mL vial contains procainamide hydrochloride 500 mg; methylparaben 1 mg and sodium metabisulfite 1.8 mg added in water for injection. Each milliliter of the 10 mL vial contains procainamide hydrochloride 100 mg; methylparaben 1 mg and sodium metabisulfite 0.8 mg added in water for injection. In both formulations, the solution may contain hydrochloric acid and/or sodium hydroxide for pH adjustment. pH 5.0 (4.0 to 6.0). Headspace nitrogen gassed.
- Procainamide Hydrochloride Injection is intended for intravenous or intramuscular administration.
- Procainamide hydrochloride, a Group 1A cardiac antiarrhythmic drug, is ρ-amino-N- benzamide mono-hydrochloride. It has the following structural formula:
- It differs from procaine which is the p-aminobenzoyl ester of 2-(diethylamino)-ethanol. Procainamide as the free base has a pKa of 9.23; the monohydrochloride is very soluble in water.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Procainamide in the drug label.
## Pharmacokinetics
- A significant fraction of the circulating PA may be metabolized in hepatocytes to N-acetylprocainamide (NAPA), ranging from 16 to 21 percent of an administered dose in “slow acetylators” to 24 to 33 percent in “fast-acetylators”. Since NAPA also has significant antiarrhythmic activity and somewhat slower renal clearance than PA, both hepatic acetylation rate capability and renal function, as well as age, have significant effects on the effective biologic half-time of therapeutic action of administered PA and the NAPA derivative. Trace amounts may be excreted in the urine as free and conjugated ρ-aminobenzoic acid, 30 to 60 percent as unchanged PA, and 6 to 52 percent as the NAPA derivative. Both PA and NAPA are eliminated by active tubular secretion as well as by glomerular filtration. Action of PA on the central nervous system is not prominent, but high plasma concentrations may cause tremors. While therapeutic plasma levels for PA have been reported to be 3 to 10 mcg/mL certain patients such as those with sustained ventricular tachycardia, may need higher levels for adequate control. This may justify the increased risk of toxicity. Where programmed ventricular stimulation has been used to evaluate efficacy of PA in preventing recurrent ventricular tachyarrhythmias, higher plasma levels (mean, 13.6 mcg/mL) of PA were found necessary for adequate control.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long-term studies in animals have not been performed.
# Clinical Studies
There is limited information regarding Clinical Studies of Procainamide in the drug label.
# How Supplied
- Procainamide Hydrochloride Injection, USP is available in multiple-dose 10 mL vials providing 100 mg procainamide hydrochloride per mL and 2 mL vials providing 500 mg procainamide hydrochloride per mL.
- The solutions, which are clear and colorless initially, may develop a slightly yellow color in time. This does not indicate a change which should preclude its use, but a solution any darker than light amber or otherwise discolored should not be used.
- Store at 20 to 25°C (68 to 77°F).
## Storage
There is limited information regarding Procainamide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- The patient should be encouraged to disclose any past history of drug sensitivity, especially to procaine or other local anesthetic agents, or aspirin, and to report any history of kidney disease, congestive heart failure, myasthenia gravis, liver disease, or lupus erythematosus.
- The patient should be counseled to report any symptoms of arthralgia, myalgia, fever, chills, skin rash, easy bruising, sore throat or sore mouth, infections, dark urine or icterus, wheezing, muscular weakness, chest or abdominal pain, palpitations, nausea, vomiting, anorexia, diarrhea, hallucinations, dizziness, or depression.
# Precautions with Alcohol
- Alcohol-Procainamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Procanbid®
# Look-Alike Drug Names
- Procanbid® — probenecid
- Procanbid® — Procan SR®
# Drug Shortage Status
# Price | Procainamide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi
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# Black Box Warning
# Overview
Procainamide is an antiarrhythmic that is FDA approved for the {{{indicationType}}} of ventricular arrhythmias, such as sustained ventricular tachycardia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension and dysrhythmia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Procainamide is useful for arrhythmias which require immediate suppression and for maintenance of arrhythmia control. Intravenous therapy allows most rapid control of serious arrhythmias, including those following myocardial infarction; it should be carried out in circumstances where close observation and monitoring of the patient are possible, such as in hospital or emergency facilities. Intramuscular administration is less apt to produce temporary high plasma levels but therapeutic plasma levels are not obtained as rapidly as with intravenous administration. Oral procainamide dosage forms are preferable for less urgent arrhythmias as well as for long-term maintenance after initial parenteral PA therapy.
- Intramuscular administration may be used as an alternative to the oral route for patients with less threatening arrhythmias but who are nauseated or vomiting, who are ordered to receive nothing by mouth preoperatively, or who may have malabsorptive problems. An initial daily dose of 50 mg per kg body weight may be estimated. This amount should be divided into fractional doses of one-eighth to one-quarter to be injected intramuscularly every three to six hours until oral therapy is possible. If more than three injections are given, the physician may wish to assess patient factors such as age and renal function, clinical response and, if available, blood levels of PA and NAPA in adjusting further doses for that individual. For treatment of arrhythmias associated with anesthesia or surgical operation, the suggested dose is 100 to 500 mg by intramuscular injection.
- Intravenous administration of Procainamide should be done cautiously to avoid a possible hypotensive response. Initial arrhythmia control, under ECG monitoring, may usually be accomplished safely within a half-hour by either of the two methods which follows:
- Direct injection into a vein or into tubing of an established infusion line should be done slowly at a rate not to exceed 50 mg per minute. It is advisable to dilute either the 100 mg/mL or the 500 mg/mL concentrations of procainamide hydrochloride prior to intravenous injection to facilitate control of dosage rate. Doses of 100 mg may be administered every 5 minutes at this rate until the arrhythmia is suppressed or until 500 mg has been administered, after which it is advisable to wait 10 minutes or longer to allow for more distribution into tissues before resuming.
- Alternatively, a loading infusion containing 20 mg of Procainamide Hydrochloride per mL (1 g diluted to 50 mL with 5% Dextrose Injection, USP) may be administered at a constant rate of 1 mL per minute for 25 to 30 minutes to deliver 500 to 600 mg of PA. Some effects may be seen after infusion of the first 100 or 200 mg; it is unusual to require more than 600 mg to achieve satisfactory antiarrhythmic effects.
- The maximum advisable dosage to be given either by repeated bolus injections or such loading infusion is 1 g.
- To maintain therapeutic levels, a more dilute intravenous infusion at a concentration of 2 mg/mL is convenient (1000 mg procainamide HCl in 500 mL of 5% Dextrose Injection, USP), and may be administered at 1 to 3 mL/minute. If daily total fluid intake must be limited, a 4 mg/mL concentration (1 g of Procainamide Hydrochloride Injection in 250 mL of 5% Dextrose Injection, USP) administered at 0.5 to 1.5 mL/minute will deliver an equivalent 2 to 6 mg per minute. The amount needed in a given patient to maintain the therapeutic level should be assessed principally from the clinical response, and will depend upon the patient’s weight and age, renal elimination, hepatic acetylation rate, and cardiac status, but should be adjusted for each patient based upon close observation. A maintenance infusion rate of 50 mcg/min/kg body weight to a person with a normal renal PA elimination half-time of three hours may be expected to produce a plasma level of approximately 6.5 mcg/mL.
- Since the principal route for elimination of PA and NAPA is renal excretion, reduced excretion will prolong the half-life of elimination and lower the dose rate needed to maintain therapeutic levels. Advancing age reduces the renal excretion of PA and NAPA independently of reductions in creatinine clearance; compared to normal young adults, there is approximately 25 percent reduction at age 50 and 50 percent at age 75.
- Intravenous therapy should be terminated if persistent conduction disturbances or hypotension develop. As soon as the patient’s basic cardiac rhythm appears to be stabilized, oral antiarrhythmic maintenance therapy is preferable, if indicated and possible. A period of about three to four hours (one half-time for renal elimination, ordinarily) should elapse after the last intravenous dose before administering the first dose of Procainamide Hydrochloride tablets or capsules.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: ACC/AHA
- Class of Recommendation: Class IIa
- Strength of Evidence: Level B
- For patients who are stable with likely VT, IV antiarrhythmic drugs or elective cardioversion is the preferred treatment strategy. Procainamide can be administered at a rate of 20 to 50 mg/min until the arrhythmia is suppressed, hypotension ensues, QRS duration increases >50%, or the maximum dose of 17 mg/kg is given. Maintenance infusion is 1 to 4 mg/min. Procainamide should be avoided in patients with prolonged QT and congestive heart failure.[1]
- Developed by: ACC/AHA
- Class of Recommendation: Class I
- Strength of Evidence: Level B
- In patients with pre-excited AF and rapid ventricular response who are hemodynamically stable, IV procainamide (1 g over 30 minutes, followed by an infusion of 2 mg/minute over 1 hour) may be used to slow ventricular rate and convert to sinus rhythm.[2]
### Non–Guideline-Supported Use
- Procainamide is effective for the treatment and prophylaxis of ventricular arrhythmias associated with acute myocardial infarction.[3][4][5]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Procainamide in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- A loading dose of 3 mg/kg over 20 minutes, a continuous infusion was initiated at a rate of 20 mcg/kg/min and increased, in 10 mcg/kg increments every 30 min, to 40 to 120 mcg/kg/min, until the heart rate decreased below 180 beats/min.
- A higher loading dose of 10 mg/kg over 20 min, a continuous infusion was initiated at 20 mcg/kg/min and increased, in 10 mcg/kg increments every 10 to 15 min, to 40 to 120 mcg/kg/min, until the heart rate decreased below 180 beats/min.[6]
# Contraindications
- Complete Heart Block
- Procainamide should not be administered to patients with complete heart block because of its effects in suppressing nodal or ventricular pacemakers and the hazard of asystole. It may be difficult to recognize complete heart block in patients with ventricular tachycardia, but if significant slowing of ventricular rate occurs during PA treatment without evidence of A-V conduction appearing, PA should be stopped. In cases of second degree A-V block or various types of hemiblock, PA should be avoided or discontinued because of the possibility of increased severity of block, unless the ventricular rate is controlled by an electrical pacemaker.
- Idiosyncratic Hypersensitivity
- In patients sensitive to procaine or other ester-type local anesthetics, cross sensitivity to PA is unlikely. However, it should be borne in mind, and PA should not be used if it produces acute allergic dermatitis, asthma, or anaphylactic symptoms.
- Lupus Erythematosus
- An established diagnosis of systemic lupus erythematosus is a contraindication to PA therapy, since aggravation of symptoms is highly likely.
- Torsades de Pointes
- In the unusual ventricular arrhythmia called “les torsades de pointes” (twistings of the points), characterized by alternation of one or more ventricular premature beats in the directions of the QRS complexes on ECG in persons with prolonged Q-T and often enhanced U waves, Group 1A antiarrhythmic drugs are contraindicated. Administration of PA in such cases may aggravate this special type of ventricular extrasystole or tachycardia instead of suppressing it.
# Warnings
- Digitalis Intoxication
- Caution should be exercised in the use of procainamide in arrhythmias associated with digitalis intoxication. Procainamide can suppress digitalis-induced arrhythmias; however, if there is concomitant marked disturbance of atrioventricular conduction, additional depression of conduction and ventricular asystole or fibrillation may result. Therefore, use of procainamide should be considered only if discontinuation of digitalis, and therapy with potassium, lidocaine, or phenytoin are ineffective.
- First Degree Heart Block
- Caution should be exercised also if the patient exhibits or develops first degree heart block while taking PA, and dosage reduction is advised in such cases. If the block persists despite dosage reduction, continuation of PA administration must be evaluated on the basis of current benefit versus risk of increased heart block.
- Predigitalization for Atrial Flutter or Fibrillation
- Patients with atrial flutter or fibrillation should be cardioverted or digitalized prior to PA administration to avoid enhancement of A-V conduction which may result in ventricular rate acceleration beyond tolerable limits. Adequate digitalization reduces but does not eliminate the possibility of sudden increase in ventricular rate as the atrial rate is slowed by PA in these arrhythmias.
- Congestive Heart Failure
- For patients in congestive heart failure, and those with acute ischemic heart disease or cardiomyopathy, caution should be used in PA therapy, since even slight depression of myocardial contractility may further reduce cardiac output of the damaged heart.
- Concurrent Other Antiarrhythmic Agents
- Concurrent use of PA with other Group 1A antiarrhythmic agents such as quinidine or disopyramide may produce enhanced prolongation of conduction or depression of contractility and hypotension, especially in patients with cardiac decompensation. Such use should be reserved for patients with serious arrhythmias unresponsive to a single drug and employed only if close observation is possible.
- Renal Insufficiency
- Renal insufficiency may lead to accumulation of high plasma levels from conventional doses of PA, with effects similar to those of overdosage, unless dosage is adjusted for the individual patient.
- Myasthenia Gravis
- Patients with myasthenia gravis may show worsening of symptoms from PA due to its procaine-like effect on diminishing acetylcholine release at skeletal muscle motor nerve endings, so that PA administration may be hazardous without optimal adjustment of anticholinesterase medications and other precautions.
- Sulfite Sensitivity
- Procainamide Hydrochloride Injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
### Precautions
- Blood-Pressure and ECG Monitoring
- Blood pressure should be monitored with the patient supine during parenteral, especially intravenous, administration of PA. There is a possibility that relatively high although transient plasma levels of PA may be attained and cause hypotension before the PA can be distributed from the plasma volume to its full apparent volume of distribution which is approximately 50 times greater. Therefore, caution should be exercised to avoid overly rapid administration of PA. If the blood pressure falls 15 mm Hg or more, PA administration should be temporarily discontinued. Electrocardiographic (ECG) monitoring is advisable as well, both for observation of the progress and response of the arrhythmia under treatment, and for early detection of any tendency to excessive widening of the QRS complex, prolongation of the P-R interval, or any signs of heart block. Parenteral therapy with PA should be limited to use in hospitals in which monitoring and intensive supportive care are available, or to emergency situations in which equivalent observation and treatment can be provided.
- General
- Immediately after initiation of PA therapy, patients should be closely observed for possible hypersensitivity reactions. In conversion of atrial fibrillation to normal sinus rhythm by any means, dislodgement of mural thrombi may lead to embolization, which should be kept in mind.
- After achieving and maintaining therapeutic plasma concentrations and satisfactory electrocardiographic and clinical responses, continued frequent periodic monitoring of vital signs and electrocardiograms is advised. If evidence of QRS widening of more than 25 percent or marked prolongation of the Q-T interval occurs, concern for overdosage is appropriate, and interruption of the PA infusion is advisable if a 50 percent increase occurs. Elevated serum creatinine or urea nitrogen, reduced creatinine clearance or history of renal insufficiency, as well as use in older patients (over age 50), provide grounds to anticipate that less than the usual dosage or infusion rate may suffice, since the urinary elimination of PA and NAPA may be reduced, leading to gradual accumulation beyond normally-predicted amounts. If facilities are available for measurement of plasma PA and NAPA, or acetylation capability, individual dose adjustment for optimal therapeutic levels may be easier, but close observation of clinical effectiveness is the most important criterion.
- Laboratory Tests
- Laboratory tests such as complete blood count (CBC), electrocardiogram and serum creatinine or urea nitrogen may be indicated depending on the clinical situation, and periodic rechecking of the CBC and ANA may be helpful in early detection of untoward reactions.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Procainamide in the drug label.
## Postmarketing Experience
A lupus erythematosus-like syndrome of arthralgia, pleural or abdominal pain, and sometimes arthritis, pleural effusion, pericarditis, fever, chills, myalgia, and possibly related hematologic or skin lesions is fairly common after prolonged PA administration, perhaps more often in patients who are slow acetylators. While some series have reported less than 1 in 500, others have reported the syndrome in up to 30 percent of patients on long term oral PA therapy. If discontinuation of PA does not reverse the lupoid symptoms, corticosteroid treatment may be effective.
Hypotension and serious disturbances of cardiorhythm such as ventricular asystole or fibrillation are more common with intravenous administration of PA than with intramuscular administration. Because PA is a peripheral vasodilator in concentrations higher than the usual therapeutic range, transient high plasma levels which may occur especially during intravenous administration may produce temporary but at times severe lowering of blood pressure.
Anorexia, nausea, vomiting, abdominal pain, diarrhea or bitter taste may occur in 3 to 4 percent of patients taking oral procainamide.
Neutropenia, thrombocytopenia, or hemolytic anemia may rarely be encountered. Agranulocytosis has occurred after repeated use of PA, and deaths have been reported.
Dizziness or giddiness, weakness, mental depression and psychosis with hallucinations have been reported.
Angioneurotic edema, urticaria, pruritus, flushing, and maculopapular rash have also occurred.
Elevations of transaminase with and without elevations of alkaline phosphatase and bilirubin have been reported. Some patients have had clinical symptoms (e.g., malaise, right upper quadrant pain). Deaths from liver failure have been reported.
# Drug Interactions
- If other antiarrhythmic drugs are being used, additive effects on the heart may occur with PA administration, and dosage reduction may be necessary.
- Anticholinergic drugs administered concurrently with PA may produce additive antivagal effects on A-V nodal conduction, although this is not as well documented for PA as for quinidine.
- Patients taking PA who require neuromuscular blocking agents such as succinylcholine may require less than usual doses of the latter, due to PA effects on reducing acetylcholine release.
- Drug/Laboratory Test Interactions
- Suprapharmacologic concentrations of lidocaine and meprobamate may inhibit fluorescence of PA and NAPA, and propranolol shows a native fluorescence close to the PA/NAPA peak wavelengths, so that tests which depend on fluorescence measurement may be affected.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Animal reproduction studies have not been conducted with PA. It also is not known whether PA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PA should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Procainamide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Procainamide during labor and delivery.
### Nursing Mothers
- Both PA and NAPA are excreted in human milk, absorbed by the nursing infant. Because of the potential for serious adverse reactions in nursing infants, a decision to discontinue nursing or the drug should be made, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
There is no FDA guidance on the use of Procainamide with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Procainamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Procainamide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Procainamide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Procainamide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Procainamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Procainamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
- Intramuscular
### Monitoring
- Blood-Pressure and ECG Monitoring
- Blood pressure should be monitored with the patient supine during parenteral, especially intravenous, administration of PA. There is a possibility that relatively high although transient plasma levels of PA may be attained and cause hypotension before the PA can be distributed from the plasma volume to its full apparent volume of distribution which is approximately 50 times greater. Therefore, caution should be exercised to avoid overly rapid administration of PA. If the blood pressure falls 15 mm Hg or more, PA administration should be temporarily discontinued. Electrocardiographic (ECG) monitoring is advisable as well, both for observation of the progress and response of the arrhythmia under treatment, and for early detection of any tendency to excessive widening of the QRS complex, prolongation of the P-R interval, or any signs of heart block. Parenteral therapy with PA should be limited to use in hospitals in which monitoring and intensive supportive care are available, or to emergency situations in which equivalent observation and treatment can be provided.
# IV Compatibility
There is limited information regarding IV Compatibility of Procainamide in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Progressive widening of the QRS complex, prolonged Q-T and P-R intervals, lowering of the R and T waves, as well as increasing A-V block, may be seen with doses which are excessive for a given patient. Increased ventricular extrasystoles, or even ventricular tachycardia or fibrillation may occur. After intravenous administration but seldom after oral therapy, transient high plasma levels of PA may induce hypotension, affecting systolic more than diastolic pressures, especially in hypertensive patients. Such high levels may also produce central nervous depression, tremor, and even respiratory depression.
- Plasma levels above 10 mcg/mL are increasingly associated with toxic findings, which are seen occasionally in the 10 to 12 mcg/mL range, more often in the 12 to 15 mcg/mL range, and commonly in patients with plasma levels greater than 15 mcg/mL.
### Management
- Treatment of overdosage or toxic manifestations includes general supportive measures, close observation, monitoring of vital signs and possibly intravenous pressor agents and mechanical cardiorespiratory support. If available, PA and NAPA plasma levels may be helpful in assessing the potential degree of toxicity and response to therapy. Both PA and NAPA are removed from the circulation by hemodialysis but not peritoneal dialysis. No specific antidote for PA is known.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Procainamide in the drug label.
# Pharmacology
## Mechanism of Action
- Procainamide (PA) increases the effective refractory period of the atria, and to a lesser extent the bundle of His-Purkinje system and ventricles of the heart. It reduces impulse conduction velocity in the atria, His-Purkinje fibers, and ventricular muscle, but has variable effects on the atrioventricular (A-V) node, a direct slowing action and a weaker vagolytic effect which may speed A-V conduction slightly. Myocardial excitability is reduced in the atria, Purkinje fibers, papillary muscles, and ventricles by an increase in the threshold for excitation, combined with inhibition of ectopic pacemaker activity by retardation of the slow phase of diastolic depolarization, thus decreasing automaticity especially in ectopic sites. Contractility of the undamaged heart is usually not affected by therapeutic concentrations, although slight reduction of cardiac output may occur, and may be significant in the presence of myocardial damage. Therapeutic levels of PA may exert vagolytic effects and produce slight acceleration of heart rate, while high or toxic concentrations may prolong A-V conduction time or induce A-V block, or even cause abnormal automaticity and spontaneous firing by unknown mechanisms.
- The electrocardiogram may reflect these effects by showing slight sinus tachycardia (due to the anticholinergic action) and widened QRS complexes and, less regularly, prolonged Q-T and P-R intervals (due to longer systole and slower conduction), as well as some decrease in QRS and T wave amplitude. These direct effects of PA on electrical activity, conduction, responsiveness, excitability and automaticity are characteristic of a Group 1A antiarrhythmic agent, the prototype for which is quinidine; PA effects are very similar. However, PA has weaker vagal blocking action than does quinidine, does not induce alpha-adrenergic blockade, and is less depressing to cardiac contractility.
- Following intramuscular injection, procainamide is rapidly absorbed into the bloodstream, and plasma levels peak in 15 to 60 minutes, considerably faster than orally administered procainamide hydrochloride tablets or capsules which produce peak plasma levels in 90 to 120 minutes. Intravenous administration of Procainamide Hydrochloride Injection can produce therapeutic procainamide levels within minutes after infusion is started. About 15 to 20 percent of PA is reversibly bound to plasma proteins, and considerable amounts are more slowly and reversibly bound to tissues of the heart, liver, lung, and kidney. The apparent volume of distribution eventually reaches about 2 liters per kilogram body weight with a half-time of approximately five minutes. While PA has been shown in the dog to cross the blood-brain barrier, it did not concentrate in the brain at levels higher than in plasma. It is not known if PA crosses the placenta. Plasma esterases are far less active in hydrolysis of PA than of procaine. The half-time for elimination of PA is three to four hours in patients with normal renal function, but reduced creatinine clearance and advancing age each prolong the half-time of elimination of PA.
## Structure
- Procainamide Hydrochloride Injection, USP is a sterile, nonpyrogenic solution of procainamide hydrochloride in water for injection. Each milliliter of the 2 mL vial contains procainamide hydrochloride 500 mg; methylparaben 1 mg and sodium metabisulfite 1.8 mg added in water for injection. Each milliliter of the 10 mL vial contains procainamide hydrochloride 100 mg; methylparaben 1 mg and sodium metabisulfite 0.8 mg added in water for injection. In both formulations, the solution may contain hydrochloric acid and/or sodium hydroxide for pH adjustment. pH 5.0 (4.0 to 6.0). Headspace nitrogen gassed.
- Procainamide Hydrochloride Injection is intended for intravenous or intramuscular administration.
- Procainamide hydrochloride, a Group 1A cardiac antiarrhythmic drug, is ρ-amino-N-[2-(diethylamino) ethyl] benzamide mono-hydrochloride. It has the following structural formula:
- It differs from procaine which is the p-aminobenzoyl ester of 2-(diethylamino)-ethanol. Procainamide as the free base has a pKa of 9.23; the monohydrochloride is very soluble in water.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Procainamide in the drug label.
## Pharmacokinetics
- A significant fraction of the circulating PA may be metabolized in hepatocytes to N-acetylprocainamide (NAPA), ranging from 16 to 21 percent of an administered dose in “slow acetylators” to 24 to 33 percent in “fast-acetylators”. Since NAPA also has significant antiarrhythmic activity and somewhat slower renal clearance than PA, both hepatic acetylation rate capability and renal function, as well as age, have significant effects on the effective biologic half-time of therapeutic action of administered PA and the NAPA derivative. Trace amounts may be excreted in the urine as free and conjugated ρ-aminobenzoic acid, 30 to 60 percent as unchanged PA, and 6 to 52 percent as the NAPA derivative. Both PA and NAPA are eliminated by active tubular secretion as well as by glomerular filtration. Action of PA on the central nervous system is not prominent, but high plasma concentrations may cause tremors. While therapeutic plasma levels for PA have been reported to be 3 to 10 mcg/mL certain patients such as those with sustained ventricular tachycardia, may need higher levels for adequate control. This may justify the increased risk of toxicity. Where programmed ventricular stimulation has been used to evaluate efficacy of PA in preventing recurrent ventricular tachyarrhythmias, higher plasma levels (mean, 13.6 mcg/mL) of PA were found necessary for adequate control.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long-term studies in animals have not been performed.
# Clinical Studies
There is limited information regarding Clinical Studies of Procainamide in the drug label.
# How Supplied
- Procainamide Hydrochloride Injection, USP is available in multiple-dose 10 mL vials providing 100 mg procainamide hydrochloride per mL and 2 mL vials providing 500 mg procainamide hydrochloride per mL.
- The solutions, which are clear and colorless initially, may develop a slightly yellow color in time. This does not indicate a change which should preclude its use, but a solution any darker than light amber or otherwise discolored should not be used.
- Store at 20 to 25°C (68 to 77°F).
## Storage
There is limited information regarding Procainamide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- The patient should be encouraged to disclose any past history of drug sensitivity, especially to procaine or other local anesthetic agents, or aspirin, and to report any history of kidney disease, congestive heart failure, myasthenia gravis, liver disease, or lupus erythematosus.
- The patient should be counseled to report any symptoms of arthralgia, myalgia, fever, chills, skin rash, easy bruising, sore throat or sore mouth, infections, dark urine or icterus, wheezing, muscular weakness, chest or abdominal pain, palpitations, nausea, vomiting, anorexia, diarrhea, hallucinations, dizziness, or depression.
# Precautions with Alcohol
- Alcohol-Procainamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Procanbid®[7]
# Look-Alike Drug Names
- Procanbid® — probenecid[8]
- Procanbid® — Procan SR®[8]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Procainamide | |
46893b90570d15e072c9ce509badd276f00d205b | wikidoc | Procarbazine | Procarbazine
# 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
Procarbazine is an alkylating agent that is FDA approved for the treatment of Stage III and IV Hodgkin's disease used as part of the MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) regimen. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, vomiting, hemolysis, myelosuppression, neurotoxicity, peripheral neuropathy.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- procarbazine is indicated for use in combination with other anticancer drugs for the treatment of Stage III and IV Hodgkin's disease. procarbazine is used as part of the MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) regimen.
- The following doses are for administration of the drug as a single agent. When used in combination with other anticancer drugs, the procarbazine dose should be appropriately reduced, eg, in the MOPP regimen, the procarbazine dose is 100 mg/m2 daily for 14 days. All dosages are based on the patient's actual weight. However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.
- Adults: To minimize the nausea and vomiting experienced by a high percentage of patients beginning procarbazine therapy, single or divided doses of 2 to 4 mg/kg/day for the first week are recommended. Daily dosage should then be maintained at 4 to 6 mg/kg/day until maximum response is obtained or until the white blood count falls below 4000/cmm or the platelets fall below 100,000/cmm. When maximum response is obtained, the dose may be maintained at 1 to 2 mg/kg/day. Upon evidence of hematologic or other toxicity , the drug should be discontinued until there has been satisfactory recovery. After toxic side effects have subsided, therapy may then be resumed at the discretion of the physician, based on clinical evaluation and appropriate laboratory studies, at a dosage of 1 to 2 mg/kg/day.
- Pediatric Patients: Very close clinical monitoring is mandatory. Undue toxicity, evidenced by tremors, coma and convulsions, has occurred in a few cases. Dosage, therefore, should be individualized. The following dosage schedule is provided as a guideline only.
- Fifty (50) mg per square meter of body surface per day is recommended for the first week. Dosage should then be maintained at 100 mg per square meter of body surface per day until maximum response is obtained or until leukopenia or thrombocytopeniaoccurs. When maximum response is attained, the dose may be maintained at 50 mg per square meter of body surface per day. Upon evidence of hematologic or other toxicity , the drug should be discontinued until there has been satisfactory recovery, based on clinical evaluation and appropriate laboratory tests. After toxic side effects have subsided, therapy may then be resumed.
- Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-6 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of procarbazine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of procarbazine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of procarbazine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of procarbazine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of procarbazine in pediatric patients.
# Contraindications
- procarbazine is contraindicated in patients with known Hypersensitivity to the drug or inadequate marrow reserve as demonstrated by bone marrow aspiration. Due consideration of this possible state should be given to each patient who has leukopenia, thrombocytopeniaor anemia.
# Warnings
- To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because procarbazine exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (eg, amitriptyline HCI, imipramine HCI) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes.
### Precautions
- Undue toxicity may occur if procarbazine is used in patients with impairment of renal and/or hepatic function. When appropriate, hospitalization for the initial course of treatment should be considered.
- If radiation or a chemotherapeutic agent known to have marrow-depressant activity has been used, an interval of one month or longer without such therapy is recommended before starting treatment with procarbazine . The length of this interval may also be determined by evidence of bone marrow recovery based on successive bone marrow studies.
- Prompt cessation of therapy is recommended if any one of the following occurs:
- Central nervous system signs or symptoms such as paresthesias, neuropathies or confusion.
- leukopenia (white blood count under 4000).
- thrombocytopenia(platelets under 100,000).
- Hypersensitivity reaction.
- Stomatitis - The first small ulceration or persistent spot soreness around the oral cavity is a signal for cessation of therapy.
- Diarrhea - Frequent bowel movements or watery stools.
- Hemorrhage or bleeding tendencies.
- Bone marrow depression often occurs 2 to 8 weeks after the start of treatment. If leukopenia occurs, hospitalization of the patient may be needed for appropriate treatment to prevent systemic infection.
# Adverse Reactions
## Clinical Trials Experience
- leukopenia, anemia and thrombopenia occur frequently. nausea and vomiting are the most commonly reported side effects.
- Other adverse reactions are:
- Pancytopenia; eosinophilia; hemolytic anemia; bleeding tendencies such as petechiae, purpura, epistaxis and hemoptysis.
- Hepatic dysfunction, jaundice, Stomatitis, hematemesis, melena, Diarrhea, dysphagia, anorexia, abdominal pain, constipation, dry mouth.
- Coma, convulsions, neuropathy, ataxia, paresthesia, nystagmus, diminished reflexes, falling, foot drop, headache, dizziness, unsteadiness.
- Hypotension, tachycardia, syncope.
- Retinal Hemorrhage, papilledema, photophobia, diplopia, inability to focus.
- Pneumonitis, pleural effusion, cough.
- Herpes, dermatitis, pruritus, alopecia, hyperpigmentation, rash, urticaria, flushing.
- Generalized allergic reactions.
- Hematuria, urinary frequency, nocturia.
- Pain, including myalgia and arthralgia; tremors.
- Hallucinations, depression, apprehension, nervousness, confusion, nightmares.
- Gynecomastia in prepubertal and early pubertal boys.
- Intercurrent infections, hearing loss, pyrexia, diaphoresis, lethargy, weakness, fatigue, edema, chills, insomnia, slurred speech, hoarseness, drowsiness.
- Second nonlymphoid malignancies (including lung cancer, acute myelocytic leukemia and malignant myelosclerosis) and azoospermia have been reported in patients with Hodgkin's disease treated with procarbazine in combination with other chemotherapy and/or radiation. The risks of secondary lung cancer from treatment appear to be multiplied by tobacco use.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of procarbazine in the drug label.
# Drug Interactions
- No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- procarbazine hydrochloride can cause fetal harm when administered to a pregnant woman. While there are no adequate and well-controlled studies with procarbazine hydrochloride in pregnant women, there are case reports of malformations in the offspring of women who were exposed to procarbazine hydrochloride in combination with other antineoplastic agents during pregnancy. procarbazine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. procarbazine hydrochloride is teratogenic in the rat when given at doses approximately 4 to 13 times the maximum recommended human therapeutic dose of 6 mg/kg/day.
- procarbazine hydrochloride has not been adequately studied in animals for its effects on peri- and postnatal development. However, neurogenic tumors were noted in the offspring of rats given intravenous injections of 125 mg/kg of procarbazine hydrochloride on day 22 of gestation. Compounds which inhibit DNA, RNA and protein synthesis might be expected to have adverse effects on peri- and postnatal development.
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of procarbazine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of procarbazine during labor and delivery.
### Nursing Mothers
- It is not known whether procarbazine is excreted in human milk. Because of the potential for tumorigenicity shown for procarbazine hydrochloride in animal studies, mothers should not nurse while receiving this drug.
### Pediatric Use
- Undue toxicity, evidenced by tremors, coma and convulsions, has occurred in a few cases. Dosage, therefore, should be individualized . Very close clinical monitoring is mandatory.
### Geriatic Use
There is no FDA guidance on the use of procarbazine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of procarbazine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of procarbazine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of procarbazine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of procarbazine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of procarbazine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of procarbazine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Baseline laboratory data should be obtained prior to initiation of therapy. The hematologic status as indicated by hemoglobin, hematocrit, white blood count (WBC), differential, reticulocytes and platelets should be monitored closely - at least every 3 or 4 days.
- Hepatic and renal evaluation are indicated prior to beginning therapy. Urinalysis, transaminase, alkaline phosphatase and blood urea nitrogen tests should be repeated at least weekly.
# IV Compatibility
There is limited information regarding IV Compatibility of procarbazine in the drug label.
# Overdosage
- The major manifestations of overdosage with procarbazine would be anticipated to be nausea, vomiting, enteritis, Diarrhea, hypotension, tremors, convulsions and coma. Treatment should consist of either the administration of an emetic or gastric lavage. General supportive measures such as intravenous fluids are advised. Since the major toxicity of procarbazine hydrochloride is hematologic and hepatic, patients should have frequent complete blood counts and liver function tests throughout their period of recovery and for a minimum of two weeks thereafter. Should abnormalities appear in any of these determinations, appropriate measures for correction and stabilization should be immediately undertaken.
- The estimated mean lethal dose of procarbazine hydrochloride in laboratory animals varied from approximately 150 mg/kg in rabbits to 1300 mg/kg in mice.
# Pharmacology
## Mechanism of Action
- The precise mode of cytotoxic action of procarbazine has not been clearly defined. There is evidence that the drug may act by inhibition of protein, RNA and DNA synthesis. Studies have suggested that procarbazine may inhibit transmethylation of methyl groups of methionine into t-RNA. The absence of functional t-RNA could cause the cessation of protein synthesis and consequently DNA and RNA synthesis. In addition, procarbazine may directly damage DNA. Hydrogen peroxide, formed during the auto-oxidation of the drug, may attack protein sulfhydryl groups contained in residual protein which is tightly bound to DNA.
## Structure
- procarbazine (procarbazine hydrochloride), a hydrazine derivative antineoplastic agent, is available as capsules containing the equivalent of 50 mg procarbazine as the hydrochloride. Each capsule also contains cornstarch, mannitol and talc. Gelatin capsule shells contain parabens (methyl and propyl), potassium sorbate, titanium dioxide, FD&C Yellow No. 6 and D&C Yellow No. 10.
- Chemically, procarbazine hydrochloride is N-isopropyl-α-(2-methylhydrazino)-p-toluamide monohydrochloride. It is a white to pale yellow crystalline powder which is soluble but unstable in water or aqueous solutions. The molecular weight of procarbazine hydrochloride is 257.76 and the structural formula is:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of procarbazine in the drug label.
## Pharmacokinetics
- procarbazine is metabolized primarily in the liver and kidneys. The drug appears to be auto-oxidized to the azo derivative with the release of hydrogen peroxide. The azo derivative isomerizes to the hydrazone, and following hydrolysis splits into a benzylaldehyde derivative and methylhydrazine. The methylhydrazine is further degraded to CO2 and CH4 and possibly hydrazine, whereas the aldehyde is oxidized to N-isopropylterephthalamic acid, which is excreted in the urine.
- procarbazine is rapidly and completely absorbed. Following oral administration of 30 mg of 14C-labeled procarbazine, maximum peak plasma radioactive concentrations were reached within 60 minutes.
- After intravenous injection, the plasma half-life of procarbazine is approximately 10 minutes. Approximately 70% of the radioactivity is excreted in the urine as N-isopropylterephthalamic acid within 24 hours following both oral and intravenous administration of 14C-labeled procarbazine.
- procarbazine crosses the blood-brain barrier and rapidly equilibrates between plasma and cerebrospinal fluid after oral administration.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- The carcinogenicity of procarbazine hydrochloride in mice, rats and monkeys has been reported in a considerable number of studies. Instances of a second nonlymphoid malignancy, including lung cancer and acute myelocytic leukemia, have been reported in patients with Hodgkin's disease treated with procarbazine in combination with other chemotherapy and/or radiation. The risks of secondary lung cancer from treatment appear to be multiplied by tobacco use. The International Agency for Research on Cancer (IARC) considers that there is “sufficient evidence” for the human carcinogenicity of procarbazine hydrochloride when it is given in intensive regimens which include other antineoplastic agents but that there is inadequate evidence of carcinogenicity in humans given procarbazine hydrochloride alone.
- procarbazine hydrochloride has been shown to be mutagenic in a variety of bacterial and mammalian test systems.
- Azoospermia and antifertility effects associated with procarbazine hydrochloride administration in combination with other chemotherapeutic agents for treating Hodgkin's disease have been reported in human clinical studies. Since these patients received multicombination therapy, it is difficult to determine to what extent procarbazine hydrochloride alone was involved in the male germ-cell damage. The usual Segment I fertility/reproduction studies in laboratory animals have not been carried out with procarbazine hydrochloride. However, compounds which inhibit DNA, RNA and/or protein synthesis might be expected to have adverse effects on gametogenesis. Unscheduled DNA synthesis in the testis of rabbits and decreased fertility in male mice treated with procarbazine hydrochloride have been reported.
# Clinical Studies
There is limited information regarding Clinical Studies of procarbazine in the drug label.
# How Supplied
- Capsules, ivory, containing the equivalent of 50 mg procarbazine as the hydrochloride; in bottles of 100 (NDC 54482-053-01). Imprint on capsules: procarbazine σ sigma-tau.
## Storage
There is limited information regarding Procarbazine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be warned not to drink alcoholic beverages while on procarbazine therapy since there may be an Antabuse (disulfiram)-like reaction. They should also be cautioned to avoid foods with known high tyramine content such as wine, yogurt, ripe cheese and bananas. Over-the-counter drug preparations which contain antihistamines or sympathomimetic drugs should also be avoided. Patients taking procarbazine should also be warned against the use of prescription drugs without the knowledge and consent of their physician. Patients should be advised to discontinue tobacco use.
# Precautions with Alcohol
- Alcohol-procarbazine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Matulane
# Look-Alike Drug Names
There is limited information regarding Procarbazine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Procarbazine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Procarbazine is an alkylating agent that is FDA approved for the treatment of Stage III and IV Hodgkin's disease used as part of the MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) regimen. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, vomiting, hemolysis, myelosuppression, neurotoxicity, peripheral neuropathy.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- procarbazine is indicated for use in combination with other anticancer drugs for the treatment of Stage III and IV Hodgkin's disease. procarbazine is used as part of the MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) regimen.
- The following doses are for administration of the drug as a single agent. When used in combination with other anticancer drugs, the procarbazine dose should be appropriately reduced, eg, in the MOPP regimen, the procarbazine dose is 100 mg/m2 daily for 14 days. All dosages are based on the patient's actual weight. However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.
- Adults: To minimize the nausea and vomiting experienced by a high percentage of patients beginning procarbazine therapy, single or divided doses of 2 to 4 mg/kg/day for the first week are recommended. Daily dosage should then be maintained at 4 to 6 mg/kg/day until maximum response is obtained or until the white blood count falls below 4000/cmm or the platelets fall below 100,000/cmm. When maximum response is obtained, the dose may be maintained at 1 to 2 mg/kg/day. Upon evidence of hematologic or other toxicity , the drug should be discontinued until there has been satisfactory recovery. After toxic side effects have subsided, therapy may then be resumed at the discretion of the physician, based on clinical evaluation and appropriate laboratory studies, at a dosage of 1 to 2 mg/kg/day.
- Pediatric Patients: Very close clinical monitoring is mandatory. Undue toxicity, evidenced by tremors, coma and convulsions, has occurred in a few cases. Dosage, therefore, should be individualized. The following dosage schedule is provided as a guideline only.
- Fifty (50) mg per square meter of body surface per day is recommended for the first week. Dosage should then be maintained at 100 mg per square meter of body surface per day until maximum response is obtained or until leukopenia or thrombocytopeniaoccurs. When maximum response is attained, the dose may be maintained at 50 mg per square meter of body surface per day. Upon evidence of hematologic or other toxicity , the drug should be discontinued until there has been satisfactory recovery, based on clinical evaluation and appropriate laboratory tests. After toxic side effects have subsided, therapy may then be resumed.
- Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-6 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of procarbazine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of procarbazine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of procarbazine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of procarbazine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of procarbazine in pediatric patients.
# Contraindications
- procarbazine is contraindicated in patients with known Hypersensitivity to the drug or inadequate marrow reserve as demonstrated by bone marrow aspiration. Due consideration of this possible state should be given to each patient who has leukopenia, thrombocytopeniaor anemia.
# Warnings
- To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because procarbazine exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (eg, amitriptyline HCI, imipramine HCI) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes.
### Precautions
- Undue toxicity may occur if procarbazine is used in patients with impairment of renal and/or hepatic function. When appropriate, hospitalization for the initial course of treatment should be considered.
- If radiation or a chemotherapeutic agent known to have marrow-depressant activity has been used, an interval of one month or longer without such therapy is recommended before starting treatment with procarbazine . The length of this interval may also be determined by evidence of bone marrow recovery based on successive bone marrow studies.
- Prompt cessation of therapy is recommended if any one of the following occurs:
- Central nervous system signs or symptoms such as paresthesias, neuropathies or confusion.
- leukopenia (white blood count under 4000).
- thrombocytopenia(platelets under 100,000).
- Hypersensitivity reaction.
- Stomatitis - The first small ulceration or persistent spot soreness around the oral cavity is a signal for cessation of therapy.
- Diarrhea - Frequent bowel movements or watery stools.
- Hemorrhage or bleeding tendencies.
- Bone marrow depression often occurs 2 to 8 weeks after the start of treatment. If leukopenia occurs, hospitalization of the patient may be needed for appropriate treatment to prevent systemic infection.
# Adverse Reactions
## Clinical Trials Experience
- leukopenia, anemia and thrombopenia occur frequently. nausea and vomiting are the most commonly reported side effects.
- Other adverse reactions are:
- Pancytopenia; eosinophilia; hemolytic anemia; bleeding tendencies such as petechiae, purpura, epistaxis and hemoptysis.
- Hepatic dysfunction, jaundice, Stomatitis, hematemesis, melena, Diarrhea, dysphagia, anorexia, abdominal pain, constipation, dry mouth.
- Coma, convulsions, neuropathy, ataxia, paresthesia, nystagmus, diminished reflexes, falling, foot drop, headache, dizziness, unsteadiness.
- Hypotension, tachycardia, syncope.
- Retinal Hemorrhage, papilledema, photophobia, diplopia, inability to focus.
- Pneumonitis, pleural effusion, cough.
- Herpes, dermatitis, pruritus, alopecia, hyperpigmentation, rash, urticaria, flushing.
- Generalized allergic reactions.
- Hematuria, urinary frequency, nocturia.
- Pain, including myalgia and arthralgia; tremors.
- Hallucinations, depression, apprehension, nervousness, confusion, nightmares.
- Gynecomastia in prepubertal and early pubertal boys.
- Intercurrent infections, hearing loss, pyrexia, diaphoresis, lethargy, weakness, fatigue, edema, chills, insomnia, slurred speech, hoarseness, drowsiness.
- Second nonlymphoid malignancies (including lung cancer, acute myelocytic leukemia and malignant myelosclerosis) and azoospermia have been reported in patients with Hodgkin's disease treated with procarbazine in combination with other chemotherapy and/or radiation. The risks of secondary lung cancer from treatment appear to be multiplied by tobacco use.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of procarbazine in the drug label.
# Drug Interactions
- No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- procarbazine hydrochloride can cause fetal harm when administered to a pregnant woman. While there are no adequate and well-controlled studies with procarbazine hydrochloride in pregnant women, there are case reports of malformations in the offspring of women who were exposed to procarbazine hydrochloride in combination with other antineoplastic agents during pregnancy. procarbazine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. procarbazine hydrochloride is teratogenic in the rat when given at doses approximately 4 to 13 times the maximum recommended human therapeutic dose of 6 mg/kg/day.
- procarbazine hydrochloride has not been adequately studied in animals for its effects on peri- and postnatal development. However, neurogenic tumors were noted in the offspring of rats given intravenous injections of 125 mg/kg of procarbazine hydrochloride on day 22 of gestation. Compounds which inhibit DNA, RNA and protein synthesis might be expected to have adverse effects on peri- and postnatal development.
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of procarbazine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of procarbazine during labor and delivery.
### Nursing Mothers
- It is not known whether procarbazine is excreted in human milk. Because of the potential for tumorigenicity shown for procarbazine hydrochloride in animal studies, mothers should not nurse while receiving this drug.
### Pediatric Use
- Undue toxicity, evidenced by tremors, coma and convulsions, has occurred in a few cases. Dosage, therefore, should be individualized . Very close clinical monitoring is mandatory.
### Geriatic Use
There is no FDA guidance on the use of procarbazine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of procarbazine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of procarbazine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of procarbazine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of procarbazine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of procarbazine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of procarbazine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Baseline laboratory data should be obtained prior to initiation of therapy. The hematologic status as indicated by hemoglobin, hematocrit, white blood count (WBC), differential, reticulocytes and platelets should be monitored closely - at least every 3 or 4 days.
- Hepatic and renal evaluation are indicated prior to beginning therapy. Urinalysis, transaminase, alkaline phosphatase and blood urea nitrogen tests should be repeated at least weekly.
# IV Compatibility
There is limited information regarding IV Compatibility of procarbazine in the drug label.
# Overdosage
- The major manifestations of overdosage with procarbazine would be anticipated to be nausea, vomiting, enteritis, Diarrhea, hypotension, tremors, convulsions and coma. Treatment should consist of either the administration of an emetic or gastric lavage. General supportive measures such as intravenous fluids are advised. Since the major toxicity of procarbazine hydrochloride is hematologic and hepatic, patients should have frequent complete blood counts and liver function tests throughout their period of recovery and for a minimum of two weeks thereafter. Should abnormalities appear in any of these determinations, appropriate measures for correction and stabilization should be immediately undertaken.
- The estimated mean lethal dose of procarbazine hydrochloride in laboratory animals varied from approximately 150 mg/kg in rabbits to 1300 mg/kg in mice.
# Pharmacology
## Mechanism of Action
- The precise mode of cytotoxic action of procarbazine has not been clearly defined. There is evidence that the drug may act by inhibition of protein, RNA and DNA synthesis. Studies have suggested that procarbazine may inhibit transmethylation of methyl groups of methionine into t-RNA. The absence of functional t-RNA could cause the cessation of protein synthesis and consequently DNA and RNA synthesis. In addition, procarbazine may directly damage DNA. Hydrogen peroxide, formed during the auto-oxidation of the drug, may attack protein sulfhydryl groups contained in residual protein which is tightly bound to DNA.
## Structure
- procarbazine (procarbazine hydrochloride), a hydrazine derivative antineoplastic agent, is available as capsules containing the equivalent of 50 mg procarbazine as the hydrochloride. Each capsule also contains cornstarch, mannitol and talc. Gelatin capsule shells contain parabens (methyl and propyl), potassium sorbate, titanium dioxide, FD&C Yellow No. 6 and D&C Yellow No. 10.
- Chemically, procarbazine hydrochloride is N-isopropyl-α-(2-methylhydrazino)-p-toluamide monohydrochloride. It is a white to pale yellow crystalline powder which is soluble but unstable in water or aqueous solutions. The molecular weight of procarbazine hydrochloride is 257.76 and the structural formula is:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of procarbazine in the drug label.
## Pharmacokinetics
- procarbazine is metabolized primarily in the liver and kidneys. The drug appears to be auto-oxidized to the azo derivative with the release of hydrogen peroxide. The azo derivative isomerizes to the hydrazone, and following hydrolysis splits into a benzylaldehyde derivative and methylhydrazine. The methylhydrazine is further degraded to CO2 and CH4 and possibly hydrazine, whereas the aldehyde is oxidized to N-isopropylterephthalamic acid, which is excreted in the urine.
- procarbazine is rapidly and completely absorbed. Following oral administration of 30 mg of 14C-labeled procarbazine, maximum peak plasma radioactive concentrations were reached within 60 minutes.
- After intravenous injection, the plasma half-life of procarbazine is approximately 10 minutes. Approximately 70% of the radioactivity is excreted in the urine as N-isopropylterephthalamic acid within 24 hours following both oral and intravenous administration of 14C-labeled procarbazine.
- procarbazine crosses the blood-brain barrier and rapidly equilibrates between plasma and cerebrospinal fluid after oral administration.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- The carcinogenicity of procarbazine hydrochloride in mice, rats and monkeys has been reported in a considerable number of studies. Instances of a second nonlymphoid malignancy, including lung cancer and acute myelocytic leukemia, have been reported in patients with Hodgkin's disease treated with procarbazine in combination with other chemotherapy and/or radiation. The risks of secondary lung cancer from treatment appear to be multiplied by tobacco use. The International Agency for Research on Cancer (IARC) considers that there is “sufficient evidence” for the human carcinogenicity of procarbazine hydrochloride when it is given in intensive regimens which include other antineoplastic agents but that there is inadequate evidence of carcinogenicity in humans given procarbazine hydrochloride alone.
- procarbazine hydrochloride has been shown to be mutagenic in a variety of bacterial and mammalian test systems.
- Azoospermia and antifertility effects associated with procarbazine hydrochloride administration in combination with other chemotherapeutic agents for treating Hodgkin's disease have been reported in human clinical studies. Since these patients received multicombination therapy, it is difficult to determine to what extent procarbazine hydrochloride alone was involved in the male germ-cell damage. The usual Segment I fertility/reproduction studies in laboratory animals have not been carried out with procarbazine hydrochloride. However, compounds which inhibit DNA, RNA and/or protein synthesis might be expected to have adverse effects on gametogenesis. Unscheduled DNA synthesis in the testis of rabbits and decreased fertility in male mice treated with procarbazine hydrochloride have been reported.
# Clinical Studies
There is limited information regarding Clinical Studies of procarbazine in the drug label.
# How Supplied
- Capsules, ivory, containing the equivalent of 50 mg procarbazine as the hydrochloride; in bottles of 100 (NDC 54482-053-01). Imprint on capsules: procarbazine σ sigma-tau.
## Storage
There is limited information regarding Procarbazine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be warned not to drink alcoholic beverages while on procarbazine therapy since there may be an Antabuse (disulfiram)-like reaction. They should also be cautioned to avoid foods with known high tyramine content such as wine, yogurt, ripe cheese and bananas. Over-the-counter drug preparations which contain antihistamines or sympathomimetic drugs should also be avoided. Patients taking procarbazine should also be warned against the use of prescription drugs without the knowledge and consent of their physician. Patients should be advised to discontinue tobacco use.
# Precautions with Alcohol
- Alcohol-procarbazine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Matulane
# Look-Alike Drug Names
There is limited information regarding Procarbazine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Procarbazine | |
782f4cc6c602a16fcf1c2435454a58cd9a5d61b7 | wikidoc | Procyclidine | Procyclidine
Procyclidine is an anticholinergic drug principally used for the treatment of drug-induced parkinsonism, akathisia and acute dystonia; Parkinson disease; and idiopathic or secondary dystonia.
# Uses
It is used in patients with parkinsonism and akathisia, and to reduce the side effects of antipsychotic treatment given for schizophrenia. Procyclidine is also a second-line drug for the treatment of Parkinson's disease. It improves tremor but not rigidity or bradykinesia.
Procyclidine is also sometimes used for the treatment of dystonia (but not tardive dyskinesia), a rare disorder that causes abnormal muscle contraction, resulting in twisting postures of limbs, trunk, or face.
# Overdose
Signs of procyclidine overdose are those of an anticholinergic and include confusion, agitation and sleeplessness that can last up to or more than 24 hours. Pupils become dilated and unreactive to light. Tachycardia (fast heart beat), as well as auditory and visual hallucinations have also been reported.
Other known symptoms of overdose are: clumsiness or unsteadiness, being severely drowsy, having a severely dry mouth, nose, or throat, having an altered mood or other mental changes, seizures, being short of breath or having troubled breathing, a dry and warm, flushed skin.
A suspected overdose with severe life-threatening symptoms should immediately be brought to medical attention, where reversal can be attempted with physostigmine administered intravenously or subcutaneously.
# Synthesis
Procyclidine, 1-cyclohexyl-1-phenyl-3-pyrrolidinopropan-1-ol, is synthesized in exactly the same manner as was seen for trihexyphenidyl, except this time the linear synthesis begins with the preparation of 3-(1-pyrrolidino)propiophenone.
In an interesting variation, the ketone is first reacted with phenylmagnesium bromide. Catalytic hydrogenation of the carbinol thus obtained can be stopped after the reduction of only one aromatic ring. | Procyclidine
Procyclidine is an anticholinergic drug principally used for the treatment of drug-induced parkinsonism, akathisia and acute dystonia; Parkinson disease; and idiopathic or secondary dystonia.
# Uses
It is used in patients with parkinsonism and akathisia, and to reduce the side effects of antipsychotic treatment given for schizophrenia. Procyclidine is also a second-line drug for the treatment of Parkinson's disease. It improves tremor but not rigidity or bradykinesia.
Procyclidine is also sometimes used for the treatment of dystonia (but not tardive dyskinesia), a rare disorder that causes abnormal muscle contraction, resulting in twisting postures of limbs, trunk, or face.
# Overdose
Signs of procyclidine overdose are those of an anticholinergic and include confusion, agitation and sleeplessness that can last up to or more than 24 hours. Pupils become dilated and unreactive to light. Tachycardia (fast heart beat), as well as auditory and visual hallucinations have also been reported.
Other known symptoms of overdose are: clumsiness or unsteadiness, being severely drowsy, having a severely dry mouth, nose, or throat, having an altered mood or other mental changes, seizures, being short of breath or having troubled breathing, a dry and warm, flushed skin.
A suspected overdose with severe life-threatening symptoms should immediately be brought to medical attention, where reversal can be attempted with physostigmine administered intravenously or subcutaneously.
# Synthesis
Procyclidine, 1-cyclohexyl-1-phenyl-3-pyrrolidinopropan-1-ol, is synthesized in exactly the same manner as was seen for trihexyphenidyl, except this time the linear synthesis begins with the preparation of 3-(1-pyrrolidino)propiophenone.
In an interesting variation, the ketone is first reacted with phenylmagnesium bromide. Catalytic hydrogenation of the carbinol thus obtained can be stopped after the reduction of only one aromatic ring. | https://www.wikidoc.org/index.php/Procyclidine | |
4ba4a4d6dc676b3c5f15fa1244d14b9846c1904d | wikidoc | Prodynorphin | Prodynorphin
Prodynorphin is a opioid polypeptide hormone involved with chemical signal transduction and cell communication. The gene for prodynorphin is expressed in the endometrium and the striatum, and its gene map locus is 20pter-p12. Prodynorphin is a basic building block of endorphins, the chemical messengers in the brain that appear most heavily involved in the anticipation and experience of pain and the formation of deep emotional bonds, and which are also critical in learning and memory.
The gene is thought to influence perception, as well as susceptibility to drug dependence, and is expressed more readily in human beings than in other primates.
# Evolutionary implications
Most Asian populations of Homo sapiens have two copies of the gene sequence for prodynorphin, whereas East Africas, Middle Easterners and Europeans tend to have three repetitions. Most humans have multiple copies of the regulatory gene sequence for prodynorphin, which is virtually identical among all primates, whereas other primates have only a single copy.
The extent of regulatory gene disparities for prodynorphin, between human and primates, has gained the attention of scientists. There are very few genes known to be directly related to mankind's speciation from other great apes. According to computational biologist researcher Matthew W. Hahn of Indiana University, "This is the first documented instance of a neural gene that has had its regulation shaped by natural selection during human origins."
The prodynorphin enzyme is identical in humans and chimps, but the regulatory promoter sequences have been shown to exhibit marked differences. "Humans have the ability to turn on this gene more easily and more intensely than other primates. Given its function, we believe regulation of this gene was likely important in the evolution of modern humans' mental capacity," said Hahn. | Prodynorphin
Template:Onesource
Prodynorphin is a opioid polypeptide hormone involved with chemical signal transduction and cell communication. The gene for prodynorphin is expressed in the endometrium and the striatum, and its gene map locus is 20pter-p12. Prodynorphin is a basic building block of endorphins, the chemical messengers in the brain that appear most heavily involved in the anticipation and experience of pain and the formation of deep emotional bonds, and which are also critical in learning and memory.
The gene is thought to influence perception, as well as susceptibility to drug dependence, and is expressed more readily in human beings than in other primates.
# Evolutionary implications
Most Asian populations of Homo sapiens have two copies of the gene sequence for prodynorphin, whereas East Africas, Middle Easterners and Europeans tend to have three repetitions. Most humans have multiple copies of the regulatory gene sequence for prodynorphin, which is virtually identical among all primates, whereas other primates have only a single copy.
The extent of regulatory gene disparities for prodynorphin, between human and primates, has gained the attention of scientists. There are very few genes known to be directly related to mankind's speciation from other great apes. According to computational biologist researcher Matthew W. Hahn of Indiana University, "This is the first documented instance of a neural gene that has had its regulation shaped by natural selection during human origins."
The prodynorphin enzyme is identical in humans and chimps, but the regulatory promoter sequences have been shown to exhibit marked differences. "Humans have the ability to turn on this gene more easily and more intensely than other primates. Given its function, we believe regulation of this gene was likely important in the evolution of modern humans' mental capacity," said Hahn. | https://www.wikidoc.org/index.php/Prodynorphin | |
a19a86c7776a49a31775f15c8ae383c70668eddd | wikidoc | Prokineticin | Prokineticin
Prokineticin is a secreted protein that potently contracts gastrointestinal smooth muscle.
Recently, prokineticins have been recognized in humans and other vertebrates. They are thought to be involved in several important physiological processes like neurogenesis, tissue development, angiogenesis, and nociception. Other important physiological roles the Bv8/Prokineticins (PKs) are involved in may include cancer, reproduction, and regulating physiological functions that influence circadian rhythms like hormone secretion, ingestive behaviors, and the sleep/wake cycle.
Mutations in the PROK2 (also known as KAL4) gene have been implicated in hypogonadotropic hypogonadism and gynecomastia. | Prokineticin
Prokineticin is a secreted protein that potently contracts gastrointestinal smooth muscle.[2]
Recently, prokineticins have been recognized in humans and other vertebrates.[3] They are thought to be involved in several important physiological processes like neurogenesis, tissue development, angiogenesis, and nociception.[3] Other important physiological roles the Bv8/Prokineticins (PKs) are involved in may include cancer, reproduction, and regulating physiological functions that influence circadian rhythms like hormone secretion, ingestive behaviors, and the sleep/wake cycle.[4]
Mutations in the PROK2 (also known as KAL4) gene have been implicated in hypogonadotropic hypogonadism and gynecomastia.[5] | https://www.wikidoc.org/index.php/Prokineticin | |
5cd50126c65fe6c4805ab8d6d23c3cb4b010b08e | wikidoc | Prolotherapy | Prolotherapy
Note for recent edits Captcha has been blocking external links so additional references have been placed in an "Additional References" section until administration can correct that. See support desk comment "When editing, asking to type two words in a box that does not exist" (Dr Reeves)
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# Overview
Prolotherapy ("Proliferative Injection Therapy") involves injecting an otherwise non-pharmacological and non-active proliferant or irritant solution into the body, generally in the region of tendons or ligaments for the purpose of strengthening weakened connective tissue and alleviating musculoskeletal pain. In 2005, Robert D. Sheeler, MD (Medical Editor, Mayo Clinic Health letter), who first learned of prolotherapy through C. Everett Koop’s interest in the treatment, listed ankles, knees, elbows, and sacroiliac joint in the low back as areas most likely to benefit from prolotherapy treatment and stated that "unlike corticosteroid injections — which may provide temporary relief — prolotherapy involves improving the injected tissue by stimulating tissue growth."
Stimulation of tissue growth by dextrose prolotherapy was confirmed by Mayo Clinic researchers (Biomechanics Laboratory, Division of Orthopedic Research, and Department of Neurology),(Oh 2008, Yoshii 2009, Yoshii 2011, Yoshii 2014), who performed four controlled studies (three blinded) to determine if dextrose could thicken and strengthen a rabbit ligament without inflammation and with production of normal tissue without any scarring. Their purpose was to thicken the ligament that is responsible for producing carpal tunnel syndrome so that they would have an animal model for research. In the process, results in every study showed that 10% dextrose injection, compared to saline injection, consistently resulted in a increase in total energy absorption and tensile load tolerated by the ligament (transverse carpal ligament equivalent) before rupture. The ligament approximately doubled in thickness and, histologically, normal tissue was seen without scarring. This proliferation effect with normally organized fibrosis (growth of connective tissue) in the absence of scarring distinguishes prolotherapy from sclerotherapy.
Prolotherapy is often used as an treatment option rather than antiinflammatory approaches (such as steroids or non steroid antiinflammatory drugs ) in the presence of chronic pain involving ligaments and tendons, as chronic changes in ligaments and tendons are primarily degenerative in nature rather than primarily inflammatory. (Scott 2015). Prolotherapy is also used as an alternative in the presence of chronic pain involving joints, in which histologic findings are also primarily degenerative. Lack of benefit in general with anti-inflammatory approaches on the clinical course of osteoarthritis is emphasized by a recent clinical trial of saline versus steroid (triamcinolone) injection in knee osteoarthritis showing unequivocal acceleration of cartilage loss with quarterly injection of steroid for 2 years in comparison with a saline control injection, reported in JAMA. (McAlindon 2017)
Prolotherapy has enjoyed increased acceptance within the medical community, especially in light of the focus being given to regenerative medicine as a discipline. Eighteen randomized controlled trials were found on PubMed as of June, 2017. (see Evidence Based Medicine section below)
# Prolotherapy in clinical practice
## Solutions
Prolotherapy solutions are commonly injected into the area where connective tissue has been weakened or damaged through injury or strain. The injection is placed into ligaments, into joint capsules or where tendon connects to bone. Many points may require injection. The most commonly used solutions in order from most common to less commonly used and in order from least to most inflammatory include Dextrose, P2G (a combination of dextrose and low d ose Phenol and Glycerine, and sodium morrhuate.
## Mechanism
The mechanism is often described as initiation of a brief inflammatory reaction to stimulate the repair cascade, but is likely complex. (Rabago 2017-1) Time-limited reactive inflammation has been confirmed in animal models in which dextrose concentrations exceed 12.5% (Jensen 2008), some evidence of cartilage cell growth has been suggested upon repeat arthroscopy in humans,(Topol 2016), ligament growth without inflammatory required was described above in a series of controlled studies,(see overview section) and a direct therapeutic sensorineural effect has been proposed with early clinical support. (Yelland 2009 )
The theory of inflammatory prolotherapy was nicely summarized by Allen R Banks, Ph.D., in "A Rationale for Prolotherapy". Robert G. Schwartz, MD has also published a biochemical literature review on the topic "Prolotherapy: A Literature Review and Retrospective Study". Recent reviews of basic science are available in several recent publications which cover the spectrum of mechanisms. (Rabago 2017-2, Reeves 2016)
## Typical Treatment Course
Most clinicians say that at least three injections, done at 2-8 week intervals, are typically required to accomplish the desired result, but accuracy and completeness of treatment are likely key to treatment efficiency, and determination of optimal treatment approaches will require diagnosis-specific research. Given the non-proprietary nature of proliferant agents in current use, this will also take considerable time due to lack of financial incentives to support non-pharmacutical research.
## History
Injections of irritant solutions were performed in the late 1800’s to repair hernias and in the early 1900’s for jaw pain due to temporomandibular (jaw) joint laxity. Dr. George Hackett, MD developed the technique of prolotherapy in the 1940’s. Dr. Gustav Hemwall was a pioneer, beginning his studies and treatments in the 1950s and continuing until the mid 1990s. In his study of almost 10,000 prolotherapy cases, Dr. Hackett found that over 99 percent of the patients found relief from their chronic pain.
## Guidelines used by practitioners as indicators for prolotherapy
- Recurrent swelling or fullness involving a joint or muscular region
- Popping, clicking, grinding, or catching sensations with movement
- A sensation of the “leg giving way” with associated back pain
- Temporary benefit from chiropractic manipulation or manual mobilization that fails to ultimately resolve the pain
- Distinct tender points and “jump signs” along the bone at tendon or ligament attachments
- Numbness, tingling, aching, or burning, referred into an upper or lower extremity
- Recurrent headache, face pain, jaw pain, ear pain
- Chest pain with tenderness along the rib attachments on the spine or along the front of the chest
- Spine pain that does not respond to surgery, or whose origin is not clear or consistent based on extensive studies
# Evidence based medicine
General Narrative Review Articles 2005 to 2011
The first comprehensive review article on safety and potential efficacy of prolotherapy was published in 2005. (Rabago 2005) On the basis of 34 case reports or case series, 2 nonrandomized controlled trials, and 6 RCTs, prolotherapy was considered “safe when performed by an experienced clinician” but “conclusive data for prolotherapy as a treatment for musculoskeletal pain was lacking”. Since 2010 there has been an acceleration in publication of randomized controlled trials (RCTs) for dextrose prolotherapy and both general and specific systematic reviews. A 2011 review noted growing evidence to recommend use in tendinopathies and early evidence of benefit in osteoarthritis. (Distel 2011)
General Narrative Reviews 2012 to Present and Strength of Recommendations
In the field of general practice, a practical way to consider the merit of employing a specific treatment for a specific condition was developed by Ebell et al,(Ebell 2004) and has been increasingly utilized. It is called the Strength of Recommendation Taxonomy and is composed of 3 assessments, study quality (bias), study quantity (and number of subjects), and study consistency (do studies agree?). Strength of recommendations were included as part of narrative reviews beginning with Covey at al (Covey 2015) who assigned a level A strength of recommendation (SOR) (recommendation based on consistent and good-quality patient-oriented evidence) for dextrose prolotherapy for knee osteoarthritis and level B SOR (recommendation based on inconsistent or limited-quality patient-oriented evidence) for Achilles tendinopathy, lateral epicondylosis, Osgood Schlatter disease, and plantar fasciosis. Two 2016 general review articles expanded level B strength of recommendations to include low back/sacroiliac pain and rotator cuff tendinopathy. (Reeves 2016, Hauser 2016) A SOR for the use of prolotherapy in acute pain, myofascial pain or as first-line therapy, cannot be determined based on current literature. (Hauser 2016) It is important to keep in mind, when considering the assignment of strength of recommendation, that a single RCT cannot lead to a level A SOR recommendation. Thus despite a single high quality study the SOR will only be B (recommendation based on inconsistent or limited-quality patient-oriented evidence). In a field in which research is virtually all self-funded, with no proprietary interest, studies will accumulate slowly and a level B recommendation may mean a "poor quantity" of studies or low patient numbers, rather than "poor quality".
Back pain/Sacroiliac Pain Articles: Treatment Comparison Trials Rather Than Placebo Trials Due to Extensive Needling Effects
A 2007 review of prolotherapy in adults with chronic low-back pain found unclear evidence of effect. (Dagenais 2007). There was tentative evidence of benefit when used with other low back pain treatments. (Distel 2011) These prior reviews focused primarily on phenol-containing solutions, which have declined in use in favor of hypertonic dextrose which is less inflammatory and better studied. (Rabago 2017) More recent reviews of dextrose-only studies interpreted the dextrose-only controlled trials as treatment comparison studies in that the first study (Yelland 2003) utilized a control with substantial needling effect on multiple occasions and both saline and dextrose groups had a persistent benefit with "greater than 50% pain reduction in 46% and 36% of dextrose and saline groups respectively at 12 months," (Reeves 2016) and the second study favored dextrose over steroid injection (triamcinolone) for injection of the SI joint.(Kim 2010) Recent reviews conclude that evidence of benefit remains tentative (level B) for dextrose prolotherapy in low back/sacroiliac pain based on two favorable but inconsistent treatment comparison studies. (Reeves 2016. Hauser 2016)
# Criticism
In 1999, Medicare considered the low back clinical trials on prolotherapy at that time (which were with P2G only) and determined that prolotherapy would remain a non-covered service for low back pain. cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=68&fromdb=true Their concerns were insufficient patient numbers in the trials (only 160 patients to that point) and flaws in the clinical studies. Other insurers have mirrored Medicare's position, and, over the years, although randomized trials have continued to increase in numbers and quality, the number of studies in any one area have not accumulated sufficiently to challenge Medicare's determination. Level A SOR requires multiple randomized controlled trials that agree and the study numbers are diluted across a great variety of clinical conditions. Treatment of knee osteoarthritis with prolotherapy has reached a level A SOR, and some insurers cover prolotherapy for knee osteoarthritis. | Prolotherapy
Editors-In-Chief: Robert G. Schwartz, M.D. [1], Piedmont Physical Medicine and Rehabilitation, P.A.; Dean Reeves, M.D., Clinical assistant/associate professor University of Kansas Medical School, Dept of Physical Medicine and Rehabilitation 1986-2015; Felix Linetsky, M.D., Clinical Associate Professor, Department of Osteopathic Principles and Practice, Nova Southeastern College of Osteopathic Medicine [2]
Note for recent edits Captcha has been blocking external links so additional references have been placed in an "Additional References" section until administration can correct that. See support desk comment "When editing, asking to type two words in a box that does not exist" (Dr Reeves)
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# Overview
Prolotherapy ("Proliferative Injection Therapy") involves injecting an otherwise non-pharmacological and non-active proliferant or irritant solution into the body, generally in the region of tendons or ligaments for the purpose of strengthening weakened connective tissue and alleviating musculoskeletal pain. In 2005, Robert D. Sheeler, MD (Medical Editor, Mayo Clinic Health letter), who first learned of prolotherapy through C. Everett Koop’s interest in the treatment, listed ankles, knees, elbows, and sacroiliac joint in the low back as areas most likely to benefit from prolotherapy treatment and stated that "unlike corticosteroid injections — which may provide temporary relief — prolotherapy involves improving the injected tissue by stimulating tissue growth."[1]
Stimulation of tissue growth by dextrose prolotherapy was confirmed by Mayo Clinic researchers (Biomechanics Laboratory, Division of Orthopedic Research, and Department of Neurology),(Oh 2008, Yoshii 2009, Yoshii 2011, Yoshii 2014), who performed four controlled studies (three blinded) to determine if dextrose could thicken and strengthen a rabbit ligament without inflammation and with production of normal tissue without any scarring. Their purpose was to thicken the ligament that is responsible for producing carpal tunnel syndrome so that they would have an animal model for research. In the process, results in every study showed that 10% dextrose injection, compared to saline injection, consistently resulted in a increase in total energy absorption and tensile load tolerated by the ligament (transverse carpal ligament equivalent) before rupture. The ligament approximately doubled in thickness and, histologically, normal tissue was seen without scarring. This proliferation effect with normally organized fibrosis (growth of connective tissue) in the absence of scarring distinguishes prolotherapy from sclerotherapy.
Prolotherapy is often used as an treatment option rather than antiinflammatory approaches (such as steroids or non steroid antiinflammatory drugs [NSAIDS]) in the presence of chronic pain involving ligaments and tendons, as chronic changes in ligaments and tendons are primarily degenerative in nature rather than primarily inflammatory. (Scott 2015). Prolotherapy is also used as an alternative in the presence of chronic pain involving joints, in which histologic findings are also primarily degenerative. Lack of benefit in general with anti-inflammatory approaches on the clinical course of osteoarthritis is emphasized by a recent clinical trial of saline versus steroid (triamcinolone) injection in knee osteoarthritis showing unequivocal acceleration of cartilage loss with quarterly injection of steroid for 2 years in comparison with a saline control injection, reported in JAMA. (McAlindon 2017)
Prolotherapy has enjoyed increased acceptance within the medical community, especially in light of the focus being given to regenerative medicine as a discipline. Eighteen randomized controlled trials were found on PubMed as of June, 2017. (see Evidence Based Medicine section below)
# Prolotherapy in clinical practice
## Solutions
Prolotherapy solutions are commonly injected into the area where connective tissue has been weakened or damaged through injury or strain. The injection is placed into ligaments, into joint capsules or where tendon connects to bone. Many points may require injection. The most commonly used solutions in order from most common to less commonly used and in order from least to most inflammatory include Dextrose, P2G (a combination of dextrose and low d ose Phenol and Glycerine, and sodium morrhuate.
## Mechanism
The mechanism is often described as initiation of a brief inflammatory reaction to stimulate the repair cascade, but is likely complex. (Rabago 2017-1) Time-limited reactive inflammation has been confirmed in animal models in which dextrose concentrations exceed 12.5% (Jensen 2008), some evidence of cartilage cell growth has been suggested upon repeat arthroscopy in humans,(Topol 2016), ligament growth without inflammatory required was described above in a series of controlled studies,(see overview section) and a direct therapeutic sensorineural effect has been proposed with early clinical support. (Yelland 2009 )
The theory of inflammatory prolotherapy was nicely summarized by Allen R Banks, Ph.D., in "A Rationale for Prolotherapy".[2] Robert G. Schwartz, MD has also published a biochemical literature review on the topic "Prolotherapy: A Literature Review and Retrospective Study"[4]. Recent reviews of basic science are available in several recent publications which cover the spectrum of mechanisms. (Rabago 2017-2, Reeves 2016)
## Typical Treatment Course
Most clinicians say that at least three injections, done at 2-8 week intervals, are typically required to accomplish the desired result, but accuracy and completeness of treatment are likely key to treatment efficiency, and determination of optimal treatment approaches will require diagnosis-specific research. Given the non-proprietary nature of proliferant agents in current use, this will also take considerable time due to lack of financial incentives to support non-pharmacutical research.
## History
Injections of irritant solutions were performed in the late 1800’s to repair hernias and in the early 1900’s for jaw pain due to temporomandibular (jaw) joint laxity. Dr. George Hackett, MD developed the technique of prolotherapy in the 1940’s. Dr. Gustav Hemwall was a pioneer, beginning his studies and treatments in the 1950s and continuing until the mid 1990s. In his study of almost 10,000 prolotherapy cases, Dr. Hackett found that over 99 percent of the patients found relief from their chronic pain. [3]
## Guidelines used by practitioners as indicators for prolotherapy
- Recurrent swelling or fullness involving a joint or muscular region
- Popping, clicking, grinding, or catching sensations with movement
- A sensation of the “leg giving way” with associated back pain
- Temporary benefit from chiropractic manipulation or manual mobilization that fails to ultimately resolve the pain
- Distinct tender points and “jump signs” along the bone at tendon or ligament attachments
- Numbness, tingling, aching, or burning, referred into an upper or lower extremity
- Recurrent headache, face pain, jaw pain, ear pain
- Chest pain with tenderness along the rib attachments on the spine or along the front of the chest
- Spine pain that does not respond to surgery, or whose origin is not clear or consistent based on extensive studies
# Evidence based medicine
General Narrative Review Articles 2005 to 2011
The first comprehensive review article on safety and potential efficacy of prolotherapy was published in 2005. (Rabago 2005) On the basis of 34 case reports or case series, 2 nonrandomized controlled trials, and 6 RCTs, prolotherapy was considered “safe when performed by an experienced clinician” but “conclusive data for prolotherapy as a treatment for musculoskeletal pain was lacking”. Since 2010 there has been an acceleration in publication of randomized controlled trials (RCTs) for dextrose prolotherapy and both general and specific systematic reviews. A 2011 review noted growing evidence to recommend use in tendinopathies and early evidence of benefit in osteoarthritis. (Distel 2011)
General Narrative Reviews 2012 to Present and Strength of Recommendations
In the field of general practice, a practical way to consider the merit of employing a specific treatment for a specific condition was developed by Ebell et al,(Ebell 2004) and has been increasingly utilized. It is called the Strength of Recommendation Taxonomy and is composed of 3 assessments, study quality (bias), study quantity (and number of subjects), and study consistency (do studies agree?). Strength of recommendations were included as part of narrative reviews beginning with Covey at al (Covey 2015) who assigned a level A strength of recommendation (SOR) (recommendation based on consistent and good-quality patient-oriented evidence) for dextrose prolotherapy for knee osteoarthritis and level B SOR (recommendation based on inconsistent or limited-quality patient-oriented evidence) for Achilles tendinopathy, lateral epicondylosis, Osgood Schlatter disease, and plantar fasciosis. Two 2016 general review articles expanded level B strength of recommendations to include low back/sacroiliac pain and rotator cuff tendinopathy. (Reeves 2016, Hauser 2016) A SOR for the use of prolotherapy in acute pain, myofascial pain or as first-line therapy, cannot be determined based on current literature. (Hauser 2016) It is important to keep in mind, when considering the assignment of strength of recommendation, that a single RCT cannot lead to a level A SOR recommendation. Thus despite a single high quality study the SOR will only be B (recommendation based on inconsistent or limited-quality patient-oriented evidence). In a field in which research is virtually all self-funded, with no proprietary interest, studies will accumulate slowly and a level B recommendation may mean a "poor quantity" of studies or low patient numbers, rather than "poor quality".
Back pain/Sacroiliac Pain Articles: Treatment Comparison Trials Rather Than Placebo Trials Due to Extensive Needling Effects
A 2007 review of prolotherapy in adults with chronic low-back pain found unclear evidence of effect. (Dagenais 2007). There was tentative evidence of benefit when used with other low back pain treatments. (Distel 2011) These prior reviews focused primarily on phenol-containing solutions, which have declined in use in favor of hypertonic dextrose which is less inflammatory and better studied. (Rabago 2017) More recent reviews of dextrose-only studies interpreted the dextrose-only controlled trials as treatment comparison studies in that the first study (Yelland 2003) utilized a control with substantial needling effect on multiple occasions and both saline and dextrose groups had a persistent benefit with "greater than 50% pain reduction in 46% and 36% of dextrose and saline groups respectively at 12 months," (Reeves 2016) and the second study favored dextrose over steroid injection (triamcinolone) for injection of the SI joint.(Kim 2010) Recent reviews conclude that evidence of benefit remains tentative (level B) for dextrose prolotherapy in low back/sacroiliac pain based on two favorable but inconsistent treatment comparison studies. (Reeves 2016. Hauser 2016)
# Criticism
In 1999, Medicare considered the low back clinical trials on prolotherapy at that time (which were with P2G only) and determined that prolotherapy would remain a non-covered service for low back pain. cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=68&fromdb=true Their concerns were insufficient patient numbers in the trials (only 160 patients to that point) and flaws in the clinical studies. Other insurers have mirrored Medicare's position, and, over the years, although randomized trials have continued to increase in numbers and quality, the number of studies in any one area have not accumulated sufficiently to challenge Medicare's determination. Level A SOR requires multiple randomized controlled trials that agree and the study numbers are diluted across a great variety of clinical conditions. Treatment of knee osteoarthritis with prolotherapy has reached a level A SOR, and some insurers cover prolotherapy for knee osteoarthritis. | https://www.wikidoc.org/index.php/Prolotherapy | |
58fbb2d71f2596066e8d2dac1f3a812669a28595 | wikidoc | Proparacaine | Proparacaine
# 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
Proparacaine is a local anesthetic that is FDA approved for the {{{indicationType}}} of anesthesia for procedures on eye.. Common adverse reactions include ophthalmic: conjunctival hemorrhage, corneal erosion, cycloplegia (rare ), passive conjunctival congestion.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
There is limited information regarding Proparacaine FDA-Labeled Indications and Dosage (Adult) in the drug label.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Trigeminal neuralgia
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Proparacaine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness in pediatric patients have not been established; however the use of Proparacaine HCl as a topical ophthalmic anesthetic agent in pediatric patients has been cited in the literature
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Proparacaine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Proparacaine in pediatric patients.
# Contraindications
- Proparacaine ophthalmic solution should be considered contraindicated in patients with known hypersensitivity to any of the ingredients of this preparation.
# Warnings
- Not For Injection - For Topical Ophthalmic Use Only.
- Prolonged use of a topical ocular anesthetic is not recommended. It may produce permanent corneal opacification with accompanying visual loss.
# Adverse Reactions
## Clinical Trials Experience
- Occasional temporary stinging, burning and conjunctival redness may occur with the use of proparacaine. A rare, severe, immediate-type, apparently hyperallergic corneal reaction characterized by acute, intense and diffuse epithelial keratitis, a gray, ground glass appearance, sloughing of large areas of necrotic epithelium, corneal filaments and, sometimes, iritis with descemetitis has been reported.
- Allergic contact dermatitis from proparacaine with drying and fissuring of the fingertips has also been reported.
## Postmarketing Experience
There is limited information regarding Proparacaine Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Proparacaine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with Proparacaine (proparacaine hydrochloride ophthalmic solution, USP) 0.5%. It is also not known whether proparacaine hydrochloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Proparacaine hydrochloride should be administered to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Proparacaine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Proparacaine during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when proparacaine hydrochloride is administered to a nursing woman
### Pediatric Use
- Safety and effectiveness of proparacaine hydrochloride ophthalmic solution in pediatric patients have been established. Use of proparacaine hydrochloride is supported by evidence from adequate and well-controlled studies in adults and children over the age of twelve, and safety information in neonates and other pediatric patients.
### Geriatic Use
- No overall clinical differences in safety or effectiveness have been observed between the elderly and other adult patients
### Gender
There is no FDA guidance on the use of Proparacaine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Proparacaine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Proparacaine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Proparacaine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Proparacaine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Proparacaine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Proparacaine Administration in the drug label.
### Monitoring
There is limited information regarding Proparacaine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Proparacaine and IV administrations.
# Overdosage
There is limited information regarding Proparacaine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Proparacaine ophthalmic solution is a rapidly-acting topical anesthetic, with induced anesthesia lasting approximately 10-20 minutes.
## Structure
- Proparacaine (proparacaine hydrochloride ophthalmic solution, USP) 0.5% is a topical local anesthetic for ophthalmic use. The active ingredient is represented by the structural formula:
- Proparacaine Hydrochloride
- Benzoic acid, 3-amino-4-propoxy-,2-(diethylamino) ethyl ester, monohydrochloride.
- Molecular Weight: 330.85
- Each mL contains: Active: proparacaine hydrochloride 5 mg 0.5%. Preservative: benzalkonium chloride (0.01%). Inactives: glycerin and purified water. The pH may be adjusted with hydrochloric acid and/or sodium hydroxide.
## Pharmacodynamics
There is limited information regarding Proparacaine Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Proparacaine Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Proparacaine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Proparacaine Clinical Studies in the drug label.
# How Supplied
- Proparacaine (proparacaine hydrochloride ophthalmic solution, USP) 0.5% is supplied in 15 mL DROP-TAINER® dispensers.
## Storage
- Bottle must be stored in unit carton to protect contents from light. Store bottles under refrigeration at 2° - 8°C (36° - 46°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Proparacaine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Proparacaine 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 Proparacaine Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Proparacaine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Proparacaine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Proparacaine is a local anesthetic that is FDA approved for the {{{indicationType}}} of anesthesia for procedures on eye.. Common adverse reactions include ophthalmic: conjunctival hemorrhage, corneal erosion, cycloplegia (rare ), passive conjunctival congestion.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
There is limited information regarding Proparacaine FDA-Labeled Indications and Dosage (Adult) in the drug label.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Trigeminal neuralgia
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Proparacaine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness in pediatric patients have not been established; however the use of Proparacaine HCl as a topical ophthalmic anesthetic agent in pediatric patients has been cited in the literature
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Proparacaine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Proparacaine in pediatric patients.
# Contraindications
- Proparacaine ophthalmic solution should be considered contraindicated in patients with known hypersensitivity to any of the ingredients of this preparation.
# Warnings
- Not For Injection - For Topical Ophthalmic Use Only.
- Prolonged use of a topical ocular anesthetic is not recommended. It may produce permanent corneal opacification with accompanying visual loss.
# Adverse Reactions
## Clinical Trials Experience
- Occasional temporary stinging, burning and conjunctival redness may occur with the use of proparacaine. A rare, severe, immediate-type, apparently hyperallergic corneal reaction characterized by acute, intense and diffuse epithelial keratitis, a gray, ground glass appearance, sloughing of large areas of necrotic epithelium, corneal filaments and, sometimes, iritis with descemetitis has been reported.
- Allergic contact dermatitis from proparacaine with drying and fissuring of the fingertips has also been reported.
## Postmarketing Experience
There is limited information regarding Proparacaine Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Proparacaine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with Proparacaine (proparacaine hydrochloride ophthalmic solution, USP) 0.5%. It is also not known whether proparacaine hydrochloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Proparacaine hydrochloride should be administered to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Proparacaine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Proparacaine during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when proparacaine hydrochloride is administered to a nursing woman
### Pediatric Use
- Safety and effectiveness of proparacaine hydrochloride ophthalmic solution in pediatric patients have been established. Use of proparacaine hydrochloride is supported by evidence from adequate and well-controlled studies in adults and children over the age of twelve, and safety information in neonates and other pediatric patients.
### Geriatic Use
- No overall clinical differences in safety or effectiveness have been observed between the elderly and other adult patients
### Gender
There is no FDA guidance on the use of Proparacaine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Proparacaine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Proparacaine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Proparacaine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Proparacaine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Proparacaine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Proparacaine Administration in the drug label.
### Monitoring
There is limited information regarding Proparacaine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Proparacaine and IV administrations.
# Overdosage
There is limited information regarding Proparacaine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Proparacaine ophthalmic solution is a rapidly-acting topical anesthetic, with induced anesthesia lasting approximately 10-20 minutes.
## Structure
- Proparacaine (proparacaine hydrochloride ophthalmic solution, USP) 0.5% is a topical local anesthetic for ophthalmic use. The active ingredient is represented by the structural formula:
- Proparacaine Hydrochloride
- Benzoic acid, 3-amino-4-propoxy-,2-(diethylamino) ethyl ester, monohydrochloride.
- Molecular Weight: 330.85
- Each mL contains: Active: proparacaine hydrochloride 5 mg 0.5%. Preservative: benzalkonium chloride (0.01%). Inactives: glycerin and purified water. The pH may be adjusted with hydrochloric acid and/or sodium hydroxide.
## Pharmacodynamics
There is limited information regarding Proparacaine Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Proparacaine Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Proparacaine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Proparacaine Clinical Studies in the drug label.
# How Supplied
- Proparacaine (proparacaine hydrochloride ophthalmic solution, USP) 0.5% is supplied in 15 mL DROP-TAINER® dispensers.
## Storage
- Bottle must be stored in unit carton to protect contents from light. Store bottles under refrigeration at 2° - 8°C (36° - 46°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Proparacaine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Proparacaine 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 Proparacaine Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Proparacaine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Proparacaine | |
f806e9a0d665f5005fddf040776d410824e9c07f | wikidoc | Proteinase K | Proteinase K
Proteinase K (also protease K or endopeptidase K) EC 3.4.21.64 is a broad-spectrum serine protease. The enzyme was discovered in 1974 in extracts of the fungus Tritirachium album.
Proteinase K is commonly used in molecular biology to digest protein and remove contamination from preparations of nucleic acid. Addition of proteinase K to nucleic acid preparations rapidly inactivates nucleases that might otherwise degrade the DNA or RNA during purification. It is highly-suited to this application since the enzyme is active in the presence of chemicals that denature proteins, such as SDS and urea, chelating agents such as EDTA, sulfhydryl reagents, as well as trypsin or chymotrypsin inhibitors. Proteinase K is also stable over a wide pH range (4-12), with a pH optimum of pH 7.5-12.
The enzyme's activity towards native proteins is stimulated by denaturants such as SDS, but when measured using peptide substrates, the reverse is seen, with these chemicals inhibiting the enzyme. The reason for this result is that the denaturing agents unfold the protein substrates and make them more accessible to the protease. | Proteinase K
Proteinase K (also protease K or endopeptidase K) EC 3.4.21.64 is a broad-spectrum serine protease. The enzyme was discovered in 1974 in extracts of the fungus Tritirachium album.[1]
Proteinase K is commonly used in molecular biology to digest protein and remove contamination from preparations of nucleic acid. Addition of proteinase K to nucleic acid preparations rapidly inactivates nucleases that might otherwise degrade the DNA or RNA during purification. It is highly-suited to this application since the enzyme is active in the presence of chemicals that denature proteins, such as SDS and urea, chelating agents such as EDTA, sulfhydryl reagents, as well as trypsin or chymotrypsin inhibitors. Proteinase K is also stable over a wide pH range (4-12), with a pH optimum of pH 7.5-12.[1]
The enzyme's activity towards native proteins is stimulated by denaturants such as SDS, but when measured using peptide substrates, the reverse is seen, with these chemicals inhibiting the enzyme. The reason for this result is that the denaturing agents unfold the protein substrates and make them more accessible to the protease.[2] | https://www.wikidoc.org/index.php/Proteinase_K | |
5498c04805d8e8a1a7f95fc3e1ab4e86bde195fb | wikidoc | Prototaxites | Prototaxites
The genus Prototaxites (pro-toe-tax-eye-tees) describes terrestrial organisms known only from fossils dating from the Devonian period, approximately 420 to 370 million years ago. Prototaxites formed large trunk-like structures up to 1 m (3 ft.) wide, reaching 8 m (26 ft.) in height, made up of interwoven tubes just 50 μm in diameter. Whilst traditionally very difficult to assign to an Template:Wict group of organisms, current opinion is converging to a fungal home for the genus.
# Morphology
With a diameter of up to a meter, and a height reaching 9 m, Prototaxites fossils are by far the largest from its period of existence. Viewed from afar, the fossils take the form of tree-trunks, spreading slightly near their base in a fashion that suggests a connection to unpreserved root-like structures. Concentric growth rings, sometimes containing embedded plant material, suggest that the organism grew sporadically by the addition of external layers. It is probable that the preserved "trunks" represent the fruiting body, or "sporophore", of a fungus, which would have been fuelled by a net ("mycelium") of dispersed filaments ("hyphæ") . On a microscopic scale, the fossils consist of narrow tube-like structures, which weave around one another. These come in two 'flavours': skeletal "tubes", 20-50 μm across, have thick (2-6 μm) walls and are undivided for their length, and Template:Wict "filaments", which are septate - that is to say, they bear internal walls. In Prototaxites, they are also thinner (5-10 μm diameter) and branch frequently; these mesh together to form the organism's matrix.
The similarity of these tubes to structures in early plant Nematothallus has led to suggestions that the latter may represent leaves of Nematothallus. Unfortunately for this hypothesis, the two have never been found in connection — although this may be a consequence of their detachment after the organisms' death.
# History of research
First collected in 1843, it was not until 14 years later that the ey of John William Dawson, a Canadian scientist, was caught by Prototaxites fossils, which he described as partially rotten giant conifers, containing the remains of the fungi which had been decomposing them. This concept was not disputed until 1872, when a rival scientist named Carruthers poured ridicule on the idea. Such was his fervour that he rebuked the name Prototaxites — loosely translated as "first conifer" — and insisted that the name Nematophycus ("stringy plant") be adopted — a move strongly against scientific convention. Dawson fought adamantly to defend his original interpretation until studies of the microstructure made it clear that his position was untenable - whence he promptly attempted to rename the genus himself (to Nematophyton'), denying with great clout that he'd ever considered it to be a tree. Despite these political attempts to re-name the genus, the rules of convention mean that the name "Prototaxites", however inappropriate in meaning, remains in use today.
Despite the overwhelming evidence that the organism grew on land, Carruthers' interpretation - that it was a giant marine alga - was challenged just the once — in 1919, when Church suggested that Carruthers had been too quick to rule out the possibility of the fungi. Nobody paid him the blindest bit of attention. The lack of any characters diagnostic of any extant group made the presentation of a firm hypothesis difficult, and so the fossil remained an enigmatic mystery and subject of debate: it was not until 2001, after 20 years of research, that Francis Hueber, of Washington's National Museum of Natural History, published a long-awaited paper which attempted to throw out the bathwater and put Prototaxitesin its place. The paper deduced, based on its morphology, that Prototaxites was a fungus.
This idea was faced with disbelief, denial and strong scepticism, but further evidence is emerging to support it. In 2007, isotopic analyses by a team including Hueber and Kevin Boyce of the University of Chicago concluded that Prototaxites was a giant fungus. They detected a highly variable range of values of carbon isotope ratios in a range of Prototaxites specimens: autotrophs — that is, organisms such as plants and algae, that make a living via photosynthesis — living at the same time draw on the same (atmospheric) source of carbon; as organisms of the same type share the same chemical machinery, they reflect this atmospheric composition with a constant carbon isotope trace. The inconsistent ratio observed in Prototaxites appears to show that the organism did not survive by photosynthesis, and Boyce's team deduce that the organism fed on a range of substrates, such as the remains of whichever other organisms were nearby.
# Ecological context
This organism would have been the tallest living thing in its day by far; wispy Cooksonia (pictured in navigational box below) only reached 1 m, and itself towered over the "moss forests"; invertebrates such as the euglenids were the only other land-dwelling life. Prototaxites became extinct as shrubs and Template:Wict trees rose to prominence. The organism could have used its raised platform for spore dispersal, or - if Nematophytes really did form its leaves - in competition for light. The presence of bio-molecules often associated with the algae may suggest that the organism was covered by symbiotic (or parasitic) algae - or an alga itself!
Prototaxites mycelia (strands) have been fossilised invading the tissue of vascular plants; in turn, there is evidence of animals inhabiting Prototaxites: mazes of tubes have been found within some specimens, with the fungus re-growing into the voids, leading to speculation that the organisms' extinction may have been caused by such activity. | Prototaxites
The genus Prototaxites (pro-toe-tax-eye-tees) describes terrestrial organisms known only from fossils dating from the Devonian period, approximately 420 to 370 million years ago. Prototaxites formed large trunk-like structures up to 1 m (3 ft.) wide, reaching 8 m (26 ft.) in height, made up of interwoven tubes just 50 μm in diameter. Whilst traditionally very difficult to assign to an Template:Wict group of organisms, current opinion is converging to a fungal home for the genus.
# Morphology
With a diameter of up to a meter, and a height reaching 9 m, Prototaxites fossils are by far the largest from its period of existence. Viewed from afar, the fossils take the form of tree-trunks, spreading slightly near their base in a fashion that suggests a connection to unpreserved root-like structures.[2] Concentric growth rings, sometimes containing embedded plant material,[3] suggest that the organism grew sporadically by the addition of external layers. It is probable that the preserved "trunks" represent the fruiting body, or "sporophore", of a fungus, which would have been fuelled by a net ("mycelium") of dispersed filaments ("hyphæ") . On a microscopic scale, the fossils consist of narrow tube-like structures, which weave around one another. These come in two 'flavours': skeletal "tubes", 20-50 μm across, have thick (2-6 μm) walls and are undivided for their length, and Template:Wict "filaments", which are septate - that is to say, they bear internal walls. In Prototaxites, they are also thinner (5-10 μm diameter) and branch frequently; these mesh together to form the organism's matrix.
The similarity of these tubes to structures in early plant Nematothallus has led to suggestions that the latter may represent leaves of Nematothallus. Unfortunately for this hypothesis, the two have never been found in connection — although this may be a consequence of their detachment after the organisms' death.[4]
# History of research
First collected in 1843, it was not until 14 years later that the ey of John William Dawson, a Canadian scientist, was caught by Prototaxites fossils, which he described as partially rotten giant conifers, containing the remains of the fungi which had been decomposing them.[3] This concept was not disputed until 1872, when a rival scientist named Carruthers poured ridicule on the idea. Such was his fervour that he rebuked the name Prototaxites — loosely translated as "first conifer"[5] — and insisted that the name Nematophycus ("stringy plant"[verification needed]) be adopted — a move strongly against scientific convention. Dawson fought adamantly to defend his original interpretation until studies of the microstructure made it clear that his position was untenable - whence he promptly attempted to rename the genus himself (to Nematophyton'), denying with great clout that he'd ever considered it to be a tree.[3] Despite these political attempts to re-name the genus, the rules of convention mean that the name "Prototaxites", however inappropriate in meaning, remains in use today.
Despite the overwhelming evidence that the organism grew on land, Carruthers' interpretation - that it was a giant marine alga - was challenged just the once — in 1919, when Church suggested that Carruthers had been too quick to rule out the possibility of the fungi. Nobody paid him the blindest bit of attention. The lack of any characters diagnostic of any extant group made the presentation of a firm hypothesis difficult,[3] and so the fossil remained an enigmatic mystery and subject of debate: it was not until 2001, after 20 years of research, that Francis Hueber, of Washington's National Museum of Natural History, published a long-awaited paper which attempted to throw out the bathwater and put Prototaxitesin its place. The paper deduced, based on its morphology, that Prototaxites was a fungus.[3]
This idea was faced with disbelief, denial and strong scepticism, but further evidence is emerging to support it. In 2007, isotopic analyses by a team including Hueber and Kevin Boyce of the University of Chicago[1] concluded that Prototaxites was a giant fungus. They detected a highly variable range of values of carbon isotope ratios in a range of Prototaxites specimens: autotrophs — that is, organisms such as plants and algae, that make a living via photosynthesis — living at the same time draw on the same (atmospheric) source of carbon; as organisms of the same type share the same chemical machinery, they reflect this atmospheric composition with a constant carbon isotope trace. The inconsistent ratio observed in Prototaxites appears to show that the organism did not survive by photosynthesis, and Boyce's team deduce that the organism fed on a range of substrates, such as the remains of whichever other organisms were nearby.[1]
# Ecological context
This organism would have been the tallest living thing in its day by far; wispy Cooksonia (pictured in navigational box below) only reached 1 m, and itself towered over the "moss forests"; invertebrates such as the euglenids were the only other land-dwelling life. Prototaxites became extinct as shrubs and Template:Wict trees rose to prominence.[2] The organism could have used its raised platform for spore dispersal, or - if Nematophytes really did form its leaves - in competition for light.[2] The presence of bio-molecules often associated with the algae may suggest that the organism was covered by symbiotic (or parasitic) algae - or an alga itself![2][6][7]
Prototaxites mycelia (strands) have been fossilised invading the tissue of vascular plants;[3] in turn, there is evidence of animals inhabiting Prototaxites: mazes of tubes have been found within some specimens, with the fungus re-growing into the voids, leading to speculation that the organisms' extinction may have been caused by such activity.[3] | https://www.wikidoc.org/index.php/Prototaxites | |
156aa7d645472cf4d76ab2f42beecf4551872838 | wikidoc | Sipuleucel-T | Sipuleucel-T
# 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
Sipuleucel-T is an immunological agent that is FDA approved for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. Common adverse reactions include nausea, vomiting, anemia, backache, headache, citrate adverse reaction, fatigue, fever, Infusion reaction, pain, rigor, shivering.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Dose and Schedule
- Each dose of Sipuleucel-T contains a minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF.
