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f38af60ddb04af3de7eaddd2fc7a8406cde5fc6a | wikidoc | Netrin 1 | Netrin 1
Netrin-1 is a protein that in humans is encoded by the NTN1 gene.
Netrin is included in a family of laminin-related secreted proteins. The function of this gene has not yet been defined; however, netrin is thought to be involved in axon guidance and cell migration during development. Mutations and loss of expression of netrin suggest that variation in netrin may be involved in cancer development.
# Interactions
NTN1 has been shown to interact with Deleted in Colorectal Cancer. | Netrin 1
Netrin-1 is a protein that in humans is encoded by the NTN1 gene.[1][2]
Netrin is included in a family of laminin-related secreted proteins. The function of this gene has not yet been defined; however, netrin is thought to be involved in axon guidance and cell migration during development. Mutations and loss of expression of netrin suggest that variation in netrin may be involved in cancer development.[2]
# Interactions
NTN1 has been shown to interact with Deleted in Colorectal Cancer.[1][3] | https://www.wikidoc.org/index.php/Netrin_1 | |
f7243c5a592f1ff9068158343cd66a644038ad11 | wikidoc | Neurexin | Neurexin
Neurexin (NRXN) is a presynaptic protein that helps to connect neurons at the synapse. They are located mostly on the presynaptic membrane and contain a single transmembrane domain. The extracellular domain interacts with proteins in the synaptic cleft, most notably neuroligin, while the intracellular cytoplasmic portion interacts with proteins associated with exocytosis. Neurexin and neuroligin "shake hands," resulting in the connection between the two neurons and the production of a synapse. Neurexins mediate signaling across the synapse, and influence the properties of neural networks by synapse specificity. Neurexins were discovered as receptors for α-latrotoxin, a vertebrate-specific toxin in black widow spider venom that binds to presynaptic receptors and induces massive neurotransmitter release. In humans, alterations in genes encoding neurexins are implicated in autism and other cognitive diseases, such as Tourette syndrome and schizophrenia.
# Structure
In mammals, neurexin is encoded by three different genes (NRXN1, NRXN2, and NRXN3) each controlled by two different promoters, an upstream alpha (α) and a downstream beta (β), resulting in alpha-neurexins 1-3 (α-neurexins 1-3) and beta-neurexins 1-3 (β-neurexins 1-3). In addition, there are alternative splicing at 5 sites in α-neurexin and 2 in β-neurexin; more than 2000 splice variants are possible, suggesting its role in determining synapse specificity.
The encoded proteins are structurally similar to laminin, slit, and agrin, other proteins involved in axon guidance and synaptogenesis. α-Neurexins and β-neurexins have identical intracellular domains but different extracellular domains. The extracellular domain of α-neurexin is composed of three neurexin repeats which each contain LNS (laminin, neurexin, sex-hormone binding globulin) – EGF (epidermal growth factor) – LNS domains. N1α binds to a variety of ligands including neuroligins and GABA receptors, though neurons of every receptor type express neurexins. β-Neurexins are shorter versions of α-neurexins, containing only one LNS domain. β-Neurexins (located presynaptically) act as receptors for neuroligin (located postsynaptically). Additionally, β-Neurexin has also been found to play a role in angiogenesis.
The C terminus of the short intracellular section of both types of neurexins binds to synaptotagmin and to the PDZ (postsynaptic density (PSD)-95/discs large/zona-occludens-1) domains of CASK and Mint. These interactions form connections between intracellular synaptic vesicles and fusion proteins. Thus neurexins play an important role in assembling presynaptic and postsynaptic machinery.
Trans-synapse, the extracellular LNS domains have a functional region, the hyper-variable surface, formed by loops carrying 3 splice inserts. This region surrounds a coordinated Ca2+ ion and is the site of neuroligin binding, resulting in a neurexin-neuroligin Ca2+-dependent complex at the junction of chemical synapses.
# Expression and function
Neurexins are diffusely distributed in neurons and become concentrated at presynaptic terminals as neurons mature. There exists a trans-synaptic dialog between neurexin and neuroligin, meaning neuroligin can induce the expression of neurexin and vice versa. This bi-directional trigger aids in the formation of synapses and is a key component to modifying the neuronal network. Over-expression of either of these proteins causes an increase in synapse forming sites, thus providing evidence that neurexin plays a functional role in synaptogenesis. Conversely, the blocking of β-neurexin interactions reduces the number of excitatory and inhibitory synapses. It is not clear how exactly neurexin promotes the formation of synapses. One possibility is that actin is polymerized on the tail end of β-neurexin, which traps and stabilizes accumulating synaptic vesicles. This forms a forward feeding cycle, where small clusters of β-neurexins recruit more β-neurexins and scaffolding proteins to form a large synaptic adhesive contact.
# Neurexin-neuroligin binding
The different combinations of neurexin to neuroligin, and alternative splicing of neuroligin and neurexin genes, control binding between neuroligins and neurexins, adding to synapse specificity. Neurexins alone are capable of recruiting neuroligins in postsynaptic cells to a dendritic surface, resulting in clustered neurotransmitter receptors and other postsynaptic proteins and machinery. Their neuroligin partners can induce presynaptic terminals by recruiting neurexins. Synapse formation can therefore be triggered in either direction by these proteins. Neuroligins and neurexins can also regulate formation of glutamatergic (excitatory) synapses, and GABAergic (inhibitory) contacts using a neuroligin link. Regulating these contacts suggests neurexin-neuroligin binding could balance synaptic input, or maintain an optimal ratio of excitatory to inhibitory contacts.
## Additional Interacting Partners
Neurexins not only bind to neuroligin. Additional binding partners of neurexin are dystroglycan and neuroexophilins. Dystroglycan is Ca2+-dependant and binds preferentially to α-neurexins on LNS domains that lack splice inserts. In mice, a deletion of dystroglycan causes long-term potentiation impairment and developmental abnormalities similar to muscular dystrophy; however baseline synaptic transmission is normal. Neuroexophilins are Ca2+-independent and bind exclusively to α-neurexins on the second LNS domain. The increased startle responses and impaired motor coordination of neuroexophilin knockout mice indicates that neuroexophilins have a functional role in certain circuits. The significance of the relationship between neurexin and dystroglycan or neuroexophilins is still unclear.
# Species distribution
Members of the neurexin family are found across all animals, including basal metazoans such as porifera (sponges), cnidaria (jellyfish) and ctenophora (comb jellies). Porifera lack synapses so its role in these organisms is unclear.
Homologues of α-neurexin have also been found in several invertebrate species including Drosophila, Caenorhabditis elegans, honeybees and Aplysia. In Drosophila melanogaster, NRXN genes (only one α-neurexin) are critical in the assembly of glutamatergic neuromuscular junctions but are much simpler. Their functional roles in insects are likely similar to those in vertebrates.
# Role in synaptic maturation
Neurexin and neuroligin have been found to be active in synapse maturation and adaptation of synaptic strength. Studies in knockout mice show that the trans-synaptic binding team does not increase the number of synaptic sites, but rather increases the strength of the existing synapses. Deletion of the neurexin genes in the mice significantly impaired synaptic function, but did not alter synaptic structure. This is attributed to the impairment of specific voltage gated ion channels. While neuroligin and neurexin are not required for synaptic formation, they are essential components for proper function.
# Clinical importance and applications
Recent studies link mutations in genes encoding neurexin and neuroligin to a spectrum of cognitive disorders, such as autism spectrum disorders (ASDs), schizophrenia, and mental retardation. Cognitive diseases remain difficult to understand, as they are characterized by subtle changes in a subgroup of synapses in a circuit rather than impairment of all systems in all circuits. Depending on the circuit, these subtle synapse changes may produce different neurological symptoms, leading to classification of different diseases. Counterarguments to the relationship between cognitive disorders and these mutations exist, prompting further investigation into the underlying mechanisms producing these cognitive disorders.
## Autism
Autism is a neurodevelopmental disorder characterized by qualitative deficits in social behavior and communication, often including restricted, repetitive patterns of behavior. It includes a subset of three disorders: childhood disintegrative disorder (CDD), Asperger syndrome (AS), and pervasive developmental disorder – not otherwise specified (PDD-NOS). A small percentage of ASD patients present with single mutations in genes encoding neuroligin-neurexin cell adhesion molecules. Neurexin is crucial to synaptic function and connectivity, as highlighted in wide spectrum of neurodevelopmental phenotypes in individuals with neurexin deletions. This provides strong evidence that neurexin deletions result in increased risk of ASDs, and indicate synapse dysfunction as the possible site of autism origin. Dr. Steven Clapcote et al.'s α-neurexin II (Nrxn2α) KO mice experiments demonstrate a causal role for the loss of Nrxn2α in the genesis of autism-related behaviors in mice.
## Schizophrenia
Schizophrenia is a debilitating neuropsychiatric illness with multiple genes and environmental exposures involved in its genesis. Further research indicates that deletion of the NRXN1 gene increases the risk of schizophrenia. Genomic duplications and deletions on a micro-level – known as copy number variants (CNVs) – often underlie neurodevelopmental syndromes. Genomic-wide scans suggest that individuals with schizophrenia have rare structural variants that deleted or duplicated one or more genes. As these studies only indicate an increased risk, further research is necessary to elucidate the underlying mechanisms of the genesis of cognitive diseases.
## Intellectual disability and Tourette syndrome
Similar to schizophrenia, studies have shown that intellectual disability and Tourette syndrome are also associated with NRXN1 deletions. A recent study shows that NRXN genes 1-3 are essential for survival and play a pivotal and overlapping role with each other in neurodevelopment. These genes have been directly disrupted in Tourette syndrome by independent genomic rearrangements. Another study suggests that NLGN4 mutations can be associated with a wide spectrum of neuropsychiatric conditions and that carriers may be affected with milder symptoms. | Neurexin
Neurexin (NRXN) is a presynaptic protein that helps to connect neurons at the synapse.[1] They are located mostly on the presynaptic membrane and contain a single transmembrane domain. The extracellular domain interacts with proteins in the synaptic cleft, most notably neuroligin, while the intracellular cytoplasmic portion interacts with proteins associated with exocytosis.[2] Neurexin and neuroligin "shake hands," resulting in the connection between the two neurons and the production of a synapse.[3] Neurexins mediate signaling across the synapse, and influence the properties of neural networks by synapse specificity. Neurexins were discovered as receptors for α-latrotoxin, a vertebrate-specific toxin in black widow spider venom that binds to presynaptic receptors and induces massive neurotransmitter release.[4] In humans, alterations in genes encoding neurexins are implicated in autism and other cognitive diseases, such as Tourette syndrome and schizophrenia.[4]
# Structure
In mammals, neurexin is encoded by three different genes (NRXN1, NRXN2, and NRXN3) each controlled by two different promoters, an upstream alpha (α) and a downstream beta (β), resulting in alpha-neurexins 1-3 (α-neurexins 1-3) and beta-neurexins 1-3 (β-neurexins 1-3).[5] In addition, there are alternative splicing at 5 sites in α-neurexin and 2 in β-neurexin; more than 2000 splice variants are possible, suggesting its role in determining synapse specificity.[6]
The encoded proteins are structurally similar to laminin, slit, and agrin, other proteins involved in axon guidance and synaptogenesis.[6] α-Neurexins and β-neurexins have identical intracellular domains but different extracellular domains. The extracellular domain of α-neurexin is composed of three neurexin repeats which each contain LNS (laminin, neurexin, sex-hormone binding globulin) – EGF (epidermal growth factor) – LNS domains. N1α binds to a variety of ligands including neuroligins and GABA receptors,[2] though neurons of every receptor type express neurexins. β-Neurexins are shorter versions of α-neurexins, containing only one LNS domain.[7] β-Neurexins (located presynaptically) act as receptors for neuroligin (located postsynaptically). Additionally, β-Neurexin has also been found to play a role in angiogenesis.[8]
The C terminus of the short intracellular section of both types of neurexins binds to synaptotagmin and to the PDZ (postsynaptic density (PSD)-95/discs large/zona-occludens-1) domains of CASK and Mint. These interactions form connections between intracellular synaptic vesicles and fusion proteins.[9] Thus neurexins play an important role in assembling presynaptic and postsynaptic machinery.
Trans-synapse, the extracellular LNS domains have a functional region, the hyper-variable surface, formed by loops carrying 3 splice inserts.[2] This region surrounds a coordinated Ca2+ ion and is the site of neuroligin binding,[9] resulting in a neurexin-neuroligin Ca2+-dependent complex at the junction of chemical synapses.[10]
# Expression and function
Neurexins are diffusely distributed in neurons and become concentrated at presynaptic terminals as neurons mature. There exists a trans-synaptic dialog between neurexin and neuroligin, meaning neuroligin can induce the expression of neurexin and vice versa.[11] This bi-directional trigger aids in the formation of synapses and is a key component to modifying the neuronal network. Over-expression of either of these proteins causes an increase in synapse forming sites, thus providing evidence that neurexin plays a functional role in synaptogenesis.[7] Conversely, the blocking of β-neurexin interactions reduces the number of excitatory and inhibitory synapses. It is not clear how exactly neurexin promotes the formation of synapses. One possibility is that actin is polymerized on the tail end of β-neurexin, which traps and stabilizes accumulating synaptic vesicles. This forms a forward feeding cycle, where small clusters of β-neurexins recruit more β-neurexins and scaffolding proteins to form a large synaptic adhesive contact.[7]
# Neurexin-neuroligin binding
The different combinations of neurexin to neuroligin, and alternative splicing of neuroligin and neurexin genes, control binding between neuroligins and neurexins, adding to synapse specificity.[7] Neurexins alone are capable of recruiting neuroligins in postsynaptic cells to a dendritic surface, resulting in clustered neurotransmitter receptors and other postsynaptic proteins and machinery. Their neuroligin partners can induce presynaptic terminals by recruiting neurexins. Synapse formation can therefore be triggered in either direction by these proteins.[9] Neuroligins and neurexins can also regulate formation of glutamatergic (excitatory) synapses, and GABAergic (inhibitory) contacts using a neuroligin link. Regulating these contacts suggests neurexin-neuroligin binding could balance synaptic input,[6] or maintain an optimal ratio of excitatory to inhibitory contacts.
## Additional Interacting Partners
Neurexins not only bind to neuroligin. Additional binding partners of neurexin are dystroglycan and neuroexophilins.[9] Dystroglycan is Ca2+-dependant and binds preferentially to α-neurexins on LNS domains that lack splice inserts. In mice, a deletion of dystroglycan causes long-term potentiation impairment and developmental abnormalities similar to muscular dystrophy; however baseline synaptic transmission is normal. Neuroexophilins are Ca2+-independent and bind exclusively to α-neurexins on the second LNS domain. The increased startle responses and impaired motor coordination of neuroexophilin knockout mice indicates that neuroexophilins have a functional role in certain circuits.[9] The significance of the relationship between neurexin and dystroglycan or neuroexophilins is still unclear.
# Species distribution
Members of the neurexin family are found across all animals, including basal metazoans such as porifera (sponges), cnidaria (jellyfish) and ctenophora (comb jellies). Porifera lack synapses so its role in these organisms is unclear.
Homologues of α-neurexin have also been found in several invertebrate species including Drosophila, Caenorhabditis elegans, honeybees and Aplysia.[11] In Drosophila melanogaster, NRXN genes (only one α-neurexin) are critical in the assembly of glutamatergic neuromuscular junctions but are much simpler.[5] Their functional roles in insects are likely similar to those in vertebrates.[12]
# Role in synaptic maturation
Neurexin and neuroligin have been found to be active in synapse maturation and adaptation of synaptic strength. Studies in knockout mice show that the trans-synaptic binding team does not increase the number of synaptic sites, but rather increases the strength of the existing synapses.[11] Deletion of the neurexin genes in the mice significantly impaired synaptic function, but did not alter synaptic structure. This is attributed to the impairment of specific voltage gated ion channels. While neuroligin and neurexin are not required for synaptic formation, they are essential components for proper function.[11]
# Clinical importance and applications
Recent studies link mutations in genes encoding neurexin and neuroligin to a spectrum of cognitive disorders, such as autism spectrum disorders (ASDs), schizophrenia, and mental retardation.[4] Cognitive diseases remain difficult to understand, as they are characterized by subtle changes in a subgroup of synapses in a circuit rather than impairment of all systems in all circuits. Depending on the circuit, these subtle synapse changes may produce different neurological symptoms, leading to classification of different diseases. Counterarguments to the relationship between cognitive disorders and these mutations exist, prompting further investigation into the underlying mechanisms producing these cognitive disorders.
## Autism
Autism is a neurodevelopmental disorder characterized by qualitative deficits in social behavior and communication, often including restricted, repetitive patterns of behavior.[13] It includes a subset of three disorders: childhood disintegrative disorder (CDD), Asperger syndrome (AS), and pervasive developmental disorder – not otherwise specified (PDD-NOS). A small percentage of ASD patients present with single mutations in genes encoding neuroligin-neurexin cell adhesion molecules. Neurexin is crucial to synaptic function and connectivity, as highlighted in wide spectrum of neurodevelopmental phenotypes in individuals with neurexin deletions. This provides strong evidence that neurexin deletions result in increased risk of ASDs, and indicate synapse dysfunction as the possible site of autism origin.[14] Dr. Steven Clapcote et al.'s α-neurexin II (Nrxn2α) KO mice experiments demonstrate a causal role for the loss of Nrxn2α in the genesis of autism-related behaviors in mice.[15]
## Schizophrenia
Schizophrenia is a debilitating neuropsychiatric illness with multiple genes and environmental exposures involved in its genesis.[16] Further research indicates that deletion of the NRXN1 gene increases the risk of schizophrenia.[17] Genomic duplications and deletions on a micro-level – known as copy number variants (CNVs) – often underlie neurodevelopmental syndromes. Genomic-wide scans suggest that individuals with schizophrenia have rare structural variants that deleted or duplicated one or more genes.[16] As these studies only indicate an increased risk, further research is necessary to elucidate the underlying mechanisms of the genesis of cognitive diseases.[18]
## Intellectual disability and Tourette syndrome
Similar to schizophrenia, studies have shown that intellectual disability and Tourette syndrome are also associated with NRXN1 deletions.[4][16] A recent study shows that NRXN genes 1-3 are essential for survival and play a pivotal and overlapping role with each other in neurodevelopment. These genes have been directly disrupted in Tourette syndrome by independent genomic rearrangements.[19] Another study suggests that NLGN4 mutations can be associated with a wide spectrum of neuropsychiatric conditions and that carriers may be affected with milder symptoms.[20] | https://www.wikidoc.org/index.php/Neurexin | |
22c6ae814f65843a3920b9ae62fbbd12df51e60f | wikidoc | NeuroArm | NeuroArm
NeuroArm, the world’s first MRI-compatible surgical robot, was engineered using plastics, titanium and other non-magnetic materials.. NeuroArm is a tool that aims to revolutionize neurosurgery and other branches of operative medicine by reducing the constraints of the human hand while maintaining the tactile feedback important to the surgeons. The machine uses something called "motion scaling" which allows the surgeon to be precise within 0.01 mm (compare to 2mm by neurosurgeons with years of experience). With NeuroArm, experience neurosurgeons can join together vessels that are much smaller.
When performing surgery, NeuroArm will be used in conjunction with the iMotion 1.5 Tesla Magnet. The iMotion magnet will move to the patient, "gliding in and out of place as needed, without affecting surgical, anesthetic, and nursing management."
"Tests will be conducted on mannequins, cadavers and tissues to prove to Health Canada and the U.S. Food and Drug Administration that it is safe for people. Officials hope neuroArm will be used to treat its first patient this summer ."
# History
The $27-million NeuroArm project began in 2001 when the namesakes of the Seaman Family MR Research Centre, Calgary philanthropists and brothers Doc, B.J. and Don Seaman provided $2 million to begin planning neuroArm.
NeuroArm is the creation of neurosurgeon Dr. Garnette Sutherland and his team. Dr. Sutherland has spent six years leading a team of Canadian scientists, in cooperation with MacDonald Dettwiler and Associates's MD Robotics division to design and build a machine “that represents a milestone in medical technology.”
NeuroArm was unveiled on April 17, 2007 in Calgary. | NeuroArm
NeuroArm, the world’s first MRI-compatible surgical robot, was engineered using plastics, titanium and other non-magnetic materials.[1]. NeuroArm is a tool that aims to revolutionize neurosurgery and other branches of operative medicine by reducing the constraints of the human hand while maintaining the tactile feedback important to the surgeons.[2] The machine uses something called "motion scaling" which allows the surgeon to be precise within 0.01 mm (compare to 2mm by neurosurgeons with years of experience).[1] With NeuroArm, experience neurosurgeons can join together vessels that are much smaller.[1]
When performing surgery, NeuroArm will be used in conjunction with the iMotion 1.5 Tesla Magnet. The iMotion magnet will move to the patient, "gliding in and out of place as needed, without affecting surgical, anesthetic, and nursing management."[3]
"Tests will be conducted on mannequins, cadavers and tissues to prove to Health Canada and the U.S. Food and Drug Administration that it is safe for people. Officials hope neuroArm will be used to treat its first patient this summer [2007]."[1]
# History
The $27-million[4] NeuroArm project began in 2001 when the namesakes of the Seaman Family MR Research Centre, Calgary philanthropists and brothers Doc, B.J. and Don Seaman provided $2 million to begin planning neuroArm.[2]
NeuroArm is the creation of neurosurgeon Dr. Garnette Sutherland and his team. Dr. Sutherland has spent six years leading a team of Canadian scientists, in cooperation with MacDonald Dettwiler and Associates's MD Robotics division to design and build a machine “that represents a milestone in medical technology.”[2]
NeuroArm was unveiled on April 17, 2007 in Calgary. | https://www.wikidoc.org/index.php/NeuroArm | |
864303fb0beee33628fbcb55bd542ef45b1a8b8c | wikidoc | Neurocan | Neurocan
Neurocan core protein is a protein that in humans is encoded by the NCAN gene.
Neurocan is a member of the lectican / chondroitin sulfate proteoglycan protein families and consists of neurocan core protein and chondroitin sulfate. It is thought to be involved in the modulation of cell adhesion and migration.
# Role in bipolar disorder
Neurocan is a significant component of the extracellular matrix, and its levels are modulated by a variety of factors, but mice in which the NCAN gene has been knocked out show no easily observable defects in brain development or behavior. However, a genome-wide association study published in 2011 identified Neurocan as a susceptibility factor for bipolar disorder. A more comprehensive study published in 2012 confirmed that association. The 2012 study examined correlations between NCAN alleles and various symptoms of bipolar disorder, and also examined the behavior of NCAN knockout mice. In the human subjects, it was found that NCAN genotype was strongly associated with manic symptoms but not with depressive symptoms. In the mice, the absence of functional Neurocan resulted in a variety of manic-like behaviors, which could be normalized by administering lithium. | Neurocan
Neurocan core protein is a protein that in humans is encoded by the NCAN gene.[1][2]
Neurocan is a member of the lectican / chondroitin sulfate proteoglycan protein families and consists of neurocan core protein and chondroitin sulfate. It is thought to be involved in the modulation of cell adhesion and migration.[2]
# Role in bipolar disorder
Neurocan is a significant component of the extracellular matrix, and its levels are modulated by a variety of factors, but mice in which the NCAN gene has been knocked out show no easily observable defects in brain development or behavior.[3] However, a genome-wide association study published in 2011 identified Neurocan as a susceptibility factor for bipolar disorder.[4] A more comprehensive study published in 2012 confirmed that association.[5] The 2012 study examined correlations between NCAN alleles and various symptoms of bipolar disorder, and also examined the behavior of NCAN knockout mice. In the human subjects, it was found that NCAN genotype was strongly associated with manic symptoms but not with depressive symptoms. In the mice, the absence of functional Neurocan resulted in a variety of manic-like behaviors, which could be normalized by administering lithium. | https://www.wikidoc.org/index.php/Neurocan | |
4b139bb83494328a7b3ba22aa31af6db3030051b | wikidoc | Neurolaw | Neurolaw
Neurolaw is an emerging field of study that seeks to explore the effects of discoveries in neuroscience on law and legal standards. It is also the subject of a 2007 article in the New York Times Magazine entitled "The Brain on the Stand".