- The recommended course of therapy for Sipuleucel-T is 3 complete doses, given at approximately 2-week intervals. In controlled clinical trials, the median dosing interval between infusions was 2 weeks (range 1 to 15 weeks); the maximum dosing interval has not been established.
- If, for any reason, the patient is unable to receive a scheduled infusion of Sipuleucel-T the patient will need to undergo an additional leukapheresis procedure if the course of treatment is to be continued. Patients should be advised of this possibility prior to initiating treatment.
### Premedication
- To minimize potential acute infusion reactions such as chills and/or fever, it is recommended that patients be premedicated orally with acetaminophen and an antihistamine such as diphenhydramine approximately 30 minutes prior to administration of Sipuleucel-T.
### Handling Precautions for Control of Infectious Disease
- Sipuleucel-T is not routinely tested for transmissible infectious diseases. Therefore, patient leukapheresis material and Sipuleucel-T may carry the risk of transmitting infectious diseases to health care professionals handling the product. Employ universal precautions in handling leukapheresis material or Sipuleucel-T.
### Storage
- The Sipuleucel-T infusion bag must remain within the insulated polyurethane container until the time of administration. Do not remove the insulated polyurethane container from the outer cardboard shipping box.
### Confirm Product Release Before Infusion
- Do not infuse Sipuleucel-T until confirmation of product release has been received from Dendreon. Dendreon will send a cell product disposition form containing the patient identifiers, expiration date and time, and the disposition status (approved for infusion or rejected), to the infusion site.
- Sipuleucel-T is intended solely for autologous use. Confirm the proper product has been received according to the label on the outside of the insulated polyurethane container. Prior to Sipuleucel-T infusion, match the patient's identity with the patient identifiers on the cell product disposition form and the Sipuleucel-T infusion bag.
- Remove the infusion bag from the insulated polyurethane container and inspect the bag for signs of leakage. Do not administer if the bag leaks.
- Contents of the bag will be slightly cloudy, with a cream-to-pink color. Gently mix and re-suspend the contents of the bag, inspecting for clumps and clots. Small clumps of cellular material should disperse with gentle manual mixing. Do not administer if the bag leaks during handling or if clumps remain in the bag.
### Administration
- Infusion must begin prior to the expiration date and time indicated on the cell product disposition form and Product Label. Do not initiate infusion of expired Sipuleucel-T.
- Administer Sipuleucel-T via intravenous infusion over a period of approximately 60 minutes. Do not use a cell filter. Sipuleucel-T is supplied in a sealed, patient-specific infusion bag; the entire volume of the bag should be infused.
- Observe the patient for at least 30 minutes following each infusion.
### Administration Modification for Infusion Reactions
- Acute infusion reactions such as chills, fatigue, fever, nausea, and joint ache were frequently observed in studies of Sipuleucel-T To mitigate such reactions, premedication, consisting of acetaminophen and an antihistamine such as diphenhydramine, was administered in clinical studies prior to infusion.
- In the event of an acute infusion reaction, the infusion may be interrupted or slowed, depending on the severity of the reaction. Appropriate medical therapy should be administered as needed. In controlled clinical trials, symptoms of acute infusion reactions were treated with acetaminophen, intravenous H1 and/or H2 blockers, and low dose intravenous meperidine.
- If the infusion of Sipuleucel-T must be interrupted, the infusion should not be resumed if the Sipuleucel-T infusion bag will be held at room temperature for more than 3 hours.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sipuleucel-T in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sipuleucel-T in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Sipuleucel-T 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 Sipuleucel-T in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sipuleucel-T in pediatric patients.
# Contraindications
None
# Warnings
### Acute Infusion Reactions
- Acute infusion reactions (reported within 1 day of infusion) included, but were not limited to, fever, chills, respiratory events (dyspnea, hypoxia, and bronchospasm), nausea, vomiting, fatigue, hypertension, and tachycardia. In controlled clinical trials, 71.2% of patients in the Sipuleucel-T group developed an acute infusion reaction. The most common events (≥ 20%) were chills, fever, and fatigue. In 95.1% of patients reporting acute infusion reactions, the events were mild or moderate. Fevers and chills generally resolved within 2 days (71.9% and 89.0%, respectively).
- In controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the Sipuleucel-T group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The incidence of severe events was greater following the second infusion (2.1% vs. 0.8% following the first infusion), and decreased to 1.3% following the third infusion. Some (1.2%) patients in the Sipuleucel-T group were hospitalized within 1 day of infusion for management of acute infusion reactions. No Grade 4 or 5 acute infusion reactions were reported in patients in the Sipuleucel-T group.
- Closely monitor patients with cardiac or pulmonary conditions. In the event of an acute infusion reaction, the infusion rate may be decreased, or the infusion stopped, depending on the severity of the reaction. Appropriate medical therapy should be administered as needed.
### Handling Precautions for Control of Infectious Disease
- Sipuleucel-T is not routinely tested for transmissible infectious diseases. Therefore, patient leukapheresis material and Sipuleucel-T may carry the risk of transmitting infectious diseases to health care professionals handling the product. Accordingly, health care professionals should employ universal precautions when handling leukapheresis material or Sipuleucel-T.
### Concomitant Chemotherapy or Immunosuppressive Therapy
- Use of either chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given concurrently with the leukapheresis procedure or Sipuleucel-T has not been studied. Sipuleucel-T is designed to stimulate the immune system, and concurrent use of immunosuppressive agents may alter the efficacy and/or safety of Sipuleucel-T Therefore, patients should be carefully evaluated to determine whether it is medically appropriate to reduce or discontinue immunosuppressive agents prior to treatment with Sipuleucel-T.
### Product Safety Testing
- Sipuleucel-T is released for infusion based on the microbial and sterility results from several tests: microbial contamination determination by Gram stain, endotoxin content, and in-process sterility with a 2-day incubation to determine absence of microbial growth. The final (7-day incubation) sterility test results are not available at the time of infusion. If the sterility results become positive for microbial contamination after Sipuleucel-T has been approved for infusion, Dendreon will notify the treating physician. Dendreon will attempt to identify the microorganism, perform antibiotic sensitivity testing on recovered microorganisms, and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety evaluation of Sipuleucel-T is based on 601 prostate cancer patients in the Sipuleucel-T group who underwent at least 1 leukapheresis procedure in four randomized, controlled clinical trials. The control was non-activated autologous peripheral blood mononuclear cells.
- Almost all (98.3%) patients in the Sipuleucel-T group and 96.0% in the control group reported an adverse event. The most common adverse events, reported in patients in the Sipuleucel-T group at a rate ≥ 15%, were chills, fatigue, fever, back pain, nausea, joint ache, and headache. In 67.4% of patients in the Sipuleucel-T group, these adverse events were mild or moderate in severity. Severe (Grade 3) and life-threatening (Grade 4) adverse events were reported in 23.6% and 4.0% of patients in the Sipuleucel-T group compared with 25.1% and 3.3% of patients in the control group. Fatal (Grade 5) adverse events were reported in 3.3% of patients in the Sipuleucel-T group compared with 3.6% of patients in the control group. The most common (≥ 2%) Grade 3-5 adverse events reported in the Sipuleucel-T group were back pain and chills.
- Serious adverse events were reported in 24.0% of patients in the Sipuleucel-T group and 25.1% of patients in the control group. Serious adverse events in the Sipuleucel-T group included acute infusion reactions, cerebrovascular events, and single case reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare.
- Sipuleucel-T was discontinued in 1.5% of patients in Study 1 due to adverse events. Some patients who required central venous catheters for treatment with Sipuleucel-T developed infections, including sepsis. A small number of these patients discontinued treatment as a result. Monitoring for infectious sequelae in patients with central venous catheters is recommended.
- Each dose of Sipuleucel-T requires a standard leukapheresis procedure approximately 3 days prior to the infusion. Adverse events that were reported ≤ 1 day following a leukapheresis procedure in ≥ 5% of patients in controlled clinical trials included citrate toxicity (14.2%), oral paresthesia (12.6%), paresthesia (11.4%), and fatigue (8.3%).
TABLE 1 provides the frequency and severity of adverse events reported in ≥ 5% of patients in the Sipuleucel-T group of randomized, controlled trials of men with prostate cancer. The population included 485 patients with metastatic castrate resistant prostate cancer and 116 patients with non-metastatic androgen dependent prostate cancer who were scheduled to receive 3 infusions of Sipuleucel-T at approximately 2-week intervals. The population was age 40 to 91 years (median 70 years), and 90.6% of patients were Caucasian.
- In controlled clinical trials, cerebrovascular events, including hemorrhagic and ischemic strokes, were observed in 3.5% of patients in the Sipuleucel-T group compared with 2.6% of patients in the control group.
## Postmarketing Experience
There is limited information regarding Sipuleucel-T Postmarketing Experience in the drug label.
# Drug Interactions
- No studies of drug interactions have been performed with Sipuleucel-T.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Sipuleucel-T in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sipuleucel-T in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Sipuleucel-T during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Sipuleucel-T in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Sipuleucel-T in pediatric settings.
### Geriatic Use
In controlled clinical trials, 72.9% of patients (438 of 601) in the Sipuleucel-T group were ≥ 65 years of age. There were no apparent differences in the safety of Sipuleucel-T between patients ≥ 65 years of age and younger patients.
In a survival analysis of the controlled clinical trials of Sipuleucel-T in metastatic castrate resistant prostate cancer, 78.3% of randomized patients (382 of 488) were ≥ 65 years of age. The median survival of patients in the Sipuleucel-T group ≥ 65 years of age was 23.4 months (95% confidence interval 22.0, 27.1), compared with 17.3 months in the control group (95% confidence interval: 13.5, 21.5).
### Gender
There is no FDA guidance on the use of Sipuleucel-T with respect to specific gender populations.
### Race
In controlled clinical trials, 90.6% of patients were Caucasian, 5.8% were African American, and 3.7% were “Other”. Due to the low numbers of non-Caucasian patients in the trials, no conclusions can be made regarding the safety or efficacy of Sipuleucel-T by race.
### Renal Impairment
There is no FDA guidance on the use of Sipuleucel-T in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sipuleucel-T in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sipuleucel-T in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sipuleucel-T in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Sipuleucel-T Administration in the drug label.
### Monitoring
There is limited information regarding Sipuleucel-T Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Sipuleucel-T and IV administrations.
# Overdosage
- Each Sipuleucel-T infusion comprises the maximum number of cells that can be manufactured from a single leukapheresis procedure. The number of cells in Sipuleucel-T does not exceed the number of cells collected from the leukapheresis. There are no known instances of overdosage from either a single infusion or a full course of therapy with Sipuleucel-T.
# Pharmacology
## Mechanism of Action
There is limited information regarding Sipuleucel-T Mechanism of Action in the drug label.
## Structure
There is limited information regarding Sipuleucel-T Structure in the drug label.
## Pharmacodynamics
- Sipuleucel-T is classified as an autologous cellular immunotherapy. While the precise mechanism of action is unknown, Sipuleucel-T is designed to induce an immune response targeted against PAP, an antigen expressed in most prostate cancers. During ex vivo culture with PAP-GM-CSF, APCs take up and process the recombinant target antigen into small peptides that are then displayed on the APC surface.
- In Study 1, 237 out of the 512 patients randomized were evaluated for the development of humoral and T cell immune responses (proliferative and gamma-interferon (γIFN) ELISPOT) to the target antigens at Baseline, and at Weeks 6, 14, and 26. Antibody (IgM and IgG) responses against PAP-GM-CSF and PAP antigen alone were observed through the follow-up period in the Sipuleucel-T group. Neutralizing antibody responses to GM-CSF were transient. T cell proliferative and γIFN ELISPOT responses to PAP-GM-CSF fusion protein were observed in cells collected from peripheral blood of patients through the follow-up period in the Sipuleucel-T treatment group but not in controls. In some patients a response to PAP antigen alone was observed. No conclusions could be made regarding the clinical significance of the observed immune responses.
## Pharmacokinetics
There is limited information regarding Sipuleucel-T Pharmacokinetics in the drug label.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- No carcinogenicity or mutagenicity studies of Sipuleucel-T in animals were conducted. No studies on the effects of Sipuleucel-T on fertility have been conducted.
# Clinical Studies
The effect of Sipuleucel-T on patients with metastatic castrate resistant (hormone refractory) prostate cancer was studied in three similar randomized, double-blind, placebo-controlled, multicenter trials. Following randomization, patients from both treatment groups underwent a series of 3 leukapheresis procedures (at approximately Weeks 0, 2, and 4). Each leukapheresis was followed approximately 3 days later by infusion of Sipuleucel-T or control. The control was autologous peripheral blood mononuclear cells that had not been activated. Following disease progression, patients were treated at the physician's discretion with other anti-cancer interventions.
### Study 1
- Study 1 was a randomized, double-blind, placebo-controlled, multicenter trial in patients with asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. Eligible patients had metastatic disease in the soft tissue and/or bone with evidence of progression either at these sites or by serial Prostate Specific Antigen (PSA) measurements. Exclusion criteria included visceral (liver, lung, or brain) metastases, moderate to severe prostate cancer-related pain, and use of narcotics for cancer-related pain.
- A total of 512 patients were randomized in a 2:1 ratio to receive Sipuleucel-T (n=341) or control (n=171). The median age was 71, and 90% of the patients were Caucasian. Thirty-five percent of patients had undergone radical prostatectomy, 54% had received local radiotherapy, and 82% had received combined androgen blockade. All patients had baseline testosterone levels < 50 ng/mL. Forty-eight percent of patients were receiving bisphosphonates and 18% had received prior chemotherapy, including docetaxel. Eighty-two percent of patients had an ECOG performance status of 0; 58% had primary Gleason scores of four or more; 44% had bone and soft tissue disease; 48% had bone-only disease; 7% had soft tissue-only disease; and 43% had greater than ten bony metastases.
### Supportive Studies
- Study 2 was a randomized, double-blind, placebo-controlled, multicenter trial in patients with metastatic castrate resistant prostate cancer and no cancer-related pain. The primary endpoint was time to disease progression; analysis of the primary endpoint did not reach statistical significance. All patients were to be followed for survival; however, the survival analysis was not pre-specified. A third study, similar in design to Study 2, was terminated prior to completion of planned accrual.
### Summary of Study Results
- FIGURE 1 and TABLE 2 present overall survival results observed in two randomized, Phase 3 studies of Sipuleucel-T in men with metastatic castrate resistant prostate cancer. The survival findings were consistent across multiple subgroups. Analyses of time to disease progression did not meet statistical significance in any Phase 3 study of Sipuleucel-T.
Figure 1 Kaplan-Meier Overall Survival Curve for Study 1
# How Supplied
- Sipuleucel-T is a 250 mL suspension containing a minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF in Lactated Ringer's Injection, USP, and supplied in an infusion bag labeled for the specific recipient.
NDC 30237-8900-6: one bag individually packed in a carton.
- NDC 30237-8900-6: one bag individually packed in a carton.
## Storage
- Store Refrigerated 2-8°C. DO NOT FREEZE.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Sipuleucel-T Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Sipuleucel-T interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Provenge
# Look-Alike Drug Names
There is limited information regarding Sipuleucel-T Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Sipuleucel-T
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Sipuleucel-T is an immunological agent that is FDA approved for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. Common adverse reactions include nausea, vomiting, anemia, backache, headache, citrate adverse reaction, fatigue, fever, Infusion reaction, pain, rigor, shivering.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Dose and Schedule
- Each dose of Sipuleucel-T contains a minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF.
- The recommended course of therapy for Sipuleucel-T is 3 complete doses, given at approximately 2-week intervals. In controlled clinical trials, the median dosing interval between infusions was 2 weeks (range 1 to 15 weeks); the maximum dosing interval has not been established.
- If, for any reason, the patient is unable to receive a scheduled infusion of Sipuleucel-T the patient will need to undergo an additional leukapheresis procedure if the course of treatment is to be continued. Patients should be advised of this possibility prior to initiating treatment.
### Premedication
- To minimize potential acute infusion reactions such as chills and/or fever, it is recommended that patients be premedicated orally with acetaminophen and an antihistamine such as diphenhydramine approximately 30 minutes prior to administration of Sipuleucel-T.
### Handling Precautions for Control of Infectious Disease
- Sipuleucel-T is not routinely tested for transmissible infectious diseases. Therefore, patient leukapheresis material and Sipuleucel-T may carry the risk of transmitting infectious diseases to health care professionals handling the product. Employ universal precautions in handling leukapheresis material or Sipuleucel-T.
### Storage
- The Sipuleucel-T infusion bag must remain within the insulated polyurethane container until the time of administration. Do not remove the insulated polyurethane container from the outer cardboard shipping box.
### Confirm Product Release Before Infusion
- Do not infuse Sipuleucel-T until confirmation of product release has been received from Dendreon. Dendreon will send a cell product disposition form containing the patient identifiers, expiration date and time, and the disposition status (approved for infusion or rejected), to the infusion site.
- Sipuleucel-T is intended solely for autologous use. Confirm the proper product has been received according to the label on the outside of the insulated polyurethane container. Prior to Sipuleucel-T infusion, match the patient's identity with the patient identifiers on the cell product disposition form and the Sipuleucel-T infusion bag.
- Remove the infusion bag from the insulated polyurethane container and inspect the bag for signs of leakage. Do not administer if the bag leaks.
- Contents of the bag will be slightly cloudy, with a cream-to-pink color. Gently mix and re-suspend the contents of the bag, inspecting for clumps and clots. Small clumps of cellular material should disperse with gentle manual mixing. Do not administer if the bag leaks during handling or if clumps remain in the bag.
### Administration
- Infusion must begin prior to the expiration date and time indicated on the cell product disposition form and Product Label. Do not initiate infusion of expired Sipuleucel-T.
- Administer Sipuleucel-T via intravenous infusion over a period of approximately 60 minutes. Do not use a cell filter. Sipuleucel-T is supplied in a sealed, patient-specific infusion bag; the entire volume of the bag should be infused.
- Observe the patient for at least 30 minutes following each infusion.
### Administration Modification for Infusion Reactions
- Acute infusion reactions such as chills, fatigue, fever, nausea, and joint ache were frequently observed in studies of Sipuleucel-T To mitigate such reactions, premedication, consisting of acetaminophen and an antihistamine such as diphenhydramine, was administered in clinical studies prior to infusion.
- In the event of an acute infusion reaction, the infusion may be interrupted or slowed, depending on the severity of the reaction. Appropriate medical therapy should be administered as needed. In controlled clinical trials, symptoms of acute infusion reactions were treated with acetaminophen, intravenous H1 and/or H2 blockers, and low dose intravenous meperidine.
- If the infusion of Sipuleucel-T must be interrupted, the infusion should not be resumed if the Sipuleucel-T infusion bag will be held at room temperature for more than 3 hours.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sipuleucel-T in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sipuleucel-T in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Sipuleucel-T 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 Sipuleucel-T in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sipuleucel-T in pediatric patients.
# Contraindications
None
# Warnings
### Acute Infusion Reactions
- Acute infusion reactions (reported within 1 day of infusion) included, but were not limited to, fever, chills, respiratory events (dyspnea, hypoxia, and bronchospasm), nausea, vomiting, fatigue, hypertension, and tachycardia. In controlled clinical trials, 71.2% of patients in the Sipuleucel-T group developed an acute infusion reaction. The most common events (≥ 20%) were chills, fever, and fatigue. In 95.1% of patients reporting acute infusion reactions, the events were mild or moderate. Fevers and chills generally resolved within 2 days (71.9% and 89.0%, respectively).
- In controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the Sipuleucel-T group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The incidence of severe events was greater following the second infusion (2.1% vs. 0.8% following the first infusion), and decreased to 1.3% following the third infusion. Some (1.2%) patients in the Sipuleucel-T group were hospitalized within 1 day of infusion for management of acute infusion reactions. No Grade 4 or 5 acute infusion reactions were reported in patients in the Sipuleucel-T group.
- Closely monitor patients with cardiac or pulmonary conditions. In the event of an acute infusion reaction, the infusion rate may be decreased, or the infusion stopped, depending on the severity of the reaction. Appropriate medical therapy should be administered as needed.
### Handling Precautions for Control of Infectious Disease
- Sipuleucel-T is not routinely tested for transmissible infectious diseases. Therefore, patient leukapheresis material and Sipuleucel-T may carry the risk of transmitting infectious diseases to health care professionals handling the product. Accordingly, health care professionals should employ universal precautions when handling leukapheresis material or Sipuleucel-T.
### Concomitant Chemotherapy or Immunosuppressive Therapy
- Use of either chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given concurrently with the leukapheresis procedure or Sipuleucel-T has not been studied. Sipuleucel-T is designed to stimulate the immune system, and concurrent use of immunosuppressive agents may alter the efficacy and/or safety of Sipuleucel-T Therefore, patients should be carefully evaluated to determine whether it is medically appropriate to reduce or discontinue immunosuppressive agents prior to treatment with Sipuleucel-T.
### Product Safety Testing
- Sipuleucel-T is released for infusion based on the microbial and sterility results from several tests: microbial contamination determination by Gram stain, endotoxin content, and in-process sterility with a 2-day incubation to determine absence of microbial growth. The final (7-day incubation) sterility test results are not available at the time of infusion. If the sterility results become positive for microbial contamination after Sipuleucel-T has been approved for infusion, Dendreon will notify the treating physician. Dendreon will attempt to identify the microorganism, perform antibiotic sensitivity testing on recovered microorganisms, and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety evaluation of Sipuleucel-T is based on 601 prostate cancer patients in the Sipuleucel-T group who underwent at least 1 leukapheresis procedure in four randomized, controlled clinical trials. The control was non-activated autologous peripheral blood mononuclear cells.
- Almost all (98.3%) patients in the Sipuleucel-T group and 96.0% in the control group reported an adverse event. The most common adverse events, reported in patients in the Sipuleucel-T group at a rate ≥ 15%, were chills, fatigue, fever, back pain, nausea, joint ache, and headache. In 67.4% of patients in the Sipuleucel-T group, these adverse events were mild or moderate in severity. Severe (Grade 3) and life-threatening (Grade 4) adverse events were reported in 23.6% and 4.0% of patients in the Sipuleucel-T group compared with 25.1% and 3.3% of patients in the control group. Fatal (Grade 5) adverse events were reported in 3.3% of patients in the Sipuleucel-T group compared with 3.6% of patients in the control group. The most common (≥ 2%) Grade 3-5 adverse events reported in the Sipuleucel-T group were back pain and chills.
- Serious adverse events were reported in 24.0% of patients in the Sipuleucel-T group and 25.1% of patients in the control group. Serious adverse events in the Sipuleucel-T group included acute infusion reactions, cerebrovascular events, and single case reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare.
- Sipuleucel-T was discontinued in 1.5% of patients in Study 1 due to adverse events. Some patients who required central venous catheters for treatment with Sipuleucel-T developed infections, including sepsis. A small number of these patients discontinued treatment as a result. Monitoring for infectious sequelae in patients with central venous catheters is recommended.
- Each dose of Sipuleucel-T requires a standard leukapheresis procedure approximately 3 days prior to the infusion. Adverse events that were reported ≤ 1 day following a leukapheresis procedure in ≥ 5% of patients in controlled clinical trials included citrate toxicity (14.2%), oral paresthesia (12.6%), paresthesia (11.4%), and fatigue (8.3%).
TABLE 1 provides the frequency and severity of adverse events reported in ≥ 5% of patients in the Sipuleucel-T group of randomized, controlled trials of men with prostate cancer. The population included 485 patients with metastatic castrate resistant prostate cancer and 116 patients with non-metastatic androgen dependent prostate cancer who were scheduled to receive 3 infusions of Sipuleucel-T at approximately 2-week intervals. The population was age 40 to 91 years (median 70 years), and 90.6% of patients were Caucasian.
- In controlled clinical trials, cerebrovascular events, including hemorrhagic and ischemic strokes, were observed in 3.5% of patients in the Sipuleucel-T group compared with 2.6% of patients in the control group.
## Postmarketing Experience
There is limited information regarding Sipuleucel-T Postmarketing Experience in the drug label.
# Drug Interactions
- No studies of drug interactions have been performed with Sipuleucel-T.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Sipuleucel-T in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sipuleucel-T in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Sipuleucel-T during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Sipuleucel-T in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Sipuleucel-T in pediatric settings.
### Geriatic Use
In controlled clinical trials, 72.9% of patients (438 of 601) in the Sipuleucel-T group were ≥ 65 years of age. There were no apparent differences in the safety of Sipuleucel-T between patients ≥ 65 years of age and younger patients.
In a survival analysis of the controlled clinical trials of Sipuleucel-T in metastatic castrate resistant prostate cancer, 78.3% of randomized patients (382 of 488) were ≥ 65 years of age. The median survival of patients in the Sipuleucel-T group ≥ 65 years of age was 23.4 months (95% confidence interval 22.0, 27.1), compared with 17.3 months in the control group (95% confidence interval: 13.5, 21.5).
### Gender
There is no FDA guidance on the use of Sipuleucel-T with respect to specific gender populations.
### Race
In controlled clinical trials, 90.6% of patients were Caucasian, 5.8% were African American, and 3.7% were “Other”. Due to the low numbers of non-Caucasian patients in the trials, no conclusions can be made regarding the safety or efficacy of Sipuleucel-T by race.
### Renal Impairment
There is no FDA guidance on the use of Sipuleucel-T in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sipuleucel-T in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sipuleucel-T in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sipuleucel-T in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Sipuleucel-T Administration in the drug label.
### Monitoring
There is limited information regarding Sipuleucel-T Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Sipuleucel-T and IV administrations.
# Overdosage
- Each Sipuleucel-T infusion comprises the maximum number of cells that can be manufactured from a single leukapheresis procedure. The number of cells in Sipuleucel-T does not exceed the number of cells collected from the leukapheresis. There are no known instances of overdosage from either a single infusion or a full course of therapy with Sipuleucel-T.
# Pharmacology
## Mechanism of Action
There is limited information regarding Sipuleucel-T Mechanism of Action in the drug label.
## Structure
There is limited information regarding Sipuleucel-T Structure in the drug label.
## Pharmacodynamics
- Sipuleucel-T is classified as an autologous cellular immunotherapy. While the precise mechanism of action is unknown, Sipuleucel-T is designed to induce an immune response targeted against PAP, an antigen expressed in most prostate cancers. During ex vivo culture with PAP-GM-CSF, APCs take up and process the recombinant target antigen into small peptides that are then displayed on the APC surface.
- In Study 1, 237 out of the 512 patients randomized were evaluated for the development of humoral and T cell immune responses (proliferative and gamma-interferon (γIFN) ELISPOT) to the target antigens at Baseline, and at Weeks 6, 14, and 26. Antibody (IgM and IgG) responses against PAP-GM-CSF and PAP antigen alone were observed through the follow-up period in the Sipuleucel-T group. Neutralizing antibody responses to GM-CSF were transient. T cell proliferative and γIFN ELISPOT responses to PAP-GM-CSF fusion protein were observed in cells collected from peripheral blood of patients through the follow-up period in the Sipuleucel-T treatment group but not in controls. In some patients a response to PAP antigen alone was observed. No conclusions could be made regarding the clinical significance of the observed immune responses.
## Pharmacokinetics
There is limited information regarding Sipuleucel-T Pharmacokinetics in the drug label.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- No carcinogenicity or mutagenicity studies of Sipuleucel-T in animals were conducted. No studies on the effects of Sipuleucel-T on fertility have been conducted.
# Clinical Studies
The effect of Sipuleucel-T on patients with metastatic castrate resistant (hormone refractory) prostate cancer was studied in three similar randomized, double-blind, placebo-controlled, multicenter trials. Following randomization, patients from both treatment groups underwent a series of 3 leukapheresis procedures (at approximately Weeks 0, 2, and 4). Each leukapheresis was followed approximately 3 days later by infusion of Sipuleucel-T or control. The control was autologous peripheral blood mononuclear cells that had not been activated. Following disease progression, patients were treated at the physician's discretion with other anti-cancer interventions.
### Study 1
- Study 1 was a randomized, double-blind, placebo-controlled, multicenter trial in patients with asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. Eligible patients had metastatic disease in the soft tissue and/or bone with evidence of progression either at these sites or by serial Prostate Specific Antigen (PSA) measurements. Exclusion criteria included visceral (liver, lung, or brain) metastases, moderate to severe prostate cancer-related pain, and use of narcotics for cancer-related pain.
- A total of 512 patients were randomized in a 2:1 ratio to receive Sipuleucel-T (n=341) or control (n=171). The median age was 71, and 90% of the patients were Caucasian. Thirty-five percent of patients had undergone radical prostatectomy, 54% had received local radiotherapy, and 82% had received combined androgen blockade. All patients had baseline testosterone levels < 50 ng/mL. Forty-eight percent of patients were receiving bisphosphonates and 18% had received prior chemotherapy, including docetaxel. Eighty-two percent of patients had an ECOG performance status of 0; 58% had primary Gleason scores of four or more; 44% had bone and soft tissue disease; 48% had bone-only disease; 7% had soft tissue-only disease; and 43% had greater than ten bony metastases.
### Supportive Studies
- Study 2 was a randomized, double-blind, placebo-controlled, multicenter trial in patients with metastatic castrate resistant prostate cancer and no cancer-related pain. The primary endpoint was time to disease progression; analysis of the primary endpoint did not reach statistical significance. All patients were to be followed for survival; however, the survival analysis was not pre-specified. A third study, similar in design to Study 2, was terminated prior to completion of planned accrual.
### Summary of Study Results
- FIGURE 1 and TABLE 2 present overall survival results observed in two randomized, Phase 3 studies of Sipuleucel-T in men with metastatic castrate resistant prostate cancer. The survival findings were consistent across multiple subgroups. Analyses of time to disease progression did not meet statistical significance in any Phase 3 study of Sipuleucel-T.
Figure 1 Kaplan-Meier Overall Survival Curve for Study 1
# How Supplied
- Sipuleucel-T is a 250 mL suspension containing a minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF in Lactated Ringer's Injection, USP, and supplied in an infusion bag labeled for the specific recipient.
NDC 30237-8900-6: one bag individually packed in a carton.
- NDC 30237-8900-6: one bag individually packed in a carton.
## Storage
- Store Refrigerated 2-8°C. DO NOT FREEZE.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Sipuleucel-T Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Sipuleucel-T interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Provenge
# Look-Alike Drug Names
There is limited information regarding Sipuleucel-T Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Provenge | |
cfc89d6fd44f505b4b9731fa7d546f3599abe99c | wikidoc | Prucalopride | Prucalopride
# Overview
Prucalopride (brand name Resolor, developed by Johnson & Johnson and licensed to Movetis) is a drug acting as a selective, high affinity 5-HT4 receptor agonist which targets the impaired motility associated with chronic constipation, thus normalising bowel movements. Prucalopride was approved for use in Europe in 2009 and in Canada (named Resotran) on December 7, 2011 but it has not been approved by the Food and Drug Administration for use in the United States. The drug has also been tested for the treatment of chronic intestinal pseudo-obstruction.
# Mechanism of action
Prucalopride, a first in class dihydro-benzofuran-carboxamide, is a selective, high affinity serotonin (5-HT4) receptor agonist with enterokinetic activities. Prucalopride alters colonic motility patterns via serotonin 5-HT4 receptor stimulation: it stimulates colonic mass movements, which provide the main propulsive force for defecation.
The observed effects are exerted via highly selective action on 5-HT4 receptors: prucalopride has >150-fold higher affinity for 5-HT4 receptors than for other receptors. Prucalopride differs from other 5-HT4 agonists such as tegaserod and cisapride, which at therapeutic concentrations also interact with other receptors (5-HT1B/D and the cardiac human ether-a-go-go K+ or hERG channel respectively) and this may account for the adverse cardiovascular events that have resulted in the restricted availability of these drugs. Clinical trials evaluating the effect of prucalopride on QT interval and related adverse events have not demonstrated significant differences compared with placebo.
# Pharmacokinetics
Prucalopride is rapidly absorbed (Cmax attained 2–3 hours after single 2 mg oral dose) and is extensively distributed. Metabolism is not the major route of elimination. In vitro, human liver metabolism is very slow and only minor amounts of metabolites are found. A large fraction of the active substance is excreted unchanged (about 60% of the administered dose in urine and at least 6% in faeces). Renal excretion of unchanged prucalopride involves both passive filtration and active secretion. Plasma clearance averages 317 ml/min, terminal half-life is 24–30 hours, and steady-state is reached within 3–4 days. On once daily treatment with 2 mg prucalopride, steady-state plasma concentrations fluctuate between trough and peak values of 2.5 and 7 ng/ml, respectively.
In vitro data indicate that prucalopride has a low interaction potential, and therapeutic concentrations of prucalopride are not expected to affect the CYP-mediated metabolism of co-medicated medicinal products.
# Efficacy
The primary measure of efficacy in the clinical trials is three or more spontaneous complete bowel movements per week; a secondary measure is an increase of at least one complete spontaneous bowel movement per week. Further measures are improvements in PAC-QOL (a quality of life measure) and PAC-SYM (a range of stool, abdominal, and rectal symptoms associated with chronic constipation). Infrequent bowel movements, bloating, straining, abdominal pain, and defecation urge with inability to evacuate can be severe symptoms, significantly affecting quality of life.
In three large clinical trials, 12 weeks of treatment with prucalopride 2 and 4 mg/day resulted in a significantly higher proportion of patients reaching the primary efficacy endpoint of an average of ≥3 spontaneous complete bowel movements than with placebo. There was also significantly improved bowel habit and associated symptoms, patient satisfaction with bowel habit and treatment, and HR-QOL in patients with severe chronic constipation, including those who did not experience adequate relief with prior therapies (>80% of the trial participants). The improvement in patient satisfaction with bowel habit and treatment was maintained during treatment for up to 24 months; prucalopride therapy was generally well tolerated.
# Side effects
Prucalopride has been given orally to ~2700 patients with chronic constipation in controlled clinical trials. The most frequently reported side effects are headache and gastrointestinal symptoms (abdominal pain, nausea or diarrhoea). Such reactions occur predominantly at the start of therapy and usually disappear within a few days with continued treatment.
# Prescribing information
In the EEA, prucalopride is approved for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. The recommended dosage in adults is 2 mg administered orally once daily; exceeding this dosage is not expected to increase efficacy. The recommended starting dose in elderly patients (>65 years) is 1 mg once daily; thereafter the dosage can be increased to 2 mg once daily, if needed.
# Contraindications
Prucalopride is contraindicated where there is hypersensitivity to the active substance or to any of the excipients, renal impairment requiring dialysis, intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract, such as Crohn's disease, and ulcerative colitis and toxic megacolon/megarectum. | Prucalopride
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
Prucalopride (brand name Resolor, developed by Johnson & Johnson and licensed to Movetis) is a drug acting as a selective, high affinity 5-HT4 receptor agonist[1] which targets the impaired motility associated with chronic constipation, thus normalising bowel movements.[2][3][4][5][6][7] Prucalopride was approved for use in Europe in 2009[8] and in Canada (named Resotran) on December 7, 2011[9] but it has not been approved by the Food and Drug Administration for use in the United States. The drug has also been tested for the treatment of chronic intestinal pseudo-obstruction.[10][11]
# Mechanism of action
Prucalopride, a first in class dihydro-benzofuran-carboxamide, is a selective, high affinity serotonin (5-HT4) receptor agonist with enterokinetic activities.[12] Prucalopride alters colonic motility patterns via serotonin 5-HT4 receptor stimulation: it stimulates colonic mass movements, which provide the main propulsive force for defecation.
The observed effects are exerted via highly selective action on 5-HT4 receptors:[12] prucalopride has >150-fold higher affinity for 5-HT4 receptors than for other receptors.[1][13] Prucalopride differs from other 5-HT4 agonists such as tegaserod and cisapride, which at therapeutic concentrations also interact with other receptors (5-HT1B/D and the cardiac human ether-a-go-go K+ or hERG channel respectively) and this may account for the adverse cardiovascular events that have resulted in the restricted availability of these drugs.[13] Clinical trials evaluating the effect of prucalopride on QT interval and related adverse events have not demonstrated significant differences compared with placebo.[12]
# Pharmacokinetics
Prucalopride is rapidly absorbed (Cmax attained 2–3 hours after single 2 mg oral dose) and is extensively distributed. Metabolism is not the major route of elimination. In vitro, human liver metabolism is very slow and only minor amounts of metabolites are found. A large fraction of the active substance is excreted unchanged (about 60% of the administered dose in urine and at least 6% in faeces). Renal excretion of unchanged prucalopride involves both passive filtration and active secretion. Plasma clearance averages 317 ml/min, terminal half-life is 24–30 hours,[14] and steady-state is reached within 3–4 days. On once daily treatment with 2 mg prucalopride, steady-state plasma concentrations fluctuate between trough and peak values of 2.5 and 7 ng/ml, respectively.[12]
In vitro data indicate that prucalopride has a low interaction potential, and therapeutic concentrations of prucalopride are not expected to affect the CYP-mediated metabolism of co-medicated medicinal products.[12]
# Efficacy
The primary measure of efficacy in the clinical trials is three or more spontaneous complete bowel movements per week; a secondary measure is an increase of at least one complete spontaneous bowel movement per week.[7][15][16] Further measures are improvements in PAC-QOL[17] (a quality of life measure) and PAC-SYM[18] (a range of stool, abdominal, and rectal symptoms associated with chronic constipation). Infrequent bowel movements, bloating, straining, abdominal pain, and defecation urge with inability to evacuate can be severe symptoms, significantly affecting quality of life.[19][20][21][22][23]
In three large clinical trials, 12 weeks of treatment with prucalopride 2 and 4 mg/day resulted in a significantly higher proportion of patients reaching the primary efficacy endpoint of an average of ≥3 spontaneous complete bowel movements than with placebo.[7][15][16] There was also significantly improved bowel habit and associated symptoms, patient satisfaction with bowel habit and treatment, and HR-QOL in patients with severe chronic constipation, including those who did not experience adequate relief with prior therapies (>80% of the trial participants).[7][15][16] The improvement in patient satisfaction with bowel habit and treatment was maintained during treatment for up to 24 months; prucalopride therapy was generally well tolerated.[24][25]
# Side effects
Prucalopride has been given orally to ~2700 patients with chronic constipation in controlled clinical trials. The most frequently reported side effects are headache and gastrointestinal symptoms (abdominal pain, nausea or diarrhoea). Such reactions occur predominantly at the start of therapy and usually disappear within a few days with continued treatment.[12]
# Prescribing information
In the EEA, prucalopride is approved for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. The recommended dosage in adults is 2 mg administered orally once daily; exceeding this dosage is not expected to increase efficacy. The recommended starting dose in elderly patients (>65 years) is 1 mg once daily; thereafter the dosage can be increased to 2 mg once daily, if needed.[12]
# Contraindications
Prucalopride is contraindicated where there is hypersensitivity to the active substance or to any of the excipients, renal impairment requiring dialysis, intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract, such as Crohn's disease, and ulcerative colitis and toxic megacolon/megarectum.[12] | https://www.wikidoc.org/index.php/Prucalopride | |
314146cd25526ab9dda92ab17a2b46e5c127afb2 | wikidoc | Pseudolesion | Pseudolesion
# Overview
A pseudolesion is a stenosis that appears in an artery after the coronary gidewire is placed in the artery.
# Risk Factors
Pseudolesions appear in tortuous sections of vessels that have been straightened out by the guidewire. Tortuous right coronary arteries and left internal mammary arteries are at risk for pseudolesion formation.
# Differential Diagnosis
A pseudolesion must be distinguished from a dissection or coronary spasm.
# Diagnosis
A pseudolesion will usually disappear if the wire is withdrawn to the distal edge of the lesion and the vessel is allowed to assume its normal shape. Sometimes replacement of a stiff wire with a more flexible floppy wire eliminates that pseudolesion. In addition, either a microcatheter or a balloon catheter can be placed distal to the lesion and this will sometimes eliminate the pseudolesion. If the balloon kinks at the site of vessel tortuosity, then it can be hard to reintroduce the wire. A pseudolesion should completely disappear after the wire is withdrawn from the coronary artery.
# Treatment
Pseudolesions should not be stented or dilated!
# Complications
In some cases pseudolesions may cause hemodynamic compromise and ischemia. Inadvertent stenting of pseudolesions by overzealous interventional cardiologists. | Pseudolesion
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A pseudolesion is a stenosis that appears in an artery after the coronary gidewire is placed in the artery.
# Risk Factors
Pseudolesions appear in tortuous sections of vessels that have been straightened out by the guidewire. Tortuous right coronary arteries and left internal mammary arteries are at risk for pseudolesion formation.
# Differential Diagnosis
A pseudolesion must be distinguished from a dissection or coronary spasm.
# Diagnosis
A pseudolesion will usually disappear if the wire is withdrawn to the distal edge of the lesion and the vessel is allowed to assume its normal shape. Sometimes replacement of a stiff wire with a more flexible floppy wire eliminates that pseudolesion. In addition, either a microcatheter or a balloon catheter can be placed distal to the lesion and this will sometimes eliminate the pseudolesion. If the balloon kinks at the site of vessel tortuosity, then it can be hard to reintroduce the wire. A pseudolesion should completely disappear after the wire is withdrawn from the coronary artery.
# Treatment
Pseudolesions should not be stented or dilated!
# Complications
In some cases pseudolesions may cause hemodynamic compromise and ischemia. Inadvertent stenting of pseudolesions by overzealous interventional cardiologists. | https://www.wikidoc.org/index.php/Pseudolesion | |
2b84faa19ac8abc01bea56870cb5118fdc537002 | wikidoc | Psychiatrist | Psychiatrist
A psychiatrist is a physician who specializes in psychiatry and is certified in treating mental illness. As part of their evaluation of the patient, psychiatrists are one of only a few mental health professionals who may prescribe psychiatric medication, conduct physical examinations, order and interpret laboratory tests and electroencephalograms, and may order brain imaging studies such as computed tomography or computed axial tomography, magnetic resonance imaging, and positron emission tomography scanning.
# Psychiatry in the professional world
Psychiatrists are doctors of medicine or osteopathy and are certified in treating mental illness using the biomedical approach to mental disorders. Psychiatrists may also go through significant training to conduct psychotherapy, psychoanalysis, and/or cognitive behavioral therapy, but it is their medical training that differentiates them from other mental health professionals.
## Subspecialties
The field of psychiatry itself can be divided into various subspecialties. These include:
- Child and adolescent psychiatry
- Adult psychiatry
- Psychiatry of Old Age (Geropsychiatry)
- Learning disability
- Behavioral medicine
- Consultation-liaison psychiatry
- Emergency psychiatry
- Addiction psychiatry
- Forensic psychiatry
- Combined Internal Medicine and Psychiatry (Med-Psych)
- Combined Family Medicine and Psychiatry
- Combined Neurology and Psychiatry
- Combined Pediatrics, Psychiatry and Child Psychiatry
Some psychiatric practitioners specialize in helping certain age groups; child and adolescent psychiatrists work with children and teenagers in addressing psychological problems. Those who work with the elderly are called geriatric psychiatrists or geropsychiatrists. Those who practice psychiatry in the workplace are called industrial psychiatrists in the US (occupational psychology is the name used for the most similar discipline in the UK). Psychiatrists working in the courtroom and reporting to the judge and jury, in both criminal and civil court cases, are called forensic psychiatrists, who also treat mentally disordered offenders and other patients whose condition is such that they have to be treated in secure units.
Other psychiatrists and mental health professionals in the field of psychiatry may also specialize in psychopharmacology, neuropsychiatry, eating disorders, psychosomatics, and early psychosis intervention.
# Professional requirements
Typically the requirements to become a psychiatrist are substantial but differ from country to country.
In the United Kingdom, the Republic of Ireland, and other parts of the world, one must pursue a Bachelor of Medicine and Surgery, or a "first MB." These degrees are often abbreviated MB BChir, MB BCh, MB ChB, BM BS, or MB BS. Following this, the individual will act as a "foundation programme trainee" for two additional years. The foundation programme allows students to experience the different specialties of medicine, as well as learn important attributes and qualities of becoming a doctor. Upon completion, a student can apply for training to specialize in psychiatry. Following acceptance, this specialized training will last for about 6 years. After training is successfully completed, the individual can apply for a consultant post and start a career as a licensed psychiatrist.
In the United States and Canada one must first complete their Bachelor's degree. Students may typically decide any major of their choice, however they must enroll in specific courses, usually outlined in a pre-medical program. One must then apply to and attend 4 years of medical school in order to earn their MD or DO and to complete their medical education. Following this, the individual must practice as a psychiatric resident for another four years (five years in Canada). Psychiatry residents are often required to complete at least four post-graduate months of internal medicine or pediatrics and two months of neurology during the first year. After completing their training, psychiatrists take written and then oral board examinations. The total amount of time required to complete post-baccalaureate work in the field of psychiatry in the United States is typically 8 to 9 years. | Psychiatrist
A psychiatrist is a physician who specializes in psychiatry and is certified in treating mental illness.[1] As part of their evaluation of the patient, psychiatrists are one of only a few mental health professionals who may prescribe psychiatric medication, conduct physical examinations, order and interpret laboratory tests and electroencephalograms, and may order brain imaging studies such as computed tomography or computed axial tomography, magnetic resonance imaging, and positron emission tomography scanning.[1][2]
# Psychiatry in the professional world
Psychiatrists are doctors of medicine or osteopathy and are certified in treating mental illness using the biomedical approach to mental disorders.[3] Psychiatrists may also go through significant training to conduct psychotherapy, psychoanalysis, and/or cognitive behavioral therapy, but it is their medical training that differentiates them from other mental health professionals.[3]
## Subspecialties
The field of psychiatry itself can be divided into various subspecialties.[4] These include:
- Child and adolescent psychiatry
- Adult psychiatry
- Psychiatry of Old Age (Geropsychiatry)
- Learning disability
- Behavioral medicine
- Consultation-liaison psychiatry
- Emergency psychiatry
- Addiction psychiatry
- Forensic psychiatry
- Combined Internal Medicine and Psychiatry (Med-Psych)
- Combined Family Medicine and Psychiatry
- Combined Neurology and Psychiatry
- Combined Pediatrics, Psychiatry and Child Psychiatry
Some psychiatric practitioners specialize in helping certain age groups; child and adolescent psychiatrists work with children and teenagers in addressing psychological problems.[4] Those who work with the elderly are called geriatric psychiatrists or geropsychiatrists.[4] Those who practice psychiatry in the workplace are called industrial psychiatrists in the US (occupational psychology is the name used for the most similar discipline in the UK).[4] Psychiatrists working in the courtroom and reporting to the judge and jury, in both criminal and civil court cases, are called forensic psychiatrists, who also treat mentally disordered offenders and other patients whose condition is such that they have to be treated in secure units.[4][5]
Other psychiatrists and mental health professionals in the field of psychiatry may also specialize in psychopharmacology, neuropsychiatry, eating disorders, psychosomatics, and early psychosis intervention.[4][5]
# Professional requirements
Typically the requirements to become a psychiatrist are substantial but differ from country to country.[4][6]
In the United Kingdom, the Republic of Ireland, and other parts of the world, one must pursue a Bachelor of Medicine and Surgery, or a "first MB."[4] These degrees are often abbreviated MB BChir, MB BCh, MB ChB, BM BS, or MB BS. Following this, the individual will act as a "foundation programme trainee" for two additional years.[4] The foundation programme allows students to experience the different specialties of medicine, as well as learn important attributes and qualities of becoming a doctor.[4] Upon completion, a student can apply for training to specialize in psychiatry.[4] Following acceptance, this specialized training will last for about 6 years.[4] After training is successfully completed, the individual can apply for a consultant post and start a career as a licensed psychiatrist.[4]
In the United States and Canada one must first complete their Bachelor's degree.[6] Students may typically decide any major of their choice, however they must enroll in specific courses, usually outlined in a pre-medical program.[6] One must then apply to and attend 4 years of medical school in order to earn their MD or DO and to complete their medical education.[6] Following this, the individual must practice as a psychiatric resident for another four years (five years in Canada). Psychiatry residents are often required to complete at least four post-graduate months of internal medicine or pediatrics and two months of neurology during the first year.[6] After completing their training, psychiatrists take written and then oral board examinations.[6] The total amount of time required to complete post-baccalaureate work in the field of psychiatry in the United States is typically 8 to 9 years. | https://www.wikidoc.org/index.php/Psychiatrist | |
cf84e71c42ecbba09698948c8a3a1b17eadfd8f6 | wikidoc | Psycholeptic | Psycholeptic
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In pharmacology, a psycholeptic is a medication which produces a calming effect upon the patient.
The psycholeptics are classified under N05 in the Anatomical Therapeutic Chemical Classification System. | Psycholeptic
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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In pharmacology, a psycholeptic is a medication which produces a calming effect upon the patient.
The psycholeptics are classified under N05 in the Anatomical Therapeutic Chemical Classification System.
# External links
- http://www.m-w.com/medical/psycholeptic+
- http://cancerweb.ncl.ac.uk/cgi-bin/omd?psycholeptic
Template:Anxiolytics
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Psycholeptic | |
d3fb378ec15d83631228d01e42d260b9168528c7 | wikidoc | Pulled elbow | Pulled elbow
Pulled elbow is a traumatically induced medical affliction experienced only by children below the age of approximately three years.
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The forearm contains two bones, the radius and the ulna. These bones are attached to each other both at the proximal, or elbow, end and also at the distal, or wrist end. Among other movements, the forearm is capable of pronation and supination, which is to say rotation about the long axis of the forearm. In this movement the ulna, which is connected to the humerus by a simple hinge-joint, remains stationary, while the radius rotates, carrying the wrist and hand with it. To allow this rotation, the proximal (elbow) end of the radius is held in proximity to the ulna by a ligament known as the annular ligament. This is a circular ligamentous structure within which the radius is free, with constraints existing elsewhere in the forearm, to rotate.The proximal end of the radius in young children is conical, with the wider end of the cone nearest the elbow. With the passage of time the shape of this bone changes, becoming more cylindrical but with the proximal end being widened.
If the forearm of a young child is pulled, by an impatient parent or for whatever reason, it is possible for this traction to pull the radius into the annular ligament with enough force to cause it to be jammed therein. This causes significant pain, partial limitation of flexion/extension of the elbow and total loss of pronation/supination in the affected arm. The situation cannot arise in adults, or in older children, because the changing shape of the radius associated with growth prevents it.
The condition can be treated by a primary care practitioner, and needs only minimal skill and total confidence. To resolve the problem, the affected arm must be held by the attending physician with one hand just above the elbow and the other grasping the hand. While applying compression between these two hands, the forearm of the patient is rapidly supinated. The physician will feel a "click", the child will scream, the parent (unless warned) will be upset, and the forearm will thereafter function well and painlessly. | Pulled elbow
Pulled elbow is a traumatically induced medical affliction experienced only by children below the age of approximately three years.
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
The forearm contains two bones, the radius and the ulna. These bones are attached to each other both at the proximal, or elbow, end and also at the distal, or wrist end. Among other movements, the forearm is capable of pronation and supination, which is to say rotation about the long axis of the forearm. In this movement the ulna, which is connected to the humerus by a simple hinge-joint, remains stationary, while the radius rotates, carrying the wrist and hand with it. To allow this rotation, the proximal (elbow) end of the radius is held in proximity to the ulna by a ligament known as the annular ligament. This is a circular ligamentous structure within which the radius is free, with constraints existing elsewhere in the forearm, to rotate.The proximal end of the radius in young children is conical, with the wider end of the cone nearest the elbow. With the passage of time the shape of this bone changes, becoming more cylindrical but with the proximal end being widened.
If the forearm of a young child is pulled, by an impatient parent or for whatever reason, it is possible for this traction to pull the radius into the annular ligament with enough force to cause it to be jammed therein. This causes significant pain, partial limitation of flexion/extension of the elbow and total loss of pronation/supination in the affected arm. The situation cannot arise in adults, or in older children, because the changing shape of the radius associated with growth prevents it.
The condition can be treated by a primary care practitioner, and needs only minimal skill and total confidence. To resolve the problem, the affected arm must be held by the attending physician with one hand just above the elbow and the other grasping the hand. While applying compression between these two hands, the forearm of the patient is rapidly supinated. The physician will feel a "click", the child will scream, the parent (unless warned) will be upset, and the forearm will thereafter function well and painlessly.
Template:SIB
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Pulled_elbow | |
43582bc4c7f9abac261593f384f730acf4babd73 | wikidoc | Punicic acid | Punicic acid
Punicic acid (also called trichosanic acid) is a polyunsaturated fatty acid, 18:3 (n-5). It is named for the pomegranate, (Punica granatum), and is obtained from pomegranate seed oil.
It is also found in the seed oils of snake gourd and bitter gourd.
Punicic acid is a conjugated linolenic acid or ClnA; i.e. it has three conjugated double bonds. It is chemically similar to the conjugated linoleic acids, or CLA, which have two.
In lab rats, it was found that punicic acid was converted to the CLA rumenic acid (9Z11E-CLA). In vitro, it shows anticancer activity against prostate cancer cells. OLETF rats—a strain which becomes obese—remained relatively lean when punicic acid was added to their feed. Fat cells undergo programmed cell death when exposed to punicic acid from bitter-gourd oil. | Punicic acid
Punicic acid (also called trichosanic acid) is a polyunsaturated fatty acid, 18:3 (n-5). It is named for the pomegranate, (Punica granatum), and is obtained from pomegranate seed oil.
It is also found in the seed oils of snake gourd and bitter gourd.[1]
Punicic acid is a conjugated linolenic acid or ClnA; i.e. it has three conjugated double bonds. It is chemically similar to the conjugated linoleic acids, or CLA, which have two.
In lab rats, it was found that punicic acid was converted to the CLA rumenic acid (9Z11E-CLA).[2] In vitro, it shows anticancer activity against prostate cancer cells.[3] OLETF rats—a strain which becomes obese—remained relatively lean when punicic acid was added to their feed.[4] Fat cells undergo programmed cell death when exposed to punicic acid from bitter-gourd oil.[5] | https://www.wikidoc.org/index.php/Punicic_acid | |
4e09e82bae81ec7791d380196e4a8a51b9d70ce3 | wikidoc | Purple drank | Purple drank
Purple Drank is an illegal recreational drink popular amongst the hip-hop community of the Southern United States. Its main ingredients are prescription-strength cough syrup containing codeine and promethazine.
The purple-ish hue of Purple Drank comes from dyes in the cough syrup. Recently, the term has expanded to cover mixtures including over-the-counter cough syrup. Other terms for Purple Drank include Sizzurp, Drank, Purple Tonic, Texas Tea, Memphis Mud, Lean, Oil, Tsikuni, Barre, and Sir.
# History
Houston, Texas producer DJ Screw first popularized the concoction, which is widely attributed as a source of inspiration for the "chopped & screwed" style of hip hop music. Originally, the active ingredient of "Syrup" was cough syrup containing promethazine and codeine. The concoction first gained popularity in the underground Houston, Texas rap scene and later spread to other southern states.
In June of 2000, Three 6 Mafia's single "Sippin On Some Syrup," featuring UGK and Project Pat brought the term "purple stuff" to a nationwide audience. On November 16, 2000, several months after the video to Three 6 Mafia's single debuted, DJ Screw died of a suspected overdose of codeine and alcohol.. The mixture has also been referenced in lyrics of other rappers, including UGK's "Sippin and Spinnin" and "Purple Drank", as well as tracks by Paul Wall, Mike Jones, T.I., Chamillionaire, Big Moe, Slim Thug, and Z-Ro. In September of 2006, Terrence Kiel, a San Diego Chargers player, was arrested during practice for the possession with intent to sell of what authorities referred to as "Lean"..
New Orleans rapper Lil' Wayne frequently mentions drinking Purple Drank. In the Duffle Bag Boy music video he can be seen holding a Styrofoam cup with "RIP DJ Screw" written on it. In the remix to "Throw Some D's" on his mixtape Da Drought 3 he claims "I'm not a rookie, I'm a promethazine fiend." He also refers to the substance in the song "We Takin' Over," where he says that "I like my Sprite Easter pink," an overt reference to the color of the beverage.
# Ingredients
## Active ingredients
The active ingredient of purple drank is codeine, a narcotic medication contained in prescription cough syrup. It is not made with over-the-counter cough syrups such as Robitussin, which contain dextromethorphan. Although dextromethorphan is sometimes used recreationally, it has different effects. Some prescription cough syrups also contain antihistamine medications, such as promethazine, which have a mild sedative effect. When taken in large quantities, both medications can lead to sedation and altered levels of consciousness.
The syrup usually used in purple drank contains 10mg of codeine and 6.25 mg of promethazine per 5 mL. | Purple drank
Purple Drank is an illegal recreational drink popular amongst the hip-hop community of the Southern United States. Its main ingredients are prescription-strength cough syrup containing codeine and promethazine.[1]
The purple-ish hue of Purple Drank comes from dyes in the cough syrup. Recently, the term has expanded to cover mixtures including over-the-counter cough syrup. Other terms for Purple Drank include Sizzurp, Drank, Purple Tonic, Texas Tea, Memphis Mud, Lean, Oil, Tsikuni, Barre, and Sir.
# History
Houston, Texas producer DJ Screw first popularized the concoction, which is widely attributed as a source of inspiration for the "chopped & screwed" style of hip hop music. Originally, the active ingredient of "Syrup" was cough syrup containing promethazine and codeine. The concoction first gained popularity in the underground Houston, Texas rap scene and later spread to other southern states.
In June of 2000, Three 6 Mafia's single "Sippin On Some Syrup," featuring UGK and Project Pat brought the term "purple stuff" to a nationwide audience.[2] On November 16, 2000, several months after the video to Three 6 Mafia's single debuted, DJ Screw died of a suspected overdose of codeine and alcohol.[3]. The mixture has also been referenced in lyrics of other rappers, including UGK's "Sippin and Spinnin" and "Purple Drank", as well as tracks by Paul Wall, Mike Jones, T.I., Chamillionaire, Big Moe, Slim Thug, and Z-Ro. In September of 2006, Terrence Kiel, a San Diego Chargers player, was arrested during practice for the possession with intent to sell of what authorities referred to as "Lean".[4].
New Orleans rapper Lil' Wayne frequently mentions drinking Purple Drank. In the Duffle Bag Boy music video he can be seen holding a Styrofoam cup with "RIP DJ Screw" written on it. In the remix to "Throw Some D's" on his mixtape Da Drought 3 he claims "I'm not a rookie, I'm a promethazine fiend." He also refers to the substance in the song "We Takin' Over," where he says that "I like my Sprite Easter pink," an overt reference to the color of the beverage.
# Ingredients
## Active ingredients
The active ingredient of purple drank is codeine, a narcotic medication contained in prescription cough syrup. It is not made with over-the-counter cough syrups such as Robitussin, which contain dextromethorphan. Although dextromethorphan is sometimes used recreationally, it has different effects. Some prescription cough syrups also contain antihistamine medications, such as promethazine, which have a mild sedative effect. When taken in large quantities, both medications can lead to sedation and altered levels of consciousness.[1]
The syrup usually used in purple drank contains 10mg of codeine and 6.25 mg of promethazine per 5 mL. | https://www.wikidoc.org/index.php/Purple_drank | |
2cafec2e68647eb3c251c4ee862ba845de24974d | wikidoc | Pyloroplasty | Pyloroplasty
Pyloroplasty is a surgery performed to widen the opening at the lower part of the stomach, also known as the pylorus. When the pylorus thickens, it becomes difficult for food to pass through. The surgery is performed to widen the band of muscle known as the pyloric sphincter, a ring of smooth, muscular fibers that surrounds the pylorus and helps to regulate digestion and prevent reflux (see illustration). The widening of the pyloric sphincter enables the contents of the stomach to pass into the first part of the small intestine known as the duodenum.
# Applications
Pyloroplasty can be performed on a narrowed or thickened pylorus, but also on a normal pylorus. Pyloroplasty is used to treat those who have complications causing a blockage of the pylorus, commonly peptic ulcers. It also can be performed on patients at high risk for gastric or peptic ulcer disease (PUD). Pyloroplasty is almost never performed by itself; it is most commonly paired with another procedure like a vagotomy.
# Demographics
Nearly 4 million people in the US have PUD. It is estimated that 5 out of every 100,000 adults in US will develop a peptic ulcer. 80-90% of primary ulcers are believed to be caused by Helicobacter pylori bacteria, and infection by H. pylori occurs more often in black and Hispanic populations than white. PUD can occur in patients of all ages.
# Description and Procedure
Pyloroplasty is performed while the patient is under general anesthesia and placed in the supine position. The surgery can be performed as an open surgery or by a laparoscope. If performed as an open surgery, the surgeon will make a large surgical cut on the stomach to open the area, and cut through some of the pyloric sphincter to widen and relax it. A midline incision is most commonly used for this procedure. If performed by laparoscope, 3 to 5 small cuts are made on the stomach. The stomach is filled with gas so that the surgeon looking through the small camera can see the area. The pyloric sphincter is then widened in the same way as in an open surgery. Pyloroplasty allows for rapid emptying of the contents of the stomach into the duodenum, but may cause reflux of contents of the small intestine back into the stomach.
There are multiple types of pyloroplasty techniques. The most commonly performed pyloroplasty is known as Heineke-Mikulicz pyloroplasty. This type consists of a transversely closed longitudinal incision across the pylorus. Another technique is known as Jaboulay pyloroplasty, which is not a pylorus incision, but a side-to-side gastroduodenostomy. Lastly, Finney pyloroplasty is the same technique as Jaboulay pyloroplasty, but also with a pylorus incision.
After the surgery, the patient’s breathing, blood pressure, temperature, heart rate, fluid intake and output, respiration, and operative site will be monitored. Typically, about 8 hours after surgery the patient may be able to walk a short distance, and walk increasing distances over the next 2–3 days. Most patients are released after 24 hours and recover quickly and completely. Most people can slowly begin a regular diet within 2–3 weeks.
# Risks
Risks include those general to surgery, such as reactions to medications, bleeding, blood clots, or infection. Risks specific to pyloroplasty include damage to the intestines, chronic diarrhea, mucosal perforations, leakage of the contents of the stomach, malnutrition, bile reflux, vomiting, and hernias.
# Alternatives
Some variants of pyloroplasty are Pyloric dilatation and pyloromyotomy, which are less invasive. Alternative procedures to pyloroplasty include gastrojejunostomy and antrectomy. | Pyloroplasty
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Pyloroplasty is a surgery performed to widen the opening at the lower part of the stomach, also known as the pylorus.[1] When the pylorus thickens, it becomes difficult for food to pass through.[1] The surgery is performed to widen the band of muscle known as the pyloric sphincter, a ring of smooth, muscular fibers that surrounds the pylorus and helps to regulate digestion and prevent reflux (see illustration). [2] The widening of the pyloric sphincter enables the contents of the stomach to pass into the first part of the small intestine known as the duodenum.[1]
# Applications
Pyloroplasty can be performed on a narrowed or thickened pylorus, but also on a normal pylorus.[3] Pyloroplasty is used to treat those who have complications causing a blockage of the pylorus, commonly peptic ulcers.[1] It also can be performed on patients at high risk for gastric or peptic ulcer disease (PUD).[4] Pyloroplasty is almost never performed by itself; it is most commonly paired with another procedure like a vagotomy.[3]
# Demographics
Nearly 4 million people in the US have PUD. It is estimated that 5 out of every 100,000 adults in US will develop a peptic ulcer.[4] 80-90% of primary ulcers are believed to be caused by Helicobacter pylori bacteria, and infection by H. pylori occurs more often in black and Hispanic populations than white. PUD can occur in patients of all ages.[4]
# Description and Procedure
Pyloroplasty is performed while the patient is under general anesthesia and placed in the supine position.[1][3] The surgery can be performed as an open surgery or by a laparoscope. If performed as an open surgery, the surgeon will make a large surgical cut on the stomach to open the area, and cut through some of the pyloric sphincter to widen and relax it.[1] A midline incision is most commonly used for this procedure.[3] If performed by laparoscope, 3 to 5 small cuts are made on the stomach. The stomach is filled with gas so that the surgeon looking through the small camera can see the area. The pyloric sphincter is then widened in the same way as in an open surgery.[1] Pyloroplasty allows for rapid emptying of the contents of the stomach into the duodenum, but may cause reflux of contents of the small intestine back into the stomach.[3]
There are multiple types of pyloroplasty techniques. The most commonly performed pyloroplasty is known as Heineke-Mikulicz pyloroplasty. This type consists of a transversely closed longitudinal incision across the pylorus. Another technique is known as Jaboulay pyloroplasty, which is not a pylorus incision, but a side-to-side gastroduodenostomy. Lastly, Finney pyloroplasty is the same technique as Jaboulay pyloroplasty, but also with a pylorus incision.[3]
After the surgery, the patient’s breathing, blood pressure, temperature, heart rate, fluid intake and output, respiration, and operative site will be monitored. Typically, about 8 hours after surgery the patient may be able to walk a short distance, and walk increasing distances over the next 2–3 days.[4] Most patients are released after 24 hours and recover quickly and completely. Most people can slowly begin a regular diet within 2–3 weeks.[1]
# Risks
Risks include those general to surgery, such as reactions to medications, bleeding, blood clots, or infection. Risks specific to pyloroplasty include damage to the intestines, chronic diarrhea, mucosal perforations, leakage of the contents of the stomach, malnutrition, bile reflux, vomiting, and hernias.[1][3][4]
# Alternatives
Some variants of pyloroplasty are Pyloric dilatation and pyloromyotomy, which are less invasive. Alternative procedures to pyloroplasty include gastrojejunostomy and antrectomy.[3] | https://www.wikidoc.org/index.php/Pyloroplasty | |
f7a2fdc704e8577027bf3094de35d1279c940772 | wikidoc | Pyruvic acid | Pyruvic acid
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Pyruvic acid (CH3COCO2H) is an alpha-keto acid. Pyruvate plays an important role in biochemical processes. The carboxylate anion of pyruvic acid is known as pyruvate.
# Chemistry
Pyruvic acid is a colorless liquid with a smell similar to that of acetic acid. It is miscible with water, and soluble in ethanol and diethyl ether. In the laboratory, pyruvic acid may be prepared by heating a mixture of tartaric acid and potassium hydrogen sulfate, or by the hydrolysis of acetyl cyanide, formed by reaction of acetyl chloride with potassium cyanide:
# Biochemical role
Pyruvate is an important chemical compound in biochemistry. It is the output of the aerobic metabolism of glucose known as glycolysis. One molecule of glucose breaks down into two molecules of pyruvic acid, which are then used to provide further energy, in one of two ways. Pyruvic acid is converted into acetyl-coenzyme A, which is the main input for a series of reactions known as the Krebs cycle. Pyruvate is also converted to oxaloacetate by an anaplerotic reaction which replenishes Krebs cycle intermediates; alternatively, the oxaloacetate is used for gluconeogenesis. These reactions are named after Hans Adolf Krebs, the biochemist awarded the 1953 Nobel Prize for physiology, jointly with Fritz Lipmann, for research into metabolic processes. The cycle is also called the citric acid cycle, because citric acid is one of the intermediate compounds formed during the reactions.
If insufficient oxygen is available, the acid is broken down anaerobically, creating lactic acid in animals and ethanol in plants. Pyruvate from glycolysis is converted by anaerobic respiration to lactate using the enzyme lactate dehydrogenase and the coenzyme NADH in lactate fermentation, or to acetaldehyde and then to ethanol in alcoholic fermentation.
Pyruvic acid is a key intersection in the network of metabolic pathways. Pyruvic acid can be converted to carbohydrates via gluconeogenesis, to fatty acids or energy through acetyl-CoA, to the amino acid alanine and to ethanol. Therefore it unites several key metabolic processes.
The pyruvic acid derivative bromopyruvic acid is being studied for potential cancer treatment applications, by Young Hee Ko at Johns Hopkins University and others in ways that would support the Warburg hypothesis on the cause(s) of cancer.
## Pyruvate production by glycolysis
In glycolysis, phosphoenolpyruvate (PEP) is converted to pyruvate by pyruvate kinase. This reaction is strongly exergonic and irreversible; in gluconeogenesis it takes two enzymes, pyruvate carboxylase and PEP carboxykinase to catalyze the reverse transformation of pyruvate to PEP. The arrow indicating a reverse reaction in the Figure below is incorrect.
Compound C00074 at KEGG Pathway Database. Enzyme 2.7.1.40 at KEGG Pathway Database. Compound C00022 at KEGG Pathway Database.
## Pyruvate decarboxylation to acetyl CoA
Pyruvate decarboxylation by the pyruvate dehydrogenase complex produces acetyl-CoA.
Note that decarboxylation is only one of several possible reactions for pyruvate.
# Role in the origin of life
Current evolutionary theory on the origin of life posits that the first organisms were anaerobic because the atmosphere of prebiotic Earth was almost devoid of oxygen. As such, requisite biochemical materials must have preceded life and recent experiments indicate that pyruvate can be synthesized abiotically. In vitro, iron sulfide at sufficient pressure and temperature catalyzes the formation of pyruvic acid. Thus, argues Günter Wächtershäuser, the mixing of iron-rich crust with hydrothermal vent fluid is suspected of providing the fertile basis for the formation of life. | Pyruvic acid
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Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Pyruvic acid (CH3COCO2H) is an alpha-keto acid. Pyruvate plays an important role in biochemical processes. The carboxylate anion of pyruvic acid is known as pyruvate.
# Chemistry
Pyruvic acid is a colorless liquid with a smell similar to that of acetic acid. It is miscible with water, and soluble in ethanol and diethyl ether. In the laboratory, pyruvic acid may be prepared by heating a mixture of tartaric acid and potassium hydrogen sulfate, or by the hydrolysis of acetyl cyanide, formed by reaction of acetyl chloride with potassium cyanide:
# Biochemical role
Pyruvate is an important chemical compound in biochemistry. It is the output of the aerobic metabolism of glucose known as glycolysis. One molecule of glucose breaks down into two molecules of pyruvic acid, which are then used to provide further energy, in one of two ways. Pyruvic acid is converted into acetyl-coenzyme A, which is the main input for a series of reactions known as the Krebs cycle. Pyruvate is also converted to oxaloacetate by an anaplerotic reaction which replenishes Krebs cycle intermediates; alternatively, the oxaloacetate is used for gluconeogenesis. These reactions are named after Hans Adolf Krebs, the biochemist awarded the 1953 Nobel Prize for physiology, jointly with Fritz Lipmann, for research into metabolic processes. The cycle is also called the citric acid cycle, because citric acid is one of the intermediate compounds formed during the reactions.
If insufficient oxygen is available, the acid is broken down anaerobically, creating lactic acid in animals and ethanol in plants. Pyruvate from glycolysis is converted by anaerobic respiration to lactate using the enzyme lactate dehydrogenase and the coenzyme NADH in lactate fermentation, or to acetaldehyde and then to ethanol in alcoholic fermentation.
Pyruvic acid is a key intersection in the network of metabolic pathways. Pyruvic acid can be converted to carbohydrates via gluconeogenesis, to fatty acids or energy through acetyl-CoA, to the amino acid alanine and to ethanol. Therefore it unites several key metabolic processes.
The pyruvic acid derivative bromopyruvic acid is being studied for potential cancer treatment applications, by Young Hee Ko at Johns Hopkins University and others in ways that would support the Warburg hypothesis on the cause(s) of cancer.
## Pyruvate production by glycolysis
In glycolysis, phosphoenolpyruvate (PEP) is converted to pyruvate by pyruvate kinase. This reaction is strongly exergonic and irreversible; in gluconeogenesis it takes two enzymes, pyruvate carboxylase and PEP carboxykinase to catalyze the reverse transformation of pyruvate to PEP. The arrow indicating a reverse reaction in the Figure below is incorrect.
Compound C00074 at KEGG Pathway Database. Enzyme 2.7.1.40 at KEGG Pathway Database. Compound C00022 at KEGG Pathway Database.
## Pyruvate decarboxylation to acetyl CoA
Pyruvate decarboxylation by the pyruvate dehydrogenase complex produces acetyl-CoA.
Note that decarboxylation is only one of several possible reactions for pyruvate.
# Role in the origin of life
Current evolutionary theory on the origin of life posits that the first organisms were anaerobic because the atmosphere of prebiotic Earth was almost devoid of oxygen. As such, requisite biochemical materials must have preceded life and recent experiments indicate that pyruvate can be synthesized abiotically. In vitro, iron sulfide at sufficient pressure and temperature catalyzes the formation of pyruvic acid. Thus, argues Günter Wächtershäuser, the mixing of iron-rich crust with hydrothermal vent fluid is suspected of providing the fertile basis for the formation of life.
# External links
- "Pyruvate in Cancer Prevention and Treatment" | https://www.wikidoc.org/index.php/Pyruvate | |
d10035d721fde943bcd7f34214d751f7c02965e2 | wikidoc | Quantitative | Quantitative
A 'quantitative' attribute is one that exists in a range of magnitudes, and can therefore be measured. Measurements of any particular quantitative property are expressed as a specific quantity, referred to as a unit, multiplied by a number. Examples of physical quantities are distance, mass, and time. Many attributes in the social sciences, including abilities and personality traits, are also studied as quantitative properties and principles.
# Historical background
## The classical concept of quantity
In the classical definition of measurement, the structure quantitative property is such that different magnitudes of the quantity stand in relation to one another as ratios which, in turn, can be expressed as real numbers. Measurement is the determination or estimation of ratios of quantities. Quantity and measurement are therefore mutually defined: quantitative attributes are those which it is possible to measure, at least in principle. The classical concept of quantity can be traced back to John Wallis and Isaac Newton, and was foreshadowed in Euclid's Elements (Michell, 1993).
## The representational theory of measurement
In the representational theory, measurement is regarded as "the correlation of numbers with entities that are not numbers" (Nagel, 1932). In some forms of representational theory, numbers are assigned on the basis of correspondences or similarities between the structure of number systems and the structure of qualitative systems. A quantitative property is therefore one for which such structural similarities can be established. In other forms of representational theory, such as that implicit within the work of Stanley Smith Stevens, numbers need only be assigned according to a rule.
# Fundamental considerations in quantitative research
Whether numbers obtained through an experimental procedure are considered measurements is, on the one hand, largely a matter of how measurement is defined. On the other hand, the nature of the measurement process has important implications for scientific research. Firstly, many arithmeitic operations are only justified for measurements either in the classical sense described above, or in the sense of interval and ratio-level measurements as defined by Stevens (which arguably describe the same thing). Secondly, quantitative relationships between different properties which feature in most natural theories and laws imply that the properties have a specific type of quantitative structure; namely, the structure of a continuous quantity. The reason for this is that such theories and laws display a multiplicative structure (for example Newton's second law).
Continuous quantities are those for which magnitudes can be represented as real numbers and for which, therefore, measurements can be expressed on a continuum. Continuous quantities may be scalar or vector quantities. For example, SI units are physical units of continuous quantitative properties, phenomena, and relations such as distance, mass, heat, force and angular separation. The classical concept of quantity described above necessarily implies the concept of continuous quantity.
Recording observations with numbers does not, in itself, imply that an attribute is quantitative. For example, judges routinely assign numbers to properties such as the perceived beauty of an exercise (e.g. 1-10) without necessarily establishing quantitative structure in any sort of rigorous fashion. A researcher might also use the number 1 to mean "Susan", 2 to mean "Michael", and so on. This, however, is not a meaningful use of numbers: the researcher can arbitrarily reassign the numbers (so that 1 means "Michael" and 2 means "Susan") without losing any information. Put another way, facts about numbers (for example, that 2 is greater than 1, that 5 is two more than 3, and that 8 is twice 4) don't mean anything about the names corresponding to those numbers. A person's name is not, therefore, a quantitative property.
Whether counts of objects or observations are considered measurements is also largely a matter of how measurement is defined. Again, though, an important consideration is the manner in which resulting numbers are used. Counts are not measurements of continuous quantities. If, for example, a researcher were to count the number of grains of sand in a specified volume of space on a beach, the result denumerates how many separate grains there are; i.e. the number of separate distinguishable entities of a specific type. Arithmetic operations, such as addition, have meaning only in this specific sense. For instance, combining 5 and 4 grains of sand gives 9 grains of sand. The numbers used in this case are therefore the natural numbers.
Any object is characterized by many attributes, such as colour and mass, only some of which constitute continuous quantities. For example, the mass of a specific grain of sand is a continuous quantity whereas the grain, as an object, is not. Thus, the mass of a grain of sand can be used as a unit of mass because it is possible to estimate the ratio of the mass of another object to the mass of a grain of sand, given an appropriate instrument.
In the social sciences, it is also common to count frequencies of observations; i.e. frequencies of observable outcomes in an experiment. Examples include the number of correct scores on an assessment of an ability, and the number of statements on a questionnaire endorsed by respondents. Provided each observable outcome is the manifestation of an underlying quantitative attribute, such frequencies will generally indicate relative magnitudes of that attribute. Strictly speaking, however, counts and frequencies do not constitute measurement in terms of a unit of continuous quantity.
# Use in prosody and poetry
In prosody and poetic meter, syllable weight can be a governing principle. Many linguists use morae as a unit of syllable weight—a syllable with more morae is heavier than one with fewer morae. Commonly, syllables with naturally long vowels, diphthongs, and vowels followed by two or more consonants are said to be “heavy”, “long”, or “bimoraic”, whereas syllables with naturally short vowels, followed by only one or no consonant, are said to be “light”, “short”, or “monomoraic”. There is, however, considerable variation across the world's languages as to which coda-consonants contribute a mora to the syllable (i.e., make it heavy). At one end of the variation, only the length of the vowel determines syllable weight; at the other end each coda-consonant counts as one mora. Some languages use syllable weight in assigning word accent. Some poetic meters are based on the arrangement of heavy and light syllables. | Quantitative
A 'quantitative' attribute is one that exists in a range of magnitudes, and can therefore be measured. Measurements of any particular quantitative property are expressed as a specific quantity, referred to as a unit, multiplied by a number. Examples of physical quantities are distance, mass, and time. Many attributes in the social sciences, including abilities and personality traits, are also studied as quantitative properties and principles.
# Historical background
## The classical concept of quantity
In the classical definition of measurement, the structure quantitative property is such that different magnitudes of the quantity stand in relation to one another as ratios which, in turn, can be expressed as real numbers. Measurement is the determination or estimation of ratios of quantities. Quantity and measurement are therefore mutually defined: quantitative attributes are those which it is possible to measure, at least in principle. The classical concept of quantity can be traced back to John Wallis and Isaac Newton, and was foreshadowed in Euclid's Elements (Michell, 1993).
## The representational theory of measurement
In the representational theory, measurement is regarded as "the correlation of numbers with entities that are not numbers" (Nagel, 1932). In some forms of representational theory, numbers are assigned on the basis of correspondences or similarities between the structure of number systems and the structure of qualitative systems. A quantitative property is therefore one for which such structural similarities can be established. In other forms of representational theory, such as that implicit within the work of Stanley Smith Stevens, numbers need only be assigned according to a rule.
# Fundamental considerations in quantitative research
Whether numbers obtained through an experimental procedure are considered measurements is, on the one hand, largely a matter of how measurement is defined. On the other hand, the nature of the measurement process has important implications for scientific research. Firstly, many arithmeitic operations are only justified for measurements either in the classical sense described above, or in the sense of interval and ratio-level measurements as defined by Stevens (which arguably describe the same thing). Secondly, quantitative relationships between different properties which feature in most natural theories and laws imply that the properties have a specific type of quantitative structure; namely, the structure of a continuous quantity. The reason for this is that such theories and laws display a multiplicative structure (for example Newton's second law).
Continuous quantities are those for which magnitudes can be represented as real numbers and for which, therefore, measurements can be expressed on a continuum. Continuous quantities may be scalar or vector quantities. For example, SI units are physical units of continuous quantitative properties, phenomena, and relations such as distance, mass, heat, force and angular separation. The classical concept of quantity described above necessarily implies the concept of continuous quantity.
Recording observations with numbers does not, in itself, imply that an attribute is quantitative. For example, judges routinely assign numbers to properties such as the perceived beauty of an exercise (e.g. 1-10) without necessarily establishing quantitative structure in any sort of rigorous fashion. A researcher might also use the number 1 to mean "Susan", 2 to mean "Michael", and so on. This, however, is not a meaningful use of numbers: the researcher can arbitrarily reassign the numbers (so that 1 means "Michael" and 2 means "Susan") without losing any information. Put another way, facts about numbers (for example, that 2 is greater than 1, that 5 is two more than 3, and that 8 is twice 4) don't mean anything about the names corresponding to those numbers. A person's name is not, therefore, a quantitative property.
Whether counts of objects or observations are considered measurements is also largely a matter of how measurement is defined. Again, though, an important consideration is the manner in which resulting numbers are used. Counts are not measurements of continuous quantities. If, for example, a researcher were to count the number of grains of sand in a specified volume of space on a beach, the result denumerates how many separate grains there are; i.e. the number of separate distinguishable entities of a specific type. Arithmetic operations, such as addition, have meaning only in this specific sense. For instance, combining 5 and 4 grains of sand gives 9 grains of sand. The numbers used in this case are therefore the natural numbers.
Any object is characterized by many attributes, such as colour and mass, only some of which constitute continuous quantities. For example, the mass of a specific grain of sand is a continuous quantity whereas the grain, as an object, is not. Thus, the mass of a grain of sand can be used as a unit of mass because it is possible to estimate the ratio of the mass of another object to the mass of a grain of sand, given an appropriate instrument.
In the social sciences, it is also common to count frequencies of observations; i.e. frequencies of observable outcomes in an experiment. Examples include the number of correct scores on an assessment of an ability, and the number of statements on a questionnaire endorsed by respondents. Provided each observable outcome is the manifestation of an underlying quantitative attribute, such frequencies will generally indicate relative magnitudes of that attribute. Strictly speaking, however, counts and frequencies do not constitute measurement in terms of a unit of continuous quantity.
# Use in prosody and poetry
In prosody and poetic meter, syllable weight can be a governing principle. Many linguists use morae as a unit of syllable weight—a syllable with more morae is heavier than one with fewer morae. Commonly, syllables with naturally long vowels, diphthongs, and vowels followed by two or more consonants are said to be “heavy”, “long”, or “bimoraic”, whereas syllables with naturally short vowels, followed by only one or no consonant, are said to be “light”, “short”, or “monomoraic”. There is, however, considerable variation across the world's languages as to which coda-consonants contribute a mora to the syllable (i.e., make it heavy). At one end of the variation, only the length of the vowel determines syllable weight; at the other end each coda-consonant counts as one mora. Some languages use syllable weight in assigning word accent. Some poetic meters are based on the arrangement of heavy and light syllables. | https://www.wikidoc.org/index.php/Quantitative | |
0aef409150da4618a08725981b97a1f40e3b07b3 | wikidoc | Quinuclidone | Quinuclidone
Quinuclidones are a class of bicyclic organic compounds with chemical formula C7H11NO with two structural isomers for the base skeleton 3-quinuclidone and 2-quinuclidone.
3-Quinuclidone (1-azabicyclooctan-3-one) is an uneventful molecule that can be synthesized as the hydrochloric acid salt in a Dieckman condensation :
Organic reduction of this compound gives the compound quinuclidine, structurally related to DABCO which has one additional bridgehead nitrogen atom.
The other isomer, 2-quinuclidone, appears equally uneventful but in fact it has defied synthesis until 2006. The reason is that this molecule is very unstable due to the fact that its amide group has the amine lone pair and the carbonyl group not properly aligned as may be expected for an amide as a result of steric strain. This behaviour is predicted by Bredt's Rule and formal amide group resembles in fact an amine as evidenced by the ease of salt formation.
The organic synthesis of the tetrafluoroborate salt of 2-quinuclidone is a six-step affair starting from norcamphor the final step being an azide - ketone Schmidt reaction (38% yield) :
This compound rapidly reacts with water to the corresponding amino acid with a chemical half-life of 15 seconds. X-ray diffraction shows pyramidalization on the nitrogen atom (59° compared to 0 for reference dimethylformamide) and torsion around the carbon-nitrogen bond to an extent of 91°. Attempts to prepare the free base lead to uncontrolled polymerization.
It is nevertheless possible to estimate its basicity in an experiment in which amine pairs (the quinuclidonium salt and a reference amine such as diethylamine or indoline) are introduced into a mass spectrometer. The relative basicity is then revealed by collision induced dissociation of the heterodimer. Further analysis via the extended kinetic method allows for the determination of the proton affinity and gas phase basicity of 2-quinuclidonium. This method has determined that quinuclidone ranks among secondary and tertiary amines in terms of proton affinity. . This high basicity is hypothesized to be due to the loss of electron delocalization when the amide bond is twisted--this causes misalignment of the pi orbitals, resulting in loss of electron resonance. | Quinuclidone
Quinuclidones are a class of bicyclic organic compounds with chemical formula C7H11NO with two structural isomers for the base skeleton 3-quinuclidone and 2-quinuclidone.
3-Quinuclidone (1-azabicyclo[2.2.2]octan-3-one) is an uneventful molecule that can be synthesized as the hydrochloric acid salt in a Dieckman condensation [1]:
Organic reduction of this compound gives the compound quinuclidine, structurally related to DABCO which has one additional bridgehead nitrogen atom.
The other isomer, 2-quinuclidone, appears equally uneventful but in fact it has defied synthesis until 2006. [2] [3] [4] The reason is that this molecule is very unstable due to the fact that its amide group has the amine lone pair and the carbonyl group not properly aligned as may be expected for an amide as a result of steric strain. This behaviour is predicted by Bredt's Rule and formal amide group resembles in fact an amine as evidenced by the ease of salt formation.
The organic synthesis of the tetrafluoroborate salt of 2-quinuclidone is a six-step affair starting from norcamphor the final step being an azide - ketone Schmidt reaction (38% yield) [5]:
This compound rapidly reacts with water to the corresponding amino acid with a chemical half-life of 15 seconds. X-ray diffraction shows pyramidalization on the nitrogen atom (59° compared to 0 for reference dimethylformamide) and torsion around the carbon-nitrogen bond to an extent of 91°. Attempts to prepare the free base lead to uncontrolled polymerization.
It is nevertheless possible to estimate its basicity in an experiment in which amine pairs (the quinuclidonium salt and a reference amine such as diethylamine or indoline) are introduced into a mass spectrometer. The relative basicity is then revealed by collision induced dissociation of the heterodimer. Further analysis via the extended kinetic method allows for the determination of the proton affinity and gas phase basicity of 2-quinuclidonium. This method has determined that quinuclidone ranks among secondary and tertiary amines in terms of proton affinity. [6]. This high basicity is hypothesized to be due to the loss of electron delocalization when the amide bond is twisted--this causes misalignment of the pi orbitals, resulting in loss of electron resonance. | https://www.wikidoc.org/index.php/Quinuclidone | |
83fd0f8e7309c295cfb23569dcb33376d796a00f | wikidoc | Quinupramine | Quinupramine
# Overview
Quinupramine (Kevopril, Kinupril, Adeprim, Quinuprine) is a tricyclic antidepressant (TCA) used in Europe for the treatment of depression.
Pharmacologically, quinupramine acts in vitro as a strong muscarinic acetylcholine receptor antagonist (anticholinergic) and H1 receptor antagonist (antihistamine), moderate 5-HT2 receptor antagonist, and weak serotonin and norepinephrine reuptake inhibitor. It has negligible affinity for the α1-adrenergic, α2-adrenergic, β-adrenergic, or D2 receptor.
Clinically, quinupramine is reported to be stimulating similarly to imipramine, desipramine, and demexiptiline. It can be inferred that its in vivo metabolites may have stronger effects on the reuptake of norepinephrine and/or serotonin than quinupramine itself. | Quinupramine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Quinupramine (Kevopril, Kinupril, Adeprim, Quinuprine) is a tricyclic antidepressant (TCA) used in Europe for the treatment of depression.[1][2]
Pharmacologically, quinupramine acts in vitro as a strong muscarinic acetylcholine receptor antagonist (anticholinergic) and H1 receptor antagonist (antihistamine), moderate 5-HT2 receptor antagonist, and weak serotonin and norepinephrine reuptake inhibitor.[3] It has negligible affinity for the α1-adrenergic, α2-adrenergic, β-adrenergic, or D2 receptor.[3]
Clinically, quinupramine is reported to be stimulating similarly to imipramine, desipramine, and demexiptiline.[4] It can be inferred that its in vivo metabolites may have stronger effects on the reuptake of norepinephrine and/or serotonin than quinupramine itself.[citation needed] | https://www.wikidoc.org/index.php/Quinupramine | |
9bb955ba5bfcf0a22406cdc1202a38879a979bd5 | wikidoc | RAS syndrome | RAS syndrome
The term RAS syndrome refers to the use of one of the words that make up an initialism or acronym as well as the abbreviation itself, thus in effect repeating that word. It stands for "Redundant Acronym Syndrome syndrome," and is itself a humorous example of a redundant acronym.
Technically, this redundancy is a form of rhetorical tautology, and in many cases a pleonasm.
# Origin
The term "RAS syndrome" was coined in 2001 by the New Scientist magazine. The term "PNS syndrome" ("PIN Number Syndrome syndrome," or "Personal Identification Number Number Syndrome syndrome"), coined by Usenet users, is used as commonly as RAS Syndrome,OR and in fact pre-dates the coining of "RAS Syndrome".
Other nonce coinages continue to arise. The terms themselves are occasionally referred to as "RAP phrases" ("Redundant Acronym Phrases phrases").
# Examples
# Reasons for use
The linguistic explanation for RAS is that acronyms (such as laser) are treated as regular words (usually nouns), not as shorthand for longer phrases.
Some occurrences are in the interest of clarity; for example, when discussing a mainframe computer's requirements, the initialism "AC" might refer to air conditioning or alternating current depending on the context; the redundant phrase "AC current" is used by some to distinguish them, although the phrase "alternating current" is clear, correct, and not redundant. Also, the phrase "AC current" distinguishes from "AC voltage". The phrase "CSS style sheets" can also reduce ambiguity, where in certain contexts CSS could also refer to the content-scrambling system used on DVD video titles.
In the United Kingdom, most companies have their electrical appliances regularly checked for safety. This process is known as Portable Appliance Testing. However, it is almost universally abbreviated to "PAT testing". Presumably this is to avoid confusion with PA testing, or simply because it sounds a little ambiguous to say that one's occupation is "PAT". Sometimes similar phrases are not actually redundant; for example, a "redundant RAID" may in fact be a backup RAID in the system being described.
Acronyms and initialisms from foreign languages are also often analyzed as un-expandable nouns when they are not translated. For example, in French, "le protocole IP" (the IP protocol) is often used, and "HIV" is usually said either "le VIH" (in French, adjectives usually come after nouns) or "le virus HIV".
Another justification is that many acronyms and initialisms are trademarks, and trademark law generally treats trademarks as adjectives, which should be used with a generic noun. Examples of correct usage include "SPAM luncheon meat", "AIB Bank" and "CNN network".
Some speakers would prefer that the expansion of the acronym/initialism be used in situations where disambiguation or clarity is needed: "cascading style sheets" instead of "CSS style sheets", "alternating current" instead of "AC current", etc. However, some people may be more familiar with the acronym than the expansion, leading to potential for confusion. | RAS syndrome
The term RAS syndrome refers to the use of one of the words that make up an initialism or acronym as well as the abbreviation itself, thus in effect repeating that word. It stands for "Redundant Acronym Syndrome syndrome," and is itself a humorous example of a redundant acronym.
Technically, this redundancy is a form of rhetorical tautology, and in many cases a pleonasm.
# Origin
The term "RAS syndrome" was coined in 2001 by the New Scientist magazine.[1] The term "PNS syndrome" ("PIN Number Syndrome syndrome," or "Personal Identification Number Number Syndrome syndrome"), coined by Usenet users,[2] is used as commonly as RAS Syndrome,OR and in fact pre-dates the coining of "RAS Syndrome".[3]
Other nonce coinages continue to arise. The terms themselves are occasionally referred to as "RAP phrases" ("Redundant Acronym Phrases phrases").[4]
# Examples
# Reasons for use
The linguistic explanation for RAS is that acronyms (such as laser) are treated as regular words (usually nouns), not as shorthand for longer phrases.
Some occurrences are in the interest of clarity; for example, when discussing a mainframe computer's requirements, the initialism "AC" might refer to air conditioning or alternating current depending on the context; the redundant phrase "AC current" is used by some to distinguish them, although the phrase "alternating current" is clear, correct, and not redundant. Also, the phrase "AC current" distinguishes from "AC voltage". The phrase "CSS style sheets" can also reduce ambiguity, where in certain contexts CSS could also refer to the content-scrambling system used on DVD video titles.
In the United Kingdom, most companies have their electrical appliances regularly checked for safety. This process is known as Portable Appliance Testing. However, it is almost universally abbreviated to "PAT testing". Presumably this is to avoid confusion with PA testing, or simply because it sounds a little ambiguous to say that one's occupation is "PAT". Sometimes similar phrases are not actually redundant; for example, a "redundant RAID" may in fact be a backup RAID in the system being described.
Acronyms and initialisms from foreign languages are also often analyzed as un-expandable nouns when they are not translated. For example, in French, "le protocole IP" (the IP protocol) is often used, and "HIV" is usually said either "le VIH" (in French, adjectives usually come after nouns) or "le virus HIV".
Another justification is that many acronyms and initialisms are trademarks, and trademark law generally treats trademarks as adjectives, which should be used with a generic noun. Examples of correct usage include "SPAM luncheon meat", "AIB Bank" and "CNN network".
Some speakers would prefer that the expansion of the acronym/initialism be used in situations where disambiguation or clarity is needed: "cascading style sheets" instead of "CSS style sheets", "alternating current" instead of "AC current", etc. However, some people may be more familiar with the acronym than the expansion, leading to potential for confusion. | https://www.wikidoc.org/index.php/RAS_syndrome | |
db86b682899e26799419042d25ee1d6e2c06f1fe | wikidoc | REVEAL Trial | REVEAL Trial
# Official Title
REVEAL: Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification. A Large-scale, Randomized Placebo-controlled Trial of the Clinical Effects of Anacetrapib Among People With Established Vascular Disease
# Objective
The Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial aims to determine whether lipid modification with anacetrapib 100mg daily reduces the risk of coronary death, myocardial infarction (MI) or coronary revascularization (collectively known as major coronary events) in patients with circulatory problems who have their Low-density Lipoprotein (LDL) cholesterol level treated with a statin
# Sponsor
University of Oxford
# Timeline
The previous information was derived from ClinicalTrials.gov on 09/20/2013 using the identification number NCT01252953.
# Study Description
The previous information was derived from ClinicalTrials.gov on 09/20/2013 using the identification number NCT01252953.
# Eligibility Criteria
## Inclusion Criteria
- Patients must be aged at least 50 at the time of initial invitation, and at least one of the following inclusion criteria must be satisfied:
History of MI; or
Cerebrovascular atherosclerotic disease (i.e. history of presumed ischaemic stroke or carotid revascularization); or
Peripheral arterial disease (i.e. history of non-coronary revascularization, including aortic aneurysm repair or graft); or
Diabetes mellitus with other evidence of symptomatic coronary heart disease (i.e. treatment or hospitalization for angina, or a history of coronary revascularization or acute coronary syndrome).
- History of MI; or
- Cerebrovascular atherosclerotic disease (i.e. history of presumed ischaemic stroke or carotid revascularization); or
- Peripheral arterial disease (i.e. history of non-coronary revascularization, including aortic aneurysm repair or graft); or
- Diabetes mellitus with other evidence of symptomatic coronary heart disease (i.e. treatment or hospitalization for angina, or a history of coronary revascularization or acute coronary syndrome).
## Exclusion Criteria
- None of the following must be satisfied
Acute MI, acute coronary syndrome or stroke within 4 weeks prior to Screening Visit or during Run-in (but such individuals may be entered later, if appropriate)
Planned coronary revascularization procedure within the next 6 months (such individuals may be entered later, if appropriate)
Definite history of chronic liver disease, or abnormal liver function (i.e. alanine transaminase (ALT) >2x the upper limit of normal (ULN))
Individuals with a history of acute hepatitis are eligible provided this ALT limit is not exceeded
Severe renal insufficiency (i.e. creatinine >200 µmol/L , dialysis or functioning renal transplant)
Evidence of active inflammatory muscle disease (e.g. dermatomyositis, polymyositis), or creatine kinase (CK) >3x ULN
Previous significant adverse reaction to a statin or anacetrapib
Current treatment with any of the following lipid-lowering treatments
A regimen considered to produce substantially greater LDL cholesterol reduction than atorvastatin 80 mg daily for individuals in non-Asian countries or 20 mg daily for those in North East Asia
Fibric acid derivative ("fibrate", including gemfibrozil)
niacin (nicotinic acid) at doses above 100 mg daily
Concurrent treatment with a medication that is contraindicated with anacetrapib or atorvastatin
any potent CYP3A4 inhibitor, such as
macrolide antibiotics (erythromycin, clarithromycin, telithromycin)
systemic imidazole or triazole antifungals (e.g. itraconazole, posaconazole)
protease inhibitors (e.g. atazanavir)
nefazodone
ciclosporin
daptomycin
systemic use of fusidic acid (Individuals who are taking such drugs temporarily may be re-screened when they discontinue them, if considered appropriate)
Known to be poorly compliant with clinic visits or prescribed medication
Medical history that might limit the individual's ability to take trial treatments for the duration of the study (e.g. severe respiratory disease; history of : cancer or evidence of spread within last 5 years, other than non-melanoma skin cancer; or recent history of alcohol or substance misuse);
Women of child-bearing potential (unless using adequate contraception)
Current participation in a clinical trial with an unlicensed drug or device
- Acute MI, acute coronary syndrome or stroke within 4 weeks prior to Screening Visit or during Run-in (but such individuals may be entered later, if appropriate)
- Planned coronary revascularization procedure within the next 6 months (such individuals may be entered later, if appropriate)
- Definite history of chronic liver disease, or abnormal liver function (i.e. alanine transaminase (ALT) >2x the upper limit of normal (ULN))
- Individuals with a history of acute hepatitis are eligible provided this ALT limit is not exceeded
- Severe renal insufficiency (i.e. creatinine >200 µmol/L , dialysis or functioning renal transplant)
- Evidence of active inflammatory muscle disease (e.g. dermatomyositis, polymyositis), or creatine kinase (CK) >3x ULN
- Previous significant adverse reaction to a statin or anacetrapib
- Current treatment with any of the following lipid-lowering treatments
A regimen considered to produce substantially greater LDL cholesterol reduction than atorvastatin 80 mg daily for individuals in non-Asian countries or 20 mg daily for those in North East Asia
Fibric acid derivative ("fibrate", including gemfibrozil)
niacin (nicotinic acid) at doses above 100 mg daily
- A regimen considered to produce substantially greater LDL cholesterol reduction than atorvastatin 80 mg daily for individuals in non-Asian countries or 20 mg daily for those in North East Asia
- Fibric acid derivative ("fibrate", including gemfibrozil)
- niacin (nicotinic acid) at doses above 100 mg daily
- Concurrent treatment with a medication that is contraindicated with anacetrapib or atorvastatin
any potent CYP3A4 inhibitor, such as
macrolide antibiotics (erythromycin, clarithromycin, telithromycin)
systemic imidazole or triazole antifungals (e.g. itraconazole, posaconazole)
protease inhibitors (e.g. atazanavir)
nefazodone
ciclosporin
daptomycin
systemic use of fusidic acid (Individuals who are taking such drugs temporarily may be re-screened when they discontinue them, if considered appropriate)
- any potent CYP3A4 inhibitor, such as
macrolide antibiotics (erythromycin, clarithromycin, telithromycin)
systemic imidazole or triazole antifungals (e.g. itraconazole, posaconazole)
protease inhibitors (e.g. atazanavir)
nefazodone
ciclosporin
daptomycin
systemic use of fusidic acid (Individuals who are taking such drugs temporarily may be re-screened when they discontinue them, if considered appropriate)
- macrolide antibiotics (erythromycin, clarithromycin, telithromycin)
- systemic imidazole or triazole antifungals (e.g. itraconazole, posaconazole)
- protease inhibitors (e.g. atazanavir)
- nefazodone
- ciclosporin
- daptomycin
- systemic use of fusidic acid (Individuals who are taking such drugs temporarily may be re-screened when they discontinue them, if considered appropriate)
- Known to be poorly compliant with clinic visits or prescribed medication
- Medical history that might limit the individual's ability to take trial treatments for the duration of the study (e.g. severe respiratory disease; history of : cancer or evidence of spread within last 5 years, other than non-melanoma skin cancer; or recent history of alcohol or substance misuse);
- Women of child-bearing potential (unless using adequate contraception)
- Current participation in a clinical trial with an unlicensed drug or device
- Individuals will also be excluded at the Screening visit if it is considered unlikely that they will achieve total cholesterol <3.5 mmol/L (135 mg/dL) on the highest atorvastatin dose available in their region (atorvastatin 80 mg daily in non-Asian countries or 20 mg daily in North East Asia)
- In addition, individuals will be excluded at the Randomization visit if any of the following are true:
Total cholesterol above 4 mmol/L
Non-compliant with run-in treatment (<90% scheduled run-in medication taken)
Individual is no longer willing to be randomized into the 4-5 year trial
The individual's doctor is of the view that their patient should not be randomized
- Total cholesterol above 4 mmol/L
- Non-compliant with run-in treatment (<90% scheduled run-in medication taken)
- Individual is no longer willing to be randomized into the 4-5 year trial
- The individual's doctor is of the view that their patient should not be randomized
# Outcomes
## Primary Outcomes
Major coronary events (defined as coronary death, myocardial infarction or coronary revascularization procedure)
Primary assessment will involve an intention-to-treat comparison among all randomized participants of the effects of allocation to anacetrapib versus placebo on major coronary events (defined as the occurrence of coronary death, myocardial infarction or coronary revascularization procedure) during the scheduled treatment period.