It is distinct from bioethics and neuroethics in that it applies broader societal and philosophical discourses from those fields to the quotidian realities of the legal system.
Some questions to which neurolaw practitioners seek answers include:
- How will increasingly accurate lie detection systems impact the credibility of eyewitnesses in our court system?
- How will new insight into brain disorders affect legal notions of intent and culpability?
- Why would legal standards change in the face of developments in neuroscience? Should they change? If so, why should they change? Why not?
- Who will be responsible for the integration of new neuroscience into our legal system - judges, legislators, executive leaders, scientists, or some combination thereof? | Neurolaw
Neurolaw is an emerging field of study that seeks to explore the effects of discoveries in neuroscience on law and legal standards. It is also the subject of a 2007 article in the New York Times Magazine entitled "The Brain on the Stand".[1]
It is distinct from bioethics and neuroethics in that it applies broader societal and philosophical discourses from those fields to the quotidian realities of the legal system.
Some questions to which neurolaw practitioners seek answers include:
- How will increasingly accurate lie detection systems impact the credibility of eyewitnesses in our court system?
- How will new insight into brain disorders affect legal notions of intent and culpability?
- Why would legal standards change in the face of developments in neuroscience? Should they change? If so, why should they change? Why not?
- Who will be responsible for the integration of new neuroscience into our legal system - judges, legislators, executive leaders, scientists, or some combination thereof? | https://www.wikidoc.org/index.php/Neurolaw | |
7a58c331bc932757a60c96fa4dd8d8bc939cad5d | wikidoc | Neurosis | Neurosis
Neurosis, also known as psychoneurosis or neurotic disorder, is a "catch all" term that refers to any mental imbalance that causes distress, but, unlike a psychosis or some personality disorders, does not prevent or affect rational thought. It is particularly associated with the field of psychoanalysis, which is one school of thought in psychology or psychiatry.
# History and use of the term
To differentiate between neurosis and neurotic: "Neurotic", or affected by neurosis, has come to describe a person with any degree of depression or anxiety, depressed feelings, lack of emotions, low self-confidence, and/or emotional instability.
The term was coined by the Scottish doctor William Cullen in 1769 to refer to "disorders of sense and motion" caused by a "general affection of the nervous system." For him, it described various nervous disorders and symptoms that could not be explained physiologically. It derives from the Greek word neuron (nerve) with the suffix -osis (diseased or abnormal condition). The term was however most influentially defined by Sigmund Freud over a century later.
The American DSM-III has eliminated the category of Neurosis altogether. This largely reflects a decline in the fashionability of psychoanalysis, and the progressive expurgation of psychoanalytical terminology from the DSM. Those who retain a psychoanalytical perspective, which would include a majority of psychologists in countries such as France, continue to use the term 'neurosis'. According to The American Heritage Dictionary, however, it is "no longer in scientific use."
# Psychoanalytical account of neurosis
As an illness, neurosis represents a variety of psychiatric conditions in which emotional distress or unconscious conflict is expressed through various physical, physiological, and mental disturbances, which may include physical symptoms (e.g., hysteria). The definitive symptom is anxieties. Neurotic tendencies are common and may manifest themselves as depression, acute or chronic anxiety, obsessive-compulsive tendencies, phobias, and even personality disorders, such as borderline personality disorder or obsessive-compulsive personality disorder. It has perhaps been most simply defined as a "poor ability to adapt to one's environment, an inability to change one's life patterns, and the inability to develop a richer, more complex, more satisfying personality." Neurosis should not be mistaken for psychosis, which refers to loss of touch with reality.
The term connotes an actual disorder or disease, but under its general definition, neurosis is a normal human experience, part of the human condition. Most people are affected by neurosis in some form. A psychological problem develops when neuroses begin to interfere with, but not significantly impair, normal functioning, and thus cause the individual anxiety. Frequently, the coping mechanisms enlisted to help "ward off" the anxiety only exacerbate the situation, causing more distress. It has even been defined in terms of this coping strategy, as a "symbolic behavior in defense against excessive psychobiologic pain is self-perpetuating because symbolic satisfactions cannot fulfill real needs."
According to psychoanalytic theory, neuroses may be rooted in ego defense mechanisms, but the two concepts are not synonymous. Defense mechanisms are a normal way of developing and maintaining a consistent sense of self (i.e., an ego), while only those thought and behavior patterns that produce difficulties in living should be termed neuroses.
# Effects and symptoms
There are many different specific forms of neuroses: pyromania, obsessive-compulsive disorder, anxiety neurosis, hysteria (in which anxiety may be discharged through a physical symptom), and an endless variety of phobias. According to Dr. George Boeree, effects of neurosis can involve:
...anxiety, sadness or depression, anger, irritability, mental confusion, low sense of self-worth, etc., behavioral symptoms such as phobic avoidance, vigilance, impulsive and compulsive acts, lethargy, etc., cognitive problems such as unpleasant or disturbing thoughts, repetition of thoughts and obsession, habitual fantasizing, negativity and cynicism, etc. Interpersonally, neurosis involves dependency, aggressiveness, perfectionism, schizoid isolation, socio-culturally inappropriate behaviors, etc.
# Treatment
Although neuroses are targeted by psychoanalysis, psychotherapy, counseling, or other psychiatric techniques, there is still controversy over whether these professionals can perform accurate and reliable diagnoses, and whether many of the resulting treatments are also appropriate, effective, and reliable. Some studies show no benefit is gained from talk therapies. However, some benefit is gained from other kinds of untrained personal companionship and discussion.
# Jung's theory of neurosis
Carl Jung's theory of neurosis is based on a self-regulating psyche. A neurosis consists not only of conflicts between conscious and unconscious forces or complexes. The unconscious also produces invaluable constructive guidance. The language the unconscious uses is a universal symbolism, often of a mythological nature. The leadership role of unconscious fantasies, such as dreams and visions, is more relevant to finding the gradient along which an individual should develop than an arbitrary presumption or method. Correctly reading symbolic emanations requires, besides knowledge of mythological motifs, an understanding of the ambiguous nature of symbols and the ability to interpret them from the unconscious attitude compensating that of the ego. Jung encouraged active imagination in this process.
Jung found his approach particularly fitting for people who are successfully adjusted by normal social standards, but who nevertheless have issues with the meaning of their life.
I have frequently seen people become neurotic when they content themselves with inadequate or wrong answers to the questions of life (Jung, 1989:140).
The majority of my patients consisted not of believers but of those who had lost their faith (Jung, 1989:140).
is blind to the fact that, with all his rationality and efficiency, he is possessed by "powers" that are beyond his control. His gods and demons have not disappeared at all; they have merely got new names. They keep him on the run with restlessness, vague apprehensions, psychological complications, an insatiable need for pills, alcohol, tobacco, food – and, above all, a large array of neuroses. (Jung, 1964:82).
Jung found that the unconscious finds expression primarily through an individual’s inferior psychological function, whether it is thinking, feeling, sensing, or intuition. The characteristic effects of a neurosis on the dominant and inferior functions are discussed in Psychological Types.
Jung saw collective neuroses in politics... "Our world is, so to speak, dissociated like a neurotic" (Jung, 1964:85). | Neurosis
Neurosis, also known as psychoneurosis or neurotic disorder, is a "catch all" term that refers to any mental imbalance that causes distress, but, unlike a psychosis or some personality disorders, does not prevent or affect rational thought. It is particularly associated with the field of psychoanalysis, which is one school of thought in psychology or psychiatry.
# History and use of the term
To differentiate between neurosis and neurotic: "Neurotic", or affected by neurosis, has come to describe a person with any degree of depression or anxiety, depressed feelings, lack of emotions, low self-confidence, and/or emotional instability.
The term was coined by the Scottish doctor William Cullen in 1769 to refer to "disorders of sense and motion" caused by a "general affection of the nervous system." For him, it described various nervous disorders and symptoms that could not be explained physiologically. It derives from the Greek word neuron (nerve) with the suffix -osis (diseased or abnormal condition). The term was however most influentially defined by Sigmund Freud over a century later.
The American DSM-III has eliminated the category of Neurosis altogether. This largely reflects a decline in the fashionability of psychoanalysis, and the progressive expurgation of psychoanalytical terminology from the DSM. Those who retain a psychoanalytical perspective, which would include a majority of psychologists in countries such as France, continue to use the term 'neurosis'. According to The American Heritage Dictionary, however, it is "no longer in scientific use."[1]
# Psychoanalytical account of neurosis
As an illness, neurosis represents a variety of psychiatric conditions in which emotional distress or unconscious conflict is expressed through various physical, physiological, and mental disturbances, which may include physical symptoms (e.g., hysteria). The definitive symptom is anxieties. Neurotic tendencies are common and may manifest themselves as depression, acute or chronic anxiety, obsessive-compulsive tendencies, phobias, and even personality disorders, such as borderline personality disorder or obsessive-compulsive personality disorder. It has perhaps been most simply defined as a "poor ability to adapt to one's environment, an inability to change one's life patterns, and the inability to develop a richer, more complex, more satisfying personality." [2] Neurosis should not be mistaken for psychosis, which refers to loss of touch with reality.
The term connotes an actual disorder or disease, but under its general definition, neurosis is a normal human experience, part of the human condition. Most people are affected by neurosis in some form. A psychological problem develops when neuroses begin to interfere with, but not significantly impair, normal functioning, and thus cause the individual anxiety. Frequently, the coping mechanisms enlisted to help "ward off" the anxiety only exacerbate the situation, causing more distress. It has even been defined in terms of this coping strategy, as a "symbolic behavior in defense against excessive psychobiologic pain [which] is self-perpetuating because symbolic satisfactions cannot fulfill real needs." [3]
According to psychoanalytic theory, neuroses may be rooted in ego defense mechanisms, but the two concepts are not synonymous. Defense mechanisms are a normal way of developing and maintaining a consistent sense of self (i.e., an ego), while only those thought and behavior patterns that produce difficulties in living should be termed neuroses.
# Effects and symptoms
There are many different specific forms of neuroses: pyromania, obsessive-compulsive disorder, anxiety neurosis, hysteria (in which anxiety may be discharged through a physical symptom), and an endless variety of phobias. According to Dr. George Boeree, effects of neurosis can involve:
...anxiety, sadness or depression, anger, irritability, mental confusion, low sense of self-worth, etc., behavioral symptoms such as phobic avoidance, vigilance, impulsive and compulsive acts, lethargy, etc., cognitive problems such as unpleasant or disturbing thoughts, repetition of thoughts and obsession, habitual fantasizing, negativity and cynicism, etc. Interpersonally, neurosis involves dependency, aggressiveness, perfectionism, schizoid isolation, socio-culturally inappropriate behaviors, etc. [4]
# Treatment
Although neuroses are targeted by psychoanalysis, psychotherapy, counseling, or other psychiatric techniques, there is still controversy over whether these professionals can perform accurate and reliable diagnoses, and whether many of the resulting treatments are also appropriate, effective, and reliable. Some studies show no benefit is gained from talk therapies. However, some benefit is gained from other kinds of untrained personal companionship and discussion.
# Jung's theory of neurosis
Carl Jung's theory of neurosis is based on a self-regulating psyche. A neurosis consists not only of conflicts between conscious and unconscious forces or complexes. The unconscious also produces invaluable constructive guidance. The language the unconscious uses is a universal symbolism, often of a mythological nature. The leadership role of unconscious fantasies, such as dreams and visions, is more relevant to finding the gradient along which an individual should develop than an arbitrary presumption or method. Correctly reading symbolic emanations requires, besides knowledge of mythological motifs, an understanding of the ambiguous nature of symbols and the ability to interpret them from the unconscious attitude compensating that of the ego. Jung encouraged active imagination in this process.
Jung found his approach particularly fitting for people who are successfully adjusted by normal social standards, but who nevertheless have issues with the meaning of their life.
I have frequently seen people become neurotic when they content themselves with inadequate or wrong answers to the questions of life (Jung, [1961] 1989:140).
The majority of my patients consisted not of believers but of those who had lost their faith (Jung, [1961] 1989:140).
[Contemporary man] is blind to the fact that, with all his rationality and efficiency, he is possessed by "powers" that are beyond his control. His gods and demons have not disappeared at all; they have merely got new names. They keep him on the run with restlessness, vague apprehensions, psychological complications, an insatiable need for pills, alcohol, tobacco, food – and, above all, a large array of neuroses. (Jung, 1964:82).
Jung found that the unconscious finds expression primarily through an individual’s inferior psychological function, whether it is thinking, feeling, sensing, or intuition. The characteristic effects of a neurosis on the dominant and inferior functions are discussed in Psychological Types.
Jung saw collective neuroses in politics... "Our world is, so to speak, dissociated like a neurotic" (Jung, 1964:85). | https://www.wikidoc.org/index.php/Neurosis | |
a75696b2bd2739f0c545570b09954d9aea0a56bc | wikidoc | Pellagra | Pellagra
Please help WikiDoc by adding content here. It's easy! Click here to learn about editing.
# Overview
Pellagra is a vitamin deficiency disease caused by dietary lack of niacin (vitamin B3) and protein, especially proteins containing the essential amino acid tryptophan. Because tryptophan can be converted into niacin, foods with tryptophan but without niacin, such as milk, prevent pellagra. However, if dietary tryptophan is diverted into protein production, niacin deficiency may still result.
Tryptophan is an essential amino acid found in meat, poultry, fish, and eggs. If your diet contains these foods, your need for niacin from other sources will be reduced.
The relationship between lysine and pellagra is unclear.
# Historical Perspective
The traditional food preparation method of corn, nixtamalization, by native New World cultivators, who had domesticated corn, required treatment of the grain with lime, an alkali. It has now been shown that the lime treatment makes niacin nutritionally available and reduces the chance of developing pellagra. When corn cultivation was adopted worldwide, this preparation method was not accepted because the benefit was not understood. The original cultivators, often heavily dependent on corn, did not suffer from pellagra. Pellagra became common only when corn became a staple that was eaten without the traditional treatment.
Pellagra was first described in Spain in 1735 by Gaspar Casal, who published a first clinical description in his posthumous "Natural and Medical History of the Asturian Pricipality" (1762). This led to the disease being knownn as "Asturian leprosy", and it is recognised as the first modern pathological description of a syndrome(1). It was an endemic disease in northern Italy, where it was named "pelle agra" (pelle = skin; agra = rough) by Francesco Frapoli of Milan. Because pellagra outbreaks occurred in regions where maize was a dominant food crop, the belief for centuries was that the maize either carried a toxic substance or was a carrier of disease. It was not until later that the lack of pellagra outbreaks in Mesoamerica, where maize is a major food crop (and is processed), that the idea was considered that the causes of pellagra may be due to factors other than toxins.
In the early 1900s, pellagra reached epidemic proportions in the American South. There were 1,306 reported pellagra deaths in South Carolina during the first ten months of 1915; 100,000 Southerners were affected in 1916. At this time, the scientific community held that pellagra was probably caused by a germ or some unknown toxin in corn. The Spartanburg Pellagra Hospital in Spartanburg, South Carolina, was the nation's first facility dedicated to discovering the cause of pellagra. It was established in 1914 with a special congressional appropriation to the U.S. Public Health Service (PHS) and set up primarily for research. In 1915 Joseph Goldberger, assigned to study pellagra by the Surgeon General of the United States, showed that pellagra was linked to diet by inducing the disease in prisoners, using the Spartanburg Pellagra Hospital as his clinic. By 1926, Goldberger established that a balanced diet or a small amount of baker's yeast prevented pellagra. Skepticism still persisted in the medical community until 1937 when Conrad Elvehjem showed that the vitamin niacin cured pellagra (manifested as black tongue) in dogs. Later studies by Tom Spies, Marion Blankenhorn and Clark Cooper established that niacin also cured pellagra in humans, for which Time Magazine dubbed them its 1938 Men of the Year in comprehensive science.
# Classification
# Pathophysiology
# Causes
## Drug Causes
- Isoniazid
# Differentiating Pellagra from Other Diseases
# Epidemiology and Demographics
Pellagra can be common in people who obtain most of their food energy from maize, since untreated corn is a poor source of niacin (vitamin B3). Corn is also a poor source of tryptophan. This disease can be common among people who live in rural South America where corn is a staplea. The symptoms usually appear during spring, increase in the summer due to greater sun exposure, and return the following spring. It is also one of several diseases of malnutrition common in Africa, and was endemic in the poorer states of the U.S. south like Mississippi and Alabama as well as among the inmates of jails and orphanages, where it was studied by Joseph Goldberger who conducted experiments in the penal colony in Rankin. Alkali treatment of the corn corrects the niacin deficiency, and was a common practice in native American cultures that grew corn. The amino acid deficiency must be balanced by consumption of other sources of protein. It was also common amongst prisoners of Soviet labor camps, the infamous Gulag. Also found in cases of chronic alcoholism.
# Risk Factors
# Screening
# Natural History, Complications, and Prognosis
## Natural History
## Complications
## Prognosis
# Diagnosis
## Diagnostic Criteria
## History and Symptoms
# Symptoms
The symptoms of pellagra include:
- High sensitivity to sunlight
- Aggression
- Dermatitis
- Smooth, beefy red glossitis
- Red skin lesions
- Insomnia
- Weakness
- Mental confusion
- Diarrhea
- Eventually dementia
The main results of pellagra can easily be remembered as "the four D's": diarrhea, dermatitis, dementia, and death.
## Physical Examination
# Physical Examination
### Skin
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
- Pellagra. With permission from Dermatology Atlas.
## Laboratory Findings
## Imaging Findings
## Other Diagnostic Studies
# Treatment
## Medical Therapy
## Surgery
## Prevention | Pellagra
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Please help WikiDoc by adding content here. It's easy! Click here to learn about editing.
# Overview
Pellagra is a vitamin deficiency disease caused by dietary lack of niacin (vitamin B3) and protein, especially proteins containing the essential amino acid tryptophan.[1] Because tryptophan can be converted into niacin, foods with tryptophan but without niacin, such as milk, prevent pellagra. However, if dietary tryptophan is diverted into protein production, niacin deficiency may still result.
Tryptophan is an essential amino acid found in meat, poultry, fish, and eggs. If your diet contains these foods, your need for niacin from other sources will be reduced.[2]
The relationship between lysine and pellagra is unclear.[3]
# Historical Perspective
The traditional food preparation method of corn, nixtamalization, by native New World cultivators, who had domesticated corn, required treatment of the grain with lime, an alkali. It has now been shown that the lime treatment makes niacin nutritionally available and reduces the chance of developing pellagra. When corn cultivation was adopted worldwide, this preparation method was not accepted because the benefit was not understood. The original cultivators, often heavily dependent on corn, did not suffer from pellagra. Pellagra became common only when corn became a staple that was eaten without the traditional treatment.
Pellagra was first described in Spain in 1735 by Gaspar Casal, who published a first clinical description in his posthumous "Natural and Medical History of the Asturian Pricipality" (1762). This led to the disease being knownn as "Asturian leprosy", and it is recognised as the first modern pathological description of a syndrome(1). It was an endemic disease in northern Italy, where it was named "pelle agra" (pelle = skin; agra = rough) by Francesco Frapoli of Milan.[4] Because pellagra outbreaks occurred in regions where maize was a dominant food crop, the belief for centuries was that the maize either carried a toxic substance or was a carrier of disease. It was not until later that the lack of pellagra outbreaks in Mesoamerica, where maize is a major food crop (and is processed), that the idea was considered that the causes of pellagra may be due to factors other than toxins.
In the early 1900s, pellagra reached epidemic proportions in the American South. There were 1,306 reported pellagra deaths in South Carolina during the first ten months of 1915; 100,000 Southerners were affected in 1916. At this time, the scientific community held that pellagra was probably caused by a germ or some unknown toxin in corn.[5] The Spartanburg Pellagra Hospital in Spartanburg, South Carolina, was the nation's first facility dedicated to discovering the cause of pellagra. It was established in 1914 with a special congressional appropriation to the U.S. Public Health Service (PHS) and set up primarily for research. In 1915 Joseph Goldberger, assigned to study pellagra by the Surgeon General of the United States, showed that pellagra was linked to diet by inducing the disease in prisoners, using the Spartanburg Pellagra Hospital as his clinic. By 1926, Goldberger established that a balanced diet or a small amount of baker's yeast prevented pellagra. Skepticism still persisted in the medical community until 1937 when Conrad Elvehjem showed that the vitamin niacin cured pellagra (manifested as black tongue) in dogs. Later studies by Tom Spies, Marion Blankenhorn and Clark Cooper established that niacin also cured pellagra in humans, for which Time Magazine dubbed them its 1938 Men of the Year in comprehensive science.
# Classification
# Pathophysiology
# Causes
## Drug Causes
- Isoniazid
# Differentiating Pellagra from Other Diseases
# Epidemiology and Demographics
Pellagra can be common in people who obtain most of their food energy from maize, since untreated corn is a poor source of niacin (vitamin B3). Corn is also a poor source of tryptophan. This disease can be common among people who live in rural South America where corn is a staplea. The symptoms usually appear during spring, increase in the summer due to greater sun exposure, and return the following spring. It is also one of several diseases of malnutrition common in Africa, and was endemic in the poorer states of the U.S. south like Mississippi and Alabama as well as among the inmates of jails and orphanages, where it was studied by Joseph Goldberger who conducted experiments in the penal colony in Rankin. Alkali treatment of the corn corrects the niacin deficiency, and was a common practice in native American cultures that grew corn. The amino acid deficiency must be balanced by consumption of other sources of protein. It was also common amongst prisoners of Soviet labor camps, the infamous Gulag. Also found in cases of chronic alcoholism.
# Risk Factors
# Screening
# Natural History, Complications, and Prognosis
## Natural History
## Complications
## Prognosis
# Diagnosis
## Diagnostic Criteria
## History and Symptoms
# Symptoms
The symptoms of pellagra include:
- High sensitivity to sunlight
- Aggression
- Dermatitis
- Smooth, beefy red glossitis
- Red skin lesions
- Insomnia
- Weakness
- Mental confusion
- Diarrhea
- Eventually dementia
The main results of pellagra can easily be remembered as "the four D's": diarrhea, dermatitis, dementia, and death.[6]
## Physical Examination
# Physical Examination
### Skin
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
- Pellagra. With permission from Dermatology Atlas.[7]
## Laboratory Findings
## Imaging Findings
## Other Diagnostic Studies
# Treatment
## Medical Therapy
## Surgery
## Prevention | https://www.wikidoc.org/index.php/Niacin_deficiency | |
8861f6222416d3374150039b2f6580401a69614b | wikidoc | Nicoderm | Nicoderm
NicoDerm, also known as NicoDerm CQ (short for Committed Quit or Committed Quitter) is a branded over the counter palliative nicotine replacement therapy which is used to ameliorate the withdrawal effects involved in quitting smoking.
Alternative brand names include Prostep®, Habitrol®, NiQuitin®, Nicotrol®, Nicorette, and Commit®.
# History
NicoDerm is manufactured by ALZA Corporation, based in Mountain View, California. It is marketed by GlaxoSmithKline (GSK), Aventis and Pfizer.
NicoDerm was approved by the FDA in 1991, touted as the original "nicotine transdermal system."
NicoDerm was the second product to provide an alternative to the withdrawal symptoms of quitting smoking. Nicotine gums, such as Pfizer's Nicotrol gum (no longer in production) were already quite popular with consumers.
Shortly after NicoDerm's release, Clear NicoDerm was released, as some users complained about the patch's inability to match a wide variety of skin colors. Over the past several years, NicoDerm has become the most popular topical nicotine alternative.
Also shortly after NicoDerm's release, many other pharmaceutical companies began releasing many nicotine replacement therapies, such as Nicotrol, which for a time encompassed Pfizer's entire line of products, including Nicotine gum, lozenges, inhalers and nasal sprays. Of the Pfizer line of products, the Nicotrol inhaler and nasal spray are the only two products that appear to still be in production.
# Functioning
Unlike adhesive bandages, topical patches generally use a solid plastic backing, occasionally with a fabric covering on the outside to look like an adhesive bandage. Topical patches also use a much stronger adhesive, allowing them to maintain their hold without having to wrap around to themselves, be covered or taped.
Like any other topical patch currently available on the market right now, NicoDerm's adhesive also mediates the release of the medication through the skin.
NicoDerm comes in 3 different variations ranging from 7 mg to 21 mg. The main difference between each level is not the amount of nicotine placed between the backing and the adhesive, but the size of the patch. This is due to the nature of the adhesive. For the adhesive to maintain its hold properly, the consistency of it must remain the same, thereby allowing only a specific amount of nicotine through. | Nicoderm
NicoDerm, also known as NicoDerm CQ (short for Committed Quit or Committed Quitter) is a branded over the counter palliative nicotine replacement therapy which is used to ameliorate the withdrawal effects involved in quitting smoking.
Alternative brand names include Prostep®, Habitrol®, NiQuitin®, Nicotrol®, Nicorette, and Commit®.
# History
NicoDerm is manufactured by ALZA Corporation, based in Mountain View, California. It is marketed by GlaxoSmithKline (GSK), Aventis and Pfizer.
NicoDerm was approved by the FDA in 1991, touted as the original "nicotine transdermal system."
NicoDerm was the second product to provide an alternative to the withdrawal symptoms of quitting smoking. Nicotine gums, such as Pfizer's Nicotrol gum (no longer in production) were already quite popular with consumers.
Shortly after NicoDerm's release, Clear NicoDerm was released, as some users complained about the patch's inability to match a wide variety of skin colors. Over the past several years, NicoDerm has become the most popular topical nicotine alternative.
Also shortly after NicoDerm's release, many other pharmaceutical companies began releasing many nicotine replacement therapies, such as Nicotrol, which for a time encompassed Pfizer's entire line of products, including Nicotine gum, lozenges, inhalers and nasal sprays. Of the Pfizer line of products, the Nicotrol inhaler and nasal spray are the only two products that appear to still be in production.
# Functioning
Unlike adhesive bandages, topical patches generally use a solid plastic backing, occasionally with a fabric covering on the outside to look like an adhesive bandage. Topical patches also use a much stronger adhesive, allowing them to maintain their hold without having to wrap around to themselves, be covered or taped.
Like any other topical patch currently available on the market right now, NicoDerm's adhesive also mediates the release of the medication through the skin.
NicoDerm comes in 3 different variations ranging from 7 mg to 21 mg. The main difference between each level is not the amount of nicotine placed between the backing and the adhesive, but the size of the patch. This is due to the nature of the adhesive. For the adhesive to maintain its hold properly, the consistency of it must remain the same, thereby allowing only a specific amount of nicotine through. | https://www.wikidoc.org/index.php/Nicoderm | |
aa17f713693b9e4ee9c70325db84b30d7677591a | wikidoc | Nicotine | Nicotine
# Overview
Nicotine is a potent parasympathomimetic alkaloid found in the nightshade family of plants (Solanaceae) and a stimulant drug. Nicotine is a nicotinic acetylcholine receptor (nAChR) agonist, except at nAChRα9 and nAChRα10 where it acts as an antagonist. It is made in the roots of and accumulates in the leaves of the nightshade family of plants.
It constitutes approximately 0.6–3.0% of the dry weight of tobacco and is present in the range of 2–7 µg/kg of various edible plants.
It functions as an antiherbivore chemical; consequently, nicotine was widely used as an insecticide in the past
and nicotine analogs such as imidacloprid are currently widely used.
In lesser doses (an average cigarette yields about 2 mg of absorbed nicotine), the substance acts as a stimulant in mammals, while high amounts (50–100 mg) can be harmful.
This stimulant effect is a major contributing factor to the addictive properties of tobacco smoking.
# Uses
## Medical
The primary therapeutic use of nicotine is in treating nicotine dependence in order to eliminate smoking with the damage it does to health. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges, electronic/substitute cigarettes or nasal sprays in an effort to wean them off their dependence.
Studies have found that these therapies increase the chance of success of quitting by 50 to 70%, though reductions in the population as a whole has not been demonstrated.
## Enhancing performance
Nicotine is frequently used for its performance enhancing effects on cognition, alertness and focus. It is second only to caffeine as the most widely used nootropic in the world.
## Recreational
Nicotine is commonly consumed as a recreational drug for its stimulant effects.
# Psychoactive effects
Nicotine's mood-altering effects are different by report: in particular it is both a stimulant and a relaxant. First causing a release of glucose from the liver and epinephrine (adrenaline) from the adrenal medulla, it causes stimulation. Users report feelings of relaxation, sharpness, calmness, and alertness. Like any stimulant, it may very rarely cause the often uncomfortable neuropsychiatric effect of akathisia. By reducing the appetite and raising the metabolism, some smokers may lose weight as a consequence.
When a cigarette is smoked, nicotine-rich blood passes from the lungs to the brain within seven seconds and immediately stimulates the release of many chemical messengers such as acetylcholine, norepinephrine, epinephrine, arginine vasopressin, serotonin, dopamine, and beta-endorphin. This release of neurotransmitters and hormones is responsible for most of nicotine's psychoactive effects. Nicotine appears to enhance concentration and memory due to the increase of acetylcholine. It also appears to enhance alertness due to the increases of acetylcholine and norepinephrine. Arousal is increased by the increase of norepinephrine. Pain is reduced by the increases of acetylcholine and beta-endorphin. Anxiety is reduced by the increase of beta-endorphin. Nicotine also extends the duration of positive effects of dopamine and increases sensitivity in brain reward systems. Most cigarettes (in the smoke inhaled) contain 1 to 3 milligrams of nicotine.
Studies suggest that when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine. This stimulates nerve transmission. When they wish to relax, they take deep puffs, which produce a higher level of blood nicotine, which depresses the passage of nerve impulses, producing a mild sedative effect. At low doses, nicotine potently enhances the actions of norepinephrine and dopamine in the brain, causing a drug effect typical of those of psychostimulants. At higher doses, nicotine enhances the effect of serotonin and opiate activity, producing a calming, pain-killing effect. Nicotine is unique in comparison to most drugs, as its profile changes from stimulant to sedative/pain killer in increasing dosages and use, a phenomenon described by Paul Nesbitt in his doctoral dissertation and subsequently referred to as "Nesbitt's Paradox".
# Adverse effects
## Vascular system
Nicotine increases blood pressure and heart rate. Nicotine can also induce potentially atherogenic genes in human coronary artery endothelial cells. Microvascular injury can result through its action on nicotinic acetylcholine receptors (nAChRs).
## Carcinogen
Historically, nicotine has not been regarded as a carcinogen. The IARC has not evaluated nicotine in its standalone form or assigned it to an official carcinogen group. While no epidemiological evidence supports that nicotine alone acts as a carcinogen in the formation of human cancer, research over the last decade has identified nicotine's carcinogenic potential in animal models and cell culture. Indirectly, nicotine increases cholinergic signalling (and adrenergic signalling in the case of colon cancer), thereby impeding apoptosis (programmed cell death), promoting tumor growth, and activating growth factors and cellular mitogenic factors such as 5-LOX, and EGF. Nicotine also promotes cancer growth by stimulating angiogenesis and neovascularization. In one study, nicotine administered to mice with tumors caused increases in tumor size (twofold increase), metastasis (nine-fold increase), and tumor recurrence (threefold increase). N-Nitrosonornicotine (NNN), classified by the IARC as a Group 1 carcinogen, has been shown to form in vitro in amounts less than 0.01% the active substance, when human saliva is incurbated with nornicotine.
Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis.
## Fetal development
In pregnancy, a 2013 review noted that "nicotine is only 1 of more than 4000 compounds to which the fetus is exposed through maternal smoking. Of these, ∼30 compounds have been associated with adverse health outcomes. Although the exact mechanisms by which nicotine produces adverse fetal effects are unknown, it is likely that hypoxia, undernourishment of the fetus, and direct vasoconstrictor effects on the placental and umbilical vessels all play a role. Nicotine also has been shown to have significant deleterious effects on brain development, including alterations in brain metabolism and neurotransmitter systems and abnormal brain development." It also notes that "abnormalities of newborn neurobehavior, including impaired orientation and autonomic regulation and abnormalities of muscle tone, have been identified in a number of prenatal nicotine exposure studies" and that there is weak data associating fetal nicotine exposure with newborn facial clefts, and that there is no good evidence for newborns suffering nicotine withdrawal from fetal exposure to nicotine.
Effective April 1, 1990, the Office of Environmental Health Hazard Assessment (OEHHA) of the California Environmental Protection Agency added nicotine to the list of chemicals known to cause developmental toxicity.
## Dependence and withdrawal
Difficulty concentrating and deficits in task performance are symptoms of nicotine withdrawal. These symptoms begin as soon as 30 minutes after tobacco cessation begins, and can last for several weeks.
Nicotine appears to have significant performance enhancing effects, particularly in fine motor skills, attention, and memory. These beneficial cognitive effects may play a role in the initiation and maintenance of tobacco dependence.
Studies suggest a correlation between smoking and schizophrenia, with estimates near 75% for the proportion of schizophrenic patients who smoke. Although the nature of this association remains unclear, it has been argued that the increased level of smoking in schizophrenia may be due to a desire to self-medicate with nicotine. Other research found that mildly dependent users got some benefit from nicotine, but not those who were highly dependent.
# Overdose
The Template:LD50 of nicotine is 50 mg/kg for rats and 3 mg/kg for mice. 30–60 mg (0.5–1.0 mg/kg) can be a lethal dosage for adult humans. However the widely used human LD50 estimate of 0.5–1.0 mg/kg was questioned in a 2013 review, in light of several documented cases of humans surviving much higher doses; the 2013 review suggests that the lower limit causing fatal outcomes is 500–1000 mg of ingested nicotine, corresponding to 6.5–13 mg/kg orally. Nevertheless nicotine has a relatively high toxicity in comparison to many other alkaloids such as caffeine, which has an LD50of 127 mg/kg when administered to mice.
It is unlikely that a person would overdose on nicotine through smoking alone, the US Food and Drug Administration (FDA) states in 2013 "There are no significant safety concerns associated with using more than one OTC NRT at the same time, or using an OTC NRT at the same time as another nicotine-containing product—including a cigarette." Spilling a high concentration of nicotine onto the skin can cause intoxication or even death, since nicotine readily passes into the bloodstream following dermal contact.
## Addiction
Nicotine is addictive. Nicotine activates the mesolimbic pathway and induces long-term ΔFosB expression in the nucleus accumbens when inhaled or injected, but not necessarily when ingested. Consequently, repeated daily exposure (possibly excluding oral route) to nicotine can result in accumbal ΔFosB overexpression, in turn causing nicotine addiction.
# Pharmacology
## Pharmacodynamics
### Central nervous system
By binding to nicotinic acetylcholine receptors, nicotine increases the levels of several neurotransmitters – acting as a sort of "volume control". It is thought that increased levels of dopamine in the reward circuits of the brain are a major contributor to the apparent euphoria and relaxation, and addiction caused by nicotine consumption. Nicotine-induced dopamine release occurs via the cholinergic–dopaminergic reward link, which is mediated by the neuropeptide ghrelin in the ventral tegmentum. Nicotine has a higher affinity for acetylcholine receptors in the brain than those in skeletal muscle, though at toxic doses it can induce contractions and respiratory paralysis. Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.
Tobacco smoke contains anabasine, anatabine, and nornicotine. It also contains the monoamine oxidase inhibitors harman and norharman. These beta-carboline compounds significantly decrease MAO activity in smokers. MAO enzymes break down monoaminergic neurotransmitters such as dopamine, norepinephrine, and serotonin. It is thought that the powerful interaction between the MAOIs and the nicotine is responsible for most of the addictive properties of tobacco smoking. The addition of five minor tobacco alkaloids increases nicotine-induced hyperactivity, sensitization and intravenous self-administration in rats.
Chronic nicotine exposure via tobacco smoking up-regulates alpha4beta2- nAChR in cerebellum and brainstem regions but not habenulopeduncular structures. Alpha4beta2 and alpha6beta2 receptors, present in the ventral tegmental area, play a crucial role in mediating the reinforcement effects of nicotine.
Research published in 2011 found that nicotine inhibits class I and II histone deacetylases, chromatin-modifying enzymes involved in epigenetics. This inhibition has been shown to increase susceptibility to cocaine addiction in rodents.
### Sympathetic nervous system
Nicotine also activates the sympathetic nervous system, acting via splanchnic nerves to the adrenal medulla, stimulating the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing the release of epinephrine (and noradrenaline) into the bloodstream. Nicotine also has an affinity for melanin-containing tissues due to its precursor function in melanin synthesis or due to the irreversible binding of melanin and nicotine. This has been suggested to underlie the increased nicotine dependence and lower smoking cessation rates in darker pigmented individuals. However, further research is warranted before a definite conclusive link can be inferred.
### Adrenal medulla
By binding to ganglion type nicotinic receptors in the adrenal medulla, nicotine increases flow of adrenaline (epinephrine), a stimulating hormone and neurotransmitter. By binding to the receptors, it causes cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and thus the release of epinephrine (and norepinephrine) into the bloodstream. The release of epinephrine (adrenaline) causes an increase in heart rate, blood pressure and respiration, as well as higher blood glucose levels.
Nicotine has a half-life of 1 to 2 hours. Cotinine is an active metabolite of nicotine that remains in the blood for 18 to 20 hours, making it easier to analyze due to its longer half-life.
## Pharmacokinetics
As nicotine enters the body, it is distributed quickly through the bloodstream and crosses the blood–brain barrier reaching the brain within 10–20 seconds after inhalation. The elimination half-life of nicotine in the body is around two hours.
The amount of nicotine absorbed by the body from smoking can depend on many factors, including the types of tobacco, whether the smoke is inhaled, and whether a filter is used. However, it has been found that the nicotine yield of individual products has only a small effect (4.4%) on the blood concentration of nicotine, suggesting "the assumed health advantage of switching to lower-tar and lower-nicotine cigarettes may be largely offset by the tendency of smokers to compensate by increasing inhalation".
Nicotine acts on nicotinic acetylcholine receptors, specifically the α3β4 ganglion type nicotinic receptor, present in the autonomic ganglia and adrenal medulla, and a central nervous system (CNS) α4β2 nicotinic receptor. In small concentrations, nicotine increases the activity of these cholinergic receptors and indirectly on a variety of other neurotransmitters such as dopamine.
Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine. Other primary metabolites include nicotine N'-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine and nicotine glucuronide. Under some conditions, other substances may be formed such as myosmine.
Glucuronidation and oxidative metabolism of nicotine to cotinine are both inhibited by menthol, an additive to mentholated cigarettes, thus increasing the half-life of nicotine in vivo.
# Physical and chemical properties
Nicotine is a hygroscopic, colorless oily liquid that is readily soluble in alcohol, ether or light petroleum. It is miscible with water in its base form between 60 °C and 210 °C. As a nitrogenous base, nicotine forms salts with acids that are usually solid and water soluble. Its flash point is 95 °C and its auto-ignition temperature is 244 °C.
Nicotine is optically active, having two enantiomeric forms. The naturally occurring form of nicotine is levorotatory with a specific rotation of D = –166.4° ((−)-nicotine). The dextrorotatory form, (+)-nicotine is physiologically less active than (–)-nicotine. (−)-nicotine is more toxic than (+)-nicotine. The salts of (+)-nicotine are usually dextrorotatory. The hydrochloride and sulphate salts become optically inactive if heated in a closed vessel above 180 °C.
On exposure to ultraviolet light or various oxidizing agents, nicotine is converted to nicotine oxide, nicotinic acid (vitamin B3), and methylamine.
## Occurrence and biosynthesis
Nicotine is a natural product of tobacco, occurring in the leaves in a range of 0.5 to 7.5% depending on variety. Nicotine also naturally occurs in smaller amounts in plants from the family Solanaceae (such as potatoes, tomatoes, and eggplant).
The biosynthetic pathway of nicotine involves a coupling reaction between the two cyclic structures that compose nicotine. Metabolic studies show that the pyridine ring of nicotine is derived from niacin (nicotinic acid) while the pyrrolidone is derived from N-methyl-Δ1-pyrrollidium cation. Biosynthesis of the two component structures proceeds via two independent syntheses, the NAD pathway for niacin and the tropane pathway for N-methyl-Δ1-pyrrollidium cation.
The NAD pathway in the genus nicotiana begins with the oxidation of aspartic acid into α-imino succinate by aspartate oxidase (AO). This is followed by a condensation with glyceraldehyde-3-phosphate and a cyclization catalyzed by quinolinate synthase (QS) to give quinolinic acid. Quinolinic acid then reacts with phosphoriboxyl pyrophosphate catalyzed by quinolinic acid phosphoribosyl transferase (QPT) to form niacin mononucleotide (NaMN). The reaction now proceeds via the NAD salvage cycle to produce niacin via the conversion of nicotinamide by the enzyme nicotinamidase.
The N-methyl-Δ1-pyrrollidium cation used in the synthesis of nicotine is an intermediate in the synthesis of tropane-derived alkaloids. Biosynthesis begins with decarboxylation of ornithine by ornithine decarboxylase (ODC) to produce putrescine. Putrescine is then converted into N-methyl putrescine via methylation by SAM catalyzed by putrescine N-methyltransferase (PMT). N-methylputrescine then undergoes deamination into 4-methylaminobutanal by the N-methylputrescine oxidase (MPO) enzyme, 4-methylaminobutanal then spontaneously cyclize into N-methyl-Δ1-pyrrollidium cation.
The final step in the synthesis of nicotine is the coupling between N-methyl-Δ1-pyrrollidium cation and niacin. Although studies conclude some form of coupling between the two component structures, the definite process and mechanism remains undetermined. The current agreed theory involves the conversion of niacin into 2,5-dihydropyridine through 3,6-dihydronicotinic acid. The 2,5-dihydropyridine intermediate would then react with N-methyl-Δ1-pyrrollidium cation to form enantiomerically pure (–)-nicotine.
## Measurement in body fluids
Nicotine can be quantified in blood, plasma, or urine to confirm a diagnosis of poisoning or to facilitate a medicolegal death investigation. Urinary or salivary cotinine concentrations are frequently measured for the purposes of pre-employment and health insurance medical screening programs. Careful interpretation of results is important, since passive exposure to cigarette smoke can result in significant accumulation of nicotine, followed by the appearance of its metabolites in various body fluids. Nicotine use is not regulated in competitive sports programs.
# History
Nicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after the French ambassador in Portugal, Jean Nicot de Villemain, who sent tobacco and seeds to Paris in 1560, presented to the French King, and who promoted their medicinal use. The tobacco and its seeds were brought to Ambassador Nicot from Brazil by Luis de Gois, a Portuguese colonist in São Paulo.Smoking was believed to protect against illness, particularly the plague.
Tobacco was introduced to Europe in 1559, and by the late 17th century, it was used not only for smoking but also as an insecticide. After World War II, over 2,500 tons of nicotine insecticide were used worldwide, but by the 1980s the use of nicotine insecticide had declined below 200 tons. This was due to the availability of other insecticides that are cheaper and less harmful to mammals.
Currently, nicotine, even in the form of tobacco dust, is prohibited as a pesticide for organic farming in the United States.
In 2008, the EPA received a request, from the registrant, to cancel the registration of the last nicotine pesticide registered in the United States. This request was granted, and since 1 January 2014, this pesticide has not been available for sale.
## Chemical identification
Nicotine was first isolated from the tobacco plant in 1828 by physician Wilhelm Heinrich Posselt and chemist Karl Ludwig Reimann of Germany, who considered it a poison. Its chemical empirical formula was described by Melsens in 1843, its structure was
discovered by Adolf Pinner and Richard Wolffenstein in 1893, and it was first synthesized by Amé Pictet and A. Rotschy in 1904.
# Society and culture
The nicotine content of popular American-brand cigarettes has slowly increased over the years, and one study found that there was an average increase of 1.78% per year between the years of 1998 and 2005.
# Research
While acute/initial nicotine intake causes activation of nicotine receptors, chronic low doses of nicotine use leads to desensitisation of nicotine receptors (due to the development of tolerance) and results in an antidepressant effect, with research showing low dose nicotine patches being an effective treatment of major depressive disorder in non-smokers., However the original research concluded that: "Nicotine patches produced short-term improvement of depression with minor side effects. Because of nicotine's high risk to health, nicotine patches are not recommended for clinical use in depression."
Though tobacco smoking is associated with an increased risk of Alzheimer's disease, there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease.
Research into nicotine's most predominant metabolite, cotinine, suggests that some, if not most, of nicotine's psychoactive effects may actually be mediated by complex interactions with cotinine, or perhaps even by cotinine alone rather than strictly by nicotine as conventionally thought.
Little research is available in humans but animal research suggests there is potential benefit from nicotine in Parkinson's disease. | Nicotine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Nicotine is a potent parasympathomimetic alkaloid found in the nightshade family of plants (Solanaceae) and a stimulant drug. Nicotine is a nicotinic acetylcholine receptor (nAChR) agonist,[2][3] except at nAChRα9 and nAChRα10 where it acts as an antagonist.[2] It is made in the roots of and accumulates in the leaves of the nightshade family of plants.
It constitutes approximately 0.6–3.0% of the dry weight of tobacco[4] and is present in the range of 2–7 µg/kg of various edible plants.[5]
It functions as an antiherbivore chemical; consequently, nicotine was widely used as an insecticide in the past[6][7]
and nicotine analogs such as imidacloprid are currently widely used.
In lesser doses (an average cigarette yields about 2 mg of absorbed nicotine), the substance acts as a stimulant in mammals, while high amounts (50–100 mg) can be harmful.[8][9][10]
This stimulant effect is a major contributing factor to the addictive properties of tobacco smoking.
# Uses
## Medical
The primary therapeutic use of nicotine is in treating nicotine dependence in order to eliminate smoking with the damage it does to health. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges, electronic/substitute cigarettes or nasal sprays in an effort to wean them off their dependence.