## Secondary Outcomes
Not provided
# Publications
## Results
Pending
## Conclusion
Pending | REVEAL Trial
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Official Title
REVEAL: Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification. A Large-scale, Randomized Placebo-controlled Trial of the Clinical Effects of Anacetrapib Among People With Established Vascular Disease
# Objective
The Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial aims to determine whether lipid modification with anacetrapib 100mg daily reduces the risk of coronary death, myocardial infarction (MI) or coronary revascularization (collectively known as major coronary events) in patients with circulatory problems who have their Low-density Lipoprotein (LDL) cholesterol level treated with a statin
# Sponsor
University of Oxford
# Timeline
The previous information was derived from ClinicalTrials.gov on 09/20/2013 using the identification number NCT01252953.
# Study Description
The previous information was derived from ClinicalTrials.gov on 09/20/2013 using the identification number NCT01252953.
# Eligibility Criteria
## Inclusion Criteria
- Patients must be aged at least 50 at the time of initial invitation, and at least one of the following inclusion criteria must be satisfied:
History of MI; or
Cerebrovascular atherosclerotic disease (i.e. history of presumed ischaemic stroke or carotid revascularization); or
Peripheral arterial disease (i.e. history of non-coronary revascularization, including aortic aneurysm repair or graft); or
Diabetes mellitus with other evidence of symptomatic coronary heart disease (i.e. treatment or hospitalization for angina, or a history of coronary revascularization or acute coronary syndrome).
- History of MI; or
- Cerebrovascular atherosclerotic disease (i.e. history of presumed ischaemic stroke or carotid revascularization); or
- Peripheral arterial disease (i.e. history of non-coronary revascularization, including aortic aneurysm repair or graft); or
- Diabetes mellitus with other evidence of symptomatic coronary heart disease (i.e. treatment or hospitalization for angina, or a history of coronary revascularization or acute coronary syndrome).
## Exclusion Criteria
- None of the following must be satisfied
Acute MI, acute coronary syndrome or stroke within 4 weeks prior to Screening Visit or during Run-in (but such individuals may be entered later, if appropriate)
Planned coronary revascularization procedure within the next 6 months (such individuals may be entered later, if appropriate)
Definite history of chronic liver disease, or abnormal liver function (i.e. alanine transaminase (ALT) >2x the upper limit of normal (ULN))
Individuals with a history of acute hepatitis are eligible provided this ALT limit is not exceeded
Severe renal insufficiency (i.e. creatinine >200 µmol/L [2.3 mg/dL], dialysis or functioning renal transplant)
Evidence of active inflammatory muscle disease (e.g. dermatomyositis, polymyositis), or creatine kinase (CK) >3x ULN
Previous significant adverse reaction to a statin or anacetrapib
Current treatment with any of the following lipid-lowering treatments
A regimen considered to produce substantially greater LDL cholesterol reduction than atorvastatin 80 mg daily for individuals in non-Asian countries or 20 mg daily for those in North East Asia
Fibric acid derivative ("fibrate", including gemfibrozil)
niacin (nicotinic acid) at doses above 100 mg daily
Concurrent treatment with a medication that is contraindicated with anacetrapib or atorvastatin
any potent CYP3A4 inhibitor, such as
macrolide antibiotics (erythromycin, clarithromycin, telithromycin)
systemic imidazole or triazole antifungals (e.g. itraconazole, posaconazole)
protease inhibitors (e.g. atazanavir)
nefazodone
ciclosporin
daptomycin
systemic use of fusidic acid (Individuals who are taking such drugs temporarily may be re-screened when they discontinue them, if considered appropriate)
Known to be poorly compliant with clinic visits or prescribed medication
Medical history that might limit the individual's ability to take trial treatments for the duration of the study (e.g. severe respiratory disease; history of : cancer or evidence of spread within last 5 years, other than non-melanoma skin cancer; or recent history of alcohol or substance misuse);
Women of child-bearing potential (unless using adequate contraception)
Current participation in a clinical trial with an unlicensed drug or device
- Acute MI, acute coronary syndrome or stroke within 4 weeks prior to Screening Visit or during Run-in (but such individuals may be entered later, if appropriate)
- Planned coronary revascularization procedure within the next 6 months (such individuals may be entered later, if appropriate)
- Definite history of chronic liver disease, or abnormal liver function (i.e. alanine transaminase (ALT) >2x the upper limit of normal (ULN))
- Individuals with a history of acute hepatitis are eligible provided this ALT limit is not exceeded
- Severe renal insufficiency (i.e. creatinine >200 µmol/L [2.3 mg/dL], dialysis or functioning renal transplant)
- Evidence of active inflammatory muscle disease (e.g. dermatomyositis, polymyositis), or creatine kinase (CK) >3x ULN
- Previous significant adverse reaction to a statin or anacetrapib
- Current treatment with any of the following lipid-lowering treatments
A regimen considered to produce substantially greater LDL cholesterol reduction than atorvastatin 80 mg daily for individuals in non-Asian countries or 20 mg daily for those in North East Asia
Fibric acid derivative ("fibrate", including gemfibrozil)
niacin (nicotinic acid) at doses above 100 mg daily
- A regimen considered to produce substantially greater LDL cholesterol reduction than atorvastatin 80 mg daily for individuals in non-Asian countries or 20 mg daily for those in North East Asia
- Fibric acid derivative ("fibrate", including gemfibrozil)
- niacin (nicotinic acid) at doses above 100 mg daily
- Concurrent treatment with a medication that is contraindicated with anacetrapib or atorvastatin
any potent CYP3A4 inhibitor, such as
macrolide antibiotics (erythromycin, clarithromycin, telithromycin)
systemic imidazole or triazole antifungals (e.g. itraconazole, posaconazole)
protease inhibitors (e.g. atazanavir)
nefazodone
ciclosporin
daptomycin
systemic use of fusidic acid (Individuals who are taking such drugs temporarily may be re-screened when they discontinue them, if considered appropriate)
- any potent CYP3A4 inhibitor, such as
macrolide antibiotics (erythromycin, clarithromycin, telithromycin)
systemic imidazole or triazole antifungals (e.g. itraconazole, posaconazole)
protease inhibitors (e.g. atazanavir)
nefazodone
ciclosporin
daptomycin
systemic use of fusidic acid (Individuals who are taking such drugs temporarily may be re-screened when they discontinue them, if considered appropriate)
- macrolide antibiotics (erythromycin, clarithromycin, telithromycin)
- systemic imidazole or triazole antifungals (e.g. itraconazole, posaconazole)
- protease inhibitors (e.g. atazanavir)
- nefazodone
- ciclosporin
- daptomycin
- systemic use of fusidic acid (Individuals who are taking such drugs temporarily may be re-screened when they discontinue them, if considered appropriate)
- Known to be poorly compliant with clinic visits or prescribed medication
- Medical history that might limit the individual's ability to take trial treatments for the duration of the study (e.g. severe respiratory disease; history of : cancer or evidence of spread within last 5 years, other than non-melanoma skin cancer; or recent history of alcohol or substance misuse);
- Women of child-bearing potential (unless using adequate contraception)
- Current participation in a clinical trial with an unlicensed drug or device
- Individuals will also be excluded at the Screening visit if it is considered unlikely that they will achieve total cholesterol <3.5 mmol/L (135 mg/dL) on the highest atorvastatin dose available in their region (atorvastatin 80 mg daily in non-Asian countries or 20 mg daily in North East Asia)
- In addition, individuals will be excluded at the Randomization visit if any of the following are true:
Total cholesterol above 4 mmol/L [155 mg/dL]
Non-compliant with run-in treatment (<90% scheduled run-in medication taken)
Individual is no longer willing to be randomized into the 4-5 year trial
The individual's doctor is of the view that their patient should not be randomized
- Total cholesterol above 4 mmol/L [155 mg/dL]
- Non-compliant with run-in treatment (<90% scheduled run-in medication taken)
- Individual is no longer willing to be randomized into the 4-5 year trial
- The individual's doctor is of the view that their patient should not be randomized
# Outcomes
## Primary Outcomes
Major coronary events (defined as coronary death, myocardial infarction or coronary revascularization procedure) [ Time Frame: Median follow-up of 4 years ] [ Designated as safety issue: No ]
Primary assessment will involve an intention-to-treat comparison among all randomized participants of the effects of allocation to anacetrapib versus placebo on major coronary events (defined as the occurrence of coronary death, myocardial infarction or coronary revascularization procedure) during the scheduled treatment period.
## Secondary Outcomes
Not provided
# Publications
## Results
Pending
## Conclusion
Pending | https://www.wikidoc.org/index.php/REVEAL_Trial | |
260a5f2a021b334faaa9378032610865bc760259 | wikidoc | RNA splicing | RNA splicing
In molecular biology, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation. For many eukaryotic introns, splicing is done in a series of reactions which are catalyzed by the spliceosome, a complex of small nuclear ribonucleoproteins (snRNPs), but there are also self-splicing introns.
# Splicing pathways
Several methods of RNA splicing occur in nature: the type of splicing depends on the structure of the spliced intron and the catalysts required for splicing to occur.
## Spliceosomal introns
Spliceosomal introns often reside in eukaryotic protein-coding genes. Within the intron, a 3' splice site, 5' splice site, and branch site are required for splicing. Splicing is catalyzed by the spliceosome which is a large RNA-protein complex composed of five small nuclear ribonucleoproteins (snRNPs, pronounced 'snurps' ). The RNA components of snRNPs interact with the intron and may be involved in catalysis. Two types of spliceosomes have been identified (the major and minor) which contain different snRNPs.
- Major
- E Complex-U1 binds to the GU sequence at the 5' splice site, along with accessory proteins/enzymes ASF/SF2, U2AF (binds at the Py-AG site), SF1/BBP (BBP=Branch Binding Protein);
- A Complex-U2 binds to the branch site, and ATP is hydrolyzed;
- B1 Complex-U5/U4/U6 trimer binds, and the U5 binds exons at the 5' site, with U6 binding to U2;
- B2 Complex-U1 is released, U5 shifts from exon to intron and the U6 binds at the 5' splice site;
- C1 Complex-U4 is released, U6/U2 catalyzes transesterification, U5 binds exon at 3' splice site, and the 5' site is cleaved, resulting in the formation of the lariat;
- C2 Complex-U2/U5/U6 remain bound to the lariat, and the 3' site is cleaved and exons are ligated using ATP hydrolysis. The spliced RNA is released and the lariat debranches.
- Minor
- Trans-splicing
## Self-splicing
Self-splicing occurs for rare introns that form a ribozyme, performing the functions of the spliceosome by RNA alone. There are three kinds of self-splicing introns, Group I, Group II and Group III. Group I and II introns perform splicing similar to the spliceosome without requiring any protein. This similarity suggests that Group I and II introns may be evolutionarily related to the spliceosome. Self-splicing may also be very ancient, and may have existed in an RNA world that was present before protein. Although the two splicing mechanisms described below do not require any proteins to occur, 5 additional RNA molecules and over 50 proteins are used and hydrolyzes many ATP molecules. The splicing mechanisms use ATP in order to accurately splice mRNA's. If the cell were to not use any ATP's, the process would be highly inaccurate and many mistakes would occur.
Two transesterifications characterize the mechanism in which group I introns are sliced:
1) 3'OH of a free guanine nucleoside (or one located in the intron) or a nucleotide cofactor (GMP, GDP, GTP) attacks phosphate at the 5' splice site.
2) 3'OH of the 5'exon becomes a nucleophile and the second transesterification results in the joining of the two exons.
The mechanism in which group II introns are spliced (two transesterification reaction like group I introns) is as follows:
1)The 2'OH of a specific adenosine in the intron attacks the 5' splice site, thereby forming the lariat
2) The 3'OH of the 5' exon triggers the second transesterification at the 3' splice site thereby joining the exons together.
## tRNA splicing
tRNA (also tRNA-like) splicing is another rare form of splicing that usually occurs in tRNA. The splicing reaction involves a different biochemistry than the spliceomsomal and self-splicing pathways. Ribonucleases cleave the RNA and ligases join the exons together.
# Evolution
Splicing occurs in all the kingdoms or domains of life, however, the extent and types of splicing can be very different between the major divisions. Eukaryotes splice many protein-coding messenger RNAs and some non-coding RNAs. Prokaryotes, on the other hand, splice rarely, but mostly non-coding RNAs. Another important difference between these two groups of organisms is that prokaryotes completely lack the spliceosomal pathway.
Because spliceosomal introns are not conserved in all species, there is debate concerning when spliceosomal splicing evolved. Two models have been proposed: the intron late and intron early models (see intron evolution).
# Biochemical mechanism
Spliceosomal splicing and self-splicing involves a two-step biochemical process. Both steps involve transesterification reactions that occur between RNA nucleotides. tRNA splicing, however, is an exception and does not occur by transesterification.
Spliceosomal and self-splicing transesterification reactions occur via two sequential transesterification reactions. First, the 2'OH of a specific branch-point nucleotide within the intron that is defined during spliceosome assembly performs a nucleophilic attack on the first nucleotide of the intron at the 5' splice site forming the lariat intermediate. Second, the 3'OH of the released 5' exon then performs a nucleophilic attack at the last nucleotide of the intron at the 3' splice site thus joining the exons and releasing the intron lariat.
# Alternative splicing
In many cases, the splicing process can create a range of unique proteins by varying the exon composition of the same messenger RNA. This phenomenon is then called alternative splicing.
# Experimental manipulation of splicing
Splicing events can be experimentally altered by binding steric-blocking antisense oligos such as Morpholinos or Peptide nucleic acids to snRNP binding sites, to the branchpoint nucleotide that closes the lariat, or to splice-regulatory element binding sites.
# Splicing errors
Common errors:
- Mutation of a splice site resulting in loss of function of that site. Results in exposure of a premature stop codon, loss of an exon, or inclusion of an intron.
- Mutation of a splice site reducing specificity. May result in variation in the splice location, causing insertion or deletion of amino acids, or most likely, a loss of the reading frame.
- Transposition of a splice site, leading to inclusion or exclusion of more RNA than expected, resulting in longer or shorter exons.
# Protein splicing
Not only pre-mRNA but also proteins can undergo splicing. Although the biomolecular mechanisms are different, the principle is the same, that parts of the protein, called inteins instead of introns, are removed. The remaining parts, called exteins instead of exons, are fused together.
Protein splicing has been observed in lower organisms, yeast, plants and animals, including in humans. | RNA splicing
In molecular biology, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation. For many eukaryotic introns, splicing is done in a series of reactions which are catalyzed by the spliceosome, a complex of small nuclear ribonucleoproteins (snRNPs), but there are also self-splicing introns.
# Splicing pathways
Several methods of RNA splicing occur in nature: the type of splicing depends on the structure of the spliced intron and the catalysts required for splicing to occur.
## Spliceosomal introns
Spliceosomal introns often reside in eukaryotic protein-coding genes. Within the intron, a 3' splice site, 5' splice site, and branch site are required for splicing. Splicing is catalyzed by the spliceosome which is a large RNA-protein complex composed of five small nuclear ribonucleoproteins (snRNPs, pronounced 'snurps' ). The RNA components of snRNPs interact with the intron and may be involved in catalysis. Two types of spliceosomes have been identified (the major and minor) which contain different snRNPs.
- Major
- E Complex-U1 binds to the GU sequence at the 5' splice site, along with accessory proteins/enzymes ASF/SF2, U2AF (binds at the Py-AG site), SF1/BBP (BBP=Branch Binding Protein);
- A Complex-U2 binds to the branch site, and ATP is hydrolyzed;
- B1 Complex-U5/U4/U6 trimer binds, and the U5 binds exons at the 5' site, with U6 binding to U2;
- B2 Complex-U1 is released, U5 shifts from exon to intron and the U6 binds at the 5' splice site;
- C1 Complex-U4 is released, U6/U2 catalyzes transesterification, U5 binds exon at 3' splice site, and the 5' site is cleaved, resulting in the formation of the lariat;
- C2 Complex-U2/U5/U6 remain bound to the lariat, and the 3' site is cleaved and exons are ligated using ATP hydrolysis. The spliced RNA is released and the lariat debranches.
- Minor
- Trans-splicing
## Self-splicing
Self-splicing occurs for rare introns that form a ribozyme, performing the functions of the spliceosome by RNA alone. There are three kinds of self-splicing introns, Group I, Group II and Group III. Group I and II introns perform splicing similar to the spliceosome without requiring any protein. This similarity suggests that Group I and II introns may be evolutionarily related to the spliceosome. Self-splicing may also be very ancient, and may have existed in an RNA world that was present before protein. Although the two splicing mechanisms described below do not require any proteins to occur, 5 additional RNA molecules and over 50 proteins are used and hydrolyzes many ATP molecules. The splicing mechanisms use ATP in order to accurately splice mRNA's. If the cell were to not use any ATP's, the process would be highly inaccurate and many mistakes would occur.
Two transesterifications characterize the mechanism in which group I introns are sliced:
1) 3'OH of a free guanine nucleoside (or one located in the intron) or a nucleotide cofactor (GMP, GDP, GTP) attacks phosphate at the 5' splice site.
2) 3'OH of the 5'exon becomes a nucleophile and the second transesterification results in the joining of the two exons.
The mechanism in which group II introns are spliced (two transesterification reaction like group I introns) is as follows:
1)The 2'OH of a specific adenosine in the intron attacks the 5' splice site, thereby forming the lariat
2) The 3'OH of the 5' exon triggers the second transesterification at the 3' splice site thereby joining the exons together.
## tRNA splicing
tRNA (also tRNA-like) splicing is another rare form of splicing that usually occurs in tRNA. The splicing reaction involves a different biochemistry than the spliceomsomal and self-splicing pathways. Ribonucleases cleave the RNA and ligases join the exons together.
# Evolution
Splicing occurs in all the kingdoms or domains of life, however, the extent and types of splicing can be very different between the major divisions. Eukaryotes splice many protein-coding messenger RNAs and some non-coding RNAs. Prokaryotes, on the other hand, splice rarely, but mostly non-coding RNAs. Another important difference between these two groups of organisms is that prokaryotes completely lack the spliceosomal pathway.
Because spliceosomal introns are not conserved in all species, there is debate concerning when spliceosomal splicing evolved. Two models have been proposed: the intron late and intron early models (see intron evolution).
# Biochemical mechanism
Spliceosomal splicing and self-splicing involves a two-step biochemical process. Both steps involve transesterification reactions that occur between RNA nucleotides. tRNA splicing, however, is an exception and does not occur by transesterification.
Spliceosomal and self-splicing transesterification reactions occur via two sequential transesterification reactions. First, the 2'OH of a specific branch-point nucleotide within the intron that is defined during spliceosome assembly performs a nucleophilic attack on the first nucleotide of the intron at the 5' splice site forming the lariat intermediate. Second, the 3'OH of the released 5' exon then performs a nucleophilic attack at the last nucleotide of the intron at the 3' splice site thus joining the exons and releasing the intron lariat.
# Alternative splicing
In many cases, the splicing process can create a range of unique proteins by varying the exon composition of the same messenger RNA. This phenomenon is then called alternative splicing.
# Experimental manipulation of splicing
Splicing events can be experimentally altered[4] by binding steric-blocking antisense oligos such as Morpholinos or Peptide nucleic acids to snRNP binding sites, to the branchpoint nucleotide that closes the lariat,[5] or to splice-regulatory element binding sites.[6]
# Splicing errors
Common errors:
- Mutation of a splice site resulting in loss of function of that site. Results in exposure of a premature stop codon, loss of an exon, or inclusion of an intron.
- Mutation of a splice site reducing specificity. May result in variation in the splice location, causing insertion or deletion of amino acids, or most likely, a loss of the reading frame.
- Transposition of a splice site, leading to inclusion or exclusion of more RNA than expected, resulting in longer or shorter exons.
# Protein splicing
Not only pre-mRNA but also proteins can undergo splicing. Although the biomolecular mechanisms are different, the principle is the same, that parts of the protein, called inteins instead of introns, are removed. The remaining parts, called exteins instead of exons, are fused together.
Protein splicing has been observed in lower organisms, yeast, plants and animals, including in humans.[7] | https://www.wikidoc.org/index.php/RNA_splicing | |
18e6e19f116ec9975e7d1f423a05356cc8c6a85a | wikidoc | Radial nerve | Radial nerve
The radial nerve is a nerve in the human body that supplies the triceps brachii muscle of the arm, as well as all 12 muscles in the posterior osteofascial compartment of the forearm.
It originates from the posterior cord of the brachial plexus with roots from C5, 6, 7, 8, & T1.
The radial nerve and its branches supply the dorsal muscles, such as triceps brachii, the extrinsic extensors of the wrist and hands, and the cutaneous nerve supply to most of the back of the hand. (The ulnar nerve cutaneously innervates the back of the little finger.)
The radial nerve divides into a deep branch, (which becomes the posterior interosseous nerve), and continues as the superficial branch which goes on to innervate the dorsum (back) of the hand.
# Course
The radial nerve originates as a terminal branch of the posterior cord of the brachial plexus. It goes through the arm, first in the posterior compartment of the arm, and later in the anterior compartment of the arm, and continues in the forearm.
## In arm
From the brachial plexus, it travels posteriorly through what often called the triangular interval (US) or lower triangular space (UK).
The radial nerve enters the arm behind the axillary artery/brachial artery, and it then travels posteriorly on the medial side of the arm.
After giving off branches to the long and lateral heads of the triceps brachii, it enters a groove on the humerus, the radial sulcus.
Along with the deep brachial artery, the radial nerve winds around in the groove (between the medial and lateral heads of the triceps) towards the forearm, running laterally on the posterior aspect of the humerus.
While in the groove, it gives off a branch to the medial head of the triceps brachii.
The radial nerve emerges from the groove on the lateral aspect of the humerus.
At this point, it pierces the lateral intermuscular septum and enters the anterior compartment of the arm.
It continues its journey inferiorly between the brachialis and brachioradialis muscles.
When the radial nerve reaches the distal part of the humerus, it passes in front of the lateral epicondyle and continues in the forearm.
## In forearm
In the forearm, it branches into a superficial branch (primarily sensory) and a deep branch (primarily motor).
- The superficial branch of the radial nerve descends in the forearm under the brachioradialis. It eventually pierces the deep fascia near the back of the wrist.
- The deep branch of the radial nerve pierces the supinator muscle, after which it is known as the posterior interosseous nerve.
# Branches/Innervations
The following are branches/innervations of the radial nerve (including the superficial branch of the radial nerve and the deep branch of the radial nerve/posterior interosseous nerve).
## Cutaneous
Cutaneous innervation is provided by the following nerves:
- Posterior cutaneous nerve of arm (originates in axilla)
- Inferior lateral cutaneous nerve of arm (originates in arm)
- Posterior cutaneous nerve of forearm (originates in arm)
The superficial branch of the radial nerve provides sensory innervation to much of the back of the hand, including the web of skin between the thumb and index finger.
## Motor
Muscular branches of the radial nerve:
- Triceps brachii
- Anconeus
- Brachioradialis
- Extensor carpi radialis longus
Deep branch of the radial nerve:
- Extensor carpi radialis brevis
- Supinator
Posterior interosseous nerve (a continuation of the deep branch after the supinator):
- Extensor digitorum
- Extensor digiti minimi
- Extensor carpi ulnaris
- Abductor pollicis longus
- Extensor pollicis brevis
- Extensor pollicis longus
- Extensor indicis
The radial nerve (and its deep branch) provides motor innervation to the muscles in the posterior compartment of the arm and forearm, which are mostly extensors.
# Additional images
- Brachial plexus
- Cross-section through the middle of upper arm.
- Cross-section through the middle of the forearm.
- The brachial artery.
- Suprascapular and axillary nerves of right side, seen from behind.
- Cutaneous nerves of right upper extremity. Posterior view.
- Diagram of segmental distribution of the cutaneous nerves of the right upper extremity. Posterior view.
- Superficial palmar nerves.
- Nerves of the left upper extremity.
- Deep palmar nerves.
- Front of right upper extremity, showing surface markings for bones, arteries, and nerves.
- Back of right upper extremity, showing surface markings for bones and nerves. | Radial nerve
Template:Infobox Nerve
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The radial nerve is a nerve in the human body that supplies the triceps brachii muscle of the arm, as well as all 12 muscles in the posterior osteofascial compartment of the forearm.
It originates from the posterior cord of the brachial plexus with roots from C5, 6, 7, 8, & T1.
The radial nerve and its branches supply the dorsal muscles, such as triceps brachii, the extrinsic extensors of the wrist and hands, and the cutaneous nerve supply to most of the back of the hand. (The ulnar nerve cutaneously innervates the back of the little finger.)
The radial nerve divides into a deep branch, (which becomes the posterior interosseous nerve), and continues as the superficial branch which goes on to innervate the dorsum (back) of the hand.
# Course
The radial nerve originates as a terminal branch of the posterior cord of the brachial plexus. It goes through the arm, first in the posterior compartment of the arm, and later in the anterior compartment of the arm, and continues in the forearm.
## In arm
From the brachial plexus, it travels posteriorly through what often called the triangular interval (US) or lower triangular space (UK).
The radial nerve enters the arm behind the axillary artery/brachial artery, and it then travels posteriorly on the medial side of the arm.
After giving off branches to the long and lateral heads of the triceps brachii, it enters a groove on the humerus, the radial sulcus.
Along with the deep brachial artery, the radial nerve winds around in the groove (between the medial and lateral heads of the triceps) towards the forearm, running laterally on the posterior aspect of the humerus.
While in the groove, it gives off a branch to the medial head of the triceps brachii.
The radial nerve emerges from the groove on the lateral aspect of the humerus.
At this point, it pierces the lateral intermuscular septum and enters the anterior compartment of the arm.
It continues its journey inferiorly between the brachialis and brachioradialis muscles.
When the radial nerve reaches the distal part of the humerus, it passes in front of the lateral epicondyle and continues in the forearm.
## In forearm
In the forearm, it branches into a superficial branch (primarily sensory) and a deep branch (primarily motor).
- The superficial branch of the radial nerve descends in the forearm under the brachioradialis. It eventually pierces the deep fascia near the back of the wrist.
- The deep branch of the radial nerve pierces the supinator muscle, after which it is known as the posterior interosseous nerve.
# Branches/Innervations
The following are branches/innervations of the radial nerve (including the superficial branch of the radial nerve and the deep branch of the radial nerve/posterior interosseous nerve).
## Cutaneous
Cutaneous innervation is provided by the following nerves:
- Posterior cutaneous nerve of arm (originates in axilla)
- Inferior lateral cutaneous nerve of arm (originates in arm)
- Posterior cutaneous nerve of forearm (originates in arm)
The superficial branch of the radial nerve provides sensory innervation to much of the back of the hand, including the web of skin between the thumb and index finger.
## Motor
Muscular branches of the radial nerve:
- Triceps brachii
- Anconeus
- Brachioradialis
- Extensor carpi radialis longus
Deep branch of the radial nerve:
- Extensor carpi radialis brevis
- Supinator
Posterior interosseous nerve (a continuation of the deep branch after the supinator):
- Extensor digitorum
- Extensor digiti minimi
- Extensor carpi ulnaris
- Abductor pollicis longus
- Extensor pollicis brevis
- Extensor pollicis longus
- Extensor indicis
The radial nerve (and its deep branch) provides motor innervation to the muscles in the posterior compartment of the arm and forearm, which are mostly extensors.
# Additional images
- Brachial plexus
- Cross-section through the middle of upper arm.
- Cross-section through the middle of the forearm.
- The brachial artery.
- Suprascapular and axillary nerves of right side, seen from behind.
- Cutaneous nerves of right upper extremity. Posterior view.
- Diagram of segmental distribution of the cutaneous nerves of the right upper extremity. Posterior view.
- Superficial palmar nerves.
- Nerves of the left upper extremity.
- Deep palmar nerves.
- Front of right upper extremity, showing surface markings for bones, arteries, and nerves.
- Back of right upper extremity, showing surface markings for bones and nerves. | https://www.wikidoc.org/index.php/Radial_nerve | |
145cd396ee15ff06cf6826214c8406e11e2f3879 | wikidoc | Radionuclide | Radionuclide
# Overview
A radionuclide is an atom with an unstable nucleus, which is a nucleus characterized by excess energy which is available to be imparted either to a newly-created radiation particle within the nucleus, or else to an atomic electron (see internal conversion) . The radionuclide, in this process, undergoes radioactive decay, and emits a gamma ray(s) and/or subatomic particles. These particles constitute ionizing radiation. Radionuclides may occur naturally, but can also be artificially produced.
Radionuclides are often referred to by chemists and physicists as radioactive isotopes or radioisotopes, and play an important part in the technologies that provide us with food, water and good health. However, they can also constitute real or perceived dangers.
# Origin
Naturally occurring radionuclides fall into three categories: primordial radionuclides, secondary radionuclides and cosmogenic radionuclides. Primordial radionuclides originate mainly from the interiors of stars and, like uranium and thorium, are still present because their half-lives are so long that they have not yet completely decayed. Secondary radionuclides are radiogenic isotopes derived from the decay of primordial radionuclides. They have shorter half-lives than primordial radionuclides. Cosmogenic isotopes, such as carbon-14, are present because they are continually being formed in the atmosphere due to cosmic rays. Despite their relatively "short" half-lives, they are found in nature because their supply is always being replenished.
Artificially produced radionuclides can be produced by nuclear reactors, particle accelerators or by radionuclide generators:
- Radioisotopes produced with nuclear reactors exploit the high flux of neutrons present. The neutrons activate elements placed within the reactor. A typical product from a nuclear reactor is thallium-201 and Iridium-192. The elements that have a large propensity to take up the neutrons in the reactor have a high Barnes Number.
- Particle accelerators such as cyclotrons accelerate particles to bombard a target to produce radionuclides. Cyclotrons accelerate protons at a target to produce positron emitting radioisotopes e.g. fluorine-18.
- Radionuclide generators contain a parent isotope that decays to produce a radioisotope. The parent is usually produced in a nuclear reactor. A typical example is the technetium-99m generator used in nuclear medicine. The parent produced in the reactor is molybdenum-99.
Trace radionuclides are those that occur in tiny amounts in nature either due to inherent rarity, or to half-lives that are significantly shorter than the age of the Earth. Synthetic isotopes are not naturally occurring on Earth, but they can be created by nuclear reactions.
# Uses
Radionuclides are used in two major ways: for their chemical properties and as sources of radiation.
Radionuclides of familiar elements such as carbon can serve as tracers because they are chemically very similar to the non-radioactive nuclides, so most chemical, biological, and ecological processes treat them in a near identical way. One can then examine the result with a radiation detector, such as a geiger counter, to determine where the provided atoms ended up. For example, one might culture plants in an environment in which the carbon dioxide contained radioactive carbon; then the parts of the plant that had laid down atmospheric carbon would be radioactive.
In nuclear medicine, radioisotopes are used for diagnosis, treatment, and research. Radioactive chemical tracers emitting gamma rays or positrons can provide diagnostic information about a person's internal anatomy and the functioning of specific organs. This is used in some forms of tomography: single photon emission computed tomography and positron emission tomography scanning.
Radioisotopes are also a promising method of treatment in hemopoietic forms of tumors, while the success for treatment of solid tumors has been limited so far. More powerful gamma sources sterilise syringes and other medical equipment. About one in two people in Western countries are likely to experience the benefits of nuclear medicine in their lifetime.
In biochemistry and genetics, radionuclides label molecules and allow tracing chemical and physiological processes occurring in living organisms, such as DNA replication or amino acid transport.
In food preservation, radiation is used to stop the sprouting of root crops after harvesting, to kill parasites and pests, and to control the ripening of stored fruit and vegetables.
In agriculture and animal husbandry, radionuclides also play an important role. They produce high intake of crops, disease and weather resistant varieties of crops, to study how fertilisers and insecticides work, and to improve the production and health of domestic animals.
Industrially, and in mining, radionuclides examine welds, to detect leaks, to study the rate of wear, erosion and corrosion of metals, and for on-stream analysis of a wide range of minerals and fuels.
Most household smoke detectors contain the radionuclide americium formed in nuclear reactors, saving many lives.
Radionuclides trace and analyze pollutants, to study the movement of surface water, and to measure water runoffs from rain and snow, as well as the flow rates of streams and rivers.
Natural radionuclides are used in geology, archaeology, and paleontology to measure ages of rocks, minerals, and fossil materials.
# Dangers
If radionuclides are released into the environment, through accident, poor disposal, or other means, they can potentially cause harmful effects of radioactive contamination. They can also cause damage if they are excessively used during treatment or in other ways applied to living beings. This is called radiation poisoning. Radionuclides can also cause malfunction of electrical devices. | Radionuclide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A radionuclide is an atom with an unstable nucleus, which is a nucleus characterized by excess energy which is available to be imparted either to a newly-created radiation particle within the nucleus, or else to an atomic electron (see internal conversion) . The radionuclide, in this process, undergoes radioactive decay, and emits a gamma ray(s) and/or subatomic particles. These particles constitute ionizing radiation. Radionuclides may occur naturally, but can also be artificially produced.
Radionuclides are often referred to by chemists and physicists as radioactive isotopes or radioisotopes, and play an important part in the technologies that provide us with food, water and good health. However, they can also constitute real or perceived dangers.
# Origin
Naturally occurring radionuclides fall into three categories: primordial radionuclides, secondary radionuclides and cosmogenic radionuclides. Primordial radionuclides originate mainly from the interiors of stars and, like uranium and thorium, are still present because their half-lives are so long that they have not yet completely decayed. Secondary radionuclides are radiogenic isotopes derived from the decay of primordial radionuclides. They have shorter half-lives than primordial radionuclides. Cosmogenic isotopes, such as carbon-14, are present because they are continually being formed in the atmosphere due to cosmic rays. Despite their relatively "short" half-lives, they are found in nature because their supply is always being replenished.
Artificially produced radionuclides can be produced by nuclear reactors, particle accelerators or by radionuclide generators:
- Radioisotopes produced with nuclear reactors exploit the high flux of neutrons present. The neutrons activate elements placed within the reactor. A typical product from a nuclear reactor is thallium-201 and Iridium-192. The elements that have a large propensity to take up the neutrons in the reactor have a high Barnes Number.
- Particle accelerators such as cyclotrons accelerate particles to bombard a target to produce radionuclides. Cyclotrons accelerate protons at a target to produce positron emitting radioisotopes e.g. fluorine-18.
- Radionuclide generators contain a parent isotope that decays to produce a radioisotope. The parent is usually produced in a nuclear reactor. A typical example is the technetium-99m generator used in nuclear medicine. The parent produced in the reactor is molybdenum-99.
Trace radionuclides are those that occur in tiny amounts in nature either due to inherent rarity, or to half-lives that are significantly shorter than the age of the Earth. Synthetic isotopes are not naturally occurring on Earth, but they can be created by nuclear reactions.
# Uses
Radionuclides are used in two major ways: for their chemical properties and as sources of radiation.
Radionuclides of familiar elements such as carbon can serve as tracers because they are chemically very similar to the non-radioactive nuclides, so most chemical, biological, and ecological processes treat them in a near identical way. One can then examine the result with a radiation detector, such as a geiger counter, to determine where the provided atoms ended up. For example, one might culture plants in an environment in which the carbon dioxide contained radioactive carbon; then the parts of the plant that had laid down atmospheric carbon would be radioactive.
In nuclear medicine, radioisotopes are used for diagnosis, treatment, and research. Radioactive chemical tracers emitting gamma rays or positrons can provide diagnostic information about a person's internal anatomy and the functioning of specific organs. This is used in some forms of tomography: single photon emission computed tomography and positron emission tomography scanning.
Radioisotopes are also a promising method of treatment in hemopoietic forms of tumors, while the success for treatment of solid tumors has been limited so far. More powerful gamma sources sterilise syringes and other medical equipment. About one in two people in Western countries are likely to experience the benefits of nuclear medicine in their lifetime.
In biochemistry and genetics, radionuclides label molecules and allow tracing chemical and physiological processes occurring in living organisms, such as DNA replication or amino acid transport.
In food preservation, radiation is used to stop the sprouting of root crops after harvesting, to kill parasites and pests, and to control the ripening of stored fruit and vegetables.
In agriculture and animal husbandry, radionuclides also play an important role. They produce high intake of crops, disease and weather resistant varieties of crops, to study how fertilisers and insecticides work, and to improve the production and health of domestic animals.
Industrially, and in mining, radionuclides examine welds, to detect leaks, to study the rate of wear, erosion and corrosion of metals, and for on-stream analysis of a wide range of minerals and fuels.
Most household smoke detectors contain the radionuclide americium formed in nuclear reactors, saving many lives.
Radionuclides trace and analyze pollutants, to study the movement of surface water, and to measure water runoffs from rain and snow, as well as the flow rates of streams and rivers.
Natural radionuclides are used in geology, archaeology, and paleontology to measure ages of rocks, minerals, and fossil materials.
# Dangers
If radionuclides are released into the environment, through accident, poor disposal, or other means, they can potentially cause harmful effects of radioactive contamination. They can also cause damage if they are excessively used during treatment or in other ways applied to living beings. This is called radiation poisoning. Radionuclides can also cause malfunction of electrical devices. | https://www.wikidoc.org/index.php/Radioactive_isotope | |
6748811fab15c938224144453a17334fbc60e97c | wikidoc | Radiosurgery | Radiosurgery
# Overview
Radiosurgery is a medical procedure which allows non-invasive brain surgery, i.e., without actually opening the skull, by means of directed beams of ionizing radiation. It is a relatively recent technique (1951), which is used to destroy, by means of a precise dosage of radiation, intracranial tumors and other lesions that could be otherwise inaccessible or inadequate for open surgery. There are many nervous diseases for which conventional surgical treatment is difficult or has many deleterious consequences for the patient, due to arteries, nerves, and other vital structures being damaged.
# Definition and applications
Doctors make use of highly sophisticated, highly precise and complex instruments, such as stereotactic devices, linear accelerators, computers and laser beams. In the last 20 years, radiosurgery has been used as a first approach, by exclusion or failure of other techniques or as supplements to them, such as other kinds of brain surgery, chemotherapy and radiotherapy. The highly precise irradiation of targets within the brain is planned by the surgeon and medical physicist with basis on images, such as computed tomography (CT), magnetic resonance imaging (MRI), and angiography of the brain. The radiation is applied from an external source, under precise mechanical orientation by a specialized apparatus. Multiple beams are directed (collimated) and centered at the intracranial lesion to be treated. In this way, healthy tissues around the target are preserved.
Patients can be treated within one day of hospital stay, or even as outpatients. By comparison, the average hospital stay for a craniotomy (conventional neurosurgery, requiring the opening of the skull) is about 15 days. Radiosurgery costs about the same as a conventional surgery, but it avoids mortality, pain and post-surgical complications, such as hemorrhage and infection. The period of recovery is minimal, and in the day following the treatment the patient may return to his or her normal life style, without any discomfort. The major disadvantage of radiosurgery in relation to open surgery (craniotomy) is the duration of time required to achieve the desired effects, while its non-invasive character is perhaps its major advantage.
# History
Radiosurgery started with Dr. Lars Leksell from the Karolinska Institute of Stockholm, Sweden, in 1949, in a joint development with Bjorn Larsson, a radiobiologist from Uppsala University. Leksell initially used protons from a cyclotron to irradiate brain tumor lesions.
In 1968, they developed the Gamma Knife, a new device exclusively for radiosurgery, which consisted of radioactive sources of Cobalt-60 placed in a kind of helmet with central channels for irradiation, using gamma rays. In the last version of this device, 201 sources of radioactive cobalt direct gamma radiation to the center of a helmet, where the patient's head is inserted.
In order to achieve a high degree of precision, the patient's head is placed on a rigid frame of reference called a stereotactic frame that is inserted into a metal helmet. The device utilizes a coordinate system for each structure of the brain. By consulting a published cranial 'atlas', the surgeon knows the precise point of gamma ray convergance.
Gamma Knife surgery is used for stereotactic surgery as a relatively safe and selective method to irradiate tumors and arteriovenous malformations of the brain. The Gamma Knife requires only a single treatment session on a single day. In fact, the Gamma Knife surgery is so established that all insurance providers cover it and Medicare has given it its own authorization code.
LINAC is another type of radiosurgery which has enjoyed great dissemination in neurosurgury. It was developed at the University of Florida College of Medicine and introduced by Betti and Colombo in the mid 1980's and utilizes a linear accelerator. High energy, narrowly focused beams of x-rays are employed.
This system differs from the Gamma Knife in the way the radiation beams are delivered to the patient's head. In a similar way, a stereotactic device is used to provide a geometric coordinates reference, but the radiation beams are emitted by a single source, which rotates slowly around the patient's head.
Finally, at some medical centers such as in Boston and in California, particle accelerators built for doing research in high energy physics have been used since the 1960's for the treatment of brain tumors and arteriovenous malformations of the brain in humans. A still experimental type of radiosurgery, that utilizes a nuclear reactor for the nuclear fission of uranium, is the Neutron Capture Therapy (NCT) which was started in the United States at the nuclear reactor of the Massachusetts Institute of Technology (MIT) in the 60's, with promising results. Nowadays it is carried out as a promising advanced clinical research in several countries, due to the progress and to the results obtained in Japan by Dr. Hiroshi Hatanaka. He used NCT in more than 100 cases in the treatment of malignant tumors and of gigantic arterio-venous malformations.
# How it works
The fundamental principle of radiosurgery is that of selective ionization of the tissue to be operated upon, by means of high-energy beams of radiation. Ionization is the production of ions and free radicals which are usually deleterious to the cells. These ions and radicals, which may be formed from the water in the cell or from the biological materials can produce irreparable damage to these structures and then the cell's death. Thus, biological inactivation is carried out in a volume of tissue to be treated, with a precise destructive effect. The radiation dose absorbed by the treated mass of tissue is what defines the degree of biological inactivation. It usually is measured in grays, where one gray (Gy) is the absorption of one joule per kilogram of mass. A unit that attempts to take into account both the different organs that are irradiated and the type of radiation is the sievert, a unit that describes both the amount of energy deposited and the biological effectiveness.
In order to perform optimal therapy, the neurosurgeon, assisted by physicists specialized in radiation therapy and often in conjunction with a radiation oncologist, chooses the best type of radiation to be used and how it will be delivered. Usually, the total dose of radiation required to kill a tumor, for example, is not delivered in a single, massive section, because this would cause undesirable effects on the patient. Instead, it is divided into several sessions of smaller duration and energy dose, in a procedure called dose fractioning. The aim of dose fractioning is to minimize the undesirable damage to healthy tissues, as healthy tissue cells are better than cancerous cells at repairing radiation induced damage between irradiations. In order to plan the radiation incidence and dosage, the physicists calculate a map portraying the lines of equal absorbed dose of radiation upon the patient's head (this is called an isodose map). Information about the tumor's location is obtained from a series of computerized tomograms, which are then fed to special planning computer software.
There are six types of irradiation currently used in radiosurgery: electromagnetical waves (gamma rays and x-rays), subatomic particles ( electrons, protons and neutrons), and carbon ions.
The first type of radiation is gamma rays, which are beams of high energy photons that interact with the corona of electrons of the atoms that compose the irradiated tissue, ionizing them. Gamma radiation is used in the Gamma Knife device, where they are produced by fixed sources of radioactive cobalt. The Gamma Knife treatment is the gold standard in brain tumor and arteriovenous malformation radiosurgery.
The second type of radiation, X-rays, are also high energy photons that are identical to gamma rays except for the way they are produced. Radiosurgery can be performed using a linear accelerator, the source being now a commercial medical device of universal use in radiotherapy. The Linac consists of an electron accelerator. Electrons from the accelerator can collide with a solid target to create X-radiation.
The emission head (called "gantry") is mechanically rotated around the patient, in a full or partial circle. The table where the patient is lying, the 'couch,' can also be moved in small linear or angular steps. The combination of the movements of the gantry and of the couch makes possible the computerized planning of the volume of brain tissue which is going to be irradiated. Devices with an energy of 6 MeV are the most suitable for the treatment of the brain, due to the smaller volume to be irradiated. In addition, the diameter of the energy beam leaving the emission head can be adjusted to the size of the lesion by means of interchangeable collimators (an orifice with different diameters, varying from 5 to 40 mm, in steps of 5 mm). There are also multileaf collimators, which consist of a number of metal leaflets that can be moved dynamically during treatment in order to shape the radiation beam to conform to the mass to be ablated.
The third type of radiation, electrons, will have very similar characteristics to that of gamma or X-rays. The depth of penetration is less than that of the above-mentioned photon sources.
The fourth type of radiation, protons, is used in Proton Beam Therapy (PBT). Protons are produced by a medical synchrotron, extracting them from proton donor materials and accelerating them in successive travels through a circular, evacuated conduit, using powerful magnets, until they reach sufficient energy (usually about 200 MeV) to enable them to approximately traverse a human body, then stop. They are then released toward the irradiation target which is region in the patient's body. In some machines, which deliver only a certain energy of protons, a custom mask made of plastic will be interposed between the initial beam and the patient, in order to adjust the beam energy for a proper amount of penetration. Because of the Bragg Peak effect, proton therapy has advantages over other the other forms of radiation, since most of the proton's energy is deposited within a limited distance, so tissue beyond this range (and so some extent also tissue inside this range) is spared from the effects of radiation. This property of protons, which has been called the "depth charge effect" allows for conformal dose distributions to be created around even very irregularly shaped targets, and for higher doses to targets surrounded or backstopped by radiation-sensitive structures such as the optic chiasm or brainstem. In recent years, however, so-called "intensity modulated" techniques have allowed for similar conformities to be attained using linear accelerator radiosurgery.
Neutrons, the fifth type of radiation, are used in Boron neutron capture therapy (BNCT). BCNT depends on the interaction of slow neutrons with boron-10 to produce alpha particles, another type of radiation. Patients are first given an intravenous injection of a boron-10 tagged chemical that preferentially binds tumor cells. The neutrons are created either in a nuclear reactor or by colliding high-energy protons into a Lithium target. The neutrons pass through a moderator, which shapes the neutron energy spectrum suitable for BNCT treatment. Before entering the patient the neutron beam is shaped by a beam collimator. While passing through the tissue of the patient, the neutrons are slowed by collisions and become low energy thermal neutrons. The thermal neutrons undergo reaction with the boron-10 nuclei, forming an unstable boron-11 nucleus which then undergoes spontaneous decay to lithium-7 and an alpha particle. Both the alpha particle and the lithium ion produce closely spaced ionizations in the immediate vicinity of the reaction, with a range of approximately 10 micrometres, or one cell diameter. This technique is advantageous since the radiation damage occurs over a short range and thus normal tissues can be spared. Also, there are two mechanisms for tumor selectivity, since both the boron compound is made to bind to tumor cells and the neutron beam is aimed at the location of the tumor. BNCT has been developed in only in an experimental basis, and it has not entered surgical routine.
The selection of the proper kind of radiation and device depends on many factors including lesion type, size and location in relation to critical structures. Data suggests that similar clinical outcomes are possible with all of these methods. More important than the device used are issues regarding indications for treatment, total dose delivered, fractionation schedule and conformity of the treatment plan.
Latest generation Linacs are capable of achieving extremely narrow beam geometries, such as 0.15 to 0.3 mm. Therefore, they can be used for several kinds of surgeries which hitherto are carried out by open or endoscopic surgery, such as for trigeminal neuralgia, etc.
# Radiosurgery of brain tumors
Radiosurgery has been especially helpful for the localized, highly precise treatment of brain tumors. Due to the steep fall of the irradiation fields (isodoses) from the center of the target to be destroyed, the biological inactivation happens only on it; while the brain, and other vascular and neural structures around it, are protected. This is achieved through the high mechanical precision of the radiation source, and the assured reproducibility of the target. The precision in the positioning of the patient, in the calculation of dosages, and in the safety of the patient, are all extremely high.
Radiosurgery is indicated primarily for the therapy of tumors, vascular lesions and functional disorders. Significant clinical judgment must be used with this technique and considerations must include lesion type, pathology if available, size, location and age and general health of the patient. General contraindications to radiosurgery include excessively large size of the target lesion or lesions too numerous for practical treatment.
The non-interference with the quality of life of the patient in the post-operatory period competes with the inconvenience of the latency of months until the result of the radiosurgery is accomplished. Patients with a bad general state of health and those with tumors which are unreachable by conventional means, are especially helped.
Outcome may not be evident for months after the treatment. Since radiosurgery does not remove the tumor, but results in a biological inactivation of the tumor, lack of growth of the lesion is normally considered to be treatment success. Radiosurgery has been used to treat many kinds of brain tumors, such as acoustic neuromas, astrocytomas, gliomas, germinomas, meningiomas, among others. Even highly fatal cancerous metastases in the brainstem can be reduced, leaving the patient neurologically intact. It has been demonstrated by the thousands of successfully treated cases, that radiosurgery can be a very safe and efficient method for the management of many difficult brain lesions, while it avoids the loss in quality of life associated to other more invasive methods. For many indications, such as acoustic neuroma, brain arteriovenous malformations and skull base tumors, radiosurgery has emerged as the treatment of choice.
Patients are being treated for lesions which only radiosurgery can solve, or because they prefer it as a first treatment, after receiving complete information of its risks and benefits as compared to the conventional surgery, when the choice is available.
In the future, advanced computer methods, such as intensity-modulated radiosurgery will be used to improve the accuracy and scope of radiosurgery. For now, the Gamma Knife is the standard for brain tumor treatment. Gamma Knife only takes one treatment session and is the most accurate surgery on the market. | Radiosurgery
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Radiosurgery is a medical procedure which allows non-invasive brain surgery, i.e., without actually opening the skull, by means of directed beams of ionizing radiation. It is a relatively recent technique (1951), which is used to destroy, by means of a precise dosage of radiation, intracranial tumors and other lesions that could be otherwise inaccessible or inadequate for open surgery. There are many nervous diseases for which conventional surgical treatment is difficult or has many deleterious consequences for the patient, due to arteries, nerves, and other vital structures being damaged.
# Definition and applications
Doctors make use of highly sophisticated, highly precise and complex instruments, such as stereotactic devices, linear accelerators, computers and laser beams. In the last 20 years, radiosurgery has been used as a first approach, by exclusion or failure of other techniques or as supplements to them, such as other kinds of brain surgery, chemotherapy and radiotherapy. The highly precise irradiation of targets within the brain is planned by the surgeon and medical physicist with basis on images, such as computed tomography (CT), magnetic resonance imaging (MRI), and angiography of the brain. The radiation is applied from an external source, under precise mechanical orientation by a specialized apparatus. Multiple beams are directed (collimated) and centered at the intracranial lesion to be treated. In this way, healthy tissues around the target are preserved.
Patients can be treated within one day of hospital stay, or even as outpatients. By comparison, the average hospital stay for a craniotomy (conventional neurosurgery, requiring the opening of the skull) is about 15 days. Radiosurgery costs about the same as a conventional surgery, but it avoids mortality, pain and post-surgical complications, such as hemorrhage and infection. The period of recovery is minimal, and in the day following the treatment the patient may return to his or her normal life style, without any discomfort. The major disadvantage of radiosurgery in relation to open surgery (craniotomy) is the duration of time required to achieve the desired effects, while its non-invasive character is perhaps its major advantage.
# History
Radiosurgery started with Dr. Lars Leksell from the Karolinska Institute of Stockholm, Sweden, in 1949, in a joint development with Bjorn Larsson, a radiobiologist from Uppsala University. Leksell initially used protons from a cyclotron to irradiate brain tumor lesions.
In 1968, they developed the Gamma Knife, a new device exclusively for radiosurgery, which consisted of radioactive sources of Cobalt-60 placed in a kind of helmet with central channels for irradiation, using gamma rays. In the last version of this device, 201 sources of radioactive cobalt direct gamma radiation to the center of a helmet, where the patient's head is inserted.
In order to achieve a high degree of precision, the patient's head is placed on a rigid frame of reference called a stereotactic frame that is inserted into a metal helmet. The device utilizes a coordinate system for each structure of the brain. By consulting a published cranial 'atlas', the surgeon knows the precise point of gamma ray convergance.
Gamma Knife surgery is used for stereotactic surgery as a relatively safe and selective method to irradiate tumors and arteriovenous malformations of the brain. The Gamma Knife requires only a single treatment session on a single day. In fact, the Gamma Knife surgery is so established that all insurance providers cover it and Medicare has given it its own authorization code.[citation needed]
LINAC is another type of radiosurgery which has enjoyed great dissemination in neurosurgury. It was developed at the University of Florida College of Medicine and introduced by Betti and Colombo in the mid 1980's and utilizes a linear accelerator. High energy, narrowly focused beams of x-rays are employed.
This system differs from the Gamma Knife in the way the radiation beams are delivered to the patient's head. In a similar way, a stereotactic device is used to provide a geometric coordinates reference, but the radiation beams are emitted by a single source, which rotates slowly around the patient's head.
Finally, at some medical centers such as in Boston and in California, particle accelerators built for doing research in high energy physics have been used since the 1960's for the treatment of brain tumors and arteriovenous malformations of the brain in humans. A still experimental type of radiosurgery, that utilizes a nuclear reactor for the nuclear fission of uranium, is the Neutron Capture Therapy (NCT) which was started in the United States at the nuclear reactor of the Massachusetts Institute of Technology (MIT) in the 60's, with promising results.[1] Nowadays it is carried out as a promising advanced clinical research in several countries, due to the progress and to the results obtained in Japan by Dr. Hiroshi Hatanaka. He used NCT in more than 100 cases in the treatment of malignant tumors and of gigantic arterio-venous malformations.
# How it works
The fundamental principle of radiosurgery is that of selective ionization of the tissue to be operated upon, by means of high-energy beams of radiation. Ionization is the production of ions and free radicals which are usually deleterious to the cells. These ions and radicals, which may be formed from the water in the cell or from the biological materials can produce irreparable damage to these structures and then the cell's death. Thus, biological inactivation is carried out in a volume of tissue to be treated, with a precise destructive effect. The radiation dose absorbed by the treated mass of tissue is what defines the degree of biological inactivation. It usually is measured in grays, where one gray (Gy) is the absorption of one joule per kilogram of mass. A unit that attempts to take into account both the different organs that are irradiated and the type of radiation is the sievert, a unit that describes both the amount of energy deposited and the biological effectiveness.
In order to perform optimal therapy, the neurosurgeon, assisted by physicists specialized in radiation therapy and often in conjunction with a radiation oncologist, chooses the best type of radiation to be used and how it will be delivered. Usually, the total dose of radiation required to kill a tumor, for example, is not delivered in a single, massive section, because this would cause undesirable effects on the patient. Instead, it is divided into several sessions of smaller duration and energy dose, in a procedure called dose fractioning. The aim of dose fractioning is to minimize the undesirable damage to healthy tissues, as healthy tissue cells are better than cancerous cells at repairing radiation induced damage between irradiations. In order to plan the radiation incidence and dosage, the physicists calculate a map portraying the lines of equal absorbed dose of radiation upon the patient's head (this is called an isodose map). Information about the tumor's location is obtained from a series of computerized tomograms, which are then fed to special planning computer software.
There are six types of irradiation currently used in radiosurgery: electromagnetical waves (gamma rays and x-rays), subatomic particles ( electrons, protons and neutrons), and carbon ions.
The first type of radiation is gamma rays, which are beams of high energy photons that interact with the corona of electrons of the atoms that compose the irradiated tissue, ionizing them. Gamma radiation is used in the Gamma Knife device, where they are produced by fixed sources of radioactive cobalt. The Gamma Knife treatment is the gold standard in brain tumor and arteriovenous malformation radiosurgery.
The second type of radiation, X-rays, are also high energy photons that are identical to gamma rays except for the way they are produced. Radiosurgery can be performed using a linear accelerator, the source being now a commercial medical device of universal use in radiotherapy. The Linac consists of an electron accelerator. Electrons from the accelerator can collide with a solid target to create X-radiation.
The emission head (called "gantry") is mechanically rotated around the patient, in a full or partial circle. The table where the patient is lying, the 'couch,' can also be moved in small linear or angular steps. The combination of the movements of the gantry and of the couch makes possible the computerized planning of the volume of brain tissue which is going to be irradiated. Devices with an energy of 6 MeV are the most suitable for the treatment of the brain, due to the smaller volume to be irradiated. In addition, the diameter of the energy beam leaving the emission head can be adjusted to the size of the lesion by means of interchangeable collimators (an orifice with different diameters, varying from 5 to 40 mm, in steps of 5 mm). There are also multileaf collimators, which consist of a number of metal leaflets that can be moved dynamically during treatment in order to shape the radiation beam to conform to the mass to be ablated.
The third type of radiation, electrons, will have very similar characteristics to that of gamma or X-rays. The depth of penetration is less than that of the above-mentioned photon sources.
The fourth type of radiation, protons, is used in Proton Beam Therapy (PBT). Protons are produced by a medical synchrotron, extracting them from proton donor materials and accelerating them in successive travels through a circular, evacuated conduit, using powerful magnets, until they reach sufficient energy (usually about 200 MeV) to enable them to approximately traverse a human body, then stop. They are then released toward the irradiation target which is region in the patient's body. In some machines, which deliver only a certain energy of protons, a custom mask made of plastic will be interposed between the initial beam and the patient, in order to adjust the beam energy for a proper amount of penetration. Because of the Bragg Peak effect, proton therapy has advantages over other the other forms of radiation, since most of the proton's energy is deposited within a limited distance, so tissue beyond this range (and so some extent also tissue inside this range) is spared from the effects of radiation. This property of protons, which has been called the "depth charge effect" allows for conformal dose distributions to be created around even very irregularly shaped targets, and for higher doses to targets surrounded or backstopped by radiation-sensitive structures such as the optic chiasm or brainstem. In recent years, however, so-called "intensity modulated" techniques have allowed for similar conformities to be attained using linear accelerator radiosurgery.
Neutrons, the fifth type of radiation, are used in Boron neutron capture therapy (BNCT). BCNT depends on the interaction of slow neutrons with boron-10 to produce alpha particles, another type of radiation. Patients are first given an intravenous injection of a boron-10 tagged chemical that preferentially binds tumor cells. The neutrons are created either in a nuclear reactor or by colliding high-energy protons into a Lithium target. The neutrons pass through a moderator, which shapes the neutron energy spectrum suitable for BNCT treatment. Before entering the patient the neutron beam is shaped by a beam collimator. While passing through the tissue of the patient, the neutrons are slowed by collisions and become low energy thermal neutrons. The thermal neutrons undergo reaction with the boron-10 nuclei, forming an unstable boron-11 nucleus which then undergoes spontaneous decay to lithium-7 and an alpha particle. Both the alpha particle and the lithium ion produce closely spaced ionizations in the immediate vicinity of the reaction, with a range of approximately 10 micrometres, or one cell diameter. This technique is advantageous since the radiation damage occurs over a short range and thus normal tissues can be spared. Also, there are two mechanisms for tumor selectivity, since both the boron compound is made to bind to tumor cells and the neutron beam is aimed at the location of the tumor. BNCT has been developed in only in an experimental basis, and it has not entered surgical routine.
The selection of the proper kind of radiation and device depends on many factors including lesion type, size and location in relation to critical structures. Data suggests that similar clinical outcomes are possible with all of these methods. More important than the device used are issues regarding indications for treatment, total dose delivered, fractionation schedule and conformity of the treatment plan.
Latest generation Linacs are capable of achieving extremely narrow beam geometries, such as 0.15 to 0.3 mm. Therefore, they can be used for several kinds of surgeries which hitherto are carried out by open or endoscopic surgery, such as for trigeminal neuralgia, etc.
# Radiosurgery of brain tumors
Radiosurgery has been especially helpful for the localized, highly precise treatment of brain tumors. Due to the steep fall of the irradiation fields (isodoses) from the center of the target to be destroyed, the biological inactivation happens only on it; while the brain, and other vascular and neural structures around it, are protected. This is achieved through the high mechanical precision of the radiation source, and the assured reproducibility of the target. The precision in the positioning of the patient, in the calculation of dosages, and in the safety of the patient, are all extremely high.
Radiosurgery is indicated primarily for the therapy of tumors, vascular lesions and functional disorders. Significant clinical judgment must be used with this technique and considerations must include lesion type, pathology if available, size, location and age and general health of the patient. General contraindications to radiosurgery include excessively large size of the target lesion or lesions too numerous for practical treatment.
The non-interference with the quality of life of the patient in the post-operatory period competes with the inconvenience of the latency of months until the result of the radiosurgery is accomplished. Patients with a bad general state of health and those with tumors which are unreachable by conventional means, are especially helped.
Outcome may not be evident for months after the treatment. Since radiosurgery does not remove the tumor, but results in a biological inactivation of the tumor, lack of growth of the lesion is normally considered to be treatment success. Radiosurgery has been used to treat many kinds of brain tumors, such as acoustic neuromas, astrocytomas, gliomas, germinomas, meningiomas, among others. Even highly fatal cancerous metastases in the brainstem can be reduced, leaving the patient neurologically intact. It has been demonstrated by the thousands of successfully treated cases, that radiosurgery can be a very safe and efficient method for the management of many difficult brain lesions, while it avoids the loss in quality of life associated to other more invasive methods. For many indications, such as acoustic neuroma, brain arteriovenous malformations and skull base tumors, radiosurgery has emerged as the treatment of choice.
Patients are being treated for lesions which only radiosurgery can solve, or because they prefer it as a first treatment, after receiving complete information of its risks and benefits as compared to the conventional surgery, when the choice is available.
In the future, advanced computer methods, such as intensity-modulated radiosurgery will be used to improve the accuracy and scope of radiosurgery. For now, the Gamma Knife is the standard for brain tumor treatment. Gamma Knife only takes one treatment session and is the most accurate surgery on the market. | https://www.wikidoc.org/index.php/Radiosurgery | |
f2e739b5cf784a540f9a5cfa9296c61748917c96 | wikidoc | Raney nickel | Raney nickel
Raney nickel (Template:PronEng) is a solid catalyst composed of fine grains of a nickel-aluminium alloy, used in many industrial processes. It was developed in 1926 by American engineer Murray Raney as an alternative catalyst for the hydrogenation of vegetable oils in industrial processes. More recently it is used as a heterogeneous catalyst in a variety of organic syntheses, most commonly for hydrogenation reactions.
Raney nickel is produced when a block of nickel-aluminium alloy is treated with concentrated sodium hydroxide. This treatment, called "activation", dissolves most of the aluminium out of the alloy. The porous structure left behind has a large surface area, which gives high catalytic activity. A typical catalyst is around 85-percent nickel by mass, corresponding to about two atoms of nickel for every atom of aluminium. The aluminium which remains helps to preserve the pore structure of the overall catalyst.
Since Raney is a registered trademark of W. R. Grace and Company, only those products by its Grace Davison division are properly called "Raney nickel". Alternatively, the more generic terms "skeletal catalyst" or "sponge-metal catalyst" may be used to refer to catalysts that have physical and chemical properties similar to those of Raney nickel.
# Preparation
## Alloy preparation
Alloys are prepared commercially by melting the active metal (nickel in this case, but iron and copper "Raney-type" catalysts can be prepared as well) and aluminium in a crucible and quenching the resultant melt, which is then crushed into a fine powder. This powder may be screened for a specific particle size range depending on the application the catalyst may be required for.
The initial alloy composition is important because the quenching process produces a number of different Ni/Al phases that have different leaching properties. This may result in markedly different porosities in the end product. The most common starting alloy used in industry contains an equal amount per weight of nickel and aluminium, incidentally, the same ratio Murray Raney used in his discovery of Raney nickel.
During the quenching procedure, small amounts of a third metal, such as zinc or chromium, may be added. This is done to enhance catalytic activity, and as such this third metal is called a "promoter". Note that the addition of a promoter changes the alloy and its resulting phase diagram to that of a ternary alloy, leading to different quenching and leaching properties during activation.
## Activation
The porous structure of the catalyst arises from the selective removal of aluminium from alloy particles using concentrated sodium hydroxide solution. The simplified leaching reaction is given by the following chemical equation:
The formation of sodium aluminate (Na) requires that solutions of high concentration of sodium hydroxide are used in order to avoid the formation of aluminium hydroxide, which precipitates as bayerite. Hence sodium hydroxide solutions with concentrations of up to 5 molar are used. Bayerite may cause blocking of the pores formed during leaching, and with the subsequent loss of surface area, it can reduce the efficiency and activity of the catalyst.
The temperature used to leach the alloy has a marked effect on the surface properties of the catalyst. Commonly used temperatures range from 70 to 100 °C. The surface area of Raney nickel (and skeletal catalysts in general) tends to decrease with increasing leaching temperature. This is due to structural rearrangements within the alloy that may be considered analogous to sintering, where alloy ligaments would start adhering to each other at higher temperatures leading to the loss of the porous structure.
Before storage, the catalyst can be washed with distilled water at ambient temperature in order to remove any remaining traces of sodium aluminate. Oxygen-free water is preferred for storage in order to prevent oxidation of the catalyst, which would accelerate its aging process and result in reduced catalytic activity.
# Properties
Macroscopically Raney nickel looks like a finely divided gray powder. Microscopically, each particle of this powder looks like a three-dimensional mesh, with pores of irregular size and shape of which the vast majority are created during the leaching process. Raney nickel is notable for being thermally and structurally stable as well has having a large BET surface area. These properties are a direct result of the activation process and contribute to a relatively high catalytic activity.
During the activation process, aluminium is leached out the NiAl3 and Ni2Al3 phases that are present in the alloy, while most of the aluminium that remains does so in the form of NiAl. The removal of aluminium from some phases but not others is known as "selective leaching". It has been shown that the NiAl phase provides the structural and thermal stability to the catalyst. As a result the catalyst is quite resistant to decomposition ("breaking down", commonly known as "aging"). This resistance allows Raney nickel to be stored and reused for an extended period; however, fresh preparations are usually preferred for laboratory use. For this reason commercial Raney nickel is available in both "active" and "inactive" forms.
The surface area is typically determined via a BET measurement using a gas that will be preferentially adsorbed on metallic surfaces, such as hydrogen. Using this type of measurement, it has been shown that almost all the exposed area in a particle of the catalyst has nickel on its surface. Since nickel is the active metal of the catalyst, a large nickel surface area implies that there is a large surface available for reactions to occur simultaneously, which is reflected in an increased catalyst activity. Commercially available Raney nickel has an average nickel surface area of 100 m² per gram of catalyst.
A high catalytic activity, coupled with the fact that hydrogen is absorbed within the pores of the catalyst during activation, makes Raney nickel a useful catalyst for many hydrogenation reactions. Its structural and thermal stability (i.e., the fact that it does not decompose at high temperatures) allows its use under a wide range of reaction conditions. Additionally, the solubility of Raney nickel is negligible in most common laboratory solvents, with the exception of mineral acids such as hydrochloric acid, and its relatively high density (between 6 and 7 g/cm³) also facilitates its separation off a liquid phase after a reaction is completed.
# Applications
Raney nickel is used in a large number of industrial processes and in organic synthesis because of its stability and high catalytic activity at room temperature.
## Industrial applications
A practical example of the use of Raney nickel in industry is shown in the following reaction, where benzene is reduced to cyclohexane. Reduction of the hexa structure of the benzene ring is very hard to achieve through other chemical means, but can be effected by using Raney nickel. Other heterogeneous catalysts, such as those using platinum group elements, may be used instead to similar effect, but these tend to be more expensive to produce than Raney nickel. After this reaction cyclohexane may be used in the synthesis of adipic acid, a raw material used in the industrial production of polyamides such as nylon.
## Applications in organic synthesis
### Desulfurization
The main usage of Raney nickel in organic synthesis is desulfurization. For example, thioacetals will be reduced to hydrocarbons:
Thiols, and sulfides can be removed from aliphatic, aromatic, or heteroaromatic compounds. Likewise, Raney nickel will remove the sulfur of thiophene to give a saturated alkane.
### Reduction of functional groups
It is typically used in the reduction of compounds that have multiple bonds, such as alkynes, alkenes, nitriles, dienes, aromatics and carbonyl containing compounds. Additionally, Raney nickel will reduce heteroatom-heteroatom bonds such as hydrazines, nitro groups, and nitrosamines. (For further information see Reduction of nitro compounds.) It has also found use in the reductive alkylation of amines and the amination of alcohols.
When reducing a carbon-carbon double bond, Raney nickel will add hydrogen in a syn fashion.
# Safety
Due to its large surface area and high volume of contained hydrogen gas, dry, activated Raney nickel is a pyrophoric material that should be handled under an inert atmosphere. Raney nickel is typically supplied as a 50-percent slurry in water. Care should be taken never to expose Raney nickel to air. Even after reaction, Raney nickel contains significant amounts of hydrogen gas, and will ignite when exposed to air.
Raney nickel will produce hazardous fumes when burning, and therefore the use of a gas mask is recommended when extinguishing fires caused by it. Additionally, acute exposure to Raney nickel may cause irritation of the respiratory tract, nasal cavities and causes pulmonary fibrosis if inhaled. Ingestion may lead to convulsions and intestinal disorders. It can also cause eye and skin irritation. Chronic exposure may lead to pneumonitis and other signs of sensitization to nickel like skin rashes ("nickel itch").
Nickel is also rated as being a possible human carcinogen by the IARC (Group 2B, EU category 3) and teratogen, while the inhalation of fine aluminium oxide particles is associated with Shaver's disease. Care should be taken when handling these raw materials during laboratory preparation of Raney nickel. Moreover, activation of Raney nickel produces large amounts of hydrogen gas as a by-product, which is also highly flammable.
# Development
Murray Raney graduated as a Mechanical Engineer from the University of Kentucky in 1909. In 1915 he joined the Lookout Oil and Refining Company in Tennessee and was responsible for the installation of electrolytic cells for the production of hydrogen which was used in the hydrogenation of vegetable oils. During that time the industry used a nickel catalyst prepared from nickel(II) oxide. Believing that better catalysts could be produced, around 1921 he started to perform independent research while still working for Lookout Oil. In 1924 a 1:1 ratio Ni/Si alloy was produced, which after treatment with sodium hydroxide, was found to be five times more active than the best catalyst used in the hydrogenation of cottonseed oil. A patent for this discovery was issued in December 1925.
Subsequently, Raney produced a 1:1 Ni/Al alloy following a procedure similar to the one used for the nickel-silicon catalyst. He found that the resulting catalyst was even more active and filed a patent application in 1926. It may be of interest to note that Raney's choice of nickel-aluminium ratio was fortuitous and without any real scientific basis. However, this is the preferred alloy composition for production of Raney nickel catalysts currently in use.
Following the development of Raney nickel, other alloy systems with aluminium were considered, of which the most notable include copper, ruthenium and cobalt. Further research showed that adding a small amount of a third metal to the binary alloy would promote the activity of the catalyst. Some widely used promoters are zinc, molybdenum and chromium. Recently, a way of preparing enantioselective Raney nickel has been devised by surface adsorbtion of tartaric acid. | Raney nickel
Template:Featured article
Raney nickel (Template:PronEng) is a solid catalyst composed of fine grains of a nickel-aluminium alloy, used in many industrial processes. It was developed in 1926 by American engineer Murray Raney[1] as an alternative catalyst for the hydrogenation of vegetable oils in industrial processes. More recently it is used as a heterogeneous catalyst in a variety of organic syntheses, most commonly for hydrogenation reactions.
Raney nickel is produced when a block of nickel-aluminium alloy is treated with concentrated sodium hydroxide. This treatment, called "activation", dissolves most of the aluminium out of the alloy. The porous structure left behind has a large surface area, which gives high catalytic activity. A typical catalyst is around 85-percent nickel by mass, corresponding to about two atoms of nickel for every atom of aluminium. The aluminium which remains helps to preserve the pore structure of the overall catalyst.
Since Raney is a registered trademark of W. R. Grace and Company, only those products by its Grace Davison division are properly called "Raney nickel". Alternatively, the more generic terms "skeletal catalyst" or "sponge-metal catalyst" may be used to refer to catalysts that have physical and chemical properties similar to those of Raney nickel.
# Preparation
## Alloy preparation
Alloys are prepared commercially by melting the active metal (nickel in this case, but iron and copper "Raney-type" catalysts can be prepared as well) and aluminium in a crucible and quenching the resultant melt, which is then crushed into a fine powder.[2] This powder may be screened for a specific particle size range depending on the application the catalyst may be required for.
The initial alloy composition is important because the quenching process produces a number of different Ni/Al phases that have different leaching properties. This may result in markedly different porosities in the end product. The most common starting alloy used in industry contains an equal amount per weight of nickel and aluminium, incidentally, the same ratio Murray Raney used in his discovery of Raney nickel.
During the quenching procedure, small amounts of a third metal, such as zinc or chromium, may be added. This is done to enhance catalytic activity, and as such this third metal is called a "promoter".[2] Note that the addition of a promoter changes the alloy and its resulting phase diagram to that of a ternary alloy, leading to different quenching and leaching properties during activation.
## Activation
The porous structure of the catalyst arises from the selective removal of aluminium from alloy particles using concentrated sodium hydroxide solution. The simplified leaching reaction is given by the following chemical equation:
The formation of sodium aluminate (Na[Al(OH)4]) requires that solutions of high concentration of sodium hydroxide are used in order to avoid the formation of aluminium hydroxide, which precipitates as bayerite.[2] Hence sodium hydroxide solutions with concentrations of up to 5 molar are used. Bayerite may cause blocking of the pores formed during leaching, and with the subsequent loss of surface area, it can reduce the efficiency and activity of the catalyst.
The temperature used to leach the alloy has a marked effect on the surface properties of the catalyst. Commonly used temperatures range from 70 to 100 °C. The surface area of Raney nickel (and skeletal catalysts in general) tends to decrease with increasing leaching temperature.[3] This is due to structural rearrangements within the alloy that may be considered analogous to sintering, where alloy ligaments would start adhering to each other at higher temperatures leading to the loss of the porous structure.
Before storage, the catalyst can be washed with distilled water at ambient temperature in order to remove any remaining traces of sodium aluminate. Oxygen-free water is preferred for storage in order to prevent oxidation of the catalyst, which would accelerate its aging process and result in reduced catalytic activity.[2]
# Properties
Macroscopically Raney nickel looks like a finely divided gray powder. Microscopically, each particle of this powder looks like a three-dimensional mesh, with pores of irregular size and shape of which the vast majority are created during the leaching process. Raney nickel is notable for being thermally and structurally stable as well has having a large BET surface area. These properties are a direct result of the activation process and contribute to a relatively high catalytic activity.
During the activation process, aluminium is leached out the NiAl3 and Ni2Al3 phases that are present in the alloy, while most of the aluminium that remains does so in the form of NiAl. The removal of aluminium from some phases but not others is known as "selective leaching". It has been shown that the NiAl phase provides the structural and thermal stability to the catalyst. As a result the catalyst is quite resistant to decomposition ("breaking down", commonly known as "aging").[3] This resistance allows Raney nickel to be stored and reused for an extended period; however, fresh preparations are usually preferred for laboratory use. For this reason commercial Raney nickel is available in both "active" and "inactive" forms.
The surface area is typically determined via a BET measurement using a gas that will be preferentially adsorbed on metallic surfaces, such as hydrogen. Using this type of measurement, it has been shown that almost all the exposed area in a particle of the catalyst has nickel on its surface.[2] Since nickel is the active metal of the catalyst, a large nickel surface area implies that there is a large surface available for reactions to occur simultaneously, which is reflected in an increased catalyst activity. Commercially available Raney nickel has an average nickel surface area of 100 m² per gram of catalyst.[2]
A high catalytic activity, coupled with the fact that hydrogen is absorbed within the pores of the catalyst during activation, makes Raney nickel a useful catalyst for many hydrogenation reactions. Its structural and thermal stability (i.e., the fact that it does not decompose at high temperatures) allows its use under a wide range of reaction conditions. Additionally, the solubility of Raney nickel is negligible in most common laboratory solvents, with the exception of mineral acids such as hydrochloric acid, and its relatively high density (between 6 and 7 g/cm³) also facilitates its separation off a liquid phase after a reaction is completed.
# Applications
Raney nickel is used in a large number of industrial processes and in organic synthesis because of its stability and high catalytic activity at room temperature.[2][4][5]
## Industrial applications
A practical example of the use of Raney nickel in industry is shown in the following reaction, where benzene is reduced to cyclohexane. Reduction of the hexa structure of the benzene ring is very hard to achieve through other chemical means, but can be effected by using Raney nickel. Other heterogeneous catalysts, such as those using platinum group elements, may be used instead to similar effect, but these tend to be more expensive to produce than Raney nickel. After this reaction cyclohexane may be used in the synthesis of adipic acid, a raw material used in the industrial production of polyamides such as nylon.[6]
## Applications in organic synthesis
### Desulfurization
The main usage of Raney nickel in organic synthesis is desulfurization. For example, thioacetals will be reduced to hydrocarbons:[6]
Thiols[7], and sulfides[8] can be removed from aliphatic, aromatic, or heteroaromatic compounds. Likewise, Raney nickel will remove the sulfur of thiophene to give a saturated alkane.[9]
### Reduction of functional groups
It is typically used in the reduction of compounds that have multiple bonds, such as alkynes, alkenes,[10] nitriles,[11] dienes, aromatics[12] and carbonyl containing compounds. Additionally, Raney nickel will reduce heteroatom-heteroatom bonds such as hydrazines[13], nitro groups, and nitrosamines.[14] (For further information see Reduction of nitro compounds.) It has also found use in the reductive alkylation of amines[15] and the amination of alcohols.
When reducing a carbon-carbon double bond, Raney nickel will add hydrogen in a syn fashion.[6]
# Safety
Due to its large surface area and high volume of contained hydrogen gas, dry, activated Raney nickel is a pyrophoric material that should be handled under an inert atmosphere. Raney nickel is typically supplied as a 50-percent slurry in water. Care should be taken never to expose Raney nickel to air. Even after reaction, Raney nickel contains significant amounts of hydrogen gas, and will ignite when exposed to air.
Raney nickel will produce hazardous fumes when burning, and therefore the use of a gas mask is recommended when extinguishing fires caused by it. Additionally, acute exposure to Raney nickel may cause irritation of the respiratory tract, nasal cavities and causes pulmonary fibrosis if inhaled. Ingestion may lead to convulsions and intestinal disorders. It can also cause eye and skin irritation. Chronic exposure may lead to pneumonitis and other signs of sensitization to nickel like skin rashes ("nickel itch").[16]
Nickel is also rated as being a possible human carcinogen by the IARC (Group 2B, EU category 3) and teratogen, while the inhalation of fine aluminium oxide particles is associated with Shaver's disease. Care should be taken when handling these raw materials during laboratory preparation of Raney nickel. Moreover, activation of Raney nickel produces large amounts of hydrogen gas as a by-product, which is also highly flammable.[16]
# Development
Murray Raney graduated as a Mechanical Engineer from the University of Kentucky in 1909. In 1915 he joined the Lookout Oil and Refining Company in Tennessee and was responsible for the installation of electrolytic cells for the production of hydrogen which was used in the hydrogenation of vegetable oils. During that time the industry used a nickel catalyst prepared from nickel(II) oxide. Believing that better catalysts could be produced, around 1921 he started to perform independent research while still working for Lookout Oil. In 1924 a 1:1 ratio Ni/Si alloy was produced, which after treatment with sodium hydroxide, was found to be five times more active than the best catalyst used in the hydrogenation of cottonseed oil. A patent for this discovery was issued in December 1925.[17]
Subsequently, Raney produced a 1:1 Ni/Al alloy following a procedure similar to the one used for the nickel-silicon catalyst. He found that the resulting catalyst was even more active and filed a patent application in 1926.[1] It may be of interest to note that Raney's choice of nickel-aluminium ratio was fortuitous and without any real scientific basis.[citation needed] However, this is the preferred alloy composition for production of Raney nickel catalysts currently in use.
Following the development of Raney nickel, other alloy systems with aluminium were considered, of which the most notable include copper, ruthenium and cobalt. Further research showed that adding a small amount of a third metal to the binary alloy would promote the activity of the catalyst. Some widely used promoters are zinc, molybdenum and chromium. Recently, a way of preparing enantioselective Raney nickel has been devised by surface adsorbtion of tartaric acid.[18] | https://www.wikidoc.org/index.php/Raney_nickel | |
3c4b8007c89cbf21e9fba7664a187283ee2e475b | wikidoc | Ranunculales | Ranunculales
Ranunculales is an order of flowering plants. Of necessity it contains the family Ranunculaceae, the buttercup family.
The APG system (1998) and the APG II system (2003) both recognize the order and place it among the basal eudicots, not assigned to a further clade. These systems use this circumscription:
- order Ranunculales
family Berberidaceae
family Circaeasteraceae
family Eupteleaceae
family Lardizabalaceae
family Menispermaceae
family Papaveraceae
family Ranunculaceae
Note: "+ ..." = optional segregrate family, that may be split off from the preceding family.
Under this definition, well-known members of Ranunculales include buttercups, clematis, columbines, delphiniums, and poppies.
The Cronquist system (1981) also recognised the order, but placed it in the subclass Magnoliidae, in class Magnoliopsida . It used this circumscription:
- order Ranunculales
family Ranunculaceae
family Circaeasteraceae
family Berberidaceae
family Sargentodoxaceae
family Lardizabalaceae
family Menispermaceae
family Coriariaceae
family Sabiaceae
In the Cronquist system the Papaveraceae and Fumariaceae (including the plants in the optional family Pteridophyllaceae) were treated as a separate order Papaverales, placed in this same subclass Magnoliidae. | Ranunculales
Ranunculales is an order of flowering plants. Of necessity it contains the family Ranunculaceae, the buttercup family.
The APG system (1998) and the APG II system (2003) both recognize the order and place it among the basal eudicots, not assigned to a further clade. These systems use this circumscription:
- order Ranunculales
family Berberidaceae
family Circaeasteraceae
[+ family Kingdoniaceae ]
family Eupteleaceae
family Lardizabalaceae
family Menispermaceae
family Papaveraceae
[+ family Fumariaceae ]
[+ family Pteridophyllaceae ]
family Ranunculaceae
Note: "+ ..." = optional segregrate family, that may be split off from the preceding family.
Under this definition, well-known members of Ranunculales include buttercups, clematis, columbines, delphiniums, and poppies.
The Cronquist system (1981) also recognised the order, but placed it in the subclass Magnoliidae, in class Magnoliopsida [= dicotyledons]. It used this circumscription:
- order Ranunculales
family Ranunculaceae
family Circaeasteraceae
family Berberidaceae
family Sargentodoxaceae
family Lardizabalaceae
family Menispermaceae
family Coriariaceae
family Sabiaceae
In the Cronquist system the Papaveraceae and Fumariaceae (including the plants in the optional family Pteridophyllaceae) were treated as a separate order Papaverales, placed in this same subclass Magnoliidae.
# External links
- NCBI Taxonomy Browser
bg:Ranunculales
ca:Ranunculal
da:Ranunkel-ordenen
de:Hahnenfußartige
et:Tulikalaadsed
he:נוריתאים
ko:미나리아재비목
it:Ranunculales
hu:Boglárkák
nl:Ranunculales
no:Ranunculales
fi:Ranunculales
sv:Ranunculales
sr:Ranunculales
Template:WS | https://www.wikidoc.org/index.php/Ranunculales | |
0d50a35ee30423e0ad5c2d78ef9b4eee4edad2fc | wikidoc | Raphe nuclei | Raphe nuclei
# Overview
The raphe nuclei (Latin for 'the bit in a fold or seam') is a moderate-size cluster of nuclei found in the brain stem, and releases serotonin to the rest of the brain. Selective serotonin reuptake inhibitor (SSRI) antidepressants are believed to act in these nuclei, as well as at their targets .
# Anatomy
The raphe nuclei are traditionally considered to be the medial portion of the reticular formation, and they
appear as a ridge of cells in the center and most medial portion of the brain stem.
In order from caudal to rostral, the raphe nuclei are known as the nucleus raphe obscurus, the raphe magnus, the raphe pontis, the raphe pallidus, the nucleus centralis superior, nucleus raphe dorsalis, nuclei linearis intermedius and linearis rostralis.
Some scientists chose to group the linearis nuclei into one nucleus, shrinking the number of raphe to seven, e.g.,
NeuroNames makes the following ordering:
- Raphe nuclei of medulla
Nucleus raphe obscurus (nucleus raphe obscurus)
Nucleus raphe magnus (raphe magnus)
Nucleus pallidus (raphe pallidus)
- Nucleus raphe obscurus (nucleus raphe obscurus)
- Nucleus raphe magnus (raphe magnus)
- Nucleus pallidus (raphe pallidus)
- Raphe nuclei of the pontine reticular formation
Pontine raphe nucleus (raphe pontis)
Inferior central nucleus
- Pontine raphe nucleus (raphe pontis)
- Inferior central nucleus
- Raphe nuclei of the midbrain reticular formation
Superior central nucleus (nucleus centralis superior)
Dorsal raphe nucleus (nucleus raphe dorsalis)
- Superior central nucleus (nucleus centralis superior)
- Dorsal raphe nucleus (nucleus raphe dorsalis)
# Projections
All of these nuclei have fascinating interactions with almost every pertinent portion of the brain, but only a few of them have specifically independent interaction worth exploring in their own right. These select nuclei are discussed as follows.
Overall, the caudal raphe nuclei, including the raphe magnus, pallidus and raphe obscurus, all project towards the spinal cord and brain stem. The more-rostral nuclei, including the raphe pontis, centralis (also called median), dorsal, tend to project towards the brain areas of higher function.
The 8 raphe nuclei receive afferent connections from some of the most fascinating spots in the brain, only to project back to them and alter their processes.
# Function
The raphe nuclei have a vast impact upon the central nervous system.
The raphe nuclei can be of particular interest to neurologists and psychologists since many of the neurons in the nuclei (but not the majority) are serotonergic, i.e., contain serotonin - a type of monoamine neurotransmitter.
Serotonin, also called 5-HT, seems to be the culprit in many of our modern psycho-pharmaceutical problems, such as anorexia, depression, and sleep disorders. It is not the sole culprit in the aforementioned disorders, but it is the area that the pharmacologists know how to affect in the best manner. It is important to note that pharmacology traditionally affects global serotonin levels, while the actions of the raphe nuclei are dependent on the complex interplay between nuclei.
# Further reading
- Currie, David (2005). "A Lecture, Higher Brain Function: Activation of the Brain and Levels of Consciousness". East Tennessee State University. Retrieved April 18. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Sari, Youssef (2004). "Serotonin1B receptors: from protein to physiological function and behavior". Neuroscience & Biobehavioral Reviews. 28 (6): 565&ndash, 582. doi:10.1016/j.neubiorev.2004.08.008. Retrieved 2006-04-18. Unknown parameter |month= ignored (help) | Raphe nuclei
Template:Infobox Brain
# Overview
The raphe nuclei (Latin for 'the bit in a fold or seam') is a moderate-size cluster of nuclei found in the brain stem, and releases serotonin to the rest of the brain.[1] Selective serotonin reuptake inhibitor (SSRI) antidepressants are believed to act in these nuclei, as well as at their targets [2].
# Anatomy
The raphe nuclei are traditionally considered to be the medial portion of the reticular formation, and they
appear as a ridge of cells in the center and most medial portion of the brain stem.
In order from caudal to rostral, the raphe nuclei are known as the nucleus raphe obscurus, the raphe magnus, the raphe pontis, the raphe pallidus, the nucleus centralis superior, nucleus raphe dorsalis, nuclei linearis intermedius and linearis rostralis.[3]
Some scientists chose to group the linearis nuclei into one nucleus, shrinking the number of raphe to seven, e.g.,
NeuroNames makes the following ordering:[4]
- Raphe nuclei of medulla
Nucleus raphe obscurus (nucleus raphe obscurus)
Nucleus raphe magnus (raphe magnus)
Nucleus pallidus (raphe pallidus)
- Nucleus raphe obscurus (nucleus raphe obscurus)
- Nucleus raphe magnus (raphe magnus)
- Nucleus pallidus (raphe pallidus)
- Raphe nuclei of the pontine reticular formation
Pontine raphe nucleus (raphe pontis)
Inferior central nucleus
- Pontine raphe nucleus (raphe pontis)
- Inferior central nucleus
- Raphe nuclei of the midbrain reticular formation
Superior central nucleus (nucleus centralis superior)
Dorsal raphe nucleus (nucleus raphe dorsalis)
- Superior central nucleus (nucleus centralis superior)
- Dorsal raphe nucleus (nucleus raphe dorsalis)
# Projections
All of these nuclei have fascinating interactions with almost every pertinent portion of the brain, but only a few of them have specifically independent interaction worth exploring in their own right. These select nuclei are discussed as follows.
Overall, the caudal raphe nuclei, including the raphe magnus, pallidus and raphe obscurus, all project towards the spinal cord and brain stem. The more-rostral nuclei, including the raphe pontis, centralis (also called median), dorsal, tend to project towards the brain areas of higher function.[5]
The 8 raphe nuclei receive afferent connections from some of the most fascinating spots in the brain, only to project back to them and alter their processes.
# Function
The raphe nuclei have a vast impact upon the central nervous system.
The raphe nuclei can be of particular interest to neurologists and psychologists since many of the neurons in the nuclei (but not the majority) are serotonergic, i.e., contain serotonin - a type of monoamine neurotransmitter.
Serotonin, also called 5-HT, seems to be the culprit in many of our modern psycho-pharmaceutical problems, such as anorexia, depression, and sleep disorders. It is not the sole culprit in the aforementioned disorders, but it is the area that the pharmacologists know how to affect in the best manner. It is important to note that pharmacology traditionally affects global serotonin levels, while the actions of the raphe nuclei are dependent on the complex interplay between nuclei.
# Further reading
- Currie, David (2005). "A Lecture, Higher Brain Function: Activation of the Brain and Levels of Consciousness". East Tennessee State University. Retrieved April 18. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Sari, Youssef (2004). "Serotonin1B receptors: from protein to physiological function and behavior". Neuroscience & Biobehavioral Reviews. 28 (6): 565&ndash, 582. doi:10.1016/j.neubiorev.2004.08.008. Retrieved 2006-04-18. Unknown parameter |month= ignored (help) | https://www.wikidoc.org/index.php/Raphe_nuclei | |
1e308863f569dc4f15769019e1ab0519213c0f35 | wikidoc | Small GTPase | Small GTPase
# Overview
In biology, small GTPases are small (20-25 kDa) proteins that bind to guanosine triphosphate (GTP). This family of proteins is homologous to Ras GTPases and also called the Ras superfamily GTPases. Together with heterotrimeric G-proteins they constitute the G-proteins. They are all GTPases and share common features, but small GTPases have slightly different structures and mechanisms of action.
A typical G-protein is active when bound to GTP and inactive when bound to GDP (i.e. when the GTP is hydrolyzed to GDP). The GDP can be then replaced by free GTP. Therefore, a G-protein can be switched on and off. GTP hydrolysis is accelerated by GTPase accelating proteins (GAPs), while GTP exchange is catalyzed by Guanine nucleotide exchange factors (GEFs). Activation of a GEF typically activates its cognate G-protein, while activation of a GAP results in inactivation of the cognate G-protein.
Small GTPases regulate a wide variety of processes in the cell, including growth, cellular differentiation, cell movement and lipid vesicle transport.
# The Ras superfamily
There are more than a hundred proteins in the Ras superfamily. Based on structure, sequence and function, the Ras superfamily is divided into eight main families, each of which is further divided into subfamilies: Ras, Rho, Rab, Rap, Arf, Ran, Rheb, Rad and Rit. Miro is a recent contributor to the superfamily.
Each subfamily shares the common core G domain, which provides essential GTPase and nucleotide exchange activity.
The surrounding sequence helps determine the functional specificity of the small GTPase, for example the 'Insert Loop', common to the Rho subfamily, specifically contributes to binding to effector proteins such as IQGAP and WASP.
The Ras family is generally responsible for cell proliferation, Rho for cell morphology, nuclear transport for Ran and vesicle transport for Rab and Arf: | Small GTPase
# Overview
In biology, small GTPases are small (20-25 kDa) proteins that bind to guanosine triphosphate (GTP). This family of proteins is homologous to Ras GTPases and also called the Ras superfamily GTPases. Together with heterotrimeric G-proteins they constitute the G-proteins. They are all GTPases and share common features, but small GTPases have slightly different structures and mechanisms of action.
A typical G-protein is active when bound to GTP and inactive when bound to GDP (i.e. when the GTP is hydrolyzed to GDP). The GDP can be then replaced by free GTP. Therefore, a G-protein can be switched on and off. GTP hydrolysis is accelerated by GTPase accelating proteins (GAPs), while GTP exchange is catalyzed by Guanine nucleotide exchange factors (GEFs). Activation of a GEF typically activates its cognate G-protein, while activation of a GAP results in inactivation of the cognate G-protein.
Small GTPases regulate a wide variety of processes in the cell, including growth, cellular differentiation, cell movement and lipid vesicle transport.
# The Ras superfamily
There are more than a hundred proteins in the Ras superfamily. Based on structure, sequence and function, the Ras superfamily is divided into eight main families, each of which is further divided into subfamilies: Ras, Rho, Rab, Rap, Arf, Ran, Rheb, Rad and Rit. Miro is a recent contributor to the superfamily.
Each subfamily shares the common core G domain, which provides essential GTPase and nucleotide exchange activity.
The surrounding sequence helps determine the functional specificity of the small GTPase, for example the 'Insert Loop', common to the Rho subfamily, specifically contributes to binding to effector proteins such as IQGAP and WASP.
The Ras family is generally responsible for cell proliferation, Rho for cell morphology, nuclear transport for Ran and vesicle transport for Rab and Arf:[1] | https://www.wikidoc.org/index.php/Ras_superfamily | |
b96ddcc1afa800812e422d2668be262bd61651d5 | wikidoc | Red Defender | Red Defender
The Red Defender is a cartoon character used in a public service advertising campaign promoting blood donation.
The blood donation campaign was created pro bono by ad agency Euro RSCG Worldwide New York. The Red Defender character was created in 2006 by animator J. J. Sedelmaier (known for his work on Saturday Night Live’s TV Funhouse) for the Advertising Council's blood donation campaign. The ads' tagline is “Saving the world isn’t easy, but saving a life is.”
The campaign is targeted at young adults, especially 17-24 year olds, and aims to increase awareness of the need for regular blood donation and to set the foundation for lifelong donor behavior.
The blood donation campaign was distributed nationally throughout the United States to more than 28,000 media outlets in September 2006. | Red Defender
Template:WikiDoc Cardiology News
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The Red Defender is a cartoon character used in a public service advertising campaign promoting blood donation.
The blood donation campaign was created pro bono by ad agency Euro RSCG Worldwide New York. The Red Defender character was created in 2006 by animator J. J. Sedelmaier (known for his work on Saturday Night Live’s TV Funhouse) for the Advertising Council's blood donation campaign. The ads' tagline is “Saving the world isn’t easy, but saving a life is.”
The campaign is targeted at young adults, especially 17-24 year olds, and aims to increase awareness of the need for regular blood donation and to set the foundation for lifelong donor behavior.
The blood donation campaign was distributed nationally throughout the United States to more than 28,000 media outlets in September 2006.
# External links
- http://www.bloodsaves.com/
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Red_Defender | |
b6daa52d57bb822e29417eaa5873e154398fb463 | wikidoc | Rejuvenation | Rejuvenation
# Introduction
Rejuvenation is the procedure of reversing the aging process, thus regaining youth. As people get older, their health worsens, strength and intelligence generally diminish, and beauty is thought by many to go away.
Rejuvenation is distinct from life extension. Life extension strategies often study the causes of aging and try to oppose those causes in order to slow aging. Rejuvenation is the reversal of aging and thus requires a different strategy, namely repair of the damage that is associated with aging or replacement of damaged tissue with new tissue. Rejuvenation can be a means of life extension, but most life extension strategies do not involve rejuvenation.
# Historical and Cultural Background
Various myths tell the stories about the quest for rejuvenation. It was believed that magic or intervention of a supernatural power can bring back the youth and many mythical adventurers set out on a journey to do that, for themselves, their relatives or some authority that sent them.
An ancient Chinese emperor actually sent out ships of young men and women to find a pearl that would rejuvenate him. This led to a myth among modern Chinese that Japan was founded by these people.
In some religions people were to be rejuvenated after death prior to placing them in heaven.
The stories continued well into the 16th century. A famous Spanish explorer Juan Ponce de León led the expedition around the Caribbean islands and into Florida to find the Fountain of Youth. Led by the rumours, the expedition continued the search and many perished. The Fountain was nowhere to be found as locals were unaware of its exact location.
Since the emergence of philosophy, sages and self-proclaimed wizards always made enormous efforts to find the secret of youth, both for themselves and for their noble patrons and sponsors. It was widely believed that some potions may restore the youth.
Another commonly cited approach was attempting to transfer the essence of youth from young people to old. Some examples of this approach were sleeping with virgins or children (sometimes literally sleeping, not necessarily having sex), bathing in or drinking their blood.