Studies have found that these therapies increase the chance of success of quitting by 50 to 70%,[11] though reductions in the population as a whole has not been demonstrated.[12]
## Enhancing performance
Nicotine is frequently used for its performance enhancing effects on cognition, alertness and focus.[13][14] It is second only to caffeine as the most widely used nootropic in the world.[citation needed]
## Recreational
Nicotine is commonly consumed as a recreational drug for its stimulant effects.[15]
# Psychoactive effects
Nicotine's mood-altering effects are different by report: in particular it is both a stimulant and a relaxant.[16] First causing a release of glucose from the liver and epinephrine (adrenaline) from the adrenal medulla, it causes stimulation. Users report feelings of relaxation, sharpness, calmness, and alertness.[17] Like any stimulant, it may very rarely cause the often uncomfortable neuropsychiatric effect of akathisia. By reducing the appetite and raising the metabolism, some smokers may lose weight as a consequence.[18][19]
When a cigarette is smoked, nicotine-rich blood passes from the lungs to the brain within seven seconds and immediately stimulates the release of many chemical messengers such as acetylcholine, norepinephrine, epinephrine, arginine vasopressin, serotonin, dopamine, and beta-endorphin.[20][21] This release of neurotransmitters and hormones is responsible for most of nicotine's psychoactive effects. Nicotine appears to enhance concentration[22] and memory due to the increase of acetylcholine. It also appears to enhance alertness due to the increases of acetylcholine and norepinephrine. Arousal is increased by the increase of norepinephrine. Pain is reduced by the increases of acetylcholine and beta-endorphin. Anxiety is reduced by the increase of beta-endorphin. Nicotine also extends the duration of positive effects of dopamine[23] and increases sensitivity in brain reward systems.[24] Most cigarettes (in the smoke inhaled) contain 1 to 3 milligrams of nicotine.[25]
Studies suggest that when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine.[26] This stimulates nerve transmission. When they wish to relax, they take deep puffs, which produce a higher level of blood nicotine, which depresses the passage of nerve impulses, producing a mild sedative effect. At low doses, nicotine potently enhances the actions of norepinephrine and dopamine in the brain, causing a drug effect typical of those of psychostimulants. At higher doses, nicotine enhances the effect of serotonin and opiate activity, producing a calming, pain-killing effect. Nicotine is unique in comparison to most drugs, as its profile changes from stimulant to sedative/pain killer in increasing dosages and use, a phenomenon described by Paul Nesbitt in his doctoral dissertation[27] and subsequently referred to as "Nesbitt's Paradox".[28]
# Adverse effects
## Vascular system
Nicotine increases blood pressure and heart rate.[29] Nicotine can also induce potentially atherogenic genes in human coronary artery endothelial cells.[30] Microvascular injury can result through its action on nicotinic acetylcholine receptors (nAChRs).[31]
## Carcinogen
Historically, nicotine has not been regarded as a carcinogen.[32] The IARC has not evaluated nicotine in its standalone form or assigned it to an official carcinogen group. While no epidemiological evidence supports that nicotine alone acts as a carcinogen in the formation of human cancer, research over the last decade has identified nicotine's carcinogenic potential in animal models and cell culture.[33][34][35] Indirectly, nicotine increases cholinergic signalling (and adrenergic signalling in the case of colon cancer[36]), thereby impeding apoptosis (programmed cell death), promoting tumor growth, and activating growth factors and cellular mitogenic factors such as 5-LOX, and EGF. Nicotine also promotes cancer growth by stimulating angiogenesis and neovascularization.[37][38] In one study, nicotine administered to mice with tumors caused increases in tumor size (twofold increase), metastasis (nine-fold increase), and tumor recurrence (threefold increase).[39] N-Nitrosonornicotine (NNN), classified by the IARC as a Group 1 carcinogen, has been shown to form in vitro in amounts less than 0.01% the active substance, when human saliva is incurbated with nornicotine.[40]
Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis.[41]
## Fetal development
In pregnancy, a 2013 review noted that "nicotine is only 1 of more than 4000 compounds to which the fetus is exposed through maternal smoking. Of these, ∼30 compounds have been associated with adverse health outcomes. Although the exact mechanisms by which nicotine produces adverse fetal effects are unknown, it is likely that hypoxia, undernourishment of the fetus, and direct vasoconstrictor effects on the placental and umbilical vessels all play a role. Nicotine also has been shown to have significant deleterious effects on brain development, including alterations in brain metabolism and neurotransmitter systems and abnormal brain development." It also notes that "abnormalities of newborn neurobehavior, including impaired orientation and autonomic regulation and abnormalities of muscle tone, have been identified in a number of prenatal nicotine exposure studies" and that there is weak data associating fetal nicotine exposure with newborn facial clefts, and that there is no good evidence for newborns suffering nicotine withdrawal from fetal exposure to nicotine.[42]
Effective April 1, 1990, the Office of Environmental Health Hazard Assessment (OEHHA) of the California Environmental Protection Agency added nicotine to the list of chemicals known to cause developmental toxicity.[43]
## Dependence and withdrawal
Difficulty concentrating and deficits in task performance are symptoms of nicotine withdrawal. These symptoms begin as soon as 30 minutes after tobacco cessation begins, and can last for several weeks.[44]
Nicotine appears to have significant performance enhancing effects, particularly in fine motor skills, attention, and memory. These beneficial cognitive effects may play a role in the initiation and maintenance of tobacco dependence.[44]
Studies suggest a correlation between smoking and schizophrenia, with estimates near 75% for the proportion of schizophrenic patients who smoke. Although the nature of this association remains unclear, it has been argued that the increased level of smoking in schizophrenia may be due to a desire to self-medicate with nicotine.[45][46] Other research found that mildly dependent users got some benefit from nicotine, but not those who were highly dependent.[47]
# Overdose
The Template:LD50 of nicotine is 50 mg/kg for rats and 3 mg/kg for mice. 30–60 mg (0.5–1.0 mg/kg) can be a lethal dosage for adult humans.[8][48] However the widely used human LD50 estimate of 0.5–1.0 mg/kg was questioned in a 2013 review, in light of several documented cases of humans surviving much higher doses; the 2013 review suggests that the lower limit causing fatal outcomes is 500–1000 mg of ingested nicotine, corresponding to 6.5–13 mg/kg orally.[10] Nevertheless nicotine has a relatively high toxicity in comparison to many other alkaloids such as caffeine, which has an LD50of 127 mg/kg when administered to mice.[49]
It is unlikely that a person would overdose on nicotine through smoking alone, the US Food and Drug Administration (FDA) states in 2013 "There are no significant safety concerns associated with using more than one OTC NRT at the same time, or using an OTC NRT at the same time as another nicotine-containing product—including a cigarette."[50] Spilling a high concentration of nicotine onto the skin can cause intoxication or even death, since nicotine readily passes into the bloodstream following dermal contact.[51]
## Addiction
Nicotine is addictive.[52][53] Nicotine activates the mesolimbic pathway and induces long-term ΔFosB expression in the nucleus accumbens when inhaled or injected, but not necessarily when ingested.[52][53][54] Consequently, repeated daily exposure (possibly excluding oral route) to nicotine can result in accumbal ΔFosB overexpression, in turn causing nicotine addiction.[52][53]
# Pharmacology
## Pharmacodynamics
### Central nervous system
By binding to nicotinic acetylcholine receptors, nicotine increases the levels of several neurotransmitters – acting as a sort of "volume control". It is thought that increased levels of dopamine in the reward circuits of the brain are a major contributor to the apparent euphoria and relaxation, and addiction caused by nicotine consumption. Nicotine-induced dopamine release occurs via the cholinergic–dopaminergic reward link, which is mediated by the neuropeptide ghrelin in the ventral tegmentum.[55] Nicotine has a higher affinity for acetylcholine receptors in the brain than those in skeletal muscle, though at toxic doses it can induce contractions and respiratory paralysis.[56] Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.[57]
Tobacco smoke contains anabasine, anatabine, and nornicotine. It also contains the monoamine oxidase inhibitors harman and norharman.[58] These beta-carboline compounds significantly decrease MAO activity in smokers.[58][59] MAO enzymes break down monoaminergic neurotransmitters such as dopamine, norepinephrine, and serotonin. It is thought that the powerful interaction between the MAOIs and the nicotine is responsible for most of the addictive properties of tobacco smoking.[60] The addition of five minor tobacco alkaloids increases nicotine-induced hyperactivity, sensitization and intravenous self-administration in rats.[61]
Chronic nicotine exposure via tobacco smoking up-regulates alpha4beta2* nAChR in cerebellum and brainstem regions[62][63] but not habenulopeduncular structures.[64] Alpha4beta2 and alpha6beta2 receptors, present in the ventral tegmental area, play a crucial role in mediating the reinforcement effects of nicotine.[65]
Research published in 2011 found that nicotine inhibits class I and II histone deacetylases, chromatin-modifying enzymes involved in epigenetics. This inhibition has been shown to increase susceptibility to cocaine addiction in rodents.[66][67]
### Sympathetic nervous system
Nicotine also activates the sympathetic nervous system,[68] acting via splanchnic nerves to the adrenal medulla, stimulating the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing the release of epinephrine (and noradrenaline) into the bloodstream. Nicotine also has an affinity for melanin-containing tissues due to its precursor function in melanin synthesis or due to the irreversible binding of melanin and nicotine. This has been suggested to underlie the increased nicotine dependence and lower smoking cessation rates in darker pigmented individuals. However, further research is warranted before a definite conclusive link can be inferred.[69]
### Adrenal medulla
By binding to ganglion type nicotinic receptors in the adrenal medulla, nicotine increases flow of adrenaline (epinephrine), a stimulating hormone and neurotransmitter. By binding to the receptors, it causes cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and thus the release of epinephrine (and norepinephrine) into the bloodstream. The release of epinephrine (adrenaline) causes an increase in heart rate, blood pressure and respiration, as well as higher blood glucose levels.[70]
Nicotine has a half-life of 1 to 2 hours. Cotinine is an active metabolite of nicotine that remains in the blood for 18 to 20 hours, making it easier to analyze due to its longer half-life.[71]
## Pharmacokinetics
As nicotine enters the body, it is distributed quickly through the bloodstream and crosses the blood–brain barrier reaching the brain within 10–20 seconds after inhalation.[72] The elimination half-life of nicotine in the body is around two hours.[73]
The amount of nicotine absorbed by the body from smoking can depend on many factors, including the types of tobacco, whether the smoke is inhaled, and whether a filter is used. However, it has been found that the nicotine yield of individual products has only a small effect (4.4%) on the blood concentration of nicotine,[74] suggesting "the assumed health advantage of switching to lower-tar and lower-nicotine cigarettes may be largely offset by the tendency of smokers to compensate by increasing inhalation".
Nicotine acts on nicotinic acetylcholine receptors, specifically the α3β4 ganglion type nicotinic receptor, present in the autonomic ganglia and adrenal medulla, and a central nervous system (CNS) α4β2 nicotinic receptor. In small concentrations, nicotine increases the activity of these cholinergic receptors and indirectly on a variety of other neurotransmitters such as dopamine.
Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine. Other primary metabolites include nicotine N'-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine and nicotine glucuronide.[75] Under some conditions, other substances may be formed such as myosmine.[76]
Glucuronidation and oxidative metabolism of nicotine to cotinine are both inhibited by menthol, an additive to mentholated cigarettes, thus increasing the half-life of nicotine in vivo.[77]
# Physical and chemical properties
Template:NFPA 704
Nicotine is a hygroscopic, colorless oily liquid that is readily soluble in alcohol, ether or light petroleum. It is miscible with water in its base form between 60 °C and 210 °C. As a nitrogenous base, nicotine forms salts with acids that are usually solid and water soluble. Its flash point is 95 °C and its auto-ignition temperature is 244 °C.[78]
Nicotine is optically active, having two enantiomeric forms. The naturally occurring form of nicotine is levorotatory with a specific rotation of [α]D = –166.4° ((−)-nicotine). The dextrorotatory form, (+)-nicotine is physiologically less active than (–)-nicotine. (−)-nicotine is more toxic than (+)-nicotine.[79] The salts of (+)-nicotine are usually dextrorotatory. The hydrochloride and sulphate salts become optically inactive if heated in a closed vessel above 180 °C.[80]
On exposure to ultraviolet light or various oxidizing agents, nicotine is converted to nicotine oxide, nicotinic acid (vitamin B3), and methylamine.[80]
## Occurrence and biosynthesis
Nicotine is a natural product of tobacco, occurring in the leaves in a range of 0.5 to 7.5% depending on variety.[81] Nicotine also naturally occurs in smaller amounts in plants from the family Solanaceae (such as potatoes, tomatoes, and eggplant).[82]
The biosynthetic pathway of nicotine involves a coupling reaction between the two cyclic structures that compose nicotine. Metabolic studies show that the pyridine ring of nicotine is derived from niacin (nicotinic acid) while the pyrrolidone is derived from N-methyl-Δ1-pyrrollidium cation.[83][84] Biosynthesis of the two component structures proceeds via two independent syntheses, the NAD pathway for niacin and the tropane pathway for N-methyl-Δ1-pyrrollidium cation.
The NAD pathway in the genus nicotiana begins with the oxidation of aspartic acid into α-imino succinate by aspartate oxidase (AO). This is followed by a condensation with glyceraldehyde-3-phosphate and a cyclization catalyzed by quinolinate synthase (QS) to give quinolinic acid. Quinolinic acid then reacts with phosphoriboxyl pyrophosphate catalyzed by quinolinic acid phosphoribosyl transferase (QPT) to form niacin mononucleotide (NaMN). The reaction now proceeds via the NAD salvage cycle to produce niacin via the conversion of nicotinamide by the enzyme nicotinamidase.[citation needed]
The N-methyl-Δ1-pyrrollidium cation used in the synthesis of nicotine is an intermediate in the synthesis of tropane-derived alkaloids. Biosynthesis begins with decarboxylation of ornithine by ornithine decarboxylase (ODC) to produce putrescine. Putrescine is then converted into N-methyl putrescine via methylation by SAM catalyzed by putrescine N-methyltransferase (PMT). N-methylputrescine then undergoes deamination into 4-methylaminobutanal by the N-methylputrescine oxidase (MPO) enzyme, 4-methylaminobutanal then spontaneously cyclize into N-methyl-Δ1-pyrrollidium cation.[citation needed]
The final step in the synthesis of nicotine is the coupling between N-methyl-Δ1-pyrrollidium cation and niacin. Although studies conclude some form of coupling between the two component structures, the definite process and mechanism remains undetermined. The current agreed theory involves the conversion of niacin into 2,5-dihydropyridine through 3,6-dihydronicotinic acid. The 2,5-dihydropyridine intermediate would then react with N-methyl-Δ1-pyrrollidium cation to form enantiomerically pure (–)-nicotine.[85]
## Measurement in body fluids
Nicotine can be quantified in blood, plasma, or urine to confirm a diagnosis of poisoning or to facilitate a medicolegal death investigation. Urinary or salivary cotinine concentrations are frequently measured for the purposes of pre-employment and health insurance medical screening programs. Careful interpretation of results is important, since passive exposure to cigarette smoke can result in significant accumulation of nicotine, followed by the appearance of its metabolites in various body fluids.[86][87] Nicotine use is not regulated in competitive sports programs.[88]
# History
Nicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after the French ambassador in Portugal, Jean Nicot de Villemain, who sent tobacco and seeds to Paris in 1560, presented to the French King,[89] and who promoted their medicinal use. The tobacco and its seeds were brought to Ambassador Nicot from Brazil by Luis de Gois, a Portuguese colonist in São Paulo.[citation needed]Smoking was believed to protect against illness, particularly the plague.[89]
Tobacco was introduced to Europe in 1559, and by the late 17th century, it was used not only for smoking but also as an insecticide. After World War II, over 2,500 tons of nicotine insecticide were used worldwide, but by the 1980s the use of nicotine insecticide had declined below 200 tons. This was due to the availability of other insecticides that are cheaper and less harmful to mammals.[7]
Currently, nicotine, even in the form of tobacco dust, is prohibited as a pesticide for organic farming in the United States.[90][91]
In 2008, the EPA received a request, from the registrant, to cancel the registration of the last nicotine pesticide registered in the United States.[92] This request was granted, and since 1 January 2014, this pesticide has not been available for sale.[93]
## Chemical identification
Nicotine was first isolated from the tobacco plant in 1828 by physician Wilhelm Heinrich Posselt and chemist Karl Ludwig Reimann of Germany, who considered it a poison.[94][95] Its chemical empirical formula was described by Melsens in 1843,[96] its structure was
discovered by Adolf Pinner and Richard Wolffenstein in 1893,[97][98][99][clarification needed] and it was first synthesized by Amé Pictet and A. Rotschy in 1904.[100]
# Society and culture
The nicotine content of popular American-brand cigarettes has slowly increased over the years, and one study found that there was an average increase of 1.78% per year between the years of 1998 and 2005.[101]
# Research
While acute/initial nicotine intake causes activation of nicotine receptors, chronic low doses of nicotine use leads to desensitisation of nicotine receptors (due to the development of tolerance) and results in an antidepressant effect, with research showing low dose nicotine patches being an effective treatment of major depressive disorder in non-smokers.,[102] However the original research concluded that: "Nicotine patches produced short-term improvement of depression with minor side effects. Because of nicotine's high risk to health, nicotine patches are not recommended for clinical use in depression."[103]
Though tobacco smoking is associated with an increased risk of Alzheimer's disease,[104] there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease.[105]
Research into nicotine's most predominant metabolite, cotinine, suggests that some, if not most, of nicotine's psychoactive effects may actually be mediated by complex interactions with cotinine, or perhaps even by cotinine alone rather than strictly by nicotine as conventionally thought.[106][107]
Little research is available in humans but animal research suggests there is potential benefit from nicotine in Parkinson's disease.[108] | https://www.wikidoc.org/index.php/Nicotine | |
a394cbf73be5058413d8fe1b94545a7776799ce9 | wikidoc | Nocardia | Nocardia
# Overview
Nocardia is a genus of Gram-positive, catalase-positive, rod-shaped bacteria; some species are pathogenic (nocardiosis). Nocardia are found worldwide in soil that is rich with organic matter. Most Nocardia infections are acquired by inhalation of the bacteria or through traumatic introduction.
# Culture and staining
Nocardia colonies have a variable appearance, but most species appear to have aerial hyphae when viewed with a dissecting microscope, particularly when they have been grown on nutritionally-limiting media. Nocardia grow slowly on non-selective culture media, and are strict aerobes with the ability to grow in a wide temperature range. Some species are partially acid fast due to the presence of intermediate-length mycolic acids in their cell wall.
# Virulence
The various species of Nocardia are pathogenic bacteria with low virulence; therefore clinically significant disease most frequently occurs as an opportunistic infection in those with a weak immune system, such as small children, the elderly, and the immunocompromised. Nocardial virulence factors are the enzymes catalase and superoxide dismutase (which inactive reactive oxygen species that would otherwise prove toxic to the bacteria), as well as a "cord factor" (which interferes with phagocytosis by macrophages by preventing the fusion of the phagosome with the lysosome).
# Clinical disease
Nocardia asteroides is the species of Nocardia most frequently infecting humans, and most cases occur as an opportunistic infection in immunocompromised patents.
The most common form of human nocardial disease is a slowly progressive pneumonia, whose common symptoms include cough, dyspnoea (shortness of breath), and fever. It is not uncommon for this infection to spread to the pleura. Pre-existing pulmonary disease, especially pulmonary alveolar proteinosis, increases the risk of contracting a Nocardia pneumonia.
Nocardia may also cause a variety of cutaneous infections such as actinomycetoma (especially Nocardia brasiliensis), lymphocutaneous disease, cellulitis and subcutaneous abscesses.
About 33% of people with Nocardia infection, this will take the form of encephalitis and/or cerebral abscess formation.
# Treatment
Antibiotic therapy with a sulfonamide is the treatment of choice. The most common sulfonamide used is trimethoprim-sulfamethoxazole. People who take trimethoprim-sulfamethoxazole for other reasons, such as prevention of pneumocystis jiroveci infection in AIDS, have fewer nocardia infections. High-dose imipenem and amikacin have also been used in refractory cases. Antibiotic therapy may have to be continued for six months to a year. Proper wound care is also critical.
# Genetics
Despite that Nocardia has interesting and important features such as production of antibiotics and aromatic compound-degrading or converting enzymes, the genetic study of this organism has been hampered by the lack of genetic tools. However, practical Nocardia–E. coli shuttle vectors have been developed recently. | Nocardia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Nocardia is a genus of Gram-positive, catalase-positive, rod-shaped bacteria; some species are pathogenic (nocardiosis).[1] Nocardia are found worldwide in soil that is rich with organic matter. Most Nocardia infections are acquired by inhalation of the bacteria or through traumatic introduction.
# Culture and staining
Nocardia colonies have a variable appearance, but most species appear to have aerial hyphae when viewed with a dissecting microscope, particularly when they have been grown on nutritionally-limiting media. Nocardia grow slowly on non-selective culture media, and are strict aerobes with the ability to grow in a wide temperature range. Some species are partially acid fast due to the presence of intermediate-length mycolic acids in their cell wall.
# Virulence
The various species of Nocardia are pathogenic bacteria with low virulence; therefore clinically significant disease most frequently occurs as an opportunistic infection in those with a weak immune system, such as small children, the elderly, and the immunocompromised. Nocardial virulence factors are the enzymes catalase and superoxide dismutase (which inactive reactive oxygen species that would otherwise prove toxic to the bacteria), as well as a "cord factor" (which interferes with phagocytosis by macrophages by preventing the fusion of the phagosome with the lysosome).
# Clinical disease
Nocardia asteroides is the species of Nocardia most frequently infecting humans, and most cases occur as an opportunistic infection in immunocompromised patents.
The most common form of human nocardial disease is a slowly progressive pneumonia, whose common symptoms include cough, dyspnoea (shortness of breath), and fever. It is not uncommon for this infection to spread to the pleura. Pre-existing pulmonary disease, especially pulmonary alveolar proteinosis, increases the risk of contracting a Nocardia pneumonia.
Nocardia may also cause a variety of cutaneous infections such as actinomycetoma (especially Nocardia brasiliensis), lymphocutaneous disease, cellulitis and subcutaneous abscesses.
About 33% of people with Nocardia infection, this will take the form of encephalitis and/or cerebral abscess formation.
# Treatment
Antibiotic therapy with a sulfonamide is the treatment of choice. The most common sulfonamide used is trimethoprim-sulfamethoxazole. People who take trimethoprim-sulfamethoxazole for other reasons, such as prevention of pneumocystis jiroveci infection in AIDS, have fewer nocardia infections. High-dose imipenem and amikacin have also been used in refractory cases. Antibiotic therapy may have to be continued for six months to a year. Proper wound care is also critical.
# Genetics
Despite that Nocardia has interesting and important features such as production of antibiotics and aromatic compound-degrading or converting enzymes, the genetic study of this organism has been hampered by the lack of genetic tools. However, practical Nocardia–E. coli shuttle vectors have been developed recently.[2] | https://www.wikidoc.org/index.php/Nocardia | |
0484f80e2f3b83e9b9d417deacd80485e2641664 | wikidoc | Nonmetal | Nonmetal
Nonmetal is a term used in chemistry when classifying the chemical elements. On the basis of their general physical and chemical properties, every element in the periodic table can be termed either a metal or a non-metal. (A few elements with intermediate properties are referred to as metalloids.)
The elements generally regarded as nonmetals are:
- hydrogen (H)
- In Group 14: carbon (C)
- In Group 15 (the pnictogens): nitrogen (N), phosphorus (P)
- Several elements in Group 16, the chalcogens: oxygen (O), sulfur (S), selenium (Se)
- All elements in Group 17 - the halogens
- All elements in Group 18 - the noble gases
There is no rigorous definition for the term "nonmetal" - it covers a general spectrum of behaviour. Common properties considered characteristic of a nonmetal include:
- poor conductors of heat and electricity when compared to metals
- they form acidic oxides (whereas metals generally form basic oxides)
- in solid form, they are dull and brittle, rather than metals which are lustrous, ductile or malleable
- usually have lower densities than metals
- they have significantly lower melting points and boiling points than metals
- non-metals have high electronegativity
- nonmetals usually have little or no luster
Only eighteen elements in the periodic table are generally considered nonmetals, compared to over eighty metals, but nonmetals make up most of the crust, atmosphere and oceans of the earth. Bulk tissues of living organisms are composed almost entirely of nonmetals. Many nonmetals (hydrogen, nitrogen, oxygen, fluorine, chlorine, bromine, and iodine) are diatomic, and most of the rest are polyatomic.
# Metallisation at huge pressures
Nevertheless, even these 20 elements tend to become metallic at large enough pressures (see nearby periodic table at ~300 GPa). | Nonmetal
Nonmetal is a term used in chemistry when classifying the chemical elements. On the basis of their general physical and chemical properties, every element in the periodic table can be termed either a metal or a non-metal. (A few elements with intermediate properties are referred to as metalloids.)
The elements generally regarded as nonmetals are:
- hydrogen (H)
- In Group 14: carbon (C)
- In Group 15 (the pnictogens): nitrogen (N), phosphorus (P)
- Several elements in Group 16, the chalcogens: oxygen (O), sulfur (S), selenium (Se)
- All elements in Group 17 - the halogens
- All elements in Group 18 - the noble gases
There is no rigorous definition for the term "nonmetal" - it covers a general spectrum of behaviour. Common properties considered characteristic of a nonmetal include:
- poor conductors of heat and electricity when compared to metals
- they form acidic oxides (whereas metals generally form basic oxides)
- in solid form, they are dull and brittle, rather than metals which are lustrous, ductile or malleable
- usually have lower densities than metals
- they have significantly lower melting points and boiling points than metals
- non-metals have high electronegativity
- nonmetals usually have little or no luster
Only eighteen elements in the periodic table are generally considered nonmetals, compared to over eighty metals, but nonmetals make up most of the crust, atmosphere and oceans of the earth. Bulk tissues of living organisms are composed almost entirely of nonmetals. Many nonmetals (hydrogen, nitrogen, oxygen, fluorine, chlorine, bromine, and iodine) are diatomic, and most of the rest are polyatomic.