The quest for rejuvenation reached its height with Alchemy. All around the Europe and also beyond alchemists were looking for the Philosopher's Stone, the mythical substance that, as it was believed, could not only turn lead into gold, but also prolong life and restore youth. Although the set goal was not achieved, Alchemy paved the way to the scientific method and so to the medical advances of today.
Serge Abrahamovitch Voronoff was a French surgeon born in Russia who gained fame for his technique of grafting monkey testicle tissue on to the testicles of men while working in France in the 1920s and 1930s. Which was one of the first medically accepted Rejuvenation Therapy (before he was proved to be wrong around 1930-1940). The technique brought him a great deal of money, although he was already independently wealthy. As his work fell out of favor, he went from being highly respected surgeon to a subject of ridicule. By the early 1930s, over 500 men had been treated in France by his rejuvenation technique, and thousands more around the world, such as in a special clinic set up in Algiers. Noteworthy people who had the surgery included Harold McCormick, chairman of the board of International Harvester Company, and the ageing premier of Turkey.
In fiction, there is an increasing amount of work being done on possibilities of rejuvenation treatments, and the effect this would have on society. Misspent Youth as well as the Commonwealth Saga by Peter F. Hamilton are one of the most well known examples of this, dealing with the short and long term effects of a near perfect 80 year old to 20 year old body change with mind intact. Also the Mars trilogy deals with a much more imperfect type of rejuvenation, including problems such as long term memory loss and sheer boredom that comes with such age. Also the post mortal characters in the Revelation Space series often illustrate this issue with long term or essentially infinite lifespans, sheer boredom induces them to undertake activities of extreme risk.
# Ancient developments
The dream of longevity is a common heritage of humanity. The ancient researchers and practitioners of Siddha Vaidya in the east had developed strategies for the same reason, some of which were very effective. Our current understanding of biology, physiology, immunology and biochemistry is helping us to decipher the rationale of these therapies. Ranging from detoxification of the body to targeted nutrition these therapies can even produce invivo stimulation and deferentiation of stem cells into useful mature cells. Many of these longevity techniques are still practiced in South India.
# Modern developments
Aging is an accumulation of damage to macromolecules, cells, tissues and organs. If any of that damage can be repaired, the result is rejuvenation.
There have been many experiments which have been shown to increase the maximum life span of laboratory animals, thereby achieving life extension. A few experimental methods such as replacing hormones to youthful levels have had considerable success in partially rejuvenating laboratory animals and humans. There are at least eight important hormones that decline with age: 1. human growth hormone (HGH); 2. the sexual hormones: testosterone or estrogen/progesterone; 3. erithropoietin EPO; 4. insulin; 5. DHEA; 6. melatonin; 7. thyroid; 8. pregnenolone. In theory, if all or some of these hormones are replaced, the body will respond to them as it did when it was younger, thus repairing and restoring many body functions. This seems to be borne out in hundreds of thousands of persons who have replaced hormones for many years, especially human growth hormone (HGH, a.k.a. GH).
Most attempts at genetic repair have traditionally involved the use of a retrovirus to insert a new gene into a random position on a chromosome. But by attaching zinc fingers (which determine where transcription factors bind) to endonucleases (which break DNA strands) homologous recombination can be induced to correct and replace defective (or undesired) DNA sequences. The first applications of this technology are to isolate stem cells from the bone marrow of patients having blood disease mutations, to correct those mutations in laboratory dishes using zinc finger endonucleases and to transplant the stem cells back into the patients .
Regenerative medicine uses three different strategies:
- Implantation of stem cells from culture into an existing tissue structure
- Implantation of stem cells into a tissue scaffold that guides restoration or
- Induction of residual cells of a tissue structure to regenerate the necessary body part.
A salamander can not only regenerate a limb, but can regenerate the lens or retina of an eye and can regenerate an intestine. For regeneration the salamander tissues form a blastema by de-differentiation of mesenchymal cells, and the blastema functions as a self-organizing system to regenerate the limb .
Yet another option involves cosmetic changes to the individual to create the appearance of youth. These are generally superficial and do little to make the person healthier or live longer, but the real improvement in a person's appearance may elevate their mood and have positive side effects normally correlated with happiness. Cosmetic surgery is a large industry offering treatments such as removal of wrinkles ("face lift"), removal of extra fat (liposuction) and reshaping or augmentation of various body parts (abdomen, breasts, face).
There are also, as always in history, many fake rejuvenation products that do not work. Chief among these are powders and sprays and gels and homeopathic that claim to be "growth hormone". Authentic growth hormone can only be injected, because the 191 amino-acid protein is too large to be absorbed through the mucous membranes, and would break up in the stomach if it is swallowed.
Eastern medical approaches offers us yet another treasure of techniques that can be used for tissue regeneration and invivo stem cell evolution and stimulation. According to Rajkumar Reghunathan, the inbuilt mechanism of inflammation and repair holds many keys for tissue renovation.
# Strategies for Engineered Negligible Senescence (SENS)
The leading modern exponent of scientific rejuvenation is the biomedical gerontologist Dr. Aubrey de Grey. He calls his project to reverse the damage we call aging "SENS" (Strategies for Engineered Negligible Senescence). He has proposed seven strategies for what he calls the "seven deadly sins":
- Cell loss can be repaired (reversed) just by suitable exercise in the case of muscle. For other tissues it needs various growth factors to stimulate cell division, or in some cases it needs stem cells.
- Senescent cells, can be removed by activating the immune system against them. Or they can be destroyed by gene therapy to introduce "suicide genes" that only kill senescent cells.
- Protein cross-linking can largely be reversed by drugs that break the links. But to break some of the cross-links we may need to develop enzymatic methods.
- Extracellular garbage (like amyloid) can be eliminated by vaccination that gets immune cells to "eat" the garbage.
- For intracellular junk we need to introduce new enzymes, possibly enzymes from soil bacteria, that can degrade the junk (lipofuscin) that our own natural enzymes cannot degrade.
- For mitochondrial mutations the plan is not to repair them but to prevent harm from the mutations by putting suitably modified copies of the mitochondrial genes into the cell nucleus by gene therapy. The mitochondrial DNA experiences a high degree of mutagenic damage because most free radicals are generated in the mitochondria. A copy of the mitochondrial DNA located in the nucleus will be better protected from free radicals, and there will be better DNA repair when damage occurs. All mitochondrial proteins would then be imported into the mitochondria.
- For cancer (the most lethal consequence of mutations) the strategy is to use gene therapy to delete the genes for telomerase and to eliminate telomerase-independent mechanisms of turning normal cells into "immortal" cancer cells. To compensate for the loss of telomerase in stem cells we would introduce new stem cells every decade or so.
Dr. de Grey has created the Methuselah Mouse Prize, which awards money to researchers who can rejuvenate mice.
# Scientific Journal
- Rejuvenation Research Editor: Aubrey de Grey. Publisher: Mary Ann Liebert, Inc. ISSN 1549-1684 - Published Quarterly. | Rejuvenation
Template:AB
# Introduction
Rejuvenation is the procedure of reversing the aging process, thus regaining youth. As people get older, their health worsens, strength and intelligence generally diminish, and beauty is thought by many to go away.
Rejuvenation is distinct from life extension. Life extension strategies often study the causes of aging and try to oppose those causes in order to slow aging. Rejuvenation is the reversal of aging and thus requires a different strategy, namely repair of the damage that is associated with aging or replacement of damaged tissue with new tissue. Rejuvenation can be a means of life extension, but most life extension strategies do not involve rejuvenation.
# Historical and Cultural Background
Various myths tell the stories about the quest for rejuvenation. It was believed that magic or intervention of a supernatural power can bring back the youth and many mythical adventurers set out on a journey to do that, for themselves, their relatives or some authority that sent them.
An ancient Chinese emperor actually sent out ships of young men and women to find a pearl that would rejuvenate him. This led to a myth among modern Chinese that Japan was founded by these people.
In some religions people were to be rejuvenated after death prior to placing them in heaven.
The stories continued well into the 16th century. A famous Spanish explorer Juan Ponce de León led the expedition around the Caribbean islands and into Florida to find the Fountain of Youth. Led by the rumours, the expedition continued the search and many perished. The Fountain was nowhere to be found as locals were unaware of its exact location.
Since the emergence of philosophy, sages and self-proclaimed wizards always made enormous efforts to find the secret of youth, both for themselves and for their noble patrons and sponsors. It was widely believed that some potions may restore the youth.
Another commonly cited approach was attempting to transfer the essence of youth from young people to old. Some examples of this approach were sleeping with virgins or children (sometimes literally sleeping, not necessarily having sex)[1], bathing in or drinking their blood.
The quest for rejuvenation reached its height with Alchemy. All around the Europe and also beyond alchemists were looking for the Philosopher's Stone, the mythical substance that, as it was believed, could not only turn lead into gold, but also prolong life and restore youth. Although the set goal was not achieved, Alchemy paved the way to the scientific method and so to the medical advances of today.
Serge Abrahamovitch Voronoff was a French surgeon born in Russia who gained fame for his technique of grafting monkey testicle tissue on to the testicles of men while working in France in the 1920s and 1930s. Which was one of the first medically accepted Rejuvenation Therapy (before he was proved to be wrong around 1930-1940). The technique brought him a great deal of money, although he was already independently wealthy. As his work fell out of favor, he went from being highly respected surgeon to a subject of ridicule. By the early 1930s, over 500 men had been treated in France by his rejuvenation technique, and thousands more around the world, such as in a special clinic set up in Algiers.[2] Noteworthy people who had the surgery included Harold McCormick, chairman of the board of International Harvester Company,[3] and the ageing premier of Turkey.[4]
In fiction, there is an increasing amount of work being done on possibilities of rejuvenation treatments, and the effect this would have on society. Misspent Youth as well as the Commonwealth Saga by Peter F. Hamilton are one of the most well known examples of this, dealing with the short and long term effects of a near perfect 80 year old to 20 year old body change with mind intact. Also the Mars trilogy deals with a much more imperfect type of rejuvenation, including problems such as long term memory loss and sheer boredom that comes with such age. Also the post mortal characters in the Revelation Space series often illustrate this issue with long term or essentially infinite lifespans, sheer boredom induces them to undertake activities of extreme risk.
# Ancient developments
The dream of longevity is a common heritage of humanity. The ancient researchers and practitioners of Siddha Vaidya in the east had developed strategies for the same reason, some of which were very effective. Our current understanding of biology, physiology, immunology and biochemistry is helping us to decipher the rationale of these therapies. Ranging from detoxification of the body to targeted nutrition these therapies can even produce invivo stimulation and deferentiation of stem cells into useful mature cells. Many of these longevity techniques are still practiced in South India.
# Modern developments
Aging is an accumulation of damage to macromolecules, cells, tissues and organs. If any of that damage can be repaired, the result is rejuvenation.
There have been many experiments which have been shown to increase the maximum life span of laboratory animals, thereby achieving life extension. A few experimental methods such as replacing hormones to youthful levels have had considerable success in partially rejuvenating laboratory animals and humans. There are at least eight important hormones that decline with age: 1. human growth hormone (HGH); 2. the sexual hormones: testosterone or estrogen/progesterone; 3. erithropoietin EPO; 4. insulin; 5. DHEA; 6. melatonin; 7. thyroid; 8. pregnenolone. In theory, if all or some of these hormones are replaced, the body will respond to them as it did when it was younger, thus repairing and restoring many body functions. This seems to be borne out in hundreds of thousands of persons who have replaced hormones for many years, especially human growth hormone (HGH, a.k.a. GH).
Most attempts at genetic repair have traditionally involved the use of a retrovirus to insert a new gene into a random position on a chromosome. But by attaching zinc fingers (which determine where transcription factors bind) to endonucleases (which break DNA strands) homologous recombination can be induced to correct and replace defective (or undesired) DNA sequences. The first applications of this technology are to isolate stem cells from the bone marrow of patients having blood disease mutations, to correct those mutations in laboratory dishes using zinc finger endonucleases and to transplant the stem cells back into the patients [5].
Regenerative medicine uses three different strategies:
- Implantation of stem cells from culture into an existing tissue structure
- Implantation of stem cells into a tissue scaffold that guides restoration or
- Induction of residual cells of a tissue structure to regenerate the necessary body part.
A salamander can not only regenerate a limb, but can regenerate the lens or retina of an eye and can regenerate an intestine. For regeneration the salamander tissues form a blastema by de-differentiation of mesenchymal cells, and the blastema functions as a self-organizing system to regenerate the limb [6].
Yet another option involves cosmetic changes to the individual to create the appearance of youth. These are generally superficial and do little to make the person healthier or live longer, but the real improvement in a person's appearance may elevate their mood and have positive side effects normally correlated with happiness. Cosmetic surgery is a large industry offering treatments such as removal of wrinkles ("face lift"), removal of extra fat (liposuction) and reshaping or augmentation of various body parts (abdomen, breasts, face).
There are also, as always in history, many fake rejuvenation products that do not work. Chief among these are powders and sprays and gels and homeopathic that claim to be "growth hormone". Authentic growth hormone can only be injected, because the 191 amino-acid protein is too large to be absorbed through the mucous membranes, and would break up in the stomach if it is swallowed.
Eastern medical approaches offers us yet another treasure of techniques that can be used for tissue regeneration and invivo stem cell evolution and stimulation. According to Rajkumar Reghunathan, the inbuilt mechanism of inflammation and repair holds many keys for tissue renovation.
# Strategies for Engineered Negligible Senescence (SENS)
The leading modern exponent of scientific rejuvenation is the biomedical gerontologist Dr. Aubrey de Grey. He calls his project to reverse the damage we call aging "SENS" (Strategies for Engineered Negligible Senescence). He has proposed seven strategies for what he calls the "seven deadly sins":
- Cell loss can be repaired (reversed) just by suitable exercise in the case of muscle. For other tissues it needs various growth factors to stimulate cell division, or in some cases it needs stem cells.
- Senescent cells, can be removed by activating the immune system against them. Or they can be destroyed by gene therapy to introduce "suicide genes" that only kill senescent cells.
- Protein cross-linking can largely be reversed by drugs that break the links. But to break some of the cross-links we may need to develop enzymatic methods.
- Extracellular garbage (like amyloid) can be eliminated by vaccination that gets immune cells to "eat" the garbage.
- For intracellular junk we need to introduce new enzymes, possibly enzymes from soil bacteria, that can degrade the junk (lipofuscin) that our own natural enzymes cannot degrade.
- For mitochondrial mutations the plan is not to repair them but to prevent harm from the mutations by putting suitably modified copies of the mitochondrial genes into the cell nucleus by gene therapy. The mitochondrial DNA experiences a high degree of mutagenic damage because most free radicals are generated in the mitochondria. A copy of the mitochondrial DNA located in the nucleus will be better protected from free radicals, and there will be better DNA repair when damage occurs. All mitochondrial proteins would then be imported into the mitochondria.
- For cancer (the most lethal consequence of mutations) the strategy is to use gene therapy to delete the genes for telomerase and to eliminate telomerase-independent mechanisms of turning normal cells into "immortal" cancer cells. To compensate for the loss of telomerase in stem cells we would introduce new stem cells every decade or so.
Dr. de Grey has created the Methuselah Mouse Prize, which awards money to researchers who can rejuvenate mice.
# Scientific Journal
- Rejuvenation Research Editor: Aubrey de Grey. Publisher: Mary Ann Liebert, Inc. ISSN 1549-1684 - Published Quarterly. | https://www.wikidoc.org/index.php/Rejuvenation | |
1e4390bff967245739a2d6166261aa5c29701d31 | wikidoc | Remifentanil | Remifentanil
# Disclaimer
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# Overview
Remifentanil is an analgesic opioid that is FDA approved for the {{{indicationType}}} of general anesthesia; adjunct, monitored anesthesia care sedation, analgesic component; adjunct, postoperative pain, immediate postoperative period. Common adverse reactions include cardiovascular: hypotension (19% or less ), dermatologic: pruritus (less than 1% to 18% ), gastrointestinal: nausea (less than 1% to 44% ), vomiting (less than 1% to 22% ), musculoskeletal: muscle rigidity (11% or less) , neurologic: headache (18% or less ).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Exceeding the recommended dose (greater than 1 and up to 20 mcg/kg) or exceeding the recommended infusion rate (starting dose greater than 0.1 mcg/kg/min) results in higher incidence of adverse events.
- Administering bolus doses to spontaneously breathing patients is not recommended.
- Analgesia for a mechanically ventilated patient, ICU: continuous infusion, 0.1 to 0.15 mcg/kg/min IV initially (using ideal body weight), with titration to a max dose of 0.2 to 0.4 mcg/kg/min IV (clinical studies).
- General anesthesia; adjunct: induction, 0.5 to 1 mcg/kg/min IV; 1 mcg/kg IV over 30 to 60 seconds if intubated within 8 minutes of initiation.
- General anesthesia; adjunct: maintenance, 0.25 mcg/kg/min IV (range 0.05 to 2 mcg/kg/min) plus isoflurane or propofol; supplemental bolus of 1 mcg/kg every 2 to 5 minutes if needed.
- General anesthesia; adjunct: maintenance, 0.4 mcg/kg/min IV (range 0.1 to 2 mcg/kg/min IV) plus nitrous oxide; supplemental bolus of 1 mcg/kg every 2 to 5 minutes if needed.
- General anesthesia; adjunct: CABG, during induction through intubation, 1 mcg/kg/min IV.
- General anesthesia; adjunct: CABG, during maintenance of anesthesia, 1 mcg/kg/min IV (range 0.125 to 4 mcg/kg/min); supplemental bolus of 0.5 to 1 mcg/kg if needed.
- Monitored anesthesia care sedation, analgesic component; adjunct: single dose, used with midazolam, 0.5 mcg/kg IV injection over 30 to 60 seconds as single dose 90 seconds before administration of local anesthetic.
- Monitored anesthesia care sedation, analgesic component; adjunct: single dose, used alone 1 mcg/kg IV injection over 30 to 60 seconds as single dose 90 seconds before administration of local anesthetic.
- Monitored anesthesia care sedation, analgesic component; adjunct: continuous infusion, used WITH midazolam, 0.05 mcg/kg/min IV infusion 5 minutes before placement of local or regional block; after placement of block, decrease dose to 0.025 mcg/kg/min (range 0.025 to 0.2 mcg/kg/min), adjust dose in 0.025 mcg/kg/min increments at 5-minute intervals.
- Monitored anesthesia care sedation, analgesic component; adjunct: continuous infusion, used alone, 0.1 mcg/kg/min IV infusion 5 minutes before placement of local or regional block; after placement of block, decrease dose to 0.05 mcg/kg/min (range 0.025 to 0.2 mcg/kg/min), adjust dose in 0.025 mcg/kg/min increments at 5-minute intervals.
- Postoperative pain, immediate postoperative period: 0.1 mcg/kg/min IV, adjust infusion every 5 minutes in 0.025 mcg/kg/min increments to reach desired effect (range 0.025 to 0.2 mcg/kg/min).
- Postoperative pain, Immediate postoperative period: CABG, 1 mcg/kg/min IV infusion (range 0.05 to 1 mcg/kg/min).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Analgesia for a mechanically ventilated patient, ICU.
- Procedural sedation.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Remifentanil in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Efficacy for use in pediatric patients during the immediate postoperative period or for use as a component of monitored anesthesia care has not been established.
- Administering bolus doses to spontaneously breathing patients is not recommended.
- Analgesia for a mechanically ventilated patient, ICU: (infants) continuous infusion, 0.075 to 0.15 mcg/kg/min IV initially, with titration to a max dose of 0.5 to 0.94 mcg/kg/min IV (clinical studies).
- Analgesia for a mechanically ventilated patient, ICU: (children) continuous infusion, 0.1 mcg/kg/min IV (clinical study)
- General anesthesia; Adjunct: (age birth to 2 months) maintenance, 0.4 mcg/kg/min IV (range 0.4 to 1 mcg/kg/min) plus nitrous oxide; supplemental bolus of 1 mcg/kg every 2 to 5 minutes if needed.
- General anesthesia; Adjunct: (age 1 year to 12 years) maintenance, 0.25 mcg/kg/min IV (range 0.05 to 1.3 mcg/kg/min) plus halothane, sevoflurane, or isoflurane; supplemental bolus of 1 mcg/kg every 2 to 5 minutes if needed.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of remifentanil in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of remifentanil in pediatric patients.
# Contraindications
- Due to the presence of glycine in the formulation, remifentanil is contraindicated for epidural or intrathecal administration. Remifentanil is also contraindicated in patients with known hypersensitivity to fentanyl analogs.
# Warnings
- Continuous infusions of remifentanil should be administered only by an infusion device. IV bolus administration of remifentanil should be used only during the maintenance of general anesthesia. In nonintubated patients, single doses of remifentanil should be administered over 30 to 60 seconds.
- Interruption of an infusion of remifentanil will result in rapid offset of effect. Rapid clearance and lack of drug accumulation result in rapid dissipation of respiratory depressant and analgesic effects upon discontinuation of remifentanil at recommended doses. Discontinuation of an infusion of remifentanil should be preceded by the establishment of adequate postoperative analgesia.
- Injections of remifentanil should be made into IV tubing at or close to the venous cannula. Upon discontinuation of remifentanil, the IV tubing should be cleared to prevent the inadvertent administration of remifentanil at a later point in time. Failure to adequately clear the IV tubing to remove residual remifentanil has been associated with the appearance of respiratory depression, apnea, and muscle rigidity upon the administration of additional fluids or medications through the same IV tubing.
- Use of remifentanil is associated with apnea and respiratory depression. Remifentanil should be administered only by persons specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, including respiratory and cardiac resuscitation of patients in the age group being treated. such training must include the establishment and maintenance of a patent airway and assisted ventilation.
- Remifentanil should not be used in diagnostic or therapeutic procedures outside the monitored anesthesia care setting. Patients receiving monitored anesthesia care should be continuously monitored by persons not involved in the conduct of the surgical or diagnostic procedure. oxygen saturation should be monitored on a continuous basis.
- Resuscitative and intubation equipment, oxygen, and an opioid antagonist must be readily available.
- Respiratory depression in spontaneously breathing patients is generally managed by decreasing the rate of the infusion of remifentanil by 50% or by temporarily discontinuing the infusion.
- Skeletal muscle rigidity can be caused by remifentanil and is related to the dose and speed of administration. Remifentanil may cause chest wall rigidity (inability to ventilate) after single doses of >1 mcg/kg administered over 30 to 60 seconds, or after infusion rates >0.1 mcg/kg/min. Single doses <1 mcg/kg may cause chest wall rigidity when given concurrently with a continuous infusion of remifentanil.
- Muscle rigidity induced by remifentanil should be managed in the context of the patient's clinical condition. Muscle rigidity occurring during the induction of anesthesia should be treated by the administration of a neuromuscular blocking agent and the concurrent induction medications.
- Muscle rigidity seen during the use of remifentanil in spontaneously breathing patients may be treated by stopping or decreasing the rate of administration of remifentanil . Resolution of muscle rigidity after discontinuing the infusion of remifentanil occurs within minutes. In the case of life-threatening muscle rigidity, a rapid onset neuromuscular blocker or naloxone may be administered.
- Remifentanil should not be administered into the same IV tubing with blood due to potential inactivation by nonspecific esterases in blood products.
# Adverse Reactions
## Clinical Trials Experience
- Remifentanil produces adverse events that are characteristic of µ-opioids, such as respiratory depression, bradycardia, hypotension, and skeletal muscle rigidity. These adverse events dissipate within minutes of discontinuing or decreasing the infusion rate of remifentanil. See Clinical Pharmacology, Warnings, and Precautions on the management of these events.
- Adverse event information is derived from controlled clinical trials that were conducted in a variety of surgical procedures of varying duration, using a variety of premedications and other anesthetics, and in patient populations with diverse characteristics including underlying disease.
- Approximately 2770 adult patients were exposed to remifentanil in controlled clinical trials. The frequencies of adverse events during general anesthesia with the recommended doses of remifentanil are given in Table 3. Each patient was counted once for each type of adverse event.
- The frequencies of adverse events from the clinical studies at the recommended doses of remifentanil in monitored anesthesia care are given in Table 5.
- Other Adverse Events in Adult Patients
- The frequencies of less commonly reported adverse clinical events from all controlled general anesthesia and monitored anesthesia care studies are presented below.
- Event frequencies are calculated as the number of patients who were administered remifentanil and reported an event divided by the total number of patients exposed to remifentanil in all controlled studies including cardiac dose-ranging and neurosurgery studies (n = 1883 general anesthesia, n = 609 monitored anesthesia care).
- Incidence Less than 1%
- Digestive: constipation, abdominal discomfort, xerostomia, gastro-esophageal reflux, dysphagia, diarrhea, heartburn, ileus.
- Cardiovascular: various atrial and ventricular arrhythmias, heart block, ECG change consistent with myocardial ischemia, elevated CPK-MB level, syncope.
- Musculoskeletal: muscle stiffness, musculoskeletal chest pain.
- Respiratory: cough, dyspnea, bronchospasm, laryngospasm, rhonchi, stridor, nasal congestion, pharyngitis, pleural effusion, hiccup(s), pulmonary edema, rales, bronchitis, rhinorrhea.
- Nervous: anxiety, involuntary movement, prolonged emergence from anesthesia, confusion, awareness under anesthesia without pain, rapid awakening from anesthesia, tremors, disorientation, dysphoria, nightmare(s), hallucinations, paresthesia, nystagmus, twitch, sleep disorder, seizure, amnesia.
- Body as a Whole: decreased body temperature, anaphylactic reaction, delayed recovery from neuromuscular block.
- Skin: rash, urticaria.
- Urogenital: urine retention, oliguria, dysuria, urine incontinence.
- Infusion Site Reaction: erythema, pruritus, rash.
- Metabolic and Nutrition: abnormal liver function, hyperglycemia, electrolyte disorders, increased CPK level.
- Hematologic and Lymphatic: anemia, lymphopenia, leukocytosis, thrombocytopenia.
- The frequencies of adverse events from the clinical studies at the recommended doses of remifentanil in cardiac surgery are given in Tables 6, 7, and 8. These tables represent adverse events collected during discrete phases of cardiac surgery. Any event should be viewed as temporally associated with drug administration and the phase indicated should not be perceived as the only time the event might occur.
- Remifentanil has been studied in 342 pediatric patients in controlled clinical trials for maintenance of general anesthesia. In the pediatric population (birth to 12 years), the most commonly reported events were nausea, vomiting, and shivering.
- The frequencies of adverse events during general anesthesia with the recommended doses of remifentanil are given in Table 9. Each patient was counted once for each type of adverse event. There were no adverse events ≥1% for any treatment group during the maintenance period in the pediatric patient general anesthesia studies.
- Observed During Clinical Practice
- In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of remifentanil in conjunction with one or more anesthetic agents in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to remifentanil.
- Cardiovascular: Asystole.
- Non-Site Specific: Anaphylactic/anaphylactoid responses, which in some cases have been severe (e.g., shock).
## Postmarketing Experience
There is limited information regarding Remifentanil Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Remifentanil Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Remifentanil in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Remifentanil in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Remifentanil during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Remifentanil in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Remifentanil in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Remifentanil in geriatric settings.
### Gender
There is no FDA guidance on the use of Remifentanil with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Remifentanil with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Remifentanil in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Remifentanil in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Remifentanil in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Remifentanil in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Remifentanil Administration in the drug label.
### Monitoring
There is limited information regarding Remifentanil Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Remifentanil and IV administrations.
# Overdosage
- As with all potent opioid analgesics, overdosage would be manifested by an extension of the pharmacological actions of remifentanil . Expected signs and symptoms of overdosage include: apnea, chest-wall rigidity, seizures, hypoxemia, hypotension, and bradycardia.
- In case of overdosage or suspected overdosage, discontinue administration of remifentanil , maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function. If depressed respiration is associated with muscle rigidity, a neuromuscular blocking agent or a µ-opioid antagonist may be required to facilitate assisted or controlled respiration. Intravenous fluids and vasopressors for the treatment of hypotension and other supportive measures may be employed. Glycopyrrolate or atropine may be useful for the treatment of bradycardia and/or hypotension.
- Intravenous administration of an opioid antagonist such as naloxone may be employed as a specific antidote to manage severe respiratory depression or muscle rigidity. Respiratory depression from overdosage with remifentanil is not expected to last longer than the opioid antagonist, naloxone. Reversal of the opioid effects may lead to acute pain and sympathetic hyperactivity.
# Pharmacology
## Mechanism of Action
- Remifentanil is a µ-opioid agonist with rapid onset and peak effect, and short duration of action. The µ-opioid activity of remifentanil is antagonized by opioid antagonists such as naloxone.
- Unlike other opioids, remifentanil is rapidly metabolized by hydrolysis of the propanoic acid-methyl ester linkage by nonspecific blood and tissue esterases. Remifentanil is not a substrate for plasma cholinesterase (pseudocholinesterase) and, therefore, patients with atypical cholinesterase are expected to have a normal duration of action.
## Structure
Remifentanil (remifentanil hydrochloride) for Injection is a µ-opioid agonist chemically designated as a 3--1-piperidine]propanoic acid methyl ester, hydrochloride salt, C20H28N2O5HCl, with a molecular weight of 412.91. It has the following chemical structure:
- Remifentanil is a sterile, nonpyrogenic, preservative-free, white to off-white lyophilized powder for intravenous (IV) administration after reconstitution and dilution. Each vial contains 1, 2, or 5 mg of remifentanil base; 15 mg glycine; and hydrochloric acid to buffer the solutions to a nominal pH of 3 after reconstitution. When reconstituted as directed, solutions of remifentanil are clear and colorless and contain remifentanil hydrochloride (HCl) equivalent to 1 mg/mL of remifentanil base. The pH of reconstituted solutions of remifentanil ranges from 2.5 to 3.5. Remifentanil HCl has a pKa of 7.07. remifentanil HCl has an n-octanol:water partition coefficient of 17.9 at pH 7.3.
## Pharmacodynamics
- The analgesic effects of remifentanil are rapid in onset and offset. Its effects and side effects are dose dependent and similar to other µ-opioids. Remifentanil in humans has a rapid blood-brain equilibration half-time of 1 ± 1 minutes (mean ± SD) and a rapid onset of action. The pharmacodynamic effects of remifentanil closely follow the measured blood concentrations, allowing direct correlation between dose, blood levels, and response. Blood concentration decreases 50% in 3 to 6 minutes after a 1-minute infusion or after prolonged continuous infusion due to rapid distribution and elimination processes and is independent of duration of drug administration. Recovery from the effects of remifentanil occurs rapidly (within 5 to 10 minutes). New steady-state concentrations occur within 5 to 10 minutes after changes in infusion rate. When used as a component of an anesthetic technique, remifentanil can be rapidly titrated to the desired depth of anesthesia/analgesia (e.g., as required by varying levels of intraoperative stress) by changing the continuous infusion rate or by administering an IV bolus injection.
- In premedicated patients undergoing anesthesia, 1-minute infusions of 2 mcg/kg (up to 30 mcg/kg) do not produce any further decreases in heart rate or blood pressure, the duration of the hemodynamic change is increased in proportion to the blood concentrations achieved. Peak hemodynamic effects occur within 3 to 5 minutes of a single dose of remifentanil or an infusion rate increase. Glycopyrrolate, atropine, and vagolytic neuromuscular blocking agents attenuate the hemodynamic effects associated with remifentanil . When appropriate, bradycardia and hypotension can be reversed by reduction of the rate of infusion of remifentanil , or the dose of concurrent anesthetics, or by the administration of fluids or vasopressors.
- Remifentanil depresses respiration in a dose-related fashion. Unlike other fentanyl analogs, the duration of action of remifentanil at a given dose does not increase with increasing duration of administration, due to lack of drug accumulation. When remifentanil and alfentanil were dosed to equal levels of respiratory depression, recovery of respiratory drive after 3-hour infusions was more rapid and less variable with remifentanil (see Figure 1).
- Spontaneous respiration occurs at blood concentrations of 4 to 5 ng/mL in the absence of other anesthetic agents; for example, after discontinuation of a 0.25-mcg/kg/min infusion of remifentanil, these blood concentrations would be reached in 2 to 4 minutes. In patients undergoing general anesthesia, the rate of respiratory recovery depends upon the concurrent anesthetic; N2O < propofol < isoflurane (see Clinical trials: Recovery).
- Skeletal muscle rigidity can be caused by remifentanil and is related to the dose and speed of administration. remifentanil may cause chest wall rigidity (inability to ventilate) after single doses of >1 mcg/kg administered over 30 to 60 seconds or infusion rates >0.1 mcg/kg/min; peripheral muscle rigidity may occur at lower doses. Administration of doses <1 mcg/kg may cause chest wall rigidity when given concurrently with a continuous infusion of remifentanil . Prior or concurrent administration of a hypnotic (propofol or thiopental) or a neuromuscular blocking agent may attenuate the development of muscle rigidity. Excessive muscle rigidity can be treated by decreasing the rate or discontinuing the infusion of remifentanil or by administering a neuromuscular blocking agent.
- Assays of histamine in patients and normal volunteers have shown no elevation in plasma histamine levels after administration of remifentanil in doses up to 30 mcg/kg over 60 seconds.
- Infusions of 0.05 to 0.1 mcg/kg/min, producing blood concentrations of 1 to 3 ng/mL, are typically associated with analgesia with minimal decrease in respiratory rate. Supplemental doses of 0.5 to 1 mcg/kg, incremental increases in infusion rate >0.05 mcg/kg/min, and blood concentrations exceeding 5 ng/mL (typically produced by infusions of 0.2 mcg/kg/min) have been associated with transient and reversible respiratory depression, apnea, and muscle rigidity.
- Remifentanil is synergistic with the activity of hypnotics (propofol and thiopental), inhaled anesthetics, and benzodiazepines (see Clinical Trials, Precautions, and Dosage And Administration).
- The pharmacodynamic activity of remifentanil (as measured by the EC50 for development of delta waves on the EEG) increases with increasing age. The EC50 of remifentanil for this measure was 50% less in patients over 65 years of age when compared to healthy volunteers (25 years of age) (see Dosage and Administration).
- No differences have been shown in the pharmacodynamic activity (as measured by the EEG) of remifentanil between men and women.
- In animals the duration of muscle paralysis from succinylcholine is not prolonged by remifentanil.
- There was no change in intraocular pressure after the administration of remifentanil prior to ophthalmic surgery under monitored anesthesia care.
- Under isoflurane-nitrous oxide anesthesia (PaCO2 <30 mmHg), a 1-minute infusion of remifentanil (0.5 or 1.0 mcg/kg) produced no change in intracranial pressure. Mean arterial pressure and cerebral perfusion decreased as expected with opioids. In patients receiving remifentanil and nitrous oxide anesthesia, cerebrovascular reactivity to carbon dioxide remained intact. In humans, no epileptiform activity was seen on the EEG (n = 44) at remifentanil doses up to 8 mcg/kg/min.
- The pharmacodynamics of remifentanil (ventilatory response to hypercarbia) are unaltered in patients with end stage renal disease (creatinine clearance <10 mL/min).
- The pharmacodynamics of remifentanil (ventilatory response to hypercarbia) are unaltered in patients with severe hepatic dysfunction awaiting liver transplant.
## Pharmacokinetics
- After IV doses administered over 60 seconds, the pharmacokinetics of remifentanil fit a three-compartment model with a rapid distribution half-life of 1 minute, a slower distribution half-life of 6 minutes, and a terminal elimination half-life of 10 to 20 minutes. Since the terminal elimination component contributes less than 10% of the overall area under the concentration versus time curve (AUC), the effective biological half-life of remifentanil is 3 to 10 minutes. This is similar to the 3- to 10-minute half-life measured after termination of prolonged infusions (up to 4 hours; see Figure 2) and correlates with recovery times observed in the clinical setting after infusions up to 12 hours. Concentrations of remifentanil are proportional to the dose administered throughout the recommended dose range. The pharmacokinetics of remifentanil are unaffected by the presence of renal or hepatic impairment.
- The initial volume of distribution (Vd) of remifentanil is approximately 100 mL/kg and represents distribution throughout the blood and rapidly perfused tissues. remifentanil subsequently distributes into peripheral tissues with a steady-state volume of distribution of approximately 350 mL/kg. These two distribution volumes generally correlate with total body weight (except in severely obese patients when they correlate better with ideal body weight ). remifentanil is approximately 70% bound to plasma proteins of which two-thirds is binding to alpha-1-acid-glycoprotein.
- Remifentanil is an esterase-metabolized opioid. A labile ester linkage renders this compound susceptible to hydrolysis by nonspecific esterases in blood and tissues. This hydrolysis results in the production of the carboxylic acid metabolite (3--1-piperidine]propanoic acid), and represents the principal metabolic pathway for remifentanil (>95%). The carboxylic acid metabolite is essentially inactive (1/4600 as potent as remifentanil in dogs) and is excreted by the kidneys with an elimination half-life of approximately 90 minutes. remifentanil is not metabolized by plasma cholinesterase (pseudocholinesterase) and is not appreciably metabolized by the liver or lung.
- The clearance of remifentanil in young, healthy adults is approximately 40 mL/min/kg. Clearance generally correlates with total body weight (except in severely obese patients when it correlates better with IBW). The high clearance of remifentanil combined with a relatively small volume of distribution produces a short elimination half-life of approximately 3 to 10 minutes (see Figure 2). This value is consistent with the time taken for blood or effect site concentrations to fall by 50% (context-sensitive half-times) which is approximately 3 to 6 minutes. Unlike other fentanyl analogs, the duration of action does not increase with prolonged administration.
- The rapid elimination of remifentanil permits the titration of infusion rate without concern for prolonged duration. In general, every 0.1-mcg/kg/min change in the IV infusion rate will lead to a corresponding 2.5-ng/mL change in blood remifentanil concentration within 5 to 10 minutes. In intubated patients only, a more rapid increase (within 3 to 5 minutes) to a new steady state can be achieved with a 1.0-mcg/kg bolus dose in conjunction with an infusion rate increase.
- Pediatrics
- In pediatric patients, 5 days to 17 years of age (n = 47), the clearance and volume of distribution of remifentanil were increased in younger children and declined to young healthy adult values by age 17. The average clearance of remifentanil in neonates (less than 2 months of age) was approximately 90.5 ± 36.8 mL/min/kg (mean ± SD) while in adolescents (13 to 16 years) this value was 57.2 ± 21.1 mL/min/kg. The total (steady-state) volume of distribution in neonates was 452 ± 144 mL/kg versus 223 ± 30.6 mL/kg in adolescents. The half-life of remifentanil was the same in neonates and adolescents. Clearance of remifentanil was maintained at or above normal adult values in patients 5 days to 17 years of age.
- Renal Impairment
- The pharmacokinetic profile of remifentanil is not changed in patients with end stage renal disease (creatinine clearance <10 mL/min). In anephric patients, the half-life of the carboxylic acid metabolite increases from 90 minutes to 30 hours. The metabolite is removed by hemodialysis with a dialysis extraction ratio of approximately 30%.
- Hepatic Impairment
- The pharmacokinetics of remifentanil and its carboxylic acid metabolite are unchanged in patients with severe hepatic impairment.
- Elderly
- The clearance of remifentanil is reduced (approximately 25%) in the elderly (>65 years of age) compared to young adults (average 25 years of age). However, remifentanil blood concentrations fall as rapidly after termination of administration in the elderly as in young adults.
- Gender
- There is no significant difference in the pharmacokinetics of remifentanil in male and female patients after correcting for differences in weight.
- Obesity
- There is no difference in the pharmacokinetics of remifentanil in non-obese versus obese (greater than 30% over IBW) patients when normalized to IBW.
- Cardiopulmonary Bypass (CPB)
- Remifentanil clearance is reduced by approximately 20% during hypothermic CPB.
- Drug Interactions
- Remifentanil clearance is not altered by concomitant administration of thiopental, isoflurane, propofol, or temazepam during anesthesia. In vitro studies with atracurium, mivacurium, esmolol, echothiophate, neostigmine, physostigmine, and midazolam revealed no inhibition of remifentanil hydrolysis in whole human blood by these drugs.
## Nonclinical Toxicology
There is limited information regarding Remifentanil Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Remifentanil Clinical Studies in the drug label.
# How Supplied
- ULTIVA should be stored at 2° to 25°C (36° to 77°F). ULTIVA for IV use is supplied as follows:
## Storage
There is limited information regarding Remifentanil Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Remifentanil Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-remifentanil 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 Remifentanil Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Remifentanil Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Remifentanil
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
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# Overview
Remifentanil is an analgesic opioid that is FDA approved for the {{{indicationType}}} of general anesthesia; adjunct, monitored anesthesia care sedation, analgesic component; adjunct, postoperative pain, immediate postoperative period. Common adverse reactions include cardiovascular: hypotension (19% or less ), dermatologic: pruritus (less than 1% to 18% ), gastrointestinal: nausea (less than 1% to 44% ), vomiting (less than 1% to 22% ), musculoskeletal: muscle rigidity (11% or less) , neurologic: headache (18% or less ).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Exceeding the recommended dose (greater than 1 and up to 20 mcg/kg) or exceeding the recommended infusion rate (starting dose greater than 0.1 mcg/kg/min) results in higher incidence of adverse events.
- Administering bolus doses to spontaneously breathing patients is not recommended.
- Analgesia for a mechanically ventilated patient, ICU: continuous infusion, 0.1 to 0.15 mcg/kg/min IV initially (using ideal body weight), with titration to a max dose of 0.2 to 0.4 mcg/kg/min IV (clinical studies).
- General anesthesia; adjunct: induction, 0.5 to 1 mcg/kg/min IV; 1 mcg/kg IV over 30 to 60 seconds if intubated within 8 minutes of initiation.
- General anesthesia; adjunct: maintenance, 0.25 mcg/kg/min IV (range 0.05 to 2 mcg/kg/min) plus isoflurane or propofol; supplemental bolus of 1 mcg/kg every 2 to 5 minutes if needed.
- General anesthesia; adjunct: maintenance, 0.4 mcg/kg/min IV (range 0.1 to 2 mcg/kg/min IV) plus nitrous oxide; supplemental bolus of 1 mcg/kg every 2 to 5 minutes if needed.
- General anesthesia; adjunct: CABG, during induction through intubation, 1 mcg/kg/min IV.
- General anesthesia; adjunct: CABG, during maintenance of anesthesia, 1 mcg/kg/min IV (range 0.125 to 4 mcg/kg/min); supplemental bolus of 0.5 to 1 mcg/kg if needed.
- Monitored anesthesia care sedation, analgesic component; adjunct: single dose, used with midazolam, 0.5 mcg/kg IV injection over 30 to 60 seconds as single dose 90 seconds before administration of local anesthetic.
- Monitored anesthesia care sedation, analgesic component; adjunct: single dose, used alone 1 mcg/kg IV injection over 30 to 60 seconds as single dose 90 seconds before administration of local anesthetic.
- Monitored anesthesia care sedation, analgesic component; adjunct: continuous infusion, used WITH midazolam, 0.05 mcg/kg/min IV infusion 5 minutes before placement of local or regional block; after placement of block, decrease dose to 0.025 mcg/kg/min (range 0.025 to 0.2 mcg/kg/min), adjust dose in 0.025 mcg/kg/min increments at 5-minute intervals.
- Monitored anesthesia care sedation, analgesic component; adjunct: continuous infusion, used alone, 0.1 mcg/kg/min IV infusion 5 minutes before placement of local or regional block; after placement of block, decrease dose to 0.05 mcg/kg/min (range 0.025 to 0.2 mcg/kg/min), adjust dose in 0.025 mcg/kg/min increments at 5-minute intervals.
- Postoperative pain, immediate postoperative period: 0.1 mcg/kg/min IV, adjust infusion every 5 minutes in 0.025 mcg/kg/min increments to reach desired effect (range 0.025 to 0.2 mcg/kg/min).
- Postoperative pain, Immediate postoperative period: CABG, 1 mcg/kg/min IV infusion (range 0.05 to 1 mcg/kg/min).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Analgesia for a mechanically ventilated patient, ICU.
- Procedural sedation.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Remifentanil in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Efficacy for use in pediatric patients during the immediate postoperative period or for use as a component of monitored anesthesia care has not been established.
- Administering bolus doses to spontaneously breathing patients is not recommended.
- Analgesia for a mechanically ventilated patient, ICU: (infants) continuous infusion, 0.075 to 0.15 mcg/kg/min IV initially, with titration to a max dose of 0.5 to 0.94 mcg/kg/min IV (clinical studies).
- Analgesia for a mechanically ventilated patient, ICU: (children) continuous infusion, 0.1 mcg/kg/min IV (clinical study) [9]
- General anesthesia; Adjunct: (age birth to 2 months) maintenance, 0.4 mcg/kg/min IV (range 0.4 to 1 mcg/kg/min) plus nitrous oxide; supplemental bolus of 1 mcg/kg every 2 to 5 minutes if needed.
- General anesthesia; Adjunct: (age 1 year to 12 years) maintenance, 0.25 mcg/kg/min IV (range 0.05 to 1.3 mcg/kg/min) plus halothane, sevoflurane, or isoflurane; supplemental bolus of 1 mcg/kg every 2 to 5 minutes if needed.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of remifentanil in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of remifentanil in pediatric patients.
# Contraindications
- Due to the presence of glycine in the formulation, remifentanil is contraindicated for epidural or intrathecal administration. Remifentanil is also contraindicated in patients with known hypersensitivity to fentanyl analogs.
# Warnings
- Continuous infusions of remifentanil should be administered only by an infusion device. IV bolus administration of remifentanil should be used only during the maintenance of general anesthesia. In nonintubated patients, single doses of remifentanil should be administered over 30 to 60 seconds.
- Interruption of an infusion of remifentanil will result in rapid offset of effect. Rapid clearance and lack of drug accumulation result in rapid dissipation of respiratory depressant and analgesic effects upon discontinuation of remifentanil at recommended doses. Discontinuation of an infusion of remifentanil should be preceded by the establishment of adequate postoperative analgesia.
- Injections of remifentanil should be made into IV tubing at or close to the venous cannula. Upon discontinuation of remifentanil, the IV tubing should be cleared to prevent the inadvertent administration of remifentanil at a later point in time. Failure to adequately clear the IV tubing to remove residual remifentanil has been associated with the appearance of respiratory depression, apnea, and muscle rigidity upon the administration of additional fluids or medications through the same IV tubing.
- Use of remifentanil is associated with apnea and respiratory depression. Remifentanil should be administered only by persons specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, including respiratory and cardiac resuscitation of patients in the age group being treated. such training must include the establishment and maintenance of a patent airway and assisted ventilation.
- Remifentanil should not be used in diagnostic or therapeutic procedures outside the monitored anesthesia care setting. Patients receiving monitored anesthesia care should be continuously monitored by persons not involved in the conduct of the surgical or diagnostic procedure. oxygen saturation should be monitored on a continuous basis.
- Resuscitative and intubation equipment, oxygen, and an opioid antagonist must be readily available.
- Respiratory depression in spontaneously breathing patients is generally managed by decreasing the rate of the infusion of remifentanil by 50% or by temporarily discontinuing the infusion.
- Skeletal muscle rigidity can be caused by remifentanil and is related to the dose and speed of administration. Remifentanil may cause chest wall rigidity (inability to ventilate) after single doses of >1 mcg/kg administered over 30 to 60 seconds, or after infusion rates >0.1 mcg/kg/min. Single doses <1 mcg/kg may cause chest wall rigidity when given concurrently with a continuous infusion of remifentanil.
- Muscle rigidity induced by remifentanil should be managed in the context of the patient's clinical condition. Muscle rigidity occurring during the induction of anesthesia should be treated by the administration of a neuromuscular blocking agent and the concurrent induction medications.
- Muscle rigidity seen during the use of remifentanil in spontaneously breathing patients may be treated by stopping or decreasing the rate of administration of remifentanil . Resolution of muscle rigidity after discontinuing the infusion of remifentanil occurs within minutes. In the case of life-threatening muscle rigidity, a rapid onset neuromuscular blocker or naloxone may be administered.
- Remifentanil should not be administered into the same IV tubing with blood due to potential inactivation by nonspecific esterases in blood products.
# Adverse Reactions
## Clinical Trials Experience
- Remifentanil produces adverse events that are characteristic of µ-opioids, such as respiratory depression, bradycardia, hypotension, and skeletal muscle rigidity. These adverse events dissipate within minutes of discontinuing or decreasing the infusion rate of remifentanil. See Clinical Pharmacology, Warnings, and Precautions on the management of these events.
- Adverse event information is derived from controlled clinical trials that were conducted in a variety of surgical procedures of varying duration, using a variety of premedications and other anesthetics, and in patient populations with diverse characteristics including underlying disease.
- Approximately 2770 adult patients were exposed to remifentanil in controlled clinical trials. The frequencies of adverse events during general anesthesia with the recommended doses of remifentanil are given in Table 3. Each patient was counted once for each type of adverse event.
- The frequencies of adverse events from the clinical studies at the recommended doses of remifentanil in monitored anesthesia care are given in Table 5.
- Other Adverse Events in Adult Patients
- The frequencies of less commonly reported adverse clinical events from all controlled general anesthesia and monitored anesthesia care studies are presented below.
- Event frequencies are calculated as the number of patients who were administered remifentanil and reported an event divided by the total number of patients exposed to remifentanil in all controlled studies including cardiac dose-ranging and neurosurgery studies (n = 1883 general anesthesia, n = 609 monitored anesthesia care).
- Incidence Less than 1%
- Digestive: constipation, abdominal discomfort, xerostomia, gastro-esophageal reflux, dysphagia, diarrhea, heartburn, ileus.
- Cardiovascular: various atrial and ventricular arrhythmias, heart block, ECG change consistent with myocardial ischemia, elevated CPK-MB level, syncope.
- Musculoskeletal: muscle stiffness, musculoskeletal chest pain.
- Respiratory: cough, dyspnea, bronchospasm, laryngospasm, rhonchi, stridor, nasal congestion, pharyngitis, pleural effusion, hiccup(s), pulmonary edema, rales, bronchitis, rhinorrhea.
- Nervous: anxiety, involuntary movement, prolonged emergence from anesthesia, confusion, awareness under anesthesia without pain, rapid awakening from anesthesia, tremors, disorientation, dysphoria, nightmare(s), hallucinations, paresthesia, nystagmus, twitch, sleep disorder, seizure, amnesia.
- Body as a Whole: decreased body temperature, anaphylactic reaction, delayed recovery from neuromuscular block.
- Skin: rash, urticaria.
- Urogenital: urine retention, oliguria, dysuria, urine incontinence.
- Infusion Site Reaction: erythema, pruritus, rash.
- Metabolic and Nutrition: abnormal liver function, hyperglycemia, electrolyte disorders, increased CPK level.
- Hematologic and Lymphatic: anemia, lymphopenia, leukocytosis, thrombocytopenia.
- The frequencies of adverse events from the clinical studies at the recommended doses of remifentanil in cardiac surgery are given in Tables 6, 7, and 8. These tables represent adverse events collected during discrete phases of cardiac surgery. Any event should be viewed as temporally associated with drug administration and the phase indicated should not be perceived as the only time the event might occur.
- Remifentanil has been studied in 342 pediatric patients in controlled clinical trials for maintenance of general anesthesia. In the pediatric population (birth to 12 years), the most commonly reported events were nausea, vomiting, and shivering.
- The frequencies of adverse events during general anesthesia with the recommended doses of remifentanil are given in Table 9. Each patient was counted once for each type of adverse event. There were no adverse events ≥1% for any treatment group during the maintenance period in the pediatric patient general anesthesia studies.
- Observed During Clinical Practice
- In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of remifentanil in conjunction with one or more anesthetic agents in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to remifentanil.
- Cardiovascular: Asystole.
- Non-Site Specific: Anaphylactic/anaphylactoid responses, which in some cases have been severe (e.g., shock).
## Postmarketing Experience
There is limited information regarding Remifentanil Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Remifentanil Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Remifentanil in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Remifentanil in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Remifentanil during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Remifentanil in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Remifentanil in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Remifentanil in geriatric settings.
### Gender
There is no FDA guidance on the use of Remifentanil with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Remifentanil with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Remifentanil in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Remifentanil in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Remifentanil in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Remifentanil in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Remifentanil Administration in the drug label.
### Monitoring
There is limited information regarding Remifentanil Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Remifentanil and IV administrations.
# Overdosage
- As with all potent opioid analgesics, overdosage would be manifested by an extension of the pharmacological actions of remifentanil . Expected signs and symptoms of overdosage include: apnea, chest-wall rigidity, seizures, hypoxemia, hypotension, and bradycardia.
- In case of overdosage or suspected overdosage, discontinue administration of remifentanil , maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function. If depressed respiration is associated with muscle rigidity, a neuromuscular blocking agent or a µ-opioid antagonist may be required to facilitate assisted or controlled respiration. Intravenous fluids and vasopressors for the treatment of hypotension and other supportive measures may be employed. Glycopyrrolate or atropine may be useful for the treatment of bradycardia and/or hypotension.
- Intravenous administration of an opioid antagonist such as naloxone may be employed as a specific antidote to manage severe respiratory depression or muscle rigidity. Respiratory depression from overdosage with remifentanil is not expected to last longer than the opioid antagonist, naloxone. Reversal of the opioid effects may lead to acute pain and sympathetic hyperactivity.
# Pharmacology
## Mechanism of Action
- Remifentanil is a µ-opioid agonist with rapid onset and peak effect, and short duration of action. The µ-opioid activity of remifentanil is antagonized by opioid antagonists such as naloxone.
- Unlike other opioids, remifentanil is rapidly metabolized by hydrolysis of the propanoic acid-methyl ester linkage by nonspecific blood and tissue esterases. Remifentanil is not a substrate for plasma cholinesterase (pseudocholinesterase) and, therefore, patients with atypical cholinesterase are expected to have a normal duration of action.
## Structure
Remifentanil (remifentanil hydrochloride) for Injection is a µ-opioid agonist chemically designated as a 3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid methyl ester, hydrochloride salt, C20H28N2O5•HCl, with a molecular weight of 412.91. It has the following chemical structure:
- Remifentanil is a sterile, nonpyrogenic, preservative-free, white to off-white lyophilized powder for intravenous (IV) administration after reconstitution and dilution. Each vial contains 1, 2, or 5 mg of remifentanil base; 15 mg glycine; and hydrochloric acid to buffer the solutions to a nominal pH of 3 after reconstitution. When reconstituted as directed, solutions of remifentanil are clear and colorless and contain remifentanil hydrochloride (HCl) equivalent to 1 mg/mL of remifentanil base. The pH of reconstituted solutions of remifentanil ranges from 2.5 to 3.5. Remifentanil HCl has a pKa of 7.07. remifentanil HCl has an n-octanol:water partition coefficient of 17.9 at pH 7.3.
## Pharmacodynamics
- The analgesic effects of remifentanil are rapid in onset and offset. Its effects and side effects are dose dependent and similar to other µ-opioids. Remifentanil in humans has a rapid blood-brain equilibration half-time of 1 ± 1 minutes (mean ± SD) and a rapid onset of action. The pharmacodynamic effects of remifentanil closely follow the measured blood concentrations, allowing direct correlation between dose, blood levels, and response. Blood concentration decreases 50% in 3 to 6 minutes after a 1-minute infusion or after prolonged continuous infusion due to rapid distribution and elimination processes and is independent of duration of drug administration. Recovery from the effects of remifentanil occurs rapidly (within 5 to 10 minutes). New steady-state concentrations occur within 5 to 10 minutes after changes in infusion rate. When used as a component of an anesthetic technique, remifentanil can be rapidly titrated to the desired depth of anesthesia/analgesia (e.g., as required by varying levels of intraoperative stress) by changing the continuous infusion rate or by administering an IV bolus injection.
- In premedicated patients undergoing anesthesia, 1-minute infusions of <2 mcg/kg of remifentanil cause dose-dependent hypotension and bradycardia. While additional doses >2 mcg/kg (up to 30 mcg/kg) do not produce any further decreases in heart rate or blood pressure, the duration of the hemodynamic change is increased in proportion to the blood concentrations achieved. Peak hemodynamic effects occur within 3 to 5 minutes of a single dose of remifentanil or an infusion rate increase. Glycopyrrolate, atropine, and vagolytic neuromuscular blocking agents attenuate the hemodynamic effects associated with remifentanil . When appropriate, bradycardia and hypotension can be reversed by reduction of the rate of infusion of remifentanil , or the dose of concurrent anesthetics, or by the administration of fluids or vasopressors.
- Remifentanil depresses respiration in a dose-related fashion. Unlike other fentanyl analogs, the duration of action of remifentanil at a given dose does not increase with increasing duration of administration, due to lack of drug accumulation. When remifentanil and alfentanil were dosed to equal levels of respiratory depression, recovery of respiratory drive after 3-hour infusions was more rapid and less variable with remifentanil (see Figure 1).
- Spontaneous respiration occurs at blood concentrations of 4 to 5 ng/mL in the absence of other anesthetic agents; for example, after discontinuation of a 0.25-mcg/kg/min infusion of remifentanil, these blood concentrations would be reached in 2 to 4 minutes. In patients undergoing general anesthesia, the rate of respiratory recovery depends upon the concurrent anesthetic; N2O < propofol < isoflurane (see Clinical trials: Recovery).
- Skeletal muscle rigidity can be caused by remifentanil and is related to the dose and speed of administration. remifentanil may cause chest wall rigidity (inability to ventilate) after single doses of >1 mcg/kg administered over 30 to 60 seconds or infusion rates >0.1 mcg/kg/min; peripheral muscle rigidity may occur at lower doses. Administration of doses <1 mcg/kg may cause chest wall rigidity when given concurrently with a continuous infusion of remifentanil . Prior or concurrent administration of a hypnotic (propofol or thiopental) or a neuromuscular blocking agent may attenuate the development of muscle rigidity. Excessive muscle rigidity can be treated by decreasing the rate or discontinuing the infusion of remifentanil or by administering a neuromuscular blocking agent.
- Assays of histamine in patients and normal volunteers have shown no elevation in plasma histamine levels after administration of remifentanil in doses up to 30 mcg/kg over 60 seconds.
- Infusions of 0.05 to 0.1 mcg/kg/min, producing blood concentrations of 1 to 3 ng/mL, are typically associated with analgesia with minimal decrease in respiratory rate. Supplemental doses of 0.5 to 1 mcg/kg, incremental increases in infusion rate >0.05 mcg/kg/min, and blood concentrations exceeding 5 ng/mL (typically produced by infusions of 0.2 mcg/kg/min) have been associated with transient and reversible respiratory depression, apnea, and muscle rigidity.
- Remifentanil is synergistic with the activity of hypnotics (propofol and thiopental), inhaled anesthetics, and benzodiazepines (see Clinical Trials, Precautions, and Dosage And Administration).
- The pharmacodynamic activity of remifentanil (as measured by the EC50 for development of delta waves on the EEG) increases with increasing age. The EC50 of remifentanil for this measure was 50% less in patients over 65 years of age when compared to healthy volunteers (25 years of age) (see Dosage and Administration).
- No differences have been shown in the pharmacodynamic activity (as measured by the EEG) of remifentanil between men and women.
- In animals the duration of muscle paralysis from succinylcholine is not prolonged by remifentanil.
- There was no change in intraocular pressure after the administration of remifentanil prior to ophthalmic surgery under monitored anesthesia care.
- Under isoflurane-nitrous oxide anesthesia (PaCO2 <30 mmHg), a 1-minute infusion of remifentanil (0.5 or 1.0 mcg/kg) produced no change in intracranial pressure. Mean arterial pressure and cerebral perfusion decreased as expected with opioids. In patients receiving remifentanil and nitrous oxide anesthesia, cerebrovascular reactivity to carbon dioxide remained intact. In humans, no epileptiform activity was seen on the EEG (n = 44) at remifentanil doses up to 8 mcg/kg/min.
- The pharmacodynamics of remifentanil (ventilatory response to hypercarbia) are unaltered in patients with end stage renal disease (creatinine clearance <10 mL/min).
- The pharmacodynamics of remifentanil (ventilatory response to hypercarbia) are unaltered in patients with severe hepatic dysfunction awaiting liver transplant.
## Pharmacokinetics
- After IV doses administered over 60 seconds, the pharmacokinetics of remifentanil fit a three-compartment model with a rapid distribution half-life of 1 minute, a slower distribution half-life of 6 minutes, and a terminal elimination half-life of 10 to 20 minutes. Since the terminal elimination component contributes less than 10% of the overall area under the concentration versus time curve (AUC), the effective biological half-life of remifentanil is 3 to 10 minutes. This is similar to the 3- to 10-minute half-life measured after termination of prolonged infusions (up to 4 hours; see Figure 2) and correlates with recovery times observed in the clinical setting after infusions up to 12 hours. Concentrations of remifentanil are proportional to the dose administered throughout the recommended dose range. The pharmacokinetics of remifentanil are unaffected by the presence of renal or hepatic impairment.
- The initial volume of distribution (Vd) of remifentanil is approximately 100 mL/kg and represents distribution throughout the blood and rapidly perfused tissues. remifentanil subsequently distributes into peripheral tissues with a steady-state volume of distribution of approximately 350 mL/kg. These two distribution volumes generally correlate with total body weight (except in severely obese patients when they correlate better with ideal body weight [IBW]). remifentanil is approximately 70% bound to plasma proteins of which two-thirds is binding to alpha-1-acid-glycoprotein.
- Remifentanil is an esterase-metabolized opioid. A labile ester linkage renders this compound susceptible to hydrolysis by nonspecific esterases in blood and tissues. This hydrolysis results in the production of the carboxylic acid metabolite (3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid), and represents the principal metabolic pathway for remifentanil (>95%). The carboxylic acid metabolite is essentially inactive (1/4600 as potent as remifentanil in dogs) and is excreted by the kidneys with an elimination half-life of approximately 90 minutes. remifentanil is not metabolized by plasma cholinesterase (pseudocholinesterase) and is not appreciably metabolized by the liver or lung.
- The clearance of remifentanil in young, healthy adults is approximately 40 mL/min/kg. Clearance generally correlates with total body weight (except in severely obese patients when it correlates better with IBW). The high clearance of remifentanil combined with a relatively small volume of distribution produces a short elimination half-life of approximately 3 to 10 minutes (see Figure 2). This value is consistent with the time taken for blood or effect site concentrations to fall by 50% (context-sensitive half-times) which is approximately 3 to 6 minutes. Unlike other fentanyl analogs, the duration of action does not increase with prolonged administration.
- The rapid elimination of remifentanil permits the titration of infusion rate without concern for prolonged duration. In general, every 0.1-mcg/kg/min change in the IV infusion rate will lead to a corresponding 2.5-ng/mL change in blood remifentanil concentration within 5 to 10 minutes. In intubated patients only, a more rapid increase (within 3 to 5 minutes) to a new steady state can be achieved with a 1.0-mcg/kg bolus dose in conjunction with an infusion rate increase.
- Pediatrics
- In pediatric patients, 5 days to 17 years of age (n = 47), the clearance and volume of distribution of remifentanil were increased in younger children and declined to young healthy adult values by age 17. The average clearance of remifentanil in neonates (less than 2 months of age) was approximately 90.5 ± 36.8 mL/min/kg (mean ± SD) while in adolescents (13 to 16 years) this value was 57.2 ± 21.1 mL/min/kg. The total (steady-state) volume of distribution in neonates was 452 ± 144 mL/kg versus 223 ± 30.6 mL/kg in adolescents. The half-life of remifentanil was the same in neonates and adolescents. Clearance of remifentanil was maintained at or above normal adult values in patients 5 days to 17 years of age.
- Renal Impairment
- The pharmacokinetic profile of remifentanil is not changed in patients with end stage renal disease (creatinine clearance <10 mL/min). In anephric patients, the half-life of the carboxylic acid metabolite increases from 90 minutes to 30 hours. The metabolite is removed by hemodialysis with a dialysis extraction ratio of approximately 30%.
- Hepatic Impairment
- The pharmacokinetics of remifentanil and its carboxylic acid metabolite are unchanged in patients with severe hepatic impairment.
- Elderly
- The clearance of remifentanil is reduced (approximately 25%) in the elderly (>65 years of age) compared to young adults (average 25 years of age). However, remifentanil blood concentrations fall as rapidly after termination of administration in the elderly as in young adults.
- Gender
- There is no significant difference in the pharmacokinetics of remifentanil in male and female patients after correcting for differences in weight.
- Obesity
- There is no difference in the pharmacokinetics of remifentanil in non-obese versus obese (greater than 30% over IBW) patients when normalized to IBW.
- Cardiopulmonary Bypass (CPB)
- Remifentanil clearance is reduced by approximately 20% during hypothermic CPB.
- Drug Interactions
- Remifentanil clearance is not altered by concomitant administration of thiopental, isoflurane, propofol, or temazepam during anesthesia. In vitro studies with atracurium, mivacurium, esmolol, echothiophate, neostigmine, physostigmine, and midazolam revealed no inhibition of remifentanil hydrolysis in whole human blood by these drugs.
## Nonclinical Toxicology
There is limited information regarding Remifentanil Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Remifentanil Clinical Studies in the drug label.
# How Supplied
- ULTIVA should be stored at 2° to 25°C (36° to 77°F). ULTIVA for IV use is supplied as follows:
## Storage
There is limited information regarding Remifentanil Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Remifentanil Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-remifentanil 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 Remifentanil Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Remifentanil Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Remifentanil | |
d808af412225ea56225bcc4d59bc4e7fa220860d | wikidoc | Renal artery | Renal artery
The renal arteries normally arise off the side of the abdominal aorta, immediately below the superior mesenteric artery, and supply the kidneys with blood. Each is directed across the crus of the diaphragm, so as to form nearly a right angle with the aorta.
The renal arteries carry a large portion of total blood flow to the kidneys. Up to a third of total cardiac output can pass through the renal arteries to be filtered by the kidneys.
The arterial supply of the kidneys is variable and there may be one or more renal arteries supplying each kidney. It is located above the renal vein.
# Asymmetries before reaching kidney
Due to the position of the aorta, the inferior vena cava and the kidneys in the body, the right renal artery is normally longer than the left renal artery.
- The right passes behind the inferior vena cava, the right renal vein, the head of the pancreas, and the descending part of the duodenum.
- The left is somewhat higher than the right; it lies behind the left renal vein, the body of the pancreas and the lienal vein, and is crossed by the inferior mesenteric vein.
# At kidney
Before reaching the hilus of the kidney, each artery divides into four or five branches; the greater number of these lie between the renal vein and ureter, the vein being in front, the ureter behind, but one or more branches are usually situated behind the ureter.
Each vessel gives off some small inferior suprarenal branches to the suprarenal gland, the ureter, and the surrounding cellular tissue and muscles.
One or two accessory renal arteries are frequently found, more especially on the left side they usually arise from the aorta, and may come off above or below the main artery, the former being the more common position. Instead of entering the kidney at the hilus, they usually pierce the upper or lower part of the gland.
# Diseases of the renal arteries
Renal artery stenosis, or narrowing of one or both renal arteries will lead to hypertension as the affected kidneys release renin to increase blood pressure to preserve perfusion to the kidneys. RAS is diagnosed with an MRA (magnet-resonance scan) of abdomen. It is treated with the use of balloon angioplasty and stents, if necessary.
Atherosclerosis can also affect the renal arteries and can lead to poor perfusion of the kidneys leading to reduced kidney function and, possibly, renal failure.
# Additional images
- Frontal section through the kidney
- Abdominal portion of the sympathetic trunk, with the celiac and hypogastric plexuses.
- The posterior surfaces of the kidneys, showing areas of relation to the parietes.
- Front of abdomen, showing surface markings for arteries and inguinal canal. | Renal artery
Template:Infobox Artery
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The renal arteries normally arise off the side of the abdominal aorta, immediately below the superior mesenteric artery, and supply the kidneys with blood. Each is directed across the crus of the diaphragm, so as to form nearly a right angle with the aorta.
The renal arteries carry a large portion of total blood flow to the kidneys. Up to a third of total cardiac output can pass through the renal arteries to be filtered by the kidneys.
The arterial supply of the kidneys is variable and there may be one or more renal arteries supplying each kidney. It is located above the renal vein.
# Asymmetries before reaching kidney
Due to the position of the aorta, the inferior vena cava and the kidneys in the body, the right renal artery is normally longer than the left renal artery.
- The right passes behind the inferior vena cava, the right renal vein, the head of the pancreas, and the descending part of the duodenum.
- The left is somewhat higher than the right; it lies behind the left renal vein, the body of the pancreas and the lienal vein, and is crossed by the inferior mesenteric vein.
# At kidney
Before reaching the hilus of the kidney, each artery divides into four or five branches; the greater number of these lie between the renal vein and ureter, the vein being in front, the ureter behind, but one or more branches are usually situated behind the ureter.
Each vessel gives off some small inferior suprarenal branches to the suprarenal gland, the ureter, and the surrounding cellular tissue and muscles.
One or two accessory renal arteries are frequently found, more especially on the left side they usually arise from the aorta, and may come off above or below the main artery, the former being the more common position. Instead of entering the kidney at the hilus, they usually pierce the upper or lower part of the gland.
# Diseases of the renal arteries
Renal artery stenosis, or narrowing of one or both renal arteries will lead to hypertension as the affected kidneys release renin to increase blood pressure to preserve perfusion to the kidneys. RAS is diagnosed with an MRA (magnet-resonance scan) of abdomen. It is treated with the use of balloon angioplasty and stents, if necessary.
Atherosclerosis can also affect the renal arteries and can lead to poor perfusion of the kidneys leading to reduced kidney function and, possibly, renal failure.
# Additional images
- Frontal section through the kidney
- Abdominal portion of the sympathetic trunk, with the celiac and hypogastric plexuses.
- The posterior surfaces of the kidneys, showing areas of relation to the parietes.
- Front of abdomen, showing surface markings for arteries and inguinal canal.
# External links
- Template:MedlinePlusImage
- Template:SUNYAnatomyLabs - "Posterior Abdominal Wall: Branches of the Abdominal Aorta"
Template:Arteries of thorax and abdomen
Template:Kidney
de:Arteria renalis
fi:Munuaisvaltimo
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Renal_arteries | |
afb9c0848ecb77b289bd1f36329577439f70928b | wikidoc | Renal pelvis | Renal pelvis
The renal pelvis is the funnel-like dilated proximal part of the ureter in the kidney.
It is the point of convergence of two or three major calyces. Each renal papilla is surrounded by a branch of the renal pelvis called a calyx.
The major function of the renal pelvis is to act as a funnel for urine flowing to the ureter. | Renal pelvis
Template:Infobox Anatomy
The renal pelvis is the funnel-like dilated proximal part of the ureter in the kidney.
It is the point of convergence of two or three major calyces. Each renal papilla is surrounded by a branch of the renal pelvis called a calyx.
The major function of the renal pelvis is to act as a funnel for urine flowing to the ureter.
# External links
- Template:SUNYAnatomyFigs - "Section of the kidney, anterior view."
- Template:SUNYAnatomyImage
- Template:UCDavisOrganology - "Mammal, renal pelvis (Gross, Medium)"
- Template:UCDavisOrganology - "Mammal, renal pelvis (LM, Medium)"
# Additional images
- Primitive kidney and bladder, from a reconstruction.
- Vertical section of kidney. | https://www.wikidoc.org/index.php/Renal_pelvis | |
9f4643810e531a666c14124d0e8353ad485ad919 | wikidoc | Renovo, plc. | Renovo, plc.
Renovo, plc. (Template:Lse) is a biopharmaceutical company based in Manchester, UK. It is the world leader in scar prevention and reduction research, and it aims "to be first to market with a scar prevention pharmaceutical drug in the US and Europe" in 2009.
The US commercial market for prevention and reduction of scarring in the skin is valued at approximately US$4 billion per annum, and the market is larger in patient volume than Depression, Osteoporosis, Asthma and Diabetes.
# Products
Currently the company doesn't have a marketed product, though its pipeline includes one drug that has recently initiated phase III clinical development, three drugs in phase II clinical development, and 13 other pre-clinical candidates. | Renovo, plc.
Template:Infobox Company
Renovo, plc. (Template:Lse) is a biopharmaceutical company based in Manchester, UK. It is the world leader in scar prevention and reduction research[1], and it aims "to be first to market with a scar prevention pharmaceutical drug in the US and Europe"[2] in 2009.
The US commercial market for prevention and reduction of scarring in the skin is valued at approximately US$4 billion per annum, and the market is larger in patient volume than Depression, Osteoporosis, Asthma and Diabetes[3].
# Products
Currently the company doesn't have a marketed product, though its pipeline includes one drug that has recently initiated phase III clinical development, three drugs in phase II clinical development, and 13 other pre-clinical candidates. | https://www.wikidoc.org/index.php/Renovo,_plc. | |
a33f0ca1ddd3e7dd9d9b5b207f2ace72ebd09436 | wikidoc | Troglitazone | Troglitazone
Troglitazone (Rezulin®, Resulin® or Romozin®) is a member of the drug class of the thiazolidinediones. It was introduced in the late 1990s but turned out to be associated with an idiosyncratic reaction leading to drug-induced hepatitis. It was withdrawn from the USA market on 21 March 2000, and from other markets soon afterwards.
Troglitazone, like the other thiazolidinediones (pioglitazone and rosiglitazone), works by activating PPARs (peroxisome proliferator-activated receptors).
Troglitazone is a ligand to both PPARα and - more strongly - PPARγ. Troglitazone also contains an α-tocopheroyl moiety, potentially giving it vitamin E-like activity in addition to its PPAR activation. It has been shown (Aljada et al) to reduce inflammation: troglitazone use was associated with a decrease of nuclear factor kappa-B (NFκB) and a concomitant increase in its inhibitor (IκB). NFκB is an important cellular transcription regulator for the immune response. | Troglitazone
Troglitazone (Rezulin®, Resulin® or Romozin®) is a member of the drug class of the thiazolidinediones. It was introduced in the late 1990s but turned out to be associated with an idiosyncratic reaction leading to drug-induced hepatitis. It was withdrawn from the USA market on 21 March 2000, and from other markets soon afterwards.
Troglitazone, like the other thiazolidinediones (pioglitazone and rosiglitazone), works by activating PPARs (peroxisome proliferator-activated receptors).
Troglitazone is a ligand to both PPARα and - more strongly - PPARγ. Troglitazone also contains an α-tocopheroyl moiety, potentially giving it vitamin E-like activity in addition to its PPAR activation. It has been shown (Aljada et al) to reduce inflammation: troglitazone use was associated with a decrease of nuclear factor kappa-B (NFκB) and a concomitant increase in its inhibitor (IκB). NFκB is an important cellular transcription regulator for the immune response. | https://www.wikidoc.org/index.php/Resulin | |
5e901425b60724a2a8e8be859d4abd841706d8dd | wikidoc | Reticulocyte | Reticulocyte
# Overview
Reticulocytes are immature red blood cells, typically composing about 1% of the red cells in the human body.
Reticulocytes develop and mature in the red bone marrow and then circulate for about a day in the blood stream before developing into mature red blood cells. Like mature red blood cells, reticulocytes do not have a cell nucleus.
They are called reticulocytes because of a reticular (mesh-like) network of ribosomal RNA that becomes visible under a microscope with certain stains such as new methylene blue.
# Differential Diagnosis of Reticulocytosis
An elevation in the number of reticulocytes is called reticulocytosis. There are numerous causes of reticulocytosis.
## By Organ System
## In Alphabetical Order
- Acquired sideroblastic anemia
- Addison's disease (chronic adrenal insufficiency)
- Adrenocorticoid (Isolated) Deficiency
- AML (AML)
- Androgen insensitivity syndrome
- Anemia of chronic disease
- Anemia of malnutrition
- Anemia of uremia
- Antimetabolite medication Administration/Toxicity
- Aplastic anemia
- Aplastic anemia crisis
- Bacteremia/Septicemia
- Chemotherapy, cancer (anti-neoplastic)
- Chronic alcoholism
- Chronic liver disease
- Chronic renal failure
- Combined system disease/pernicious anemia
- Congenital aplastic anemia
- Congenital folate malabsorption
- Drug induced anemia
- Drug induced Bone marrow suppression.
- Fanconi's pancytopenia-dysmelia syndrome
- Folate depletion
- Folic acid deficiency anemia
- Folic acid dependency/metabolic defect
- Hemoglobin H disease
- Hereditary elliptocytosis
- Hereditary sideroblastic anemia
- Hypogonadism,
- Hypothyroidism (myxedema)
- Impaired folic acid metabolism
- Inadequate Folic acid in diet
- Infected organ, Abscesses
- Iron deficiency anemia
- Iron deficient diet
- Klinefelter's syndrome
- Kwashiorkor (severe protein deficiency)
- Lead poisoning
- Leukemia
- Liver disease/Liver disorders
- Malabsorption of folic acid
- Malnutrition/Starvation
- Megaloblastic anemia
- Megaloblastic anemia of pregnancy
- Methotrexate (Rheumatrex) Administration/Toxicity
- Myeloid metaplasia pathophysiology
- Myelophthisic anemia
- Myeloproliferative disease
- Non-Hodgkins lymphoma/malignant,
- Parvovirus Infection/Parvovirus B19
- Pellagra/niacin deficiency
- Pernicious anemia
- Posthepatitic aplastic anemia
- Postirradiation effects
- Primary Myelofibrosis/Myeloid metaplasia
- Radiation exposure
- Refractory megaloblastic anemia
- Secondary myelofibrosis
- Severe, acute Radiation sickness
- Sideroblastic Anemia Siderochrestic
- Tetraethyl lead poisoning
- Thalassemia major
- Thalassemia minor
- Thalassemia-hemoglobin C disease
- Tuberculosis of bone marrow
- Vitamin B12 deficiency
# Diagnosis
## Laboratory Findings
- Reticulocytes appear slightly bluer than other red cells when looked at with the normal Romanowsky stain.
- Reticulocytes are also slightly larger, which can be picked up as a high MCV (mean corpuscular volume) with a full blood count done by a trained medical scientist, who has specialized in haematology, or a machine.
- The reticulocyte count is the percentage of circulating red blood cells that are in the reticulocyte stage.
- To accurately measure reticulocyte counts, automated counters that use lasers mark cell samples with fluorescent dye that marks RNA and DNA (such as thiazole orange).
- This distinguishes reticulocytes as the middle ground of dye response to laser light, between red blood cells (which have neither RNA nor DNA) and lymphocytes (which have a large amount of DNA, unlike reticulocytes).
- The normal range of values for reticulocytes in the blood depends on the clinical situation and the lab, but broadly speaking is 0.5% to 1.5%.
- However, if a person has anaemia, their reticulocyte percentage should be higher than "normal" if the bone marrow's ability to produce new blood cells remains intact.
- Thus, calculating the reticulocyte production index is an important step in understanding whether the reticulocyte count is appropriate or inappropriate to the situation.
- This is often a more important question than whether the percentage is in the normal range; for instance, if someone is anemic but only has a reticulocyte percentage of 1%, this means that the bone marrow is likely not producing new blood cells at a rate that will correct the anemia.
- The number of reticulocytes is a good indicator of bone marrow activity, because it represents recent production.
- This means that the reticulocyte count, and the reticulocyte production index that can be calculated from it, can be used to determine whether a production problem is contributing to the anaemia, and can also be used to monitor the progress of treatment for anaemia.
- The specimen requirement for a reticulocyte count is EDTA anti-coagulated whole blood (lavender-top bottle if using the Vacutainer®, Vacuette® or Monoject® systems; red-top if using the S-Monovette® system).
- When there is an increased production of red blood cells to overcome chronic or severe loss of mature red blood cells, such as in a haemolytic anaemia, people often have a markedly high number and percentage of reticulocytes.
- A very high number of reticulocytes in the blood can be described as reticulocytosis.
- Abnormally low numbers of reticulocytes can be attributed to chemotherapy, aplastic anaemia, pernicious anaemia, bone marrow malignancies, problems of erythropoietin production, or other causes of anaemia due to poor RBC production.
- Reticulocyte (Courtesy of Melih Aktan M.D.)
- Reticulocyte (Courtesy of Melih Aktan M.D.)
- Reticulocyte
- Erythrocyte
# Related Chapters
- Reticulocyte index | Reticulocyte
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Varun Kumar, M.B.B.S. [2]
# Overview
Reticulocytes are immature red blood cells, typically composing about 1% of the red cells in the human body.
Reticulocytes develop and mature in the red bone marrow and then circulate for about a day in the blood stream before developing into mature red blood cells. Like mature red blood cells, reticulocytes do not have a cell nucleus.
They are called reticulocytes because of a reticular (mesh-like) network of ribosomal RNA that becomes visible under a microscope with certain stains such as new methylene blue.
# Differential Diagnosis of Reticulocytosis
An elevation in the number of reticulocytes is called reticulocytosis. There are numerous causes of reticulocytosis.
## By Organ System
## In Alphabetical Order
- Acquired sideroblastic anemia
- Addison's disease (chronic adrenal insufficiency)
- Adrenocorticoid (Isolated) Deficiency
- AML (AML)
- Androgen insensitivity syndrome
- Anemia of chronic disease
- Anemia of malnutrition
- Anemia of uremia
- Antimetabolite medication Administration/Toxicity
- Aplastic anemia
- Aplastic anemia crisis
- Bacteremia/Septicemia
- Chemotherapy, cancer (anti-neoplastic)
- Chronic alcoholism
- Chronic liver disease
- Chronic renal failure
- Combined system disease/pernicious anemia
- Congenital aplastic anemia
- Congenital folate malabsorption
- Drug induced anemia
- Drug induced Bone marrow suppression.
- Fanconi's pancytopenia-dysmelia syndrome
- Folate depletion
- Folic acid deficiency anemia
- Folic acid dependency/metabolic defect
- Hemoglobin H disease
- Hereditary elliptocytosis
- Hereditary sideroblastic anemia
- Hypogonadism,
- Hypothyroidism (myxedema)
- Impaired folic acid metabolism
- Inadequate Folic acid in diet
- Infected organ, Abscesses
- Iron deficiency anemia
- Iron deficient diet
- Klinefelter's syndrome
- Kwashiorkor (severe protein deficiency)
- Lead poisoning
- Leukemia
- Liver disease/Liver disorders
- Malabsorption of folic acid
- Malnutrition/Starvation
- Megaloblastic anemia
- Megaloblastic anemia of pregnancy
- Methotrexate (Rheumatrex) Administration/Toxicity
- Myeloid metaplasia pathophysiology
- Myelophthisic anemia
- Myeloproliferative disease
- Non-Hodgkins lymphoma/malignant,
- Parvovirus Infection/Parvovirus B19
- Pellagra/niacin deficiency
- Pernicious anemia
- Posthepatitic aplastic anemia
- Postirradiation effects
- Primary Myelofibrosis/Myeloid metaplasia
- Radiation exposure
- Refractory megaloblastic anemia
- Secondary myelofibrosis
- Severe, acute Radiation sickness
- Sideroblastic Anemia Siderochrestic
- Tetraethyl lead poisoning
- Thalassemia major
- Thalassemia minor
- Thalassemia-hemoglobin C disease
- Tuberculosis of bone marrow
- Vitamin B12 deficiency
# Diagnosis
## Laboratory Findings
- Reticulocytes appear slightly bluer than other red cells when looked at with the normal Romanowsky stain.
- Reticulocytes are also slightly larger, which can be picked up as a high MCV (mean corpuscular volume) with a full blood count done by a trained medical scientist, who has specialized in haematology, or a machine. [1] [2] [3]
- The reticulocyte count is the percentage of circulating red blood cells that are in the reticulocyte stage.
- To accurately measure reticulocyte counts, automated counters that use lasers mark cell samples with fluorescent dye that marks RNA and DNA (such as thiazole orange).[4]
- This distinguishes reticulocytes as the middle ground of dye response to laser light, between red blood cells (which have neither RNA nor DNA) and lymphocytes (which have a large amount of DNA, unlike reticulocytes).[5]
- The normal range of values for reticulocytes in the blood depends on the clinical situation and the lab, but broadly speaking is 0.5% to 1.5%.
- However, if a person has anaemia, their reticulocyte percentage should be higher than "normal" if the bone marrow's ability to produce new blood cells remains intact.
- Thus, calculating the reticulocyte production index is an important step in understanding whether the reticulocyte count is appropriate or inappropriate to the situation.
- This is often a more important question than whether the percentage is in the normal range; for instance, if someone is anemic but only has a reticulocyte percentage of 1%, this means that the bone marrow is likely not producing new blood cells at a rate that will correct the anemia.
- The number of reticulocytes is a good indicator of bone marrow activity, because it represents recent production.
- This means that the reticulocyte count, and the reticulocyte production index that can be calculated from it, can be used to determine whether a production problem is contributing to the anaemia, and can also be used to monitor the progress of treatment for anaemia.
- The specimen requirement for a reticulocyte count is EDTA anti-coagulated whole blood (lavender-top bottle if using the Vacutainer®, Vacuette® or Monoject® systems; red-top if using the S-Monovette® system).
- When there is an increased production of red blood cells to overcome chronic or severe loss of mature red blood cells, such as in a haemolytic anaemia, people often have a markedly high number and percentage of reticulocytes.
- A very high number of reticulocytes in the blood can be described as reticulocytosis.
- Abnormally low numbers of reticulocytes can be attributed to chemotherapy, aplastic anaemia, pernicious anaemia, bone marrow malignancies, problems of erythropoietin production, or other causes of anaemia due to poor RBC production.
- Reticulocyte (Courtesy of Melih Aktan M.D.)
- Reticulocyte (Courtesy of Melih Aktan M.D.)
- Reticulocyte
- Erythrocyte
# Related Chapters
- Reticulocyte index | https://www.wikidoc.org/index.php/Reticulocyte | |
e5aa8d4a55924e635dde84464b41c16de1b3798b | wikidoc | Rheumatology | Rheumatology
# Overview
Rheumatology, a subspecialty of internal medicine and pediatrics is devoted to the diagnosis and therapy of rheumatic diseases. The term originates from the Greek rheuma, meaning "that which flows as a river or stream" and the suffix -ology, meaning "the study of". Rheumatologists mainly deal with problems involving the joints and the allied conditions of connective tissue.
Rheumatology is a rapidly evolving specialty; new scientific discoveries related to this specialty are largely related to better understanding of immunology of these disorders. Pathogenesis of major rheumatological disorders is now described as auto immune disorders. Immunology explains pathogenesis and the characteristics of rheumatological disorders, and the new treatment modalities are also based on immunology, better understanding of genetic basis of rheumatological disorders makes rheumatology a specialty rapidly developing as a specialty based on new scientific discoveries. New treatment modalities are based on scientific research on immunology, cytokines, T lymphocytes, B lymphocytes and the future therapies may be directed more towards gene therapy as well. Currently, practice of rheumatology is largely based on clinical research, evidence based medical treatment of rheumatological disorders has helped patients with rheumatism lead a near normal life without any disabilities. Those clinicians specialized on this specialty are called rheumatologists.
# Rheumatism
Rheumatism is a non-specific term used to describe any painful disorder affecting the loco-motor system including joints, muscles, connective tissues, soft tissues around the joints and bones. The term rheumatism is also used to describe rheumatic fever affecting heart valves. However, the medical profession use specific terms to describe rheumatological disorders such as rheumatoid arthritis, ankylosing spondylitis, gout and systemic lupus erythematosus and so on in the medical literature.
Rheumatology is now emerging as an important clinical specialty all over the world, along with well organized post graduate training programs organized for the postgraduate trainees in this field. The term describing clinicians as "rheumatologists" is now a well established term in the medical community, even though it is not well described in language dictionaries. Rheumatologists all over the world are now capable of treating most of the chronic rheumatological disorders with a much better outcome for the patients that is with the discovery of new disease modifying agents called biologics which is now a well established form of treatment for the patients suffering with chronic and disabling joint disorders. Large proportion of patients with rheumatoid arthritis, up to seventy percent according to some studies can now be cured with the introduction and wide spread use of biologic treatment for the treatment of arthritic disorders since the beginning of twenty first century.
# Rheumatologist
Rheumatologist. (Consultant Rheumatologist.)
Rheumatologist is a clinician specialized in the field of medical subspecialty called rheumatology and hold either a Doctor of Osteopathy degree (D.O.) or Doctor of Medicine Degree (M.D.). Training in this field requires four years undergraduate school, 4 years of medical school, and then postgraduate training. Rheumatologists are internists, physicians or pediatricians who are qualified by additional postgraduate training and experience in the diagnosis and treatment of arthritis and other diseases of the joints, muscles and bones. Many rheumatologists also conduct research to determine the cause and better treatments for these disabling and sometimes fatal diseases. Treatment modalities are also based on scientific research, currently, practice of rheumatology is largely evidence based. Those clinicians specialized on this specialty are called rheumatologists.
Rheumatologists treat arthritis, certain autoimmune diseases, musculoskeletal pain disorders and osteoporosis. There are more than 200 types of these diseases, including rheumatoid arthritis, osteoarthritis, gout, lupus, back pain, osteoporosis, fibromyalgia and tendinitis. Some of these are very serious diseases that can be difficult to diagnose and treat. They treat soft tissue problems related to musculoskeletal system sports related soft tissue disorders and the specialty is also interrelated with physiotherapy, physical medicine and rehabilitation of disabled patients. Patient education programmes and occupational therapy is also goes hand in hand with this specialty.
There are many international organizations representing Rheumatologists all over the world. American College of Rheumatology( ACR), the European League Against Rheumatism (EULAR), Asia Pacific League of Associations for Rheumatology(APLAR), International League of Associations for Rheumatology (ILAR) are the main international organizations established and organizing many activities related to this specialty, these organizations strive to propagate and consolidate Rheumatology endeavors internationally , furthermore, there are Associations and Colleges of Rheumatology representing Rheumatologists from each and every nation scattered throughout the world which represent the above mentioned organizations from each nation. Rheumatologists are physicians specialized in rheumatic diseases.
For example, there are approximately 480 consultant rheumatologists in the UK. Rheumatologists are increasing in numbers in all countries, as there is an increasing demand for specialists on this field with an increasing population of ageing patients who need specialized treatment.
# Diseases
Diseases diagnosed or managed by the rheumatologist include:
- Rheumatoid arthritis
- lupus erythematosus
- Sjögren's syndrome
- scleroderma (systemic sclerosis)
- dermatomyositis
- polychondritis
- polymyositis
- polymyalgia rheumatica
- osteoarthritis
- septic arthritis
- fibromyalgia
- sarcoidosis
- gout, pseudogout
- spondyloarthropathies
ankylosing spondylitis
reactive arthritis
psoriatic arthropathy
enteropathic spondylitis
reactive arthropathy
- ankylosing spondylitis
- reactive arthritis
- psoriatic arthropathy
- enteropathic spondylitis
- reactive arthropathy
- vasculitis
polyarteritis nodosa
Henoch-Schönlein purpura
serum sickness
Wegener's granulomatosis
giant cell arteritis
temporal arteritis
Takayasu's arteritis
Behçet's syndrome
Kawasaki's disease (mucocutaneous lymph node syndrome)
Buerger's disease (thromboangiitis obliterans)
- polyarteritis nodosa
- Henoch-Schönlein purpura
- serum sickness
- Wegener's granulomatosis
- giant cell arteritis
- temporal arteritis
- Takayasu's arteritis
- Behçet's syndrome
- Kawasaki's disease (mucocutaneous lymph node syndrome)
- Buerger's disease (thromboangiitis obliterans)
- Juvenile Idiopathic Arthritis (JIA)
# Diagnosis
Apart from an extensive medical history, there are useful methods of diagnosis both performed easy enough in a physical examination and, on the other hand, more complicated ones, often requiring a rheumatologist or other specialised physicians.
## Physical examination
Following are examples of methods of diagnosis able to be performed in a normal physical examination.
- Schober's test tests the flexion of the lower back.
## Specialised
- Laboratory tests (e.g. erythrocyte sedimentation rate, rheumatoid factor)
- X-rays of affected joints and other imaging methods
- Cytology and chemical pathology of fluid aspirated from affected joints (e.g. to differentiate between septic arthritis and gout)
# Treatment
Most rheumatic diseases are treated with analgesics, NSAIDs (Non-Steroid Anti-Inflammatory Drugs), steroids (in serious cases), DMARDs (Disease-Modifying Anti-Rheumatic Drugs), monoclonal antibodies, such as infliximab and adalimumab, and the soluble TNF receptor etanercept.
Physiotherapy is vital in the treatment of many rheumatological disorders. Occupational therapy can help patients finding alternative ways for common movements which would otherwise be restricted by their disease.
# Scientific research
Recently, a large body of scientific research deals with the background of autoimmune disease, the cause of many rheumatic disorders. Also, the field of osteoimmunology has emerged to further examine the interactions between the immune system, joints and bones. Epidemiological studies and medication trials are also being conducted. | Rheumatology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ayesha A. Khan, MD[2]
# Overview
Rheumatology, a subspecialty of internal medicine and pediatrics is devoted to the diagnosis and therapy of rheumatic diseases. The term originates from the Greek rheuma, meaning "that which flows as a river or stream" and the suffix -ology, meaning "the study of". Rheumatologists mainly deal with problems involving the joints and the allied conditions of connective tissue.
Rheumatology is a rapidly evolving specialty; new scientific discoveries related to this specialty are largely related to better understanding of immunology of these disorders. Pathogenesis of major rheumatological disorders is now described as auto immune disorders. Immunology explains pathogenesis and the characteristics of rheumatological disorders, and the new treatment modalities are also based on immunology, better understanding of genetic basis of rheumatological disorders makes rheumatology a specialty rapidly developing as a specialty based on new scientific discoveries. New treatment modalities are based on scientific research on immunology, cytokines, T lymphocytes, B lymphocytes and the future therapies may be directed more towards gene therapy as well. Currently, practice of rheumatology is largely based on clinical research, evidence based medical treatment of rheumatological disorders has helped patients with rheumatism lead a near normal life without any disabilities. Those clinicians specialized on this specialty are called rheumatologists.
# Rheumatism
Rheumatism is a non-specific term used to describe any painful disorder affecting the loco-motor system including joints, muscles, connective tissues, soft tissues around the joints and bones. The term rheumatism is also used to describe rheumatic fever affecting heart valves. However, the medical profession use specific terms to describe rheumatological disorders such as rheumatoid arthritis, ankylosing spondylitis, gout and systemic lupus erythematosus and so on in the medical literature.
Rheumatology is now emerging as an important clinical specialty all over the world, along with well organized post graduate training programs organized for the postgraduate trainees in this field. The term describing clinicians as "rheumatologists" is now a well established term in the medical community, even though it is not well described in language dictionaries. Rheumatologists all over the world are now capable of treating most of the chronic rheumatological disorders with a much better outcome for the patients that is with the discovery of new disease modifying agents called biologics which is now a well established form of treatment for the patients suffering with chronic and disabling joint disorders. Large proportion of patients with rheumatoid arthritis, up to seventy percent according to some studies can now be cured with the introduction and wide spread use of biologic treatment for the treatment of arthritic disorders since the beginning of twenty first century.
# Rheumatologist
Rheumatologist. (Consultant Rheumatologist.)
Rheumatologist is a clinician specialized in the field of medical subspecialty called rheumatology and hold either a Doctor of Osteopathy degree (D.O.) or Doctor of Medicine Degree (M.D.). Training in this field requires four years undergraduate school, 4 years of medical school, and then postgraduate training. Rheumatologists are internists, physicians or pediatricians who are qualified by additional postgraduate training and experience in the diagnosis and treatment of arthritis and other diseases of the joints, muscles and bones. Many rheumatologists also conduct research to determine the cause and better treatments for these disabling and sometimes fatal diseases. Treatment modalities are also based on scientific research, currently, practice of rheumatology is largely evidence based. Those clinicians specialized on this specialty are called rheumatologists.
Rheumatologists treat arthritis, certain autoimmune diseases, musculoskeletal pain disorders and osteoporosis. There are more than 200 types of these diseases, including rheumatoid arthritis, osteoarthritis, gout, lupus, back pain, osteoporosis, fibromyalgia and tendinitis. Some of these are very serious diseases that can be difficult to diagnose and treat. They treat soft tissue problems related to musculoskeletal system sports related soft tissue disorders and the specialty is also interrelated with physiotherapy, physical medicine and rehabilitation of disabled patients. Patient education programmes and occupational therapy is also goes hand in hand with this specialty.
There are many international organizations representing Rheumatologists all over the world. American College of Rheumatology( ACR), the European League Against Rheumatism (EULAR), Asia Pacific League of Associations for Rheumatology(APLAR), International League of Associations for Rheumatology (ILAR) are the main international organizations established and organizing many activities related to this specialty, these organizations strive to propagate and consolidate Rheumatology endeavors internationally , furthermore, there are Associations and Colleges of Rheumatology representing Rheumatologists from each and every nation scattered throughout the world which represent the above mentioned organizations from each nation. Rheumatologists are physicians specialized in rheumatic diseases.
For example, there are approximately 480 consultant rheumatologists in the UK. Rheumatologists are increasing in numbers in all countries, as there is an increasing demand for specialists on this field with an increasing population of ageing patients who need specialized treatment.
# Diseases
Diseases diagnosed or managed by the rheumatologist include:
- Rheumatoid arthritis
- lupus erythematosus
- Sjögren's syndrome
- scleroderma (systemic sclerosis)
- dermatomyositis
- polychondritis
- polymyositis
- polymyalgia rheumatica
- osteoarthritis
- septic arthritis
- fibromyalgia
- sarcoidosis
- gout, pseudogout
- spondyloarthropathies
ankylosing spondylitis
reactive arthritis
psoriatic arthropathy
enteropathic spondylitis
reactive arthropathy
- ankylosing spondylitis
- reactive arthritis
- psoriatic arthropathy
- enteropathic spondylitis
- reactive arthropathy
- vasculitis
polyarteritis nodosa
Henoch-Schönlein purpura
serum sickness
Wegener's granulomatosis
giant cell arteritis
temporal arteritis
Takayasu's arteritis
Behçet's syndrome
Kawasaki's disease (mucocutaneous lymph node syndrome)
Buerger's disease (thromboangiitis obliterans)
- polyarteritis nodosa
- Henoch-Schönlein purpura
- serum sickness
- Wegener's granulomatosis
- giant cell arteritis
- temporal arteritis
- Takayasu's arteritis
- Behçet's syndrome
- Kawasaki's disease (mucocutaneous lymph node syndrome)
- Buerger's disease (thromboangiitis obliterans)
- Juvenile Idiopathic Arthritis (JIA)
# Diagnosis
Apart from an extensive medical history, there are useful methods of diagnosis both performed easy enough in a physical examination and, on the other hand, more complicated ones, often requiring a rheumatologist or other specialised physicians.
## Physical examination
Following are examples of methods of diagnosis able to be performed in a normal physical examination.
- Schober's test tests the flexion of the lower back.
## Specialised
- Laboratory tests (e.g. erythrocyte sedimentation rate, rheumatoid factor)
- X-rays of affected joints and other imaging methods
- Cytology and chemical pathology of fluid aspirated from affected joints (e.g. to differentiate between septic arthritis and gout)
# Treatment
Most rheumatic diseases are treated with analgesics, NSAIDs (Non-Steroid Anti-Inflammatory Drugs), steroids (in serious cases), DMARDs (Disease-Modifying Anti-Rheumatic Drugs), monoclonal antibodies, such as infliximab and adalimumab, and the soluble TNF receptor etanercept.
Physiotherapy is vital in the treatment of many rheumatological disorders. Occupational therapy can help patients finding alternative ways for common movements which would otherwise be restricted by their disease.
# Scientific research
Recently, a large body of scientific research deals with the background of autoimmune disease, the cause of many rheumatic disorders. Also, the field of osteoimmunology has emerged to further examine the interactions between the immune system, joints and bones. Epidemiological studies and medication trials are also being conducted.
# External links
- IFR: Institut Ferran de Reumatologia.
- APLAR
de:Rheumatologie
et:Reumatoloogia
eu:Erreumatologia
io:Reumatologio
id:Rematologi
it:Reumatologia
he:ראומטולוגיה
no:Revmatologi
sv:Reumatologi
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Rheumatic | |
86d4efae00818a777a350d4bb69df9daf65fa2ea | wikidoc | Right-handed | Right-handed
One who is right-handed is more dexterous with one's right hand than with one's left hand: one will probably write with their right hand, and probably also use this hand for tasks such as personal care, cooking, and so on. According to different studies, 85% to 90% of the population is right-handed, while most of the remaining are left-handed. A small percentage of the population can use both hands equally well; a person with this ability is deemed to be ambidextrous.
# Why is the population right-hand dominant?
There is no prevailing theory that explains why right-handedness is so much more prevalent than left-handedness.. Neurologically, the motor skills of the right side of the body are controlled by the left hemisphere of the brain, so researchers believe the explanation may ultimately be found in the differences between the two halves of the brain. For example, a recent study found that right-handers use the right side of the brain to focus on an entire image, but the left side of the brain to focus on details within an image.. This observed difference, like many others, shows the effects of right-handedness but does not clearly indicate its cause.
# Left/right-footedness and ocular dominance
Being right-handed does not always mean that the favoured foot is also on the right side. When playing football for instance, many people prefer using their left foot rather than the right, despite being right-handed.
People typically also have a dominant eye, a preference known as ocular dominance. There is only a weak correlation between being right handed and left eyed.
# Theories explaining right-hand dominance
- Warrior and his shield theory: This theory attempts to explain right-handedness by the position of a warrior's shield and his heart. Basically, since the heart is slightly nearer to the left side of the body, a right-handed warrior (who holds his shield with his left hand to free the right hand for a weapon) would be better able to protect his heart and therefore more likely to survive.
- Brain hemisphere division of labor: The premise of this theory is that since both speaking and handiwork require fine motor skills, having one hemisphere of the brain do both would be more efficient than having it divided up.
# Right-handedness in society
In the past, many schools around the world forced left-handed children to write right-handed. In Hinduism, the right hand must be used for all auspicious and respectful activity, including eating, giving, receiving, and worshipful offering. The left hand is used in times of inauspiciousness, as a sign of disrespect, and for wiping oneself after using the bathroom. In Islam as well, one is required to use the left hand for tasks such as wiping oneself after using the bathroom and the right hand for eating.
A good number of technological devices are made primarily for right-handers; examples of everyday objects primarily designed for right-handers include refrigerators, scissors, microwaves, can-openers, button-down shirts, computer mice, and padded kitchen mittens (padded on one side only). Left-handed golf clubs are more difficult to find than right-handed ones. Many classical-era Japanese swords were (and even modern cooking knives are) favored to cut more efficiently for the right-hander. Musical instruments such as guitars are also set up for right-handers. Military rifles designed to be shot only from the right shoulder have resulted in injuries from spent cartridge casings hitting left-handers in the eye and head. | Right-handed
One who is right-handed is more dexterous with one's right hand than with one's left hand: one will probably write with their right hand, and probably also use this hand for tasks such as personal care, cooking, and so on. According to different studies, 85% to 90%[1] of the population is right-handed, while most of the remaining are left-handed. A small percentage of the population can use both hands equally well; a person with this ability is deemed to be ambidextrous.
# Why is the population right-hand dominant?
There is no prevailing theory that explains why right-handedness is so much more prevalent than left-handedness.[1]. Neurologically, the motor skills of the right side of the body are controlled by the left hemisphere of the brain, so researchers believe the explanation may ultimately be found in the differences between the two halves of the brain. For example, a recent study found that right-handers use the right side of the brain to focus on an entire image, but the left side of the brain to focus on details within an image.[2]. This observed difference, like many others, shows the effects of right-handedness but does not clearly indicate its cause.
# Left/right-footedness and ocular dominance
Being right-handed does not always mean that the favoured foot is also on the right side. When playing football for instance, many people prefer using their left foot rather than the right, despite being right-handed.[3]
People typically also have a dominant eye, a preference known as ocular dominance. There is only a weak correlation between being right handed and left eyed.
[4]
# Theories explaining right-hand dominance
- Warrior and his shield theory: This theory attempts to explain right-handedness by the position of a warrior's shield and his heart. Basically, since the heart is slightly nearer to the left side of the body, a right-handed warrior (who holds his shield with his left hand to free the right hand for a weapon) would be better able to protect his heart and therefore more likely to survive.
- Brain hemisphere division of labor: The premise of this theory is that since both speaking and handiwork require fine motor skills, having one hemisphere of the brain do both would be more efficient than having it divided up.
# Right-handedness in society
In the past, many schools around the world forced left-handed children to write right-handed.[5] In Hinduism, the right hand must be used for all auspicious and respectful activity, including eating, giving, receiving, and worshipful offering. The left hand is used in times of inauspiciousness, as a sign of disrespect, and for wiping oneself after using the bathroom. In Islam as well, one is required to use the left hand for tasks such as wiping oneself after using the bathroom and the right hand for eating.[6]
A good number of technological devices are made primarily for right-handers; examples of everyday objects primarily designed for right-handers include refrigerators, scissors, microwaves, can-openers, button-down shirts, computer mice, and padded kitchen mittens (padded on one side only). Left-handed golf clubs are more difficult to find than right-handed ones. Many classical-era Japanese swords were (and even modern cooking knives are) favored to cut more efficiently for the right-hander. Musical instruments such as guitars are also set up for right-handers. Military rifles designed to be shot only from the right shoulder have resulted in injuries from spent cartridge casings hitting left-handers in the eye and head.[7] | https://www.wikidoc.org/index.php/Right-handed | |
25705d8ab0fe3c9bf2f5ff3eb80518f1d75303d4 | wikidoc | Right atrium | Right atrium
# Overview
The right atrium (in older texts termed the right auricle) is one of four chambers (two atria and two ventricles) in the human heart. It receives de-oxygenated blood from the superior and inferior vena cavae and the coronary sinus, and pumps it into the right ventricle through the tricuspid valve.
The sinoatrial node (SAN) is located within this chamber next to the vena cava. This is a group of pacemaker cells which spontaneously depolarise to create an action potential. The cardiac action potential then spreads across both atria causing them to contract forcing the blood they hold into their corresponding ventricles.
In early life, when a fetus is in the womb, the right atrium has a hole within its septum through to the left atrium, this makes them continuous with each other which is essential for fetal circulation. This junction is called the foramen ovale. Once born (usually within a year's time) the foreman ovale seals over and it is renamed as the fossa ovalis. The fossa ovalis is seen as an embryonic remnant. In some cases, the formane ovale fails to close and is present in 20% of the general population, however it does not cause problems in the vast majority. This is known as patent foramen ovale.
Within the fetal right atrium, blood from the inferior vena cava and the superior vena flow in separate streams to different locations in the heart, and this has been reported to occur through the Coanda effect.
The right atrium also holds the coronary sinus which is the opening of the vein that drains the myocardium itself.
Attached to the right atrium is the right auricular appendix.
# Additional images
- Heart seen from above. | Right atrium
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The right atrium (in older texts termed the right auricle) is one of four chambers (two atria and two ventricles) in the human heart. It receives de-oxygenated blood from the superior and inferior vena cavae and the coronary sinus, and pumps it into the right ventricle through the tricuspid valve.
The sinoatrial node (SAN) is located within this chamber next to the vena cava. This is a group of pacemaker cells which spontaneously depolarise to create an action potential. The cardiac action potential then spreads across both atria causing them to contract forcing the blood they hold into their corresponding ventricles.
In early life, when a fetus is in the womb, the right atrium has a hole within its septum through to the left atrium, this makes them continuous with each other which is essential for fetal circulation. This junction is called the foramen ovale. Once born (usually within a year's time) the foreman ovale seals over and it is renamed as the fossa ovalis. The fossa ovalis is seen as an embryonic remnant. In some cases, the formane ovale fails to close and is present in 20% of the general population, however it does not cause problems in the vast majority. This is known as patent foramen ovale.
Within the fetal right atrium, blood from the inferior vena cava and the superior vena flow in separate streams to different locations in the heart, and this has been reported to occur through the Coanda effect.[1]
The right atrium also holds the coronary sinus which is the opening of the vein that drains the myocardium itself.
Attached to the right atrium is the right auricular appendix.
# Additional images
- Heart seen from above. | https://www.wikidoc.org/index.php/Right_atria | |
6486166e5485b578c3dd5d0ced7ba9023b8f85df | wikidoc | Right to die | Right to die
The term "right to die" refers to various issues around the death of an individual when that person could continue to live with the aid of life support, or in a diminished or enfeebled capacity. In some cases, it refers to the idea that a person with a terminal illness and in serious condition should be allowed to commit suicide before death would otherwise occur. The concept is often referred to as dying with dignity.
In most countries in the Western world, people do not, legally speaking, have the right to die.
Suicide is often frowned upon, and euthanasia is only legal in a handful of countries. In some East Asian countries, suicide may be acceptable in cases such as ritual suicide.
Most often, the idea of the right to die is related to a person's wish that caregivers allow death—for example, by not providing life support or vital medication— under certain conditions when recovery is highly unlikely or impossible. It may also refer to issues regarding physician-assisted suicide. It may be called passive euthanasia in cases where the patient is unable to make decisions about treatment. Living wills and Do Not Resuscitate orders are legal instruments that make a patient's treatment decisions known ahead of time; allowing a patient to die based on such decisions is not considered to be euthanasia. Usually these patients have also made explicit their wish to receive only palliative care to reduce pain and suffering.
Although specialized legal instruments differ from place to place, there are two more that are important in this context. The Five Wishes document allows a person to state in advance the priorities and values they wish to have honored at the end of life. And the Medical Durable Power of Attorney (or MDPOA) designates an agent to make decisions in case of incapacity, and can be used to give written guidance regarding end of life decision making. The MDPOA is generally considered to be the most powerful of all such instruments. All others may require interpretation on the part of health care providers or even court-appointed guardians; the MDPOA takes the job of interpretation out of the hands of strangers and gives it to a person selected and trusted by the individual. | Right to die
The term "right to die" refers to various issues around the death of an individual when that person could continue to live with the aid of life support, or in a diminished or enfeebled capacity. In some cases, it refers to the idea that a person with a terminal illness and in serious condition should be allowed to commit suicide before death would otherwise occur. The concept is often referred to as dying with dignity.
In most countries in the Western world, people do not, legally speaking, have the right to die.
Suicide is often frowned upon, and euthanasia is only legal in a handful of countries. In some East Asian countries, suicide may be acceptable in cases such as ritual suicide.
Most often, the idea of the right to die is related to a person's wish that caregivers allow death—for example, by not providing life support or vital medication— under certain conditions when recovery is highly unlikely or impossible. It may also refer to issues regarding physician-assisted suicide. It may be called passive euthanasia in cases where the patient is unable to make decisions about treatment. Living wills and Do Not Resuscitate orders are legal instruments that make a patient's treatment decisions known ahead of time; allowing a patient to die based on such decisions is not considered to be euthanasia. Usually these patients have also made explicit their wish to receive only palliative care to reduce pain and suffering.
Although specialized legal instruments differ from place to place, there are two more that are important in this context. The Five Wishes document allows a person to state in advance the priorities and values they wish to have honored at the end of life. And the Medical Durable Power of Attorney (or MDPOA) designates an agent to make decisions in case of incapacity, and can be used to give written guidance regarding end of life decision making. The MDPOA is generally considered to be the most powerful of all such instruments. All others may require interpretation on the part of health care providers or even court-appointed guardians; the MDPOA takes the job of interpretation out of the hands of strangers and gives it to a person selected and trusted by the individual. | https://www.wikidoc.org/index.php/Right_to_die | |
24d9f8bad44aec9202b586a949423993fb3d60cb | wikidoc | Rigor mortis | Rigor mortis
Rigor mortis is one of the recognizable signs of death (Latin mors, mortis) that is caused by a chemical change in the muscles after death, causing the limbs of the corpse to become stiff (Latin rigor) and difficult to move or manipulate. Eerily, during rigor mortis, muscles may contract in seemingly random and bizarre ways even though the body is dead.
# Biochemistry
After a muscle contracts, ATP expenditure is required to release the myosin head of a thick filament from its binding site on the thin filament. Since all metabolic processes have come to a halt in a dead body, no ATP is being produced. Therefore, because of a lack of ATP, the myosin head cannot be released from the actin filament, and the sarcomere cannot relax.
Because this happens in muscles all over the body, they become "stiff" and "locked" into place.
To understand the contractions associated with rigor mortis, it's important to know that ATP is required to reuptake calcium into the sarcomere's sarcoplasmic reticulum. Additionally, when a muscle is relaxed, the myosin heads are returned to their "high energy" position, ready and waiting for a binding site on the actin filament to become available. Because there is no ATP available, previously released calcium ions cannot be reuptaken into the SR. These leftover calcium ions move around inside the sarcomere and may eventually find their way to a binding site on the thin filament's regulatory protein. Since the myosin head is already ready to bind, no addition ATP expenditure is required and the sarcomere contracts. When this process occurs on a larger scale, the disturbing twitches and gruesome postures associated with rigor mortis can occur.
After about 72 hours, the body relaxes again, this time as a result of decomposition. This is known as resolution of rigor.
# Rigor mortis and the meat industry
Rigor mortis is very important in meat technology. The onset of rigor mortis and its resolution partially determines the tenderness of meat. If the post-slaughter meat is immediately chilled to 15 °C, a phenomenon known as cold shortening occurs, where the muscle shrinks to a third of its original size. This will lead to the loss of water from the meat along with many of the vitamins, minerals, and water soluble proteins. The loss of water makes the meat hard and interferes with the manufacturing of several meat products like cutlet and sausage.
Cold shortening is caused by the release of stored calcium ions from the sarcoplasmic reticulum of muscle fibers in response to the cold stimulus. The calcium ions trigger powerful muscle contraction aided by ATP molecules. To prevent cold shortening, a process known as electrical stimulation is carried out, especially in beef carcass, immediately after slaughter and skinning. In this process, the carcass is stimulated with alternating current, causing it to contract and relax, which depletes the ATP reserve from the carcass and prevents cold shortening. | Rigor mortis
Template:Signs of death
Template:Otheruses1
Rigor mortis is one of the recognizable signs of death (Latin mors, mortis) that is caused by a chemical change in the muscles after death, causing the limbs of the corpse to become stiff (Latin rigor) and difficult to move or manipulate[1]. Eerily, during rigor mortis, muscles may contract in seemingly random and bizarre ways even though the body is dead.
## Biochemistry
After a muscle contracts, ATP expenditure is required to release the myosin head of a thick filament from its binding site on the thin filament[1]. Since all metabolic processes have come to a halt in a dead body, no ATP is being produced. Therefore, because of a lack of ATP, the myosin head cannot be released from the actin filament, and the sarcomere cannot relax.
Because this happens in muscles all over the body, they become "stiff" and "locked" into place.
To understand the contractions associated with rigor mortis, it's important to know that ATP is required to reuptake calcium into the sarcomere's sarcoplasmic reticulum. Additionally, when a muscle is relaxed, the myosin heads are returned to their "high energy" position, ready and waiting for a binding site on the actin filament to become available. Because there is no ATP available, previously released calcium ions cannot be reuptaken into the SR. These leftover calcium ions move around inside the sarcomere and may eventually find their way to a binding site on the thin filament's regulatory protein. Since the myosin head is already ready to bind, no addition ATP expenditure is required and the sarcomere contracts. When this process occurs on a larger scale, the disturbing twitches and gruesome postures associated with rigor mortis can occur.
After about 72 hours, the body relaxes again, this time as a result of decomposition. This is known as resolution of rigor.
## Rigor mortis and the meat industry
Rigor mortis is very important in meat technology. The onset of rigor mortis and its resolution partially determines the tenderness of meat. If the post-slaughter meat is immediately chilled to 15 °C, a phenomenon known as cold shortening occurs, where the muscle shrinks to a third of its original size. This will lead to the loss of water from the meat along with many of the vitamins, minerals, and water soluble proteins. The loss of water makes the meat hard and interferes with the manufacturing of several meat products like cutlet and sausage.
Cold shortening is caused by the release of stored calcium ions from the sarcoplasmic reticulum of muscle fibers in response to the cold stimulus. The calcium ions trigger powerful muscle contraction aided by ATP molecules. To prevent cold shortening, a process known as electrical stimulation is carried out, especially in beef carcass, immediately after slaughter and skinning. In this process, the carcass is stimulated with alternating current, causing it to contract and relax, which depletes the ATP reserve from the carcass and prevents cold shortening. | https://www.wikidoc.org/index.php/Rigor_mortis | |
e453226eee825b9cb07a7641b109d229dd1c49d6 | wikidoc | Risankizumab | Risankizumab
# Disclaimer
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# Overview
Risankizumab is an interleukin-23 antagonist that is FDA approved for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. Common adverse reactions include upper respiratory infections, headache, fatigue, injection site reactions, and tinea infections.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Indication
- Risankizumab is indicated for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.
Dosage
- 150 mg (two 75 mg injections) administered by subcutaneous injection at Week 0, Week 4 and every 12 weeks thereafter.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding risankizumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding risankizumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and efficacy of risankizumab in pediatric patients less than 18 years of age have not yet been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding risankizumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding risankizumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
None.
# Warnings
- Risankizumab may increase the risk of infections. In clinical studies, infections occurred in 22.1% of the risankizumab group compared to 14.7% of the placebo group through 16 weeks of treatment. Upper respiratory tract infections and tinea infections occurred more frequently in the risankizumab group than in the placebo group. Subjects with known chronic or acute infections were not enrolled in clinical studies.
- The rate of serious infections for the risankizumab group and the placebo group was ≤ 0.4%. Treatment with risankizumab should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated.
- In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing risankizumab. Instruct patients to seek medical advice if signs or symptoms of clinically important infection occur. If a patient develops such an infection or is not responding to standard therapy, monitor the patient closely and do not administer risankizumab until the infection resolves.
- Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with risankizumab. Across the Phase 3 psoriasis clinical studies, of the 72 subjects with latent TB who were concurrently treated with risankizumab and appropriate TB prophylaxis during the studies, none developed active TB during the mean follow-up of 61 weeks on risankizumab. Two subjects taking isoniazid for treatment of latent TB discontinued treatment due to liver injury. Of the 31 subjects from the IMMHANCE study with latent TB who did not receive prophylaxis during the study, none developed active TB during the mean follow-up of 55 weeks on risankizumab. Consider anti-TB therapy prior to initiating risankizumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Monitor patients for signs and symptoms of active TB during and after risankizumab treatment. Do not administer risankizumab to patients with active TB.
- Prior to initiating therapy with risankizumab, consider completion of all age appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with risankizumab. No data are available on the response to live or inactive vaccines.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse drug 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 2234 subjects were treated with risankizumab in clinical development studies in plaque psoriasis. Of these, 1208 subjects with psoriasis were exposed to risankizumab for at least one year.
- Data from placebo- and active-controlled studies were pooled to evaluate the safety of risankizumab for up to 16 weeks. In total, 1306 subjects were evaluated in the risankizumab 150 mg group.
- Table 1 summarizes the adverse drug reactions that occurred at a rate of at least 1% and at a higher rate in the risankizumab group than the placebo group during the 16-week controlled period of pooled clinical studies.
- Adverse drug reactions that occurred in 0.1% of subjects in the risankizumab group and at a higher rate than in the placebo group through Week 16 were folliculitis and urticaria.
Specific Adverse Drug Reactions
Infections
- In the first 16 weeks, infections occurred in 22.1% of the risankizumab group (90.8 events per 100 subject-years) compared to 14.7% of the placebo group (56.5 events per 100 subject-years) and did not lead to discontinuation of risankizumab. The rates of serious infections for the risankizumab group and the placebo group were ≤0.4%. Serious infections in the risankizumab group included cellulitis, osteomyelitis, sepsis and herpes zoster. In ULTIMMA-1 and ULTIMMA-2, through Week 52, the rate of infections (73.9 events per 100 subject-years) was similar to the rate observed during the first 16 weeks of treatment.
Safety through Week 52
- Through Week 52, no new adverse reactions were identified and the rates of the adverse reactions were similar to those observed during the first 16 weeks of treatment. During this period, serious infections that led to study discontinuation included pneumonia.
- 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 in the studies described below with the incidence of antibodies in other studies or to other products, including other risankizumab products, may be misleading.
- By Week 52, approximately 24% (263/1079) of subjects treated with risankizumab at the recommended dose developed antibodies to risankizumab-rzaa. Of the subjects who developed antibodies to risankizumab-rzaa, approximately 57% (14% of all subjects treated with risankizumab) had antibodies that were classified as neutralizing. Higher antibody titers in approximately 1% of subjects treated with risankizumab were associated with lower risankizumab-rzaa concentrations and reduced clinical response.
## Postmarketing Experience
There is limited information regarding Risankizumab Postmarketing Experience in the drug label.
# Drug Interactions
- Avoid use of live vaccines in patients treated with risankizumab.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- Limited available data with risankizumab use in pregnant women are insufficient to evaluate a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcome. Human IgG is known to cross the placental barrier; therefore, risankizumab may be transmitted from the mother to the developing fetus.
- In an enhanced pre- and post-natal developmental toxicity study, pregnant cynomolgus monkeys were administered subcutaneous doses of 5 and 50 mg/kg risankizumab-rzaa once weekly during the period of organogenesis up to parturition. At the 50 mg/kg dose , increased fetal/infant loss was noted in pregnant monkeys (see Data). No risankizumab-rzaa-related effects on functional or immunological development were observed in infant monkeys from birth through 6 months of age. The clinical significance of these findings for humans is unknown.
- All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Animal Data
- An enhanced pre- and post-natal developmental toxicity study was conducted in cynomolgus monkeys. Pregnant cynomolgus monkeys were administered weekly subcutaneous doses of risankizumab-rzaa of 5 or 50 mg/kg from gestation day 20 to parturition and the cynomolgus monkeys (mother and infants) were monitored for 6 months after delivery. No maternal toxicity was noted in this study. There were no treatment-related effects on growth and development, malformations, developmental immunotoxicology or neurobehavioral development. However, a dose-dependent increase in fetal/infant loss was noted in the risankizumab-rzaa-treated groups (32% and 43% in the 5 mg/kg and 50 mg/kg groups, respectively) compared to the vehicle control group (19%). The increased fetal/infant loss in the 50 mg/kg group was considered to be related to risankizumab-rzaa treatment. The no observed adverse effect level (NOAEL) for maternal toxicity was identified as 50 mg/kg (20 times the MRHD, based on mg/kg comparison) and the NOAEL for developmental toxicity was identified as 5 mg/kg (2 times the MRHD, based on mg/kg comparison). In the infants, mean serum concentrations increased in a dose-dependent manner and were approximately 17-86% of the respective maternal concentrations. Following delivery, most adult female cynomolgus monkeys and all infants from the risankizumab-rzaa‑treated groups had measurable serum concentrations of risankizumab-rzaa up to 91 days postpartum. Serum concentrations were below detectable levels at 180 days postpartum.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Risankizumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Risankizumab during labor and delivery.
### Nursing Mothers
- There are no data on the presence of risankizumab-rzaa in human milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for risankizumab and any potential adverse effects on the breastfed infant from risankizumab or from the underlying maternal condition.
### Pediatric Use
- The safety and efficacy of risankizumab in pediatric patients less than 18 years of age have not yet been established.
### Geriatic Use
- Of the 2234 subjects with plaque psoriasis exposed to risankizumab, 243 subjects were 65 years or older and 24 subjects were 75 years or older. No overall differences in risankizumab-rzaa exposure, safety or effectiveness were observed between older and younger subjects who received risankizumab. However, the number of subjects aged 65 years and older was not sufficient to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Risankizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Risankizumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Risankizumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Risankizumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Risankizumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Risankizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- The recommended dose is 150 mg (two 75 mg injections) administered by subcutaneous injection at Week 0, Week 4, and every 12 weeks thereafter.
- Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with risankizumab.
- Administer risankizumab subcutaneously. Inject two separate 75 mg single-dose prefilled syringes for the full 150 mg dose. Discard prefilled syringes after use. Do not reuse.
- For each dose, administer the injections at different anatomic locations (such as thighs or abdomen), and not into areas where the skin is tender, bruised, erythematous, indurated or affected by psoriasis. Administration of risankizumab in the upper, outer arm may only be performed by a healthcare professional or caregiver.
- If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.
- Risankizumab is intended for use under the guidance and supervision of a healthcare professional. Patients may self-inject risankizumab after training in subcutaneous injection technique. Provide proper training to patients and/or caregivers on the subcutaneous injection technique of risankizumab. Instruct the patient that two separate 75 mg single-dose injections are required to achieve the 150 mg dose.
- The risankizumab “Instructions for Use” contains more detailed instructions on the preparation and administration of risankizumab. Instruct the patient to read the Instructions for Use before administration (see Patient Counseling Information).
- Before injecting, patients may remove the carton from the refrigerator and allow to reach room temperature out of direct sunlight (15 to 30 minutes) without removing the prefilled syringes from the carton.
- Visually inspect risankizumab for particulate matter and discoloration prior to administration. Risankizumab is a colorless to slightly yellow and clear to slightly opalescent solution. It may contain a few translucent to white particles. Do not use if the solution contains large particles or is cloudy or discolored.
### Monitoring
There is limited information regarding Risankizumab Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Risankizumab and IV administrations.
# Overdosage
- In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and administer appropriate symptomatic treatment immediately.
# Pharmacology
## Mechanism of Action
- Risankizumab-rzaa is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively binds to the p19 subunit of human interleukin 23 (IL-23) cytokine and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses.
- Risankizumab-rzaa inhibits the release of pro-inflammatory cytokines and chemokines.
## Structure
There is limited information regarding Risankizumab Structure in the drug label.
## Pharmacodynamics
- No formal pharmacodynamics studies have been conducted with risankizumab-rzaa.
## Pharmacokinetics
- Risankizumab-rzaa plasma concentrations increased dose-proportionally from 90 to 180 mg and from 18 to 300 mg (0.6 to 1.2 and 0.12 to 2.0 times the approved recommended dosage) following subcutaneous administration in subjects with plaque psoriasis and healthy volunteers, respectively. Steady-state concentrations were achieved by Week 16 following subcutaneous administration of risankizumab-rzaa at Weeks 0, 4, and every 12 weeks thereafter. At the 150 mg dose, the estimated steady-state peak concentration (Cmax) and trough concentration (Ctrough) were approximately 12 mcg/mL and 2 mcg/mL, respectively.
Absorption
- The absolute bioavailability of risankizumab-rzaa was estimated to be 89% following subcutaneous injection. Cmax was reached by 3-14 days.
Distribution
- The estimated steady-state volume of distribution (inter-subject CV%) was 11.2 L (34%) in subjects with plaque psoriasis.
Elimination
- The estimated systemic clearance (inter-subject CV%) was 0.31 L/day (24%) and terminal elimination half-life was approximately 28 days in subjects with plaque psoriasis.
Metabolism
- The metabolic pathway of risankizumab-rzaa has not been characterized. As a humanized IgG1 monoclonal antibody, risankizumab-rzaa is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.
Specific Populations
- No clinically significant differences in the pharmacokinetics of risankizumab-rzaa were observed based on age (≥18 years). No specific studies have been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of risankizumab-rzaa.
Body Weight
- Risankizumab-rzaa clearance and volume of distribution increase and plasma concentrations decrease as body weight increases; however, no dose adjustment is recommended based on body weight.
Drug Interaction Studies
- Cytochrome P450 Substrates: No clinically significant changes in exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), metoprolol (CYP2D6 substrate), or midazolam (CYP3A substrate) were observed when used concomitantly with risankizumab-rzaa 150 mg administered subcutaneously at Weeks 0, 4, 8 and 12 (more frequent than the approved recommended dosing frequency) in subjects with plaque psoriasis.
## Nonclinical Toxicology
- Carcinogenicity and mutagenicity studies have not been conducted with risankizumab.
- No effects on male fertility parameters were observed in sexually mature male cynomolgus monkeys subcutaneously treated with 50 mg/kg risankizumab-rzaa (at 20 times the clinical exposure at the MRHD, based on mg/kg comparison) once weekly for 26 weeks.
# Clinical Studies
- Four multicenter, randomized, double-blind studies enrolled 2109 subjects 18 years of age and older with moderate to severe plaque psoriasis who had a body surface area (BSA) involvement of ≥10%, a static Physician’s Global Assessment (sPGA) score of ≥3 (“moderate”) in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on a severity scale of 0 to 4, and a Psoriasis Area and Severity Index (PASI) score ≥12.
- Overall, subjects had a median baseline PASI score of 17.8 and a median BSA of 20.0%. Baseline sPGA score was 4 (“severe”) in 19% of subjects. A total of 10% of study subjects had a history of diagnosed psoriatic arthritis.
- Across all studies, 38% of subjects had received prior phototherapy, 48% had received prior non-biologic systemic therapy, and 42% had received prior biologic therapy for the treatment of psoriasis.
ULTIMMA-1 and ULTIMMA-2
- In ULTIMMA-1 and ULTIMMA-2, 997 subjects were enrolled (including 598 subjects randomized to the risankizumab 150 mg group, 200 subjects randomized to the placebo group, and 199 to the biologic active control group). Subjects received treatment at Weeks 0, 4, and every 12 weeks thereafter.
- Both studies assessed the responses at Week 16 compared to placebo for the two co-primary endpoints:
the proportion of subjects who achieved an sPGA score of 0 (“clear”) or 1 (“almost clear”)
the proportion of subjects who achieved at least a 90% reduction from baseline PASI (PASI 90)
- the proportion of subjects who achieved an sPGA score of 0 (“clear”) or 1 (“almost clear”)
- the proportion of subjects who achieved at least a 90% reduction from baseline PASI (PASI 90)
- Secondary endpoints included the proportion of subjects who achieved PASI 100, sPGA 0, and PSS 0 at Week 16.
- The results are presented in Table 2.
- Examination of age, gender, race, body weight, baseline PASI score and previous treatment with systemic or biologic agents did not identify differences in response to risankizumab among these subgroups at Week 16.
- In ULTIMMA-1 and ULTIMMA-2 at Week 52, subjects receiving risankizumab achieved sPGA 0 (58% and 60%, respectively), PASI 90 (82% and 81%, respectively), and PASI 100 (56% and 60%, respectively).
Patient Reported Outcomes
- Improvements in signs and symptoms related to pain, redness, itching and burning at Week 16 compared to placebo were observed in both studies as assessed by the Psoriasis Symptom Scale (PSS). In ULTIMMA-1 and ULTIMMA-2, about 30% of the subjects who received risankizumab achieved PSS 0 (“none”) at Week 16 compared to 1% of the subjects who received placebo.
IMMHANCE
- IMMHANCE enrolled 507 subjects (407 randomized to risankizumab 150 mg and 100 to placebo). Subjects received treatment at Weeks 0, 4, and every 12 weeks thereafter.
- At Week 16, risankizumab was superior to placebo on the co-primary endpoints of sPGA 0 or 1 (84% risankizumab and 7% placebo) and PASI 90 (73% risankizumab and 2% placebo). The respective response rates for risankizumab and placebo at Week 16 were: sPGA 0 (46% risankizumab and 1% placebo); PASI 100 (47% risankizumab and 1% placebo); and PASI 75 (89% risankizumab and 8% placebo).
Maintenance and Durability of Response
- In ULTIMMA-1 and ULTIMMA-2, among the subjects who received risankizumab and had PASI 100 at Week 16, 80% (206/258) of the subjects who continued on risankizumab had PASI 100 at Week 52. For PASI 90 responders at Week 16, 88% (398/450) of the subjects had PASI 90 at Week 52.
- In IMMHANCE, subjects who were originally on risankizumab and had sPGA 0 or 1 at Week 28 were re-randomized to continue risankizumab every 12 weeks or withdrawal of therapy. At Week 52, 87% (97/111) of the subjects re-randomized to continue treatment with risankizumab had sPGA 0 or 1 compared to 61% (138/225) who were re-randomized to withdrawal of risankizumab.
# How Supplied
- Risankizumab injection is a sterile, preservative-free, colorless to slightly yellow and clear to slightly opalescent solution. The product is supplied in a 1 mL glass syringe with a fixed 29 gauge ½ inch needle with needle guard.
-ne carton containing two prefilled syringes and two alcohol pad
- one carton containing two prefilled syringes and two alcohol pad
## Storage
- Store in a refrigerator at 2°C to 8°C (36°F to 46° F).
- Do not freeze.
- Do not shake.
- Keep the prefilled syringes in the outer carton to protect from light.
- Not made with natural rubber latex.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) before starting risankizumab therapy and to reread the Medication Guide each time the prescription is renewed. Advise patients of the potential benefits and risks of risankizumab.
Infections
- Inform patients that risankizumab may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to the healthcare provider and contacting their healthcare provider if they develop any symptoms of an infection.
Administration Instruction
- Instruct patients or caregivers to perform the first self-injected dose under the supervision and guidance of a qualified healthcare professional for training in preparation and administration of risankizumab, including choosing anatomical sites for administration, and proper subcutaneous injection technique.
- Instruct patients or caregivers to administer two 75 mg single-dose syringes to achieve the 150 mg dose of risankizumab.
- Instruct patients or caregivers in the technique of needle and syringe disposal.
# Precautions with Alcohol
Alcohol-Risankizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Skyrizi
# Look-Alike Drug Names
There is limited information regarding Risankizumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Risankizumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [2]
# Disclaimer
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# Overview
Risankizumab is an interleukin-23 antagonist that is FDA approved for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. Common adverse reactions include upper respiratory infections, headache, fatigue, injection site reactions, and tinea infections.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Indication
- Risankizumab is indicated for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.
Dosage
- 150 mg (two 75 mg injections) administered by subcutaneous injection at Week 0, Week 4 and every 12 weeks thereafter.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding risankizumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding risankizumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and efficacy of risankizumab in pediatric patients less than 18 years of age have not yet been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding risankizumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding risankizumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
None.
# Warnings
- Risankizumab may increase the risk of infections. In clinical studies, infections occurred in 22.1% of the risankizumab group compared to 14.7% of the placebo group through 16 weeks of treatment. Upper respiratory tract infections and tinea infections occurred more frequently in the risankizumab group than in the placebo group. Subjects with known chronic or acute infections were not enrolled in clinical studies.
- The rate of serious infections for the risankizumab group and the placebo group was ≤ 0.4%. Treatment with risankizumab should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated.
- In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing risankizumab. Instruct patients to seek medical advice if signs or symptoms of clinically important infection occur. If a patient develops such an infection or is not responding to standard therapy, monitor the patient closely and do not administer risankizumab until the infection resolves.
- Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with risankizumab. Across the Phase 3 psoriasis clinical studies, of the 72 subjects with latent TB who were concurrently treated with risankizumab and appropriate TB prophylaxis during the studies, none developed active TB during the mean follow-up of 61 weeks on risankizumab. Two subjects taking isoniazid for treatment of latent TB discontinued treatment due to liver injury. Of the 31 subjects from the IMMHANCE study with latent TB who did not receive prophylaxis during the study, none developed active TB during the mean follow-up of 55 weeks on risankizumab. Consider anti-TB therapy prior to initiating risankizumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Monitor patients for signs and symptoms of active TB during and after risankizumab treatment. Do not administer risankizumab to patients with active TB.
- Prior to initiating therapy with risankizumab, consider completion of all age appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with risankizumab. No data are available on the response to live or inactive vaccines.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse drug 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 2234 subjects were treated with risankizumab in clinical development studies in plaque psoriasis. Of these, 1208 subjects with psoriasis were exposed to risankizumab for at least one year.
- Data from placebo- and active-controlled studies were pooled to evaluate the safety of risankizumab for up to 16 weeks. In total, 1306 subjects were evaluated in the risankizumab 150 mg group.
- Table 1 summarizes the adverse drug reactions that occurred at a rate of at least 1% and at a higher rate in the risankizumab group than the placebo group during the 16-week controlled period of pooled clinical studies.
- Adverse drug reactions that occurred in < 1% but > 0.1% of subjects in the risankizumab group and at a higher rate than in the placebo group through Week 16 were folliculitis and urticaria.
Specific Adverse Drug Reactions
Infections
- In the first 16 weeks, infections occurred in 22.1% of the risankizumab group (90.8 events per 100 subject-years) compared to 14.7% of the placebo group (56.5 events per 100 subject-years) and did not lead to discontinuation of risankizumab. The rates of serious infections for the risankizumab group and the placebo group were ≤0.4%. Serious infections in the risankizumab group included cellulitis, osteomyelitis, sepsis and herpes zoster. In ULTIMMA-1 and ULTIMMA-2, through Week 52, the rate of infections (73.9 events per 100 subject-years) was similar to the rate observed during the first 16 weeks of treatment.
Safety through Week 52
- Through Week 52, no new adverse reactions were identified and the rates of the adverse reactions were similar to those observed during the first 16 weeks of treatment. During this period, serious infections that led to study discontinuation included pneumonia.
- 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 in the studies described below with the incidence of antibodies in other studies or to other products, including other risankizumab products, may be misleading.
- By Week 52, approximately 24% (263/1079) of subjects treated with risankizumab at the recommended dose developed antibodies to risankizumab-rzaa. Of the subjects who developed antibodies to risankizumab-rzaa, approximately 57% (14% of all subjects treated with risankizumab) had antibodies that were classified as neutralizing. Higher antibody titers in approximately 1% of subjects treated with risankizumab were associated with lower risankizumab-rzaa concentrations and reduced clinical response.
## Postmarketing Experience
There is limited information regarding Risankizumab Postmarketing Experience in the drug label.
# Drug Interactions
- Avoid use of live vaccines in patients treated with risankizumab.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- Limited available data with risankizumab use in pregnant women are insufficient to evaluate a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcome. Human IgG is known to cross the placental barrier; therefore, risankizumab may be transmitted from the mother to the developing fetus.
- In an enhanced pre- and post-natal developmental toxicity study, pregnant cynomolgus monkeys were administered subcutaneous doses of 5 and 50 mg/kg risankizumab-rzaa once weekly during the period of organogenesis up to parturition. At the 50 mg/kg dose [20 times the maximum recommended human dose (MRHD); 2.5 mg/kg based on administration of a 150 mg dose to a 60 kg individual], increased fetal/infant loss was noted in pregnant monkeys (see Data). No risankizumab-rzaa-related effects on functional or immunological development were observed in infant monkeys from birth through 6 months of age. The clinical significance of these findings for humans is unknown.
- All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Animal Data
- An enhanced pre- and post-natal developmental toxicity study was conducted in cynomolgus monkeys. Pregnant cynomolgus monkeys were administered weekly subcutaneous doses of risankizumab-rzaa of 5 or 50 mg/kg from gestation day 20 to parturition and the cynomolgus monkeys (mother and infants) were monitored for 6 months after delivery. No maternal toxicity was noted in this study. There were no treatment-related effects on growth and development, malformations, developmental immunotoxicology or neurobehavioral development. However, a dose-dependent increase in fetal/infant loss was noted in the risankizumab-rzaa-treated groups (32% and 43% in the 5 mg/kg and 50 mg/kg groups, respectively) compared to the vehicle control group (19%). The increased fetal/infant loss in the 50 mg/kg group was considered to be related to risankizumab-rzaa treatment. The no observed adverse effect level (NOAEL) for maternal toxicity was identified as 50 mg/kg (20 times the MRHD, based on mg/kg comparison) and the NOAEL for developmental toxicity was identified as 5 mg/kg (2 times the MRHD, based on mg/kg comparison). In the infants, mean serum concentrations increased in a dose-dependent manner and were approximately 17-86% of the respective maternal concentrations. Following delivery, most adult female cynomolgus monkeys and all infants from the risankizumab-rzaa‑treated groups had measurable serum concentrations of risankizumab-rzaa up to 91 days postpartum. Serum concentrations were below detectable levels at 180 days postpartum.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Risankizumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Risankizumab during labor and delivery.
### Nursing Mothers
- There are no data on the presence of risankizumab-rzaa in human milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for risankizumab and any potential adverse effects on the breastfed infant from risankizumab or from the underlying maternal condition.
### Pediatric Use
- The safety and efficacy of risankizumab in pediatric patients less than 18 years of age have not yet been established.
### Geriatic Use
- Of the 2234 subjects with plaque psoriasis exposed to risankizumab, 243 subjects were 65 years or older and 24 subjects were 75 years or older. No overall differences in risankizumab-rzaa exposure, safety or effectiveness were observed between older and younger subjects who received risankizumab. However, the number of subjects aged 65 years and older was not sufficient to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Risankizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Risankizumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Risankizumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Risankizumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Risankizumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Risankizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- The recommended dose is 150 mg (two 75 mg injections) administered by subcutaneous injection at Week 0, Week 4, and every 12 weeks thereafter.
- Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with risankizumab.
- Administer risankizumab subcutaneously. Inject two separate 75 mg single-dose prefilled syringes for the full 150 mg dose. Discard prefilled syringes after use. Do not reuse.
- For each dose, administer the injections at different anatomic locations (such as thighs or abdomen), and not into areas where the skin is tender, bruised, erythematous, indurated or affected by psoriasis. Administration of risankizumab in the upper, outer arm may only be performed by a healthcare professional or caregiver.
- If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.
- Risankizumab is intended for use under the guidance and supervision of a healthcare professional. Patients may self-inject risankizumab after training in subcutaneous injection technique. Provide proper training to patients and/or caregivers on the subcutaneous injection technique of risankizumab. Instruct the patient that two separate 75 mg single-dose injections are required to achieve the 150 mg dose.
- The risankizumab “Instructions for Use” contains more detailed instructions on the preparation and administration of risankizumab. Instruct the patient to read the Instructions for Use before administration (see Patient Counseling Information).
- Before injecting, patients may remove the carton from the refrigerator and allow to reach room temperature out of direct sunlight (15 to 30 minutes) without removing the prefilled syringes from the carton.
- Visually inspect risankizumab for particulate matter and discoloration prior to administration. Risankizumab is a colorless to slightly yellow and clear to slightly opalescent solution. It may contain a few translucent to white particles. Do not use if the solution contains large particles or is cloudy or discolored.
### Monitoring
There is limited information regarding Risankizumab Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Risankizumab and IV administrations.
# Overdosage
- In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and administer appropriate symptomatic treatment immediately.
# Pharmacology
## Mechanism of Action
- Risankizumab-rzaa is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively binds to the p19 subunit of human interleukin 23 (IL-23) cytokine and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses.
- Risankizumab-rzaa inhibits the release of pro-inflammatory cytokines and chemokines.
## Structure
There is limited information regarding Risankizumab Structure in the drug label.
## Pharmacodynamics
- No formal pharmacodynamics studies have been conducted with risankizumab-rzaa.
## Pharmacokinetics
- Risankizumab-rzaa plasma concentrations increased dose-proportionally from 90 to 180 mg and from 18 to 300 mg (0.6 to 1.2 and 0.12 to 2.0 times the approved recommended dosage) following subcutaneous administration in subjects with plaque psoriasis and healthy volunteers, respectively. Steady-state concentrations were achieved by Week 16 following subcutaneous administration of risankizumab-rzaa at Weeks 0, 4, and every 12 weeks thereafter. At the 150 mg dose, the estimated steady-state peak concentration (Cmax) and trough concentration (Ctrough) were approximately 12 mcg/mL and 2 mcg/mL, respectively.
Absorption
- The absolute bioavailability of risankizumab-rzaa was estimated to be 89% following subcutaneous injection. Cmax was reached by 3-14 days.
Distribution
- The estimated steady-state volume of distribution (inter-subject CV%) was 11.2 L (34%) in subjects with plaque psoriasis.
Elimination
- The estimated systemic clearance (inter-subject CV%) was 0.31 L/day (24%) and terminal elimination half-life was approximately 28 days in subjects with plaque psoriasis.
Metabolism
- The metabolic pathway of risankizumab-rzaa has not been characterized. As a humanized IgG1 monoclonal antibody, risankizumab-rzaa is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.
Specific Populations
- No clinically significant differences in the pharmacokinetics of risankizumab-rzaa were observed based on age (≥18 years). No specific studies have been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of risankizumab-rzaa.
Body Weight
- Risankizumab-rzaa clearance and volume of distribution increase and plasma concentrations decrease as body weight increases; however, no dose adjustment is recommended based on body weight.
Drug Interaction Studies
- Cytochrome P450 Substrates: No clinically significant changes in exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), metoprolol (CYP2D6 substrate), or midazolam (CYP3A substrate) were observed when used concomitantly with risankizumab-rzaa 150 mg administered subcutaneously at Weeks 0, 4, 8 and 12 (more frequent than the approved recommended dosing frequency) in subjects with plaque psoriasis.
## Nonclinical Toxicology
- Carcinogenicity and mutagenicity studies have not been conducted with risankizumab.
- No effects on male fertility parameters were observed in sexually mature male cynomolgus monkeys subcutaneously treated with 50 mg/kg risankizumab-rzaa (at 20 times the clinical exposure at the MRHD, based on mg/kg comparison) once weekly for 26 weeks.
# Clinical Studies
- Four multicenter, randomized, double-blind studies [ULTIMMA-1 (NCT02684370), ULTIMMA-2 (NCT02684357), IMMHANCE (NCT02672852), and IMMVENT (NCT02694523)] enrolled 2109 subjects 18 years of age and older with moderate to severe plaque psoriasis who had a body surface area (BSA) involvement of ≥10%, a static Physician’s Global Assessment (sPGA) score of ≥3 (“moderate”) in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on a severity scale of 0 to 4, and a Psoriasis Area and Severity Index (PASI) score ≥12.
- Overall, subjects had a median baseline PASI score of 17.8 and a median BSA of 20.0%. Baseline sPGA score was 4 (“severe”) in 19% of subjects. A total of 10% of study subjects had a history of diagnosed psoriatic arthritis.
- Across all studies, 38% of subjects had received prior phototherapy, 48% had received prior non-biologic systemic therapy, and 42% had received prior biologic therapy for the treatment of psoriasis.
ULTIMMA-1 and ULTIMMA-2
- In ULTIMMA-1 and ULTIMMA-2, 997 subjects were enrolled (including 598 subjects randomized to the risankizumab 150 mg group, 200 subjects randomized to the placebo group, and 199 to the biologic active control group). Subjects received treatment at Weeks 0, 4, and every 12 weeks thereafter.
- Both studies assessed the responses at Week 16 compared to placebo for the two co-primary endpoints:
the proportion of subjects who achieved an sPGA score of 0 (“clear”) or 1 (“almost clear”)
the proportion of subjects who achieved at least a 90% reduction from baseline PASI (PASI 90)
- the proportion of subjects who achieved an sPGA score of 0 (“clear”) or 1 (“almost clear”)
- the proportion of subjects who achieved at least a 90% reduction from baseline PASI (PASI 90)
- Secondary endpoints included the proportion of subjects who achieved PASI 100, sPGA 0, and PSS 0 at Week 16.
- The results are presented in Table 2.
- Examination of age, gender, race, body weight, baseline PASI score and previous treatment with systemic or biologic agents did not identify differences in response to risankizumab among these subgroups at Week 16.
- In ULTIMMA-1 and ULTIMMA-2 at Week 52, subjects receiving risankizumab achieved sPGA 0 (58% and 60%, respectively), PASI 90 (82% and 81%, respectively), and PASI 100 (56% and 60%, respectively).
Patient Reported Outcomes
- Improvements in signs and symptoms related to pain, redness, itching and burning at Week 16 compared to placebo were observed in both studies as assessed by the Psoriasis Symptom Scale (PSS). In ULTIMMA-1 and ULTIMMA-2, about 30% of the subjects who received risankizumab achieved PSS 0 (“none”) at Week 16 compared to 1% of the subjects who received placebo.
IMMHANCE
- IMMHANCE enrolled 507 subjects (407 randomized to risankizumab 150 mg and 100 to placebo). Subjects received treatment at Weeks 0, 4, and every 12 weeks thereafter.
- At Week 16, risankizumab was superior to placebo on the co-primary endpoints of sPGA 0 or 1 (84% risankizumab and 7% placebo) and PASI 90 (73% risankizumab and 2% placebo). The respective response rates for risankizumab and placebo at Week 16 were: sPGA 0 (46% risankizumab and 1% placebo); PASI 100 (47% risankizumab and 1% placebo); and PASI 75 (89% risankizumab and 8% placebo).
Maintenance and Durability of Response
- In ULTIMMA-1 and ULTIMMA-2, among the subjects who received risankizumab and had PASI 100 at Week 16, 80% (206/258) of the subjects who continued on risankizumab had PASI 100 at Week 52. For PASI 90 responders at Week 16, 88% (398/450) of the subjects had PASI 90 at Week 52.
- In IMMHANCE, subjects who were originally on risankizumab and had sPGA 0 or 1 at Week 28 were re-randomized to continue risankizumab every 12 weeks or withdrawal of therapy. At Week 52, 87% (97/111) of the subjects re-randomized to continue treatment with risankizumab had sPGA 0 or 1 compared to 61% (138/225) who were re-randomized to withdrawal of risankizumab.
# How Supplied
- Risankizumab injection is a sterile, preservative-free, colorless to slightly yellow and clear to slightly opalescent solution. The product is supplied in a 1 mL glass syringe with a fixed 29 gauge ½ inch needle with needle guard.
one carton containing two prefilled syringes and two alcohol pad
- one carton containing two prefilled syringes and two alcohol pad
## Storage
- Store in a refrigerator at 2°C to 8°C (36°F to 46° F).
- Do not freeze.
- Do not shake.
- Keep the prefilled syringes in the outer carton to protect from light.
- Not made with natural rubber latex.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) before starting risankizumab therapy and to reread the Medication Guide each time the prescription is renewed. Advise patients of the potential benefits and risks of risankizumab.
Infections
- Inform patients that risankizumab may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to the healthcare provider and contacting their healthcare provider if they develop any symptoms of an infection.
Administration Instruction
- Instruct patients or caregivers to perform the first self-injected dose under the supervision and guidance of a qualified healthcare professional for training in preparation and administration of risankizumab, including choosing anatomical sites for administration, and proper subcutaneous injection technique.
- Instruct patients or caregivers to administer two 75 mg single-dose syringes to achieve the 150 mg dose of risankizumab.
- Instruct patients or caregivers in the technique of needle and syringe disposal.
# Precautions with Alcohol
Alcohol-Risankizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Skyrizi
# Look-Alike Drug Names
There is limited information regarding Risankizumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Risankizumab | |
a8bbe28cba5f54ad8929c0253be27481db5b17d0 | wikidoc | Rome process | Rome process
# Overview
The "Rome Process" is an international effort to define and categorize the functional gastrointestinal disorders, or FGIDs, (of unknown cause) such as Irritable bowel syndrome and Functional dyspepsia. This approach represents a substantial change in thinking given that doctors have usually relied on basic science and palpable “evidence” to diagnose all kinds of ailments. More than half of gut disorders encountered by physicians are functional (i.e. disorders of gut function) and there is no structural or biochemical explanation for them, so it was necessary to develop alternate methods to identify them. This process is akin to that followed by psychiatrists to categorize and diagnose psychiatric entities, which culminated in the DSM-IV criteria. These should not be “diagnoses of exclusion"; they demand a more positive approach.
# History
There were systematic approaches that attempted to classify the then hazy area of functional gastrointestinal disorders from as early as 1962 when Chaudhary and Truelove published a retrospective review of IBS patients at Oxford, England. Later on, the "Manning Criteria" for irritable bowel syndrome were derived from a paper published in 1978 by Manning and colleagues. This seminal classification started a new era and, from then on, scientific work on functional gastrointestinal disorders proceeded with increased enthusiasm.
The Rome criteria have been evolving from the first set of criteria issued in 1989 (The Rome Guidelines for IBS) through the Rome Classification System for FGIDs (1990), or Rome-1, the Rome I Criteria for IBS (1992) and the FGIDs (1994), the Rome II Criteria for IBS (1999) and the FGIDs (1999) to the recent Rome III Criteria (2006). "Rome II" and "Rome III" incorporated pediatric criteria to the consensus.
# Process
The Rome criteria are achieved and finally issued through a consensual process, using the Delphi method (or Delphi Technique). The effort is organised by the Rome Coordinating Committee. This process typically takes many months of work by investigators, organized into committees. The committees work by mail and telephone conferences until the final, defining meeting, which (logically) takes place in Rome, Italy. The Rome III effort encompassed 87 participants from 18 countries in 14 committees. Members were added from countries outside the more industrialized Western nations; this time there were members from China, Brazil, Chile, Venezuela, Hungary, and Romania. Additional working teams were created to work on issues like: gender, society, patient, and social issues; and pharmacology and pharmacokinetics. Two committees (neonate/toddler and child/adolescent), rather than one, served the pediatrics FGIDs.
# Classification
## Adult patients
In the Rome III classification, the Functional GI Disorders (FGIDs) are classified into six major
domains for adults:
- Esophageal (category A)
- Gastroduodenal (category B)
- Bowel (category C)
- Functional Abdominal Pain Syndrome (category D)
- Biliary (category E)
- Anorectal (category F)
The functional bowel disorders (category C) include: Irritable bowel syndrome (C1); Functional bloating (C2); Functional constipation (C3); Functional diarrhea (C4)
Irritable bowel syndrome (C1) is more specifically defined as pain associated with change in bowel habit, which is different from functional diarrhea.
## Pediatric patients
The pediatric domains are classified first by age range and then by symptom pattern or area of symptom. Each domain contains several disorders, each with relatively specific clinical features.
- Neonate/Toddler (category G)
G1. Infant regurgitation
G2. Infant rumination syndrome
G3. Cyclic vomiting syndrome
G4. Infant colic
G5. Functional diarrhea
G6. Infant dyschezia
G7. Functional constipation
- G1. Infant regurgitation
- G2. Infant rumination syndrome
- G3. Cyclic vomiting syndrome
- G4. Infant colic
- G5. Functional diarrhea
- G6. Infant dyschezia
- G7. Functional constipation
- Child/Adolescent (category H)
H1. Vomiting and aerophagia: H1a. Adolescent rumination syndrome; H1b. Cyclic vomiting syndrome; H1c. Aerophagia
H2. Abdominal pain–related FGIDs: H2a. Functional dyspepsia; H2b. Irritable bowel syndrome; H2c. Abdominal migraine; H2d. Childhood functional abdominal pain
H3. Constipation and incontinence: H3a. Functional constipation; H3b. Nonretentive fecal incontinence
- H1. Vomiting and aerophagia: H1a. Adolescent rumination syndrome; H1b. Cyclic vomiting syndrome; H1c. Aerophagia
- H2. Abdominal pain–related FGIDs: H2a. Functional dyspepsia; H2b. Irritable bowel syndrome; H2c. Abdominal migraine; H2d. Childhood functional abdominal pain
- H3. Constipation and incontinence: H3a. Functional constipation; H3b. Nonretentive fecal incontinence
## Rome Process for Diagnosing IBS
Physicians rely on a variety of procedures and laboratory tests to confirm a diagnosis. The cardinal requirement for the diagnosis of IBS is abdominal pain. The Rome II criteria is used to diagnose IBS after a careful examination of the patient's medical history and physical abdominal examination which looks for any 'red flag' symptoms. More recently, the Rome III criteria, incorporating some changes over the previous set of criteria, have been issued. The Rome II and III efforts have integrated pediatric contents to their set of criteria.
According to the Rome II committees and the Functional Brain Gut Research Group,
IBS can be diagnosed based on at least 12 weeks, which need not be consecutive, of the preceding 12 months there was abdominal discomfort or pain that had two out of three of these features:
- Relieved with defecation; and/or
- Onset associated with a change in frequency of stool; and/or
- Onset associated with a change in form (appearance) of stool.
Symptoms that cumulatively support the diagnosis of IBS:
- Abnormal stool frequency (for research purposes, "abnormal" may be defined as greater than 3 bowel movements per day and less than 3 bowel movements per week);
- Abnormal stool form (lumpy/hard or loose/watery stool);
- Abnormal stool passage (straining, urgency, or feeling of incomplete evacuation);
- Bloating or feeling of abdominal distention.
Supportive symptoms of IBS:
- A) Fewer than three bowel movements a week
- B) More than three bowel movements a day
- C) Hard or lumpy stools
- D) Loose (mushy) or watery stools
- E) Straining during a bowel movement
- F) Urgency (having to rush to have a bowel movement)
- G) Feeling of incomplete bowel movement
- H) Passing mucus (white material) during a bowel movement
- I) Abdominal fullness, bloating, or swelling
Diarrhea-predominant: At least 1 of B, D, F and none of A, C, E; or at least 2 of B, D, F and one of A or E.
Constipation-predominant: At least 1 of A, C, E and none of B, D, F; or at least 2 of A, C, E and one of B, D, F.
Red flag symptoms which are not typical of IBS:
- Pain that awakens/interferes with sleep
- Diarrhea that awakens/interferes with sleep
- Blood in the stool (visible or occult)
- Weight loss
- Fever
- Abnormal physical examination
An update to these criteria was issued at the Rome III conference and published in May 2006. The validity of subtypes is called into question:
- The validity and stability of such subtypes over time is unknown and should be the subject of future research.
- Because of the characteristic symptom instability, we prefer the terms IBS with constipation and IBS with diarrhea instead of constipation- and diarrhea-predominant IBS. In this categorical system, many people whose features place them close to a subtype boundary change pattern without a major change in pathophysiology. Moreover, the heterogeneity and variable natural history of IBS significantly limit clinical trials of motility-active drugs and drug therapy in practice.
In addition to meeting these positive criteria, patients have initial laboratory testing with a complete blood count, basic chemistry panel, and an erythrocyte sedimentation rate. Diagnostic accuracy for IBS is over 95% when Rome II criteria are met, history and physical exam do not suggest any other cause, and initial laboratory testing is negative.
In the past it was thought that the diagnosis of IBS relied on a diagnosis of exclusion; that is, if one cannot find a cause then IBS is the diagnosis. Currently the diagnosis of IBS relies on meeting Rome II inclusion criteria (updated by Rome III criteria) and excluding other illnesses based on history, physical exam, and laboratory testing. Although the Rome II and III criteria were not designed to be a management guideline, it is currently a "gold standard" for the diagnosis of IBS. Unfortunately, an IBS diagnosis in an adult patient is still only useful as a tool to rule out more serious problems unless further investigation is employed to discern an addressable condition.
# References and Sources
- ↑ Thompson WG, Longstreth GL, Drossman DA et al. (2000). Functional Bowel Disorders. In: Drossman DA, Corazziari E, Talley NJ et al. (eds.), Rome II: The Functional Gastrointestinal Disorders. Diagnosis, Pathophysiology and Treatment. A Multinational Consensus. Lawrence, KS: Allen Press. ISBN 0-9656837-2-9.
- ↑ "Diagnostic Criteria". Irritable Bowel Syndrome Self Help and Support Group. 2005. Retrieved 2005-12-04..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}
- ↑ Longstreth GL, Thompson WG, Chey WD, Houghton LA, Mearin F, and Spiller RC. (2006). Functional Bowel Disorders. Gastroenterology 2006; 130:1480–1491'
- Gastroenterology (Journal) 2006;130:1552–1556
- The Rome Criteria | Rome process
# Overview
The "Rome Process" is an international effort to define and categorize the functional gastrointestinal disorders, or FGIDs, (of unknown cause) such as Irritable bowel syndrome and Functional dyspepsia. This approach represents a substantial change in thinking given that doctors have usually relied on basic science and palpable “evidence” to diagnose all kinds of ailments. More than half of gut disorders encountered by physicians are functional (i.e. disorders of gut function) and there is no structural or biochemical explanation for them, so it was necessary to develop alternate methods to identify them. This process is akin to that followed by psychiatrists to categorize and diagnose psychiatric entities, which culminated in the DSM-IV criteria. These should not be “diagnoses of exclusion"; they demand a more positive approach.
# History
There were systematic approaches that attempted to classify the then hazy area of functional gastrointestinal disorders from as early as 1962 when Chaudhary and Truelove published a retrospective review of IBS patients at Oxford, England. Later on, the "Manning Criteria" for irritable bowel syndrome were derived from a paper published in 1978 by Manning and colleagues. This seminal classification started a new era and, from then on, scientific work on functional gastrointestinal disorders proceeded with increased enthusiasm.
The Rome criteria have been evolving from the first set of criteria issued in 1989 (The Rome Guidelines for IBS) through the Rome Classification System for FGIDs (1990), or Rome-1, the Rome I Criteria for IBS (1992) and the FGIDs (1994), the Rome II Criteria for IBS (1999) and the FGIDs (1999) to the recent Rome III Criteria (2006). "Rome II" and "Rome III" incorporated pediatric criteria to the consensus.
# Process
The Rome criteria are achieved and finally issued through a consensual process, using the Delphi method (or Delphi Technique). The effort is organised by the Rome Coordinating Committee. This process typically takes many months of work by investigators, organized into committees. The committees work by mail and telephone conferences until the final, defining meeting, which (logically) takes place in Rome, Italy. The Rome III effort encompassed 87 participants from 18 countries in 14 committees. Members were added from countries outside the more industrialized Western nations; this time there were members from China, Brazil, Chile, Venezuela, Hungary, and Romania. Additional working teams were created to work on issues like: gender, society, patient, and social issues; and pharmacology and pharmacokinetics. Two committees (neonate/toddler and child/adolescent), rather than one, served the pediatrics FGIDs.
# Classification
## Adult patients
In the Rome III classification, the Functional GI Disorders (FGIDs) are classified into six major
domains for adults:
- Esophageal (category A)
- Gastroduodenal (category B)
- Bowel (category C)
- Functional Abdominal Pain Syndrome (category D)
- Biliary (category E)
- Anorectal (category F)
The functional bowel disorders (category C) include: Irritable bowel syndrome (C1); Functional bloating (C2); Functional constipation (C3); Functional diarrhea (C4)
Irritable bowel syndrome (C1) is more specifically defined as pain associated with change in bowel habit, which is different from functional diarrhea.
## Pediatric patients
The pediatric domains are classified first by age range and then by symptom pattern or area of symptom. Each domain contains several disorders, each with relatively specific clinical features.
- Neonate/Toddler (category G)
G1. Infant regurgitation
G2. Infant rumination syndrome
G3. Cyclic vomiting syndrome
G4. Infant colic
G5. Functional diarrhea
G6. Infant dyschezia
G7. Functional constipation
- G1. Infant regurgitation
- G2. Infant rumination syndrome
- G3. Cyclic vomiting syndrome
- G4. Infant colic
- G5. Functional diarrhea
- G6. Infant dyschezia
- G7. Functional constipation
- Child/Adolescent (category H)
H1. Vomiting and aerophagia: H1a. Adolescent rumination syndrome; H1b. Cyclic vomiting syndrome; H1c. Aerophagia
H2. Abdominal pain–related FGIDs: H2a. Functional dyspepsia; H2b. Irritable bowel syndrome; H2c. Abdominal migraine; H2d. Childhood functional abdominal pain
H3. Constipation and incontinence: H3a. Functional constipation; H3b. Nonretentive fecal incontinence
- H1. Vomiting and aerophagia: H1a. Adolescent rumination syndrome; H1b. Cyclic vomiting syndrome; H1c. Aerophagia
- H2. Abdominal pain–related FGIDs: H2a. Functional dyspepsia; H2b. Irritable bowel syndrome; H2c. Abdominal migraine; H2d. Childhood functional abdominal pain
- H3. Constipation and incontinence: H3a. Functional constipation; H3b. Nonretentive fecal incontinence
## Rome Process for Diagnosing IBS
Physicians rely on a variety of procedures and laboratory tests to confirm a diagnosis. The cardinal requirement for the diagnosis of IBS is abdominal pain. The Rome II criteria is used to diagnose IBS after a careful examination of the patient's medical history and physical abdominal examination which looks for any 'red flag' symptoms. More recently, the Rome III criteria, incorporating some changes over the previous set of criteria, have been issued. The Rome II and III efforts have integrated pediatric contents to their set of criteria.
According to the Rome II committees and the Functional Brain Gut Research Group,[1]
IBS can be diagnosed based on at least 12 weeks, which need not be consecutive, of the preceding 12 months there was abdominal discomfort or pain that had two out of three of these features:[2]
- Relieved with defecation; and/or
- Onset associated with a change in frequency of stool; and/or
- Onset associated with a change in form (appearance) of stool.
Symptoms that cumulatively support the diagnosis of IBS:
- Abnormal stool frequency (for research purposes, "abnormal" may be defined as greater than 3 bowel movements per day and less than 3 bowel movements per week);
- Abnormal stool form (lumpy/hard or loose/watery stool);
- Abnormal stool passage (straining, urgency, or feeling of incomplete evacuation);
- Bloating or feeling of abdominal distention.
Supportive symptoms of IBS:
- A) Fewer than three bowel movements a week
- B) More than three bowel movements a day
- C) Hard or lumpy stools
- D) Loose (mushy) or watery stools
- E) Straining during a bowel movement
- F) Urgency (having to rush to have a bowel movement)
- G) Feeling of incomplete bowel movement
- H) Passing mucus (white material) during a bowel movement
- I) Abdominal fullness, bloating, or swelling
Diarrhea-predominant: At least 1 of B, D, F and none of A, C, E; or at least 2 of B, D, F and one of A or E.
Constipation-predominant: At least 1 of A, C, E and none of B, D, F; or at least 2 of A, C, E and one of B, D, F.
Red flag symptoms which are not typical of IBS:
- Pain that awakens/interferes with sleep
- Diarrhea that awakens/interferes with sleep
- Blood in the stool (visible or occult)
- Weight loss
- Fever
- Abnormal physical examination
An update to these criteria was issued at the Rome III conference and published in May 2006.[3] The validity of subtypes is called into question:
- The validity and stability of such subtypes over time is unknown and should be the subject of future research.
- Because of the characteristic symptom instability, we prefer the terms IBS with constipation and IBS with diarrhea instead of constipation- and diarrhea-predominant IBS. In this categorical system, many people whose features place them close to a subtype boundary change pattern without a major change in pathophysiology. Moreover, the heterogeneity and variable natural history of IBS significantly limit clinical trials of motility-active drugs and drug therapy in practice.
In addition to meeting these positive criteria, patients have initial laboratory testing with a complete blood count, basic chemistry panel, and an erythrocyte sedimentation rate. Diagnostic accuracy for IBS is over 95% when Rome II criteria are met, history and physical exam do not suggest any other cause, and initial laboratory testing is negative.
In the past it was thought that the diagnosis of IBS relied on a diagnosis of exclusion; that is, if one cannot find a cause then IBS is the diagnosis. Currently the diagnosis of IBS relies on meeting Rome II inclusion criteria (updated by Rome III criteria) and excluding other illnesses based on history, physical exam, and laboratory testing. Although the Rome II and III criteria were not designed to be a management guideline, it is currently a "gold standard" for the diagnosis of IBS. Unfortunately, an IBS diagnosis in an adult patient is still only useful as a tool to rule out more serious problems unless further investigation is employed to discern an addressable condition.
# References and Sources
- ↑ Thompson WG, Longstreth GL, Drossman DA et al. (2000). Functional Bowel Disorders. In: Drossman DA, Corazziari E, Talley NJ et al. (eds.), Rome II: The Functional Gastrointestinal Disorders. Diagnosis, Pathophysiology and Treatment. A Multinational Consensus. Lawrence, KS: Allen Press. ISBN 0-9656837-2-9.
- ↑ "Diagnostic Criteria". Irritable Bowel Syndrome Self Help and Support Group. 2005. Retrieved 2005-12-04..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}
- ↑ Longstreth GL, Thompson WG, Chey WD, Houghton LA, Mearin F, and Spiller RC. (2006). Functional Bowel Disorders. Gastroenterology 2006; 130:1480–1491'
- Gastroenterology (Journal) 2006;130:1552–1556
- The Rome Criteria
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Rome_process | |
2bd7740432c95799e6ca46121e4fad5e29bdbedd | wikidoc | Vestigiality | Vestigiality
Vestigiality describes homologous characters of organisms which have lost all or most of their original function in a species through evolution. These may take various forms such as anatomical structures, behaviors and biochemical pathways. Some of these disappear early in embryonic development, but others are retained in adulthood. All such characters can in turn can be traced to the genes which code for such characters. Some genes no longer code for anything, and can thus be said vestigial themselves, or junk DNA.
Vestigial structures are often called vestigial organs, although many of them are not actually organs. These are typically in a degenerate, atrophied, or rudimentary condition, and tend to be much more variable than similar parts. Although structures usually called "vestigial" are largely or entirely functionless, a vestigial structure may retain lesser functions or develop minor new ones. However, care must be taken not to apply the label of vestigiality to exaptations, in which a structure originally used for one purpose is modified for a new one. For example, the wings of penguin would not be vestigial, as they have been modified for a substantial new purpose (underwater locomotion), while those of an emu would be, as they have no major purpose anymore (not even for display as in ostriches).
Vestigial characters range on a continuum from detrimental through neutral to marginally useful. Some may be of some limited utility to an organism but still degenerate over time; the important point is not that they are without utility, but that they do not confer a significant enough advantage in terms of fitness to avoid the random force of disorder that is mutation. It is difficult however to say that a vestigial character is detrimental to the organism in the long term - the future is unpredictable, and that which is of no use in the present may develop into something useful in the future. Vestigiality is one of several lines of evidence for biological evolution.
# History
Vestigial structures have been noticed since ancient times, and the reason for their existence was long speculated upon before Darwinian evolution provided a widely-accepted explanation. In the 4th century BC, Aristotle was one of the earliest writers to comment, in his History of Animals, on the vestigial eyes of moles, calling them "stunted in development". However, only in recent centuries have anatomical vestiges become a subject of serious study. In 1798, Étienne Geoffroy Saint-Hilaire noted on vestigial structures:
His colleague, Jean-Baptiste Lamarck, named a number of vestigial structures in his 1809 book Philosophie Zoologique. Lamarck noted "Olivier's Spalax, which lives underground like the mole, and is apparently exposed to daylight even less than the mole, has altogether lost the use of sight: so that it shows nothing more than vestiges of this organ."
Charles Darwin was very familiar with the concept of vestigial structures, though the term for them did not yet exist. He listed a number of them in The Descent of Man, including the muscles of the ear, wisdom teeth, the appendix, the tail bone, body hair, and the semilunar fold in the corner of the eye. Darwin also noted, in The Origin of Species, that a vestigial structure could be useless for its primary function, but still retain secondary anatomical roles: "An organ serving for two purposes, may become rudimentary or utterly aborted for one, even the more important purpose, and remain perfectly efficient for the other.... n organ may become rudimentary for its proper purpose, and be used for a distinct object."
Darwin however still often refers to the 'use and disuse' of structures having some role in heredity, with inheritance of acquired characters being treated as an important aspect besides the central force of natural selection. In the final chapter of The Origin of Species he describes the process: "This has been effected chiefly through the natural selection of numerous successive, slight, favourable variations; aided in an important manner by the inherited effects of the use and disuse of parts".
In 1893, Robert Wiedersheim published a list of 86 human organs that had, in his words, "lost their original physiological significance". Theorizing that they were vestiges of evolution, he called them "vestigial". Since his time, the function of some of these structures has been discovered, while other anatomical vestiges have been unearthed, making the list primarily of interest as a record of the knowledge of human anatomy at the time. Later versions of Wiedersheim's list were expanded to as many as 180 human "vestigial organs". This is why the zoologist Newman stated in the Scopes Monkey Trial that "There are, according to Wiedersheim, no less than 180 vestigial structures in the human body, sufficient to make of a man a veritable walking museum of antiquities."
# Common descent and evolutionary history
Vestigial structures are often homologous to structures that are functioning normally in other species. Therefore, vestigial structures can be considered evidence for evolution, the process by which beneficial heritable traits arise in populations over an extended period of time. The existence of vestigial traits can be attributed to changes in the environment and behavior patterns of the organism in question. As the function of the trait is no longer beneficial for survival, the likelihood that future offspring will inherit the "normal" form of it decreases. In some cases the structure becomes detrimental to the organism (for example the eyes of a mole can become infected). In many cases the structure is of no direct harm, yet all structures require extra energy in terms of development, maintenance, and weight, and are also a risk in terms of disease (e.g. infection, cancer), providing some selective pressure for the removal of parts that do not contribute to an organism's fitness. A structure that is not harmful will obviously take longer to be 'phased out' than one that is. However, some vestigial structures may persist due to limitations in development, such that complete loss of the structure could not occur without major alterations of the organism's developmental pattern, and such alterations would likely produce numerous negative side-effects. The toes of many animals such as horses, who stand on a single toe, are still evident in a vestigial form and may become evident, although rarely, from time to time in individuals.
The vestigial versions of the structure can be compared to the original version of the structure in other species in order to determine the homology of a vestigial structure. Homologous structures indicate common ancestry with those organisms that have a functional version of the structure.
Vestigial traits are still considered adaptations. This is because an adaptation is defined as a trait that has been favored by natural selection. Adaptations therefore need not be adaptive, as long as they were at some point.
# Examples
## Animals
In whales and other cetaceans, one can find small vestigial leg bones deeply buried within the back of the body. These are remnants of their land-living ancestors' legs. Many whales also have undeveloped, unused, pelvis bones in the anterior part of their torsos.
The wings of ostriches, emus, and other flightless birds are vestigial; they are remnants of their flying ancestors' wings.
The eyes of certain cavefish and salamanders are vestigial, as they no longer allow the organism to see, and are remnants of their ancestors' functional eyes.
Boas and replace.pys have vestigial pelvis remanents which are externally visible as two small anal spurs on each side of the cloaca. These spurs are sometimes used in copulation, but are not essential, as no colubroid snake (the vast majority of species) possesses these remnants. Furthermore, in most snakes the left lung is greatly reduced or absent. Amphisbaenians, which independently evolved limblessness, also retain vestiges of the pelvis as well as the pectoral girdle, and have lost their right lung.
Crabs have small tails tucked between their rear legs that are probably vestigial, as they are no longer in use. The working version of these tails can be found in their close crustacean relative, the lobster.
Certain species of moths (for example the Gypsy moth) have females that, although flightless, still carry small wings. These wings have no use, and are vestigial to the versions in species whose females can fly.
The fruit fly can be bred in high school experiments to produce off-spring with vestigial wings, to better understand basic genetics in biology.
### Humans
Human vestigiality is related to human evolution, and includes a variety of characters occurring in the human species. Many of these are also vestigial in other primates and related animals. The relative usefulness of these characters is a subject of debate. Structures that have been or still are considered vestigial no longer include the vermiform appendix, which produces good bacteria. Darwin, Charles (1871). The Descent of Man, and Selection in Relation to Sex. John Murray: London. the coccyx, or tailbone (a remnant of a lost tail); the plica semilunaris on the inside corner of the eye (a remnant of the nictitating membrane); and, as pictured, muscles in the ear and other parts of the body.
Humans also bear some vestigial behaviors and reflexes. The formation of goose bumps in humans under stress is a vestigial reflex; its function in human ancestors was to raise the body's hair, making the ancestor appear larger and scaring off predators. Raising the hair is also used to trap an extra layer of air, keeping an animal warm. This reflex formation of goosebumps when cold is not vestigial in humans, but the reflex to form them under stress is. Infants are also able to support their own weight while hanging from a rod, responding to certain tacticle stimuli. An ancestral primate would have had sufficient body hair for an infant to cling to, allowing its mother to escape from danger, such as climbing up a tree in the presence of a predator.
There are also vestigial molecular structures in humans, which are no longer in use but may indicate common ancestry with other species. One example of this is L-gulonolactone oxidase, a gene, that is functional in most other mammals, which produces a enzyme that can make vitamin C. A mutation inactivated the gene in an ancestor of the current group of primates, and it now remains in the human genome as a vestigial sequence called a pseudogene.
## Plants and other organisms
Vestigial structures are not only found in animals; plants also are known to have vestigial parts. Dandelions and other asexually reproducing plants produce unneeded flower petals. These petals were once used to attract pollinating insects, but are now no longer needed. | Vestigiality
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Vestigiality describes homologous characters of organisms which have lost all or most of their original function in a species through evolution. These may take various forms such as anatomical structures, behaviors and biochemical pathways. Some of these disappear early in embryonic development, but others are retained in adulthood. All such characters can in turn can be traced to the genes which code for such characters. Some genes no longer code for anything, and can thus be said vestigial themselves, or junk DNA.
Vestigial structures are often called vestigial organs, although many of them are not actually organs. These are typically in a degenerate, atrophied, or rudimentary condition,[1] and tend to be much more variable than similar parts. Although structures usually called "vestigial" are largely or entirely functionless, a vestigial structure may retain lesser functions or develop minor new ones.[2] However, care must be taken not to apply the label of vestigiality to exaptations, in which a structure originally used for one purpose is modified for a new one. For example, the wings of penguin would not be vestigial, as they have been modified for a substantial new purpose (underwater locomotion), while those of an emu would be, as they have no major purpose anymore (not even for display as in ostriches).
Vestigial characters range on a continuum from detrimental through neutral to marginally useful. Some may be of some limited utility to an organism but still degenerate over time; the important point is not that they are without utility, but that they do not confer a significant enough advantage in terms of fitness to avoid the random force of disorder that is mutation. It is difficult however to say that a vestigial character is detrimental to the organism in the long term - the future is unpredictable, and that which is of no use in the present may develop into something useful in the future. Vestigiality is one of several lines of evidence for biological evolution.
# History
Vestigial structures have been noticed since ancient times, and the reason for their existence was long speculated upon before Darwinian evolution provided a widely-accepted explanation. In the 4th century BC, Aristotle was one of the earliest writers to comment, in his History of Animals, on the vestigial eyes of moles, calling them "stunted in development".[3] However, only in recent centuries have anatomical vestiges become a subject of serious study. In 1798, Étienne Geoffroy Saint-Hilaire noted on vestigial structures:
Template:Cquotetxt
His colleague, Jean-Baptiste Lamarck, named a number of vestigial structures in his 1809 book Philosophie Zoologique. Lamarck noted "Olivier's Spalax, which lives underground like the mole, and is apparently exposed to daylight even less than the mole, has altogether lost the use of sight: so that it shows nothing more than vestiges of this organ."[4]
Charles Darwin was very familiar with the concept of vestigial structures, though the term for them did not yet exist. He listed a number of them in The Descent of Man, including the muscles of the ear, wisdom teeth, the appendix, the tail bone, body hair, and the semilunar fold in the corner of the eye. Darwin also noted, in The Origin of Species, that a vestigial structure could be useless for its primary function, but still retain secondary anatomical roles: "An organ serving for two purposes, may become rudimentary or utterly aborted for one, even the more important purpose, and remain perfectly efficient for the other.... [A]n organ may become rudimentary for its proper purpose, and be used for a distinct object."[5]
Darwin however still often refers to the 'use and disuse' of structures having some role in heredity, with inheritance of acquired characters being treated as an important aspect besides the central force of natural selection.[6] In the final chapter of The Origin of Species he describes the process: "This has been effected chiefly through the natural selection of numerous successive, slight, favourable variations; aided in an important manner by the inherited effects of the use and disuse of parts".[5]
In 1893, Robert Wiedersheim published a list of 86 human organs that had, in his words, "lost their original physiological significance". Theorizing that they were vestiges of evolution, he called them "vestigial".[7] Since his time, the function of some of these structures has been discovered, while other anatomical vestiges have been unearthed, making the list primarily of interest as a record of the knowledge of human anatomy at the time. Later versions of Wiedersheim's list were expanded to as many as 180 human "vestigial organs". This is why the zoologist Newman stated in the Scopes Monkey Trial that "There are, according to Wiedersheim, no less than 180 vestigial structures in the human body, sufficient to make of a man a veritable walking museum of antiquities."[8]
# Common descent and evolutionary history
Vestigial structures are often homologous to structures that are functioning normally in other species. Therefore, vestigial structures can be considered evidence for evolution, the process by which beneficial heritable traits arise in populations over an extended period of time. The existence of vestigial traits can be attributed to changes in the environment and behavior patterns of the organism in question. As the function of the trait is no longer beneficial for survival, the likelihood that future offspring will inherit the "normal" form of it decreases. In some cases the structure becomes detrimental to the organism (for example the eyes of a mole can become infected[5]). In many cases the structure is of no direct harm, yet all structures require extra energy in terms of development, maintenance, and weight, and are also a risk in terms of disease (e.g. infection, cancer), providing some selective pressure for the removal of parts that do not contribute to an organism's fitness. A structure that is not harmful will obviously take longer to be 'phased out' than one that is. However, some vestigial structures may persist due to limitations in development, such that complete loss of the structure could not occur without major alterations of the organism's developmental pattern, and such alterations would likely produce numerous negative side-effects. The toes of many animals such as horses, who stand on a single toe, are still evident in a vestigial form and may become evident, although rarely, from time to time in individuals.
The vestigial versions of the structure can be compared to the original version of the structure in other species in order to determine the homology of a vestigial structure. Homologous structures indicate common ancestry with those organisms that have a functional version of the structure.[9]
Vestigial traits are still considered adaptations. This is because an adaptation is defined as a trait that has been favored by natural selection. Adaptations therefore need not be adaptive, as long as they were at some point. [10]
# Examples
## Animals
In whales and other cetaceans, one can find small vestigial leg bones deeply buried within the back of the body.[11] These are remnants of their land-living ancestors' legs. Many whales also have undeveloped, unused, pelvis bones in the anterior part of their torsos.
The wings of ostriches, emus, and other flightless birds are vestigial; they are remnants of their flying ancestors' wings.
The eyes of certain cavefish and salamanders are vestigial, as they no longer allow the organism to see, and are remnants of their ancestors' functional eyes.
Boas and replace.pys have vestigial pelvis remanents which are externally visible as two small anal spurs on each side of the cloaca. These spurs are sometimes used in copulation, but are not essential, as no colubroid snake (the vast majority of species) possesses these remnants. Furthermore, in most snakes the left lung is greatly reduced or absent. Amphisbaenians, which independently evolved limblessness, also retain vestiges of the pelvis as well as the pectoral girdle, and have lost their right lung.
Crabs have small tails tucked between their rear legs that are probably vestigial, as they are no longer in use. The working version of these tails can be found in their close crustacean relative, the lobster.[citation needed]
Certain species of moths (for example the Gypsy moth) have females that, although flightless, still carry small wings. These wings have no use, and are vestigial to the versions in species whose females can fly.[citation needed]
The fruit fly can be bred in high school experiments to produce off-spring with vestigial wings, to better understand basic genetics in biology.
### Humans
Human vestigiality is related to human evolution, and includes a variety of characters occurring in the human species. Many of these are also vestigial in other primates and related animals. The relative usefulness of these characters is a subject of debate. Structures that have been or still are considered vestigial no longer include the vermiform appendix, which produces good bacteria. Darwin, Charles (1871). The Descent of Man, and Selection in Relation to Sex. John Murray: London. the coccyx, or tailbone (a remnant of a lost tail); the plica semilunaris on the inside corner of the eye (a remnant of the nictitating membrane); and, as pictured, muscles in the ear and other parts of the body.
Humans also bear some vestigial behaviors and reflexes. The formation of goose bumps in humans under stress is a vestigial reflex;[12] its function in human ancestors was to raise the body's hair, making the ancestor appear larger and scaring off predators. Raising the hair is also used to trap an extra layer of air, keeping an animal warm. This reflex formation of goosebumps when cold is not vestigial in humans, but the reflex to form them under stress is. Infants are also able to support their own weight while hanging from a rod,[13] responding to certain tacticle stimuli. An ancestral primate would have had sufficient body hair for an infant to cling to, allowing its mother to escape from danger, such as climbing up a tree in the presence of a predator.
There are also vestigial molecular structures in humans, which are no longer in use but may indicate common ancestry with other species. One example of this is L-gulonolactone oxidase, a gene, that is functional in most other mammals, which produces a enzyme that can make vitamin C. A mutation inactivated the gene in an ancestor of the current group of primates, and it now remains in the human genome as a vestigial sequence called a pseudogene.[14]
## Plants and other organisms
Vestigial structures are not only found in animals; plants also are known to have vestigial parts.[15] Dandelions and other asexually reproducing plants produce unneeded flower petals. These petals were once used to attract pollinating insects, but are now no longer needed.[citation needed] | https://www.wikidoc.org/index.php/Rudiment_(biology) | |
5ac4fc8f5d2bf0116c0ed862ec484970bf6d921b | wikidoc | Rumenic acid | Rumenic acid
Rumenic acid is a conjugated linoleic acid (CLA) found in the fat of ruminants and in dairy products. It is a omega-7 trans fat. Its lipid shorthand name is cis-9, trans-11 18:2 acid.
The name was proposed by Kramer et al in 1998. It is formed along with vaccenic acid by biohydrogenation of dietary polyunsaturated fatty acids in the rumen.
It can be considered as the principal dietary form, accounting for as much as 85-90% of the total CLA content in dairy products.
# Biological properties
Laboratory studies indicate that rumenic acid shows anticarcinogenic properties. | Rumenic acid
Rumenic acid is a conjugated linoleic acid (CLA) found in the fat of ruminants and in dairy products. It is a omega-7 trans fat. Its lipid shorthand name is cis-9, trans-11 18:2 acid.
The name was proposed by Kramer et al in 1998.[1] It is formed along with vaccenic acid by biohydrogenation of dietary polyunsaturated fatty acids in the rumen.[2]
It can be considered as the principal dietary form, accounting for as much as 85-90% of the total CLA content in dairy products.[3]
# Biological properties
Laboratory studies indicate that rumenic acid shows anticarcinogenic properties.[4] | https://www.wikidoc.org/index.php/Rumenic_acid | |
9adbd578d5af0c060393e6cae9d9ace354f09ad4 | wikidoc | SATURN Trial | SATURN Trial
# Objective
To compare the effects of two intensive lipid lowering treatment regimens (statins) on the progression of coronary atherosclerosis and to assess their safety and side-effect profiles.
# Methods
Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) trial was a randomized trial which enrolled 1049 patients with known coronary artery disease, to study the effects of rosuvastatin and atorvastatin on the progression of coronary atherosclerosis. Percent atheroma volume and total atheroma volume were assessed by intravascular ultrasound (IVUS) at baseline and after 104 weeks of treatment with either rosuvastatin 40 daily and atorvastatin 80 mg daily.
# Results
At the end of 104 weeks:
- Serum LDL-C levels were lower in the rosuvastatin group than atorvastatin group.
- Similarly serum HDL-C levels were higher in the rosuvastatin group than in atorvastatin group.
- Percent atheroma volume (PAV), decreased by 0.99% with atorvastatin and by 1.22% with rosuvastatin.
# Conclusion
Maximal doses of rosuvastatin and atorvastatin resulted in significant regression of coronary atherosclerosis. Even though rosuvastatin achieved a lower LDL-C and higher HDL-C levels compared to atorvastatin, a similar degree of regression of PAV was observed in both the treatment groups. | SATURN Trial
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Click here to download slides for SATURN Trial.
# Objective
To compare the effects of two intensive lipid lowering treatment regimens (statins) on the progression of coronary atherosclerosis and to assess their safety and side-effect profiles.
# Methods
Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) trial was a randomized trial which enrolled 1049 patients with known coronary artery disease, to study the effects of rosuvastatin and atorvastatin on the progression of coronary atherosclerosis. Percent atheroma volume and total atheroma volume were assessed by intravascular ultrasound (IVUS) at baseline and after 104 weeks of treatment with either rosuvastatin 40 daily and atorvastatin 80 mg daily.
# Results
At the end of 104 weeks:
- Serum LDL-C levels were lower in the rosuvastatin group than atorvastatin group.
- Similarly serum HDL-C levels were higher in the rosuvastatin group than in atorvastatin group.
- Percent atheroma volume (PAV), decreased by 0.99% with atorvastatin and by 1.22% with rosuvastatin.
# Conclusion
Maximal doses of rosuvastatin and atorvastatin resulted in significant regression of coronary atherosclerosis. Even though rosuvastatin achieved a lower LDL-C and higher HDL-C levels compared to atorvastatin, a similar degree of regression of PAV was observed in both the treatment groups. | https://www.wikidoc.org/index.php/SATURN_Trial | |
8a5291a8c0f2cdfb2a14d2f634e260eb1544cc2a | wikidoc | SCN1A (gene) | SCN1A (gene)
The SCN1A gene is located on chromosome 2 of humans, and is made up of 26 exons spanning a total length of 6030 nucleotide base pairs (bp). Alternative splicing of exon 5 gives rise to two alternate exons. The promoter has been identified 2.5 kilobase pairs (kb) upstream of the transcription start site, and the 5’- untranslated exons may enhance expression of the SCN1A gene in SH-SY5Y cells, a human cell line derived from a neuroblastoma.
The SCN1A gene codes for the alpha subunit of the voltage-gated sodium ion channel making it a member of ten paralogous gene families which code for the voltage-gated sodium transmembrane proteins NaV1.1. Within the family of genes which code for other portions of voltage-gated sodium channels, the SCN1A mutations were the first identified, since mutations to this gene caused epilepsy and febrile seizures. Indeed, the SCN1A gene is one of the most commonly mutated genes in the human genome associated with epilepsy, which has given it the title of a ‘super culprit gene’. There are 900 distinct mutations reported for the SCN1A gene, approximately half of the reported mutations are truncations which result in no protein. The remaining half of mutations are missense mutations, which are predicted to either cause loss-of-function or gain-of-function, though very few have been tested for functionality in the lab.
Subtle differences in voltage-gated sodium ion channels can have devastating physiological effects and underlie abnormal neurological functioning. Mutations to the SCN1A gene most often results in different forms of seizure disorders, the most common forms of seizure disorders are Dravet Syndrome (DS), Intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC), and severe myoclonic epilepsy borderline (SMEB). Clinically, 70-80% of patients with DS have identified mutations specific to the SCN1A gene, which are caused by de novo heterozygous mutations of the SCN1A gene There are currently two databases on SCN1A mutations, Infobase and the SCN1A variant database.
Mice with knock-in SCN1A mutations, who are model organisms for DS quickly develop seizures, indicative of a significant reduction in the function of NaV1.1. It has been hypothesized that reduced sodium currents due to NaV1.1 mutations may cause hyper-excitability in GABAergic inhibitory interneurons leading to epilepsy. Mice in both the homozygous and heterozygous states develop the seizure phenotype and ataxia. Though homozygous mice die on average during the second to third week of life and approximately 50% of heterozygous null mice survive into adulthood.
- From a gene symbol: This is a redirect from a Human Genome Organisation (HUGO) symbol for a gene to an article about the gene. | SCN1A (gene)
The SCN1A gene is located on chromosome 2 of humans, and is made up of 26 exons spanning a total length of 6030 nucleotide base pairs (bp).[1][2] Alternative splicing of exon 5 gives rise to two alternate exons.[3] The promoter has been identified 2.5 kilobase pairs (kb) upstream of the transcription start site, and the 5’- untranslated exons may enhance expression of the SCN1A gene in SH-SY5Y cells, a human cell line derived from a neuroblastoma.[4]
The SCN1A gene codes for the alpha subunit of the voltage-gated sodium ion channel making it a member of ten paralogous gene families which code for the voltage-gated sodium transmembrane proteins NaV1.1. Within the family of genes which code for other portions of voltage-gated sodium channels, the SCN1A mutations were the first identified, since mutations to this gene caused epilepsy and febrile seizures.[5] Indeed, the SCN1A gene is one of the most commonly mutated genes in the human genome associated with epilepsy, which has given it the title of a ‘super culprit gene’.[6] There are 900 distinct mutations reported for the SCN1A gene, approximately half of the reported mutations are truncations which result in no protein.[7][8] The remaining half of mutations are missense mutations, which are predicted to either cause loss-of-function or gain-of-function, though very few have been tested for functionality in the lab.[1]
Subtle differences in voltage-gated sodium ion channels can have devastating physiological effects and underlie abnormal neurological functioning.[9][10] Mutations to the SCN1A gene most often results in different forms of seizure disorders, the most common forms of seizure disorders are Dravet Syndrome (DS), Intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC), and severe myoclonic epilepsy borderline (SMEB).[7] Clinically, 70-80% of patients with DS have identified mutations specific to the SCN1A gene, which are caused by de novo heterozygous mutations of the SCN1A gene[11] There are currently two databases on SCN1A mutations, Infobase and the SCN1A variant database.
Mice with knock-in SCN1A mutations, who are model organisms for DS quickly develop seizures, indicative of a significant reduction in the function of NaV1.1.[2] It has been hypothesized that reduced sodium currents due to NaV1.1 mutations may cause hyper-excitability in GABAergic inhibitory interneurons leading to epilepsy.[4] Mice in both the homozygous and heterozygous states develop the seizure phenotype and ataxia. Though homozygous mice die on average during the second to third week of life and approximately 50% of heterozygous null mice survive into adulthood.[2][4][12]
- From a gene symbol: This is a redirect from a Human Genome Organisation (HUGO) symbol for a gene to an article about the gene. | https://www.wikidoc.org/index.php/SCN1A_(gene) | |
7f35848060039a20211de36d56832882e8b34c0c | wikidoc | SEARCH Study | SEARCH Study
# Objective
To study the efficacy and safety of prolonged use of more intensive cholesterol-lowering therapy in patients at high cardiovascular risk.
# Methods
Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH) was a randomized, double blinded study which enrolled 12,064 men and women aged 18-80 years with a history of myocardial infarction. In addition these patients were randomly assigned to homocysteine lowering with folic acid 2 mg plus vitamin B12 1 mg daily versus matching placebo. The primary endpoint was major vascular events, defined as coronary death, myocardial infarction, stroke, or arterial revascularization.
# Results
- Major vascular events occurred in 24.5% of patients receiving 80 mg simvastatin versus 25.7% of those receiving 20 mg.
- An average of 0.35 mmol/L greater reduction in LDL-C was observed in the group receiving 80 mg simvastatin compared to those receiving 20 mg.
- Overall 6% reduction in major vascular events was observed in the 80 mg group compared with the 20 mg group.
- Myopathy occurred in 0.9% patients taking 80 mg simvastatin compared with 0.03% patients in the 20 mg simvastatin group.
# Conclusion
The SEARCH study failed to find a benefit with more intensive therapy as a significant number of patients in the 20 mg simvastatin group took an additional statin off protocol as more intensive LDL-C goals were promulgated. | SEARCH Study
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Objective
To study the efficacy and safety of prolonged use of more intensive cholesterol-lowering therapy in patients at high cardiovascular risk.
# Methods
Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH) was a randomized, double blinded study which enrolled 12,064 men and women aged 18-80 years with a history of myocardial infarction. In addition these patients were randomly assigned to homocysteine lowering with folic acid 2 mg plus vitamin B12 1 mg daily versus matching placebo. The primary endpoint was major vascular events, defined as coronary death, myocardial infarction, stroke, or arterial revascularization.
# Results
- Major vascular events occurred in 24.5% of patients receiving 80 mg simvastatin versus 25.7% of those receiving 20 mg.
- An average of 0.35 mmol/L greater reduction in LDL-C was observed in the group receiving 80 mg simvastatin compared to those receiving 20 mg.
- Overall 6% reduction in major vascular events was observed in the 80 mg group compared with the 20 mg group.
- Myopathy occurred in 0.9% patients taking 80 mg simvastatin compared with 0.03% patients in the 20 mg simvastatin group.
# Conclusion
The SEARCH study failed to find a benefit with more intensive therapy as a significant number of patients in the 20 mg simvastatin group took an additional statin off protocol as more intensive LDL-C goals were promulgated.[1][2] | https://www.wikidoc.org/index.php/SEARCH_Study | |
a0f787105b83e79fbccab414752c7fbb75595620 | wikidoc | SN1 reaction | SN1 reaction
The SN1 reaction is a substitution reaction in organic chemistry. "SN" stands for nucleophilic substitution and the "1" represents the fact that the rate-determining step is unimolecular . It involves a carbocation intermediate and is commonly seen in reactions of secondary or tertiary alkyl halides or, under strongly acidic conditions, with secondary or tertiary alcohols. With primary alkyl halides, the alternative SN2 reaction occurs. Among inorganic chemists, SN1 is referred to perhaps more accessibly as a dissociative mechanism. A reaction mechanism was first proposed by Christopher Ingold et al in 1940
# Mechanism
The SN1 reaction between a molecule A and a nucleophile B takes place in three steps:
- Formation of a carbocation from A by separation of a leaving group from the carbon; this step is slow and reversible .
- Nucleophilic attack: B reacts with A. If the nucleophile is a neutral molecule (i.e. a solvent) a third step is required to complete the reaction. When the solvent is water, the intermediate is an oxonium ion.
- Deprotonation: Removal of a proton on the protonated nucleophile by a nearby ion or molecule.
# Kinetics
In contrast to SN2, SN1 reactions take place in two steps (excluding any protonation or deprotonation). The rate determining step is the first step, so the rate of the overall reaction is essentially equal to that of carbocation formation and does not involve the attacking nucleophile. Thus nucleophilicity is irrelevant and the overall reaction rate depends on the concentration of the reactant only.
In 1954 it was found that addition of a small amount of lithium perchlorate certain acetolysis reactions (for example that of the tosylate of cholesterol) led to a remarkable reaction rate increase . Based on this special salt effect the general mechanism was refined to include a contact ion pair (CIP) with cation and anion together in a solvent cage which then dissociates to a so-called solvent-separated ion pair (SSIP) and then on to free ions (FI). All the interconversions are reversible and the added salt prevents the reformation of CIP from SSIP.
In some cases the SN1 reaction will occur at an abnormally high rate due to neighbouring group participation (NGP). NGP often lowers the energy barrier required for the formation of the carbocation intermediate.
# Scope of the reaction
The SN1 mechanism tends to dominate when the central carbon atom is surrounded by bulky groups because such groups sterically hinder the SN2 reaction. Additionally, bulky substituents on the central carbon increase the rate of carbocation formation because of the relief of steric strain that occurs. The resultant carbocation is also stabilized by both inductive stabilization and hyperconjugation from attached alkyl groups. The Hammond-Leffler postulate suggests that this too will increase the rate of carbocation formation. The SN1 mechanism therefore dominates in reactions at tertiary alkyl centers and is further observed at secondary alkyl centers in the presence of weak nucleophiles.
# Stereochemistry
Because the intermediate carbocation is planar, the central carbon is not a stereocenter. Even if it were a stereocenter prior to becoming a carbocation, the original configuration at that atom is lost. Rather, the central carbon can be prochiral. Nucleophilic attack can occur from either side of the plane, so the product might consist of a mixture of two stereoisomers. In fact, if the central carbon is the only stereocenter in the reaction, racemization may occur. This stands in contrast to the SN2 mechanism, where the chiral configuration of the substrate is inverted. However, an excess of inversion is usually observed, as the leaving group can remain in proximity to the carbocation intermediate for a short time and block nucleophilic attack. For example, in the reaction of 3S-chloro-3-methylhexane with iodide ion, if the carbocation intermediate is free of the leaving group then it is achiral and stands an equal chance of attack on either side. This leads to a mixture of 3R-iodo-3-methylhexane and 3S-iodo-3-methylhexane:
# Side reactions
Two common side reactions are elimination reactions and carbocation rearrangement. If the reaction is performed under warm or hot conditions (which favor an increase in entropy), E1 elimination is likely to predominate, leading to formation of an alkene. Even if the reaction is performed cold, some alkene may be formed. If an attempt is made to perform an SN1 reaction using a strongly basic nucleophile such as hydroxide or methoxide ion, the alkene will again be formed, this time via an E2 elimination. This will be especially true if the reaction is heated. Finally, if the carbocation intermediate can rearrange to a more stable carbocation, it will give a product derived from the more stable carbocation rather than the simple substitution product.