## Metallisation at huge pressures
Nevertheless, even these 20 elements tend to become metallic at large enough pressures (see nearby periodic table at ~300 GPa). | https://www.wikidoc.org/index.php/Non-metal | |
ffd09765f1318cff35bfae026917d6940f8b9f31 | wikidoc | Nonunion | Nonunion
Nonunion is permanent failure of healing following a broken bone.
Nonunion is a serious complication of a fracture and may occur when the fracture moves too much, has a poor blood supply or gets infected. Patients who smoke have a higher incidence of nonunion. The normal process of bone healing is interrupted or stalled. In some cases a pseudo-joint (pseudarthrosis) develops between the two fragments with cartilage formation and a joint cavity. More commonly the tissue between the ununited fragments is scar tissue.
Since the process of bone healing is quite variable, a nonunion may go on to heal without intervention in a very few cases. In general, if a nonunion is still evident at 6 months post injury it will remain unhealed without specific treatment, usually orthopedic surgery. A non-union which does go on to heal is called a delayed union.
# Clinical features
A history of a broken bone is usually apparent. The patient complains of persistent pain at the fracture site and may also notice abnormal movement or clicking at the level of the fracture. An x-ray plate of the fractured bone shows a persistent radiolucent line at the fracture. Callus formation may be evident but callus does not bridge across the fracture. If there is doubt about the interpretation of the Xray, stress Xrays, tomograms or CT scan may be used to make sure.
# Untreated prognosis
By definition, a nonunion will not heal if left alone. Therefore the patient's symptoms will not be improved and the function of the limb will remain impaired. It will be painful to bear weight on it and it may be deformed or unstable.
# Treatment
Surgical treatment includes removal of all scar tissue from between the fracture fragments, immobilization of the fracture with metal plates, rods or pins and bone graft. In simple cases healing may be evident within 3 months. Ilizarov revolutionized the treatment of recalcitrant nonunions demonstrating that the affected area of the bone could be removed, the fresh ends "docked" and the remaining bone lengthened using an external fixator device. The time course of healing after such treatment is longer than normal bone healing. Usually there are signs of union within 3 months, but the treatment may continue for many months beyond that.
# Treated prognosis
This depends on many factors including the age and general health of the patient, the time since the original injury, the number of previous surgeries, smoking history, the patient's ability to cooperate with the treatment. In the region of 80% of nonunions heal after the first operation. The success rate with subsequent surgeries is less. | Nonunion
Nonunion is permanent failure of healing following a broken bone.
Nonunion is a serious complication of a fracture and may occur when the fracture moves too much, has a poor blood supply or gets infected. Patients who smoke have a higher incidence of nonunion. The normal process of bone healing is interrupted or stalled. In some cases a pseudo-joint (pseudarthrosis) develops between the two fragments with cartilage formation and a joint cavity. More commonly the tissue between the ununited fragments is scar tissue.
Since the process of bone healing is quite variable, a nonunion may go on to heal without intervention in a very few cases. In general, if a nonunion is still evident at 6 months post injury it will remain unhealed without specific treatment, usually orthopedic surgery. A non-union which does go on to heal is called a delayed union.
# Clinical features
A history of a broken bone is usually apparent. The patient complains of persistent pain at the fracture site and may also notice abnormal movement or clicking at the level of the fracture. An x-ray plate of the fractured bone shows a persistent radiolucent line at the fracture. Callus formation may be evident but callus does not bridge across the fracture. If there is doubt about the interpretation of the Xray, stress Xrays, tomograms or CT scan may be used to make sure.
# Untreated prognosis
By definition, a nonunion will not heal if left alone. Therefore the patient's symptoms will not be improved and the function of the limb will remain impaired. It will be painful to bear weight on it and it may be deformed or unstable.
# Treatment
Surgical treatment includes removal of all scar tissue from between the fracture fragments, immobilization of the fracture with metal plates, rods or pins and bone graft. In simple cases healing may be evident within 3 months. Ilizarov revolutionized the treatment of recalcitrant nonunions demonstrating that the affected area of the bone could be removed, the fresh ends "docked" and the remaining bone lengthened using an external fixator device. The time course of healing after such treatment is longer than normal bone healing. Usually there are signs of union within 3 months, but the treatment may continue for many months beyond that.
# Treated prognosis
This depends on many factors including the age and general health of the patient, the time since the original injury, the number of previous surgeries, smoking history, the patient's ability to cooperate with the treatment. In the region of 80% of nonunions heal after the first operation. The success rate with subsequent surgeries is less. | https://www.wikidoc.org/index.php/Nonunion | |
5a9e978aedf81b99807d670304f7c47c73811e28 | wikidoc | Noritate | Noritate
Noritate is a topical cream usually prescribed for rosacea, a disease of the skin commonly associated with adult acne and most notably frequent to constant flushing of the face around the cheeks and chin area.
Noritate contains 1% anti-inflammatory drug metronidazole designed to reduce redness in inflamed areas.
While noritate may get rid of some pustules and reduce redness , it has been shown to result in acne in an exceptionally small number of users. The drug information pamphlet claims only 1% of users see ill effects. In many cases, users see no reduction in general redness associated with rosacea and sometimes even a worsening effect. Similar results are reported for Metrogel, which contains the same 1% metronidazole. | Noritate
Noritate is a topical cream usually prescribed for rosacea, a disease of the skin commonly associated with adult acne and most notably frequent to constant flushing of the face around the cheeks and chin area.
Noritate contains 1% anti-inflammatory drug metronidazole designed to reduce redness in inflamed areas.
While noritate may get rid of some pustules and reduce redness , it has been shown to result in acne in an exceptionally small number of users. The drug information pamphlet claims only 1% of users see ill effects. In many cases, users see no reduction in general redness associated with rosacea and sometimes even a worsening effect. Similar results are reported for Metrogel, which contains the same 1% metronidazole. | https://www.wikidoc.org/index.php/Noritate | |
62e19d07029a93264c4fa1a32851ab19a678afb0 | wikidoc | Procaine | Procaine
# 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
Procaine is a local anesthetic that is FDA approved for the {{{indicationType}}} of local Anesthetic for local infiltration and peripheral nerve block. Common adverse reactions include myocardial depression, hypotension, hypertension, bradycardia, ventricular arrhythmias, cardiac arrest,nausea / vomiting, cutaneous lesions of delayed onset, urticaria, edema related to allergic reactions , nervousness, dizziness, blurred vision, tremors may occur due to systemic toxicity, drowsiness or convulsions with subsequent unconsciousness and respiratory arrest..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Procaine 0.25% to 0.5% solutions in doses of 350 to 600 milligrams may be used for Infiltration Anesthesia. Epinephrine may be added for vasoconstrictive effect to give a final concentration of 1:200,000.
- For, Procaine 0.5% solution (up to 200 milliliters), 1% solution (up to 100 milliliters), or 2% solution (up to 50 milliliters) is recommended. The 2% solution is generally limited to procedures requiring a small volume of anesthetic, ie, 10 to 25 milliliters (mL). An anesthetic solution of 0.5 mL to 1 mL of Epinephrine 1:1,000 per 100 mL may be used to promote vasoconstriction (1:200,000 or 1:100,000).
- To prepare 60 milliliters (mL) of a 0.5% solution (5 milligrams/mL), dilute 30 mL of the 1% solution with 30 mL sodium chloride 0.9% injection. To prepare 60 mL of a 0.25% solution (2.5 milligrams/mL), dilute 15 mL of the 1% solution with 45 mL sodium chloride 0.9% injection .
- A dose of procaine 50 milligrams of a 10% solution mixed with an equal amount of diluent may be used for Anesthesia of the perineum; 100 milligrams (1 milliliter) diluted with an equal amount of diluent for the perineum and lower extremities; and up to 200 milligrams (2 milliliters) with 1 milliliter of diluent for anesthesia of the costal margin.
- Usual total dose of Procaine during one treatment should not exceed 1000 milligrams.
- The serum half-life of Procaine has been prolonged in some uremic patients.
- The serum half-life of Procaine has been prolonged in patients with liver disease; dosage reductions are recommended.
- Patient response to Procaine varies, and reduced doses should be given to elderly or acutely ill patients (Prod Info Procaine(R), 1990a).
- Procaine doses should be reduced in patients with cardiac disease.
- Reduced doses of procaine may be necessary for obstetric delivery and in patients with increased intra-abdominal pressure.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Procaine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Procaine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- For Infiltration Anesthesia, the maximum recommended Procaine dose is 15 milligrams/kilogram of a 0.5% solution in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Procaine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Procaine in pediatric patients.
# Contraindications
- Procaine is contraindicated in patients with a known hypersensitivity to procaine, drugs of a similar chemical configuration, or para-aminobenzoic acid or its derivatives.
- It is also contraindicated in patients with a known hypersensitivity to other components of solutions of Procaine.
# Warnings
- Contains acetone sodium bisulfite, 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.
- Local anesthetics should only be employed by clinicians who are well versed in diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed, and then only after insuring the immediate availability of oxygen, other resuscitative drugs, cardiopulmonary resuscitative equipment, and the personnel resources needed for proper management of toxic reactions and related emergencies. (see also adverse reactions and precautions.) delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest, and, possibly, death.
- It is essential that aspiration for blood or cerebrospinal fluid, where applicable, be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or subarachnoid injection. However, a negative aspiration does not ensure against an intravascular or subarachnoid injection.
- Reactions resulting in fatality have occurred on rare occasions with the use of local anesthetics, even in the absence of a history of hypersensitivity. Large doses of local anesthetics should not be used in patients with heartblock.
- Procaine with epinephrine or other vasopressors should not be used concomitantly with ergot-type oxytocic drugs, because a severe persistent hypertension may occur. Likewise, solutions of Procaine containing a vasoconstrictor, such as epinephrine, should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types, because severe prolonged hypertension or disturbances of cardiac rhythm may occur.
- Local anesthetic procedures should be used with caution when there is inflammation and/or sepsis in the region of the proposed injection.
- Mixing or the prior or intercurrent use of any local anesthetic with Procaine cannot be recommended because of insufficient data on the clinical use of such mixtures.
# Adverse Reactions
## Clinical Trials Experience
- Reactions to procaine are characteristic of those associated with other ester-type local anesthetics. A major cause of adverse reactions to this group of drugs is excessive plasma levels which may be due to overdosage, rapid absorption, inadvertent intravascular injection, or slow metabolic degradation.
- A small number of reactions may result from hypersensitivity, idiosyncrasy, or diminished tolerance to normal dosage.
- The most commonly encountered acute adverse experiences which demand immediate countermeasures are related to the central nervous system and the cardiovascular system. These adverse experiences are generally dose related and due to high plasma levels which may result from overdosage, rapid absorption from the injection site, diminished tolerance, or from unintentional intravascular injection of the local anesthetic solution. In addition to systemic dose-related toxicity, unintentional subarachnoid injection of drug during the intended performance of nerve blocks near the vertebral column (especially in the head and neck region), may result in underventilation or apnea (“Total or High Spinal”). Factors influencing plasma protein binding, such as acidosis, systemic diseases which alter protein production, or competition of other drugs for protein binding sites may diminish individual tolerance.
- Plasma cholinesterase deficiency may also account for diminished tolerance to ester-type local anesthetics.
- These are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest.
- The incidence of convulsions associated with the use of local anesthetics varies with the procedure used and the total dose administered.
- High doses or inadvertent intravascular injection may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, heartblock, hypotension (or sometimes hypertension), bradycardia, ventricular arrhythmias, and cardiac arrest. (See Warnings, Precautions, and Overdosage sections.)
- Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic or to other formulation ingredients, such as the antimicrobial preservative chlorobutanol contained in multiple-dose vials. These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and, possibly, anaphylactoid-like symptomatology (including severe hypotension). Cross sensitivity among members of the ester-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitely established.
- The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered, and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Many of these effects may be related to local anesthetic techniques, with or without a contribution from the drug.
## Postmarketing Experience
There is limited information regarding Procaine Postmarketing Experience in the drug label.
# Drug Interactions
- The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential.
- Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents.
- Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine.
- The clinical observation has been made that despite adequate sulfonamide therapy, local infections have occurred in areas infiltrated with procaine hydrochloride prior to diagnostic punctures and drainage procedures. Therefore, Procaine should not be used in any condition in which a sulfonamide drug is being employed since para-aminobenzoic acid inhibits the action of the sulfonamide.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with Procaine. It is not known whether procaine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Procaine should be given to a pregnant woman only if clearly needed and the potential benefits outweigh the risk. This does not exclude the use of procaine hydrochloride at term for obstetrical anesthesia or analgesia. (See Labor and Delivery.)
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Procaine in women who are pregnant.
### Labor and Delivery
- Local anesthetics rapidly cross the placenta, and when used for paracervical or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity. (See Clinical pharmacology.) The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus, and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function.
- Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously and electronic fetal monitoring is highly advisable.
- Paracervical or pudendal anesthesia may alter the forces at parturition through changes in uterine contractility or maternal expulsive efforts. In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation. The use of obstetrical anesthesia may increase the need for forceps assistance.
- The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. The long-term significance of these observations is unknown.
- Fetal bradycardia which frequently follows paracervical block may be indicative of high fetal blood concentrations of procaine with resultant fetal acidosis. Fetal heart rate should be monitored prior to and during paracervical block. Added risk appears to be present in prematurity, toxemia of pregnancy, and fetal distress. The physician should weigh the considering paracervical block in these conditions. Careful adherence to recommended dosage is of the utmost importance in paracervical block. Failure to achieve adequate analgesia with these doses should arouse suspicion of intravascular or fetal injection.
- Cases compatible with unintended fetal intracranial injection of local anesthetic solution have been reported following intended paracervical or pudendal block or both. Babies so affected present with unexplained neonatal depression at birth, which correlates with high local anesthetic serum levels, and usually manifest seizures within six hours. Prompt use of supportive measures combined with forced urinary excretion of the local anesthetic has been used successfully to manage this complication.
- Case reports of maternal convulsions and cardiovascular collapse following use of some local anesthetics for paracervical block in early pregnancy (as anesthesia for elective abortion) suggest that systemic absorption under these circumstances may be rapid. The recommended maximum dose of the local anesthetic should not be exceeded. Injection should be made slowly and with frequent aspiration. Allow a five-minute interval between sides.
- It is extremely important to avoid aortocaval compression by the gravid uterus during administration of regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus position or a blanket roll or sandbag may be placed beneath the right hip and the gravid uterus displaced to the left.
### Nursing Mothers
- It is not known whether local anesthetic drugs are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when local anesthetics are administered to a nursing woman.
### Pediatric Use
- In pediatric patients 15 mg/kg of a 0.5% solution for local infiltration is the maximum recommended dose.
### Geriatic Use
There is no FDA guidance on the use of Procaine in geriatric settings.
### Gender
There is no FDA guidance on the use of Procaine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Procaine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Procaine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Procaine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Procaine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Procaine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Procaine Administration in the drug label.
### Monitoring
There is limited information regarding Procaine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Procaine and IV administrations.
# Overdosage
Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution. (See Adverse Reactions, Warnings, And Precautions.)
- The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs, and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered.
- The first step in the management of systemic toxic reactions, as well as underventilation or apnea due to unintentional subarachnoid injection of drug solution, consists of immediate attention to the establishment and maintenance of a patent airway, and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. This may prevent convulsions if they have not already occurred.
- If necessary, use drugs to control the convulsions. A 50 mg to 100 mg bolus IV injection of succinylcholine will paralyze the patient without depressing the central nervous or cardiovascular systems and facilitate ventilation. A bolus IV dose of 5 mg to 10 mg of diazepam or 50 mg to 100 mg of thiopental will permit ventilation and counteract central nervous system stimulation, but these drugs also depress central nervous system, respiratory and cardiac function, add to postictal depression, and may result in apnea. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered by those familiar with their use. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should he evaluated. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine or epinephrine to enhance myocardial contractile force).
- Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated, after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated.
- Recent clinical data from patients experiencing local anesthetic-induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions, and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest.
- If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus myocardial depression from the direct effects of the local anesthetic may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. Underventilation or apnea due to unintentional subarachnoid injection of local anesthetic solution may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted and maintained for a prolonged period if necessary. Recovery has been reported after prolonged resuscitative efforts.
- The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. Therefore, during treatment of systemic toxicity, maternal hypotension, or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels be accomplished.
- The intravenous and subcutaneous and intraperitoneal LD50 of procaine hydrochloride in mice is 46 mg/kg to 80 mg/kg and 400 mg/kg and 200 mg/kg respectively.
# Pharmacology
## Mechanism of Action
- Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows:
- Pain
- Temperature
- Touch
- Proprioception
- Skeletal muscle tone.
- Procaine lacks topical anesthetic activity.
## Structure
- Procaine hydrochloride is benzoic acid, 4-amino-, 2-(diethylamino) ethyl ester, monohydrochloride, the ester of diethylaminoethanol and para-aminobenzoic acid, with the following structural formula:
- The solutions are made isotonic with sodium chloride and the pH is adjusted between 3 and 5.5 with sodium hydroxide and/or hydrochloric acid.
- Procaine hydrochloride is related chemically and pharmacologically to the ester-type local anesthetics. It contains an ester linkage between the aromatic nucleus and the amino group.
- Procaine is available as sterile solutions in concentrations of 1% and 2% for injection via local infiltration and peripheral nerve block.
## Pharmacodynamics
- Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block and ultimately to cardiac arrest. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure.
- Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression, or both. Apparent central stimulation is manifested as restlessness, tremors and shivering, progressing to convulsions, followed by depression, and coma progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited stage.
## Pharmacokinetics
- The rate of systemic absorption of local anesthetics is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution. A dilute concentration of epinephrine (1:200,000 or 5 μg/mL) usually reduces the rate of absorption and plasma concentration of Procaine. It also will promote local hemostasis and increase the duration of anesthesia.
- Onset of anesthesia with Procaine is rapid, the time of onset for sensory block ranging from about two to five minutes depending upon such factors as the anesthetic technique, the type of block, the concentration of the solution, and the individual patient. The degree of motor blockade produced is dependent on the concentration of the solution.
- The duration of anesthesia also varies depending upon the technique and type of block, the concentration, and the individual. Procaine will normally provide anesthesia which is adequate for one hour.
- Local anesthetics are bound to plasma proteins in varying degrees. Generally, the lower the plasma concentration of drug, the higher the percentage of drug bound to plasma.
- Local anesthetics appear to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by the degree of plasma protein binding, the degree of ionization, and the degree at lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid, soluble nonionized drugs readily enter the fetalblood from the maternal circulation.
- Depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain.
- Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the route of drug administration, and the age of the patient. The in vitro plasma half-life of Procaine in adults is 40 ± 9 seconds and in neonates 84 ± 30 seconds.
- Procaine is readily absorbed following parenteral administration and is rapidly hydrolyzed by plasma cholinesterase to para-aminobenzoic acid and diethylaminoethanol.
- The para-aminobenzoic acid metabolite inhibits the action of the sulfonamides. (See Precautions.)
- For Procaine, approximately 90% of the para-aminobenzoic acid metabolite and its conjugates and 33% of the diethylaminoethanol metabolite are recovered in the urine, while less than 2% of the administered dose is recovered unchanged in the urine.
## Nonclinical Toxicology
There is limited information regarding Procaine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Procaine Clinical Studies in the drug label.
# How Supplied
- Single-dose containers and multiple-dose containers of Procaine may be sterilized by autoclaving at 15-pound pressure, 121°C (250°F) for 15 minutes. Do not use solutions if crystals, cloudiness, or discoloration is observed. Examine solution carefully before use.
## Storage
There is limited information regarding Procaine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- When appropriate, patients should be informed, in advance, that they may experience temporary loss of sensation and motor activity following proper administration of regional anesthesia. Also, when appropriate, the physician should discuss other information including adverse reactions in the package insert.
# Precautions with Alcohol
Alcohol-Procaine 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 Procaine Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Procaine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Procaine
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
Procaine is a local anesthetic that is FDA approved for the {{{indicationType}}} of local Anesthetic for local infiltration and peripheral nerve block. Common adverse reactions include myocardial depression, hypotension, hypertension, bradycardia, ventricular arrhythmias, cardiac arrest,nausea / vomiting, cutaneous lesions of delayed onset, urticaria, edema related to allergic reactions , nervousness, dizziness, blurred vision, tremors may occur due to systemic toxicity, drowsiness or convulsions with subsequent unconsciousness and respiratory arrest..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Procaine 0.25% to 0.5% solutions in doses of 350 to 600 milligrams may be used for Infiltration Anesthesia. Epinephrine may be added for vasoconstrictive effect to give a final concentration of 1:200,000.
- For, Procaine 0.5% solution (up to 200 milliliters), 1% solution (up to 100 milliliters), or 2% solution (up to 50 milliliters) is recommended. The 2% solution is generally limited to procedures requiring a small volume of anesthetic, ie, 10 to 25 milliliters (mL). An anesthetic solution of 0.5 mL to 1 mL of Epinephrine 1:1,000 per 100 mL may be used to promote vasoconstriction (1:200,000 or 1:100,000).
- To prepare 60 milliliters (mL) of a 0.5% solution (5 milligrams/mL), dilute 30 mL of the 1% solution with 30 mL sodium chloride 0.9% injection. To prepare 60 mL of a 0.25% solution (2.5 milligrams/mL), dilute 15 mL of the 1% solution with 45 mL sodium chloride 0.9% injection .
- A dose of procaine 50 milligrams of a 10% solution mixed with an equal amount of diluent may be used for Anesthesia of the perineum; 100 milligrams (1 milliliter) diluted with an equal amount of diluent for the perineum and lower extremities; and up to 200 milligrams (2 milliliters) with 1 milliliter of diluent for anesthesia of the costal margin.
- Usual total dose of Procaine during one treatment should not exceed 1000 milligrams.
- The serum half-life of Procaine has been prolonged in some uremic patients.
- The serum half-life of Procaine has been prolonged in patients with liver disease; dosage reductions are recommended.
- Patient response to Procaine varies, and reduced doses should be given to elderly or acutely ill patients (Prod Info Procaine(R), 1990a).
- Procaine doses should be reduced in patients with cardiac disease.
- Reduced doses of procaine may be necessary for obstetric delivery and in patients with increased intra-abdominal pressure.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Procaine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Procaine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- For Infiltration Anesthesia, the maximum recommended Procaine dose is 15 milligrams/kilogram of a 0.5% solution in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Procaine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Procaine in pediatric patients.
# Contraindications
- Procaine is contraindicated in patients with a known hypersensitivity to procaine, drugs of a similar chemical configuration, or para-aminobenzoic acid or its derivatives.
- It is also contraindicated in patients with a known hypersensitivity to other components of solutions of Procaine.
# Warnings
- Contains acetone sodium bisulfite, 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.
- Local anesthetics should only be employed by clinicians who are well versed in diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed, and then only after insuring the immediate availability of oxygen, other resuscitative drugs, cardiopulmonary resuscitative equipment, and the personnel resources needed for proper management of toxic reactions and related emergencies. (see also adverse reactions and precautions.) delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest, and, possibly, death.
- It is essential that aspiration for blood or cerebrospinal fluid, where applicable, be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or subarachnoid injection. However, a negative aspiration does not ensure against an intravascular or subarachnoid injection.
- Reactions resulting in fatality have occurred on rare occasions with the use of local anesthetics, even in the absence of a history of hypersensitivity. Large doses of local anesthetics should not be used in patients with heartblock.