# Solvent effects
Since the SN1 reaction involves formation of an unstable carbocation intermediate in the rate-determining step, anything that can facilitate this will speed up the reaction. The normal solvents of choice are both polar (to stabilise ionic intermediates in general) and protic (to solvate the leaving group in particular). Typical polar protic solvents include water and alcohols, which will also act as nucleophiles.
The Y scale correlates solvolysis reaction rates of any solvent (k) with that of a standard solvent (80% v/v ethanol/water) (k0) through
\log { \left ( \frac{k}{k_0} \right ) } = mY \,
with m a reactant constant (m = 1 for tert-butyl chloride) and Y a solvent parameter For example 100% ethanol gives Y = - 2.3, 50% ethanol in water Y = +1.65 and 15% concentration Y = +3.2 | SN1 reaction
Template:Downsize
The SN1 reaction is a substitution reaction in organic chemistry. "SN" stands for nucleophilic substitution and the "1" represents the fact that the rate-determining step is unimolecular [1] [2]. It involves a carbocation intermediate and is commonly seen in reactions of secondary or tertiary alkyl halides or, under strongly acidic conditions, with secondary or tertiary alcohols. With primary alkyl halides, the alternative SN2 reaction occurs. Among inorganic chemists, SN1 is referred to perhaps more accessibly as a dissociative mechanism. A reaction mechanism was first proposed by Christopher Ingold et al in 1940 [3]
# Mechanism
The SN1 reaction between a molecule A and a nucleophile B takes place in three steps:
- Formation of a carbocation from A by separation of a leaving group from the carbon; this step is slow and reversible [4].
- Nucleophilic attack: B reacts with A. If the nucleophile is a neutral molecule (i.e. a solvent) a third step is required to complete the reaction. When the solvent is water, the intermediate is an oxonium ion.
- Deprotonation: Removal of a proton on the protonated nucleophile by a nearby ion or molecule.
# Kinetics
In contrast to SN2, SN1 reactions take place in two steps (excluding any protonation or deprotonation). The rate determining step is the first step, so the rate of the overall reaction is essentially equal to that of carbocation formation and does not involve the attacking nucleophile. Thus nucleophilicity is irrelevant and the overall reaction rate depends on the concentration of the reactant only.
In 1954 it was found that addition of a small amount of lithium perchlorate certain acetolysis reactions (for example that of the tosylate of cholesterol) led to a remarkable reaction rate increase [5]. Based on this special salt effect the general mechanism was refined to include a contact ion pair (CIP) with cation and anion together in a solvent cage which then dissociates to a so-called solvent-separated ion pair (SSIP) and then on to free ions (FI). All the interconversions are reversible and the added salt prevents the reformation of CIP from SSIP.
In some cases the SN1 reaction will occur at an abnormally high rate due to neighbouring group participation (NGP). NGP often lowers the energy barrier required for the formation of the carbocation intermediate.
# Scope of the reaction
The SN1 mechanism tends to dominate when the central carbon atom is surrounded by bulky groups because such groups sterically hinder the SN2 reaction. Additionally, bulky substituents on the central carbon increase the rate of carbocation formation because of the relief of steric strain that occurs. The resultant carbocation is also stabilized by both inductive stabilization and hyperconjugation from attached alkyl groups. The Hammond-Leffler postulate suggests that this too will increase the rate of carbocation formation. The SN1 mechanism therefore dominates in reactions at tertiary alkyl centers and is further observed at secondary alkyl centers in the presence of weak nucleophiles.
# Stereochemistry
Because the intermediate carbocation is planar, the central carbon is not a stereocenter. Even if it were a stereocenter prior to becoming a carbocation, the original configuration at that atom is lost. Rather, the central carbon can be prochiral. Nucleophilic attack can occur from either side of the plane, so the product might consist of a mixture of two stereoisomers. In fact, if the central carbon is the only stereocenter in the reaction, racemization may occur. This stands in contrast to the SN2 mechanism, where the chiral configuration of the substrate is inverted. However, an excess of inversion is usually observed, as the leaving group can remain in proximity to the carbocation intermediate for a short time and block nucleophilic attack. For example, in the reaction of 3S-chloro-3-methylhexane with iodide ion, if the carbocation intermediate is free of the leaving group then it is achiral and stands an equal chance of attack on either side. This leads to a mixture of 3R-iodo-3-methylhexane and 3S-iodo-3-methylhexane:
# Side reactions
Two common side reactions are elimination reactions and carbocation rearrangement. If the reaction is performed under warm or hot conditions (which favor an increase in entropy), E1 elimination is likely to predominate, leading to formation of an alkene. Even if the reaction is performed cold, some alkene may be formed. If an attempt is made to perform an SN1 reaction using a strongly basic nucleophile such as hydroxide or methoxide ion, the alkene will again be formed, this time via an E2 elimination. This will be especially true if the reaction is heated. Finally, if the carbocation intermediate can rearrange to a more stable carbocation, it will give a product derived from the more stable carbocation rather than the simple substitution product.
# Solvent effects
Since the SN1 reaction involves formation of an unstable carbocation intermediate in the rate-determining step, anything that can facilitate this will speed up the reaction. The normal solvents of choice are both polar (to stabilise ionic intermediates in general) and protic (to solvate the leaving group in particular). Typical polar protic solvents include water and alcohols, which will also act as nucleophiles.
The Y scale correlates solvolysis reaction rates of any solvent (k) with that of a standard solvent (80% v/v ethanol/water) (k0) through
<math> \log { \left ( \frac{k}{k_0} \right ) } = mY \,</math>
with m a reactant constant (m = 1 for tert-butyl chloride) and Y a solvent parameter [6]For example 100% ethanol gives Y = - 2.3, 50% ethanol in water Y = +1.65 and 15% concentration Y = +3.2 [7] | https://www.wikidoc.org/index.php/SN1 | |
052301f7c1dae791bdd6c4699d5e0ce2d4d365b9 | wikidoc | SN2 reaction | SN2 reaction
# Overview
The SN2 reaction (also known as bimolecular substitution nucleophilic) is a type of nucleophilic substitution, where a lone pair from a nucleophile attacks an electron deficient electrophilic center and bonds to it, expelling another group called a leaving group. Thus the incoming group replaces the leaving group in one step. Since two reacting species are involved in the slow, rate-determining step of the reaction, this leads to the name bimolecular nucleophilic substitution, or SN2. The somewhat more transparently named analog to SN2 among inorganic chemists is the interchange mechanism.
# Reaction mechanism
The reaction most often occurs at an aliphatic sp3 carbon center with an electronegative, stable leaving group attached to it - 'X' - frequently a halide atom. The breaking of the C-X bond and the formation of the new C-Nu bond occur simultaneously to form a transition state in which the carbon under nucleophilic attack is pentavalent, and approximately sp2 hybridised. The nucleophile attacks the carbon at 180° to the leaving group, since this provides the best overlap between the nucleophile's lone pair and the C-X σ- antibonding orbital. The leaving group is then pushed off the opposite side and the product is formed.
If the substrate under nucleophilic attack is chiral, this leads to an inversion of stereochemistry, called the Walden inversion.
In an example of the SN2 reaction, the attack of OH− (the nucleophile) on a bromoethane (the electrophile) results in ethanol, with bromide ejected as the leaving group.
SN2 attack occurs if the backside route of attack is not sterically hindered by substituents on the substrate. Therefore this mechanism usually occurs at an unhindered primary carbon centre. If there is steric crowding on the substrate near the leaving group, such as at a tertiary carbon centre, the substitution will involve an SN1 rather than an SN2 mechanism, (an SN1 would also be more likely in this case because a sufficiently stable carbocation intermediary could be formed.)
# Reaction kinetics
The rate of an SN2 reaction is second order, as the rate-determining step depends on the nucleophile concentration, as well as the concentration of substrate, .
This is a key difference between the SN1 and SN2 mechanisms. In the SN1 reaction the nucleophile attacks after the rate-limiting step is over, whereas in SN2 the nucleophile forces off the leaving group in the limiting step. In cases where both mechanisms are possible (for example at a secondary carbon centre), the mechanism depends on solvent, temperature, concentration of the nucleophile or on the leaving group.
SN2 reactions are generally favoured in primary alkyl halides or secondary alkyl halides with an aprotic solvent. They occur at a negligible rate in tertiary alkyl halides due to steric hindrance.
It is important to understand that SN2 and SN1 are two extremes of a sliding scale of reactions, it is possible to find many reactions which exhibit both SN2 and SN1 character in their mechanisms. For instance, it is possible to get a contact ion pairs formed from an alkyl halide in which the ions are not fully separated. When these undergo substitution the stereochemistry will be inverted (as in SN2) for many of the reacting molecules but a few may show retention of configuration.
# E2 Competition
A common side reaction taking place with SN2 reactions is E2 elimination when the incoming anion, acting as a base rather than as the nucleophile, abstracts a proton and forms the alkene. This effect can be demonstated in the gas-phase reaction between an phenoxide and a simple alkyl bromide taking place inside a mass spectrometer :
With ethyl bromide the reaction product is predominantly the substitution product but as steric hindrance around the electrophilic center increases as in isopropyl bromide elimination takes the upper hand. Other factors favoring elimination are the strength of the base. With the less basic benzoate substrate isopropyl bromide reacts with 55% substitution. In general gas phase reaction and solution phase reactions of this type follow the same trends even though in the first solvent effects are eliminated. | SN2 reaction
Template:Downsize
# Overview
The SN2 reaction (also known as bimolecular substitution nucleophilic) is a type of nucleophilic substitution, where a lone pair from a nucleophile attacks an electron deficient electrophilic center and bonds to it, expelling another group called a leaving group. Thus the incoming group replaces the leaving group in one step. Since two reacting species are involved in the slow, rate-determining step of the reaction, this leads to the name bimolecular nucleophilic substitution, or SN2. The somewhat more transparently named analog to SN2 among inorganic chemists is the interchange mechanism.
# Reaction mechanism
The reaction most often occurs at an aliphatic sp3 carbon center with an electronegative, stable leaving group attached to it - 'X' - frequently a halide atom. The breaking of the C-X bond and the formation of the new C-Nu bond occur simultaneously to form a transition state in which the carbon under nucleophilic attack is pentavalent, and approximately sp2 hybridised. The nucleophile attacks the carbon at 180° to the leaving group, since this provides the best overlap between the nucleophile's lone pair and the C-X σ* antibonding orbital. The leaving group is then pushed off the opposite side and the product is formed.
If the substrate under nucleophilic attack is chiral, this leads to an inversion of stereochemistry, called the Walden inversion.
In an example of the SN2 reaction, the attack of OH− (the nucleophile) on a bromoethane (the electrophile) results in ethanol, with bromide ejected as the leaving group.
SN2 attack occurs if the backside route of attack is not sterically hindered by substituents on the substrate. Therefore this mechanism usually occurs at an unhindered primary carbon centre. If there is steric crowding on the substrate near the leaving group, such as at a tertiary carbon centre, the substitution will involve an SN1 rather than an SN2 mechanism, (an SN1 would also be more likely in this case because a sufficiently stable carbocation intermediary could be formed.)
# Reaction kinetics
The rate of an SN2 reaction is second order, as the rate-determining step depends on the nucleophile concentration, [Nu−] as well as the concentration of substrate, [RX].
This is a key difference between the SN1 and SN2 mechanisms. In the SN1 reaction the nucleophile attacks after the rate-limiting step is over, whereas in SN2 the nucleophile forces off the leaving group in the limiting step. In cases where both mechanisms are possible (for example at a secondary carbon centre), the mechanism depends on solvent, temperature, concentration of the nucleophile or on the leaving group.
SN2 reactions are generally favoured in primary alkyl halides or secondary alkyl halides with an aprotic solvent. They occur at a negligible rate in tertiary alkyl halides due to steric hindrance.
It is important to understand that SN2 and SN1 are two extremes of a sliding scale of reactions, it is possible to find many reactions which exhibit both SN2 and SN1 character in their mechanisms. For instance, it is possible to get a contact ion pairs formed from an alkyl halide in which the ions are not fully separated. When these undergo substitution the stereochemistry will be inverted (as in SN2) for many of the reacting molecules but a few may show retention of configuration.
# E2 Competition
A common side reaction taking place with SN2 reactions is E2 elimination when the incoming anion, acting as a base rather than as the nucleophile, abstracts a proton and forms the alkene. This effect can be demonstated in the gas-phase reaction between an phenoxide and a simple alkyl bromide taking place inside a mass spectrometer [1][2]:
With ethyl bromide the reaction product is predominantly the substitution product but as steric hindrance around the electrophilic center increases as in isopropyl bromide elimination takes the upper hand. Other factors favoring elimination are the strength of the base. With the less basic benzoate substrate isopropyl bromide reacts with 55% substitution. In general gas phase reaction and solution phase reactions of this type follow the same trends even though in the first solvent effects are eliminated. | https://www.wikidoc.org/index.php/SN2 | |
c2cfc40f5611c181c3ec9617aec4a9b7abd66744 | wikidoc | SPARCL Study | SPARCL Study
# Objective
To study the effects of statins on incidence of recurrent stroke after a recent episode of stroke or transient ischemic attack
# Methods
Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) was a double blinded study with subjects who had at least one episode of stroke in the last one to six months and LDL levels of 100 to 190 mg/dl with no history of coronary artery disease. These patients were randomly assorted to receive either 80 mg of atorvastatin daily or placebo. The primary end point for the study was first fatal or non-fatal stroke.
# Results
- During the mean follow up period of 4.9 years, 11.2% of patients from the atorvastatin group and 13.1% of patients from the placebo experienced fatal/non-fatal stroke, with a 5 year absolute risk reduction of 2.2%.
- The 5 year absolute risk reduction in major cardiovascular events was 3.5%.
- The overall mortality rates were similar in both the groups.
# Conclusion
Atorvastatin (80 mg daily) reduced the incidence of recurrent stroke and cardiovascular events in patients with a recent episode of stroke or transient ischemic attacks. However, the incidence of hemorrhagic stroke increased in the atorvastatin group. | SPARCL Study
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Objective
To study the effects of statins on incidence of recurrent stroke after a recent episode of stroke or transient ischemic attack
# Methods
Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) was a double blinded study with subjects who had at least one episode of stroke in the last one to six months and LDL levels of 100 to 190 mg/dl with no history of coronary artery disease. These patients were randomly assorted to receive either 80 mg of atorvastatin daily or placebo. The primary end point for the study was first fatal or non-fatal stroke.
# Results
- During the mean follow up period of 4.9 years, 11.2% of patients from the atorvastatin group and 13.1% of patients from the placebo experienced fatal/non-fatal stroke, with a 5 year absolute risk reduction of 2.2%.
- The 5 year absolute risk reduction in major cardiovascular events was 3.5%.
- The overall mortality rates were similar in both the groups.
# Conclusion
Atorvastatin (80 mg daily) reduced the incidence of recurrent stroke and cardiovascular events in patients with a recent episode of stroke or transient ischemic attacks. However, the incidence of hemorrhagic stroke increased in the atorvastatin group.[1] | https://www.wikidoc.org/index.php/SPARCL_Study | |
88466d5520c64176b0e1b734fe5f7890642474fc | wikidoc | STAT protein | STAT protein
# Overview
The Signal Transducers and Activator of Transcription (STAT) proteins regulate many aspects of cell growth, survival and differentiation. The transcription factors of this family are activated by the Janus Kinase JAK and dysregulation of this pathway is frequently observed in primary tumors and leads to increased angiogenesis, enhanced survival of tumors and immunosuppression. Knockout studies have provided evidence that STAT proteins are involved in the development and function of the immune system and play a role in maintaining immune tolerance and tumor surveillance.
# STAT family
The first two STAT proteins were identified in the interferon system
The seven mammalian STAT family members identified are: STAT1, STAT2, STAT3, STAT4, STAT5 a and b, and STAT6.
STAT1 homodimers are involved in type II interferon signalling, and binds to the GAS (Interferon-Gamma Activated Sequence) promoter to induce expression of ISG (Interferon Stimulated Genes). In type I interferon signaling, STAT1-STAT2 heterodimer combines with IRF9 (Interferon Response Factor) to form ISGF3 (Interferon Stimulated Gene Factor), which binds to the ISRE (Interferon Stimulated Response Element) promoter to induce ISG expression.
# Function
STAT proteins were originally described as latent cytoplasmic transcription factors that require phosphorylation for nuclear retention. The unphosphorylated STAT proteins shuttles between cytosol and the nucleus waiting for its activation signal. Once the activated transcription factors reaches the nucleus it binds to consensus DNA-recognition motif called gamma activated sites (GAS) in the promoter region of cytokine inducible genes and activates transcription of these genes.
# Activation
Extracellular binding of cytokines induces activation of the intracellular Janus kinase that phosphorylates a specific tyrosine residue in the STAT protein which promotes the dimerization of STAT monomers via their SH2 domain. The phosphorylated dimer is then actively transported in the nucleus via importin a/b and RanGDP complex. Once inside the nucleus the active STAT dimer binds to cytokine inducible promoter regions of genes containing gamma activated site (GAS) motif and activate transcription of these genes. The STAT protein can be dephosphorylated by nuclear phosphatases which leads to inactivation of STAT and the transcription factor becomes transported out of the nucleus by exportin crm1/RanGTP. | STAT protein
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The Signal Transducers and Activator of Transcription (STAT) proteins regulate many aspects of cell growth, survival and differentiation. The transcription factors of this family are activated by the Janus Kinase JAK and dysregulation of this pathway is frequently observed in primary tumors and leads to increased angiogenesis, enhanced survival of tumors and immunosuppression. Knockout studies have provided evidence that STAT proteins are involved in the development and function of the immune system and play a role in maintaining immune tolerance and tumor surveillance.
# STAT family
The first two STAT proteins were identified in the interferon system
The seven mammalian STAT family members identified are: STAT1, STAT2, STAT3, STAT4, STAT5 a and b, and STAT6.
STAT1 homodimers are involved in type II interferon signalling, and binds to the GAS (Interferon-Gamma Activated Sequence) promoter to induce expression of ISG (Interferon Stimulated Genes). In type I interferon signaling, STAT1-STAT2 heterodimer combines with IRF9 (Interferon Response Factor) to form ISGF3 (Interferon Stimulated Gene Factor), which binds to the ISRE (Interferon Stimulated Response Element) promoter to induce ISG expression.
# Function
STAT proteins were originally described as latent cytoplasmic transcription factors that require phosphorylation for nuclear retention. The unphosphorylated STAT proteins shuttles between cytosol and the nucleus waiting for its activation signal. Once the activated transcription factors reaches the nucleus it binds to consensus DNA-recognition motif called gamma activated sites (GAS) in the promoter region of cytokine inducible genes and activates transcription of these genes.
# Activation
Extracellular binding of cytokines induces activation of the intracellular Janus kinase that phosphorylates a specific tyrosine residue in the STAT protein which promotes the dimerization of STAT monomers via their SH2 domain. The phosphorylated dimer is then actively transported in the nucleus via importin a/b and RanGDP complex. Once inside the nucleus the active STAT dimer binds to cytokine inducible promoter regions of genes containing gamma activated site (GAS) motif and activate transcription of these genes. The STAT protein can be dephosphorylated by nuclear phosphatases which leads to inactivation of STAT and the transcription factor becomes transported out of the nucleus by exportin crm1/RanGTP. | https://www.wikidoc.org/index.php/STAT | |
e2a36d9bdd1629c7de5e3a13aed80b7d250a087d | wikidoc | SUMO protein | SUMO protein
# Overview
Small Ubiquitin-related Modifier or SUMO proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. SUMOylation is a post-translational modification involved in various cellular processes, such as nuclear-cytosolic transport, transcriptional regulation, apoptosis, protein stability, response to stress, and progression through the cell cycle.
SUMO proteins are similar to ubiquitin, and SUMOylation is directed by an enzymatic cascade analogous to that involved in ubiquitination. In contrast to ubiquitin, SUMO is not used to tag proteins for degradation. Mature SUMO is produced when the last four amino acids of the C-terminus have been cleaved off.
SUMO family members often have dissimilar names; the SUMO1 homologue in yeast, for example, is called SMT3 (suppressor of mif two 3). Several pseudogenes have been reported for this gene.
# Function
SUMO modification of proteins has many functions. Among the most frequent and best studied are protein stability, nuclear-cytosolic transport, transcriptional regulation (mostly transcriptional repression). Unlike ubiquitin modification which targets proteins for degradation, SUMOylation increases a protein's lifetime. It can also change a protein's location in the cell. For example, the Sumo modification of hNinein leads to its movement from the centrosome to the nucleus . In most cases Sumo attachment to transcriptional regulators correlates with inhibition of transcription . There are many more proposed functions. Refer to the GeneRIFs of the Sumo proteins, e.g. human SUMO1 , to find out more.
SUMO-1 is the main SUMO in human cells and is the one that organisms like yeast show the most similarity to. However, there are a further 3 isoforms in humans. SUMO-2/3 show high similarity to each other more so then to SUMO-1. On stress the free SUMO-2/3 pool disappears and a range of specific SUMO-2/3 modifications occur. They seem to be involved specifically in the stress response. SUMO-4 shows similarity to -2/3. Until recently it was thought SUMO-4 was either tissue specific (pancreas) or a pseudo gene. Evidence is now indicating it is the former and SUMO-4 defects may be involved in Type-1 and -2 diabetes.
# Structure
Sumo proteins are small proteins; most are around 100 amino acids in length and 12 kDa in mass. The exact length and mass varies between Sumo family members and depends on which organism the protein comes from. For example, human SUMO1, also shown in the figures, is 101 residues long and has a mass of 11.6 kDa. Its homologues in rat and mice are also 101 residues long, while the presumed relative in C. elegans has only 91 amino acids.
The structure of human SUMO1 is depicted on the right. It shows SUMO1 as a globular protein with both ends of the amino acid chain (shown in red and blue) sticking out of the protein's centre. The spherical core consists of an alpha helix and a beta sheet. The diagrams shown are based on an NMR analysis of the protein in solution.
# Prediction of SUMO attachment
Most SUMO-modified proteins contain the tetrapeptide motif B-K-x-D/E where B is a hydrophobic residue, K is the lysine conjugated to SUMO, x is any amino acid (aa), D or E is an acidic residue. Substrate specificity appears to be derived directly from Ubc9 and the respective substrate motif. SUMOplot™ is an online free access software developed to predict the probability for the SUMO consensus sequence (SUMO-CS) to be engaged in SUMO attachment. The SUMOplot™ score system is based on two criteria: 1) direct amino acid match to the SUMO-CS observed and shown to bind Ubc9, and 2) substitution of the consensus amino acid residues with amino acid residues exhibiting similar hydrophobicity. SUMOplot™ has been extensively used in the past to predict Ubc9 dependent sites. Seventeen (17) articles have been published so far for the complete list click here.
# SUMO Conjugation
SUMO conjugation to its target is analogous to that of Ubiquitin (as it is for the other Ubiquitin-like proteins such as NEDD 8). A C-terminal peptide is cleaved from SUMO by a protease (in human these are the SENP proteases or Ulp1 in yeast) using ATP to reveal a di-glycine motif. SUMO then becomes bound to an E1 enzyme (SUMO Activating Enzyme (SAE)) which is a heterodimer. It is then passed to an E2 which is a conjugating enzyme (Ubc9). Unlike with Ubiquitin the SUMO pathway consists of only 1 E1 and E2. Whilst in ubiquitination an E3 is essential to add ubiquitin to its target evidence suggests that the conjugator is sufficient in Sumoylation as long as the consensus sequence is present. It is thought that the E3 ligase aids enhancement of Sumoylation and facilitates attachment when this consensus sequence is absent. The B-K-x-D/E motif is not an absolut requirement for SUMO binding. E3 ligases are more abundant than E1 and E2 for SUMO. The most common are the PIAS proteins of which Nse2 (Mms21) a member of the Smc5/6 complex and Pias-gamma are the most well known. There are also the HECT proteins and E3's are known to arise from a complex of proteins such as with RanGap. Recent evidence has shown that PIAS-gamma is required for the sumoylation of the transcription factor yy1 but it is independent of the zinc-RING finger (identified as the functional domain of the E3 ligases). It is as yet unknown whether there is another dimension to SUMO conjugation or if this is specific to yy1. Sumoylation is reversible and is removed from targets by a protease in an ATP dependant manner. The Ulp2 protease is found bound at the nuclear pore and maybe very important in regulating the localisation of proteins to the nucleous; a known role of SUMO. SUMO has also been shown to form chains. It is thought that these preassemble on the conjugator and are then passed to the target. The biological significance of these is yet unknown. | SUMO protein
# Overview
Small Ubiquitin-related Modifier or SUMO proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. SUMOylation is a post-translational modification involved in various cellular processes, such as nuclear-cytosolic transport, transcriptional regulation, apoptosis, protein stability, response to stress, and progression through the cell cycle.
SUMO proteins are similar to ubiquitin, and SUMOylation is directed by an enzymatic cascade analogous to that involved in ubiquitination. In contrast to ubiquitin, SUMO is not used to tag proteins for degradation. Mature SUMO is produced when the last four amino acids of the C-terminus have been cleaved off.
SUMO family members often have dissimilar names; the SUMO1 homologue in yeast, for example, is called SMT3 (suppressor of mif two 3). Several pseudogenes have been reported for this gene.
# Function
SUMO modification of proteins has many functions. Among the most frequent and best studied are protein stability, nuclear-cytosolic transport, transcriptional regulation (mostly transcriptional repression). Unlike ubiquitin modification which targets proteins for degradation, SUMOylation increases a protein's lifetime. It can also change a protein's location in the cell. For example, the Sumo modification of hNinein leads to its movement from the centrosome to the nucleus [1]. In most cases Sumo attachment to transcriptional regulators correlates with inhibition of transcription [2]. There are many more proposed functions. Refer to the GeneRIFs of the Sumo proteins, e.g. human SUMO1 [3], to find out more.
SUMO-1 is the main SUMO in human cells and is the one that organisms like yeast show the most similarity to. However, there are a further 3 isoforms in humans. SUMO-2/3 show high similarity to each other more so then to SUMO-1. On stress the free SUMO-2/3 pool disappears and a range of specific SUMO-2/3 modifications occur. They seem to be involved specifically in the stress response. SUMO-4 shows similarity to -2/3. Until recently it was thought SUMO-4 was either tissue specific (pancreas) or a pseudo gene. Evidence is now indicating it is the former and SUMO-4 defects may be involved in Type-1 and -2 diabetes.
# Structure
Sumo proteins are small proteins; most are around 100 amino acids in length and 12 kDa in mass. The exact length and mass varies between Sumo family members and depends on which organism the protein comes from. For example, human SUMO1, also shown in the figures, is 101 residues long and has a mass of 11.6 kDa. Its homologues in rat and mice are also 101 residues long, while the presumed relative in C. elegans has only 91 amino acids.
The structure of human SUMO1 is depicted on the right. It shows SUMO1 as a globular protein with both ends of the amino acid chain (shown in red and blue) sticking out of the protein's centre. The spherical core consists of an alpha helix and a beta sheet. The diagrams shown are based on an NMR analysis of the protein in solution.
# Prediction of SUMO attachment
Most SUMO-modified proteins contain the tetrapeptide motif B-K-x-D/E where B is a hydrophobic residue, K is the lysine conjugated to SUMO, x is any amino acid (aa), D or E is an acidic residue. Substrate specificity appears to be derived directly from Ubc9 and the respective substrate motif. SUMOplot™ is an online free access software developed to predict the probability for the SUMO consensus sequence (SUMO-CS) to be engaged in SUMO attachment.[1] The SUMOplot™ score system is based on two criteria: 1) direct amino acid match to the SUMO-CS observed and shown to bind Ubc9, and 2) substitution of the consensus amino acid residues with amino acid residues exhibiting similar hydrophobicity. SUMOplot™ has been extensively used in the past to predict Ubc9 dependent sites. Seventeen (17) articles have been published so far for the complete list click here.[2]
# SUMO Conjugation
SUMO conjugation to its target is analogous to that of Ubiquitin (as it is for the other Ubiquitin-like proteins such as NEDD 8). A C-terminal peptide is cleaved from SUMO by a protease (in human these are the SENP proteases or Ulp1 in yeast) using ATP to reveal a di-glycine motif. SUMO then becomes bound to an E1 enzyme (SUMO Activating Enzyme (SAE)) which is a heterodimer. It is then passed to an E2 which is a conjugating enzyme (Ubc9). Unlike with Ubiquitin the SUMO pathway consists of only 1 E1 and E2. Whilst in ubiquitination an E3 is essential to add ubiquitin to its target evidence suggests that the conjugator is sufficient in Sumoylation as long as the consensus sequence is present. It is thought that the E3 ligase aids enhancement of Sumoylation and facilitates attachment when this consensus sequence is absent. The B-K-x-D/E motif is not an absolut requirement for SUMO binding. E3 ligases are more abundant than E1 and E2 for SUMO. The most common are the PIAS proteins of which Nse2 (Mms21) a member of the Smc5/6 complex and Pias-gamma are the most well known. There are also the HECT proteins and E3's are known to arise from a complex of proteins such as with RanGap. Recent evidence has shown that PIAS-gamma is required for the sumoylation of the transcription factor yy1 but it is independent of the zinc-RING finger (identified as the functional domain of the E3 ligases). It is as yet unknown whether there is another dimension to SUMO conjugation or if this is specific to yy1. Sumoylation is reversible and is removed from targets by a protease in an ATP dependant manner. The Ulp2 protease is found bound at the nuclear pore and maybe very important in regulating the localisation of proteins to the nucleous; a known role of SUMO. SUMO has also been shown to form chains. It is thought that these preassemble on the conjugator and are then passed to the target. The biological significance of these is yet unknown. | https://www.wikidoc.org/index.php/SUMO_protein | |
3bfaaf848a9d0c80e5bc3edc6585b352c6a87cdd | wikidoc | Sal ammoniac | Sal ammoniac
Sal ammoniac is a rare mineral composed of ammonium chloride, NH4Cl. It forms colorless to white to yellow-brown crystals in the isometric-hexoctahedral class. It has very poor cleavage and a brittle to conchoidal fracture. It is quite soft, with a Mohs hardness of 1.5 to 2, and has a low specific gravity of 1.5. It is water-soluble.
It typically forms as encrustations formed by sublimation around volcanic vents. It is found around volcanic fumaroles, guano deposits and burning coal seams. Associated minerals include sodium alum, native sulfur and other fumarole minerals. Notable occurrences include Tadzhikistan; Mt. Vesuvius, Italy; and Parícutin, Michoacan, Mexico.
Sal ammoniac is also the archaic name for the chemical compound ammonium chloride; from Greek, ἅλς ἀμμωνιακός hals ammoniakos, salt of Ammon, because of its early manufacture in Egypt.
It is commonly used as a flux in the soldering of stained-glass windows. In both jewelery-making and the refining of precious metals, potassium carbonate (cream of tartar) is added to gold and silver in a borax-coated crucible to purify iron or steel filings that may have contaminated the scrap. It is then air-cooled and remelted with a one-to-one mixture of powdered charcoal and sal ammoniac to yield a sturdy ingot of the respective metal or alloy in the case of sterling silver (0.75% copper) or karated gold. Anything other than 24-karat gold has silver and copper added. Usually the addition of silica, zinc, and deoxidants in very small amounts relative to the pennyweight (dwt.) of gold are processed into gold from as low as 8-karat to as high as 23.5-karat gold. This is added to prevent porosity or cracking while milling the ingot further into wire, sheet, or tubing. Without those additives an otherwise poor-quality ingot will result in open crucible melting with a hand torch or blowpipe and flame, as was done before electric melting furnaces were invented for use in the precious metals industry. These practices are still used by metalsmiths and jewelers today.
Sal ammoniac has also been used in the past in bakery products to give cookies a very crisp texture, although that application is rapidly dying due to the general disuse of it as an ingredient. However, in some areas of Europe, particularly Scandinavia, it is still widely used in the production of salty licorice candy known as Salmiak. The term sal ammoniac has largely fallen out of general use in the 20th century. | Sal ammoniac
Template:Infobox mineral
Sal ammoniac is a rare mineral composed of ammonium chloride, NH4Cl. It forms colorless to white to yellow-brown crystals in the isometric-hexoctahedral class. It has very poor cleavage and a brittle to conchoidal fracture. It is quite soft, with a Mohs hardness of 1.5 to 2, and has a low specific gravity of 1.5. It is water-soluble.
It typically forms as encrustations formed by sublimation around volcanic vents. It is found around volcanic fumaroles, guano deposits and burning coal seams. Associated minerals include sodium alum, native sulfur and other fumarole minerals. Notable occurrences include Tadzhikistan; Mt. Vesuvius, Italy; and Parícutin, Michoacan, Mexico.
Sal ammoniac is also the archaic name for the chemical compound ammonium chloride; from Greek, ἅλς ἀμμωνιακός hals ammoniakos, salt of Ammon, because of its early manufacture in Egypt.
It is commonly used as a flux in the soldering of stained-glass windows. In both jewelery-making and the refining of precious metals, potassium carbonate (cream of tartar) is added to gold and silver in a borax-coated crucible to purify iron or steel filings that may have contaminated the scrap. It is then air-cooled and remelted with a one-to-one mixture of powdered charcoal and sal ammoniac to yield a sturdy ingot of the respective metal or alloy in the case of sterling silver (0.75% copper) or karated gold. Anything other than 24-karat gold has silver and copper added. Usually the addition of silica, zinc, and deoxidants in very small amounts relative to the pennyweight (dwt.) of gold are processed into gold from as low as 8-karat to as high as 23.5-karat gold. This is added to prevent porosity or cracking while milling the ingot further into wire, sheet, or tubing. Without those additives an otherwise poor-quality ingot will result in open crucible melting with a hand torch or blowpipe and flame, as was done before electric melting furnaces were invented for use in the precious metals industry. These practices are still used by metalsmiths and jewelers today.
Sal ammoniac has also been used in the past in bakery products to give cookies a very crisp texture, although that application is rapidly dying due to the general disuse of it as an ingredient. However, in some areas of Europe, particularly Scandinavia, it is still widely used in the production of salty licorice candy known as Salmiak. The term sal ammoniac has largely fallen out of general use in the 20th century. | https://www.wikidoc.org/index.php/Sal_ammoniac | |
3212850e1b68b5fe94408336d195245a826bef84 | wikidoc | Salvinorin A | Salvinorin A
Salvinorin A is the main active psychotropic molecule in Salvia divinorum, a Mexican plant which has a long history of use as an entheogen by indigenous Mazatec shamans. Salvinorin A is a hallucinogenic compound with dissociative effects. It is structurally quite distinct from other naturally occurring hallucinogens such as N,N-dimethyltryptamine, psilocybin, and mescaline and from synthetic hallucinogens such as lysergic acid diethylamide (LSD), and ketamine. Salvinorin A has been reported to be the most potent naturally occurring psychoactive drug known to date, with an effective dose in humans in the 200- to 1,000-µg range when smoked. In that way Salvinorin A's qualitative potency may be compared with LSD, though it is otherwise dissimilar, having quite different effects and timeframes. Salvinorin A can produce psychoactive experiences in humans with a typical duration of action being several minutes to an hour or so, depending on the method of ingestion.
Salvinorin A is found together with several other structurally related salvinorins. Salvinorin is a trans-neoclerodane diterpenoid. It acts as a kappa opioid receptor agonist and is the first known compound acting on this receptor that is not an alkaloid. Salvinorin A was isolated in 1982 by Alfredo Ortega in Mexico. Its pharmacological mechanism was elucidated in the laboratory of Bryan L. Roth.
# Chemistry
Salvinorin A is a trans-neoclerodane diterpenoid, chemical formula C23H28O8. Unlike other known opioid-receptor ligands, salvinorin A is not an alkaloid — it does not contain a basic nitrogen atom. Salvinorin A has no actions at the 5-HT2A serotonin receptor, the principal molecular target responsible for the actions of 'classical' psychedelics such as LSD and mescaline.
Salvinorin A is the most potent naturally-occurring psychoactive compound known. It is active at doses as low as 200 µg. Recent research has shown that salvinorin A is a potent and selective κ (kappa) opioid receptor agonist. It has been reported that the effects of salvinorin A in mice are blocked by kappa opioid receptor antagonists. This makes it unlikely that another mechanism contributes independently to the compound’s observed effects in mice. Salvinorin A is unique in that it is the only naturally occurring substance known to induce a visionary state via this mode of action (although there are a few other synthetic kappa opioid agonists, such as enadoline, which show similar hallucinatory and dissociative effects).
Salvinorin's potency should not be confused with toxicity. Rodents chronically exposed to dosages many times greater than those to which humans are exposed did not show signs of organ damage.
Many other terpenoids have been isolated from S. divinorum, including other salvinorins and related compounds named divinatorins and salvinicins. None of these compounds has shown significant (sub-micromolar) affinity at the kappa opioid receptor, and there is no evidence that they contribute to the plant's psychoactivity.
# Salvinorin extraction
According to Daniel Siebert in his Salvia Divinorum FAQ, the extraction and purification of salvinorin A should only be attempted by qualified researchers with experience in chemistry and the proper laboratory equipment, particularly as measurement of safe dosages is difficult.
Though salvinorin A can be vaporized and inhaled, the overwhelming potency of even minute quantities of salvinorin A makes a sophisticated analytical balance essential for measuring a safe dose. However, rather than trying to obtain pure salvinorin crystals, many less technically qualified choose to produce a concentrate, starting from a given amount of leaf mass, for the purpose of making enhanced strength leaf. The resulting wax/crystal mix from such partial extraction is then returned to a smaller amount of leaf or a substrate. By choosing the amount of leaf or substrate to deposit the mix onto, the dosage is controlled by the ratio of substrate to original leaf mass.
# Salvinorin A synthesis
A significant attempt at the synthesis of salvinorin A has been published by a group at RMIT University, adopting a convergent
synthesis of a functionalized cyclohexanone with a α,β-unsaturated lactone.
A total asymmetric synthesis of salvinorin A was achieved recently by Evans and co-workers.
# Salvinorins A - F
Salvinorin A is one of several structurally related salvinorins. Salvinorin A can be synthesized from the inactive salvinorin B by acetylation. The des-acetylated analog salvinorin B is devoid of human activity. It was speculated that salvinorin C might be even more potent than salvinorin A, but human tests and receptor binding assays could not confirm this. Salvinorin A seems to be the only active naturally occurring salvinorin. | Salvinorin A
Template:Chembox new
Salvinorin A is the main active psychotropic molecule in Salvia divinorum, a Mexican plant which has a long history of use as an entheogen by indigenous Mazatec shamans. Salvinorin A is a hallucinogenic compound with dissociative effects. It is structurally quite distinct from other naturally occurring hallucinogens such as N,N-dimethyltryptamine, psilocybin, and mescaline and from synthetic hallucinogens such as lysergic acid diethylamide (LSD), and ketamine. Salvinorin A has been reported to be the most potent naturally occurring psychoactive drug known to date, with an effective dose in humans in the 200- to 1,000-µg range when smoked. In that way Salvinorin A's qualitative potency may be compared with LSD, though it is otherwise dissimilar, having quite different effects and timeframes. Salvinorin A can produce psychoactive experiences in humans with a typical duration of action being several minutes to an hour or so, depending on the method of ingestion.[1]
Salvinorin A is found together with several other structurally related salvinorins. Salvinorin is a trans-neoclerodane diterpenoid. It acts as a kappa opioid receptor agonist and is the first known compound acting on this receptor that is not an alkaloid. Salvinorin A was isolated in 1982 by Alfredo Ortega in Mexico. Its pharmacological mechanism was elucidated in the laboratory of Bryan L. Roth.
# Chemistry
Salvinorin A is a trans-neoclerodane diterpenoid, chemical formula C23H28O8.[2] Unlike other known opioid-receptor ligands, salvinorin A is not an alkaloid — it does not contain a basic nitrogen atom.[3] Salvinorin A has no actions at the 5-HT2A serotonin receptor, the principal molecular target responsible for the actions of 'classical' psychedelics such as LSD and mescaline.[3]
Salvinorin A is the most potent naturally-occurring psychoactive compound known.[4] It is active at doses as low as 200 µg.[2][4][5] Recent research has shown that salvinorin A is a potent and selective κ (kappa) opioid receptor agonist.[2] It has been reported that the effects of salvinorin A in mice are blocked by kappa opioid receptor antagonists.[6] This makes it unlikely that another mechanism contributes independently to the compound’s observed effects in mice. Salvinorin A is unique in that it is the only naturally occurring substance known to induce a visionary state via this mode of action (although there are a few other synthetic kappa opioid agonists, such as enadoline, which show similar hallucinatory and dissociative effects).
Salvinorin's potency should not be confused with toxicity. Rodents chronically exposed to dosages many times greater than those to which humans are exposed did not show signs of organ damage.[7]
Many other terpenoids have been isolated from S. divinorum, including other salvinorins and related compounds named divinatorins and salvinicins. None of these compounds has shown significant (sub-micromolar) affinity at the kappa opioid receptor, and there is no evidence that they contribute to the plant's psychoactivity.[8][9]
# Salvinorin extraction
Template:Refimprovesect
According to Daniel Siebert in his Salvia Divinorum FAQ, the extraction and purification of salvinorin A should only be attempted by qualified researchers with experience in chemistry and the proper laboratory equipment, particularly as measurement of safe dosages is difficult.[10]
Though salvinorin A can be vaporized and inhaled, the overwhelming potency of even minute quantities of salvinorin A makes a sophisticated analytical balance essential for measuring a safe dose. However, rather than trying to obtain pure salvinorin crystals, many less technically qualified choose to produce a concentrate, starting from a given amount of leaf mass, for the purpose of making enhanced strength leaf. The resulting wax/crystal mix from such partial extraction is then returned to a smaller amount of leaf or a substrate. By choosing the amount of leaf or substrate to deposit the mix onto, the dosage is controlled by the ratio of substrate to original leaf mass.
# Salvinorin A synthesis
A significant attempt at the synthesis of salvinorin A has been published by a group at RMIT University, adopting a convergent
synthesis of a functionalized cyclohexanone with a α,β-unsaturated lactone.[11]
A total asymmetric synthesis of salvinorin A was achieved recently by Evans and co-workers.[12]
# Salvinorins A - F
Salvinorin A is one of several structurally related salvinorins. Salvinorin A can be synthesized from the inactive salvinorin B by acetylation. The des-acetylated analog salvinorin B is devoid of human activity. It was speculated that salvinorin C might be even more potent than salvinorin A, but human tests and receptor binding assays could not confirm this. Salvinorin A seems to be the only active naturally occurring salvinorin.[9] | https://www.wikidoc.org/index.php/Salvinorin_A | |
de62352dfda5545cad8068aab96b0df6928a4729 | wikidoc | Samuel Armas | Samuel Armas
# Background
Samuel Armas, Template:Birth date and age, is the child who featured in a famous photograph by Michael Clancy as he seemed to grasp his surgeon's hand from a hole in his mother's uterus during open fetal surgery for spina bifida.
# Story behind the photo
The photograph was taken during a pioneering surgical procedure undertaken on August 19 1999 to fix the spina bifida lesion of a 21-week-old fetus in the womb. The operation was performed by a surgical team at Vanderbilt University in Nashville. The team, Dr. Joseph Bruner and Dr. Noel Tulipan, had been developing a technique for correcting certain fetal problems in mid-pregnancy. Their procedure involved temporarily opening the uterus, draining the amniotic fluid, partially extracting and performing surgery on the tiny fetus, then restoring the fetus to the uterus back inside the mother.
## Samuel Armas
Alex and Julie Armas first discovered that their baby had spina bifida during an ultrasound at 14 weeks after conception mark. The Armases came across the Vanderbilt procedure while researching their options online.
The baby Samuel Armas was the 54th fetus operated on by the surgical team. During the operation Dr. Joseph Bruner was successfully able to alleviate the effects of the opening in Samuel's spine caused by the spina bifida.
# Around the world
Pictures from the surgery were printed in a number of newspapers in the U.S. and around the world, including USA Today. As a result of the operation, Armas was healthy when he was delivered on December 02, 1999.
On September 25, 2003 the boy's parents, Alex and Julie, testified before the U.S. Senate Subcommittee on Science, Technology, and Space about the photo and their experience with in-utero surgery.
# Matt Drudge
In 1999 Matt Drudge hosted a Saturday night television show called Drudge on the Fox News Channel. In Nov 1999 he attempted to show Samuel's picture on his Fox News program, but was not allowed to by the network. This led to his leaving of the show for what he claimed to be the network's censorship. Fox news directors didn't want to use the picture because they feared Drudge would use it to support an anti-abortion argument. They viewed this would be misleading because the tabloid photo dealt not with abortion but with an emergency operation on the fetus for spina bifida.
# Controversy
The picture attracted a lot of attention as when it was released it was seized upon by opponents of abortion who asserted that that the baby reached through the womb and grabbed the doctor's hand thus showing signs of life at the 21st week of pregnancy. Indeed the photograph and many of the texts which often accompany it seem to support this view including the account of the photographer Michael Clancy:
However the surgeon later stated that Samuel and his mother, Julie, were under anesthesia and could not move. "The baby did not reach out," Dr Bruner said. "The baby was anesthetized. The baby was not aware of what was going on." .
# Cultural References
The event has been referenced in two medical TV series; the drama House, in the episode Fetal Position and the sitcom Scrubs, in the episode My Road to Nowhere. | Samuel Armas
Template:Infobox Person
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
Samuel Armas, Template:Birth date and age, is the child who featured in a famous photograph by Michael Clancy as he seemed to grasp his surgeon's hand from a hole in his mother's uterus during open fetal surgery for spina bifida.
# Story behind the photo
The photograph was taken during a pioneering surgical procedure undertaken on August 19 1999 to fix the spina bifida lesion of a 21-week-old fetus in the womb. The operation was performed by a surgical team at Vanderbilt University in Nashville. The team, Dr. Joseph Bruner and Dr. Noel Tulipan, had been developing a technique for correcting certain fetal problems in mid-pregnancy. Their procedure involved temporarily opening the uterus, draining the amniotic fluid, partially extracting and performing surgery on the tiny fetus, then restoring the fetus to the uterus back inside the mother.
## Samuel Armas
Alex and Julie Armas first discovered that their baby had spina bifida during an ultrasound at 14 weeks after conception mark. The Armases came across the Vanderbilt procedure while researching their options online.[1]
The baby Samuel Armas was the 54th fetus operated on by the surgical team[2]. During the operation Dr. Joseph Bruner was successfully able to alleviate the effects of the opening in Samuel's spine caused by the spina bifida.
# Around the world
Pictures from the surgery were printed in a number of newspapers in the U.S. and around the world, including USA Today. As a result of the operation, Armas was healthy when he was delivered on December 02, 1999.
On September 25, 2003 the boy's parents, Alex and Julie, testified before the U.S. Senate Subcommittee on Science, Technology, and Space about the photo and their experience with in-utero surgery.
Template:Cquote2
# Matt Drudge
In 1999 Matt Drudge hosted a Saturday night television show called Drudge on the Fox News Channel. In Nov 1999 he attempted to show Samuel's picture on his Fox News program, but was not allowed to by the network. This led to his leaving of the show for what he claimed to be the network's censorship. Fox news directors didn't want to use the picture because they feared Drudge would use it to support an anti-abortion argument. They viewed this would be misleading because the tabloid photo dealt not with abortion but with an emergency operation on the fetus for spina bifida.[3]
# Controversy
The picture attracted a lot of attention as when it was released it was seized upon by opponents of abortion who asserted that that the baby reached through the womb and grabbed the doctor's hand thus showing signs of life at the 21st week of pregnancy. Indeed the photograph and many of the texts which often accompany it seem to support this view including the account of the photographer Michael Clancy:
Template:Cquote2
However the surgeon later stated that Samuel and his mother, Julie, were under anesthesia and could not move. "The baby did not reach out," Dr Bruner said. "The baby was anesthetized. The baby was not aware of what was going on." [4].
# Cultural References
The event has been referenced in two medical TV series; the drama House, in the episode Fetal Position and the sitcom Scrubs, in the episode My Road to Nowhere. | https://www.wikidoc.org/index.php/Samuel_Armas | |
c5d6a49060b4a632eaca8f7630dfb9b598425014 | wikidoc | Samuel Orton | Samuel Orton
Samuel Torrey Orton (October 15, 1879–November 17, 1948) was an American physician who pioneered the study of learning disabilities. He is best known for his work examining the causes and treatment of reading disability, or dyslexia.
Orton's interest in learning disabilities stemmed from his early work as a pathologist in Massachusetts, where he worked with adult patients with brain damage. This led him to study why some children with apparently intact neurological functioning have language disabilities. In 1919, Orton was hired as the founding director of the State Psychopathic Hospital in Iowa City, Iowa, and chairman of the Department of Psychiatry at the University of Iowa College of Medicine. In 1925, Orton set up a 2-week mobile clinic in Greene County, Iowa to evaluate students referred by teachers because they "were retarded or failing in their school work." Orton found that 14 of the students who were referred primarily because they had great difficulty in learning to read, in fact had near-average, average, or above-average IQ scores.
Orton's study of reading difficulties in children led him to hypothesize that these individuals have failed to establish appropriate cerebral organization to support the association of visual words with their spoken forms.. He termed this difficulty strephosymbolia, meaning "twisted symbols". This term stemmed from Orton’s observation that many of the children he worked with tended to reverse letters or transpose their order. Orton also reported that some of his research subjects could read more easily if they held pages up to a mirror, and a few were rapid mirror writers.
Working in the 1920’s, Orton did not have access to modern brain scanning equipment,
but he knew from his work with brain damaged adults that injuries to the left
hemisphere produced symptoms similar to those he observed in children. Many of the children Orton studied were also ambidextrous or had mixed handedness. This led Orton to theorize that the children's reading problems stemmed from the failure of the left hemisphere to become dominant over the right. Some of Orton's theories about brain structure and organization would later be confirmed by modern brain researchers, such as Dr. Albert Galaburda, who compared the brains of deceased dyslexic and non-dyslexic adults in the late 1970s.
Dr. Orton’s key contribution to the field of education was the concept of “multisensory” teaching–integrating kinesthetic (movement-based) and tactile (sensory-based) learning
strategies with teaching of visual and auditory concepts. Dr. Orton wanted a way to teach reading that would integrate right and left brain functions. He was influenced by the work of fellow psychiatrist Grace Fernald, who had developed a kinesthetic approach involving writing in the air and tracing words in large written or scripted format, while simultaneously saying the names and sounds of the letters.
Later, Orton began working with psychologist Anna Gillingham, who introduced a systematic and orderly approach of categorizing and teaching a set of 70 phonograms, single
letters and letter pairs representing the 44 discrete sounds (or phonemes) found in
English. In the years since Dr. Orton's death in 1948, his name has come to be strongly associated with the Orton-Gillingham teaching method, which remains the basis of the most prevalent form of remediation and tutoring for children with dyslexia. | Samuel Orton
Samuel Torrey Orton (October 15, 1879–November 17, 1948) was an American physician who pioneered the study of learning disabilities. He is best known for his work examining the causes and treatment of reading disability, or dyslexia.
Orton's interest in learning disabilities stemmed from his early work as a pathologist in Massachusetts, where he worked with adult patients with brain damage. This led him to study why some children with apparently intact neurological functioning have language disabilities. In 1919, Orton was hired as the founding director of the State Psychopathic Hospital in Iowa City, Iowa, and chairman of the Department of Psychiatry at the University of Iowa College of Medicine.[1] In 1925, Orton set up a 2-week mobile clinic in Greene County, Iowa to evaluate students referred by teachers because they "were retarded or failing in their school work." Orton found that 14 of the students who were referred primarily because they had great difficulty in learning to read, in fact had near-average, average, or above-average IQ scores.[2]
Orton's study of reading difficulties in children led him to hypothesize that these individuals have failed to establish appropriate cerebral organization to support the association of visual words with their spoken forms.[3]. He termed this difficulty strephosymbolia, meaning "twisted symbols". This term stemmed from Orton’s observation that many of the children he worked with tended to reverse letters or transpose their order. Orton also reported that some of his research subjects could read more easily if they held pages up to a mirror, and a few were rapid mirror writers.
Working in the 1920’s, Orton did not have access to modern brain scanning equipment,
but he knew from his work with brain damaged adults that injuries to the left
hemisphere produced symptoms similar to those he observed in children. Many of the children Orton studied were also ambidextrous or had mixed handedness. This led Orton to theorize that the children's reading problems stemmed from the failure of the left hemisphere to become dominant over the right. Some of Orton's theories about brain structure and organization would later be confirmed by modern brain researchers, such as Dr. Albert Galaburda, who compared the brains of deceased dyslexic and non-dyslexic adults in the late 1970s.
Dr. Orton’s key contribution to the field of education was the concept of “multisensory” teaching–integrating kinesthetic (movement-based) and tactile (sensory-based) learning
strategies with teaching of visual and auditory concepts. Dr. Orton wanted a way to teach reading that would integrate right and left brain functions. He was influenced by the work of fellow psychiatrist Grace Fernald, who had developed a kinesthetic approach involving writing in the air and tracing words in large written or scripted format, while simultaneously saying the names and sounds of the letters.
Later, Orton began working with psychologist Anna Gillingham, who introduced a systematic and orderly approach of categorizing and teaching a set of 70 phonograms, single
letters and letter pairs representing the 44 discrete sounds (or phonemes) found in
English. In the years since Dr. Orton's death in 1948, his name has come to be strongly associated with the Orton-Gillingham teaching method, which remains the basis of the most prevalent form of remediation and tutoring for children with dyslexia. | https://www.wikidoc.org/index.php/Samuel_Orton | |
770c41658f62329a32a83a04f0e17c3b4d9403a7 | wikidoc | Sanbox:Kamal | Sanbox:Kamal
==References==
# Differentiating NHL
- ↑ Shelly D, Gujral S (2017). "Early T-Cell Precursor Acute Lymphoblastic Leukaemia/Lymphoma: Immunohistochemical Evaluation of Four Lymph Node Biopsies". J Clin Diagn Res. 11 (7): EL01–EL02. doi:10.7860/JCDR/2017/29352.10164. PMC 5583929. PMID 28892922..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}
- ↑ You MJ, Medeiros LJ, Hsi ED (2015). "T-lymphoblastic leukemia/lymphoma". Am J Clin Pathol. 144 (3): 411–22. doi:10.1309/AJCPMF03LVSBLHPJ. PMID 26276771.CS1 maint: Multiple names: authors list (link)
- ↑ Rose, M. G. (2004). "T-Cell Large Granular Lymphocyte Leukemia and Related Disorders". The Oncologist. 9 (3): 247–258. doi:10.1634/theoncologist.9-3-247. ISSN 1083-7159.
- ↑ Liu EB, Chen HS, Zhang PH, Li ZQ, Sun Q, Yang QY; et al. (2012). "". Zhonghua Bing Li Xue Za Zhi. 41 (4): 229–33. doi:10.3760/cma.j.issn.0529-5807.2012.04.004. PMID 22800517.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Osuji N, Matutes E, Catovsky D, Lampert I, Wotherspoon A (2005). "Histopathology of the spleen in T-cell large granular lymphocyte leukemia and T-cell prolymphocytic leukemia: a comparative review". Am J Surg Pathol. 29 (7): 935–41. PMID 15958859.CS1 maint: Multiple names: authors list (link)
- ↑ Graham RL, Cooper B, Krause JR (2013). "T-cell prolymphocytic leukemia". Proc (Bayl Univ Med Cent). 26 (1): 19–21. PMC 3523759. PMID 23382603.CS1 maint: Multiple names: authors list (link)
- ↑ Matutes E (2007). "Adult T-cell leukaemia/lymphoma". J. Clin. Pathol. 60 (12): 1373–7. doi:10.1136/jcp.2007.052456. PMC 2095573. PMID 18042693.
- ↑ Matutes E (2007) Adult T-cell leukaemia/lymphoma. J Clin Pathol 60 (12):1373-7. DOI:10.1136/jcp.2007.052456 PMID: 18042693
- ↑ Shimoyama M (1991). "Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87)". Br J Haematol. 79 (3): 428–37. PMID 1751370.
- ↑ Al-Ahmad, Selma; Maertens, Vincent; Libeer, Christophe; Schelfhout, Vera; Vanhoenacker, Filip; Boeckx, Nancy; Vandevenne, Marleen (2017). "The masquerading presentation of a systemic anaplastic large cell lymphoma, ALK positive: a case report and review of the literature". Acta Clinica Belgica. 72 (6): 454–460. doi:10.1080/17843286.2017.1312057. ISSN 1784-3286.
- ↑ Yu L, Yan LL, Yang SJ (2014). "Sarcomatoid variant of ALK- anaplastic large cell lymphoma involving multiple lymph nodes and both lungs with production of proinflammatory cytokines: report of a case and review of literature". Int J Clin Exp Pathol. 7 (8): 4806–16. PMC 4152041. PMID 25197351.CS1 maint: Multiple names: authors list (link)
- ↑ de Campos FPF, Zerbini MCN, Felipe-Silva A, Simões AB, Lovisolo SM, da Fonseca LG; et al. (2014). "Unusual clinical presentation of anaplastic large cell lymphoma". Autops Case Rep. 4 (1): 21–27. doi:10.4322/acr.2014.004. PMC 5470561. PMID 28652989.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Watanabe M, Ogawa Y, Itoh K; et al. (January 2008). "Hypomethylation of CD30 CpG islands with aberrant JunB expression drives CD30 induction in Hodgkin lymphoma and anaplastic large cell lymphoma". Lab. Invest. 88 (1): 48–57. doi:10.1038/labinvest.3700696. PMID 17965727.CS1 maint: Multiple names: authors list (link)
- ↑ Foss, Francine M.; Girardi, Michael (2017). "Mycosis Fungoides and Sezary Syndrome". Hematology/Oncology Clinics of North America. 31 (2): 297–315. doi:10.1016/j.hoc.2016.11.008. ISSN 0889-8588.
- ↑ Campbell, J. J.; Clark, R. A.; Watanabe, R.; Kupper, T. S. (2010). "Sezary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors". Blood. 116 (5): 767–771. doi:10.1182/blood-2009-11-251926. ISSN 0006-4971.
- ↑ Vonderheid, Eric C.; Bernengo, Maria Grazia; Burg, Günter; Duvic, Madeleine; Heald, Peter; Laroche, Liliane; Olsen, Elise; Pittelkow, Mark; Russell-Jones, Robin; Takigawa, Masahiro; Willemze, Rein (2002). "Update on erythrodermic cutaneous T-cell lymphoma: Report of the international society for cutaneous lymphomas". Journal of the American Academy of Dermatology. 46 (1): 95–106. doi:10.1067/mjd.2002.118538. ISSN 0190-9622.
- ↑ Subcutaneous panniculitis-like T-cell lymphoma. Surveillance, Epidemiology, and End Results Program. /. Accessed on March 08, 2016
- ↑ Subcutaneous panniculitis-like T-cell lymphoma. Surveillance, Epidemiology, and End Results Program. /. Accessed on March 08, 2016
- ↑ Parveen Z, Thompson K (2009). "Subcutaneous panniculitis-like T-cell lymphoma: redefinition of diagnostic criteria in the recent World Health Organization-European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas". Arch Pathol Lab Med. 133 (2): 303–8. doi:10.1043/1543-2165-133.2.303. PMID 19195975.
- ↑ van de Meeberg MM, Derikx LA, Sinnige HA, Nooijen P, Schipper DL, Nissen LH (2016). "Hepatosplenic T-cell lymphoma in a 47-year-old Crohn's disease patient on thiopurine monotherapy". World J Gastroenterol. 22 (47): 10465–10470. doi:10.3748/wjg.v22.i47.10465. PMC 5175260. PMID 28058028.CS1 maint: Multiple names: authors list (link)
- ↑ Shi, Yang; Wang, Endi (2015). "Hepatosplenic T-Cell Lymphoma: A Clinicopathologic Review With an Emphasis on Diagnostic Differentiation From Other T-Cell/Natural Killer–Cell Neoplasms". Archives of Pathology & Laboratory Medicine. 139 (9): 1173–1180. doi:10.5858/arpa.2014-0079-RS. ISSN 0003-9985.
- ↑ Alsohaibani FI, Abdulla MA, Fagih MM (2011). "Hepatosplenic T-cell lymphoma". Indian J Hematol Blood Transfus. 27 (1): 39–42. doi:10.1007/s12288-010-0051-1. PMC 3102508. PMID 22379294.CS1 maint: Multiple names: authors list (link)
- ↑ Delabie, J.; Holte, H.; Vose, J. M.; Ullrich, F.; Jaffe, E. S.; Savage, K. J.; Connors, J. M.; Rimsza, L.; Harris, N. L.; Muller-Hermelink, K.; Rudiger, T.; Coiffier, B.; Gascoyne, R. D.; Berger, F.; Tobinai, K.; Au, W. Y.; Liang, R.; Montserrat, E.; Hochberg, E. P.; Pileri, S.; Federico, M.; Nathwani, B.; Armitage, J. O.; Weisenburger, D. D. (2011). "Enteropathy-associated T-cell lymphoma: clinical and histological findings from the International Peripheral T-Cell Lymphoma Project". Blood. 118 (1): 148–155. doi:10.1182/blood-2011-02-335216. ISSN 0006-4971.
- ↑ Bautista-Quach MA, Ake CD, Chen M, Wang J (September 2012). "Gastrointestinal lymphomas: Morphology, immunophenotype and molecular features". J Gastrointest Oncol. 3 (3): 209–25. doi:10.3978/j.issn.2078-6891.2012.024. PMC 3418529. PMID 22943012.
- ↑ Enteropathy-associated T-cell lymphoma. Surveillance, Epidemiology, and End Results Program. /. Accessed on January 26, 2016
- ↑ Extranodal Natural-Killer/T-Cell Lymphoma, Nasal Type. Hindawi Publishing Corporation. /. Accessed on February 19, 2016
- ↑ Extranodal NK-/T-cell lymphoma, nasal type. Surveillance, Epidemiology, and End Results Program. /. Accessed on February 02, 2016
- ↑ Extranodal Natural-Killer/T-Cell Lymphoma, Nasal Type. Hindawi Publishing Corporation. /. Accessed on February 18, 2016
- ↑ Swerdlow, S.H.; Campo, E.; Harris, N.L.; Jaffe, E.S.; Pileri, S.A.; Stein, H.; Thiele, J.; Vardiman, J.W (2008). "11 Mature T- and NK-cell neoplasms: Angioimmunoblastic T-cell lymphoma". WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC WHO Classification of Tumours. 2 (4th ed.). IARC. ISBN 9283224310.
- ↑ Quintanilla-Martinez L, Fend F, Moguel LR, Spilove L, Beaty MW, Kingma DW, Raffeld M, Jaffe ES. "Peripheral T-cell lymphoma with Reed-Sternberg-like cells of B-cell phenotype and genotype associated with Epstein-Barr virus infection." Am J Surg Pathol. 1999 Oct;23(10):1233-40. PMID: 10524524
- ↑ Angioimmunoblastic T-cell lymphoma. Surveillance, Epidemiology, and End Results Program. / Accessed on November 27, 2015
- ↑ Lemonnier F, Couronné L, Parrens M, Jaïs JP, Travert M, Lamant L, Tournillac O, Rousset T, Fabiani B, Cairns RA, Mak T, Bastard C, Bernard OA, de Leval L, Gaulard P (August 2012). "Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters". Blood. 120 (7): 1466–9. doi:10.1182/blood-2012-02-408542. PMID 22760778.
- ↑ Jha, KunalKishor; Gupta, SureshK; Saluja, Harpreet; Subedi, Nuwadatta (2017). "Peripheral T-cell lymphoma, not otherwise specified". Journal of Family Medicine and Primary Care. 6 (2): 427. doi:10.4103/jfmpc.jfmpc_323_16. ISSN 2249-4863. | Sanbox:Kamal
==References==
# Differentiating NHL
- ↑ Shelly D, Gujral S (2017). "Early T-Cell Precursor Acute Lymphoblastic Leukaemia/Lymphoma: Immunohistochemical Evaluation of Four Lymph Node Biopsies". J Clin Diagn Res. 11 (7): EL01–EL02. doi:10.7860/JCDR/2017/29352.10164. PMC 5583929. PMID 28892922..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}
- ↑ You MJ, Medeiros LJ, Hsi ED (2015). "T-lymphoblastic leukemia/lymphoma". Am J Clin Pathol. 144 (3): 411–22. doi:10.1309/AJCPMF03LVSBLHPJ. PMID 26276771.CS1 maint: Multiple names: authors list (link)
- ↑ Rose, M. G. (2004). "T-Cell Large Granular Lymphocyte Leukemia and Related Disorders". The Oncologist. 9 (3): 247–258. doi:10.1634/theoncologist.9-3-247. ISSN 1083-7159.
- ↑ Liu EB, Chen HS, Zhang PH, Li ZQ, Sun Q, Yang QY; et al. (2012). "[Hematopathologic features of T-cell large granular lymphocytic leukemia]". Zhonghua Bing Li Xue Za Zhi. 41 (4): 229–33. doi:10.3760/cma.j.issn.0529-5807.2012.04.004. PMID 22800517.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Osuji N, Matutes E, Catovsky D, Lampert I, Wotherspoon A (2005). "Histopathology of the spleen in T-cell large granular lymphocyte leukemia and T-cell prolymphocytic leukemia: a comparative review". Am J Surg Pathol. 29 (7): 935–41. PMID 15958859.CS1 maint: Multiple names: authors list (link)
- ↑ Graham RL, Cooper B, Krause JR (2013). "T-cell prolymphocytic leukemia". Proc (Bayl Univ Med Cent). 26 (1): 19–21. PMC 3523759. PMID 23382603.CS1 maint: Multiple names: authors list (link)
- ↑ Matutes E (2007). "Adult T-cell leukaemia/lymphoma". J. Clin. Pathol. 60 (12): 1373–7. doi:10.1136/jcp.2007.052456. PMC 2095573. PMID 18042693.
- ↑ Matutes E (2007) Adult T-cell leukaemia/lymphoma. J Clin Pathol 60 (12):1373-7. DOI:10.1136/jcp.2007.052456 PMID: 18042693
- ↑ Shimoyama M (1991). "Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87)". Br J Haematol. 79 (3): 428–37. PMID 1751370.
- ↑ Al-Ahmad, Selma; Maertens, Vincent; Libeer, Christophe; Schelfhout, Vera; Vanhoenacker, Filip; Boeckx, Nancy; Vandevenne, Marleen (2017). "The masquerading presentation of a systemic anaplastic large cell lymphoma, ALK positive: a case report and review of the literature". Acta Clinica Belgica. 72 (6): 454–460. doi:10.1080/17843286.2017.1312057. ISSN 1784-3286.
- ↑ Yu L, Yan LL, Yang SJ (2014). "Sarcomatoid variant of ALK- anaplastic large cell lymphoma involving multiple lymph nodes and both lungs with production of proinflammatory cytokines: report of a case and review of literature". Int J Clin Exp Pathol. 7 (8): 4806–16. PMC 4152041. PMID 25197351.CS1 maint: Multiple names: authors list (link)
- ↑ de Campos FPF, Zerbini MCN, Felipe-Silva A, Simões AB, Lovisolo SM, da Fonseca LG; et al. (2014). "Unusual clinical presentation of anaplastic large cell lymphoma". Autops Case Rep. 4 (1): 21–27. doi:10.4322/acr.2014.004. PMC 5470561. PMID 28652989.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Watanabe M, Ogawa Y, Itoh K; et al. (January 2008). "Hypomethylation of CD30 CpG islands with aberrant JunB expression drives CD30 induction in Hodgkin lymphoma and anaplastic large cell lymphoma". Lab. Invest. 88 (1): 48–57. doi:10.1038/labinvest.3700696. PMID 17965727.CS1 maint: Multiple names: authors list (link)
- ↑ Foss, Francine M.; Girardi, Michael (2017). "Mycosis Fungoides and Sezary Syndrome". Hematology/Oncology Clinics of North America. 31 (2): 297–315. doi:10.1016/j.hoc.2016.11.008. ISSN 0889-8588.
- ↑ Campbell, J. J.; Clark, R. A.; Watanabe, R.; Kupper, T. S. (2010). "Sezary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors". Blood. 116 (5): 767–771. doi:10.1182/blood-2009-11-251926. ISSN 0006-4971.
- ↑ Vonderheid, Eric C.; Bernengo, Maria Grazia; Burg, Günter; Duvic, Madeleine; Heald, Peter; Laroche, Liliane; Olsen, Elise; Pittelkow, Mark; Russell-Jones, Robin; Takigawa, Masahiro; Willemze, Rein (2002). "Update on erythrodermic cutaneous T-cell lymphoma: Report of the international society for cutaneous lymphomas". Journal of the American Academy of Dermatology. 46 (1): 95–106. doi:10.1067/mjd.2002.118538. ISSN 0190-9622.
- ↑ Subcutaneous panniculitis-like T-cell lymphoma. Surveillance, Epidemiology, and End Results Program. http://seer.cancer.gov/seertools/hemelymph/51f6cf56e3e27c3994bd52df/. Accessed on March 08, 2016
- ↑ Subcutaneous panniculitis-like T-cell lymphoma. Surveillance, Epidemiology, and End Results Program. http://seer.cancer.gov/seertools/hemelymph/51f6cf56e3e27c3994bd52df/. Accessed on March 08, 2016
- ↑ Parveen Z, Thompson K (2009). "Subcutaneous panniculitis-like T-cell lymphoma: redefinition of diagnostic criteria in the recent World Health Organization-European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas". Arch Pathol Lab Med. 133 (2): 303–8. doi:10.1043/1543-2165-133.2.303. PMID 19195975.
- ↑ van de Meeberg MM, Derikx LA, Sinnige HA, Nooijen P, Schipper DL, Nissen LH (2016). "Hepatosplenic T-cell lymphoma in a 47-year-old Crohn's disease patient on thiopurine monotherapy". World J Gastroenterol. 22 (47): 10465–10470. doi:10.3748/wjg.v22.i47.10465. PMC 5175260. PMID 28058028.CS1 maint: Multiple names: authors list (link)
- ↑ Shi, Yang; Wang, Endi (2015). "Hepatosplenic T-Cell Lymphoma: A Clinicopathologic Review With an Emphasis on Diagnostic Differentiation From Other T-Cell/Natural Killer–Cell Neoplasms". Archives of Pathology & Laboratory Medicine. 139 (9): 1173–1180. doi:10.5858/arpa.2014-0079-RS. ISSN 0003-9985.
- ↑ Alsohaibani FI, Abdulla MA, Fagih MM (2011). "Hepatosplenic T-cell lymphoma". Indian J Hematol Blood Transfus. 27 (1): 39–42. doi:10.1007/s12288-010-0051-1. PMC 3102508. PMID 22379294.CS1 maint: Multiple names: authors list (link)
- ↑ Delabie, J.; Holte, H.; Vose, J. M.; Ullrich, F.; Jaffe, E. S.; Savage, K. J.; Connors, J. M.; Rimsza, L.; Harris, N. L.; Muller-Hermelink, K.; Rudiger, T.; Coiffier, B.; Gascoyne, R. D.; Berger, F.; Tobinai, K.; Au, W. Y.; Liang, R.; Montserrat, E.; Hochberg, E. P.; Pileri, S.; Federico, M.; Nathwani, B.; Armitage, J. O.; Weisenburger, D. D. (2011). "Enteropathy-associated T-cell lymphoma: clinical and histological findings from the International Peripheral T-Cell Lymphoma Project". Blood. 118 (1): 148–155. doi:10.1182/blood-2011-02-335216. ISSN 0006-4971.
- ↑ Bautista-Quach MA, Ake CD, Chen M, Wang J (September 2012). "Gastrointestinal lymphomas: Morphology, immunophenotype and molecular features". J Gastrointest Oncol. 3 (3): 209–25. doi:10.3978/j.issn.2078-6891.2012.024. PMC 3418529. PMID 22943012.
- ↑ Enteropathy-associated T-cell lymphoma. Surveillance, Epidemiology, and End Results Program. http://seer.cancer.gov/seertools/hemelymph/51f6cf56e3e27c3994bd5315/. Accessed on January 26, 2016
- ↑ Extranodal Natural-Killer/T-Cell Lymphoma, Nasal Type. Hindawi Publishing Corporation. http://www.hindawi.com/journals/ah/2010/627401/. Accessed on February 19, 2016
- ↑ Extranodal NK-/T-cell lymphoma, nasal type. Surveillance, Epidemiology, and End Results Program. http://seer.cancer.gov/seertools/hemelymph/51f6cf56e3e27c3994bd530f/. Accessed on February 02, 2016
- ↑ Extranodal Natural-Killer/T-Cell Lymphoma, Nasal Type. Hindawi Publishing Corporation. http://www.hindawi.com/journals/ah/2010/627401/. Accessed on February 18, 2016
- ↑ Swerdlow, S.H.; Campo, E.; Harris, N.L.; Jaffe, E.S.; Pileri, S.A.; Stein, H.; Thiele, J.; Vardiman, J.W (2008). "11 Mature T- and NK-cell neoplasms: Angioimmunoblastic T-cell lymphoma". WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC WHO Classification of Tumours. 2 (4th ed.). IARC. ISBN 9283224310.
- ↑ [1] Quintanilla-Martinez L, Fend F, Moguel LR, Spilove L, Beaty MW, Kingma DW, Raffeld M, Jaffe ES. "Peripheral T-cell lymphoma with Reed-Sternberg-like cells of B-cell phenotype and genotype associated with Epstein-Barr virus infection." Am J Surg Pathol. 1999 Oct;23(10):1233-40. PMID: 10524524
- ↑ Angioimmunoblastic T-cell lymphoma. Surveillance, Epidemiology, and End Results Program. http://seer.cancer.gov/seertools/hemelymph/51f6cf56e3e27c3994bd52dc/ Accessed on November 27, 2015
- ↑ Lemonnier F, Couronné L, Parrens M, Jaïs JP, Travert M, Lamant L, Tournillac O, Rousset T, Fabiani B, Cairns RA, Mak T, Bastard C, Bernard OA, de Leval L, Gaulard P (August 2012). "Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters". Blood. 120 (7): 1466–9. doi:10.1182/blood-2012-02-408542. PMID 22760778.
- ↑ Jha, KunalKishor; Gupta, SureshK; Saluja, Harpreet; Subedi, Nuwadatta (2017). "Peripheral T-cell lymphoma, not otherwise specified". Journal of Family Medicine and Primary Care. 6 (2): 427. doi:10.4103/jfmpc.jfmpc_323_16. ISSN 2249-4863.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Sanbox:Kamal | |
a77aaee2870b742d2e4a4d37d11a049b256d8760 | wikidoc | Sandbox/Afib | Sandbox/Afib
# Cardioversion Strategy
# Anticoagulation Strategy
- For patients with AF and a mechanical heart valve undergoing procedures that require interruption of warfarin bridging therapy with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) is needed.
# Do's & Dont's
- IV amiodarone or digoxin may be considered to slow a rapid ventricular response in patients with ACS and AF associated with severe LV dysfunction and HF.
- Avoid beta blockers to control the ventricular rate in patients with AF and chronic obstructive pulmonary disease.
- Avoid amiodarone, adenosine, digoxin, or calcium channel antagonists (oral or intravenous) in patients with WPW syndrome who have pre-excited AF.
- In AF with HF, it is reasonable to perform AV node ablation with ventricular pacing to control heart rate when pharmacological therapy is insufficient or not tolerated.
- For patients with AF and rapid ventricular response causing or suspected of causing tachycardia induced cardiomyopathy, it is reasonable to achieve rate control by either AV nodal blockade or a rhythm-control strategy. | Sandbox/Afib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Cardioversion Strategy
# Anticoagulation Strategy
- For patients with AF and a mechanical heart valve undergoing procedures that require interruption of warfarin bridging therapy with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) is needed.
# Do's & Dont's
- IV amiodarone or digoxin may be considered to slow a rapid ventricular response in patients with ACS and AF associated with severe LV dysfunction and HF.
- Avoid beta blockers to control the ventricular rate in patients with AF and chronic obstructive pulmonary disease.
- Avoid amiodarone, adenosine, digoxin, or calcium channel antagonists (oral or intravenous) in patients with WPW syndrome who have pre-excited AF.
- In AF with HF, it is reasonable to perform AV node ablation with ventricular pacing to control heart rate when pharmacological therapy is insufficient or not tolerated.
- For patients with AF and rapid ventricular response causing or suspected of causing tachycardia induced cardiomyopathy, it is reasonable to achieve rate control by either AV nodal blockade or a rhythm-control strategy. | https://www.wikidoc.org/index.php/Sandbox/Afib | |
255e7bbb6a313d2827e9b674bb0e6227a9cbf643 | wikidoc | Sandbox/HOCM | Sandbox/HOCM
# Overview
# Causes
# FIRE: Focused Initial Rapid Evaluation
A Focused Initial Rapid Evaluation (FIRE) should be performed to identify patients in need of immediate intervention.
Boxes in red color signify that an urgent management is needed.
# Complete Diagnostic Approach to Hypertrophic Obstructive Cardiomyopathy
A complete diagnostic approach should be carried out after a focused initial rapid evaluation is conducted and following initiation of any urgent intervention.
# Treatment
# Do's
# Dont's | Sandbox/HOCM
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mugilan Poongkunran M.B.B.S [2]
# Overview
# Causes
# FIRE: Focused Initial Rapid Evaluation
A Focused Initial Rapid Evaluation (FIRE) should be performed to identify patients in need of immediate intervention.
Boxes in red color signify that an urgent management is needed.
# Complete Diagnostic Approach to Hypertrophic Obstructive Cardiomyopathy
A complete diagnostic approach should be carried out after a focused initial rapid evaluation is conducted and following initiation of any urgent intervention.
# Treatment
# Do's
# Dont's | https://www.wikidoc.org/index.php/Sandbox/HOCM | |
346df6a091dba1099c918372ebb02418a844dec5 | wikidoc | Sandbox:Asem | Sandbox:Asem
# Overview
Updog syndrome is a disease that affected Human beings in the 21st century. It was caused by the SuperBug , whose origins are still disputed, with several indications that it may have been developed by an alien species. The syndrome had a varied presentation, the common features included inattentiveness, decreased mental capacity, drooling, laziness with sudden bursts of activity, uncontrollable diarrhea, constant tweeting and an increased appetite for gluten-free products. Despite several treatment options being developed, the disease was only eradicated in the year 2069 after Emperor Joffrey gathered all affected patients in cages and then put them on rockets headed directly to the sun with the assistance of trillionaire, and first human fusion individual, Jelon Mezos, in what was known as project "Best Summer Tan".
# Historical Perspective
- File:Audience-band-concert-1105666.jpgThe burning of FyreMan, announcing the start of the fest (2041)Updog syndrome was first described in 2041 by American innovator and InstagTwitter personality @Kute_Lash_Curls854873 who documented several cases during her coverage of the 14th Burning Fyre Man Fest which took place in northeastern Venezuela. Several outbreaks were reported in the following weeks across the globe.
- In 2044, the North Korean CDC announced that it had isolated the causative pathogen, an unusual spherical bacterium with a completely opaque surface and it was named SuperBug.
# Pathophysiology
## Pathogenesis
- The pathogenesis of Updog syndrome is as follows:
- The pathogen, SuperBug, enters the host by using a laser beam to open the skin after anesthetizing the area with a Tranq-Dart.
- Afterwards, the SuperBug starts its migration to the brain by one of two ways:
- Swimming in the blood stream and going through the blood brain barrier using the laser beam but on a different setting.
- Teleportation, with the destination usually being one of the lateral ventricles, with more predilection for the left over the right.
- The SuperBug then tries to establish a connection to a neuronal body or axon to start its influence, the psychic abilities of the SuperBug seem to only work on nearby neurons and a preference for the corpus callosum has been noticed, possibly because of access to both brain hemispheres.
# Epidemiology and Demograghics
Updog syndrome was a very contagious condition. Though the exact mechanism of inter-personal transmission was not fully-understood, it was believed that a healthy individual spending as little as 5 seconds in the same room with an affected individual was enough for the SuperBug to infect the new individual, giving rise to the 5-second rule. The disease seemed to affect all groups of the human population with no regard to age, race, sexual orientation, gender identity, city of birth or eye brow thickness.
# Differentiating Updog Syndrome from Similar Conditions
Several publications introduced in the 2040s disputed Updog syndrome as an exaggeration of social media addiction. Those studies were disproven after the introduction of the Laser-Pointer-in-Eye diagnostic test.
# Risk Factors
The only confirmed risk factor for Updog syndrome was an interaction with an infected person for longer than 5 seconds. However, the American CDC announced a cautionary announcement in 2045 for people who might be at an increased risk of faster infection. The risk factors are listed in the table below:
# Screening
Until 2058, the most widely used screening test for Updog syndrome was known as the glowing 1000 degree knife challenge test. The test was developed after several influencers noted that Updogified individuals exhibited a fear of being burned. The test was conducted in a variable-size room and done by heating a vibranium knife, or any wide-blade kitchen knife really, to about 350 degrees Celsius (the 1000 degree name was for promotional purposes), at which point the knife would be glowing red. The knife is then introduced to the suspected infected person via a small robot. The patient would have to lick the knife 3 times, if no burn is sustained, that was considered to be a negative result. If the patient sustained a burn, it was considered a positive test and both patient and robot were crushed by the walls of the room and then their remains were incinerated. If the patient refused to lick the knife, the test was considered a positive and the patient and robot were treated accordingly (this was cited as one of causes for the robot revolt of 2066 by several historians).
In 2058, the Laser-Pointer-in-Eye diagnostic test was introduced by the International Federation of Jade Crystal Owners. This was a much cheaper and faster test, as the laser pointer can be used several times, unlike the knives that had to be discarded. The patient's head was fixed to a hard surface and their eyelids sewn open, a laser pointer is then directed at the pupils. Screaming, yelling, cursing and/or involuntary urination were considered positive results, and until the introduction of Red Kryptonite Crystal (RKC) treatment in 2063, infected patients were sent to a farm up state.
# Natural History, Complications and Prognosis
Updog syndrome has a very varied presentation and progression. Symptoms can present within minutes of exposure, though there were some cases reported on a Huffington Buzz Lord of the Rings Quiz in which symptoms appeared as late as 4-54 weeks after the initial exposure. Drowsiness, laughter and a twinkle in the eye are among the earliest symptoms, from that, progression of symptoms can happen over 3 days up to 2 months (3 weeks if patient was in solitary confinement), though a progression into a full blown tweeting storm can happen in as soon as 30 minutes post-exposure.
Until the introduction of the first treatment modality in 2063, prognosis was very poor with most patients reported deceased at the 3-year follow up. With the RKC treatment, mortality rates only changed slightly, as a single RKC could only be afforded by the richest 4712 people, disgraced president Frank Underwood (the world's 4713th richest person) was the last person to undergo the glowing 1000 degree knife challenge test (he managed to lick the knife only twice before attempting to choke it to death). When the MRTHA test-treatment was discovered in 2067, it managed to stop, and sometimes reverse, the progression of symptoms. Those patients were then placed under solitary maximum security quarantines, and were later chosen as involuntary volunteers to the Best Summer Tan project.
# Diagnosis
The diagnosis of Updog syndrome was very challenging due to the varied symptoms and the often long incubation period. The glowing 1000 degree knife challenge and the Laser-Pointer-in-Eye diagnostic tests were very helpful in the diagnostic courts.
The MRTHA (Martha-Related sTopping Hallucinations Auditorily) test-treatment, as the name suggests, was considered both diagnostic and therapeutic. It consisted of shaking the patient violently while yelling "SAVE MARTHA!" repeatedly, and it often resulted in stopping and/or reversing the progression of symptoms.
All physical exam, lab tests and imaging studies were inconclusive in findings to diagnose Updog syndrome.
# Treatment
The first treatment modality for Updog syndrome was introduced in 2063 (RKC). Due to inaccessibility and high prices, more research was done which resulted in the introduction of the MRTHA test-treatment in 2067, which was significantly cost effective. Treated patients were placed under solitary maximum security quarantines to insure their safety and to avoid reinfection and they were later introduced as part of the Best Summer Tan project in 2069.
After the project was completed, the remaining human population of less than 5000 people were all living in the luxurious underground bunker facilities under mount Rushmore which had a sophisticated ventilation system that drew air from special openings at the tip of president Lincoln's nose. Though they all died after Thor accidentally dropped his hammer right over the ventilation hatch and was too drunk to remember where it was. | Sandbox:Asem
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Asem Juhani, M.D.[2]
# Overview
Updog syndrome is a disease that affected Human beings in the 21st century. It was caused by the SuperBug [1], whose origins are still disputed, with several indications that it may have been developed by an alien species[2]. The syndrome had a varied presentation, the common features included inattentiveness, decreased mental capacity, drooling, laziness with sudden bursts of activity, uncontrollable diarrhea, constant tweeting and an increased appetite for gluten-free products. Despite several treatment options being developed, the disease was only eradicated in the year 2069 after Emperor Joffrey gathered all affected patients in cages and then put them on rockets headed directly to the sun with the assistance of trillionaire, and first human fusion individual, Jelon Mezos, in what was known as project "Best Summer Tan".[3]
# Historical Perspective
- File:Audience-band-concert-1105666.jpgThe burning of FyreMan, announcing the start of the fest (2041)Updog syndrome was first described in 2041 by American innovator and InstagTwitter personality @Kute_Lash_Curls854873 who documented several cases during her coverage of the 14th Burning Fyre Man Fest which took place in northeastern Venezuela. Several outbreaks were reported in the following weeks across the globe.
- In 2044, the North Korean CDC announced that it had isolated the causative pathogen, an unusual spherical bacterium with a completely opaque surface and it was named SuperBug.
# Pathophysiology
## Pathogenesis
- The pathogenesis of Updog syndrome is as follows:
- The pathogen, SuperBug, enters the host by using a laser beam to open the skin after anesthetizing the area with a Tranq-Dart.
- Afterwards, the SuperBug starts its migration to the brain by one of two ways:
- Swimming in the blood stream and going through the blood brain barrier using the laser beam but on a different setting.
- Teleportation, with the destination usually being one of the lateral ventricles, with more predilection for the left over the right.
- The SuperBug then tries to establish a connection to a neuronal body or axon to start its influence, the psychic abilities of the SuperBug seem to only work on nearby neurons and a preference for the corpus callosum has been noticed, possibly because of access to both brain hemispheres.
# Epidemiology and Demograghics
Updog syndrome was a very contagious condition. Though the exact mechanism of inter-personal transmission was not fully-understood, it was believed that a healthy individual spending as little as 5 seconds in the same room with an affected individual was enough for the SuperBug to infect the new individual, giving rise to the 5-second rule. The disease seemed to affect all groups of the human population with no regard to age, race, sexual orientation, gender identity, city of birth or eye brow thickness.
# Differentiating Updog Syndrome from Similar Conditions
Several publications introduced in the 2040s disputed Updog syndrome as an exaggeration of social media addiction. Those studies were disproven after the introduction of the Laser-Pointer-in-Eye diagnostic test.
# Risk Factors
The only confirmed risk factor for Updog syndrome was an interaction with an infected person for longer than 5 seconds. However, the American CDC announced a cautionary announcement in 2045 for people who might be at an increased risk of faster infection. The risk factors are listed in the table below:
# Screening
Until 2058, the most widely used screening test for Updog syndrome was known as the glowing 1000 degree knife challenge test. The test was developed after several influencers noted that Updogified individuals exhibited a fear of being burned. The test was conducted in a variable-size room and done by heating a vibranium knife, or any wide-blade kitchen knife really, to about 350 degrees Celsius (the 1000 degree name was for promotional purposes), at which point the knife would be glowing red. The knife is then introduced to the suspected infected person via a small robot. The patient would have to lick the knife 3 times, if no burn is sustained, that was considered to be a negative result. If the patient sustained a burn, it was considered a positive test and both patient and robot were crushed by the walls of the room and then their remains were incinerated. If the patient refused to lick the knife, the test was considered a positive and the patient and robot were treated accordingly (this was cited as one of causes for the robot revolt of 2066 by several historians).
In 2058, the Laser-Pointer-in-Eye diagnostic test [4] was introduced by the International Federation of Jade Crystal Owners. This was a much cheaper and faster test, as the laser pointer can be used several times, unlike the knives that had to be discarded. The patient's head was fixed to a hard surface and their eyelids sewn open, a laser pointer is then directed at the pupils. Screaming, yelling, cursing and/or involuntary urination were considered positive results, and until the introduction of Red Kryptonite Crystal (RKC) treatment in 2063, infected patients were sent to a farm up state.
# Natural History, Complications and Prognosis
Updog syndrome has a very varied presentation and progression. Symptoms can present within minutes of exposure, though there were some cases reported on a Huffington Buzz Lord of the Rings Quiz in which symptoms appeared as late as 4-54 weeks after the initial exposure. Drowsiness, laughter and a twinkle in the eye are among the earliest symptoms, from that, progression of symptoms can happen over 3 days up to 2 months (3 weeks if patient was in solitary confinement), though a progression into a full blown tweeting storm can happen in as soon as 30 minutes post-exposure.
Until the introduction of the first treatment modality in 2063, prognosis was very poor with most patients reported deceased at the 3-year follow up. With the RKC treatment, mortality rates only changed slightly, as a single RKC could only be afforded by the richest 4712 people, disgraced president Frank Underwood (the world's 4713th richest person) was the last person to undergo the glowing 1000 degree knife challenge test (he managed to lick the knife only twice before attempting to choke it to death). When the MRTHA test-treatment was discovered in 2067, it managed to stop, and sometimes reverse, the progression of symptoms. Those patients were then placed under solitary maximum security quarantines, and were later chosen as involuntary volunteers to the Best Summer Tan project.
# Diagnosis
The diagnosis of Updog syndrome was very challenging due to the varied symptoms and the often long incubation period. The glowing 1000 degree knife challenge and the Laser-Pointer-in-Eye diagnostic tests were very helpful in the diagnostic courts.
The MRTHA (Martha-Related sTopping Hallucinations Auditorily) test-treatment, as the name suggests, was considered both diagnostic and therapeutic. It consisted of shaking the patient violently while yelling "SAVE MARTHA!" repeatedly, and it often resulted in stopping and/or reversing the progression of symptoms.
All physical exam, lab tests and imaging studies were inconclusive in findings to diagnose Updog syndrome.
# Treatment
The first treatment modality for Updog syndrome was introduced in 2063 (RKC). Due to inaccessibility and high prices, more research was done which resulted in the introduction of the MRTHA test-treatment in 2067, which was significantly cost effective. Treated patients were placed under solitary maximum security quarantines to insure their safety and to avoid reinfection and they were later introduced as part of the Best Summer Tan project in 2069.
After the project was completed, the remaining human population of less than 5000 people were all living in the luxurious underground bunker facilities under mount Rushmore which had a sophisticated ventilation system that drew air from special openings at the tip of president Lincoln's nose. Though they all died after Thor accidentally dropped his hammer right over the ventilation hatch and was too drunk to remember where it was. | https://www.wikidoc.org/index.php/Sandbox:Asem | |
121012fde51ffcbda172ad9566cda7e0401ed912 | wikidoc | Sandbox:Asra | Sandbox:Asra
Asra Firdous,M.B.B.S.
# Anemia
# Management
# Vomiting Diagnosis
# Vomiting
# Overview
Ewing's sarcoma is the second most common malignant bone neoplasm commonly affecting children and adolescents. It usually affects patients in the second decade of life with a peak incidence around 15 years of age. It comprises 3% of all malignancies in pediatric patients and about 10-15% of childhood bone cancers. The overall incidence of Ewing's sarcoma is approximately estimated at 2.9 cases per million population in the U.S. Ewing's sarcoma is more common in males than females. It is more prevalent in whites than Africans.
# Epidemiology and Demographics
- Ewing's Sarcoma is the second most common bone malignancy in children and adolescents.
- 10-15% of childhood bone cancers are Ewing's Sarcoma.
- Ewing's Sarcoma constitutes about 4% of pediatric cancers.
- 200-250 new cases of Ewing's sarcoma are reported each year in the United States.
- Nearly, 60% of the Ewing Sarcoma cases have long-term disease-free survival.
## Incidence
- The incidence of Ewing's sarcoma has remained unchanged for 30 years.
- In the United States, the overall incidence of Ewing's sarcoma is 1 cases per million individuals.
- During 1973-2004, the average annual incidence of Ewing's Sarcoma was estimated to be 2.9 cases per million population in the United States.
- The incidence of Ewing's Sarcoma, in the United States, is estimated to be 200-250 cases annually.
## Mortality/Morbidity
The overall 5-year survival rate for patients with Ewing's Sarcoma is approximately 70% in primary lesions and 30% in metastatic disease.
## Race
- Ewing's Sarcoma is more prevalent in Caucasians than Asians or Hispanics.
- African Americans and Africans are less likely to develop Ewing's Sarcoma.
- The incidence in the Caucasians is 1.5 cases per million population.
- The incidence in the Asians is 0.8 cases per million population.
- The incidence in Africans is 0.2 cases per million population.
## Age
- Ewing's Sarcoma commonly affects children and adolescents between 10 and 20 years of age.
- The median age at diagnosis is 15 years
- In patients younger than 5 years, diagnosed in about 0.6 cases per million population.
- In patients aged 10-14 years, diagnosed in about more than 5 cases per million population.
## Gender
- Males are more commonly affected than females. The male to female ratio is around 3:2.
## Reference
# Anemia of Prematurity Symptoms
The majority of patients with Anemia of Prematurity are asymptomatic. In premature infants with severe disease, symptoms are usually vague or non-specific.
- Common symptoms of Anemia of Prematurity include
Tachycardia
Tachypnea
Decreased activity or lethargy
Difficulty feeding
Pallor
- Tachycardia
- Tachypnea
- Decreased activity or lethargy
- Difficulty feeding
- Pallor
- Less common symptoms of Anemia of Prematurity include
Poor weight gain despite adequate calorie intake
Breathing difficulties
Metabolic acidosis due to increased lactic acid production from anaerobic metabolism in the cells
Heart murmurs
- Poor weight gain despite adequate calorie intake
- Breathing difficulties
- Metabolic acidosis due to increased lactic acid production from anaerobic metabolism in the cells
- Heart murmurs
# Pathophysiology of Anemia of Prematurity
The pathogenesis of anemia of prematurity is multifactorial. Anemia of prematurity is the result of a combination of decreased erythropoietin production, increased erythropoietin metabolism, deficient iron stores, decreased RBC lifespan, and blood loss during phlebotomy.
## Physiological anemia in newborns
Normally, all the newborns experience a fall in the haemoglobin concentration during the first few weeks of life. Healthy, fullterm infants usually develop anemia around 10-12 weeks of life after birth. Hemoglobin concentration never falls below 10 g/dl in healthy infants. Physiological anemia is well tolerated by and does not require any therapy.
- After birth, an embryo transitions from a hypoxic state in-utero to an infant in a relatively hyperoxic environment
- This transition leads to an increase in blood oxygen and tissue oxygen concentration in newborns
- Increased oxygen concentration inhibits erythropoietin production and eventually stops erythropoiesis
- Due to the rapid growth and disproportionate RBC production, hemoglobin levels fall gradually in infants
- The drop in hemoglobin concentration continues until the tissue hypoxia develops which usually takes around 6-12weeks after birth
- Tissue hypoxia activates the oxygen sensors present in the kidney and liver to stimulate the erythropoietin and red blood cells production
- Fullterm newborns have enough iron stores for erythropoiesis until 20 weeks of life
- Infants have a shorter RBC lifespan and increased erythropoietin metabolism when compared to adults
## Pathological Anemia of Prematurity
In preterm infants, multiple physiological factors exaggerate and combine to result in pathological anemia. Hemoglobin levels drop rapidly to less than 10 g/dl around 4-6 weeks after birth. Infants with 1-1.5 kg of birthweight have hemoglobin levels around 8 g/dl, whereas infants with birthweight less than 1 kg have hemoglobin levels around 7 g/dl or less. The profound decrease in hemoglobin levels in premature infants produce abnormal signs and symptoms and require a blood transfusion.
- Iron transport from mother to infants and a greater proportion of fetal erythropoiesis occur during the third trimester. So, infants born prematurely have deficient iron stores required for the red blood cells production
- Blood loss during phlebotomy is the major contributor of anemia of prematurity
- Majority of preterm infants are sick and critically ill that require frequent blood sampling for various laboratory investigations needed for their clinical monitoring. The average amount of blood loss during sampling ranges from 0.8-3.1 ml/kg/day, a significant amount that requires replacement
- Preterm infants are at increased risk of nosocomial infections that lead to oxidative hemolysis
- In premature infants, liver is the major site of erythropoiesis. Liver EPO is less sensitive to anemia and tissue hypoxia
- Preterm infants have deficient Vitamin E, Vitamin B12, Folic acid stores required for red blood cells production
- A combination of blood loss, decreased erythropoietin production, deficient iron stores, increased erythropoietin metabolism, shortened RBC lifespan contribute to the development of anemia of prematurity
# Vomiting
- ↑ "Nutritional anaemias. Report of a WHO scientific group". World Health Organ Tech Rep Ser. 405: 5–37. 1968. PMID 4975372..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}
- ↑ Rodgers, GM.; Becker, PS.; Bennett, CL.; Cella, D.; Chanan-Khan, A.; Chesney, C.; Cleeland, C.; Coccia, PF.; Djulbegovic, B. (2008). "Cancer- and chemotherapy-induced anemia". J Natl Compr Canc Netw. 6 (6): 536–64. PMID 18597709. Unknown parameter |month= ignored (help)
- ↑ Beutler, E.; Waalen, J. (2006). "The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration?". Blood. 107 (5): 1747–50. doi:10.1182/blood-2005-07-3046. PMID 16189263. Unknown parameter |month= ignored (help)
- ↑ Davenport, J. (1996). "Macrocytic anemia". Am Fam Physician. 53 (1): 155–62. PMID 8546042. Unknown parameter |month= ignored (help)
- ↑ Inelmen, EM.; D'Alessio, M.; Gatto, MR.; Baggio, MB.; Jimenez, G.; Bizzotto, MG.; Enzi, G. (1994). "Descriptive analysis of the prevalence of anemia in a randomly selected sample of elderly people living at home: some results of an Italian multicentric study". Aging (Milano). 6 (2): 81–9. PMID 7918735. Unknown parameter |month= ignored (help)
- ↑ Gomes, ME.; Deinum, J.; Timmers, HJ.; Lenders, JW. (2003). "Occam's razor; anaemia and orthostatic hypotension". Lancet. 362 (9392): 1282. doi:10.1016/S0140-6736(03)14572-2. PMID 14575973. Unknown parameter |month= ignored (help)
- ↑ Perera, R.; Isola, L.; Kaufmann, H. (1995). "Effect of recombinant erythropoietin on anemia and orthostatic hypotension in primary autonomic failure". Clin Auton Res. 5 (4): 211–3. PMID 8520216. Unknown parameter |month= ignored (help)
- ↑ Camaschella, C. (2013). "How I manage patients with atypical microcytic anaemia". Br J Haematol. 160 (1): 12–24. doi:10.1111/bjh.12081. PMID 23057559. Unknown parameter |month= ignored (help)
- ↑ Salisbury, AC.; Reid, KJ.; Alexander, KP.; Masoudi, FA.; Lai, SM.; Chan, PS.; Bach, RG.; Wang, TY.; Spertus, JA. (2011). "Diagnostic blood loss from phlebotomy and hospital-acquired anemia during acute myocardial infarction". Arch Intern Med. 171 (18): 1646–53. doi:10.1001/archinternmed.2011.361. PMID 21824940. Unknown parameter |month= ignored (help)
- ↑ Ewing's sarcoma. National cancer institute.#section/_1
- ↑ Stockman JA, Graeber JE, Clark DA, McClellan K, Garcia JF, Kavey RE (1984). "Anemia of prematurity: determinants of the erythropoietin response". J Pediatr. 105 (5): 786–92. doi:10.1016/s0022-3476(84)80308-x. PMID 6502312.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 12.0 12.1 12.2 Strauss RG (2010). "Anaemia of prematurity: pathophysiology and treatment". Blood Rev. 24 (6): 221–5. doi:10.1016/j.blre.2010.08.001. PMC 2981681. PMID 20817366.
- ↑ Widness JA, Veng-Pedersen P, Peters C, Pereira LM, Schmidt RL, Lowe LS (1996). "Erythropoietin pharmacokinetics in premature infants: developmental, nonlinearity, and treatment effects". J Appl Physiol (1985). 80 (1): 140–8. doi:10.1152/jappl.1996.80.1.140. PMID 8847295.CS1 maint: Multiple names: authors list (link)
- ↑ Dame C, Fahnenstich H, Freitag P, Hofmann D, Abdul-Nour T, Bartmann P; et al. (1998). "Erythropoietin mRNA expression in human fetal and neonatal tissue". Blood. 92 (9): 3218–25. PMID 9787158.CS1 maint: Multiple names: authors list (link) | Sandbox:Asra
Asra Firdous,M.B.B.S.[1]
# Anemia
# Management
# Vomiting Diagnosis
# Vomiting
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2];Associate Editor(s)-in-Chief: Suveenkrishna Pothuru, M.B,B.S. [3];Assistant Editor(s)-In-Chief: Michael Maddaleni, B.S., Asra Firdous, M.B.B.S.
# Overview
Ewing's sarcoma is the second most common malignant bone neoplasm commonly affecting children and adolescents. It usually affects patients in the second decade of life with a peak incidence around 15 years of age. It comprises 3% of all malignancies in pediatric patients and about 10-15% of childhood bone cancers. The overall incidence of Ewing's sarcoma is approximately estimated at 2.9 cases per million population in the U.S. Ewing's sarcoma is more common in males than females. It is more prevalent in whites than Africans.
# Epidemiology and Demographics
- Ewing's Sarcoma is the second most common bone malignancy in children and adolescents.
- 10-15% of childhood bone cancers are Ewing's Sarcoma.
- Ewing's Sarcoma constitutes about 4% of pediatric cancers.
- 200-250 new cases of Ewing's sarcoma are reported each year in the United States.
- Nearly, 60% of the Ewing Sarcoma cases have long-term disease-free survival.
## Incidence
- The incidence of Ewing's sarcoma has remained unchanged for 30 years.[10]
- In the United States, the overall incidence of Ewing's sarcoma is 1 cases per million individuals.
- During 1973-2004, the average annual incidence of Ewing's Sarcoma was estimated to be 2.9 cases per million population in the United States.
- The incidence of Ewing's Sarcoma, in the United States, is estimated to be 200-250 cases annually.
## Mortality/Morbidity
The overall 5-year survival rate for patients with Ewing's Sarcoma is approximately 70% in primary lesions and 30% in metastatic disease.
## Race
- Ewing's Sarcoma is more prevalent in Caucasians than Asians or Hispanics.
- African Americans and Africans are less likely to develop Ewing's Sarcoma.
- The incidence in the Caucasians is 1.5 cases per million population.
- The incidence in the Asians is 0.8 cases per million population.
- The incidence in Africans is 0.2 cases per million population.
## Age
- Ewing's Sarcoma commonly affects children and adolescents between 10 and 20 years of age.
- The median age at diagnosis is 15 years
- In patients younger than 5 years, diagnosed in about 0.6 cases per million population.
- In patients aged 10-14 years, diagnosed in about more than 5 cases per million population.
## Gender
- Males are more commonly affected than females. The male to female ratio is around 3:2.
## Reference
# Anemia of Prematurity Symptoms
The majority of patients with Anemia of Prematurity are asymptomatic. In premature infants with severe disease, symptoms are usually vague or non-specific.
- Common symptoms of Anemia of Prematurity include
Tachycardia
Tachypnea
Decreased activity or lethargy
Difficulty feeding
Pallor
- Tachycardia
- Tachypnea
- Decreased activity or lethargy
- Difficulty feeding
- Pallor
- Less common symptoms of Anemia of Prematurity include
Poor weight gain despite adequate calorie intake
Breathing difficulties
Metabolic acidosis due to increased lactic acid production from anaerobic metabolism in the cells
Heart murmurs
- Poor weight gain despite adequate calorie intake
- Breathing difficulties
- Metabolic acidosis due to increased lactic acid production from anaerobic metabolism in the cells
- Heart murmurs
# Pathophysiology of Anemia of Prematurity
The pathogenesis of anemia of prematurity is multifactorial. Anemia of prematurity is the result of a combination of decreased erythropoietin production, increased erythropoietin metabolism, deficient iron stores, decreased RBC lifespan, and blood loss during phlebotomy.[11][12]
## Physiological anemia in newborns
Normally, all the newborns experience a fall in the haemoglobin concentration during the first few weeks of life. Healthy, fullterm infants usually develop anemia around 10-12 weeks of life after birth. Hemoglobin concentration never falls below 10 g/dl in healthy infants. Physiological anemia is well tolerated by and does not require any therapy.[12]
- After birth, an embryo transitions from a hypoxic state in-utero to an infant in a relatively hyperoxic environment
- This transition leads to an increase in blood oxygen and tissue oxygen concentration in newborns
- Increased oxygen concentration inhibits erythropoietin production and eventually stops erythropoiesis
- Due to the rapid growth and disproportionate RBC production, hemoglobin levels fall gradually in infants
- The drop in hemoglobin concentration continues until the tissue hypoxia develops which usually takes around 6-12weeks after birth
- Tissue hypoxia activates the oxygen sensors present in the kidney and liver to stimulate the erythropoietin and red blood cells production
- Fullterm newborns have enough iron stores for erythropoiesis until 20 weeks of life
- Infants have a shorter RBC lifespan and increased erythropoietin metabolism when compared to adults[13]
## Pathological Anemia of Prematurity
In preterm infants, multiple physiological factors exaggerate and combine to result in pathological anemia. Hemoglobin levels drop rapidly to less than 10 g/dl around 4-6 weeks after birth. Infants with 1-1.5 kg of birthweight have hemoglobin levels around 8 g/dl, whereas infants with birthweight less than 1 kg have hemoglobin levels around 7 g/dl or less. The profound decrease in hemoglobin levels in premature infants produce abnormal signs and symptoms and require a blood transfusion. [12]
- Iron transport from mother to infants and a greater proportion of fetal erythropoiesis occur during the third trimester. So, infants born prematurely have deficient iron stores required for the red blood cells production
- Blood loss during phlebotomy is the major contributor of anemia of prematurity
- Majority of preterm infants are sick and critically ill that require frequent blood sampling for various laboratory investigations needed for their clinical monitoring. The average amount of blood loss during sampling ranges from 0.8-3.1 ml/kg/day, a significant amount that requires replacement
- Preterm infants are at increased risk of nosocomial infections that lead to oxidative hemolysis
- In premature infants, liver is the major site of erythropoiesis. Liver EPO is less sensitive to anemia and tissue hypoxia[14]
- Preterm infants have deficient Vitamin E, Vitamin B12, Folic acid stores required for red blood cells production
- A combination of blood loss, decreased erythropoietin production, deficient iron stores, increased erythropoietin metabolism, shortened RBC lifespan contribute to the development of anemia of prematurity
# Vomiting
- ↑ "Nutritional anaemias. Report of a WHO scientific group". World Health Organ Tech Rep Ser. 405: 5–37. 1968. PMID 4975372..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}
- ↑ Rodgers, GM.; Becker, PS.; Bennett, CL.; Cella, D.; Chanan-Khan, A.; Chesney, C.; Cleeland, C.; Coccia, PF.; Djulbegovic, B. (2008). "Cancer- and chemotherapy-induced anemia". J Natl Compr Canc Netw. 6 (6): 536–64. PMID 18597709. Unknown parameter |month= ignored (help)
- ↑ Beutler, E.; Waalen, J. (2006). "The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration?". Blood. 107 (5): 1747–50. doi:10.1182/blood-2005-07-3046. PMID 16189263. Unknown parameter |month= ignored (help)
- ↑ Davenport, J. (1996). "Macrocytic anemia". Am Fam Physician. 53 (1): 155–62. PMID 8546042. Unknown parameter |month= ignored (help)
- ↑ Inelmen, EM.; D'Alessio, M.; Gatto, MR.; Baggio, MB.; Jimenez, G.; Bizzotto, MG.; Enzi, G. (1994). "Descriptive analysis of the prevalence of anemia in a randomly selected sample of elderly people living at home: some results of an Italian multicentric study". Aging (Milano). 6 (2): 81–9. PMID 7918735. Unknown parameter |month= ignored (help)
- ↑ Gomes, ME.; Deinum, J.; Timmers, HJ.; Lenders, JW. (2003). "Occam's razor; anaemia and orthostatic hypotension". Lancet. 362 (9392): 1282. doi:10.1016/S0140-6736(03)14572-2. PMID 14575973. Unknown parameter |month= ignored (help)
- ↑ Perera, R.; Isola, L.; Kaufmann, H. (1995). "Effect of recombinant erythropoietin on anemia and orthostatic hypotension in primary autonomic failure". Clin Auton Res. 5 (4): 211–3. PMID 8520216. Unknown parameter |month= ignored (help)
- ↑ Camaschella, C. (2013). "How I manage patients with atypical microcytic anaemia". Br J Haematol. 160 (1): 12–24. doi:10.1111/bjh.12081. PMID 23057559. Unknown parameter |month= ignored (help)
- ↑ Salisbury, AC.; Reid, KJ.; Alexander, KP.; Masoudi, FA.; Lai, SM.; Chan, PS.; Bach, RG.; Wang, TY.; Spertus, JA. (2011). "Diagnostic blood loss from phlebotomy and hospital-acquired anemia during acute myocardial infarction". Arch Intern Med. 171 (18): 1646–53. doi:10.1001/archinternmed.2011.361. PMID 21824940. Unknown parameter |month= ignored (help)
- ↑ Ewing's sarcoma. National cancer institute.http://www.cancer.gov/types/bone/hp/ewing-treatment-pdq#section/_1
- ↑ Stockman JA, Graeber JE, Clark DA, McClellan K, Garcia JF, Kavey RE (1984). "Anemia of prematurity: determinants of the erythropoietin response". J Pediatr. 105 (5): 786–92. doi:10.1016/s0022-3476(84)80308-x. PMID 6502312.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 12.0 12.1 12.2 Strauss RG (2010). "Anaemia of prematurity: pathophysiology and treatment". Blood Rev. 24 (6): 221–5. doi:10.1016/j.blre.2010.08.001. PMC 2981681. PMID 20817366.
- ↑ Widness JA, Veng-Pedersen P, Peters C, Pereira LM, Schmidt RL, Lowe LS (1996). "Erythropoietin pharmacokinetics in premature infants: developmental, nonlinearity, and treatment effects". J Appl Physiol (1985). 80 (1): 140–8. doi:10.1152/jappl.1996.80.1.140. PMID 8847295.CS1 maint: Multiple names: authors list (link)
- ↑ Dame C, Fahnenstich H, Freitag P, Hofmann D, Abdul-Nour T, Bartmann P; et al. (1998). "Erythropoietin mRNA expression in human fetal and neonatal tissue". Blood. 92 (9): 3218–25. PMID 9787158.CS1 maint: Multiple names: authors list (link) | https://www.wikidoc.org/index.php/Sandbox:Asra | |
14758c0a1bd128cceaeb41ce7cced49b256a1318 | wikidoc | Sandbox:Diab | Sandbox:Diab
# Overview
Diab is a research fellow at BIDMC, Harvard University.
# Test Passage 1
Coagulation necrosis, characterized by Hypereosinophilia and nuclear pyknosis followed by karyorrhexis, karyolysis, total loss of nuclei and loss of cytoplasmic cross-striations is generally first visible in the period from 4,12 hours following infarction. necrotic myocytes may retain their striations for a long time
Neutrophilic infiltration (Acute inflammation) edema and hemorrhage are also first visible at 4-12 hours but generally closer to 12 hours. the interstitium at the margin of the Infarcted area is initially infiltrated with Neutrophils, then with Lymphocytes and Macrophages, who phagocytose or eat the myocyte debris; The necrotic area is surrounded and progressively invaded by granulation tissue: which will replace the infarct with a fibrous or collagenous scar (which are typical steps in wound healing). the interstitial space or the space between cells outside of blood vessels may be infiltrated with red blood cells.
Infiltration by macrophages, lymphocytes, eosinophils, fibroblasts and capillaries begins around the periphery at 3-10 days. contraction band necrosis, characterized by hypereosinophilic transverse bands of precipitated Myofibrils in dead myocytes is usually seen at the edge of an Infarct or with reperfusion for example with Thrombolytic therapy. | Sandbox:Diab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Diab, MD [2]
# Overview
Diab is a research fellow at BIDMC, Harvard University.
# Test Passage 1
Coagulation necrosis, characterized by Hypereosinophilia and nuclear pyknosis followed by karyorrhexis, karyolysis, total loss of nuclei and loss of cytoplasmic cross-striations is generally first visible in the period from 4,12 hours following infarction. necrotic myocytes may retain their striations for a long time
Neutrophilic infiltration (Acute inflammation) edema and hemorrhage are also first visible at 4-12 hours but generally closer to 12 hours. the interstitium at the margin of the Infarcted area is initially infiltrated with Neutrophils, then with Lymphocytes and Macrophages, who phagocytose or eat the myocyte debris; The necrotic area is surrounded and progressively invaded by granulation tissue: which will replace the infarct with a fibrous or collagenous scar (which are typical steps in wound healing). the interstitial space or the space between cells outside of blood vessels may be infiltrated with red blood cells.
Infiltration by macrophages, lymphocytes, eosinophils, fibroblasts and capillaries begins around the periphery at 3-10 days. contraction band necrosis, characterized by hypereosinophilic transverse bands of precipitated Myofibrils in dead myocytes is usually seen at the edge of an Infarct or with reperfusion for example with Thrombolytic therapy. | https://www.wikidoc.org/index.php/Sandbox:Diab | |
fa67b63c063e6841ae6dfd7847b227e095331cc6 | wikidoc | Sandbox:Dima | Sandbox:Dima
Scabies
Pathophysiology
# Overview
The mite Sarcoptes scabieii produces the symptoms by tunneling into the stratum corneum and depositing in the burrow. The disease is transmitted mainly by skin to skin contact.
# Pathophysiology
## Life Cycle
- The mite Sarcoptes scabiei produces intense, itchy skin rashes when the impregnated female tunnels into the stratum corneum of the skin and deposits eggs in the burrow.
- The larvae, which hatch in 3-10 days, move about on the skin, molt into a "nymphal" stage, and then mature into adult mites. The adult mites live 3-4 weeks in the host's skin.
- The action of the mites moving within the skin and on the skin itself produces an intense itch which may resemble an allergic reaction in appearance. The presence of the eggs produces a massive allergic response which, in turn, produces more itching. The symptoms are caused by an allergic reaction that the body develops over time to the mites and their by-products under the skin, thus the 4-6 week "incubation" period. There are usually relatively few mites on a normal, healthy person's skin; about 11 females in burrows. Scabies are microscopic although sometimes they are visible as a pinpoint of white. The females burrow into the skin and lay eggs there. Males roam on top of the skin, however, they can and do occasionally burrow. Both males and females surface at times, especially at night.
- They can be washed or scratched off (however scratching should be done with a washcloth to avoid cutting the skin as this can lead to infection), which, although not a cure, helps to keep the total population low. Also, humans create antibodies to the scabies mites which do kill some of them.
## Transmission
- Scabies is transmitted readily, often throughout an entire household, by skin-to-skin contact with an infected person (e.g. bed partners, schoolmates, daycare), and thus is sometimes, although inaccurately, classed as a sexually transmitted disease. Spread by clothing, bedding, or towels is a less significant risk, though possible.
- It takes approximately 4-6 weeks to develop symptoms after initial infestation. Therefore, a person may have been contagious for at least a month before being diagnosed. This means that person might have passed scabies to anyone at that time with whom they had close contact. Someone who sleeps in the same room with a person with scabies has a high possibility of having scabies as well, although they may not show symptoms.
NH, C and Prognosis
# Overview
A delayed hypersensitivity (allergic) response resulting in a papular eruption (red, elevated area on skin) often occurs 30-40 days after infestation.The rash may become secondarily infected; scratching the rash may break the skin and make secondary infection more likely. In persons with severely reduced immunity, such as those with HIV infection, or people being treated with immunosuppressive drugs like steroids, a widespread rash with thick scaling may result in Norwegian scabies.
# Natural History, Complications and Prognosis
- A delayed hypersensitivity (allergic) response resulting in a papular eruption (red, elevated area on skin) often occurs 30-40 days after infestation. While there may be hundreds of papules, fewer than 10 burrows are typically found.
- The rash may become secondarily infected; scratching the rash may break the skin and make secondary infection more likely. In persons with severely reduced immunity, such as those with HIV infection, or people being treated with immunosuppressive drugs like steroids, a widespread rash with thick scaling may result. This variety of scabies is called Norwegian scabies.
- Scabies is frequently misdiagnosed as intense pruritus (itching of healthy skin) before papular eruptions form. Upon initial pruritus the burrows appear as small, barely noticeable bumps on the hands and may be slightly shiny and dark in color rather than red. Initially the itching may not exactly correlate to the location of these bumps. As the infestation progresses, these bumps become more red in color.
- People with compromised immune systems may not develop antibodies to the mites and may develop crusted Norwegian scabies. In this case, many form scabs or develop very red skin especially in the elderly and the mentally handicapped where white or gray crusted areas develop with little itching and little or no red bumps and mite population numbers soar to hundreds, thousands, or millions in AIDS patients. These cases require additional treatment options to ensure a complete kill. Ivermectin is the treatment of choice in these patients combined with any other topical treatment.
## Evolution of the Infection
- Day 4
- Day 8 (treatment begins)
- Day 12 (under treatment)
- Healed
History and Symptoms
# Overview
The most common symptoms of scabies, itching and a skin rash, are caused by sensitization (a type of “allergic” reaction) to the proteins and feces of the parasite. Severe itching (pruritus), especially at night, is the earliest and most common symptom of scabies. A pimple-like (papular) itchy (pruritic) “scabies rash” is also common.
# History and Symptoms
- A delayed hypersensitivity (allergic) response resulting in a papular eruption (red, elevated area on skin) often occurs 30-40 days after infestation. While there may be hundreds of papules, fewer than 10 burrows are typically found. The burrow appears as a fine, wavy and slightly scaly line a few millimeters to one centimeter long. A tiny mite (0.3 to 0.9.08 mm) may sometimes be seen at the end of the burrow. Most burrows occur in the webs of fingers, flexing surfaces of the wrists, around elbows and armpits, the areolae of the breasts in females and on genitals of males, along the belt line, and on the lower buttocks. The face usually does not become involved in adults.
- Generally diagnosis is made by finding burrows, which often may be difficult because they are scarce, and they are obscured by scratch marks, or by secondary dermatitis (unrelated skin irritation). If burrows are not found in the primary areas known to be affected, the entire skin surface of the body should be examined.
Physical Exam
# Physical Examination
## Gallery
### Skin
- url = >
- url = >
- url = >
- url = >
- url = >
- url = >
- url = >
- url = >
- Scabies (common location in ventral wrist)
- url = >
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- url = >
- url = >
- url = >
- url = >
- url = >
- url = >
- url = >
- url = >
- url = >
- url = >
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- url = >
- url = >
- url = >
- url = >
- url = >
- url = >
- url = >
- url = >
- url = >
- url = >
- url = >
- url = >
- url = >
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
- Norwegian scabies. Adapted from Dermatology Atlas.
Physical exam
# Overview
Laboratory diagnosis may be confirmed by microscopy of surface scrapings, which are placed on a slide in glycerol, mineral oil or immersion in oil and covered with a coverslip.
# Laboratory Findings
- The suspicious area can be rubbed with ink from a fountain pen or alternately a topical tetracycline solution which will glow under a special light. The surface is then wiped off with an alcohol pad; if the person is infected with scabies, the characteristic zigzag or S pattern of the burrow across the skin will appear.
- When a suspected burrow is found, diagnosis may be confirmed by microscopy of surface scrapings, which are placed on a slide in glycerol, mineral oil or immersion in oil and covered with a coverslip. Avoiding potassium hydroxide is necessary because it may dissolve fecal pellets. Positive diagnosis is made when the mite, ova, or fecal pellets are found.
Medical Therapy
# Overview
Medical therapy of scabies includes either topical permethrin or oral ivermectin. Patients may become completely asymptomatic within 1-2 weeks following therapy.
# Medical Therapy
- All patients with scabies require antimicrobial therapy. Medical therapy of scabies includes either topical permethrin or oral ivermectin.
- Patients may experience worsening pruritus and erythema early during the administration of antimicrobial therapy.
- The parasite is gradually eliminated during the body's natural shedding process.
- Antimicrobial therapy
- 1. Adult
- Preferred regimen (1): Permethrin 5% cream applied to all areas of the body from the neck down and washed off after 8–14 hours
- Preferred regimen (2): Ivermectin 200 ug/kg PO qd and repeated in 2 weeks
- Alternative regimen: Lindane (1%) 1 oz of lotion or 30 g of cream applied in a thin layer to all areas of the body from the neck down and thoroughly washed off after 8 hours
- Note: Patients may experience worsening pruritus and erythema early during the administration of antimicrobial therapy
- 2. Infants and young children
- Preferred regimen: Permethrin 5% cream applied to all areas of the body from the neck down and washed off after 8–14 hours
- Note: Infants and young children aged< 10 years should not be treated with lindane
- 3. Crusted Scabies
- Preferred regimen: (Topical scabicide 5% topical Benzyl benzoate 5% OR topical Permethrin 5% cream (full-body application to be repeated daily for 7 days then twice weekly until discharge or cure) AND treatment with Ivermectin 200 ug/kg PO on days 1,2,8,9, and 15. Additional Ivermectin treatment on days 22 and 29 might be required for severe cases
- 4.Pregnant or Lactating Women
- Preferred regimen: Permethrin 5% cream applied to all areas of the body from the neck down and washed off after 8–14 hours
Primary Prevention
# Overview
Scabies is prevented by avoiding direct skin-to-skin contact with an infested person or with items such as clothing or bedding used by an infested person. Scabies treatment usually is recommended for members of the same household, particularly for those who have had prolonged skin-to-skin contact.
# Primary Prevention
- All family and close contacts should be treated at the same time, even if asymptomatic. After treatment has been applied or taken, (or directly before treatment if you are careful and wear gloves) cleaning of environment should occur. A person can easily be reinfected with scabies.
- Without a host, scabies mites can on average survive up to 48-72 hours away from human skin. As in cases of Crusted Scabies, they can survive much longer, up to 7 days. Therefore it is recommended, after treatment, to wash all material (such as clothes, bedding, and towels) that has been in contact with all infested persons in the last three days.
- All household members should be treated at the same time and cleaning must be thorough and simultaneous. Either isolate long enough for the mites to die in a plastic bag for at least 1 week, or clean or freeze overnight.
- Vacuuming floors, carpets, and rugs.
- Disinfecting floor and bathroom surfaces by mopping (this only needs to be done after the first treatment).
- Daily washing of recently worn clothes, towels and bedding in hot water and drying in a hot dryer.
- Hot drying pillows for 30 minutes.
- Overnight freezing, in a plastic bag: stuffed animals, brushes, combs, shoes, coats, gloves, hats, robes, wetsuits, etc.
- Quarantine in a plastic bag for two weeks: things that cannot be washed, hot dried, frozen or drycleaned.
- Drycleaning: things that cannot be washed, hot dried or frozen or quarantined.
## Primary Prevention for Pets
- Pets and humans get infected with different types of mites. The mites that we get can not survive and reproduce on pets.
- ↑ Jump up to: 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 2.25 2.26 2.27 2.28 2.29 2.30 2.31 2.32 2.33 2.34 2.35 2.36 2.37 2.38 2.39 2.40 2.41 2.42 2.43 2.44 2.45 2.46 2.47 2.48 "Dermatology Atlas"..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}
- ↑ Workowski, Kimberly A.; Bolan, Gail A. (2015-06-05). "Sexually transmitted diseases treatment guidelines, 2015". MMWR. Recommendations and reports: Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control. 64 (RR-03): 1–137. ISSN 1545-8601. PMID 26042815. | Sandbox:Dima
Scabies
Pathophysiology
# Overview
The mite Sarcoptes scabieii produces the symptoms by tunneling into the stratum corneum and depositing in the burrow. The disease is transmitted mainly by skin to skin contact.
# Pathophysiology
## Life Cycle
- The mite Sarcoptes scabiei produces intense, itchy skin rashes when the impregnated female tunnels into the stratum corneum of the skin and deposits eggs in the burrow.
- The larvae, which hatch in 3-10 days, move about on the skin, molt into a "nymphal" stage, and then mature into adult mites. The adult mites live 3-4 weeks in the host's skin.
- The action of the mites moving within the skin and on the skin itself produces an intense itch which may resemble an allergic reaction in appearance. The presence of the eggs produces a massive allergic response which, in turn, produces more itching. The symptoms are caused by an allergic reaction that the body develops over time to the mites and their by-products under the skin, thus the 4-6 week "incubation" period. There are usually relatively few mites on a normal, healthy person's skin; about 11 females in burrows. Scabies are microscopic although sometimes they are visible as a pinpoint of white. The females burrow into the skin and lay eggs there. Males roam on top of the skin, however, they can and do occasionally burrow. Both males and females surface at times, especially at night.
- They can be washed or scratched off (however scratching should be done with a washcloth to avoid cutting the skin as this can lead to infection), which, although not a cure, helps to keep the total population low. Also, humans create antibodies to the scabies mites which do kill some of them.
## Transmission
- Scabies is transmitted readily, often throughout an entire household, by skin-to-skin contact with an infected person (e.g. bed partners, schoolmates, daycare), and thus is sometimes, although inaccurately, classed as a sexually transmitted disease. Spread by clothing, bedding, or towels is a less significant risk, though possible.
- It takes approximately 4-6 weeks to develop symptoms after initial infestation. Therefore, a person may have been contagious for at least a month before being diagnosed. This means that person might have passed scabies to anyone at that time with whom they had close contact. Someone who sleeps in the same room with a person with scabies has a high possibility of having scabies as well, although they may not show symptoms.
NH, C and Prognosis
# Overview
A delayed hypersensitivity (allergic) response resulting in a papular eruption (red, elevated area on skin) often occurs 30-40 days after infestation.The rash may become secondarily infected; scratching the rash may break the skin and make secondary infection more likely. In persons with severely reduced immunity, such as those with HIV infection, or people being treated with immunosuppressive drugs like steroids, a widespread rash with thick scaling may result in Norwegian scabies.
# Natural History, Complications and Prognosis
- A delayed hypersensitivity (allergic) response resulting in a papular eruption (red, elevated area on skin) often occurs 30-40 days after infestation. While there may be hundreds of papules, fewer than 10 burrows are typically found.
- The rash may become secondarily infected; scratching the rash may break the skin and make secondary infection more likely. In persons with severely reduced immunity, such as those with HIV infection, or people being treated with immunosuppressive drugs like steroids, a widespread rash with thick scaling may result. This variety of scabies is called Norwegian scabies.
- Scabies is frequently misdiagnosed as intense pruritus (itching of healthy skin) before papular eruptions form. Upon initial pruritus the burrows appear as small, barely noticeable bumps on the hands and may be slightly shiny and dark in color rather than red. Initially the itching may not exactly correlate to the location of these bumps. As the infestation progresses, these bumps become more red in color.
- People with compromised immune systems may not develop antibodies to the mites and may develop crusted Norwegian scabies. In this case, many form scabs or develop very red skin especially in the elderly and the mentally handicapped where white or gray crusted areas develop with little itching and little or no red bumps and mite population numbers soar to hundreds, thousands, or millions in AIDS patients. These cases require additional treatment options to ensure a complete kill. Ivermectin is the treatment of choice in these patients combined with any other topical treatment.
## Evolution of the Infection
- Day 4
- Day 8 (treatment begins)
- Day 12 (under treatment)
- Healed
History and Symptoms
# Overview
The most common symptoms of scabies, itching and a skin rash, are caused by sensitization (a type of “allergic” reaction) to the proteins and feces of the parasite. Severe itching (pruritus), especially at night, is the earliest and most common symptom of scabies. A pimple-like (papular) itchy (pruritic) “scabies rash” is also common.
# History and Symptoms
- A delayed hypersensitivity (allergic) response resulting in a papular eruption (red, elevated area on skin) often occurs 30-40 days after infestation. While there may be hundreds of papules, fewer than 10 burrows are typically found. The burrow appears as a fine, wavy and slightly scaly line a few millimeters to one centimeter long. A tiny mite (0.3 to 0.9.08 mm) may sometimes be seen at the end of the burrow. Most burrows occur in the webs of fingers, flexing surfaces of the wrists, around elbows and armpits, the areolae of the breasts in females and on genitals of males, along the belt line, and on the lower buttocks. The face usually does not become involved in adults.
- Generally diagnosis is made by finding burrows, which often may be difficult because they are scarce, and they are obscured by scratch marks, or by secondary dermatitis (unrelated skin irritation). If burrows are not found in the primary areas known to be affected, the entire skin surface of the body should be examined.
Physical Exam
# Physical Examination
## Gallery
### Skin
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=415>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=415>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=415>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=415>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- Scabies (common location in ventral wrist) [1]
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=415>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=415>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=416>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=416>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=416>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=416>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=414>
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
- Norwegian scabies. Adapted from Dermatology Atlas.[2]
Physical exam
# Overview
Laboratory diagnosis may be confirmed by microscopy of surface scrapings, which are placed on a slide in glycerol, mineral oil or immersion in oil and covered with a coverslip.
# Laboratory Findings
- The suspicious area can be rubbed with ink from a fountain pen or alternately a topical tetracycline solution which will glow under a special light. The surface is then wiped off with an alcohol pad; if the person is infected with scabies, the characteristic zigzag or S pattern of the burrow across the skin will appear.
- When a suspected burrow is found, diagnosis may be confirmed by microscopy of surface scrapings, which are placed on a slide in glycerol, mineral oil or immersion in oil and covered with a coverslip. Avoiding potassium hydroxide is necessary because it may dissolve fecal pellets. Positive diagnosis is made when the mite, ova, or fecal pellets are found.
Medical Therapy
# Overview
Medical therapy of scabies includes either topical permethrin or oral ivermectin. Patients may become completely asymptomatic within 1-2 weeks following therapy.
# Medical Therapy
- All patients with scabies require antimicrobial therapy. Medical therapy of scabies includes either topical permethrin or oral ivermectin.
- Patients may experience worsening pruritus and erythema early during the administration of antimicrobial therapy.
- The parasite is gradually eliminated during the body's natural shedding process.
- Antimicrobial therapy[3]
- 1. Adult
- Preferred regimen (1): Permethrin 5% cream applied to all areas of the body from the neck down and washed off after 8–14 hours
- Preferred regimen (2): Ivermectin 200 ug/kg PO qd and repeated in 2 weeks
- Alternative regimen: Lindane (1%) 1 oz of lotion or 30 g of cream applied in a thin layer to all areas of the body from the neck down and thoroughly washed off after 8 hours
- Note: Patients may experience worsening pruritus and erythema early during the administration of antimicrobial therapy
- 2. Infants and young children
- Preferred regimen: Permethrin 5% cream applied to all areas of the body from the neck down and washed off after 8–14 hours
- Note: Infants and young children aged< 10 years should not be treated with lindane
- 3. Crusted Scabies
- Preferred regimen: (Topical scabicide 5% topical Benzyl benzoate 5% OR topical Permethrin 5% cream (full-body application to be repeated daily for 7 days then twice weekly until discharge or cure) AND treatment with Ivermectin 200 ug/kg PO on days 1,2,8,9, and 15. Additional Ivermectin treatment on days 22 and 29 might be required for severe cases
- 4.Pregnant or Lactating Women
- Preferred regimen: Permethrin 5% cream applied to all areas of the body from the neck down and washed off after 8–14 hours
Primary Prevention
# Overview
Scabies is prevented by avoiding direct skin-to-skin contact with an infested person or with items such as clothing or bedding used by an infested person. Scabies treatment usually is recommended for members of the same household, particularly for those who have had prolonged skin-to-skin contact.
# Primary Prevention
- All family and close contacts should be treated at the same time, even if asymptomatic. After treatment has been applied or taken, (or directly before treatment if you are careful and wear gloves) cleaning of environment should occur. A person can easily be reinfected with scabies.
- Without a host, scabies mites can on average survive up to 48-72 hours away from human skin. [1] As in cases of Crusted Scabies, they can survive much longer, up to 7 days. Therefore it is recommended, after treatment, to wash all material (such as clothes, bedding, and towels) that has been in contact with all infested persons in the last three days.
- All household members should be treated at the same time and cleaning must be thorough and simultaneous. Either isolate long enough for the mites to die in a plastic bag for at least 1 week, or clean or freeze overnight.
- Vacuuming floors, carpets, and rugs.
- Disinfecting floor and bathroom surfaces by mopping (this only needs to be done after the first treatment).
- Daily washing of recently worn clothes, towels and bedding in hot water and drying in a hot dryer.
- Hot drying pillows for 30 minutes.
- Overnight freezing, in a plastic bag: stuffed animals, brushes, combs, shoes, coats, gloves, hats, robes, wetsuits, etc.
- Quarantine in a plastic bag for two weeks: things that cannot be washed, hot dried, frozen or drycleaned.
- Drycleaning: things that cannot be washed, hot dried or frozen or quarantined.
## Primary Prevention for Pets
- Pets and humans get infected with different types of mites. The mites that we get can not survive and reproduce on pets.
- ↑ http://picasaweb.google.com/mcmumbi/USMLEIIImages
- ↑ Jump up to: 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 2.25 2.26 2.27 2.28 2.29 2.30 2.31 2.32 2.33 2.34 2.35 2.36 2.37 2.38 2.39 2.40 2.41 2.42 2.43 2.44 2.45 2.46 2.47 2.48 "Dermatology Atlas"..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}
- ↑ Workowski, Kimberly A.; Bolan, Gail A. (2015-06-05). "Sexually transmitted diseases treatment guidelines, 2015". MMWR. Recommendations and reports: Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control. 64 (RR-03): 1–137. ISSN 1545-8601. PMID 26042815. | https://www.wikidoc.org/index.php/Sandbox:Dima | |
a4d807c9f70709863eddd54e19f6484d18654828 | wikidoc | Sandbox:Eman | Sandbox:Eman
### 1.Normal variants of growth
Familial short stature=None needed. Reassurance; monitor growth
Constitutional delay of growth and puberty=None needed. Reassurance; monitor growth; +/– treatment with sex steroids during puberty.
SGA infant, with catch-up growth=Monitor growth to distinguish from the 10% of SGA infants who do not have catch-up growth.
Systemic disorders or processes with secondary effects on growth=
Undernutrition=Reverse nutritional deficit.
Glucocorticoid therapy=Minimize glucocorticoid dose or give on alternate days if feasible; consider alternate drugs.
GI disease (especially Crohn disease and celiac disease)=Diagnose and treat underlying disease, improve nutrition, avoid glucocorticoids.
Rheumatologic disease (especially systemic onset juvenile idiopathic arthritis)=Diagnose and treat underlying disease, improve nutrition, avoid glucocorticoids
Renal disease (CKD, renal tubular acidosis)=Diagnose and treat underlying disease, maximize nutrition; GH if needed.
Cancer=Ensure adequate nutrition; treat any secondary pituitary hormone deficiencies (eg, GH deficiency)
Pulmonary disease (eg, cystic fibrosis, immune deficiencies with recurrent pulmonary infections, or severe asthma)=Diagnose and treat underlying disease, ensure adequate nutrition, avoid glucocorticoids
Immunologic disease=Diagnose and treat underlying disease
Endocrine causes of growth failure
Hypothyroidism=Thyroid hormone replacement
Cushing syndrome=Diagnose and treat underlying disease
GH deficiency=rGH
Precocious puberty=Treatment depends on type of precocious puberty
Genetic diseases with primary effects on growth
Turner syndrome=Estrogen, GH
SHOX mutations=Consider GH.
Noonan syndrome=Consider GH.
Silver-Russell syndrome=Consider GH
Skeletal dysplasias
Achondroplasia=Management of complications, which may include craniocervical junction compression, sleep apnea, spinal stenosis.
Hypochondroplasia=Surveillance for spinal stenosis, with surgery as needed.
Spondyloepiphyseal dysplasia=Surveillance for spinal disorders and osteoarthritis, with surgery as needed
Osteogenesis imperfecta=Bisphosphonates, fracture management
## Characteristics of the rash: Macules, papules, nodules, or plaques=
## Noninfectious
Erythema multiforme
Systemic lupus erythematosus
Dermatomyositis
Drug hypersensitivities
Gianotti-Crosti syndrome
Inflammatory bowel disease
Pityriasis rosea (fever rare)
Sarcoidosis
"Serum sickness"¶
Sweet syndrome (acute febrile neutrophilic dermatosis)
Still's disease (juvenile idiopathic arthritis)
## Bacterial
Arcanobacterium haemolyticum
Bacillus anthracis
Bartonella bacilliformis
Bartonella henselae (cat scratch disease)
Bartonella quintana (trench fever)
Borrelia burgdorferi (Lyme disease)*
Borrelia spp (relapsing fever)
Brucella spp (brucellosis)*
Calymmatobacterium granulomatis (donovanosis)*
Chlamydia psittaci (psittacosis)
Ehrlichiosis*
Ehrlichia chafeensis (HME)
Human granulocytic erlichiosis
Erysipelothrix rhusiopathiae (erysipeloid)
Francisella tularensis (tularemia)
Listeria monocytogenes
Leptospira spp (leptospirosis)*
Mycobacterium leprae*
Mycobacterium marinum*
Mycobacterium tuberculosis
Mycoplasma pneumoniae
Neisseria gonorrhoeae (gonorrhea)*
Neisseria meningitidis (meningococcemia)*
Pseudomonas aeruginosa
Rickettsia akari (rickettsialpox)
Rickettsia prowazekii (epidemic/louse-borne typhus)
Rickettsia rickettsii (RMSF-early lesions)*¶
Rickettsia orientalis/tsutsugamushi (scrub typhus)
Rickettsia typhi (endemic/murine typhus)
Salmonella typhi (typhoid fever)*
Spirillum minor (rat-bite fever)
## Fungal
Blastomyces dermatitidis*
Candida spp
Coccidioides immitis
Cryptococcus neoformans
Histoplasma capsulatum
Other disseminated deep fungal infections in immunocompromised patients
## Viral
Adenovirus
Arbovirus
Atypical measles*
Chikungunya virus
Colorado tick fever
Coxsackieviruses A and B
Cytomegalovirus, primary infection
Dengue virus
Epstein-Barr virus, primary infection
Echoviruses
Hepatitis B (urticaria)*
Human herpesvirus 6 (exanthem subitum)*
Human immunodeficiency virus (HIV-1)*
Kawasaki syndrome (presumed viral)
Molluscum contagiosum
Orf
Parvovirus B19 (erythema infectiosum )
Rubella (German measles)*¶
Rubeola (measles)*
Varicella (chickenpox)*
Varicella-zoster (disseminated)
Viral hemorrhagic fevers (many)
West Nile virus
Zika virus
## Vesicles, bullae, or pustules
## Noninfectious
Erythema multiforme bullosum
Toxic epidermal necrolysis
Dermatitis from plants
Drug hypersensitivities
## Bacterial
Bacillus anthracis
Ehrlichia canis
Listeria monocytogenes
Mycoplasma pneumoniae
Neisseria gonorrhoeae*
Neisseria meningitidis*
Pseudomonas aeruginosa
Rickettsia akari
Rickettsia rickettsii*
Staphylococcus aureus (TSS, SSSS)
Streptococcus group A
Treponema pallidum (secondary syphilis)
Vibrio vulnificus
## Fungal
Histoplasma capsulatum
## Viral
Colorado tick fever
Coxsackie A5, 9, 10, 16, B2, 7
Echoviruses
Eczema herpeticumΔ
Herpes simplex (disseminated)Δ
Varicella (chickenpox)Δ
Varicella-zoster (disseminated)Δ
## Purpuric macules, purpuric papules, or purpuric vesicles
## Noninfectious
"Allergic" vasculitis¶
Erythroderma
Cholesterol embolization
Disseminated intravascular coagulation (purpura fulminans)Δ
Drug hypersensitivities
Fat embolism
Henoch-Schönlein purpura
Immune thrombocytopenic purpura
Granulomatosis with polyangiitis (Wegener's)
## Bacterial
BacteremiaΔ
Borrelia spp
Clostridium spp
Infective endocarditis (many species)
Haemophilus influenzae type B
Neisseria gonorrhoeae (disseminated gonococcal infection)*¶
Neisseria meningitidis (acute or chronic meningococcemia)*¶
Pseudomonas aeruginosa
Rickettsia prowazekii
Rickettsia rickettsii¶
Spirillum minor
Staphylococcus aureus (bacteremia)
Streptobacillus moniliformis
Streptococcus group A (streptococcal toxic shock syndrome, scarlet fever)
Streptococcus pneumoniae (asplenic patient)
Vibrio vulnificus
Yersinia pestis
## Viral
Adenovirus (rare)
Atypical measles*
Chikungunya virus
Colorado tick fever
Congenital cytomegalovirus
Coxsackie A and B (rare, types A-9, B2-5)
Dengue fever
Epstein-Barr virus (rare)
Echoviruses (rare, types 3, 4, 9)
Rubella*
Varicella-zoster virus
West Nile virus
Yellow fever
## Widespread erythema with or without edema followed by desquamation
## Noninfectious
Erythroderma
Drug hypersensitivities
Graft-versus-host reaction
Stevens-Johnson syndrome
Toxic epidermal necrolysis
von Zumbusch pustular psoriasis
## Bacterial
Streptococcus group A (scarlet fever, streptococcal toxic shock syndrome)
Stapylococcus aureus (TSS, SSSS)
## Viral
Kawasaki syndrome (presumed viral)
1.Burn injuries are amongst one of the most devastating of all injuries, having a great impact on the patients physically, physiologically and psychologically. Burns are still one of the top causes of death and disability in the world. Physicians have searched for and formulated a myriad of treatments for burns over the centuries but these treatments mostly were of little benefit to the victims mainly because the fundamental understanding of the patho-physiological impact of burns was not known yet. There was an exponential increase in biomedical research and knowledge from the 18th to early 20thcentury in burn care, such as the recognition of the importance of burn surface area and skin grafting by Reverdin. However, this was not reflected in improving survival and many patients still died of shock and infection. It was not until the past 50 years that the mortality of burns has been dramatically improved, thanks to the better understanding of the patho-physiology of burn injury. The treatment of burns is a major undertaking and involves many components from the initial first aid, assessment of the burn size and depth, fluid resuscitation, wound excision, grafting and coverage, infection control and nutritional support. Progress in each of these areas has contributed significantly to the overall enhanced survival of burn victims and this article aims to explore the history of burns to identify milestones and step-changes in each of these areas in the patient’s care. As in the case of the advancement in the treatment of trauma, these step-changes were mainly related to wars. Napoleon’s surgeon’s contributions to wound management that are still applicable today is an example. In burns, fire disasters as the Rialto fire in 1921 and Coconut Grove nightclubs fire in 1942 led to research that provided the first glimpse of the modern understanding of the patho-physiology of burns.
1.overvew;Syringomyelia is a generic term referring to a disorder in which a cyst or tubular cavity forms within the spinal cord. This cyst, called a syrinx, can expand and elongate over time, destroying the spinal cord. Since the spinal cord connects the brain to nerves in the extremities, this damage may result in pain, weakness, and stiffness in the back, shoulders, arms, or legs. Other symptoms may include headaches and a loss of the ability to feel extremes of hot or cold, especially in the hands {wikipedia}= Syringomyelia is a spinal cord cavitation, which is a central dilation due to cystic degradation expands and destroyed the spinal cord. Caused by an injury, tumors or congenital malformation like hernia. The damage can Effect the brain and nerves, that leade to Bilateral loss of pain and temperature sensation in upper extremities. weakness, stiffness, hyperReflexives in lower extremities with hyposcoliosis.
2.Risk factors for the development of syringomyelia depend on the underlying etiology: = The main risk factors associated with the development of syringomyelia are based on the underlying causes.
3.The natural course of disease in syringomyelia is unpredictable(history)= The essential Course of disease in Syringomyelia is temperamental.
4.80% of patients respond to surgical treatment in terms of hault to progression of symptoms and mild relief.{prognosis)= The symptoms of 80% of patients usually end due to their response to surgical treatment, as well a mild cure.
5{.Physical examination} findings of syringomyelia may include the= The following includes how syringomyelia might be revealed
6.Spinal MRI may help to diagnose and follow up syringomyelia. It is characterized by the following findings{MRI}?
Syringomyelia may be diagnosed as an incidental finding on CT scan. However, delayed CT scan may have a diagnostic importance in early cases of syringomyelia without clinical manifestaions.(CT)?
7.It uses a contrast material combined with x ray or CT to image spinal cord in case of syringomyelia. However, CT metrimised myelography is more sensitive to diagnose syringomyelia as compared to conventional myelography.{mylogram}?
management??
reference:25,37,38,39,65
RED EYE RESIDENT SURVIVAL GUIDE (PDIATRICS)
TREATMENT:
1.Emergency--- urgent ophthalmic surgery.
2.Acute ----#SEVERA.Viral conjunctivitis=Good hygiene, such as meticulous hand washing ---decreasing the spread of acute viral conjunctivitis/ ----B.bacterial conjunctivitis=Any ophthalmic antibiotic
- .Mild allergic conjunctivitis=over-the-counter antihistamine/vasoconstrictor agent, or with a more effective second-generation topical histamine H1 receptor antagonist
- .moderate dry eye= Anti-inflammatory agents (e.g., topical cyclosporine ), topical corticosteroids, and systemic omega-3 fatty acids
3.chronic blepharitis= 1-eyelid hygiene and topical antibiotics if not benefit----- oral tetracycline or doxycycline.
## Inhalation injury in burns
The interest in pulmonary function in burns patients probably started in the 1970s when physicans started to note that pulmonary complications were common in burn patients. With improvements in the treatment of burn shock and sepsis, inhalational injury has now replaced these two causes as the main cause of mortality in burn patients. Inhalational injury by itself has been shown to be associated with pulmonary dysfunction for at least 6 months after the injury.
Pulmonary complications in burn patients can arise from direct injury to the respiratory tract via the inhalation of heated air and chemicals released by combustion, and also iatrogenic factors such as fluid-overloading during resuscitation and lung damage by mechanical ventilation.
Airway and pulmonary inflammation can also result from smoke inhalation alone. An autopsy study by Zikria et al., in 1972 showed that 70% of all burn victims who died within 12 hours of injury had inhalational injury which could be linked to the toxic products of combustion. A study by Herndon et al., in 1985 using an experimental sheep model of smoke inhalation injury showed that the pulmonary edema that occurred after smoke inhalation was the result of an increase in microvascular permeability and hypothesized that this may be secondary to neutrophil degradation. The global immunosuppression that accompanies burn injuries increases the risk of developing respiratory tract infections.
The treatment of burns itself can contribute to the development of lung injury. Moore et al., noted that although fluid resuscitation and blood transfusions prevented acute renal failure in trauma patients, these patients went on to develop pulmonary complications. Pruitt et al., hypothesized that pulmonary insufficiency in burns patients was due to a complex mechanism of interstitial edema leading to alveolar epithelial cell (type 2) damage and pulmonary circulation constriction secondary to vasoactive substances. Achauer et al., proposed a number of measures to prevent pulmonary edema including the use of pulmonary artery wedge and central venous pressure monitoring and also the supplementation of crystalloids with albumin to reduce the amount of fluid required. This was supported by animal studies by Holleman et al., which found that animals that were given only crystalloids post-scald injury had a higher water content in their lungs and recommended the addition of colloids to resuscitation fluid. The view on using colloids however, has changed in the last 40 years. Moncrief, from the U.S. Army of Surgical Research, hypothesized that the use of colloid was of no benefit in the first 24 hours due to the disturbed capillary permeability.
In addition to overhydration, Moore et al., also recognized that inhalational lung injury could be exacerbated by tracheostomy and mechanical ventilation at high oxygen tension. Traditionally, mechanical ventilation is acheived using tidal volumes of 10–15 ml per kilogram of body weight which is larger than in normal subjects at rest (7–8 ml per kilogram), which can lead to an excessive distension of the lung leading to disruption of the pulmonary epithelium and endothelium, and the release of inflammatory mediators. The use of lower tidal volumes (TV) during ventilation of patients with acute lung injury and acute respiratory distress syndrome has been shown by a landmark study by the Acute Respiratory Distress Syndrome Network in 2000 to reduce mortality by 22% and increase the number of ventilator-free days. There is evidence as well that low TV ventilation protects against pulmonary complications in patients without acute respiratory distress syndrome. Most burn centers now adopt this low TV approach to reduce ventilator-induced injury.
# Lifestyle and home remedies
To treat minor burns, follow these steps:
- Cool the burn. apply a cool water (not cold) , wet compress until the pain eases. Don't use ice. Putting ice directly on a burn can cause further damage to the tissue.
- Remove rings or other tight items. Try to do this quickly and gently, before the burned area swells.
- Don't break blisters. Fluid-filled blisters protect against infection. If a blister breaks, clean the area with water (mild soap is optional). Apply an antibiotic ointment. But if a rash appears, stop using the ointment.
- Apply lotion. Once a burn is completely cooled, apply a lotion, such as one that contains aloe vera or a moisturizer. This helps prevent drying and provides relief.
- Bandage the burn. Cover the burn with a sterile gauze bandage (not fluffy cotton). Wrap it loosely to avoid putting pressure on burned skin. Bandaging keeps air off the area, reduces pain and protects blistered skin.
- Take a pain reliever. Over-the-counter medications, such as ibuprofen (Advil, Motrin IB, others), naproxen sodium (Aleve) or acetaminophen (Tylenol, others), can help relieve pain.
- Consider a tetanus shot. Make sure that your tetanus booster is up to date. Doctors recommend that people get a tetanus shot at least every 10 years.
Whether your burn was minor or serious, use sunscreen and moisturizer regularly once the wound is healed.
## Surgical and other procedures
You may need one or more of the following procedures:
- Breathing assistance. If you've been burned on the face or neck, your throat may swell shut. If that appears likely, your doctor may insert a tube down your windpipe (trachea) to keep oxygen supplied to your lungs.
- Feeding tube. People with extensive burns or who are undernourished may need nutritional support. Your doctor may thread a feeding tube through your nose to your stomach.
- Easing blood flow around the wound. If a burn scab (eschar) goes completely around a limb, it can tighten and cut off the blood circulation. An eschar that goes completely around the chest can make it difficult to breathe. Your doctor may cut the eschar to relieve this pressure.
- Skin grafts. A skin graft is a surgical procedure in which sections of your own healthy skin are used to replace the scar tissue caused by deep burns. Donor skin from deceased donors or pigs can be used as a temporary solution.
- Plastic surgery. Plastic surgery (reconstruction) can improve the appearance of burn scars and increase the flexibility of joints affected by scarring.
Red eye
Lids/lashes
Conjunctiva
Cornea
Anterior chamber/iris
Iris/lens | Sandbox:Eman
### 1.Normal variants of growth
Familial short stature=None needed. Reassurance; monitor growth
Constitutional delay of growth and puberty=None needed. Reassurance; monitor growth; +/– treatment with sex steroids during puberty.
SGA infant, with catch-up growth=Monitor growth to distinguish from the 10% of SGA infants who do not have catch-up growth.
Systemic disorders or processes with secondary effects on growth=
Undernutrition=Reverse nutritional deficit.
Glucocorticoid therapy=Minimize glucocorticoid dose or give on alternate days if feasible; consider alternate drugs.
GI disease (especially Crohn disease and celiac disease)=Diagnose and treat underlying disease, improve nutrition, avoid glucocorticoids.
Rheumatologic disease (especially systemic onset juvenile idiopathic arthritis)=Diagnose and treat underlying disease, improve nutrition, avoid glucocorticoids
Renal disease (CKD, renal tubular acidosis)=Diagnose and treat underlying disease, maximize nutrition; GH if needed.
Cancer=Ensure adequate nutrition; treat any secondary pituitary hormone deficiencies (eg, GH deficiency)
Pulmonary disease (eg, cystic fibrosis, immune deficiencies with recurrent pulmonary infections, or severe asthma)=Diagnose and treat underlying disease, ensure adequate nutrition, avoid glucocorticoids
Immunologic disease=Diagnose and treat underlying disease
Endocrine causes of growth failure
Hypothyroidism=Thyroid hormone replacement
Cushing syndrome=Diagnose and treat underlying disease
GH deficiency=rGH
Precocious puberty=Treatment depends on type of precocious puberty
Genetic diseases with primary effects on growth
Turner syndrome=Estrogen, GH
SHOX mutations=Consider GH.
Noonan syndrome=Consider GH.
Silver-Russell syndrome=Consider GH
Skeletal dysplasias
Achondroplasia=Management of complications, which may include craniocervical junction compression, sleep apnea, spinal stenosis.
Hypochondroplasia=Surveillance for spinal stenosis, with surgery as needed.
Spondyloepiphyseal dysplasia=Surveillance for spinal disorders and osteoarthritis, with surgery as needed
Osteogenesis imperfecta=Bisphosphonates, fracture management
## Characteristics of the rash: Macules, papules, nodules, or plaques=
## Noninfectious
Erythema multiforme
Systemic lupus erythematosus
Dermatomyositis
Drug hypersensitivities
Gianotti-Crosti syndrome
Inflammatory bowel disease
Pityriasis rosea (fever rare)
Sarcoidosis
"Serum sickness"¶
Sweet syndrome (acute febrile neutrophilic dermatosis)
Still's disease (juvenile idiopathic arthritis)
## Bacterial
Arcanobacterium haemolyticum
Bacillus anthracis
Bartonella bacilliformis
Bartonella henselae (cat scratch disease)
Bartonella quintana (trench fever)
Borrelia burgdorferi (Lyme disease)*
Borrelia spp (relapsing fever)
Brucella spp (brucellosis)*
Calymmatobacterium granulomatis (donovanosis)*
Chlamydia psittaci (psittacosis)
Ehrlichiosis*
Ehrlichia chafeensis (HME)
Human granulocytic erlichiosis
Erysipelothrix rhusiopathiae (erysipeloid)
Francisella tularensis (tularemia)
Listeria monocytogenes
Leptospira spp (leptospirosis)*
Mycobacterium leprae*
Mycobacterium marinum*
Mycobacterium tuberculosis
Mycoplasma pneumoniae
Neisseria gonorrhoeae (gonorrhea)*
Neisseria meningitidis (meningococcemia)*
Pseudomonas aeruginosa
Rickettsia akari (rickettsialpox)
Rickettsia prowazekii (epidemic/louse-borne typhus)
Rickettsia rickettsii (RMSF-early lesions)*¶
Rickettsia orientalis/tsutsugamushi (scrub typhus)
Rickettsia typhi (endemic/murine typhus)
Salmonella typhi (typhoid fever)*
Spirillum minor (rat-bite fever)
## Fungal
Blastomyces dermatitidis*
Candida spp
Coccidioides immitis
Cryptococcus neoformans
Histoplasma capsulatum
Other disseminated deep fungal infections in immunocompromised patients
## Viral
Adenovirus
Arbovirus
Atypical measles*
Chikungunya virus
Colorado tick fever
Coxsackieviruses A and B
Cytomegalovirus, primary infection
Dengue virus
Epstein-Barr virus, primary infection
Echoviruses
Hepatitis B (urticaria)*
Human herpesvirus 6 (exanthem subitum)*
Human immunodeficiency virus (HIV-1)*
Kawasaki syndrome (presumed viral)
Molluscum contagiosum
Orf
Parvovirus B19 (erythema infectiosum [fifth disease])
Rubella (German measles)*¶
Rubeola (measles)*
Varicella (chickenpox)*
Varicella-zoster (disseminated)
Viral hemorrhagic fevers (many)
West Nile virus
Zika virus
## Vesicles, bullae, or pustules
## Noninfectious
Erythema multiforme bullosum
Toxic epidermal necrolysis
Dermatitis from plants
Drug hypersensitivities
## Bacterial
Bacillus anthracis
Ehrlichia canis
Listeria monocytogenes
Mycoplasma pneumoniae
Neisseria gonorrhoeae*
Neisseria meningitidis*
Pseudomonas aeruginosa
Rickettsia akari
Rickettsia rickettsii*
Staphylococcus aureus (TSS, SSSS)
Streptococcus group A
Treponema pallidum (secondary syphilis)
Vibrio vulnificus
## Fungal
Histoplasma capsulatum
## Viral
Colorado tick fever
Coxsackie A5, 9, 10, 16, B2, 7
Echoviruses
Eczema herpeticumΔ
Herpes simplex (disseminated)Δ
Varicella (chickenpox)Δ
Varicella-zoster (disseminated)Δ
## Purpuric macules, purpuric papules, or purpuric vesicles
## Noninfectious
"Allergic" vasculitis¶
Erythroderma
Cholesterol embolization
Disseminated intravascular coagulation (purpura fulminans)Δ
Drug hypersensitivities
Fat embolism
Henoch-Schönlein purpura
Immune thrombocytopenic purpura
Granulomatosis with polyangiitis (Wegener's)
## Bacterial
BacteremiaΔ
Borrelia spp
Clostridium spp
Infective endocarditis (many species)
Haemophilus influenzae type B
Neisseria gonorrhoeae (disseminated gonococcal infection)*¶
Neisseria meningitidis (acute or chronic meningococcemia)*¶
Pseudomonas aeruginosa
Rickettsia prowazekii
Rickettsia rickettsii¶
Spirillum minor
Staphylococcus aureus (bacteremia)
Streptobacillus moniliformis
Streptococcus group A (streptococcal toxic shock syndrome, scarlet fever)
Streptococcus pneumoniae (asplenic patient)
Vibrio vulnificus
Yersinia pestis
## Viral
Adenovirus (rare)
Atypical measles*
Chikungunya virus
Colorado tick fever
Congenital cytomegalovirus
Coxsackie A and B (rare, types A-9, B2-5)
Dengue fever
Epstein-Barr virus (rare)
Echoviruses (rare, types 3, 4, 9)
Rubella*
Varicella-zoster virus
West Nile virus
Yellow fever
## Widespread erythema with or without edema followed by desquamation
## Noninfectious
Erythroderma
Drug hypersensitivities
Graft-versus-host reaction
Stevens-Johnson syndrome
Toxic epidermal necrolysis
von Zumbusch pustular psoriasis
## Bacterial
Streptococcus group A (scarlet fever, streptococcal toxic shock syndrome)
Stapylococcus aureus (TSS, SSSS)
## Viral
Kawasaki syndrome (presumed viral)
1.Burn injuries are amongst one of the most devastating of all injuries, having a great impact on the patients physically, physiologically and psychologically. Burns are still one of the top causes of death and disability in the world. Physicians have searched for and formulated a myriad of treatments for burns over the centuries but these treatments mostly were of little benefit to the victims mainly because the fundamental understanding of the patho-physiological impact of burns was not known yet. There was an exponential increase in biomedical research and knowledge from the 18th to early 20thcentury in burn care, such as the recognition of the importance of burn surface area and skin grafting by Reverdin. However, this was not reflected in improving survival and many patients still died of shock and infection. It was not until the past 50 years that the mortality of burns has been dramatically improved, thanks to the better understanding of the patho-physiology of burn injury. The treatment of burns is a major undertaking and involves many components from the initial first aid, assessment of the burn size and depth, fluid resuscitation, wound excision, grafting and coverage, infection control and nutritional support. Progress in each of these areas has contributed significantly to the overall enhanced survival of burn victims and this article aims to explore the history of burns to identify milestones and step-changes in each of these areas in the patient’s care. As in the case of the advancement in the treatment of trauma, these step-changes were mainly related to wars. Napoleon’s surgeon’s contributions to wound management that are still applicable today is an example. In burns, fire disasters as the Rialto fire in 1921 and Coconut Grove nightclubs fire in 1942 led to research that provided the first glimpse of the modern understanding of the patho-physiology of burns.
1.overvew;Syringomyelia is a generic term referring to a disorder in which a cyst or tubular cavity forms within the spinal cord. This cyst, called a syrinx, can expand and elongate over time, destroying the spinal cord. Since the spinal cord connects the brain to nerves in the extremities, this damage may result in pain, weakness, and stiffness in the back, shoulders, arms, or legs. Other symptoms may include headaches and a loss of the ability to feel extremes of hot or cold, especially in the hands {wikipedia}= Syringomyelia is a spinal cord cavitation, which is a central dilation due to cystic degradation expands and destroyed the spinal cord. Caused by an injury, tumors or congenital malformation like hernia. The damage can Effect the brain and nerves, that leade to Bilateral loss of pain and temperature sensation in upper extremities. weakness, stiffness, hyperReflexives in lower extremities with hyposcoliosis.
2.Risk factors for the development of syringomyelia depend on the underlying etiology: = The main risk factors associated with the development of syringomyelia are based on the underlying causes.
3.The natural course of disease in syringomyelia is unpredictable(history)= The essential Course of disease in Syringomyelia is temperamental.
4.80% of patients respond to surgical treatment in terms of hault to progression of symptoms and mild relief.{prognosis)= The symptoms of 80% of patients usually end due to their response to surgical treatment, as well a mild cure.
5{.Physical examination} findings of syringomyelia may include the= The following includes how syringomyelia might be revealed
6.Spinal MRI may help to diagnose and follow up syringomyelia. It is characterized by the following findings{MRI}?
Syringomyelia may be diagnosed as an incidental finding on CT scan. However, delayed CT scan may have a diagnostic importance in early cases of syringomyelia without clinical manifestaions.(CT)?
7.It uses a contrast material combined with x ray or CT to image spinal cord in case of syringomyelia. However, CT metrimised myelography is more sensitive to diagnose syringomyelia as compared to conventional myelography.{mylogram}?
management??
reference:25,37,38,39,65
RED EYE RESIDENT SURVIVAL GUIDE (PDIATRICS)
TREATMENT:
1.Emergency--- urgent ophthalmic surgery.[24][25]
2.Acute ----#SEVERA.Viral conjunctivitis=Good hygiene, such as meticulous hand washing ---decreasing the spread of acute viral conjunctivitis/ ----B.bacterial conjunctivitis=Any ophthalmic antibiotic
- .Mild allergic conjunctivitis=over-the-counter antihistamine/vasoconstrictor agent, or with a more effective second-generation topical histamine H1 receptor antagonist
- .moderate dry eye= Anti-inflammatory agents (e.g., topical cyclosporine [Restasis]), topical corticosteroids, and systemic omega-3 fatty acids
3.chronic blepharitis= 1-eyelid hygiene and topical antibiotics if not benefit----- oral tetracycline or doxycycline.
## Inhalation injury in burns
The interest in pulmonary function in burns patients probably started in the 1970s when physicans started to note that pulmonary complications were common in burn patients. With improvements in the treatment of burn shock and sepsis, inhalational injury has now replaced these two causes as the main cause of mortality in burn patients.[109] Inhalational injury by itself has been shown to be associated with pulmonary dysfunction for at least 6 months after the injury.[109]
Pulmonary complications in burn patients can arise from direct injury to the respiratory tract via the inhalation of heated air and chemicals released by combustion, and also iatrogenic factors such as fluid-overloading during resuscitation and lung damage by mechanical ventilation.
Airway and pulmonary inflammation can also result from smoke inhalation alone. An autopsy study by Zikria et al., in 1972 showed that 70% of all burn victims who died within 12 hours of injury had inhalational injury which could be linked to the toxic products of combustion.[110] A study by Herndon et al., in 1985 using an experimental sheep model of smoke inhalation injury showed that the pulmonary edema that occurred after smoke inhalation was the result of an increase in microvascular permeability and hypothesized that this may be secondary to neutrophil degradation.[111] The global immunosuppression that accompanies burn injuries increases the risk of developing respiratory tract infections.[112]
The treatment of burns itself can contribute to the development of lung injury. Moore et al., noted that although fluid resuscitation and blood transfusions prevented acute renal failure in trauma patients, these patients went on to develop pulmonary complications.[113] Pruitt et al., hypothesized that pulmonary insufficiency in burns patients was due to a complex mechanism of interstitial edema leading to alveolar epithelial cell (type 2) damage and pulmonary circulation constriction secondary to vasoactive substances.[114] Achauer et al., proposed a number of measures to prevent pulmonary edema including the use of pulmonary artery wedge and central venous pressure monitoring and also the supplementation of crystalloids with albumin to reduce the amount of fluid required.[115] This was supported by animal studies by Holleman et al., which found that animals that were given only crystalloids post-scald injury had a higher water content in their lungs and recommended the addition of colloids to resuscitation fluid.[116] The view on using colloids however, has changed in the last 40 years. Moncrief, from the U.S. Army of Surgical Research, hypothesized that the use of colloid was of no benefit in the first 24 hours due to the disturbed capillary permeability.[117]
In addition to overhydration, Moore et al.,[113] also recognized that inhalational lung injury could be exacerbated by tracheostomy and mechanical ventilation at high oxygen tension. Traditionally, mechanical ventilation is acheived using tidal volumes of 10–15 ml per kilogram of body weight which is larger than in normal subjects at rest (7–8 ml per kilogram)[118], which can lead to an excessive distension of the lung leading to disruption of the pulmonary epithelium and endothelium, and the release of inflammatory mediators.[119,120] The use of lower tidal volumes (TV) during ventilation of patients with acute lung injury and acute respiratory distress syndrome has been shown by a landmark study by the Acute Respiratory Distress Syndrome Network in 2000 to reduce mortality by 22% and increase the number of ventilator-free days. There is evidence as well that low TV ventilation protects against pulmonary complications in patients without acute respiratory distress syndrome.[121] Most burn centers now adopt this low TV approach to reduce ventilator-induced injury.[122]
# Lifestyle and home remedies
To treat minor burns, follow these steps:
- Cool the burn. apply a cool water (not cold) , wet compress until the pain eases. Don't use ice. Putting ice directly on a burn can cause further damage to the tissue.
- Remove rings or other tight items. Try to do this quickly and gently, before the burned area swells.
- Don't break blisters. Fluid-filled blisters protect against infection. If a blister breaks, clean the area with water (mild soap is optional). Apply an antibiotic ointment. But if a rash appears, stop using the ointment.
- Apply lotion. Once a burn is completely cooled, apply a lotion, such as one that contains aloe vera or a moisturizer. This helps prevent drying and provides relief.
- Bandage the burn. Cover the burn with a sterile gauze bandage (not fluffy cotton). Wrap it loosely to avoid putting pressure on burned skin. Bandaging keeps air off the area, reduces pain and protects blistered skin.
- Take a pain reliever. Over-the-counter medications, such as ibuprofen (Advil, Motrin IB, others), naproxen sodium (Aleve) or acetaminophen (Tylenol, others), can help relieve pain.
- Consider a tetanus shot. Make sure that your tetanus booster is up to date. Doctors recommend that people get a tetanus shot at least every 10 years.
Whether your burn was minor or serious, use sunscreen and moisturizer regularly once the wound is healed.
## Surgical and other procedures
You may need one or more of the following procedures:
- Breathing assistance. If you've been burned on the face or neck, your throat may swell shut. If that appears likely, your doctor may insert a tube down your windpipe (trachea) to keep oxygen supplied to your lungs.
- Feeding tube. People with extensive burns or who are undernourished may need nutritional support. Your doctor may thread a feeding tube through your nose to your stomach.
- Easing blood flow around the wound. If a burn scab (eschar) goes completely around a limb, it can tighten and cut off the blood circulation. An eschar that goes completely around the chest can make it difficult to breathe. Your doctor may cut the eschar to relieve this pressure.
- Skin grafts. A skin graft is a surgical procedure in which sections of your own healthy skin are used to replace the scar tissue caused by deep burns. Donor skin from deceased donors or pigs can be used as a temporary solution.
- Plastic surgery. Plastic surgery (reconstruction) can improve the appearance of burn scars and increase the flexibility of joints affected by scarring.
Red eye
Lids/lashes
Conjunctiva
Cornea
Anterior chamber/iris
Iris/lens
- | https://www.wikidoc.org/index.php/Sandbox:Eman | |
8e8cd2c10b01b9457a24b5110b087e403ccfba5b | wikidoc | Sandbox: ATL | Sandbox: ATL
- The optimal therapy for adult T-cell leukemia depends on the clinical variant of the disease.
- Chronic and smoldering adult T-cell leukemia patients are usually managed by either observation, skin directed therapies, or a combination of idovudine and interferon therapy.
- Acute adult T-cell leukemia patients are usually managed by either chemotherapy, supportive care, allogeneic stem cell transplant, or a combination of zidovudine and interferon therapy.
- Adult T-cell lymphoma patients are usually managed by either chemotherapy, supportive care, or allogeneic stem cell transplant.
## Management of Chronic/Smoldering Adult T-cell Leukemia
- Patients may be managed by observation and close follow-up for any symptomatic deterioration. Follow up tests for such patients may include:
- Complete history and physical examination
- Serum calcium level
- Blood urea nitrogen
- Serum creatinine level
- Serum LDH
- Chest and abdominal CT scan
- Skin directed therapies for the management of localized cutaneous lesions among such patients may include:
- Topical corticosteroids
- Topical chemotherapy (mechlorethamine)
- Local radiation (8–36 Gy)
- Topical retinoids (bexarotene, tazarotene)
- Phototherapy (UVB, NB-UVB for patch/thin plaques; PUVA for thicker plaques)
- Topical imiquimod
- Zidovudine and interferon combination therapy:
- Chronic/smoldering adult T-cell leukemia patients should be evaluated for response after two months of initiating the combination therapy.
- Patients who responded to the therapy should be continued on zidovudine and interferon therapy.
- While patients who did not respond to the therapy should be managed by either chemotherapy or supportive care depending on the patients preference.
- The criteria for complete remission of adult T-cell leukemia patients includes:
- Absence of lymphadenopathy
- Absence of hepatomegaly and splenomegaly
- Absence of cutaneous lesions
- Absence of malignant on peripheral blood smear
- Absence of malignant on bone marrow biopsy
## Management of Acute Adult T-cell Leukemia
- The first line chemotherapeutic regimens used for the initial management of adult T-cell leukemia include:
- Cyclophosphamide AND doxorubicin AND vincristine AND prednisone (CHOP)
- Cyclophosphamide AND doxorubicin AND vincristine AND etoposide AND prednisone (CHOEP)
- Etoposide AND prednisone AND vincristine AND cyclophosphamide AND doxorubicin (Dose-adjusted EPOCH)
- Cyclophosphamide AND vincristine AND doxorubicin AND dexamethasone (HyperCVAD) alternating with high-dose methotrexate and cytarabine
- Consider allogeneic stem cell transplantion for patients who respond to first line chemotherapeutic agents.
- Patients who do not respond to the initial chemotherapeutic regimens may be managed by other second line chemotherapeutic agents such as:
- Bendamustine
- Belinostat
- Brentuximab vedotin for systemic CD30+ PTCL
- DHAP (dexamethasone, cisplatin, cytarabine)
- ESHAP (etoposide AND methylprednisolone AND cytarabine AND cisplatin)
- Dose-adjusted EPOCH
- GDP (gemcitabine AND dexamethasone AND cisplatin)
- GemOx (gemcitabine AND oxaliplatin)
- ICE (ifosfamide AND carboplatin AND etoposide)
- Pralatrexated
- Romidepsin
- Consider allogeneic stem cell transplantion for patients who respond to second line chemotherapeutic agents.
- Zidovudine and interferon combination therapy:
- Chronic/smoldering adult T-cell leukemia patients should be evaluated for response after two months of initiating the combination therapy.
- Patients who responded to the therapy may be further managed by either allogeneic stem cell transplantion or continue on zidovudine and interferon combination therapy.
- While patients who did not respond to the therapy should be managed by either chemotherapy or supportive care depending on the patients preference.
## Management of Adult T-cell Lymphoma
- The first line chemotherapeutic regimens used for the initial management of adult T-cell leukemia include:
- Cyclophosphamide AND doxorubicin AND vincristine AND prednisone (CHOP)
- Cyclophosphamide AND doxorubicin AND vincristine AND etoposide AND prednisone (CHOEP)
- Etoposide AND prednisone AND vincristine AND cyclophosphamide AND doxorubicin (Dose-adjusted EPOCH)
- Cyclophosphamide AND vincristine AND doxorubicin AND dexamethasone (HyperCVAD) alternating with high-dose methotrexate and cytarabine
- Consider allogeneic stem cell transplantion for patients who respond to first line chemotherapeutic agents.
- Patients who do not respond to the initial chemotherapeutic regimens may be managed by other second line chemotherapeutic agents such as:
- Bendamustine
- Belinostat
- Brentuximab vedotin for systemic CD30+ PTCL
- DHAP (dexamethasone, cisplatin, cytarabine)
- ESHAP (etoposide AND methylprednisolone AND cytarabine AND cisplatin)
- Dose-adjusted EPOCH
- GDP (gemcitabine AND dexamethasone AND cisplatin)
- GemOx (gemcitabine AND oxaliplatin)
- ICE (ifosfamide AND carboplatin AND etoposide)
- Pralatrexated
- Romidepsin
- Consider allogeneic stem cell transplantion for patients who respond to second line chemotherapeutic agents.
# Supportive Therapy
## Opportunistic Infections Prophylaxis
- Sulfamethoxazole/trimethoprim prophylaxis is recommended among adult T-cell leukemia patients to protect against opportunistic infections. | Sandbox: ATL
- The optimal therapy for adult T-cell leukemia depends on the clinical variant of the disease.
- Chronic and smoldering adult T-cell leukemia patients are usually managed by either observation, skin directed therapies, or a combination of idovudine and interferon therapy.
- Acute adult T-cell leukemia patients are usually managed by either chemotherapy, supportive care, allogeneic stem cell transplant, or a combination of zidovudine and interferon therapy.
- Adult T-cell lymphoma patients are usually managed by either chemotherapy, supportive care, or allogeneic stem cell transplant.
## Management of Chronic/Smoldering Adult T-cell Leukemia
- Patients may be managed by observation and close follow-up for any symptomatic deterioration. Follow up tests for such patients may include:
- Complete history and physical examination
- Serum calcium level
- Blood urea nitrogen
- Serum creatinine level
- Serum LDH
- Chest and abdominal CT scan
- Skin directed therapies for the management of localized cutaneous lesions among such patients may include:
- Topical corticosteroids
- Topical chemotherapy (mechlorethamine)
- Local radiation (8–36 Gy)
- Topical retinoids (bexarotene, tazarotene)
- Phototherapy (UVB, NB-UVB for patch/thin plaques; PUVA for thicker plaques)
- Topical imiquimod
- Zidovudine and interferon combination therapy:
- Chronic/smoldering adult T-cell leukemia patients should be evaluated for response after two months of initiating the combination therapy.
- Patients who responded to the therapy should be continued on zidovudine and interferon therapy.
- While patients who did not respond to the therapy should be managed by either chemotherapy or supportive care depending on the patients preference.
- The criteria for complete remission of adult T-cell leukemia patients includes:
- Absence of lymphadenopathy
- Absence of hepatomegaly and splenomegaly
- Absence of cutaneous lesions
- Absence of malignant on peripheral blood smear
- Absence of malignant on bone marrow biopsy
## Management of Acute Adult T-cell Leukemia
- The first line chemotherapeutic regimens used for the initial management of adult T-cell leukemia include:
- Cyclophosphamide AND doxorubicin AND vincristine AND prednisone (CHOP)
- Cyclophosphamide AND doxorubicin AND vincristine AND etoposide AND prednisone (CHOEP)
- Etoposide AND prednisone AND vincristine AND cyclophosphamide AND doxorubicin (Dose-adjusted EPOCH)
- Cyclophosphamide AND vincristine AND doxorubicin AND dexamethasone (HyperCVAD) alternating with high-dose methotrexate and cytarabine
- Consider allogeneic stem cell transplantion for patients who respond to first line chemotherapeutic agents.
- Patients who do not respond to the initial chemotherapeutic regimens may be managed by other second line chemotherapeutic agents such as:
- Bendamustine
- Belinostat
- Brentuximab vedotin for systemic CD30+ PTCL
- DHAP (dexamethasone, cisplatin, cytarabine)
- ESHAP (etoposide AND methylprednisolone AND cytarabine AND cisplatin)
- Dose-adjusted EPOCH
- GDP (gemcitabine AND dexamethasone AND cisplatin)
- GemOx (gemcitabine AND oxaliplatin)
- ICE (ifosfamide AND carboplatin AND etoposide)
- Pralatrexated
- Romidepsin
- Consider allogeneic stem cell transplantion for patients who respond to second line chemotherapeutic agents.
- Zidovudine and interferon combination therapy:
- Chronic/smoldering adult T-cell leukemia patients should be evaluated for response after two months of initiating the combination therapy.
- Patients who responded to the therapy may be further managed by either allogeneic stem cell transplantion or continue on zidovudine and interferon combination therapy.
- While patients who did not respond to the therapy should be managed by either chemotherapy or supportive care depending on the patients preference.
## Management of Adult T-cell Lymphoma
- The first line chemotherapeutic regimens used for the initial management of adult T-cell leukemia include:
- Cyclophosphamide AND doxorubicin AND vincristine AND prednisone (CHOP)
- Cyclophosphamide AND doxorubicin AND vincristine AND etoposide AND prednisone (CHOEP)
- Etoposide AND prednisone AND vincristine AND cyclophosphamide AND doxorubicin (Dose-adjusted EPOCH)
- Cyclophosphamide AND vincristine AND doxorubicin AND dexamethasone (HyperCVAD) alternating with high-dose methotrexate and cytarabine
- Consider allogeneic stem cell transplantion for patients who respond to first line chemotherapeutic agents.
- Patients who do not respond to the initial chemotherapeutic regimens may be managed by other second line chemotherapeutic agents such as:
- Bendamustine
- Belinostat
- Brentuximab vedotin for systemic CD30+ PTCL
- DHAP (dexamethasone, cisplatin, cytarabine)
- ESHAP (etoposide AND methylprednisolone AND cytarabine AND cisplatin)
- Dose-adjusted EPOCH
- GDP (gemcitabine AND dexamethasone AND cisplatin)
- GemOx (gemcitabine AND oxaliplatin)
- ICE (ifosfamide AND carboplatin AND etoposide)
- Pralatrexated
- Romidepsin
- Consider allogeneic stem cell transplantion for patients who respond to second line chemotherapeutic agents.
# Supportive Therapy
## Opportunistic Infections Prophylaxis
- Sulfamethoxazole/trimethoprim prophylaxis is recommended among adult T-cell leukemia patients to protect against opportunistic infections. | https://www.wikidoc.org/index.php/Sandbox:_ATL | |
4937f09ebde20ee0a6d5d69800c0c1f43d21f27d | wikidoc | Sandbox: GDS | Sandbox: GDS
For COVID-19 frequently asked inpatient questions, click here
For COVID-19 frequently asked outpatient questions, click here
# Overview
Renal transplant patients are under immunosuppression to modulate the immune response to graft. Moreover these patients have various underlying chronic kidney diseases and other co-morbidities such as diabetes and hypertension, which can impact the results in COVID-19 infection. Hence these patients are at a higher risk of developing COVID-19 associated complications. The clinical manifestations, treatment, and prognosis of COVID-19 infection may be different from the general population. It is believed that any transplant recipient presented to the infection would result in a high level of cases; however, the risk of the donor to recipient transmission is unknown.
# Historical Perspectives
The etiological agent involved is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), first detected in Wuhan, China. On March 12, 2020 the World Health Organization declared the COVID-19 outbreak a pandemic. The earlier SARS epidemic of Hong Kong is known to affect both pediatric and adult renal transplant patients where the severity of disease in adult patients was more than that in pediatric patients The first reported case of COVID-19 infection in renal transplant patient, was a 52‐year‐old man who received living‐related kidney transplantation 12 years for chronic glomerulonephritis, in Wuhan, China. He made a successful recovery and was discharged on day 13.
# Classification
Classification of COVID-19 infection in renal transplant patients depends on the severity of COVID-19 manifestations. COVID-19 infection classification according to WHO is following:
# Pathophysiology
## Genetics
Angiotensin-converting enzyme 2 and Dipeptidyl peptidase have been implicated in the uptake of SARS-Cov and MERS-CoV Several studies have indicated that viral S-protein RBD interacts with host ACE2 receptor. S protein changes thus make the human cells permissive to SARS-CoV and SARS-CoV-2 infection ACE2: ACE ratio is higher in the kidneys compared to the respiratory system. (1:1 in the kidneys VS 1:20 in the respiratory system).These receptors are found in the proximal tubules of kidneySARS-CoV2 spike(S) protein is cleaved and activated by transmembrane serine protease family (TMPRSS) after attaching to angiotensin-converting enzyme 2 (ACE2) receptors. This allows the virus to release fusion peptide that aides in membrane fusion..
There is a possibility of association between MHC class I(HLA A, B & C) with incidence of COVID-19 infection as well as severity of complications
. HLA-B*46:01 gene product is believed to show lowest binding to SARS-CoV-2 indicating decreased viral presentation to immune system. Whereas HLA-B*15:03 shows increased affinity to SARS-CoV-2leading to higher likelihood in developing immunity.
## Associated Conditions
### Acute Kidney Injury
- Acute Kidney Injury has been reported in patients with COVID-19 infection along with presence of proteinuria, hematuria. In a case observation, 4 out of 7 patients had AKI which may indicate that renal transplant patients are at higher risk AKI on being infected with COVID-19 whereas only 29% AKI was seen in critically ill patients of general population.
- Acute Kidney Injury seen in COVID-19 infection can be from the cytotropic effect (Uptake of SARS-Cov-2 virus into proximal tubule cells is possible explanation for the AKI seen in COVID patients) of the viral particles as well as systemic inflammatory response induced by the cytokines. Patients admitted with severe disease, acute respiratory distress syndrome (ARDS) or in patients admitted to ICU have a higher incidence of AKI . . Other possible reasons that can play a role in AKI development, are multi-organ failure resulting in acute tubular necrosis (ATN), volume reduction causing prerenal ATN, high fever, drug toxicity, hypotension, and contrast exposure.
- Pro-inflammatory cytokine levels are elevated in the COVID-19 infection and there is activation of T-cell response. There is higher cytokine levels and there is occurrence of cytokine storm in severe cases. In cytokine storm the, the immune system damages the healthy tissue rather than virus. According to an autopsy report of six patients, the light microscopy indicated CD68+ macrophage infiltration of the tubulointerstitium and severe ATN. The tubules showed complement 5b-9 deposition in all six cases, but deposition in glomeruli and capillaries were seldom seen. Some CD8+ T lymphocyte cells and CD56+ (natural killer) cells were seen in kidney tissue
### General COVID-19 Pathophysiology in Renal Transplant Patients
The overall presentation of COVID-19 in renal transplant patients is similar to that in general population.However, the renal transplant recipients are at remain at higher risk to catch COVID-19
and develop severe complications due to chronic immunosuppressed state which is implicated in various viral infections such as cytomegalovirus, herpes zoster, norovirus infectionsetc.
COVID-19 Pathophysiology
# Causes
## Life Threatening Causes
- Even though the CT findings in COVID-19 pneumonia were similar in renal transplant recipients and general population, due to chronic immunosuppression, the clinical features of COVID-19 in renal transplant patients may be atypical.
- In one of the study, nine of the 10 patients had fever, cough, shortness of breath, and fatigue; three had diarrhea; eight had lymphopenia; six had renal injury; and six had liver function damage.
- It needs to be verified whether the severity of COVID-19 pneumonia differs in immunocompromised transplant patients than non-immunocompromised population. According to a report from China’s Infectious Disease Information system, out of 72,314 COVID-19 cases in general population, 81% were reported as mild, whereas 19% were either severe or critical. And, in report from study in renal transplant patients, the number of severe cases were 80% compared to only 10% in their infected family members and 19% in general population. Moreover, average duration of illness was nearly twice i.e. 35 days compared to 18 days in control group and 17-20 days reported in general population.
# Differentiating from other Diseases
- As the general presentation of COVID-19 is similar in general population and renal transplant patients, it should be differentiated from other diseases presenting with cough, fever, shortness of breath, and tachypnea.
To review the differential diagnosis, click here
- To review the differential diagnosis, click here
- COVID-19 associated AKI in renal transplant patients must be differentiated from other causes of AKI , such as congestive heart failure, hemorrhage, dehydration, liver failure, urinary tract obstruction, Interstitial nephritis, glomerulonephritis and nephrotoxic medications.
For the differential diagnosis of AKI, click here.
- For the differential diagnosis of AKI, click here.
# Epidemiology and Demographics
## Incidence
- Due to the lack of broad screening that includes the general population (including asymptomatic patients) and the lack of PCR and antibody tests with acceptable sensitivity and specificity, an accurate estimate of the incidence rate of coronavirus disease 2019 (COVID-19) cannot be accurately estimated.
- Data indicates that the rate of severe complications of COVID-19 is almost 25%, and kidney is also one of the main organs affected in severe illness.. The risk is further increased in patients having chronic kidney disease(CKD), patients on chronic replacement therapies, and patients with kidney transplants.
- AKI is seen in 5-15% of the SARS-CoV and MERS-CoV infection
## Prevalence
- For details on the real-time prevalence and spread of COVID-19, click here.
- As it is prevalent in all the continents of the world, World Health Organization (WHO) has declared COVID-19 outbreak a pandemic.
- Among patients with influenza-like-illness and without risk factors for COVID-19, 5% were positive for COVID-19.
- In an analysis of 14 articles
- Median interval of transplantation - 4 years. (range .25-30.1)
- Median interval of transplantation - 4 years. (range .25-30.1)
## Case-fatality rate
- Due to limited testing of asymptomatic individuals, the potential inaccuracies of early PCR tests and antibody tests, the inconsistent reporting and lack of organized data, an accurate case-fatality rate of COVID-19 has yet to be established.
- According to analysis of recent studies
, a fatality rate of 17.4% (4/23) in renal transplant patients was reported
## Age
- Renal transplant patients of all ages are at a higher risk of COVID-19 due to immunosuppression.
- The youngest renal transplant patient who died of COVID-19 according to recent studies was 71 years old.
- In general population, COVID-19 associated AKI has higher incidence in elderly.
## Gender
- Men are more likely to be affected by COVID-19 than women.
- Women dying from COVID-19 are generally elder than men(median age: 82 vs. 79 years for women vs. men, respectively).
## Race
*According to study done in New York, 14 recipients (39%) were black, and 15 recipients (42%) were Hispanic.
# Risk Factors
There are various factors that can predispose renal transplant patients to COVID-19.
- Immunosuppression
- Chronic Renal Failure
- Co-Morbidities
Diabetes
Hypertension
Hyperlipidemia
H/o Heart Disease
- Diabetes
- Hypertension
- Hyperlipidemia
- H/o Heart Disease
- Male Sex
- Old Age
- Current or h/o smoking tobacco
- Possible a/w donor COVID-19 infection
# Screening
According to one of the COVID-19 Rapid Guidelines for renal transplant patients:
Screening for AKI
Serial monitoring of kidney function tests should be considered in renal transplant patients'
- BUN
- Creatinine
- Urine analysis
Gut Ischemia, coagulopathies, and disseminated intravascular coagulopation have been seen later in the course of illness
- The following should be measured in all patients with severe COVID-19 infection on admission to prevent and screen for coagulopathies.
D-dimer
Ferritin
Troponin
- D-dimer
- Ferritin
- Troponin
# Natural History, Complications and Prognosis
Even though the course of infection of COVID-19 in the general population and the renal transplant recipients has been the same, the mortality in COVID-19 affected renal transplant recipients have been reported to be higher than the general population. It has been widely feared that the scope of complications in the transplant recipients would be more severe than what is generally seen in the population due to a suppressed state of immunityThe incidence of AKI has also been reported to be higher in COVID-19 infection
# Diagnosis
## Diagnosis of Choice
- Renal transplant patients present with similar CT an Chest X-Ray finding which are seen in the general population, although the features of COVID-19 infection may be atypical in such patients.
- Renal Transplant patients who develop AKI can be diagnosed using KDIGO criteria:
Increase in S. Creatinine: ≥0.3 mg/dl (≥26.5 μmol/l) within 48 hours
Increase in S. Creatinine: ≥1.5 times baseline within the previous 7 days
Urine volume 6 hours
- Increase in S. Creatinine: ≥0.3 mg/dl (≥26.5 μmol/l) within 48 hours
- Increase in S. Creatinine: ≥1.5 times baseline within the previous 7 days
- Urine volume 6 hours
## Symptoms
Presenting symptoms in renal transplant patients are similar to those of non-renal transplant patients. Further symptomology depends on the clinical complications that develop due to COVID-19.
- Respiratory symptoms
Cough
Chest Pain
Shortness of breath
- Cough
- Chest Pain
- Shortness of breath
- Fever
- Hypoxia: SpO2 depends on the severity of COVID-19 infection. In moderate infection the SpO2 > or = 90%
- Diarrhea
- Fatigue
- Features of Uremia and Azotemia may be present in severe renal compromise
Further classification of patients into the severity index can be done using the WHO guidelines.
## Physical Examinationin
Physical examination of COVID-19 in renal transplant patients are similar to ones seen in general population.: COVID Physical Exam
If the patient develops Acute Kidney physical examination is remarkable for:
- Signs of dehydration, such as tachycardia, tachypnea, hypotension, and dry mucosa
- Fluid retention, leading to edema and swelling of periorbital and extremities
- Confusion due to severe dehydration and electrolyte imbalances
- Decrease in urine output:Oliguria or Anuria
- cardiac arrhythmia due to electrolyte imbalances such as high level of Potassium
## Past Medical History
- Renal transplant patients usually have chronic co-morbidities
Diabetes
Hypertension
Hyperlipidemia
Chronic renal failure
H/o Heart Disease
H/o Liver Disease
- Diabetes
- Hypertension
- Hyperlipidemia
- Chronic renal failure
- H/o Heart Disease
- H/o Liver Disease
## Laboratory Findings
- Lymphocyte count
Lower baseline values of lymphocyte count and lymphocytes percentages have been reported in patients. Furthermore the lymphocyte count continued to decrease during the course of illness.
Renal transplant patients generally have a low lymphocyte count due to immunosuppression, hence finding a further drop in the lymphocyte count can be of prognostic value.
- Lower baseline values of lymphocyte count and lymphocytes percentages have been reported in patients. Furthermore the lymphocyte count continued to decrease during the course of illness.
- Renal transplant patients generally have a low lymphocyte count due to immunosuppression, hence finding a further drop in the lymphocyte count can be of prognostic value.
- D-dimer
- Ferritin
- Troponin
Microvascular thrombosis and disseminated intravascular coagulation( with gut ischemia ) can occur later in the course of illness. They are characterized by marked increase in the levels of D-dimer particularly. D dimer, ferritin, and troponin should be measured in all patients with severe COVID-19 infection on admission and in those who fail to show any clinical improvement.
- Microvascular thrombosis and disseminated intravascular coagulation( with gut ischemia ) can occur later in the course of illness. They are characterized by marked increase in the levels of D-dimer particularly. D dimer, ferritin, and troponin should be measured in all patients with severe COVID-19 infection on admission and in those who fail to show any clinical improvement.
- High C-Reactive Protein - C‐reactive protein (CRP) was significantly elevated in patients at the time of admission. The levels of CRP remained elevated during the admission
If the renal transplant patients reports AKI then following laboratory findings can be done:
- Elevated serum creatinine
- Elevated BUN level
Plasma BUN-creatinine ratio> 20 in prerenal AKI
Plasma BUN-creatinine ratio< 15 in intrinsic AKI or acute tubular necrosis
- Plasma BUN-creatinine ratio> 20 in prerenal AKI
- Plasma BUN-creatinine ratio< 15 in intrinsic AKI or acute tubular necrosis
- Fractional excretion of sodium (FENa)
(FENa)< 1% in prerenal AKI
(FENa)> 2% in intrinsic AKI or acute tubular necrosis
- (FENa)< 1% in prerenal AKI
- (FENa)> 2% in intrinsic AKI or acute tubular necrosis
- Urinary sediment
Hyaline casts in prerenal AKI
Granular or Muddy brown casts in intrinsic AKI or acute tubular necrosis
- Hyaline casts in prerenal AKI
- Granular or Muddy brown casts in intrinsic AKI or acute tubular necrosis
- Several biomarkers have been found to diagnose and predict AKI that include:
neutrophil gelatinase-associated lipocalin (NGAL)
kidney injury molecule 1 (KIM-1)
liver-type fatty acid-binding protein
interleukin 18 (lL-18)
insulin-like growth factor-binding protein 7
tissue inhibitor of metalloproteinase 2 (TIMP-2)
calprotectin
urine angiotensinogen (AGT)
urine microRNA
- neutrophil gelatinase-associated lipocalin (NGAL)
- kidney injury molecule 1 (KIM-1)
- liver-type fatty acid-binding protein
- interleukin 18 (lL-18)
- insulin-like growth factor-binding protein 7
- tissue inhibitor of metalloproteinase 2 (TIMP-2)
- calprotectin
- urine angiotensinogen (AGT)
- urine microRNA
### Electrocardiogram
- There are no associated ECG findings due to COVID-19 complications in renal transplant patients. However hypokalemia due to AKI can cause ECG changes.
- To view the electrocardiogram findings on COVID-19, click here.
### X Ray
- X-ray findings in the renal transplant patients were similar to the findings seen in the general population.
- To view the x-ray finidings on COVID-19, click here.
## Echocardiography or Ultrasound
- If the renal transplant patient develops AKI, USG can help diagnose hydronephrosis and reduced renal blood flow.
- To view the echocardiographic findings on COVID-19, click here.
### CT
- CT scan finding in renal transplant patients infected with COVID-19 were similar to those in the general population.
- To view the CT scan findings on COVID-19, click here.
### MRI
- There are no MRI findings associated with COVID-19 in renal transplant patients.
- To view the MRI findings on COVID-19, click here.
## Other Imaging Findings
- To view other imaging findings on COVID-19, click here.
## Other Diagnostic Studies
- To view other diagnostic studies for COVID-19, click here.
# Treatment
## Medical Therapy
### Acute Pharmacotherapy
Currently, there are a variable number of protocols that have been described for the management of COVID-19 in renal transplant patients:-
According to the British Transplantation Society Guideline:-
According to a protocol described in Iranian Medical Journal
### Chronic Pharmacotherapy
In renal transplant patients, the immune responses are altered, especially the T cell response, due to generalized immunosuppression. Due to recent timeframe of outbreak of COVID-19 and insufficient scientific evidence, there is limited evidence on decreasing or changing the pattern of immunosuppression in renal transplant patients who have been infected with COVID-19.
- Clinical presentation of COVID-19 infection in renal transplant patients are like the clinical presentations of infection in general population. .Moreover, renal transplant patients are generally immunocompromised, and this predisposes them to severe infection with COVID-19. Rejection of the graft can occur if immunosuppression is reduced in these patients. Hence given the high rate of mortality in COVID-19 infections, it is suggested that a careful risk vs benefits assessment of whether to continue immunosuppression should be done.
- Managing the immunosuppression in renal transplant patients is difficult and should be based on
Age
Severity of COVID-19 infection
Presence of Co-Morbidities
Time since the transplant
- Age
- Severity of COVID-19 infection
- Presence of Co-Morbidities
- Time since the transplant
- In patients with mild to moderate infection, it has been a practice to continue or decrease the doses of immunosuppressive drugs, however this approach can cause high mortality in patients having COVID-19 infection.
Commonly followed protocols for the used immuno-suppressant drugs is as follows:-
- Antiproliferative agents such as MMF and azathioprine
Should be stopped at the time of admission to hospital
- Should be stopped at the time of admission to hospital
- Prednisolone
The dosage can be either increased or left unchanged. These can provide immunological protection to the renal graft.
Corticosteroids have beneficial effects such as
Immunomodulation and anti-inflammatory properties
Inhibition of proinflammatory cytokines
Reduction of white blood cell traffic
Vascular protective effects
Maintenance of integrity and permeability of endothelium.
- The dosage can be either increased or left unchanged. These can provide immunological protection to the renal graft.
- Corticosteroids have beneficial effects such as
Immunomodulation and anti-inflammatory properties
Inhibition of proinflammatory cytokines
Reduction of white blood cell traffic
Vascular protective effects
Maintenance of integrity and permeability of endothelium.
- Immunomodulation and anti-inflammatory properties
Inhibition of proinflammatory cytokines
Reduction of white blood cell traffic
- Inhibition of proinflammatory cytokines
- Reduction of white blood cell traffic
- Vascular protective effects
Maintenance of integrity and permeability of endothelium.
- Maintenance of integrity and permeability of endothelium.
- Tacrolimus
- Low doses of tacrolimus can be given but more evidence is required.
- Low doses of tacrolimus can be given but more evidence is required.
- The dose should be reduced to 50%. Target levels for tacrolimus should be 3-5 ng/ml.
- The dose should be reduced to 50%. Target levels for tacrolimus should be 3-5 ng/ml.
- Tocilizumab.
- COVID-19 infection has been found to cause cytokine storm and inflammation due to antiviral immune response, hence trials of anti-interleukin 6 monoclonal antibody Tocilizumab and continuing steroids in infected patients has been considered.
- COVID-19 infection has been found to cause cytokine storm and inflammation due to antiviral immune response, hence trials of anti-interleukin 6 monoclonal antibody Tocilizumab and continuing steroids in infected patients has been considered.
- Cyclosporine
Cyclosporin A has been shown to have an inhibitory effect on proliferation of corona viruses and hepatitis C virus in vitro, not seen in tacrolimus. Cyclosporin A is thought to inhibit the replication of a diverse array of coronaviruses through its impact on cyclophilin A and B.
Cyclosporine levels should be targeted at 25-50 ng/ml.
- Cyclosporin A has been shown to have an inhibitory effect on proliferation of corona viruses and hepatitis C virus in vitro, not seen in tacrolimus. Cyclosporin A is thought to inhibit the replication of a diverse array of coronaviruses through its impact on cyclophilin A and B.