- Procaine with epinephrine or other vasopressors should not be used concomitantly with ergot-type oxytocic drugs, because a severe persistent hypertension may occur. Likewise, solutions of Procaine containing a vasoconstrictor, such as epinephrine, should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types, because severe prolonged hypertension or disturbances of cardiac rhythm may occur.
- Local anesthetic procedures should be used with caution when there is inflammation and/or sepsis in the region of the proposed injection.
- Mixing or the prior or intercurrent use of any local anesthetic with Procaine cannot be recommended because of insufficient data on the clinical use of such mixtures.
# Adverse Reactions
## Clinical Trials Experience
- Reactions to procaine are characteristic of those associated with other ester-type local anesthetics. A major cause of adverse reactions to this group of drugs is excessive plasma levels which may be due to overdosage, rapid absorption, inadvertent intravascular injection, or slow metabolic degradation.
- A small number of reactions may result from hypersensitivity, idiosyncrasy, or diminished tolerance to normal dosage.
- The most commonly encountered acute adverse experiences which demand immediate countermeasures are related to the central nervous system and the cardiovascular system. These adverse experiences are generally dose related and due to high plasma levels which may result from overdosage, rapid absorption from the injection site, diminished tolerance, or from unintentional intravascular injection of the local anesthetic solution. In addition to systemic dose-related toxicity, unintentional subarachnoid injection of drug during the intended performance of nerve blocks near the vertebral column (especially in the head and neck region), may result in underventilation or apnea (“Total or High Spinal”). Factors influencing plasma protein binding, such as acidosis, systemic diseases which alter protein production, or competition of other drugs for protein binding sites may diminish individual tolerance.
- Plasma cholinesterase deficiency may also account for diminished tolerance to ester-type local anesthetics.
- These are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest.
- The incidence of convulsions associated with the use of local anesthetics varies with the procedure used and the total dose administered.
- High doses or inadvertent intravascular injection may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, heartblock, hypotension (or sometimes hypertension), bradycardia, ventricular arrhythmias, and cardiac arrest. (See Warnings, Precautions, and Overdosage sections.)
- Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic or to other formulation ingredients, such as the antimicrobial preservative chlorobutanol contained in multiple-dose vials. These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and, possibly, anaphylactoid-like symptomatology (including severe hypotension). Cross sensitivity among members of the ester-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitely established.
- The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered, and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Many of these effects may be related to local anesthetic techniques, with or without a contribution from the drug.
## Postmarketing Experience
There is limited information regarding Procaine Postmarketing Experience in the drug label.
# Drug Interactions
- The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential.
- Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents.
- Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine.
- The clinical observation has been made that despite adequate sulfonamide therapy, local infections have occurred in areas infiltrated with procaine hydrochloride prior to diagnostic punctures and drainage procedures. Therefore, Procaine should not be used in any condition in which a sulfonamide drug is being employed since para-aminobenzoic acid inhibits the action of the sulfonamide.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with Procaine. It is not known whether procaine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Procaine should be given to a pregnant woman only if clearly needed and the potential benefits outweigh the risk. This does not exclude the use of procaine hydrochloride at term for obstetrical anesthesia or analgesia. (See Labor and Delivery.)
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Procaine in women who are pregnant.
### Labor and Delivery
- Local anesthetics rapidly cross the placenta, and when used for paracervical or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity. (See Clinical pharmacology.) The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus, and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function.
- Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously and electronic fetal monitoring is highly advisable.
- Paracervical or pudendal anesthesia may alter the forces at parturition through changes in uterine contractility or maternal expulsive efforts. In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation. The use of obstetrical anesthesia may increase the need for forceps assistance.
- The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. The long-term significance of these observations is unknown.
- Fetal bradycardia which frequently follows paracervical block may be indicative of high fetal blood concentrations of procaine with resultant fetal acidosis. Fetal heart rate should be monitored prior to and during paracervical block. Added risk appears to be present in prematurity, toxemia of pregnancy, and fetal distress. The physician should weigh the considering paracervical block in these conditions. Careful adherence to recommended dosage is of the utmost importance in paracervical block. Failure to achieve adequate analgesia with these doses should arouse suspicion of intravascular or fetal injection.
- Cases compatible with unintended fetal intracranial injection of local anesthetic solution have been reported following intended paracervical or pudendal block or both. Babies so affected present with unexplained neonatal depression at birth, which correlates with high local anesthetic serum levels, and usually manifest seizures within six hours. Prompt use of supportive measures combined with forced urinary excretion of the local anesthetic has been used successfully to manage this complication.
- Case reports of maternal convulsions and cardiovascular collapse following use of some local anesthetics for paracervical block in early pregnancy (as anesthesia for elective abortion) suggest that systemic absorption under these circumstances may be rapid. The recommended maximum dose of the local anesthetic should not be exceeded. Injection should be made slowly and with frequent aspiration. Allow a five-minute interval between sides.
- It is extremely important to avoid aortocaval compression by the gravid uterus during administration of regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus position or a blanket roll or sandbag may be placed beneath the right hip and the gravid uterus displaced to the left.
### Nursing Mothers
- It is not known whether local anesthetic drugs are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when local anesthetics are administered to a nursing woman.
### Pediatric Use
- In pediatric patients 15 mg/kg of a 0.5% solution for local infiltration is the maximum recommended dose.
### Geriatic Use
There is no FDA guidance on the use of Procaine in geriatric settings.
### Gender
There is no FDA guidance on the use of Procaine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Procaine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Procaine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Procaine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Procaine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Procaine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Procaine Administration in the drug label.
### Monitoring
There is limited information regarding Procaine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Procaine and IV administrations.
# Overdosage
Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution. (See Adverse Reactions, Warnings, And Precautions.)
- The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs, and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered.
- The first step in the management of systemic toxic reactions, as well as underventilation or apnea due to unintentional subarachnoid injection of drug solution, consists of immediate attention to the establishment and maintenance of a patent airway, and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. This may prevent convulsions if they have not already occurred.
- If necessary, use drugs to control the convulsions. A 50 mg to 100 mg bolus IV injection of succinylcholine will paralyze the patient without depressing the central nervous or cardiovascular systems and facilitate ventilation. A bolus IV dose of 5 mg to 10 mg of diazepam or 50 mg to 100 mg of thiopental will permit ventilation and counteract central nervous system stimulation, but these drugs also depress central nervous system, respiratory and cardiac function, add to postictal depression, and may result in apnea. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered by those familiar with their use. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should he evaluated. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine or epinephrine to enhance myocardial contractile force).
- Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated, after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated.
- Recent clinical data from patients experiencing local anesthetic-induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions, and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest.
- If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus myocardial depression from the direct effects of the local anesthetic may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. Underventilation or apnea due to unintentional subarachnoid injection of local anesthetic solution may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted and maintained for a prolonged period if necessary. Recovery has been reported after prolonged resuscitative efforts.
- The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. Therefore, during treatment of systemic toxicity, maternal hypotension, or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels be accomplished.
- The intravenous and subcutaneous and intraperitoneal LD50 of procaine hydrochloride in mice is 46 mg/kg to 80 mg/kg and 400 mg/kg and 200 mg/kg respectively.
# Pharmacology
## Mechanism of Action
- Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows:
- Pain
- Temperature
- Touch
- Proprioception
- Skeletal muscle tone.
- Procaine lacks topical anesthetic activity.
## Structure
- Procaine hydrochloride is benzoic acid, 4-amino-, 2-(diethylamino) ethyl ester, monohydrochloride, the ester of diethylaminoethanol and para-aminobenzoic acid, with the following structural formula:
- The solutions are made isotonic with sodium chloride and the pH is adjusted between 3 and 5.5 with sodium hydroxide and/or hydrochloric acid.
- Procaine hydrochloride is related chemically and pharmacologically to the ester-type local anesthetics. It contains an ester linkage between the aromatic nucleus and the amino group.
- Procaine is available as sterile solutions in concentrations of 1% and 2% for injection via local infiltration and peripheral nerve block.
## Pharmacodynamics
- Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block and ultimately to cardiac arrest. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure.
- Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression, or both. Apparent central stimulation is manifested as restlessness, tremors and shivering, progressing to convulsions, followed by depression, and coma progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited stage.
## Pharmacokinetics
- The rate of systemic absorption of local anesthetics is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution. A dilute concentration of epinephrine (1:200,000 or 5 μg/mL) usually reduces the rate of absorption and plasma concentration of Procaine. It also will promote local hemostasis and increase the duration of anesthesia.
- Onset of anesthesia with Procaine is rapid, the time of onset for sensory block ranging from about two to five minutes depending upon such factors as the anesthetic technique, the type of block, the concentration of the solution, and the individual patient. The degree of motor blockade produced is dependent on the concentration of the solution.
- The duration of anesthesia also varies depending upon the technique and type of block, the concentration, and the individual. Procaine will normally provide anesthesia which is adequate for one hour.
- Local anesthetics are bound to plasma proteins in varying degrees. Generally, the lower the plasma concentration of drug, the higher the percentage of drug bound to plasma.
- Local anesthetics appear to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by the degree of plasma protein binding, the degree of ionization, and the degree at lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid, soluble nonionized drugs readily enter the fetalblood from the maternal circulation.
- Depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain.
- Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the route of drug administration, and the age of the patient. The in vitro plasma half-life of Procaine in adults is 40 ± 9 seconds and in neonates 84 ± 30 seconds.
- Procaine is readily absorbed following parenteral administration and is rapidly hydrolyzed by plasma cholinesterase to para-aminobenzoic acid and diethylaminoethanol.
- The para-aminobenzoic acid metabolite inhibits the action of the sulfonamides. (See Precautions.)
- For Procaine, approximately 90% of the para-aminobenzoic acid metabolite and its conjugates and 33% of the diethylaminoethanol metabolite are recovered in the urine, while less than 2% of the administered dose is recovered unchanged in the urine.
## Nonclinical Toxicology
There is limited information regarding Procaine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Procaine Clinical Studies in the drug label.
# How Supplied
- Single-dose containers and multiple-dose containers of Procaine may be sterilized by autoclaving at 15-pound pressure, 121°C (250°F) for 15 minutes. Do not use solutions if crystals, cloudiness, or discoloration is observed. Examine solution carefully before use.
## Storage
There is limited information regarding Procaine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- When appropriate, patients should be informed, in advance, that they may experience temporary loss of sensation and motor activity following proper administration of regional anesthesia. Also, when appropriate, the physician should discuss other information including adverse reactions in the package insert.
# Precautions with Alcohol
Alcohol-Procaine 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 Procaine Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Procaine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Novacaine | |
80024e541f2c3b6e6fb5e4700c6518998a14953e | wikidoc | Nucleoid | Nucleoid
In prokaryotes, the nucleoid (meaning nucleus-like and also known as the nuclear region, nuclear body or chromatin body) is an irregularly-shaped region within the cell where the genetic material is localized. The nucleic acid is a circular, double-stranded piece of DNA, and multiple copies may exist. This method of genetic storage can be contrasted against that of the eukaryotes, where DNA is packed into chromatins and sequestered within a membrane-enclosed organelle called the nucleus.
# Visualisation
The nucleoid can be clearly visualised on an electron micrograph at high magnification, where, although its appearance may differ, it is clearly visible against the cytosol. Sometimes even strands of what is thought to be DNA are visible. By staining with the Feulgen stain, which specifically stains DNA, the nucleoid can also be seen under a light microscope. The DNA-intercalating stains DAPI and ethidium bromide are widely used for fluorescence microscopy of nucleoids.
# Composition
Experimental evidence suggests that the nucleoid is largely composed of DNA, about 60%, with a small amount of RNA and protein. The latter two constituents are likely to be mainly messenger RNA and the transcription factor proteins found regulating the bacterial genome. Proteins helping to maintain the supercoiled structure of the nucleic acid are known as nucleoid proteins or nucleoid associated proteins and are distinct from histones of eukaryotic nuclei. In contrast to histones, the DNA-binding proteins of the nucleoid do not form nucleosomes. | Nucleoid
In prokaryotes, the nucleoid (meaning nucleus-like and also known as the nuclear region, nuclear body or chromatin body) is an irregularly-shaped region within the cell where the genetic material is localized. The nucleic acid is a circular, double-stranded piece of DNA, and multiple copies may exist. This method of genetic storage can be contrasted against that of the eukaryotes, where DNA is packed into chromatins and sequestered within a membrane-enclosed organelle called the nucleus.
# Visualisation
The nucleoid can be clearly visualised on an electron micrograph at high magnification, where, although its appearance may differ, it is clearly visible against the cytosol. Sometimes even strands of what is thought to be DNA are visible. By staining with the Feulgen stain, which specifically stains DNA, the nucleoid can also be seen under a light microscope. The DNA-intercalating stains DAPI and ethidium bromide are widely used for fluorescence microscopy of nucleoids.
# Composition
Experimental evidence suggests that the nucleoid is largely composed of DNA, about 60%, with a small amount of RNA and protein. The latter two constituents are likely to be mainly messenger RNA and the transcription factor proteins found regulating the bacterial genome. Proteins helping to maintain the supercoiled structure of the nucleic acid are known as nucleoid proteins or nucleoid associated proteins and are distinct from histones of eukaryotic nuclei. In contrast to histones, the DNA-binding proteins of the nucleoid do not form nucleosomes. | https://www.wikidoc.org/index.php/Nucleoid | |
29556d69ed1ea2b0490b4bd80034fefd3d758e32 | wikidoc | OSTalpha | OSTalpha
Organic solute transporter alpha, also known as OST-alpha, is a protein which in humans is encoded by the OSTA gene.
# Function
OST-alpha together with OST-beta is able to transport estrone sulfate, taurocholate, digoxin, and prostaglandin E2 across cell membranes. The Ost-alpha / Ost-beta heterodimer, but not the individual subunits, stimulates sodium-independent bile acid uptake. The heterodimer furthermore is essential for intestinal bile acid transport.
OST-alpha and OST-alpha have high expression in the testis, colon, liver, small intestine, kidney, ovary, and adrenal gland. | OSTalpha
Organic solute transporter alpha, also known as OST-alpha, is a protein which in humans is encoded by the OSTA gene.[1][2]
# Function
OST-alpha together with OST-beta is able to transport estrone sulfate, taurocholate, digoxin, and prostaglandin E2 across cell membranes.[2][3] The Ost-alpha / Ost-beta heterodimer, but not the individual subunits, stimulates sodium-independent bile acid uptake.[3] The heterodimer furthermore is essential for intestinal bile acid transport.[4]
OST-alpha and OST-alpha have high expression in the testis, colon, liver, small intestine, kidney, ovary, and adrenal gland.[2] | https://www.wikidoc.org/index.php/OSTalpha | |
2b768c3e18616fcdde98f1019ccdf2810ef0a97c | wikidoc | Obscurin | Obscurin
Obscurin is a protein that in humans is encoded by the OBSCN gene. Obscurin belongs to the family of giant sarcomeric signaling proteins that includes titin and nebulin. Obscurin is expressed in cardiac and skeletal muscle, and plays a role in the organization of myofibrils during sarcomere assembly. A mutation in the OBSCN gene has been associated with hypertrophic cardiomyopathy and altered obscurin protein properties have been associated with other muscle diseases.
# Structure
Human obscurin may exist as multiple splice variants of approximately 720 kDa, however the full-length nature of only one has been described to date. Obscurin is expressed in cardiac and skeletal muscle. The obscurin gene spans more than 150 kb, contains over 80 exons. The encoded protein contains 68 Ig domains, 2 fibronectin domains, 1 calcium/calmodulin-binding domain, 1 RhoGEF domain with an associated PH domain, and 2 serine-threonine kinase domains. The dominant location of obscurin in mature myofibrils is at the sarcomeric M-band. Titin, obscurin, obscurin-like-1 and myomesin form a ternary complex at sarcomeric M-bands that is critical for sarcomere mechanics.
# Function
Obscurin belongs to the family of giant sarcomeric signaling proteins that includes titin and nebulin, and may have a role in the organization of myofibrils during assembly and may mediate interactions between the sarcoplasmic reticulum and myofibrils. Obscurin is the major cytoplasmic ligand for small ankyrin 1 (sANK1), a sarcoplasmic reticular protein, and the scaffolding function of obscurin appears to prevent degradation of sANK1. These data indicate that obscurin serves as a signaling link between the sarcomeric and sarcoplasmic reticular domains, Obscurin plays a role in the formation of new sarcomeres during myofibril assembly. specifically, at the sarcomeric periphery where sites of initiation and progression of myofibrilogenesis lie. Obscurin appears to be necessary for the proper incorporation of myosin filaments into sarcomeres and in the assembly of A-bands. Moreover, the kinase domains of obscurin are enzymatically active and appear to be involved in the regulation of cell adhesion.
# Clinical Significance
Obscurin has been shown to exhibit a disease-related isoform switch in patients with dilated cardiomyopathy. An obscurin mutation Arg4344Gln was identified in patients with hypertrophic cardiomyopathy, which disrupted binding of obscurin to the Z9-Z10 domains of titin. Mutations found the gene encoding titin in patients with limb-girdle muscular dystrophy 2J or Salih myopathy decrease the ability of titin to bind obscurin, suggesting that this may be causative in disease manifestation.
# Interactions
Obscurin has been shown to interact with Titin, specifically, with the Novex-3 of Titin, a 6.5 kb exon located upstream of the cardiac-specific N2B exon. The C-terminal region of Obscurin interacts with the cytoplasmic domain of small ankyrin 1 and with the exon 43' region of ankyrin B. The Ig3 of obscurin binds myomesin at the linker between My4 and My5. | Obscurin
Obscurin is a protein that in humans is encoded by the OBSCN gene.[1][2][3] Obscurin belongs to the family of giant sarcomeric signaling proteins that includes titin and nebulin. Obscurin is expressed in cardiac and skeletal muscle, and plays a role in the organization of myofibrils during sarcomere assembly. A mutation in the OBSCN gene has been associated with hypertrophic cardiomyopathy and altered obscurin protein properties have been associated with other muscle diseases.
# Structure
Human obscurin may exist as multiple splice variants of approximately 720 kDa,[4][5][6][7][8] however the full-length nature of only one has been described to date.[9] Obscurin is expressed in cardiac and skeletal muscle. The obscurin gene spans more than 150 kb, contains over 80 exons.[10] The encoded protein contains 68 Ig domains, 2 fibronectin domains, 1 calcium/calmodulin-binding domain, 1 RhoGEF domain with an associated PH domain, and 2 serine-threonine kinase domains.[9] The dominant location of obscurin in mature myofibrils is at the sarcomeric M-band.[9][11] Titin, obscurin, obscurin-like-1 and myomesin form a ternary complex at sarcomeric M-bands that is critical for sarcomere mechanics.[12]
# Function
Obscurin belongs to the family of giant sarcomeric signaling proteins that includes titin and nebulin, and may have a role in the organization of myofibrils during assembly and may mediate interactions between the sarcoplasmic reticulum and myofibrils. Obscurin is the major cytoplasmic ligand for small ankyrin 1 (sANK1), a sarcoplasmic reticular protein, and the scaffolding function of obscurin appears to prevent degradation of sANK1.[13] These data indicate that obscurin serves as a signaling link between the sarcomeric and sarcoplasmic reticular domains,[14][15] Obscurin plays a role in the formation of new sarcomeres during myofibril assembly.[16] specifically, at the sarcomeric periphery where sites of initiation and progression of myofibrilogenesis lie.[17][18] Obscurin appears to be necessary for the proper incorporation of myosin filaments into sarcomeres and in the assembly of A-bands.[11][19] Moreover, the kinase domains of obscurin are enzymatically active and appear to be involved in the regulation of cell adhesion.[20]
# Clinical Significance
Obscurin has been shown to exhibit a disease-related isoform switch in patients with dilated cardiomyopathy.[21] An obscurin mutation Arg4344Gln was identified in patients with hypertrophic cardiomyopathy, which disrupted binding of obscurin to the Z9-Z10 domains of titin.[22] Mutations found the gene encoding titin in patients with limb-girdle muscular dystrophy 2J or Salih myopathy decrease the ability of titin to bind obscurin, suggesting that this may be causative in disease manifestation.[23]
# Interactions
Obscurin has been shown to interact with Titin,[1][24] specifically, with the Novex-3 of Titin, a 6.5 kb exon located upstream of the cardiac-specific N2B exon.[25] The C-terminal region of Obscurin interacts with the cytoplasmic domain of small ankyrin 1[26][27] and with the exon 43' region of ankyrin B.[28] The Ig3 of obscurin binds myomesin at the linker between My4 and My5.[23] | https://www.wikidoc.org/index.php/Obscurin | |
924bd66845c0727cba292d309f644062c13b9b53 | wikidoc | Occludin | Occludin
Occludin is a protein that in humans is encoded by the OCLN gene.
Occludin is a 65-kDa (522-amino acid polypeptide -human) integral plasma-membrane protein located at the tight junctions, described for the first time in 1993 by Shoichiro Tsukita. Together with the Claudin group of proteins, it is the main component of the tight junctions.
# Gene location
The OCLN gene is located on the long (q) arm of chromosome 5 at position q13.1. The gene starts at base pair 69,492,292 and goes to base pair 69,558,104 and is 65,813 base pairs long.
# Protein structure
Occludin's structure can be broken down into 9 domains. These domains are separated into two groups. 5 of the domains are located intracellularly and extracellularly. These 5 domains are separated by the 4 transmembrane domains of the protein. The nine domains are as follows:
- N-terminus domain (66 aa)
- transmembrane domain 1 (23 aa)
- extracellular loop 1 (46 aa)
- transmembrane domain 2 (25 aa)
- intracellular loop (10 aa)
- transmembrane domain 3 (25 aa)
- extracellular domain 2 (48 aa)
- transmembrane domain 4 (22 aa)
- C-terminus domain (257 aa)
The C-terminus domain has been shown experimentally to be required for correct assembly of tight junction barrier function. The C-terminus also interacts with several cytoplasmic proteins of the junctional plaque and interacts with signaling molecules responsible for cell survival. The N-terminus of occludin experimentally has been linked to involvement in tight junction sealing/barrier properties. The extracellular loops are thought to be involved in the regulation of paracellualr permeability and the second extracellular has been shown to be involved in the localization of occludin at the tight junction.
# Function
Occludin is an important protein in tight junction function. Studies have shown that rather than being important in tight junction assembly, occludin is important in tight junction stability and barrier function. Furthermore, studies in which mice were deprived of occludin expression showed morphological stability in several epithelial tissues but also found chronic inflammation and hyperplasia in the gastric epithelium, calcification in the brain, testicular atrophy, loss of cytoplasmic granules in straited duct cells of salivary gland, and thinning of the compact bone. The phenotypical response of these mice to the lack of occludin suggest that the function of occludin is more complex than thought and requires more work.
# Role in cancer
Occludin plays a critical role in maintaining the barrier properties of a tight junction. Thus, mutation or absence of occludin increases epithelial leakiness which is an important barrier in preventing metastasis of cancer. Loss of occludin or abnormal expression of occludin has been shown to cause increased invasion, reduced adhesion and significantly reduced tight junction function in breast cancer tissues. Furthermore, patients with metastatic disease displayed significantly lower levels of occludin suggesting that the loss of occludin and thereby loss of tight junction integrity is important in metastatic development of breast cancer.
Occludin also plays an important role in the apoptosis. The C-terminus of occludin is important in receiving and transmitting cell survival signals. In standard cells, loss or disruption of occludin and other tight junction proteins leads to initiation of apoptosis through extrinsic pathways. Studies involving high levels of expression of occludin in cancer cells have shown that occludin mitigates several important cancer proliferation properties. The presence of occludin decreased cellular invasiveness and motility, enhanced cellular sensitivity to apoptogenic factors and lowered tumorigenesis and metastasis of the cancer cells. Specifically, occludin has a strong inhibitory effect on Raf1-induced tumorigenesis. Still, the exact mechanism of how occludin prevents the progression of cancer is not known but it has been shown that cancer progression is linked to the loss of occludin or the silencing of the OCLN gene.