- Cyclosporine levels should be targeted at 25-50 ng/ml.
## Surgery and Device Based Therapy
Currently there are no suurgical intervention required for COVID-19 infection in renal transplant patients.
### Transplantation
- The risk of the donor to recipient transmission is unknown.
- The chances of a donor to recipient infection might be affected by exposure of the donor, the infectivity of the donor during the incubation period, and the degree of viremia as well as the viability of virus in the specific organ system. An avid knowledge of local epidemiology is required to identify donors and recipients who may recently be exposed. One method is to have both donor and recipient practice strict social distancingi.e. 2-week home segregation prior to transplant and PCR testing for both individuals, before transplant. The reason for swabbing at the end of the segregation period is to screen asymptomatic shedders.
- In spite of the conceivable negative outcomes, temporary interruption of kidney transplantation might be needed in regions where the rate of infection is high..
- If a life-saving procedure needs to be performed, then appropriate assessment of infection in donor and recipient must be done along with appropriate informed consent.
- If a transplant candidate is found to be infected with COVID-19, the transplant should be delayed until the patient shows clinical improvement as well as no viral detection. Viral shedding for an increased duration of time has been reported.
Patients should be tested 10-14 days after symptom onset and only once all the symptoms have resolved.
Patients should have 2 negative PCRs at least 24hrs apart
- Patients should be tested 10-14 days after symptom onset and only once all the symptoms have resolved.
- Patients should have 2 negative PCRs at least 24hrs apart
## Primary Prevention
- The kidney transplant population must comply with the recommended measures of protection in the general population. Physicians can recommend the use of a mask on an individual basis, especially when the patient goes to health center or other place with agglomeration. People who show symptoms of being infected with SARS-CoV-2 should wear masks to prevent the spread of the disease to others..
- It is prudent to approve a sick leave in patients whose profession involves a high hazard for disease.
- It is recommended to screen kidney transplant patients through teleconsultation so as to decrease the time spent in healthcare centers and decrease the risk of infection
- Maintenance of general hygiene. Washing your hands as often as possible with cleanser and water, or with a alcohol based hand sanitizer (60% alc), particularly: after utilizing the restroom, before eating, in the wake of blowing, coughing or sneezing and after direct contact with patient or their surroundings. Abstain from touching your eyes, nose and mouth before washing your hands.
- Regular cleaning of home with disinfection of objects and surfaces.
- Keep a distance of at least two metres from people with general symptoms such as fever, cough, malaise, sore throat or dyspnea). Abstain from sharing personal belongings.
- During the lockdown circumstance you should stay at home aside from the specified exemptions, as indicated by the standards built up by the political and wellbeing specialists. Telephone the kidney transplant facility at your referral community or the telephone numbers approved by the wellbeing specialists.
- Attempt to follow a right eating routine. Abstain from smoking and liquor. These substances weaken the immune system, and increase the risk of infectious diseases.
## Secondary Prevention
All kidney transplant patients with suspected symptoms of COVID-19 are advised to contact their healthcare provider (ideally by phone), to discuss the full course of their treatment and other chronic conditions that they are having. Depending upon the symptoms :-
- Mild symptoms ie
without Dyspnea or Tachypnea
Temperature <38°C
Kidney receptor with adequate functional reserves
The patient can be asked to remain in contact via teleconsultation to have the diagnostic tests performed, monitor the symptoms and communicate alarming to the transplant team every 24–48h.
- without Dyspnea or Tachypnea
- Temperature <38°C
- Kidney receptor with adequate functional reserves
The patient can be asked to remain in contact via teleconsultation to have the diagnostic tests performed, monitor the symptoms and communicate alarming to the transplant team every 24–48h.
- The patient can be asked to remain in contact via teleconsultation to have the diagnostic tests performed, monitor the symptoms and communicate alarming to the transplant team every 24–48h.
- Moderate/Severe symptoms
Temperature >38°C
Presence of Dyspnea
Presence of Tachypnea
Fragile Kidney receptor
Patient can be asked to report to Emergency Department for clinical evaluation..
- Temperature >38°C
- Presence of Dyspnea
- Presence of Tachypnea
- Fragile Kidney receptor
Patient can be asked to report to Emergency Department for clinical evaluation..
- Patient can be asked to report to Emergency Department for clinical evaluation..
## Cost Effectiveness of Therapy
Currently various investigational and experimental pharmacological therapies are being tested for COVID-19 treatment. The cost of treatment generally depends on the multitude of COVID-19 complications that an individual develops.
## Future or Investigational Therapies
Various pharmacological therapies are currently under investigation as potentials to treat COVID-19
For detailed information click here | Sandbox: GDS
For COVID-19 frequently asked inpatient questions, click here
For COVID-19 frequently asked outpatient questions, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gurmandeep Singh Sandhu,M.B.B.S.[2]
# Overview
Renal transplant patients are under immunosuppression to modulate the immune response to graft. Moreover these patients have various underlying chronic kidney diseases and other co-morbidities such as diabetes and hypertension, which can impact the results in COVID-19 infection. Hence these patients are at a higher risk of developing COVID-19 associated complications. The clinical manifestations, treatment, and prognosis of COVID-19 infection may be different from the general population. It is believed that any transplant recipient presented to the infection would result in a high level of cases; however, the risk of the donor to recipient transmission is unknown.
# Historical Perspectives
The etiological agent involved is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), first detected in Wuhan, China. On March 12, 2020 the World Health Organization declared the COVID-19 outbreak a pandemic. The earlier SARS epidemic of Hong Kong is known to affect both pediatric and adult renal transplant patients where the severity of disease in adult patients was more than that in pediatric patients The first reported case of COVID-19 infection in renal transplant patient, was a 52‐year‐old man who received living‐related kidney transplantation 12 years for chronic glomerulonephritis, in Wuhan, China. He made a successful recovery and was discharged on day 13.
# Classification
Classification of COVID-19 infection in renal transplant patients depends on the severity of COVID-19 manifestations. COVID-19 infection classification according to WHO is following:
# Pathophysiology
## Genetics
Angiotensin-converting enzyme 2 and Dipeptidyl peptidase have been implicated in the uptake of SARS-Cov and MERS-CoV Several studies have indicated that viral S-protein RBD interacts with host ACE2 receptor. S protein changes thus make the human cells permissive to SARS-CoV and SARS-CoV-2 infection ACE2: ACE ratio is higher in the kidneys compared to the respiratory system. (1:1 in the kidneys VS 1:20 in the respiratory system).These receptors are found in the proximal tubules of kidney[1][2]SARS-CoV2 spike(S) protein is cleaved and activated by transmembrane serine protease family (TMPRSS) after attaching to angiotensin-converting enzyme 2 (ACE2) receptors. This allows the virus to release fusion peptide that aides in membrane fusion..
There is a possibility of association between MHC class I(HLA A, B & C) with incidence of COVID-19 infection as well as severity of complications
. HLA-B*46:01 gene product is believed to show lowest binding to SARS-CoV-2 indicating decreased viral presentation to immune system. Whereas HLA-B*15:03 shows increased affinity to SARS-CoV-2[3]leading to higher likelihood in developing immunity.
## Associated Conditions
### Acute Kidney Injury
- Acute Kidney Injury has been reported in patients with COVID-19 infection along with presence of proteinuria, hematuria. In a case observation, 4 out of 7 patients had AKI which may indicate that renal transplant patients are at higher risk AKI on being infected with COVID-19 whereas only 29% AKI was seen in critically ill patients of general population.
- Acute Kidney Injury seen in COVID-19 infection can be from the cytotropic effect (Uptake of SARS-Cov-2 virus into proximal tubule cells is possible explanation for the AKI seen in COVID patients[1][2]) of the viral particles as well as systemic inflammatory response induced by the cytokines. Patients admitted with severe disease, acute respiratory distress syndrome (ARDS) or in patients admitted to ICU have a higher incidence of AKI . . Other possible reasons that can play a role in AKI development, are multi-organ failure resulting in acute tubular necrosis (ATN), volume reduction causing prerenal ATN, high fever, drug toxicity, hypotension, and contrast exposure.
- Pro-inflammatory cytokine levels are elevated in the COVID-19 infection and there is activation of T-cell response. There is higher cytokine levels and there is occurrence of cytokine storm in severe cases. In cytokine storm the, the immune system damages the healthy tissue rather than virus. According to an autopsy report of six patients, the light microscopy indicated CD68+ macrophage infiltration of the tubulointerstitium and severe ATN. The tubules showed complement 5b-9 deposition in all six cases, but deposition in glomeruli and capillaries were seldom seen. Some CD8+ T lymphocyte cells and CD56+ (natural killer) cells were seen in kidney tissue
### General COVID-19 Pathophysiology in Renal Transplant Patients
The overall presentation of COVID-19 in renal transplant patients is similar to that in general population.However, the renal transplant recipients are at remain at higher risk to catch COVID-19[4]
and develop severe complications due to chronic immunosuppressed state which is implicated in various viral infections such as cytomegalovirus, herpes zoster, norovirus infectionsetc.
COVID-19 Pathophysiology
# Causes
## Life Threatening Causes
- Even though the CT findings in COVID-19 pneumonia were similar in renal transplant recipients and general population, due to chronic immunosuppression, the clinical features of COVID-19 in renal transplant patients may be atypical.
- In one of the study, nine of the 10 patients had fever, cough, shortness of breath, and fatigue; three had diarrhea; eight had lymphopenia; six had renal injury; and six had liver function damage.[5]
- It needs to be verified whether the severity of COVID-19 pneumonia differs in immunocompromised transplant patients than non-immunocompromised population. According to a report from China’s Infectious Disease Information system, out of 72,314 COVID-19 cases in general population, 81% were reported as mild, whereas 19% were either severe or critical. And, in report from study in renal transplant patients, the number of severe cases were 80% compared to only 10% in their infected family members and 19% in general population. Moreover, average duration of illness was nearly twice i.e. 35 days compared to 18 days in control group and 17-20 days reported in general population.[5]
# Differentiating from other Diseases
- As the general presentation of COVID-19 is similar in general population and renal transplant patients, it should be differentiated from other diseases presenting with cough, fever, shortness of breath, and tachypnea.
To review the differential diagnosis, click here
- To review the differential diagnosis, click here
- COVID-19 associated AKI in renal transplant patients must be differentiated from other causes of AKI , such as congestive heart failure, hemorrhage, dehydration, liver failure, urinary tract obstruction, Interstitial nephritis, glomerulonephritis and nephrotoxic medications.
For the differential diagnosis of AKI, click here.
- For the differential diagnosis of AKI, click here.
# Epidemiology and Demographics
## Incidence
- Due to the lack of broad screening that includes the general population (including asymptomatic patients) and the lack of PCR and antibody tests with acceptable sensitivity and specificity, an accurate estimate of the incidence rate of coronavirus disease 2019 (COVID-19) cannot be accurately estimated.
- Data indicates that the rate of severe complications of COVID-19 is almost 25%, and kidney is also one of the main organs affected in severe illness.[6]. The risk is further increased in patients having chronic kidney disease(CKD), patients on chronic replacement therapies, and patients with kidney transplants.[7]
- AKI is seen in 5-15% of the SARS-CoV and MERS-CoV infection[7]
## Prevalence
- For details on the real-time prevalence and spread of COVID-19, click here.
- As it is prevalent in all the continents of the world, World Health Organization (WHO) has declared COVID-19 outbreak a pandemic.
- Among patients with influenza-like-illness and without risk factors for COVID-19, 5% were positive for COVID-19.
- In an analysis of 14 articles[8][9][10]
[11]
[12]
[13]
[14]
[15][16],
- Median interval of transplantation - 4 years. (range .25-30.1)
- Median interval of transplantation - 4 years. (range .25-30.1)
## Case-fatality rate
- Due to limited testing of asymptomatic individuals, the potential inaccuracies of early PCR tests and antibody tests, the inconsistent reporting and lack of organized data, an accurate case-fatality rate of COVID-19 has yet to be established.
- According to analysis of recent studies[8][9][10]
[11]
[12]
[13]
[14]
[15][16], a fatality rate of 17.4% (4/23) in renal transplant patients was reported
## Age
- Renal transplant patients of all ages are at a higher risk of COVID-19 due to immunosuppression.
- The youngest renal transplant patient who died of COVID-19 according to recent studies was 71 years old.[8][9]
[10]
[11]
[12]
[14]
[15][16]
- In general population, COVID-19 associated AKI has higher incidence in elderly.
## Gender
- Men are more likely to be affected by COVID-19 than women.
- Women dying from COVID-19 are generally elder than men(median age: 82 vs. 79 years for women vs. men, respectively).[17]
## Race
*According to study done in New York, 14 recipients (39%) were black, and 15 recipients (42%) were Hispanic.
# Risk Factors
There are various factors that can predispose renal transplant patients to COVID-19.
- Immunosuppression[4]
- Chronic Renal Failure[4]
- Co-Morbidities[4]
Diabetes
Hypertension
Hyperlipidemia
H/o Heart Disease
- Diabetes
- Hypertension
- Hyperlipidemia
- H/o Heart Disease
- Male Sex[18]
- Old Age[18][19]
- Current or h/o smoking tobacco[18]
- Possible a/w donor COVID-19 infection[19]
# Screening
According to one of the COVID-19 Rapid Guidelines for renal transplant patients:
Screening for AKI
Serial monitoring of kidney function tests should be considered in renal transplant patients'
- BUN
- Creatinine
- Urine analysis
Gut Ischemia, coagulopathies, and disseminated intravascular coagulopation have been seen later in the course of illness[20]
- The following should be measured in all patients with severe COVID-19 infection on admission to prevent and screen for coagulopathies.
D-dimer
Ferritin
Troponin
- D-dimer
- Ferritin
- Troponin
# Natural History, Complications and Prognosis
Even though the course of infection of COVID-19 in the general population and the renal transplant recipients has been the same, the mortality in COVID-19 affected renal transplant recipients have been reported to be higher than the general population. It has been widely feared that the scope of complications in the transplant recipients would be more severe than what is generally seen in the population due to a suppressed state of immunity[21]The incidence of AKI has also been reported to be higher in COVID-19 infection[22]
# Diagnosis
## Diagnosis of Choice
- Renal transplant patients present with similar CT an Chest X-Ray finding which are seen in the general population, although the features of COVID-19 infection may be atypical in such patients.
- Renal Transplant patients who develop AKI can be diagnosed using KDIGO criteria:
Increase in S. Creatinine: ≥0.3 mg/dl (≥26.5 μmol/l) within 48 hours
Increase in S. Creatinine: ≥1.5 times baseline within the previous 7 days
Urine volume < 0.5 ml/kg/h for >6 hours
- Increase in S. Creatinine: ≥0.3 mg/dl (≥26.5 μmol/l) within 48 hours
- Increase in S. Creatinine: ≥1.5 times baseline within the previous 7 days
- Urine volume < 0.5 ml/kg/h for >6 hours
## Symptoms
Presenting symptoms in renal transplant patients are similar to those of non-renal transplant patients. Further symptomology depends on the clinical complications that develop due to COVID-19.
- Respiratory symptoms
Cough
Chest Pain
Shortness of breath
- Cough
- Chest Pain
- Shortness of breath
- Fever
- Hypoxia: SpO2 depends on the severity of COVID-19 infection. In moderate infection the SpO2 > or = 90%
- Diarrhea
- Fatigue
- Features of Uremia and Azotemia may be present in severe renal compromise
Further classification of patients into the severity index can be done using the WHO guidelines.[23]
## Physical Examinationin
Physical examination of COVID-19 in renal transplant patients are similar to ones seen in general population.: COVID Physical Exam
If the patient develops Acute Kidney physical examination is remarkable for:
- Signs of dehydration, such as tachycardia, tachypnea, hypotension, and dry mucosa
- Fluid retention, leading to edema and swelling of periorbital and extremities
- Confusion due to severe dehydration and electrolyte imbalances
- Decrease in urine output:Oliguria or Anuria
- cardiac arrhythmia due to electrolyte imbalances such as high level of Potassium
## Past Medical History
- Renal transplant patients usually have chronic co-morbidities[4]
Diabetes
Hypertension
Hyperlipidemia
Chronic renal failure
H/o Heart Disease
H/o Liver Disease
- Diabetes
- Hypertension
- Hyperlipidemia
- Chronic renal failure
- H/o Heart Disease
- H/o Liver Disease
## Laboratory Findings
- Lymphocyte count
Lower baseline values of lymphocyte count and lymphocytes percentages have been reported in patients. Furthermore the lymphocyte count continued to decrease during the course of illness.[21]
Renal transplant patients generally have a low lymphocyte count due to immunosuppression, hence finding a further drop in the lymphocyte count can be of prognostic value.
- Lower baseline values of lymphocyte count and lymphocytes percentages have been reported in patients. Furthermore the lymphocyte count continued to decrease during the course of illness.[21]
- Renal transplant patients generally have a low lymphocyte count due to immunosuppression, hence finding a further drop in the lymphocyte count can be of prognostic value.
- D-dimer
- Ferritin
- Troponin
Microvascular thrombosis and disseminated intravascular coagulation( with gut ischemia ) can occur later in the course of illness. They are characterized by marked increase in the levels of D-dimer particularly. D dimer, ferritin, and troponin should be measured in all patients with severe COVID-19 infection on admission and in those who fail to show any clinical improvement.
- Microvascular thrombosis and disseminated intravascular coagulation( with gut ischemia ) can occur later in the course of illness. They are characterized by marked increase in the levels of D-dimer particularly. D dimer, ferritin, and troponin should be measured in all patients with severe COVID-19 infection on admission and in those who fail to show any clinical improvement.
- High C-Reactive Protein - C‐reactive protein (CRP) was significantly elevated in patients at the time of admission.[21] The levels of CRP remained elevated during the admission[21]
If the renal transplant patients reports AKI then following laboratory findings can be done:
- Elevated serum creatinine
- Elevated BUN level
Plasma BUN-creatinine ratio> 20 in prerenal AKI
Plasma BUN-creatinine ratio< 15 in intrinsic AKI or acute tubular necrosis
- Plasma BUN-creatinine ratio> 20 in prerenal AKI
- Plasma BUN-creatinine ratio< 15 in intrinsic AKI or acute tubular necrosis
- Fractional excretion of sodium (FENa)
(FENa)< 1% in prerenal AKI
(FENa)> 2% in intrinsic AKI or acute tubular necrosis
- (FENa)< 1% in prerenal AKI
- (FENa)> 2% in intrinsic AKI or acute tubular necrosis
- Urinary sediment
Hyaline casts in prerenal AKI
Granular or Muddy brown casts in intrinsic AKI or acute tubular necrosis
- Hyaline casts in prerenal AKI
- Granular or Muddy brown casts in intrinsic AKI or acute tubular necrosis
- Several biomarkers have been found to diagnose and predict AKI that include:
neutrophil gelatinase-associated lipocalin (NGAL)
kidney injury molecule 1 (KIM-1)
liver-type fatty acid-binding protein
interleukin 18 (lL-18)
insulin-like growth factor-binding protein 7
tissue inhibitor of metalloproteinase 2 (TIMP-2)
calprotectin
urine angiotensinogen (AGT)
urine microRNA
- neutrophil gelatinase-associated lipocalin (NGAL)
- kidney injury molecule 1 (KIM-1)
- liver-type fatty acid-binding protein
- interleukin 18 (lL-18)
- insulin-like growth factor-binding protein 7
- tissue inhibitor of metalloproteinase 2 (TIMP-2)
- calprotectin
- urine angiotensinogen (AGT)
- urine microRNA
### Electrocardiogram
- There are no associated ECG findings due to COVID-19 complications in renal transplant patients. However hypokalemia due to AKI can cause ECG changes.
- To view the electrocardiogram findings on COVID-19, click here.
### X Ray
- X-ray findings in the renal transplant patients were similar to the findings seen in the general population.
- To view the x-ray finidings on COVID-19, click here.
## Echocardiography or Ultrasound
- If the renal transplant patient develops AKI, USG can help diagnose hydronephrosis and reduced renal blood flow.
- To view the echocardiographic findings on COVID-19, click here.
### CT
- CT scan finding in renal transplant patients infected with COVID-19 were similar to those in the general population.
- To view the CT scan findings on COVID-19, click here.
### MRI
- There are no MRI findings associated with COVID-19 in renal transplant patients.
- To view the MRI findings on COVID-19, click here.
## Other Imaging Findings
- To view other imaging findings on COVID-19, click here.
## Other Diagnostic Studies
- To view other diagnostic studies for COVID-19, click here.
# Treatment
## Medical Therapy
### Acute Pharmacotherapy
Currently, there are a variable number of protocols that have been described for the management of COVID-19 in renal transplant patients:-
According to the British Transplantation Society Guideline[15]:-
According to a protocol described in Iranian Medical Journal[24]
### Chronic Pharmacotherapy
In renal transplant patients, the immune responses are altered, especially the T cell response, due to generalized immunosuppression. Due to recent timeframe of outbreak of COVID-19 and insufficient scientific evidence, there is limited evidence on decreasing or changing the pattern of immunosuppression in renal transplant patients who have been infected with COVID-19.
- Clinical presentation of COVID-19 infection in renal transplant patients are like the clinical presentations of infection in general population. [25].Moreover, renal transplant patients are generally immunocompromised, and this predisposes them to severe infection with COVID-19. Rejection of the graft can occur if immunosuppression is reduced in these patients. Hence given the high rate of mortality in COVID-19 infections, it is suggested that a careful risk vs benefits assessment of whether to continue immunosuppression should be done.
- Managing the immunosuppression in renal transplant patients is difficult and should be based on[26]
Age
Severity of COVID-19 infection
Presence of Co-Morbidities
Time since the transplant
- Age
- Severity of COVID-19 infection
- Presence of Co-Morbidities
- Time since the transplant
- In patients with mild to moderate infection, it has been a practice to continue or decrease the doses of immunosuppressive drugs, however this approach can cause high mortality in patients having COVID-19 infection.[26]
Commonly followed protocols for the used immuno-suppressant drugs is as follows:-
- Antiproliferative agents such as MMF and azathioprine
Should be stopped at the time of admission to hospital
- Should be stopped at the time of admission to hospital
- Prednisolone[27]
The dosage can be either increased or left unchanged. These can provide immunological protection to the renal graft.
Corticosteroids have beneficial effects such as
Immunomodulation and anti-inflammatory properties
Inhibition of proinflammatory cytokines
Reduction of white blood cell traffic
Vascular protective effects
Maintenance of integrity and permeability of endothelium. [27]
- The dosage can be either increased or left unchanged. These can provide immunological protection to the renal graft.
- Corticosteroids have beneficial effects such as
Immunomodulation and anti-inflammatory properties
Inhibition of proinflammatory cytokines
Reduction of white blood cell traffic
Vascular protective effects
Maintenance of integrity and permeability of endothelium. [27]
- Immunomodulation and anti-inflammatory properties
Inhibition of proinflammatory cytokines
Reduction of white blood cell traffic
- Inhibition of proinflammatory cytokines
- Reduction of white blood cell traffic
- Vascular protective effects
Maintenance of integrity and permeability of endothelium. [27]
- Maintenance of integrity and permeability of endothelium. [27]
- Tacrolimus[27]
- Low doses of tacrolimus can be given but more evidence is required.[27]
- Low doses of tacrolimus can be given but more evidence is required.[27]
- The dose should be reduced to 50%. Target levels for tacrolimus should be 3-5 ng/ml.
- The dose should be reduced to 50%. Target levels for tacrolimus should be 3-5 ng/ml.
- Tocilizumab.[27]
- COVID-19 infection has been found to cause cytokine storm and inflammation due to antiviral immune response, hence trials of anti-interleukin 6 monoclonal antibody Tocilizumab and continuing steroids in infected patients has been considered.
- COVID-19 infection has been found to cause cytokine storm and inflammation due to antiviral immune response, hence trials of anti-interleukin 6 monoclonal antibody Tocilizumab and continuing steroids in infected patients has been considered.
- Cyclosporine
Cyclosporin A has been shown to have an inhibitory effect on proliferation of corona viruses and hepatitis C virus in vitro, not seen in tacrolimus. Cyclosporin A is thought to inhibit the replication of a diverse array of coronaviruses through its impact on cyclophilin A and B.
Cyclosporine levels should be targeted at 25-50 ng/ml.[28]
- Cyclosporin A has been shown to have an inhibitory effect on proliferation of corona viruses and hepatitis C virus in vitro, not seen in tacrolimus. Cyclosporin A is thought to inhibit the replication of a diverse array of coronaviruses through its impact on cyclophilin A and B.
- Cyclosporine levels should be targeted at 25-50 ng/ml.[28]
## Surgery and Device Based Therapy
Currently there are no suurgical intervention required for COVID-19 infection in renal transplant patients.
### Transplantation
- The risk of the donor to recipient transmission is unknown.
- The chances of a donor to recipient infection might be affected by exposure of the donor, the infectivity of the donor during the incubation period, and the degree of viremia as well as the viability of virus in the specific organ system. An avid knowledge of local epidemiology is required to identify donors and recipients who may recently be exposed. One method is to have both donor and recipient practice strict social distancingi.e. 2-week home segregation prior to transplant and PCR testing for both individuals, before transplant. The reason for swabbing at the end of the segregation period is to screen asymptomatic shedders.
- In spite of the conceivable negative outcomes, temporary interruption of kidney transplantation might be needed in regions where the rate of infection is high.. [29]
- If a life-saving procedure needs to be performed, then appropriate assessment of infection in donor and recipient must be done along with appropriate informed consent.
- If a transplant candidate is found to be infected with COVID-19, the transplant should be delayed until the patient shows clinical improvement as well as no viral detection. Viral shedding for an increased duration of time has been reported[4].
Patients should be tested 10-14 days after symptom onset and only once all the symptoms have resolved.
Patients should have 2 negative PCRs at least 24hrs apart
- Patients should be tested 10-14 days after symptom onset and only once all the symptoms have resolved.
- Patients should have 2 negative PCRs at least 24hrs apart
## Primary Prevention
- The kidney transplant population must comply with the recommended measures of protection in the general population. Physicians can recommend the use of a mask on an individual basis, especially when the patient goes to health center or other place with agglomeration. People who show symptoms of being infected with SARS-CoV-2 should wear masks to prevent the spread of the disease to others..
- It is prudent to approve a sick leave in patients whose profession involves a high hazard for disease.[30]
- It is recommended to screen kidney transplant patients through teleconsultation so as to decrease the time spent in healthcare centers and decrease the risk of infection [30]
- Maintenance of general hygiene. Washing your hands as often as possible with cleanser and water, or with a alcohol based hand sanitizer (60% alc), particularly: after utilizing the restroom, before eating, in the wake of blowing, coughing or sneezing and after direct contact with patient or their surroundings. Abstain from touching your eyes, nose and mouth before washing your hands.[30]
- Regular cleaning of home with disinfection of objects and surfaces.[30]
- Keep a distance of at least two metres from people with general symptoms such as fever, cough, malaise, sore throat or dyspnea). Abstain from sharing personal belongings.[30]
- During the lockdown circumstance you should stay at home aside from the specified exemptions, as indicated by the standards built up by the political and wellbeing specialists. Telephone the kidney transplant facility at your referral community or the telephone numbers approved by the wellbeing specialists.[30]
- Attempt to follow a right eating routine. Abstain from smoking and liquor. These substances weaken the immune system, and increase the risk of infectious diseases.[30]
## Secondary Prevention
All kidney transplant patients with suspected symptoms of COVID-19 are advised to contact their healthcare provider (ideally by phone), to discuss the full course of their treatment and other chronic conditions that they are having. Depending upon the symptoms :-
- Mild symptoms ie
without Dyspnea or Tachypnea
Temperature <38°C
Kidney receptor with adequate functional reserves
The patient can be asked to remain in contact via teleconsultation to have the diagnostic tests performed, monitor the symptoms and communicate alarming to the transplant team every 24–48h.
- without Dyspnea or Tachypnea
- Temperature <38°C
- Kidney receptor with adequate functional reserves
The patient can be asked to remain in contact via teleconsultation to have the diagnostic tests performed, monitor the symptoms and communicate alarming to the transplant team every 24–48h.
- The patient can be asked to remain in contact via teleconsultation to have the diagnostic tests performed, monitor the symptoms and communicate alarming to the transplant team every 24–48h.
- Moderate/Severe symptoms
Temperature >38°C
Presence of Dyspnea
Presence of Tachypnea
Fragile Kidney receptor
Patient can be asked to report to Emergency Department for clinical evaluation..[30]
- Temperature >38°C
- Presence of Dyspnea
- Presence of Tachypnea
- Fragile Kidney receptor
Patient can be asked to report to Emergency Department for clinical evaluation..[30]
- Patient can be asked to report to Emergency Department for clinical evaluation..[30]
## Cost Effectiveness of Therapy
Currently various investigational and experimental pharmacological therapies are being tested for COVID-19 treatment. The cost of treatment generally depends on the multitude of COVID-19 complications that an individual develops.
## Future or Investigational Therapies
Various pharmacological therapies are currently under investigation as potentials to treat COVID-19
For detailed information click here | https://www.wikidoc.org/index.php/Sandbox:_GDS | |
ba6efeb53544933bc4ecd9e6019a0540a077c323 | wikidoc | Sandbox: HAR | Sandbox: HAR
For COVID-19 frequently asked inpatient questions, click here
For COVID-19 frequently asked outpatient questions, click here
Synonyms and keywords: Multisystem Inflammatory Syndrome in Children (MIS-C)
# Overview
Multisystem Inflammatory Syndrome in Children (MIS-C) is a condition that causes inflammation of some parts of the body like heart, blood vessels, kidneys, digestive system, brain, skin, or eyes. According to recent evidence, it is suggested that children with MIS-C had antibodies against COVID-19 suggesting children had COVID-19 infection in the past. This syndrome appears to be similar in presentation to Kawasaki disease, hence also called Kawasaki -like a disease. It also shares features with staphylococcal and streptococcal toxic shock syndromes, bacterial sepsis, and macrophage activation syndromes.
# Classification of Disease Severity of MIS-C
- Mild Disease
- Children with MIS-C fall under this category who-
require minimal to no respiratory support.
minimal to no organ injury
normotensive
Do not meet the criteria for ICU admission.
- require minimal to no respiratory support.
- minimal to no organ injury
- normotensive
- Do not meet the criteria for ICU admission.
- Severe Disease
- Children with MIS-C fall under this category who-
have significant oxygen requirements (HFNC, BiPAP, mechanical ventilation).
have a mild-severe organ injury and ventricular dysfunction.
have a vasoactive requirement.
meet the criteria for ICU admissions
- have significant oxygen requirements (HFNC, BiPAP, mechanical ventilation).
- have a mild-severe organ injury and ventricular dysfunction.
- have a vasoactive requirement.
- meet the criteria for ICU admissions
# Pathophysiology
- The excat pathophysiological mechanism of MIS-C is unclear. Since there is a lag time between MIS-C appearance and COVID-19 infection it is suspected to be causing by antibody dependent enhancement.
- Another hypothesis is that since coronavirus block type1 and type III interferons, it results in delayed cytokine response in children with initially high viral load or whose immune response is unable to control infections causing MIS-C. Therefore, IFN responses result in viral clearance when the viral load is low resulting in mild infection. However, when the viral load is high and /or immune system is not able to clear the virus, the cytokine storm result in multisystem inflammatory syndrome in children (MIS-C).
- It is also suspected that since MIS-C presents predominantly with gastrointestinal manifestations, it replicates predominantly in the gastrointestinal tract.
# Differentiating Any Disease from other disease
It should be differentiated from following diseases
- Bacterial sepsis
- Staphylococcal and streptococcal toxic shock syndrome
- Kawasaki disease.
- More information about the differential diagnosis could be found here.
# Epidemiology and Demographics
- According to a recent study among the 186 children with MIS-C, the rate of hospitalization was 12% between March 16 and April 15 and 88% between April 16 and May 20.
- 80% of the children were admitted to the intensive care unit and 20% of the children required mechanical ventilation.
- 4% of the children required extracorporeal membrane oxygenation.
- The mortality rate among 186 children with MIS-C was 2%.
Age
- Among the 186 children with MIS-C distribution of age group was
<1yr-7%
1-4yr-28%
5-9yr-25%
10-14yr-24%
15-20yr-16%.
- <1yr-7%
- 1-4yr-28%
- 5-9yr-25%
- 10-14yr-24%
- 15-20yr-16%.
Gender
- Among the 186 children with MIS-C
Comorbidities
- Children with MIS-C had following underlying comorbidities.
Clinically diagnosed Obesity-8%
BMI-Based Obesity-29%
Cardiovascular diasease-3%
Respiratory disease-18%
Autoimmune disease or immunocompromising condition-5%
- Clinically diagnosed Obesity-8%
- BMI-Based Obesity-29%
- Cardiovascular diasease-3%
- Respiratory disease-18%
- Autoimmune disease or immunocompromising condition-5%
Organ System Involved
- 71% of children had involvement of at least four organ systems.
The most common organ system involved in MIS-C children among a total of 186 children were.
- Gastrointestinal(92%)
- Cardiovascular(80%)
- Hematologic(76%)
- Mucocutaneous(74%)
- Pulmonary(70%)
- Historical perspective
# Complications and Prognosis
## Complications
- Severe myocardial infarction
- Cardiac failure/arrest
- ARDS
- Hypervolemia
- Acute Kidney Injury
- Peritonitis
- Thrombotic complications.
# Diagnosis
## Diagnostic Criteria
- 0–19 years of age with fever >3 days
AND
- Two of the following:
- Rash or bilateral non-purulent conjunctivitis or mucocutaneous inflammation signs (oral, hands or feet)
- Hypotension or shock
- Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including ECHO findings or elevated Troponin/NT-proBNP)
- Evidence of coagulopathy (by PT, PTT, elevated D-Dimers)
- Acute gastrointestinal problems (diarrhea, vomiting, or abdominal pain)
AND
- Elevated markers of inflammation such as ESR, C-reactive protein, or procalcitonin
AND
- No other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes
AND
- Evidence of COVID-19 (RT-PCR, antigen test or serology-positive), or likely contact with patients with COVID-19
- An individual aged 2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological);
AND
No alternative plausible diagnoses;
AND
Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or exposure to a suspected or confirmed COVID-19 case within the 4 weeks prior to the onset of symptoms.
## Signs and Symptoms
- Fever lasting 24 hours or longer.
- Vomiting
- Diarrhea
- Abdominal pain
- Skin rash
- Conjuctivitis
- High ESR
- Redness or swelling of the lips and tongue
- Lethargy
- Redness or swelling of the hands or feet
- Confusion
- Headache
- Sore throat
- Syncope
- Lymphadenopathy
Emergency Warning Signs
- Difficulty Breathing
- Chest pain
- New onset confusion
- Lethargy
- Cyanosis
- Abdominal pain
## Physical Examination
Blood Investigations
- Lymphopenia, Neutrophilia, Anemia, Thrombocytopenia have been seen in MIS-C pateints. Abnormal fibrinogen, Hypoalbuminaemia, elevated creatiine kinase (CK), LDH, triglycerides have been observed in MIS-C patients.
### Inflammatory biomarkers
Elevation of inflammatory markers including ESR, C reactive protein and procalcitonin are usually seen in MIS-C. Increased level of Interleukin-6 (IL-6), Interleukin-10(IL-10) d-dimer, serum ferritin, prothrombin time have also been seen in MIS-C.
### Cardiac biomarkers
Elevation of cardic enzymes including cardiac troponins (cardiac troponin I(cTnI) and cardiac troponin T (cTnT)) and Brain natriuretic peptide (BNP)) has been observed in MIS-C patients.
## Radiological Findings
- Following Radiological Findings are observed in MIS-C patients.
Blood Culture, Viral PCR
- Absence of other potential causative organisms. IgG levels and IgM levels of SARS-CoV-2 are detected.
# Treatment
## Medical Therapy
- All the children with MIS-C are treated as suspected COVID-19.
- Mild to Moderate cases of MIS-C are managed supportively.
- Supplemental oxygen is required in children with low oxygen saturation.
- Fluid resuscitation in 10 ml/kg aliquots with reevaluation after each bolus. Maintain euvolemia. Avoid hypervolemia.
- Anti-inflammatory treatments with Intravenous immunoglobulin(IVIG) with or without corticosteroids have shown a good response rate.
- Aspirin has been used primarily for its antiplatelet effect. It is recommended in all patients with MIS-C.
- Anakinra is considered if fevers last more than 24 hours post steroids/IVIG or in the moderate or severe presentation.
- Tocilizumab is also considered if fevers last more than 24 hours post steroids/IVIG or in the moderate or severe presentation.
- Empiric antibiotics like vancomycin, ceftriaxone, and clindamycin are given for community-acquired shock presentation until cultures are negative for 48 hours.
# Prevention of MIS-C
- MIS-C can be prevented by reducing the risk of child exposure to COVID-19 infection. | Sandbox: HAR
For COVID-19 frequently asked inpatient questions, click here
For COVID-19 frequently asked outpatient questions, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Harmeet Kharoud M.D.[2]
Synonyms and keywords: Multisystem Inflammatory Syndrome in Children (MIS-C)
# Overview
Multisystem Inflammatory Syndrome in Children (MIS-C) is a condition that causes inflammation of some parts of the body like heart, blood vessels, kidneys, digestive system, brain, skin, or eyes. According to recent evidence, it is suggested that children with MIS-C had antibodies against COVID-19 suggesting children had COVID-19 infection in the past. This syndrome appears to be similar in presentation to Kawasaki disease, hence also called Kawasaki -like a disease. It also shares features with staphylococcal and streptococcal toxic shock syndromes, bacterial sepsis, and macrophage activation syndromes.[1]
# Classification of Disease Severity of MIS-C
- Mild Disease
- Children with MIS-C fall under this category who-[2]
require minimal to no respiratory support.
minimal to no organ injury
normotensive
Do not meet the criteria for ICU admission.
- require minimal to no respiratory support.
- minimal to no organ injury
- normotensive
- Do not meet the criteria for ICU admission.
- Severe Disease
- Children with MIS-C fall under this category who-[2]
have significant oxygen requirements (HFNC, BiPAP, mechanical ventilation).
have a mild-severe organ injury and ventricular dysfunction.
have a vasoactive requirement.
meet the criteria for ICU admissions
- have significant oxygen requirements (HFNC, BiPAP, mechanical ventilation).
- have a mild-severe organ injury and ventricular dysfunction.
- have a vasoactive requirement.
- meet the criteria for ICU admissions
# Pathophysiology
- The excat pathophysiological mechanism of MIS-C is unclear. Since there is a lag time between MIS-C appearance and COVID-19 infection it is suspected to be causing by antibody dependent enhancement.[3]
- Another hypothesis is that since coronavirus block type1 and type III interferons, it results in delayed cytokine response in children with initially high viral load or whose immune response is unable to control infections causing MIS-C. Therefore, IFN responses result in viral clearance when the viral load is low resulting in mild infection. However, when the viral load is high and /or immune system is not able to clear the virus, the cytokine storm result in multisystem inflammatory syndrome in children (MIS-C).[3]
- It is also suspected that since MIS-C presents predominantly with gastrointestinal manifestations, it replicates predominantly in the gastrointestinal tract.[3]
# Differentiating Any Disease from other disease
It should be differentiated from following diseases
- Bacterial sepsis
- Staphylococcal and streptococcal toxic shock syndrome
- Kawasaki disease.
- More information about the differential diagnosis could be found here.
# Epidemiology and Demographics
- According to a recent study among the 186 children with MIS-C, the rate of hospitalization was 12% between March 16 and April 15 and 88% between April 16 and May 20.
- 80% of the children were admitted to the intensive care unit and 20% of the children required mechanical ventilation.[4]
- 4% of the children required extracorporeal membrane oxygenation.[4]
- The mortality rate among 186 children with MIS-C was 2%.[4]
Age
- Among the 186 children with MIS-C distribution of age group was[4]
<1yr-7%
1-4yr-28%
5-9yr-25%
10-14yr-24%
15-20yr-16%.
- <1yr-7%
- 1-4yr-28%
- 5-9yr-25%
- 10-14yr-24%
- 15-20yr-16%.
Gender
- Among the 186 children with MIS-C
Comorbidities
- Children with MIS-C had following underlying comorbidities.[4]
Clinically diagnosed Obesity-8%
BMI-Based Obesity-29%
Cardiovascular diasease-3%
Respiratory disease-18%
Autoimmune disease or immunocompromising condition-5%
- Clinically diagnosed Obesity-8%
- BMI-Based Obesity-29%
- Cardiovascular diasease-3%
- Respiratory disease-18%
- Autoimmune disease or immunocompromising condition-5%
Organ System Involved
- 71% of children had involvement of at least four organ systems.[4]
The most common organ system involved in MIS-C children among a total of 186 children were.[4]
- Gastrointestinal(92%)
- Cardiovascular(80%)
- Hematologic(76%)
- Mucocutaneous(74%)
- Pulmonary(70%)
- Historical perspective
# Complications and Prognosis
## Complications
- Severe myocardial infarction[4]
- Cardiac failure/arrest[4]
- ARDS[4]
- Hypervolemia[4]
- Acute Kidney Injury
- Peritonitis[4]
- Thrombotic complications.[4]
# Diagnosis
## Diagnostic Criteria
- 0–19 years of age with fever >3 days[5]
AND
- Two of the following:
- Rash or bilateral non-purulent conjunctivitis or mucocutaneous inflammation signs (oral, hands or feet)
- Hypotension or shock
- Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including ECHO findings or elevated Troponin/NT-proBNP)
- Evidence of coagulopathy (by PT, PTT, elevated D-Dimers)
- Acute gastrointestinal problems (diarrhea, vomiting, or abdominal pain)
AND
- Elevated markers of inflammation such as ESR, C-reactive protein, or procalcitonin
AND
- No other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes
AND
- Evidence of COVID-19 (RT-PCR, antigen test or serology-positive), or likely contact with patients with COVID-19
- An individual aged <21 years presenting with fever, laboratory evidence of inflammation**, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological);[6]
AND
No alternative plausible diagnoses;
AND
Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or exposure to a suspected or confirmed COVID-19 case within the 4 weeks prior to the onset of symptoms.
## Signs and Symptoms
- Fever lasting 24 hours or longer.[1]
- Vomiting[1]
- Diarrhea[1]
- Abdominal pain[1]
- Skin rash[1]
- Conjuctivitis[1]
- High ESR[1]
- Redness or swelling of the lips and tongue[1]
- Lethargy[1]
- Redness or swelling of the hands or feet[1]
- Confusion[1]
- Headache[1]
- Sore throat[1]
- Syncope[1]
- Lymphadenopathy[1]
Emergency Warning Signs
- Difficulty Breathing[1]
- Chest pain
- New onset confusion
- Lethargy
- Cyanosis
- Abdominal pain
## Physical Examination
Blood Investigations
- Lymphopenia, Neutrophilia, Anemia, Thrombocytopenia have been seen in MIS-C pateints. Abnormal fibrinogen, Hypoalbuminaemia, elevated creatiine kinase (CK), LDH, triglycerides have been observed in MIS-C patients.[1]
### Inflammatory biomarkers
Elevation of inflammatory markers including ESR, C reactive protein and procalcitonin are usually seen in MIS-C. Increased level of Interleukin-6 (IL-6), Interleukin-10(IL-10) d-dimer, serum ferritin, prothrombin time have also been seen in MIS-C.[1]
### Cardiac biomarkers
Elevation of cardic enzymes including cardiac troponins (cardiac troponin I(cTnI) and cardiac troponin T (cTnT)) and Brain natriuretic peptide (BNP)) has been observed in MIS-C patients.[1]
## Radiological Findings
- Following Radiological Findings are observed in MIS-C patients.[1]
Blood Culture, Viral PCR
- Absence of other potential causative organisms. IgG levels and IgM levels of SARS-CoV-2 are detected.
# Treatment
## Medical Therapy
- All the children with MIS-C are treated as suspected COVID-19.
- Mild to Moderate cases of MIS-C are managed supportively.[7][8]
- Supplemental oxygen is required in children with low oxygen saturation.[8]
- Fluid resuscitation in 10 ml/kg aliquots with reevaluation after each bolus. Maintain euvolemia. Avoid hypervolemia.[8]
- Anti-inflammatory treatments with Intravenous immunoglobulin(IVIG) with or without corticosteroids have shown a good response rate.[7][8]
- Aspirin has been used primarily for its antiplatelet effect. It is recommended in all patients with MIS-C.[7][8]
- Anakinra is considered if fevers last more than 24 hours post steroids/IVIG or in the moderate or severe presentation.[7][8]
- Tocilizumab is also considered if fevers last more than 24 hours post steroids/IVIG or in the moderate or severe presentation.[7][8]
- Empiric antibiotics like vancomycin, ceftriaxone, and clindamycin are given for community-acquired shock presentation until cultures are negative for 48 hours.[7][8]
# Prevention of MIS-C
- MIS-C can be prevented by reducing the risk of child exposure to COVID-19 infection. | https://www.wikidoc.org/index.php/Sandbox:_HAR | |
bda87aa2428c9763e01542b60bb703e84a588345 | wikidoc | Sandbox: HCL | Sandbox: HCL
# Laboratory Findings
## Complete Blood Count
- Decreased hemoglobin concentration
- Decreased platelets count
- Decreased WBC count
## Blood Smear
- Presence of smudge cells
## Metabolic Panel
- Elevated low-density lipoprotein level
## Quantitative Immunoglobulin Assay
- Quantitative measurement of IgA, IgG, and IgM immunoglobulins to detect hypogammaglobulinemia
- Elevated β2-microglobulin level
## Electrophoresis
- Monoclonality of kappa and lambda producing B cells is a key diagnostic feature among patients with chronic lymphocytic leukemia.
## Immunohistochemistry
- Chronic lymphocytic leukemia cells typically express CD19, CD20, CD23, and CD5 on the cell surface.
- ↑ Jump up to: 1.0 1.1 1.2 1.3 1.4 1.5 Wadhwa RK, McKenzie R (1972). "Complications of band-aid surgery for sterilization". JAMA. 222 (12): 1558. PMID 4264273..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: 2.0 2.1 2.2 2.3 2.4 Chronic Lymphocytic Leukimea. Wikipedia (2015) Accessed on October ,12 2015 | Sandbox: HCL
# Laboratory Findings
## Complete Blood Count
- Decreased hemoglobin concentration[1]
- Decreased platelets count
- Decreased WBC count
## Blood Smear
- Presence of smudge cells[1][2]
## Metabolic Panel
- Elevated low-density lipoprotein level[1][2]
## Quantitative Immunoglobulin Assay
- Quantitative measurement of IgA, IgG, and IgM immunoglobulins to detect hypogammaglobulinemia[1][2]
- Elevated β2-microglobulin level
## Electrophoresis
- Monoclonality of kappa and lambda producing B cells is a key diagnostic feature among patients with chronic lymphocytic leukemia.[1][2]
## Immunohistochemistry
- Chronic lymphocytic leukemia cells typically express CD19, CD20, CD23, and CD5 on the cell surface.[1][2]
- ↑ Jump up to: 1.0 1.1 1.2 1.3 1.4 1.5 Wadhwa RK, McKenzie R (1972). "Complications of band-aid surgery for sterilization". JAMA. 222 (12): 1558. PMID 4264273..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: 2.0 2.1 2.2 2.3 2.4 Chronic Lymphocytic Leukimea. Wikipedia (2015) https://en.wikipedia.org/wiki/B-cell_chronic_lymphocytic_leukemia Accessed on October ,12 2015 | https://www.wikidoc.org/index.php/Sandbox:_HCL | |
a2e970dcee916307a152dfa7d89d0440998b79b3 | wikidoc | Sandbox: VJP | Sandbox: VJP
# Overview
Brachial plexus injury (BPI) is an injury to brachial plexus which runs from the spine from fifth cervical vertebra(C5) to underneath the first thoracic vertebra(T1). It innervates and runs through the neck, the axilla and into arm.
BPI can significantly impair the function in one or sometimes both the upper limbs, causing inability to perform daily life activities which can lead to economic crisis, depression and also survival hardships in some cases.
# Historical Perspective
Discovery
- The first ever documentation of Obstetric type of BPI was done by Smellie in 1764.
- In 1872, Duchenne found out that traction was the cause of BPI.
- Another Scientist named Erb proposed a theory that the traction or pinching of C5 or C6 roots can also produce BPI.
- Moreover, the first scientist who published an article regarding the direct repair of the components of BPI was Thourborn in 1900.
- In 1903, Harris and Low reported the first neurotizations.
- In 1920, some of the fascicles of the pectoral nerves onto the musculocutaneous and the axillary nerves were re-routed by Vulpius and Stoffel.
- In 1947, Seddon got his method of the surgical correction of traction injuries with application of long interpositional nerve grafts published.
- In 1966, at the Paris meeting of the International Society of Orthopedic Surgery and Traumatology (SICOT), conclusion was made that surgical repair of BPI is almost impossible.
- Later Stevens precisely proposed the bio mechanics of traction in the upper limb and neck and the resultant injuries of the brachial plexus.
- Narakas, Millesi, Allieu, Brunelli, Gu, Terzis, Doi, and others introduced the microsurgical, nerve repair and nerve regeneration techniques successfully. | Sandbox: VJP
# Overview
Brachial plexus injury (BPI) is an injury to brachial plexus which runs from the spine from fifth cervical vertebra(C5) to underneath the first thoracic vertebra(T1). It innervates and runs through the neck, the axilla and into arm.
BPI can significantly impair the function in one or sometimes both the upper limbs, causing inability to perform daily life activities which can lead to economic crisis, depression and also survival hardships in some cases.
# Historical Perspective
Discovery
- The first ever documentation of Obstetric type of BPI was done by Smellie in 1764.
- In 1872, Duchenne found out that traction was the cause of BPI.
- Another Scientist named Erb proposed a theory that the traction or pinching of C5 or C6 roots can also produce BPI.
- Moreover, the first scientist who published an article regarding the direct repair of the components of BPI was Thourborn in 1900.
- In 1903, Harris and Low reported the first neurotizations.
- In 1920, some of the fascicles of the pectoral nerves onto the musculocutaneous and the axillary nerves were re-routed by Vulpius and Stoffel.
- In 1947, Seddon got his method of the surgical correction of traction injuries with application of long interpositional nerve grafts published.
- In 1966, at the Paris meeting of the International Society of Orthopedic Surgery and Traumatology (SICOT), conclusion was made that surgical repair of BPI is almost impossible.
- Later Stevens precisely proposed the bio mechanics of traction in the upper limb and neck and the resultant injuries of the brachial plexus.
- Narakas, Millesi, Allieu, Brunelli, Gu, Terzis, Doi, and others introduced the microsurgical, nerve repair and nerve regeneration techniques successfully. | https://www.wikidoc.org/index.php/Sandbox:_VJP | |
e49dca6f872e3452b1d5ab249743d24c9cdf4f63 | wikidoc | Sandbox: epi | Sandbox: epi
# Overview
Hairy cell leukemia is found to approximately comprise 2% of all leukemias in the United States. The incidence of hairy cell leukemia is approximately 3.2 per 1,000,000 individuals in the United States. The incidence of hairy cell leukemia increases with age; the median age at diagnosis is 58 years. Males are more commonly affected with hairy cell leukemia than females. The male to female ratio is approximately 4 to 1.
# Epidemiology and Demographics
## Prevalence
- Hairy cell leukemia is considered one of the least common types of leukemias in the United States.
- Hairy cell leukemia is found to approximately comprise 2% of all leukemias in the United States.
## Incidence
- The incidence of hairy cell leukemia is approximately 3.2 per 1,000,000 individuals in the United States.
- For the past 30 years, the incidence of hairy cell leukemia has been relatively constant.
## Age
- The incidence of hairy cell leukemia increases with age; the median age at diagnosis is 58 years.
## Gender
- Males are more commonly affected with hairy cell leukemia than females. The male to female ratio is approximately 4 to 1.
## Race
- Hairy cell leukemia usually affects individuals of the Caucasian race. Asian and African American individuals are less likely to develop hairy cell leukemia.
- ↑ Jump up to: 1.0 1.1 Hairy Cell Leukemia. Wikipedia (2015) #Pathophysiology Accesed on October, 20 2015
- ↑ Jump up to: 2.0 2.1 2.2 2.3 2.4 2.5 Epidemiology. HAIRY CELL LEUKEMIA FOUNDATION. (2015) / Accessed on October, 21 2015 | Sandbox: epi
# Overview
Hairy cell leukemia is found to approximately comprise 2% of all leukemias in the United States.[1] The incidence of hairy cell leukemia is approximately 3.2 per 1,000,000 individuals in the United States. The incidence of hairy cell leukemia increases with age; the median age at diagnosis is 58 years. Males are more commonly affected with hairy cell leukemia than females. The male to female ratio is approximately 4 to 1.[2]
# Epidemiology and Demographics
## Prevalence
- Hairy cell leukemia is considered one of the least common types of leukemias in the United States.[2]
- Hairy cell leukemia is found to approximately comprise 2% of all leukemias in the United States.[1]
## Incidence
- The incidence of hairy cell leukemia is approximately 3.2 per 1,000,000 individuals in the United States.
- For the past 30 years, the incidence of hairy cell leukemia has been relatively constant.[2]
## Age
- The incidence of hairy cell leukemia increases with age; the median age at diagnosis is 58 years.[2]
## Gender
- Males are more commonly affected with hairy cell leukemia than females. The male to female ratio is approximately 4 to 1.[2]
## Race
- Hairy cell leukemia usually affects individuals of the Caucasian race. Asian and African American individuals are less likely to develop hairy cell leukemia.[2]
- ↑ Jump up to: 1.0 1.1 Hairy Cell Leukemia. Wikipedia (2015) https://en.wikipedia.org/wiki/Hairy_cell_leukemia#Pathophysiology Accesed on October, 20 2015
- ↑ Jump up to: 2.0 2.1 2.2 2.3 2.4 2.5 Epidemiology. HAIRY CELL LEUKEMIA FOUNDATION. (2015) https://www.hairycellleukemia.org/professionals/epidemiology/ Accessed on October, 21 2015 | https://www.wikidoc.org/index.php/Sandbox:_epi | |
6de42997649d480393ccdd7e49641618646253ba | wikidoc | Sandbox:ajay | Sandbox:ajay
The pathophysiology of Enteropathic arthropathy:
- Although the pathogenesis of EA has not been plainly clarified, the observation that joint inflammation occurs in genetically predisposed subjects with bacterial gut infections provided an important evidence for a possible relationship between inflammation of the gut mucosa and arthritis.
- Current theories provide, in genetically predisposed subjects, an aberrant migration of intestinal lymphocytes or macrophages from inflamed gut mucosa to joints, in which an important role was played by gut bacteria.
- In fact, a dysfunctional interaction between the mucosal immune system and gut bacteria could result in an abnormal state of immunological tolerance toward flora by alterations in mucosal effector cells or by affecting regulatory cells.
- A significant evidence for the pathogenic role of gut bacteria in the pathogenesis of SpA is derived from animals models.
- Genetic factors play a predisposing role while environmental factors, such as infectious agents, may play a causative role.
- Among the genetic factors, HLA-B27 has the strongest genetic association with SpA and in particular with ankylosing spondylitis (AS).
- This association is reported in more than 90% of cases, also spondylitis in IBD is associated with the presence of HLA-B27, however, in lower frequencies than in AS (30%–80%).
- Pure asymptomatic sacroiliitis in CD is not strongly associated with HLA-B27 and a very recent study indicates a prevalence of 7%.
- In 2000, Orchard et al. described an association with HLA-DR0103, B35, and B27 in type 1 peripheral arthritis and neither B27 nor DR4 associations were observed in type 2 arthritis.
- In order to describe the role of HLA-B27 in the pathogenesis of EA, different theories have been proposed.
- One theory suggests that HLA-B27-expressing macrophages expose specific bacterial antigens that may activate CD4+ T-cells with their migration from gut to joint with the development of arthritis.
- Another theory proposes that homology between HLA-B27 sequences and bacterial antigens may activate T-cell and inflammation by antigen mimicry mechanism.
- Finally, the most recent theory is based on the endoplasmic reticulum stress: under normal conditions, the peptide-loaded HLA class I heavy chain binds the β2-microglobulin (β2m) in the endoplasmic reticulum. The folding process of the HLA-B27 heavy chain is slower than that of other HLA alleles thus leading to the generation of misfolded chains.
- Misfolded chains are usually removed in the endoplasmic reticulum, but in certain conditions, such as viral infection, they accumulate thus activating the protein BiP, the endoplasmic reticulum-unfolded-protein-response (UPR) and the nuclear factor κB (NFκB), which play a critical role in the induction of inflammation.
- Data suggest that deposition of β2m, caused by the high dissociation rate between the HLA-B27 heavy chain and β2m, occurring within synovial tissue, may lead to the initiation of chronic inflammation.
- Other HLA genes have been associated with SpA in IBD: HLA-DrB10103, HLA-B35, HLA-B24 in type 1 peripheral arthritis, and HLA-B44 in type 2 peripheral arthritis.
- Moreover, Mielants et al. showed an association between HLA-Bw62 and chronic gut lesions associated with a family history of AS and CD, with markers of inflammation, reduced axial mobility, the presence of sacroiliitis, destructive joint lesions, and a diagnosis of AS.
- Further confirming the relevance of HLA-B27 in the pathogenesis of enteroarthritis, Hammer et al. studied transgenic rats overexpressing HLA-B27 molecule. These rats developed a multisystemic inflammatory disease that had several clinical and histopathological similarities to SpA and IBD . An important finding was that these rats did not develop joint or gut inflammation when they were in a germ-free environment . This result supports the theory of the participation of microorganisms in the pathogenesis of these diseases.
- In humans with reactive arthritis, following Yersinia enterocolitica, Shigella spp. or Salmonella enteritidis and Typhimurium infection, bacterial antigens have been detected in joints . Later studies further confirmed this evidence.
- Other molecular studies found similarities between Klebsiella nitrogenase and HLA-B27 and between Klebsiella pullulanase and collagen fibers types I, III, and IV.
- Interestingly, elevated levels of antibodies against Klebsiella and collagen fibers types I, III, IV, and V were detected in patients with CD and AS.
- In addition to HLA-B27, other genes have been identified as being related to SpA and IBD. In fact, several common genetic predispositions between SpA and IBD were identified, of which the association with IL-23R polymorphisms is most prominent.
- The functional role of IL-23 receptor polymorphisms remains unclear, the fact that IL-23 signaling plays a critical role in the Th17-mediated inflammation indicates that Th17 cells may represent a common pathogenetic mechanism in both IBD and SpA.
- The first susceptibility gene that has been identified for CD is CARD15 (or NOD2). Variants within this gene increase the risk for CD by threefold for heterozygous and fortyfold for homozygous individuals.
- An association was also found in SpA patients between the carriage of CARD15 variants and the development of chronic subclinical gut inflammation.
- Although CARD15 mutations do not seem to predispose to arthritis, it might confer a risk towards the development of (sub) clinical gut inflammation in SpA patients, rendering these patients more disposed to develop IBD.
- A CARD15-mediated NFκB-dependent inflammatory reaction might be an important pathogenic process within the joints.
- The protein is expressed in the joint tissue, and bacterial cell wall components have been demonstrated in the synovium of SpA patients, supporting the idea that CARD15 can locally trigger inflammation.
- Recently, additionally shared associations between SpA and IBD were found at chromosome 1q32 near KIF21B (genome-wide significant), STAT3, IL-12B, CDKAL1, LRRK2/MUC19, and chromosome 13q14 (experiment-wise association).
- As the genes IL-23R, STAT3, and IL-12B all influence Th17 lymphocyte differentiation/activation, this provides further evidence implicating the Th17 lymphocyte subset in the pathogenesis of SpA.
- In addition to genetic susceptibility, an important role was also been given to the environmental factors in triggering the onset of disease.
- In fact, bacterial gut infections such as Yersinia enterocolitica, Salmonella typhimurium, Campylobacter jejuni, and Shigella spp may cause joint inflammation in genetically predisposed patients.
- Given the prototypical link between certain bacterial infections and the onset of reactive arthritis, several studies have aimed to assess the role of intestinal flora in disease progression, as well as the resulting changes in mucosal response.
- On the basis of these observations, the possible pathways involved in joint and gut inflammation in EA may be the following: in the acute phase of inflammation, bacterial infections can cause acute intestinal inflammation.
- Certain bacteria may survive intracellularly in macrophages that can traffic to the joint and cause arthritis in a genetically predisposed host. *Proinflammatory cytokines such as TNF and IL-23 are produced locally, with Paneth cells being the most important producers of IL-23 in the intestine.
- This expression can activate innate immune cells (NK) to produce IL-22 that may help control inflammation at mucosal sites.
- Otherwise, damage and pathogen-associated molecular pattern molecules (DAMPs and PAMPs) and cellular stretch might promote initiation of joint inflammation.
- In the transition phase, acute intestinal and articular inflammation can be sustained due to defective immune regulation by TREG cells, or by ER stress, whereas iNKT cells act as regulators to control inflammation. Proangiogenic factors such as PlGF can lead to aberrant neovascularisation. *These events may lead to chronicity, further enhanced or maintained by repetitive cellular stress.
- In this stage, stromal cells become more important, as targets for proinflammatory cytokines
- ↑ Navis ES (September 1987). "Controlling violent patients before they control you. Advice on keeping your cool when your patient is losing his". Nursing. 17 (9): 52–4. PMID 3649644..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}
- ↑ Cuvelier C, Barbatis C, Mielants H, De Vos M, Roels H, Veys E (April 1987). "Histopathology of intestinal inflammation related to reactive arthritis". Gut. 28 (4): 394–401. PMC 1432823. PMID 3495471.
- ↑ Jacques P, Elewaut D, Mielants H (July 2010). "Interactions between gut inflammation and arthritis/spondylitis". Curr Opin Rheumatol. 22 (4): 368–74. doi:10.1097/BOR.0b013e3283393807. PMID 20485176.
- ↑ Mallas EG, Mackintosh P, Asquith P, Cooke WT (November 1976). "Histocompatibility antigens in inflammatory bowel disease. Their clinical significance and their association with arthropathy with special reference to HLA-B27 (W27)". Gut. 17 (11): 906–10. PMC 1411211. PMID 1001980.
- ↑ Brown MA, Pile KD, Kennedy LG, Calin A, Darke C, Bell J, Wordsworth BP, Cornélis F (April 1996). "HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom". Ann. Rheum. Dis. 55 (4): 268–70. PMC 1010149. PMID 8733445.
- ↑ Mertz AK, Wu P, Sturniolo T, Stoll D, Rudwaleit M, Lauster R, Braun J, Sieper J (February 2000). "Multispecific CD4+ T cell response to a single 12-mer epitope of the immunodominant heat-shock protein 60 of Yersinia enterocolitica in Yersinia-triggered reactive arthritis: overlap with the B27-restricted CD8 epitope, functional properties, and epitope presentation by multiple DR alleles". J. Immunol. 164 (3): 1529–37. PMID 10640771.
- ↑ Fantini MC, Pallone F, Monteleone G (May 2009). "Common immunologic mechanisms in inflammatory bowel disease and spondylarthropathies". World J. Gastroenterol. 15 (20): 2472–8. PMC 2686905. PMID 19468997.
- ↑ Taurog JD, Richardson JA, Croft JT, Simmons WA, Zhou M, Fernández-Sueiro JL, Balish E, Hammer RE (December 1994). "The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats". J. Exp. Med. 180 (6): 2359–64. PMC 2191772. PMID 7964509.
- ↑ Laukens D, Peeters H, Marichal D, Vander Cruyssen B, Mielants H, Elewaut D, Demetter P, Cuvelier C, Van Den Berghe M, Rottiers P, Veys EM, Remaut E, Steidler L, De Keyser F, De Vos M (June 2005). "CARD15 gene polymorphisms in patients with spondyloarthropathies identify a specific phenotype previously related to Crohn's disease". Ann. Rheum. Dis. 64 (6): 930–5. doi:10.1136/ard.2004.028837. PMC 1755516. PMID 15539413.
- ↑ Rothfuss KS, Stange EF, Herrlinger KR (August 2006). "Extraintestinal manifestations and complications in inflammatory bowel diseases". World J. Gastroenterol. 12 (30): 4819–31. PMC 4087615. PMID 16937463. | Sandbox:ajay
The pathophysiology of Enteropathic arthropathy:[1][2][3][4][5][6][7][8][9][10]
- Although the pathogenesis of EA has not been plainly clarified, the observation that joint inflammation occurs in genetically predisposed subjects with bacterial gut infections provided an important evidence for a possible relationship between inflammation of the gut mucosa and arthritis.
- Current theories provide, in genetically predisposed subjects, an aberrant migration of intestinal lymphocytes or macrophages from inflamed gut mucosa to joints, in which an important role was played by gut bacteria.
- In fact, a dysfunctional interaction between the mucosal immune system and gut bacteria could result in an abnormal state of immunological tolerance toward flora by alterations in mucosal effector cells or by affecting regulatory cells.
- A significant evidence for the pathogenic role of gut bacteria in the pathogenesis of SpA is derived from animals models.
- Genetic factors play a predisposing role while environmental factors, such as infectious agents, may play a causative role.
- Among the genetic factors, HLA-B27 has the strongest genetic association with SpA and in particular with ankylosing spondylitis (AS).
- This association is reported in more than 90% of cases, also spondylitis in IBD is associated with the presence of HLA-B27, however, in lower frequencies than in AS (30%–80%).
- Pure asymptomatic sacroiliitis in CD is not strongly associated with HLA-B27 and a very recent study indicates a prevalence of 7%.
- In 2000, Orchard et al. described an association with HLA-DR0103, B35, and B27 in type 1 peripheral arthritis and neither B27 nor DR4 associations were observed in type 2 arthritis.
- In order to describe the role of HLA-B27 in the pathogenesis of EA, different theories have been proposed.
- One theory suggests that HLA-B27-expressing macrophages expose specific bacterial antigens that may activate CD4+ T-cells with their migration from gut to joint with the development of arthritis.
- Another theory proposes that homology between HLA-B27 sequences and bacterial antigens may activate T-cell and inflammation by antigen mimicry mechanism.
- Finally, the most recent theory is based on the endoplasmic reticulum stress: under normal conditions, the peptide-loaded HLA class I heavy chain binds the β2-microglobulin (β2m) in the endoplasmic reticulum. The folding process of the HLA-B27 heavy chain is slower than that of other HLA alleles thus leading to the generation of misfolded chains.
- Misfolded chains are usually removed in the endoplasmic reticulum, but in certain conditions, such as viral infection, they accumulate thus activating the protein BiP, the endoplasmic reticulum-unfolded-protein-response (UPR) and the nuclear factor κB (NFκB), which play a critical role in the induction of inflammation.
- Data suggest that deposition of β2m, caused by the high dissociation rate between the HLA-B27 heavy chain and β2m, occurring within synovial tissue, may lead to the initiation of chronic inflammation.
- Other HLA genes have been associated with SpA in IBD: HLA-DrB10103, HLA-B35, HLA-B24 in type 1 peripheral arthritis, and HLA-B44 in type 2 peripheral arthritis.
- Moreover, Mielants et al. showed an association between HLA-Bw62 and chronic gut lesions associated with a family history of AS and CD, with markers of inflammation, reduced axial mobility, the presence of sacroiliitis, destructive joint lesions, and a diagnosis of AS.
- Further confirming the relevance of HLA-B27 in the pathogenesis of enteroarthritis, Hammer et al. studied transgenic rats overexpressing HLA-B27 molecule. These rats developed a multisystemic inflammatory disease that had several clinical and histopathological similarities to SpA and IBD [54]. An important finding was that these rats did not develop joint or gut inflammation when they were in a germ-free environment [55]. This result supports the theory of the participation of microorganisms in the pathogenesis of these diseases.
- In humans with reactive arthritis, following Yersinia enterocolitica, Shigella spp. or Salmonella enteritidis and Typhimurium infection, bacterial antigens have been detected in joints [56–59]. Later studies further confirmed this evidence.
- Other molecular studies found similarities between Klebsiella nitrogenase and HLA-B27 and between Klebsiella pullulanase and collagen fibers types I, III, and IV.
- Interestingly, elevated levels of antibodies against Klebsiella and collagen fibers types I, III, IV, and V were detected in patients with CD and AS.
- In addition to HLA-B27, other genes have been identified as being related to SpA and IBD. In fact, several common genetic predispositions between SpA and IBD were identified, of which the association with IL-23R polymorphisms is most prominent.
- The functional role of IL-23 receptor polymorphisms remains unclear, the fact that IL-23 signaling plays a critical role in the Th17-mediated inflammation indicates that Th17 cells may represent a common pathogenetic mechanism in both IBD and SpA.
- The first susceptibility gene that has been identified for CD is CARD15 (or NOD2). Variants within this gene increase the risk for CD by threefold for heterozygous and fortyfold for homozygous individuals.
- An association was also found in SpA patients between the carriage of CARD15 variants and the development of chronic subclinical gut inflammation.
- Although CARD15 mutations do not seem to predispose to arthritis, it might confer a risk towards the development of (sub) clinical gut inflammation in SpA patients, rendering these patients more disposed to develop IBD.
- A CARD15-mediated NFκB-dependent inflammatory reaction might be an important pathogenic process within the joints.
- The protein is expressed in the joint tissue, and bacterial cell wall components have been demonstrated in the synovium of SpA patients, supporting the idea that CARD15 can locally trigger inflammation.
- Recently, additionally shared associations between SpA and IBD were found at chromosome 1q32 near KIF21B (genome-wide significant), STAT3, IL-12B, CDKAL1, LRRK2/MUC19, and chromosome 13q14 (experiment-wise association).
- As the genes IL-23R, STAT3, and IL-12B all influence Th17 lymphocyte differentiation/activation, this provides further evidence implicating the Th17 lymphocyte subset in the pathogenesis of SpA.
- In addition to genetic susceptibility, an important role was also been given to the environmental factors in triggering the onset of disease.
- In fact, bacterial gut infections such as Yersinia enterocolitica, Salmonella typhimurium, Campylobacter jejuni, and Shigella spp may cause joint inflammation in genetically predisposed patients.
- Given the prototypical link between certain bacterial infections and the onset of reactive arthritis, several studies have aimed to assess the role of intestinal flora in disease progression, as well as the resulting changes in mucosal response.
- On the basis of these observations, the possible pathways involved in joint and gut inflammation in EA may be the following: in the acute phase of inflammation, bacterial infections can cause acute intestinal inflammation.
- Certain bacteria may survive intracellularly in macrophages that can traffic to the joint and cause arthritis in a genetically predisposed host. *Proinflammatory cytokines such as TNF and IL-23 are produced locally, with Paneth cells being the most important producers of IL-23 in the intestine.
- This expression can activate innate immune cells (NK) to produce IL-22 that may help control inflammation at mucosal sites.
- Otherwise, damage and pathogen-associated molecular pattern molecules (DAMPs and PAMPs) and cellular stretch might promote initiation of joint inflammation.
- In the transition phase, acute intestinal and articular inflammation can be sustained due to defective immune regulation by TREG cells, or by ER stress, whereas iNKT cells act as regulators to control inflammation. Proangiogenic factors such as PlGF can lead to aberrant neovascularisation. *These events may lead to chronicity, further enhanced or maintained by repetitive cellular stress.
- In this stage, stromal cells become more important, as targets for proinflammatory cytokines
-
-
-
-
- ↑ Navis ES (September 1987). "Controlling violent patients before they control you. Advice on keeping your cool when your patient is losing his". Nursing. 17 (9): 52–4. PMID 3649644..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}
- ↑ Cuvelier C, Barbatis C, Mielants H, De Vos M, Roels H, Veys E (April 1987). "Histopathology of intestinal inflammation related to reactive arthritis". Gut. 28 (4): 394–401. PMC 1432823. PMID 3495471.
- ↑ Jacques P, Elewaut D, Mielants H (July 2010). "Interactions between gut inflammation and arthritis/spondylitis". Curr Opin Rheumatol. 22 (4): 368–74. doi:10.1097/BOR.0b013e3283393807. PMID 20485176.
- ↑ Mallas EG, Mackintosh P, Asquith P, Cooke WT (November 1976). "Histocompatibility antigens in inflammatory bowel disease. Their clinical significance and their association with arthropathy with special reference to HLA-B27 (W27)". Gut. 17 (11): 906–10. PMC 1411211. PMID 1001980.
- ↑ Brown MA, Pile KD, Kennedy LG, Calin A, Darke C, Bell J, Wordsworth BP, Cornélis F (April 1996). "HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom". Ann. Rheum. Dis. 55 (4): 268–70. PMC 1010149. PMID 8733445.
- ↑ Mertz AK, Wu P, Sturniolo T, Stoll D, Rudwaleit M, Lauster R, Braun J, Sieper J (February 2000). "Multispecific CD4+ T cell response to a single 12-mer epitope of the immunodominant heat-shock protein 60 of Yersinia enterocolitica in Yersinia-triggered reactive arthritis: overlap with the B27-restricted CD8 epitope, functional properties, and epitope presentation by multiple DR alleles". J. Immunol. 164 (3): 1529–37. PMID 10640771.
- ↑ Fantini MC, Pallone F, Monteleone G (May 2009). "Common immunologic mechanisms in inflammatory bowel disease and spondylarthropathies". World J. Gastroenterol. 15 (20): 2472–8. PMC 2686905. PMID 19468997.
- ↑ Taurog JD, Richardson JA, Croft JT, Simmons WA, Zhou M, Fernández-Sueiro JL, Balish E, Hammer RE (December 1994). "The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats". J. Exp. Med. 180 (6): 2359–64. PMC 2191772. PMID 7964509.
- ↑ Laukens D, Peeters H, Marichal D, Vander Cruyssen B, Mielants H, Elewaut D, Demetter P, Cuvelier C, Van Den Berghe M, Rottiers P, Veys EM, Remaut E, Steidler L, De Keyser F, De Vos M (June 2005). "CARD15 gene polymorphisms in patients with spondyloarthropathies identify a specific phenotype previously related to Crohn's disease". Ann. Rheum. Dis. 64 (6): 930–5. doi:10.1136/ard.2004.028837. PMC 1755516. PMID 15539413.
- ↑ Rothfuss KS, Stange EF, Herrlinger KR (August 2006). "Extraintestinal manifestations and complications in inflammatory bowel diseases". World J. Gastroenterol. 12 (30): 4819–31. PMC 4087615. PMID 16937463. | https://www.wikidoc.org/index.php/Sandbox:ajay | |
ec5388536810beef65ac320f9a88214d3baff5b1 | wikidoc | Sandbox:huda | Sandbox:huda
# Overview
This section provides a short and straight to the point overview of the disease or symptom. The first sentence of the overview must contain the name of the disease.
# Birth Control Options
### Female birth control options
Long acting reversible contraception(LARC): 99% effective, high rate of satisfaction, long-term use, quick return to fertility when discontinued
- IUDs (> 99% effective)
Copper IUD: effective for up to 10 years, used for patients with light menstrual periods, desire long-term contraception, not prefer using hormonal contraception
Progestin-releasing IUD, effective for up to 5 years, for patients with heavy menstrual bleeding and dysmenorrhea
- Copper IUD: effective for up to 10 years, used for patients with light menstrual periods, desire long-term contraception, not prefer using hormonal contraception
- Progestin-releasing IUD, effective for up to 5 years, for patients with heavy menstrual bleeding and dysmenorrhea
- Subdermal implant (> 99% effective), effective for up to 3 years, SE: unscheduled bleeding, weight gain, headache. Ovulation and fertility occur within one month after removal
- Depot Medroxyprogesterone, IM injection given every 3 months (94% effective),
- Combined hormonal contraceptives
Oral contraceptive (estrogen/progestin pills) (OCPs) (91% effective)
Birth Control Patch (91% effective)
Vaginal Ring (91% effective)
- Oral contraceptive (estrogen/progestin pills) (OCPs) (91% effective)
- Birth Control Patch (91% effective)
- Vaginal Ring (91% effective)
- Barrier Methods
Diaphragm
Cervical Cap
Sponge
- Diaphragm
- Cervical Cap
- Sponge
- Spermicide (80% failure rate if used alone). Should be used with cervical cap or diaphragm, may damage the genital epithelium and increase risk of acquiring SDIs
- Natural contraception (Natural Family Planning and Fertility Awareness)
Lactational Amenorrhea Method (LAM) (Breastfeeding can help with child spacing)
- Lactational Amenorrhea Method (LAM) (Breastfeeding can help with child spacing)
- Abstinence
- Permanent Sterilization
Emergency contraception
### Male birth control options
Barrier contraception (Condoms) (80% effective), the only type of contraception that prevent sexual transmitted infections
Vasectomy
Withdrawal (coitus interruptus) (75% effective)
Note:
- You can use IUD in a nulliparous female
- Progestin subdermal implant is more effective that IUD (failure rate .2-.8%) and female fertilization (.5% failure rate)
# Indications
- Pregnancy prevention
- Treatment of different conditions such as:
Polycystic Ovary Syndrome (PCOS): OCPs are used for menstrual regulation
Endometriosis
Amenorrhea
Dysmenorrhea
Premenstrual Syndrome (PMS)
Primary Ovarian Insufficiency (POI)
Heavy Menstrual Periods
Acne
- Polycystic Ovary Syndrome (PCOS): OCPs are used for menstrual regulation
- Endometriosis
- Amenorrhea
- Dysmenorrhea
- Premenstrual Syndrome (PMS)
- Primary Ovarian Insufficiency (POI)
- Heavy Menstrual Periods
- Acne
# Contraindications
Oral contraceptives (estrogen) alter the transport and tissue delivery of thyroid hormone by increasing the synthesis of throxine-binding globulin , relative hypothyroid state in patients with hypothyroidism. Increase the dose of levothyroxine when starting OCPs.
### Combined hormonal contraceptives
Absolute contraindications
- Less than 6 wks postpartum
- Smoking (age > 35, and >15 cigarettes per day)
- Hypertension (systolic > 160mmHg or diastolic > 100mmHg)
- Venous thromboembolism (VTE) (current of past history)
- Ischemic heart disease
- Cerebrovascular accident history
- Complicated valvular heart disease (pulmonary hypertension, atrial fibrillation, history of subacute bacterial endocarditis)
- Migraine headache with aura or focal neurological symptoms
- Breast cancer (current)
- Diabetes with retinopathy/nephropathy/neuropathy
- Severe cirrhosis
- Liver tumor (adenoma or hepatoma)
### IUDs
- Uterine anomalies
- Active pelvic infection
Relative contraindications
- Smoker over the age of 35 (< 15 cigarettes per day)
- Adequately controlled hypertension
- Hypertension (systolic 140 - 159mmHg or diastolic 90 - 99mmHg)
- Migrain headache over the age of 35
- Currently symptomatic gallbladder disease
- Mild cirrhosis
- History of combined OCP-related cholestasis
Medications that interfere with OCPs:
### Subdermal implant
- Progesterone receptor-positive breast cancer
# Do's
- Increase the levothyroxine dose in patients with hypothyroidism who started taking OCPs. OCPs (estrogen) increases the liver synthesis of thyroxin-binding globulin (TBG)
- OCPs also decrease the effect of Warfarin, so consider increasing the dose
# Don'ts
- The content in this section is in bullet points. | Sandbox:huda
# Overview
This section provides a short and straight to the point overview of the disease or symptom. The first sentence of the overview must contain the name of the disease.
# Birth Control Options
### Female birth control options
Long acting reversible contraception(LARC): 99% effective, high rate of satisfaction, long-term use, quick return to fertility when discontinued
- IUDs (> 99% effective)
Copper IUD: effective for up to 10 years, used for patients with light menstrual periods, desire long-term contraception, not prefer using hormonal contraception
Progestin-releasing IUD, effective for up to 5 years, for patients with heavy menstrual bleeding and dysmenorrhea
- Copper IUD: effective for up to 10 years, used for patients with light menstrual periods, desire long-term contraception, not prefer using hormonal contraception
- Progestin-releasing IUD, effective for up to 5 years, for patients with heavy menstrual bleeding and dysmenorrhea
- Subdermal implant (> 99% effective), effective for up to 3 years, SE: unscheduled bleeding, weight gain, headache. Ovulation and fertility occur within one month after removal
- Depot Medroxyprogesterone, IM injection given every 3 months (94% effective),
- Combined hormonal contraceptives
Oral contraceptive (estrogen/progestin pills) (OCPs) (91% effective)
Birth Control Patch (91% effective)
Vaginal Ring (91% effective)
- Oral contraceptive (estrogen/progestin pills) (OCPs) (91% effective)
- Birth Control Patch (91% effective)
- Vaginal Ring (91% effective)
- Barrier Methods
Diaphragm
Cervical Cap
Sponge
- Diaphragm
- Cervical Cap
- Sponge
- Spermicide (80% failure rate if used alone). Should be used with cervical cap or diaphragm, may damage the genital epithelium and increase risk of acquiring SDIs
- Natural contraception (Natural Family Planning and Fertility Awareness)
Lactational Amenorrhea Method (LAM) (Breastfeeding can help with child spacing)
- Lactational Amenorrhea Method (LAM) (Breastfeeding can help with child spacing)
- Abstinence
- Permanent Sterilization
Emergency contraception
### Male birth control options
Barrier contraception (Condoms) (80% effective), the only type of contraception that prevent sexual transmitted infections
Vasectomy
Withdrawal (coitus interruptus) (75% effective)
Note:
- You can use IUD in a nulliparous female
- Progestin subdermal implant is more effective that IUD (failure rate .2-.8%) and female fertilization (.5% failure rate)
# Indications
- Pregnancy prevention
- Treatment of different conditions such as:
Polycystic Ovary Syndrome (PCOS): OCPs are used for menstrual regulation
Endometriosis
Amenorrhea
Dysmenorrhea
Premenstrual Syndrome (PMS)
Primary Ovarian Insufficiency (POI)
Heavy Menstrual Periods
Acne
- Polycystic Ovary Syndrome (PCOS): OCPs are used for menstrual regulation
- Endometriosis
- Amenorrhea
- Dysmenorrhea
- Premenstrual Syndrome (PMS)
- Primary Ovarian Insufficiency (POI)
- Heavy Menstrual Periods
- Acne
# Contraindications
Oral contraceptives (estrogen) alter the transport and tissue delivery of thyroid hormone by increasing the synthesis of throxine-binding globulin , relative hypothyroid state in patients with hypothyroidism. Increase the dose of levothyroxine when starting OCPs.
### Combined hormonal contraceptives
Absolute contraindications
- Less than 6 wks postpartum
- Smoking (age > 35, and >15 cigarettes per day)
- Hypertension (systolic > 160mmHg or diastolic > 100mmHg)
- Venous thromboembolism (VTE) (current of past history)
- Ischemic heart disease
- Cerebrovascular accident history
- Complicated valvular heart disease (pulmonary hypertension, atrial fibrillation, history of subacute bacterial endocarditis)
- Migraine headache with aura or focal neurological symptoms
- Breast cancer (current)
- Diabetes with retinopathy/nephropathy/neuropathy
- Severe cirrhosis
- Liver tumor (adenoma or hepatoma)
### IUDs
- Uterine anomalies
- Active pelvic infection
Relative contraindications
- Smoker over the age of 35 (< 15 cigarettes per day)
- Adequately controlled hypertension
- Hypertension (systolic 140 - 159mmHg or diastolic 90 - 99mmHg)
- Migrain headache over the age of 35
- Currently symptomatic gallbladder disease
- Mild cirrhosis
- History of combined OCP-related cholestasis
Medications that interfere with OCPs:
### Subdermal implant
- Progesterone receptor-positive breast cancer
# Do's
- Increase the levothyroxine dose in patients with hypothyroidism who started taking OCPs. OCPs (estrogen) increases the liver synthesis of thyroxin-binding globulin (TBG)
- OCPs also decrease the effect of Warfarin, so consider increasing the dose
# Don'ts
- The content in this section is in bullet points. | https://www.wikidoc.org/index.php/Sandbox:huda | |
c3939b59d1e75646aa947a88f7f43e06df44edbf | wikidoc | Sandbox:omtx | Sandbox:omtx
# Overview
## Antimicrobial Regimens
### Hematogenous Osteomyelitis
- 1. Empiric antimicrobial therapy
- 1.1 Adult (>21 yrs)
- 1.1.1 MRSA possible
- Preferred regimen: Vancomycin 1 g IV q12h (if over 100 kg, 1.5 g IV q12h)
- 1.1.2 MRSA unlikely
- Preferred regimen: Nafcillin 2 g IV q4h OR Oxacillin 2 g IV q4h
- 1.2 Children (>4 months)
- 1.2.1 MRSA possible
- Preferred regimen: Vancomycin 40 mg/kg/day IV q6–8h
- 1.2.2 MRSA unlikely
- Preferred regimen: Nafcillin 37 mg/kg IV q6h (maximum dose 8–12 g/day) OR Oxacillin 37 mg/kg IV q6h (maximum dose 8–12 g/day)
- Note: Add Ceftazidime 50 mg/kg IV q8h or Cefepime 150 mg/kg/day IV q8h if Gram-negative bacilli on Gram stain.
- 2. Pathogen-directed antimicrobial therapy
- 2.1 MSSA
- Preferred regimen: Nafcillin 2 g IV q4h OR Oxacillin 2 g IV q4h OR Cefazolin 2 g IV q8h
- Alternative regimen: Vancomycin 1 g IV q12h (if over 100 kg, 1.5 g IV q12h)
- 2.2 MRSA
- Preferred regimen: Vancomycin 1 g IV q12h
- Alternative regimen: Linezolid 600 mg q12h IV/PO ± Rifampin 300 mg po/IV bid
### Contiguous Osteomyelitis with Vascular Insufficiency
- Osteomyelitis, contiguous with vascular insufficiency
- Debride overlying ulcer and send bone specimen for histology and culture.
- No empiric antimicrobial therapy unless acutely ill.
- Antibiotic therapy should be based on culture results
- Treatment duration is at least 6 weeks.
- Revascularize if possible.
### Open Fracture Osteomyelitis
- Long bone, post-internal fixation of fracture
- 1. S. aureus or P. aeruginosa
- Preferred regimen: Vancomycin 1 g IV q12h AND (Ceftazidime 2 g IV q8h OR Cefepime 2 g IV q8h)
- Alternative regimen (1): Linezolid 600 mg IV/PO bid AND Ceftazidime 2 g IV q8h
- Alternative regimen (2): Linezolid 600 mg IV/PO bid AND Cefepime 2 g IV q8h
- 2. Gram negative bacilli
- Preferred regimen (1): Ciprofloxacin 750 mg PO bid
- Preferred regimen (2): Levofloxacin 750 mg PO qd
### Diabetic Foot Osteomyelitis
- 1. Chronic infection or recent antibiotic use
- Preferred regimen (1): Levofloxacin 750 mg IV/PO q24h
- Preferred regimen (2): Cefoxitin 1 g IV q4h (or 2 g IV q6–8h)
- Preferred regimen (3): Ceftriaxone 1–2 g/day IV/IM q12–24h
- Preferred regimen (4): Ampicillin-Sulbactam 1.5–3 g IV/IM q6h
- Preferred regimen (5): Moxifloxacin 400 mg IV/PO q24h
- Preferred regimen (6): Ertapenem 1 g IV/IM q24h
- Preferred regimen (7): Tigecycline 100 mg IV THEN 50 mg IV q12h (active against MRSA)
- Preferred regimen (8): Imipenem-Cilastatin 0.5–1 g IV q6–8h (Not active against MRSA)
- Alternative regimen (1): Levofloxacin 750 mg IV/PO q24h AND Clindamycin 150–300 mg PO qid
- Alternative regimen (2): Ciprofloxacin 600–1200 mg/day IV q6–12h AND Clindamycin 150–300 mg PO qid
- Alternative regimen (3): Ciprofloxacin 1200–2700 mg IV q6–12h AND Clindamycin 150–300 mg PO qid (for more severe cases)
- 2. High risk for MRSA
- Preferred regimen (1): Linezolid 600 mg IV/PO q12h
- Preferred regimen (2): Daptomycin 4 mg/kg IV q24h
- Preferred regimen (3): Vancomycin 15–20 mg/kg IV q8–12h (trough: 10–20 mg/L)
- 3. High risk for Pseudomonas aeruginosa
- Preferred regimen: Piperacillin–Tazobactam 3.375 g IV q6–8h
- 4. Polymicrobial infection
- Preferred regimen: (Vancomycin 15–20 mg/kg IV q8–12h (trough: 10–20 mg/L) OR Linezolid 600 mg IV/PO q12h OR Daptomycin 4 mg/kg IV q24h) AND (Piperacillin–Tazobactam 3.375 g IV q6–8h OR Imipenem–Cilastatin 0.5–1 g IV q6–8h OR Ertapenem 1 g IV/IM q24h OR Meropenem 1 g IV q8h)
- Alternative regimen: (Vancomycin 15–20 mg/kg IV q8–12h (trough: 10–20 mg/L) OR Linezolid 600 mg IV/PO q12h OR Daptomycin 4 mg/kg IV q24h) AND (Ceftazidime 2 g IV q8h OR Cefepime 2 g IV q8h OR Aztreonam 2 g IV q6–8h) AND Metronidazole 15 mg/kg IV, then 7.5 mg/kg IV q6h
- ↑ Gilbert, David (2015). The Sanford guide to antimicrobial therapy. Sperryville, Va: Antimicrobial Therapy. ISBN 978-1930808843..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}
- ↑ Gilbert, David (2015). The Sanford guide to antimicrobial therapy. Sperryville, Va: Antimicrobial Therapy. ISBN 978-1930808843.
- ↑ Gilbert, David (2015). The Sanford guide to antimicrobial therapy. Sperryville, Va: Antimicrobial Therapy. ISBN 978-1930808843.
- ↑ Lipsky BA, Berendt AR, Cornia PB, Pile JC, Peters EJ, Armstrong DG; et al. (2013). "2012 infectious diseases society of america clinical practice guideline for the diagnosis and treatment of diabetic foot infections". J Am Podiatr Med Assoc. 103 (1): 2–7. PMID 23328846.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) | Sandbox:omtx
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1],Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]
# Overview
## Antimicrobial Regimens
### Hematogenous Osteomyelitis
- 1. Empiric antimicrobial therapy [1]
- 1.1 Adult (>21 yrs)
- 1.1.1 MRSA possible
- Preferred regimen: Vancomycin 1 g IV q12h (if over 100 kg, 1.5 g IV q12h)
- 1.1.2 MRSA unlikely
- Preferred regimen: Nafcillin 2 g IV q4h OR Oxacillin 2 g IV q4h
- 1.2 Children (>4 months)
- 1.2.1 MRSA possible
- Preferred regimen: Vancomycin 40 mg/kg/day IV q6–8h
- 1.2.2 MRSA unlikely
- Preferred regimen: Nafcillin 37 mg/kg IV q6h (maximum dose 8–12 g/day) OR Oxacillin 37 mg/kg IV q6h (maximum dose 8–12 g/day)
- Note: Add Ceftazidime 50 mg/kg IV q8h or Cefepime 150 mg/kg/day IV q8h if Gram-negative bacilli on Gram stain.
- 2. Pathogen-directed antimicrobial therapy
- 2.1 MSSA
- Preferred regimen: Nafcillin 2 g IV q4h OR Oxacillin 2 g IV q4h OR Cefazolin 2 g IV q8h
- Alternative regimen: Vancomycin 1 g IV q12h (if over 100 kg, 1.5 g IV q12h)
- 2.2 MRSA
- Preferred regimen: Vancomycin 1 g IV q12h
- Alternative regimen: Linezolid 600 mg q12h IV/PO ± Rifampin 300 mg po/IV bid
### Contiguous Osteomyelitis with Vascular Insufficiency
- Osteomyelitis, contiguous with vascular insufficiency [2]
- Debride overlying ulcer and send bone specimen for histology and culture.
- No empiric antimicrobial therapy unless acutely ill.
- Antibiotic therapy should be based on culture results
- Treatment duration is at least 6 weeks.
- Revascularize if possible.
### Open Fracture Osteomyelitis
- Long bone, post-internal fixation of fracture [3]
- 1. S. aureus or P. aeruginosa
- Preferred regimen: Vancomycin 1 g IV q12h AND (Ceftazidime 2 g IV q8h OR Cefepime 2 g IV q8h)
- Alternative regimen (1): Linezolid 600 mg IV/PO bid AND Ceftazidime 2 g IV q8h
- Alternative regimen (2): Linezolid 600 mg IV/PO bid AND Cefepime 2 g IV q8h
- 2. Gram negative bacilli
- Preferred regimen (1): Ciprofloxacin 750 mg PO bid
- Preferred regimen (2): Levofloxacin 750 mg PO qd
### Diabetic Foot Osteomyelitis
- 1. Chronic infection or recent antibiotic use [4]
- Preferred regimen (1): Levofloxacin 750 mg IV/PO q24h
- Preferred regimen (2): Cefoxitin 1 g IV q4h (or 2 g IV q6–8h)
- Preferred regimen (3): Ceftriaxone 1–2 g/day IV/IM q12–24h
- Preferred regimen (4): Ampicillin-Sulbactam 1.5–3 g IV/IM q6h
- Preferred regimen (5): Moxifloxacin 400 mg IV/PO q24h
- Preferred regimen (6): Ertapenem 1 g IV/IM q24h
- Preferred regimen (7): Tigecycline 100 mg IV THEN 50 mg IV q12h (active against MRSA)
- Preferred regimen (8): Imipenem-Cilastatin 0.5–1 g IV q6–8h (Not active against MRSA)
- Alternative regimen (1): Levofloxacin 750 mg IV/PO q24h AND Clindamycin 150–300 mg PO qid
- Alternative regimen (2): Ciprofloxacin 600–1200 mg/day IV q6–12h AND Clindamycin 150–300 mg PO qid
- Alternative regimen (3): Ciprofloxacin 1200–2700 mg IV q6–12h AND Clindamycin 150–300 mg PO qid (for more severe cases)
- 2. High risk for MRSA
- Preferred regimen (1): Linezolid 600 mg IV/PO q12h
- Preferred regimen (2): Daptomycin 4 mg/kg IV q24h
- Preferred regimen (3): Vancomycin 15–20 mg/kg IV q8–12h (trough: 10–20 mg/L)
- 3. High risk for Pseudomonas aeruginosa
- Preferred regimen: Piperacillin–Tazobactam 3.375 g IV q6–8h
- 4. Polymicrobial infection
- Preferred regimen: (Vancomycin 15–20 mg/kg IV q8–12h (trough: 10–20 mg/L) OR Linezolid 600 mg IV/PO q12h OR Daptomycin 4 mg/kg IV q24h) AND (Piperacillin–Tazobactam 3.375 g IV q6–8h OR Imipenem–Cilastatin 0.5–1 g IV q6–8h OR Ertapenem 1 g IV/IM q24h OR Meropenem 1 g IV q8h)
- Alternative regimen: (Vancomycin 15–20 mg/kg IV q8–12h (trough: 10–20 mg/L) OR Linezolid 600 mg IV/PO q12h OR Daptomycin 4 mg/kg IV q24h) AND (Ceftazidime 2 g IV q8h OR Cefepime 2 g IV q8h OR Aztreonam 2 g IV q6–8h) AND Metronidazole 15 mg/kg IV, then 7.5 mg/kg IV q6h
- ↑ Gilbert, David (2015). The Sanford guide to antimicrobial therapy. Sperryville, Va: Antimicrobial Therapy. ISBN 978-1930808843..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}
- ↑ Gilbert, David (2015). The Sanford guide to antimicrobial therapy. Sperryville, Va: Antimicrobial Therapy. ISBN 978-1930808843.
- ↑ Gilbert, David (2015). The Sanford guide to antimicrobial therapy. Sperryville, Va: Antimicrobial Therapy. ISBN 978-1930808843.
- ↑ Lipsky BA, Berendt AR, Cornia PB, Pile JC, Peters EJ, Armstrong DG; et al. (2013). "2012 infectious diseases society of america clinical practice guideline for the diagnosis and treatment of diabetic foot infections". J Am Podiatr Med Assoc. 103 (1): 2–7. PMID 23328846.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) | https://www.wikidoc.org/index.php/Sandbox:omtx | |
804141e9889c4e2012325858453dab06bd725494 | wikidoc | Sandbox:opht | Sandbox:opht
# Overview
It is important to have accurate insight when you are interpreting an imaging series such as CT scans, MRIs, or angiography. From a student's point of view, it may be needlessly complicated to look for a lesion in many frames. For this reason, creating an animated image with highlighted lesions is preferable to uploading many images, since it makes the image more accessible for all users. Here we describe how to make an animated GIF file with highlighted lesions.
# How to insert an imaging series for CT scan or MRI
If you want to present a series of images (e.g., CT scans, MRIs) instead of uploading many discrete images, you can highlight the pathologic part of the image by encircling it in yellow and then mixing the images to create a GIF file by following the steps listed below:
- The row image
- 1st highlighted image
- 2nd highlighted image
- 3rd highlighted image
- 4th highlighted image
- 5th highlighted image
- 6th highlighted image
- 7th highlighted image
- 8th highlighted image
- 9th highlighted image
- 10th highlighted image
- 11th highlighted image
Here are 2 examples for imaging series: | Sandbox:opht
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]
# Overview
It is important to have accurate insight when you are interpreting an imaging series such as CT scans, MRIs, or angiography. From a student's point of view, it may be needlessly complicated to look for a lesion in many frames. For this reason, creating an animated image with highlighted lesions is preferable to uploading many images, since it makes the image more accessible for all users. Here we describe how to make an animated GIF file with highlighted lesions.
# How to insert an imaging series for CT scan or MRI
If you want to present a series of images (e.g., CT scans, MRIs) instead of uploading many discrete images, you can highlight the pathologic part of the image by encircling it in yellow and then mixing the images to create a GIF file by following the steps listed below:
- The row image
- 1st highlighted image
- 2nd highlighted image
- 3rd highlighted image
- 4th highlighted image
- 5th highlighted image
- 6th highlighted image
- 7th highlighted image
- 8th highlighted image
- 9th highlighted image
- 10th highlighted image
- 11th highlighted image
Here are 2 examples for imaging series: | https://www.wikidoc.org/index.php/Sandbox:opht | |
743df85ae8935e902f098fc96e2c7bd2028a055c | wikidoc | Sandbox:risk | Sandbox:risk
- High risk neuroblastoma patients include:
- Patients with stage 2A/2B, 3, 4, or 4S tumor, irrespective of the age, irrespective of the grade, MYCN amplified
- Patients with stage 3 tumor, ≥ 547 days of age, unfavorable histology, MYCN not amplified
- Patients with stage 4 tumor, 365-547 days of age, unfavorable histology, DNA index=1, MYCN not amplified
- Patients with stage 4 tumor, >547 days of age, irrespective the grade, MYCN amplification state | Sandbox:risk
- High risk neuroblastoma patients include:
- Patients with stage 2A/2B, 3, 4, or 4S tumor, irrespective of the age, irrespective of the grade, MYCN amplified
- Patients with stage 3 tumor, ≥ 547 days of age, unfavorable histology, MYCN not amplified
- Patients with stage 4 tumor, 365-547 days of age, unfavorable histology, DNA index=1, MYCN not amplified
- Patients with stage 4 tumor, >547 days of age, irrespective the grade, MYCN amplification state | https://www.wikidoc.org/index.php/Sandbox:risk |
Subsets and Splits