# Disease linkage
Disruption of occludin regulation is an important aspect of a number of diseases. Strategies to prevent and/or reverse occludin downregulation may be an important therapeutic target. Mutation of occludin are thought to be a cause of band-like calcification with simple gyration and polymicrogyria (BLC-PMG). BLC-PMG is an autosomal recessive neurologic disorder.
# Interactions
Occludin has been shown to interact with Tight junction protein 2, YES1 and Tight junction protein 1. | Occludin
Occludin is a protein that in humans is encoded by the OCLN gene.[1][2]
Occludin is a 65-kDa (522-amino acid polypeptide -human) integral plasma-membrane protein located at the tight junctions, described for the first time in 1993 by Shoichiro Tsukita.[3] Together with the Claudin group of proteins, it is the main component of the tight junctions.
# Gene location
The OCLN gene is located on the long (q) arm of chromosome 5 at position q13.1. The gene starts at base pair 69,492,292 and goes to base pair 69,558,104 and is 65,813 base pairs long.[4]
# Protein structure
Occludin's structure can be broken down into 9 domains. These domains are separated into two groups. 5 of the domains are located intracellularly and extracellularly. These 5 domains are separated by the 4 transmembrane domains of the protein. The nine domains are as follows:
- N-terminus domain (66 aa)
- transmembrane domain 1 (23 aa)
- extracellular loop 1 (46 aa)
- transmembrane domain 2 (25 aa)
- intracellular loop (10 aa)
- transmembrane domain 3 (25 aa)
- extracellular domain 2 (48 aa)
- transmembrane domain 4 (22 aa)
- C-terminus domain (257 aa)
The C-terminus domain has been shown experimentally to be required for correct assembly of tight junction barrier function.[5] The C-terminus also interacts with several cytoplasmic proteins of the junctional plaque and interacts with signaling molecules responsible for cell survival.[6] The N-terminus of occludin experimentally has been linked to involvement in tight junction sealing/barrier properties.[6] The extracellular loops are thought to be involved in the regulation of paracellualr permeability and the second extracellular has been shown to be involved in the localization of occludin at the tight junction.[6]
# Function
Occludin is an important protein in tight junction function. Studies have shown that rather than being important in tight junction assembly, occludin is important in tight junction stability and barrier function. Furthermore, studies in which mice were deprived of occludin expression showed morphological stability in several epithelial tissues but also found chronic inflammation and hyperplasia in the gastric epithelium, calcification in the brain, testicular atrophy, loss of cytoplasmic granules in straited duct cells of salivary gland, and thinning of the compact bone. The phenotypical response of these mice to the lack of occludin suggest that the function of occludin is more complex than thought and requires more work.[7]
# Role in cancer
Occludin plays a critical role in maintaining the barrier properties of a tight junction. Thus, mutation or absence of occludin increases epithelial leakiness which is an important barrier in preventing metastasis of cancer. Loss of occludin or abnormal expression of occludin has been shown to cause increased invasion, reduced adhesion and significantly reduced tight junction function in breast cancer tissues. Furthermore, patients with metastatic disease displayed significantly lower levels of occludin suggesting that the loss of occludin and thereby loss of tight junction integrity is important in metastatic development of breast cancer.[8]
Occludin also plays an important role in the apoptosis. The C-terminus of occludin is important in receiving and transmitting cell survival signals. In standard cells, loss or disruption of occludin and other tight junction proteins leads to initiation of apoptosis through extrinsic pathways.[9] Studies involving high levels of expression of occludin in cancer cells have shown that occludin mitigates several important cancer proliferation properties. The presence of occludin decreased cellular invasiveness and motility, enhanced cellular sensitivity to apoptogenic factors and lowered tumorigenesis and metastasis of the cancer cells. Specifically, occludin has a strong inhibitory effect on Raf1-induced tumorigenesis. Still, the exact mechanism of how occludin prevents the progression of cancer is not known but it has been shown that cancer progression is linked to the loss of occludin or the silencing of the OCLN gene.[10]
# Disease linkage
Disruption of occludin regulation is an important aspect of a number of diseases. Strategies to prevent and/or reverse occludin downregulation may be an important therapeutic target. Mutation of occludin are thought to be a cause of band-like calcification with simple gyration and polymicrogyria (BLC-PMG). BLC-PMG is an autosomal recessive neurologic disorder.
# Interactions
Occludin has been shown to interact with Tight junction protein 2,[11][12][13] YES1[14] and Tight junction protein 1.[15][16] | https://www.wikidoc.org/index.php/Occludin | |
9a48f69b20d19248ef0b793caf6304a4b381083d | wikidoc | Odontoma | Odontoma
# Overview
An odontoma (also termed odontome) is a benign tumour of odontogenic origin (i.e. linked to tooth development). Specifically, it is a dental hamartoma, meaning that it is composed of normal dental tissue that has grown in an irregular way.
The average age of people found with an odontoma is 14. The condition is frequently associated with one or more unerupted teeth. Though most cases are found impacted within the jaw there are instances where odontomas have erupted into the oral cavity.
# Classification
There are two main types: compound and complex.
- A compound odontoma still has the three separate dental tissues (enamel, dentin and cementum), but may present a lobulated appearance where there is no definitive demarcation of separate tissues between the individual "toothlets" (or denticles). It usually appears in the anterior maxilla.
- The complex type is unrecognizable as dental tissues, usually presenting as a radioopaque area with varying densities. It usually appears in the posterior maxilla or in the mandible.
In addition to the above forms, the dilated odontoma is an infrequent developmental alteration that appears in any area of the dental arches and can affect deciduous, permanent and supernumerary teeth. Dens invaginatus is a developmental anomaly resulting from invagination of a portion of crown forming within the enamel organ during odontogenesis. The most extreme form of dens invaginatus is known as dilated odontoma.
# Epidemiology
Odontomas are thought to be the second most frequent type of odontogenic tumor worldwide (after ameloblastoma), accounting for about 20% of all cases within this relatively uncommon tumor category which shows large geographic variations in incidence.
# Notable cases
In July 2014 in Mumbai, India, surgeons at Mumbai's JJ Hospital removed 232 tooth-like growths from a complex odontoma growing in the lower jaw of a 17-year-old boy. This is thought to be the largest ever number of such growths to be identified in a patient.
Also in Mumbai an eight year old had 80 teeth growths removed.
Another exceptional case of compound odontoma was reported in November 2014, involving the extraction of 202 teeth from a 7-year old girl in Gurgaon, India. " | Odontoma
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
An odontoma (also termed odontome)[1][2] is a benign tumour[3] of odontogenic origin (i.e. linked to tooth development).[4] Specifically, it is a dental hamartoma, meaning that it is composed of normal dental tissue that has grown in an irregular way.
The average age of people found with an odontoma is 14.[5] The condition is frequently associated with one or more unerupted teeth. Though most cases are found impacted within the jaw there are instances where odontomas have erupted into the oral cavity. [6]
# Classification
There are two main types: compound and complex.[7]
- A compound odontoma still has the three separate dental tissues (enamel, dentin and cementum), but may present a lobulated appearance where there is no definitive demarcation of separate tissues between the individual "toothlets" (or denticles). It usually appears in the anterior maxilla.
- The complex type is unrecognizable as dental tissues, usually presenting as a radioopaque area with varying densities. It usually appears in the posterior maxilla or in the mandible.
In addition to the above forms, the dilated odontoma is an infrequent developmental alteration that appears in any area of the dental arches and can affect deciduous, permanent and supernumerary teeth. Dens invaginatus is a developmental anomaly resulting from invagination of a portion of crown forming within the enamel organ during odontogenesis. The most extreme form of dens invaginatus is known as dilated odontoma.
# Epidemiology
Odontomas are thought to be the second most frequent type of odontogenic tumor worldwide (after ameloblastoma), accounting for about 20% of all cases within this relatively uncommon tumor category which shows large geographic variations in incidence.[8]
# Notable cases
In July 2014 in Mumbai, India, surgeons at Mumbai's JJ Hospital removed 232 tooth-like growths from a complex odontoma growing in the lower jaw of a 17-year-old boy. This is thought to be the largest ever number of such growths to be identified in a patient.[9]
Also in Mumbai an eight year old had 80 teeth growths removed.[10]
Another exceptional case of compound odontoma was reported in November 2014, involving the extraction of 202 teeth from a 7-year old girl in Gurgaon, India. "[11] | https://www.wikidoc.org/index.php/Odontoma | |
f425d431119e79ac713bf85c208f62a8e1fc1a7b | wikidoc | Oil bath | Oil bath
An oil bath is a laboratory heating device which uses boiling oil as the temperature regulator. Since different oils have different boiling points it is possible to obtain a temperature near to the desired temperature by selecting an oil with a boiling point as close as possible to the desired temperature.
An oil bath is essentially a container of oil heated by a hot plate, open flame or other heat source.
See also bain-marie.
Another use of an oil bath is to filter particulates out of air, by leading the air stream through an (unheated) oil bath. This type of air filter was used in car engines, but has been replaced by modern paper air filters. | Oil bath
An oil bath is a laboratory heating device which uses boiling oil as the temperature regulator. Since different oils have different boiling points it is possible to obtain a temperature near to the desired temperature by selecting an oil with a boiling point as close as possible to the desired temperature.
An oil bath is essentially a container of oil heated by a hot plate, open flame or other heat source.
See also bain-marie.
Another use of an oil bath is to filter particulates out of air, by leading the air stream through an (unheated) oil bath. This type of air filter was used in car engines, but has been replaced by modern paper air filters.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Oil_bath | |
208057b18828a0ae3972a3c54007f9cad63d8247 | wikidoc | Olaparib | Olaparib
# 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
Olaparib is an antineoplastic agent that is FDA approved for the treatment of patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Common adverse reactions include cough, constipation, dysgeusia, peripheral edema, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash. leukopenia, stomatitis, peripheral neuropathy, pyrexia, hypomagnesemia, hyperglycemia, anxiety, depression, insomnia, dysuria, urinary incontinence, dry skin/ eczema, pruritis, hypertension, venous thrombosis (including pulmonary embolism), and hot flush.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Olaparib is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.
- The indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
### Dosing Information
- Select patients for the treatment of advanced ovarian cancer with Olaparib based on the presence of deleterious or suspected deleterious germline BRCA-mutations .
- The recommended dose of Olaparib is 400 mg (eight 50 mg capsules) taken twice daily, for a total daily dose of 800 mg. Continue treatment until disease progression or unacceptable toxicity.
- If a patient misses a dose of Olaparib , instruct patients to take their next dose at its scheduled time.
- Swallow capsule whole. Do not chew, dissolve, or open capsule. Do not take capsules which appear deformed or show evidence of leakage .
- To manage adverse reactions, consider dose interruption of treatment or dose reduction.
- The recommended dose reduction is to 200 mg (four 50 mg capsules) taken twice daily, for a total daily dose of 400 mg.
- If a further final dose reduction is required, then reduce to 100 mg (two 50 mg capsules) taken twice daily, for a total daily dose of 200 mg.
- Avoid concomitant use of strong and moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. If the inhibitor cannot be avoided, reduce the Olaparib dose to 150 mg (three 50 mg capsules) taken twice daily for a strong CYP3A inhibitor or 200 mg (four 50 mg capsules) taken twice daily for a moderate CYP3A inhibitor
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Olaparib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Olaparib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Olaparib in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Olaparib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Olaparib in pediatric patients.
# Contraindications
- None
# Warnings
- Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 6 out of 298 (2%) patients enrolled in a single arm trial of Olaparib monotherapy, in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with advanced ovarian cancer treated with Olaparib . Overall, MDS/AML were reported in 22 of 2,618 (2 years. All patients had previous chemotherapy with platinum agents and/or other DNA damaging agents.
- Monitor complete blood count testing at baseline and monthly thereafter. Do not start Olaparib until patients have recovered from hematological toxicity caused by previous chemotherapy (≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt Olaparib and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Olaparib .
- Pneumonitis, including fatal cases, occurred in <1% of patients treated with Olaparib . If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with Olaparib and initiate prompt investigation. If pneumonitis is confirmed, discontinue Olaparib .
- Olaparib can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus .
- Advise females of reproductive potential to avoid becoming pregnant while taking Olaparib . If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after receiving the last dose of Olaparib
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions are discussed elsewhere in the labeling:
- Myelodysplastic syndrome/Acute Myeloid Leukemia
- Pneumonitis
- 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.
- Olaparib 400 mg twice daily as monotherapy, has been studied in 300 patients with gBRCA-mutated advanced ovarian cancer, and 223 of these patients had received 3 or more prior lines of chemotherapy.
- In the 223 patients with gBRCA-mutated ovarian cancer who received 3 or more prior lines of chemotherapy (including 137 patients in Study 1 with measureable disease) , adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and discontinuation in 7%. There were 8 (4%) patients with adverse reactions leading to death, two were attributed to acute leukemia, and one each was attributed to COPD, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture. Table 1 presents the frequency of adverse reactions reported in ≥20% of 223 patients (in 6 studies) with gBRCA-mutated advanced ovarian cancer who had received 3 or more prior lines of chemotherapy who were treated with Olaparib 400 mg twice daily. The median exposure to Olaparib in these patients was 158 days.
- The following adverse reactions and laboratory abnormalities have been identified in ≥10 to <20% of the 223 patients receiving Olaparib and not included in the table: cough, constipation, dysgeusia, peripheral edema, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash. The following adverse reactions and laboratory abnormalities have been identified in ≥1 to <10% of the 223 patients receiving Olaparib and not included in the table: leukopenia, stomatitis, peripheralneuropathy, pyrexia, hypomagnesemia, hyperglycemia, anxiety, depression, insomnia, dysuria, urinary incontinence, vulvovaginal disorder, dry skin/ eczema, pruritis, hypertension, venous thrombosis (including pulmonary embolism), and hot flush.
- Table 3 presents adverse reactions reported in ≥20% of patients from a randomized trial of Olaparib 400 mg twice daily as maintenance monotherapy compared to placebo in patients with platinum sensitive, relapsed, high-grade serous ovarian cancer following treatment with 2 or more platinum-containing regimens. Table 4 presents the laboratory abnormalities in patients from this randomized trial. Of the 96 patients with gBRCA-mutation, 53 received Olaparib , and 43 received placebo. The median duration on treatment with Olaparib was 11.1 months for patients with a gBRCA mutation compared to 4.4 months for patients with gBRCA mutation on placebo.
- Adverse reactions led to dose interruptions in 26% of those receiving Olaparib and 7% of those receiving placebo; dose reductions in 15% of Olaparib and 5% of placebo patients; and discontinuation in 9% of Olaparib and 0% in placebo patients. One (2%) patient on Olaparib died as a result of an adverse reaction.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Olaparib in the drug label.
# Drug Interactions
- Olaparib is primarily metabolized by CYP3A.
- Clinical studies of Olaparib in combination with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.
- In patients (N=57), co-administration of itraconazole, a strong CYP3A inhibitor, increased AUC of olaparib by 2.7-fold. A moderate CYP3A inhibitor, fluconazole, is predicted to increase the AUC of olaparib by 2-fold.
- Avoid concomitant use of strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritinovir, lopinavir/ritinovir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and moderate CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil). If the strong or moderate CYP3A inhibitors must be co-administered, reduce the dose of Olaparib .
- Avoid grapefruit and Seville oranges during Olaparib treatment .
- In patients (N=22), co-administration of rifampicin, a strong CYP3A inducer, decreased AUC of olaparib by 87%. A moderate CYP3A inducer, efavirenz, is predicted to decrease the AUC of olaparib by 50-60%.
- Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John’s Wort) and moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin). If a moderate CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy of Olaparib
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Olaparib can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for loss of the pregnancy.
- In a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to day 6 of pregnancy, which resulted in increased post-implantation loss at a dose level of 15 mg/kg/day (with maternal systemic exposures approximately 11% of the human exposure (AUC0-24h) at the recommended dose).
- In an embryo-fetal development study, pregnant rats received oral doses of 0.05 and 0.5 mg/kg/day olaparib during the period of organogenesis. A dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.3% of human exposure (AUC0-24h) at the recommended dose) caused embryo-fetal toxicities including increased post-implantation loss and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center; fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital) and diaphragm (hernia). Additional abnormalities or variants included incomplete or absent ossification (vertebrae/sternebrae, ribs, limbs) and other findings in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter and umbilical artery. Some findings noted above in the eyes, ribs and ureter were observed at a dose of 0.05 mg/kg/day olaparib at lower incidence.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Olaparib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Olaparib during labor and delivery.
### Nursing Mothers
- It is not known whether olaparib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from olaparib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and efficacy of Olaparib has not been established in pediatric patients.
### Geriatic Use
- In clinical studies of Olaparib enrolling 735 patients with advanced solid tumors who received Olaparib 400 mg twice daily as monotherapy, 148 (20%) of patients were aged ≥65 years. The safety profile was similar irrespective of age with the exception of AEs of CTCAE ≥3 which were reported more frequently in patients aged ≥65 years (53.4%) than those <65 years (43.4%). No individual adverse event or System Organ Class accounted for this observed difference.
### Gender
There is no FDA guidance on the use of Olaparib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Olaparib with respect to specific racial populations.
### Renal Impairment
- Based on preliminary data, a 1.5 fold increase in mean exposure (AUC) was observed in patients with mild renal impairment (CLcr = 50-80 mL/min) compared to patients with normal renal function (CLcr >80 mL/min). No dose adjustment to the starting dose is required in patients with CLcr of 50 to 80 mL/min, but patients should be monitored closely for toxicity. There are no data in patients with moderate or severe renal impairment (CLcr <50 mL/min) or patients on dialysis
### Hepatic Impairment
- The effect of hepatic impairment on exposure to Olaparib has not been studied. Patients with bilirubin >1.5 X ULN and AST/ALT ≥2.5 X ULN (≥5 X ULN in the presence of liver metastases) were excluded from Olaparib clinical trials. There are no data in patients with baseline hepatic impairment (serum bilirubin >1.5 X ULN)
### Females of Reproductive Potential and Males
- Olaparib can cause fetal harm when administered to a pregnant woman . Advise female patients of reproductive potential to avoid pregnancy while taking Olaparib . If contraceptive methods are being considered, use highly effective contraception during treatment with Olaparib and for at least one month following the last dose of Olaparib . Instruct patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Olaparib .
### Immunocompromised Patients
There is no FDA guidance one the use of Olaparib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Olaparib in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Olaparib in the drug label.
# Overdosage
- There is no specific treatment in the event of Olaparib overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow general supportive measures and should treat symptomatically.
# Pharmacology
## Mechanism of Action
- Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular homeostasis, such as DNA transcription, cell cycle regulation, and DNA repair. Olaparib has been shown to inhibit growth of select tumor cell linesin vitro and decrease tumor growth in mouse xenograft models of human cancer both as monotherapy or following platinum-based chemotherapy. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation ofPARP-DNA complex, resulting in disruption of cellular homeostasis and cell death.
## Structure
- Olaparib is an inhibitor of the mammalian polyadenosine 5’-diphosphoribose polymerase (PARP) enzyme.
The chemical name is 4-carbonyl}-4-fluorophenyl)methyl]phthalazin-1(2H)-one and it has the following chemical structure:
- The empirical molecular formula for Olaparib is C24H23FN4O3 and the relative molecular mass is 434.46.
- Olaparib is a crystalline solid, is non-chiral and shows pH-independent low solubility of approximately 0.1 mg/mL across the physiological pH range.
- Olaparib is available in 50 mg capsules for oral administration. Each capsule contains olaparib as the active ingredient and the following inactive ingredients:
- Capsule content: lauroyl polyoxylglycerides
- Capsule shell: hypromellose, titanium dioxide, gellan gum, potassium acetate
- Capsule printing ink: shellac, ferrosoferric oxide
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Olaparib in the drug label.
## Pharmacokinetics
- Following oral administration of olaparib via the capsule formulation, absorption is rapid with peak plasma concentrations typically achieved between 1 to 3 hours after dosing. On multiple dosing there is no marked accumulation (accumulation ratio of 1.4 – 1.5 for twice daily dosing), with steady state exposures achieved within 3 to 4 days.
- Limited data suggest that the systemic exposure (AUC) of olaparib increases less than proportionally with dose over the dose range of 100 to 400 mg, but the PK data were variable across trials.
- Co-administration with a high fat meal slowed the rate (Tmax delayed by 2 hours) of absorption, but did not significantly alter the extent of olaparib absorption (mean AUC increased by approximately 20%).
- Olaparib had a mean (± standard deviation) apparent volume of distribution at steady state of 167 ± 196 L after a single 400 mg dose of olaparib. The in vitro protein binding of olaparib at plasma concentrations achieved following dosing at 400 mg twice daily is approximately 82%.
- In vitro, CYP3A4 was shown to be the enzyme primarily responsible for the metabolism of olaparib.
- Following oral dosing of 14C-olaparib to female patients, unchanged olaparib accounted for the majority of the circulating radioactivity in plasma (70%). It was extensively metabolized with unchanged drug accounting for 15% and 6% of radioactivity in urine and feces, respectively. The majority of the metabolism is attributable to oxidation reactions with a number of the components produced undergoing subsequent glucuronide or sulfate conjugation.
- A mean (± standard deviation) terminal plasma half-life of 11.9 ± 4.8 hours and apparent plasma clearance of 8.6 ± 7.1L/h were observed after a single 400 mg dose of olaparib.
- Following a single dose of 14C-olaparib, 86% of the dosed radioactivity was recovered within a 7-day collection period, 44% via the urine and 42% via the feces. The majority of the material was excreted as metabolites.
- Based on preliminary data from a dedicated renal impairment trial, the mean AUC and Cmax of olaparib increased by 1.5- and 1.2-fold, respectively, when olaparib was dosed in patients with mild renal impairment (CLcr = 50-80 mL/min; N=14) compared to those with normal renal function (CLcr >80 mL/min; N=8). There are no data in patients with CLcr <50 mL/min or in patients on dialysis.
- In vitro, olaparib was an inhibitor of CYP3A4 and an inducer of CYP2B6 at higher concentrations than are clinically achieved. Olaparib produced little/no inhibition of other CYP isozymes. In vitro studies have shown that olaparib is a substrate of CYP3A4.
- Based on the data from a drug-interaction trial (N=57), the AUC and Cmax of olaparib increased by 2.7-and 1.4-fold, respectively, when olaparib was administered in combination with itraconazole, a strong CYP3A inhibitor. Simulations using physiologically-based pharmacokinetic (PBPK) models suggested that a moderate CYP3A inhibitor (fluconazole) may increase the AUC and Cmax of olaparib by 2-and 1.1-fold, respectively.
- Based on the data from a drug-interaction trial (N=22), the AUC and Cmax of olaparib decreased by 87% and 71%, respectively, when olaparib was administered in combination with rifampicin, a strong CYP3A inducer. Simulations using PBPK models suggested that a moderate CYP3A inducer (efavirenz) may decrease the AUC and Cmax of olaparib by 50 - 60% and 20 - 30%, respectively.
- In vitro studies have shown that olaparib is a substrate of P-gp and an inhibitor of BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K. The clinical relevance of these findings is unknown.
## Nonclinical Toxicology
- Carcinogenicity studies have not been conducted with olaparib.
- Olaparib was clastogenic in an in vitro chromosomal aberration assay in mammalian CHO cells and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of olaparib and indicates potential for genotoxicity in humans. Olaparib was not mutagenic in a bacterial reverse mutation (Ames) test.
- In a fertility study, female rats received oral olaparib at doses of 0.05, 0.5, and 15 mg/kg/day for at least 14 days before mating through the first week of pregnancy. There were no adverse effects on mating and fertility rates at doses up to 15 mg/kg/day (maternal systemic exposures approximately 11% of the human exposure (AUC0-24h) at the recommended dose).
- In a male fertility study, olaparib had no effect on mating and fertility in rats at oral doses up to 40 mg/kg/day following at least 70 days of olaparib treatment (with systemic exposures of approximately 7% of the human exposure (AUC0-24h) at the recommended dose).
# Clinical Studies
- The efficacy of Olaparib was investigated in a single-arm study in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers (Study 1). A total of 137 patients with measurable, gBRCAm-associated ovarian cancer treated with three or more prior lines of chemotherapy were enrolled. All patients received Olaparib at a dose of 400 mg twice daily as monotherapy until disease progression or intolerable toxicity. Objective response rate (ORR) and duration of response (DOR) were assessed by the investigator according to RECIST v1.1.
- The median age of the patients was 58 years, the majority were Caucasian (94%) and 93% had an ECOG PS of 0 or 1. Deleterious or suspected deleterious, germline BRCA mutation status was verified retrospectively in 97% (59/61) of the patients for whom blood samples were available by the companion diagnostic BRACAnalysis CDx™, which is FDA approved for selection of patients for Olaparib treatment.
- Efficacy results from Study 1 are summarized in Table 5.
# How Supplied
- Olaparib 50 mg is a white, opaque, hard capsule, marked in black ink with: “OLAPARIB 50 mg” on the cap and AstraZeneca logo on the body; available in:
- Bottles of 112 capsules NDC 0310-0657-58
## Storage
- Store at 25ºC (77ºF), excursions permitted to 15-30ºC (59-86ºF)
- Olaparib should not be exposed to temperatures greater than 40ºC or 104ºF. Do not take Olaparib if it is suspected of having been exposed to temperatures greater than 40ºC or 104ºF.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Dosing Instructions: Inform patients on how to take Olaparib . Olaparib should be taken twice daily. Instruct patients that if they miss a dose of Olaparib , not to take an extra dose to make up for the one that they missed. They should take their next normal dose at the usual time. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsule. Patient should not take Olaparib with grapefruit or Seville oranges.
- MDS/AML: Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions. This may be a sign of hematological toxicity or a more serious uncommon bone marrow problem called ‘myelodysplastic syndrome’ (MDS) or ‘acute myeloid leukemia’ (AML) which have been reported in patients treated with Olaparib .
- Pneumonitis: Advise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including shortness of breath, fever, cough, or wheezing
- Pregnancy and Females of Reproductive Potential: Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy . Advise females of reproductive potential to use effective contraception during treatment with Olaparib and for at least one month after receiving the last dose of Olaparib .
- Nursing Mothers: Advise patients not to breastfeed while taking Olaparib .
- Nausea/vomiting: Advise patients that mild or moderate nausea and/or vomiting is very common in patients receiving Olaparib and that they should contact their healthcare provider who will advise on available antiemetic treatment options.
# Precautions with Alcohol
- Alcohol-Olaparib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Lynparza ®
# Look-Alike Drug Names
There is limited information regarding Olaparib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Olaparib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
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# Overview
Olaparib is an antineoplastic agent that is FDA approved for the treatment of patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Common adverse reactions include cough, constipation, dysgeusia, peripheral edema, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash. leukopenia, stomatitis, peripheral neuropathy, pyrexia, hypomagnesemia, hyperglycemia, anxiety, depression, insomnia, dysuria, urinary incontinence, dry skin/ eczema, pruritis, hypertension, venous thrombosis (including pulmonary embolism), and hot flush.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Olaparib is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.
- The indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
### Dosing Information
- Select patients for the treatment of advanced ovarian cancer with Olaparib based on the presence of deleterious or suspected deleterious germline BRCA-mutations .
- The recommended dose of Olaparib is 400 mg (eight 50 mg capsules) taken twice daily, for a total daily dose of 800 mg. Continue treatment until disease progression or unacceptable toxicity.
- If a patient misses a dose of Olaparib , instruct patients to take their next dose at its scheduled time.
- Swallow capsule whole. Do not chew, dissolve, or open capsule. Do not take capsules which appear deformed or show evidence of leakage .
- To manage adverse reactions, consider dose interruption of treatment or dose reduction.
- The recommended dose reduction is to 200 mg (four 50 mg capsules) taken twice daily, for a total daily dose of 400 mg.
- If a further final dose reduction is required, then reduce to 100 mg (two 50 mg capsules) taken twice daily, for a total daily dose of 200 mg.
- Avoid concomitant use of strong and moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. If the inhibitor cannot be avoided, reduce the Olaparib dose to 150 mg (three 50 mg capsules) taken twice daily for a strong CYP3A inhibitor or 200 mg (four 50 mg capsules) taken twice daily for a moderate CYP3A inhibitor
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Olaparib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Olaparib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Olaparib in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Olaparib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Olaparib in pediatric patients.
# Contraindications
- None
# Warnings
- Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 6 out of 298 (2%) patients enrolled in a single arm trial of Olaparib monotherapy, in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with advanced ovarian cancer treated with Olaparib . Overall, MDS/AML were reported in 22 of 2,618 (<1%) patients treated with Olaparib . The majority of MDS/AML cases (17 of 22 cases) were fatal, and the duration of therapy with Olaparib in patients who developed secondary MDS/cancer-therapy related AML varied from <6 months to >2 years. All patients had previous chemotherapy with platinum agents and/or other DNA damaging agents.
- Monitor complete blood count testing at baseline and monthly thereafter. Do not start Olaparib until patients have recovered from hematological toxicity caused by previous chemotherapy (≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt Olaparib and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Olaparib .
- Pneumonitis, including fatal cases, occurred in <1% of patients treated with Olaparib . If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with Olaparib and initiate prompt investigation. If pneumonitis is confirmed, discontinue Olaparib .
- Olaparib can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus .
- Advise females of reproductive potential to avoid becoming pregnant while taking Olaparib . If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after receiving the last dose of Olaparib
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions are discussed elsewhere in the labeling:
- Myelodysplastic syndrome/Acute Myeloid Leukemia
- Pneumonitis
- 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.
- Olaparib 400 mg twice daily as monotherapy, has been studied in 300 patients with gBRCA-mutated advanced ovarian cancer, and 223 of these patients had received 3 or more prior lines of chemotherapy.
- In the 223 patients with gBRCA-mutated ovarian cancer who received 3 or more prior lines of chemotherapy (including 137 patients in Study 1 with measureable disease) , adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and discontinuation in 7%. There were 8 (4%) patients with adverse reactions leading to death, two were attributed to acute leukemia, and one each was attributed to COPD, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture. Table 1 presents the frequency of adverse reactions reported in ≥20% of 223 patients (in 6 studies) with gBRCA-mutated advanced ovarian cancer who had received 3 or more prior lines of chemotherapy who were treated with Olaparib 400 mg twice daily. The median exposure to Olaparib in these patients was 158 days.
- The following adverse reactions and laboratory abnormalities have been identified in ≥10 to <20% of the 223 patients receiving Olaparib and not included in the table: cough, constipation, dysgeusia, peripheral edema, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash. The following adverse reactions and laboratory abnormalities have been identified in ≥1 to <10% of the 223 patients receiving Olaparib and not included in the table: leukopenia, stomatitis, peripheralneuropathy, pyrexia, hypomagnesemia, hyperglycemia, anxiety, depression, insomnia, dysuria, urinary incontinence, vulvovaginal disorder, dry skin/ eczema, pruritis, hypertension, venous thrombosis (including pulmonary embolism), and hot flush.
- Table 3 presents adverse reactions reported in ≥20% of patients from a randomized trial of Olaparib 400 mg twice daily as maintenance monotherapy compared to placebo in patients with platinum sensitive, relapsed, high-grade serous ovarian cancer following treatment with 2 or more platinum-containing regimens. Table 4 presents the laboratory abnormalities in patients from this randomized trial. Of the 96 patients with gBRCA-mutation, 53 received Olaparib , and 43 received placebo. The median duration on treatment with Olaparib was 11.1 months for patients with a gBRCA mutation compared to 4.4 months for patients with gBRCA mutation on placebo.
- Adverse reactions led to dose interruptions in 26% of those receiving Olaparib and 7% of those receiving placebo; dose reductions in 15% of Olaparib and 5% of placebo patients; and discontinuation in 9% of Olaparib and 0% in placebo patients. One (2%) patient on Olaparib died as a result of an adverse reaction.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Olaparib in the drug label.
# Drug Interactions
- Olaparib is primarily metabolized by CYP3A.
- Clinical studies of Olaparib in combination with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.
- In patients (N=57), co-administration of itraconazole, a strong CYP3A inhibitor, increased AUC of olaparib by 2.7-fold. A moderate CYP3A inhibitor, fluconazole, is predicted to increase the AUC of olaparib by 2-fold.
- Avoid concomitant use of strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritinovir, lopinavir/ritinovir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and moderate CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil). If the strong or moderate CYP3A inhibitors must be co-administered, reduce the dose of Olaparib .
- Avoid grapefruit and Seville oranges during Olaparib treatment .
- In patients (N=22), co-administration of rifampicin, a strong CYP3A inducer, decreased AUC of olaparib by 87%. A moderate CYP3A inducer, efavirenz, is predicted to decrease the AUC of olaparib by 50-60%.
- Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John’s Wort) and moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin). If a moderate CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy of Olaparib
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Olaparib can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for loss of the pregnancy.
- In a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to day 6 of pregnancy, which resulted in increased post-implantation loss at a dose level of 15 mg/kg/day (with maternal systemic exposures approximately 11% of the human exposure (AUC0-24h) at the recommended dose).
- In an embryo-fetal development study, pregnant rats received oral doses of 0.05 and 0.5 mg/kg/day olaparib during the period of organogenesis. A dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.3% of human exposure (AUC0-24h) at the recommended dose) caused embryo-fetal toxicities including increased post-implantation loss and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center; fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital) and diaphragm (hernia). Additional abnormalities or variants included incomplete or absent ossification (vertebrae/sternebrae, ribs, limbs) and other findings in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter and umbilical artery. Some findings noted above in the eyes, ribs and ureter were observed at a dose of 0.05 mg/kg/day olaparib at lower incidence.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Olaparib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Olaparib during labor and delivery.
### Nursing Mothers
- It is not known whether olaparib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from olaparib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and efficacy of Olaparib has not been established in pediatric patients.
### Geriatic Use
- In clinical studies of Olaparib enrolling 735 patients with advanced solid tumors [the majority (69%) of whom had ovarian cancer] who received Olaparib 400 mg twice daily as monotherapy, 148 (20%) of patients were aged ≥65 years. The safety profile was similar irrespective of age with the exception of AEs of CTCAE ≥3 which were reported more frequently in patients aged ≥65 years (53.4%) than those <65 years (43.4%). No individual adverse event or System Organ Class accounted for this observed difference.
### Gender
There is no FDA guidance on the use of Olaparib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Olaparib with respect to specific racial populations.
### Renal Impairment
- Based on preliminary data, a 1.5 fold increase in mean exposure (AUC) was observed in patients with mild renal impairment (CLcr = 50-80 mL/min) compared to patients with normal renal function (CLcr >80 mL/min). No dose adjustment to the starting dose is required in patients with CLcr of 50 to 80 mL/min, but patients should be monitored closely for toxicity. There are no data in patients with moderate or severe renal impairment (CLcr <50 mL/min) or patients on dialysis
### Hepatic Impairment
- The effect of hepatic impairment on exposure to Olaparib has not been studied. Patients with bilirubin >1.5 X ULN and AST/ALT ≥2.5 X ULN (≥5 X ULN in the presence of liver metastases) were excluded from Olaparib clinical trials. There are no data in patients with baseline hepatic impairment (serum bilirubin >1.5 X ULN)
### Females of Reproductive Potential and Males
- Olaparib can cause fetal harm when administered to a pregnant woman . Advise female patients of reproductive potential to avoid pregnancy while taking Olaparib . If contraceptive methods are being considered, use highly effective contraception during treatment with Olaparib and for at least one month following the last dose of Olaparib . Instruct patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Olaparib .
### Immunocompromised Patients
There is no FDA guidance one the use of Olaparib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Olaparib in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Olaparib in the drug label.
# Overdosage
- There is no specific treatment in the event of Olaparib overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow general supportive measures and should treat symptomatically.
# Pharmacology
## Mechanism of Action
- Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular homeostasis, such as DNA transcription, cell cycle regulation, and DNA repair. Olaparib has been shown to inhibit growth of select tumor cell linesin vitro and decrease tumor growth in mouse xenograft models of human cancer both as monotherapy or following platinum-based chemotherapy. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation ofPARP-DNA complex, resulting in disruption of cellular homeostasis and cell death.
## Structure
- Olaparib is an inhibitor of the mammalian polyadenosine 5’-diphosphoribose polymerase (PARP) enzyme.
The chemical name is 4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]phthalazin-1(2H)-one and it has the following chemical structure:
- The empirical molecular formula for Olaparib is C24H23FN4O3 and the relative molecular mass is 434.46.
- Olaparib is a crystalline solid, is non-chiral and shows pH-independent low solubility of approximately 0.1 mg/mL across the physiological pH range.
- Olaparib is available in 50 mg capsules for oral administration. Each capsule contains olaparib as the active ingredient and the following inactive ingredients:
- Capsule content: lauroyl polyoxylglycerides
- Capsule shell: hypromellose, titanium dioxide, gellan gum, potassium acetate
- Capsule printing ink: shellac, ferrosoferric oxide
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Olaparib in the drug label.
## Pharmacokinetics
- Following oral administration of olaparib via the capsule formulation, absorption is rapid with peak plasma concentrations typically achieved between 1 to 3 hours after dosing. On multiple dosing there is no marked accumulation (accumulation ratio of 1.4 – 1.5 for twice daily dosing), with steady state exposures achieved within 3 to 4 days.
- Limited data suggest that the systemic exposure (AUC) of olaparib increases less than proportionally with dose over the dose range of 100 to 400 mg, but the PK data were variable across trials.
- Co-administration with a high fat meal slowed the rate (Tmax delayed by 2 hours) of absorption, but did not significantly alter the extent of olaparib absorption (mean AUC increased by approximately 20%).
- Olaparib had a mean (± standard deviation) apparent volume of distribution at steady state of 167 ± 196 L after a single 400 mg dose of olaparib. The in vitro protein binding of olaparib at plasma concentrations achieved following dosing at 400 mg twice daily is approximately 82%.
- In vitro, CYP3A4 was shown to be the enzyme primarily responsible for the metabolism of olaparib.
- Following oral dosing of 14C-olaparib to female patients, unchanged olaparib accounted for the majority of the circulating radioactivity in plasma (70%). It was extensively metabolized with unchanged drug accounting for 15% and 6% of radioactivity in urine and feces, respectively. The majority of the metabolism is attributable to oxidation reactions with a number of the components produced undergoing subsequent glucuronide or sulfate conjugation.
- A mean (± standard deviation) terminal plasma half-life of 11.9 ± 4.8 hours and apparent plasma clearance of 8.6 ± 7.1L/h were observed after a single 400 mg dose of olaparib.
- Following a single dose of 14C-olaparib, 86% of the dosed radioactivity was recovered within a 7-day collection period, 44% via the urine and 42% via the feces. The majority of the material was excreted as metabolites.
- Based on preliminary data from a dedicated renal impairment trial, the mean AUC and Cmax of olaparib increased by 1.5- and 1.2-fold, respectively, when olaparib was dosed in patients with mild renal impairment (CLcr = 50-80 mL/min; N=14) compared to those with normal renal function (CLcr >80 mL/min; N=8). There are no data in patients with CLcr <50 mL/min or in patients on dialysis.
- In vitro, olaparib was an inhibitor of CYP3A4 and an inducer of CYP2B6 at higher concentrations than are clinically achieved. Olaparib produced little/no inhibition of other CYP isozymes. In vitro studies have shown that olaparib is a substrate of CYP3A4.
- Based on the data from a drug-interaction trial (N=57), the AUC and Cmax of olaparib increased by 2.7-and 1.4-fold, respectively, when olaparib was administered in combination with itraconazole, a strong CYP3A inhibitor. Simulations using physiologically-based pharmacokinetic (PBPK) models suggested that a moderate CYP3A inhibitor (fluconazole) may increase the AUC and Cmax of olaparib by 2-and 1.1-fold, respectively.
- Based on the data from a drug-interaction trial (N=22), the AUC and Cmax of olaparib decreased by 87% and 71%, respectively, when olaparib was administered in combination with rifampicin, a strong CYP3A inducer. Simulations using PBPK models suggested that a moderate CYP3A inducer (efavirenz) may decrease the AUC and Cmax of olaparib by 50 - 60% and 20 - 30%, respectively.
- In vitro studies have shown that olaparib is a substrate of P-gp and an inhibitor of BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K. The clinical relevance of these findings is unknown.
## Nonclinical Toxicology
- Carcinogenicity studies have not been conducted with olaparib.
- Olaparib was clastogenic in an in vitro chromosomal aberration assay in mammalian CHO cells and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of olaparib and indicates potential for genotoxicity in humans. Olaparib was not mutagenic in a bacterial reverse mutation (Ames) test.
- In a fertility study, female rats received oral olaparib at doses of 0.05, 0.5, and 15 mg/kg/day for at least 14 days before mating through the first week of pregnancy. There were no adverse effects on mating and fertility rates at doses up to 15 mg/kg/day (maternal systemic exposures approximately 11% of the human exposure (AUC0-24h) at the recommended dose).
- In a male fertility study, olaparib had no effect on mating and fertility in rats at oral doses up to 40 mg/kg/day following at least 70 days of olaparib treatment (with systemic exposures of approximately 7% of the human exposure (AUC0-24h) at the recommended dose).
# Clinical Studies
- The efficacy of Olaparib was investigated in a single-arm study in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers (Study 1). A total of 137 patients with measurable, gBRCAm-associated ovarian cancer treated with three or more prior lines of chemotherapy were enrolled. All patients received Olaparib at a dose of 400 mg twice daily as monotherapy until disease progression or intolerable toxicity. Objective response rate (ORR) and duration of response (DOR) were assessed by the investigator according to RECIST v1.1.
- The median age of the patients was 58 years, the majority were Caucasian (94%) and 93% had an ECOG PS of 0 or 1. Deleterious or suspected deleterious, germline BRCA mutation status was verified retrospectively in 97% (59/61) of the patients for whom blood samples were available by the companion diagnostic BRACAnalysis CDx™, which is FDA approved for selection of patients for Olaparib treatment.
- Efficacy results from Study 1 are summarized in Table 5.
# How Supplied
- Olaparib 50 mg is a white, opaque, hard capsule, marked in black ink with: “OLAPARIB 50 mg” on the cap and AstraZeneca logo on the body; available in:
- Bottles of 112 capsules NDC 0310-0657-58
## Storage
- Store at 25ºC (77ºF), excursions permitted to 15-30ºC (59-86ºF) [see USP Controlled Room Temperature]
- Olaparib should not be exposed to temperatures greater than 40ºC or 104ºF. Do not take Olaparib if it is suspected of having been exposed to temperatures greater than 40ºC or 104ºF.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Dosing Instructions: Inform patients on how to take Olaparib . Olaparib should be taken twice daily. Instruct patients that if they miss a dose of Olaparib , not to take an extra dose to make up for the one that they missed. They should take their next normal dose at the usual time. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsule. Patient should not take Olaparib with grapefruit or Seville oranges.
- MDS/AML: Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions. This may be a sign of hematological toxicity or a more serious uncommon bone marrow problem called ‘myelodysplastic syndrome’ (MDS) or ‘acute myeloid leukemia’ (AML) which have been reported in patients treated with Olaparib .
- Pneumonitis: Advise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including shortness of breath, fever, cough, or wheezing
- Pregnancy and Females of Reproductive Potential: Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy . Advise females of reproductive potential to use effective contraception during treatment with Olaparib and for at least one month after receiving the last dose of Olaparib .
- Nursing Mothers: Advise patients not to breastfeed while taking Olaparib .
- Nausea/vomiting: Advise patients that mild or moderate nausea and/or vomiting is very common in patients receiving Olaparib and that they should contact their healthcare provider who will advise on available antiemetic treatment options.
# Precautions with Alcohol
- Alcohol-Olaparib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Lynparza ®
# Look-Alike Drug Names
There is limited information regarding Olaparib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Olaparib | |
5c2a992ea6ada884beeb8ebbd71ae461597b7e9f | wikidoc | Omegaven | Omegaven
# Overview
Omegaven is a fatty acid emulsion produced by Fresenius Kabi. It is used for total parenteral nutrition (feeding directly into a venous catheter), e.g. in short bowel syndrome. It is rich in omega-3 fatty acids.
It has gained popularity in children in preference to the more commonly used Intralipid after case reports that it reduced the risk of liver damage.
A recent study indicated that the use of Omegaven may be an appropriate intervention strategy for newborns with a very low birth weight, gastrochisis, and jejunal atresia.
It is currently undergoing a clinical trial at National Taiwan University Hospital.
Although the use of Omegaven in children in the United States is experimental, the use of it in adults in Europe is less controversial. In European studies, Omegaven has been associated with a reduction in psoriasis, when contrasted to administration of omega-6 fatty acid Lipoven. Omegaven has also been associated with reduced mortality and antibiotic use during hospital stays. | Omegaven
# Overview
Omegaven is a fatty acid emulsion produced by Fresenius Kabi. It is used for total parenteral nutrition (feeding directly into a venous catheter), e.g. in short bowel syndrome. It is rich in omega-3 fatty acids.
It has gained popularity in children in preference to the more commonly used Intralipid after case reports that it reduced the risk of liver damage.[1]
A recent study indicated that the use of Omegaven may be an appropriate intervention strategy for newborns with a very low birth weight, gastrochisis, and jejunal atresia.[2]
It is currently undergoing a clinical trial at National Taiwan University Hospital.[3]
Although the use of Omegaven in children in the United States is experimental, the use of it in adults in Europe is less controversial.[4] In European studies, Omegaven has been associated with a reduction in psoriasis, when contrasted to administration of omega-6 fatty acid Lipoven.[5] Omegaven has also been associated with reduced mortality and antibiotic use during hospital stays.[6] | https://www.wikidoc.org/index.php/Omegaven | |
0772f722e911a7d4e86ea61021762f3a82939c99 | wikidoc | Omnivore | Omnivore
Omnivores (from Latin: omne all, everything; vorare to devour) are species that eat both plants and animals as their primary food source. They are opportunistic, general feeders not specifically adapted to eat and digest either meat or plant material exclusively.
Pigs are one well-known example of an omnivore.
Crows are another example of an omnivore that many people see every day. Humans themselves are omnivores.
Although there are reported cases of herbivores eating meat matter as well as examples of carnivores eating plants, the classification refers to the adaptations and main food source of the species in general so these exceptions do not make either individual animals nor the species as a whole omnivores.
Most bear species are considered omnivores, but individuals' diets can range from almost exclusively herbivorous to almost exclusively carnivorous depending on what food sources are available locally and seasonally. Polar bears can be classified as carnivores while pandas almost exclusively eat bamboo and are therefore herbivores.
# Species considered omnivorous
- Various mammals
Bears
Coatis
Canines like gray wolves or dingos eat meat and some vegetable manner
Hedgehogs
Opossums
Pigs
Some primates including chimpanzees and humans
Raccoons
Rodents, including Chipmunks, Mice, Rats and Squirrels
Skunks
Sloths
- Bears
- Coatis
- Canines like gray wolves or dingos eat meat and some vegetable manner
- Hedgehogs
- Opossums
- Pigs
- Some primates including chimpanzees and humans
- Raccoons
- Rodents, including Chipmunks, Mice, Rats and Squirrels
- Skunks
- Sloths
- Various birds (whose prey can consist of berries and nectar to insects, worms, fish, small rodents and snakes)
Cassowarys
Chickens
Corvids, including Crows, Magpies, Ravens and Rooks
Keas
Rails
Rheas
- Cassowarys
- Chickens
- Corvids, including Crows, Magpies, Ravens and Rooks
- Keas
- Rails
- Rheas
- Some fish such as Piranhas
- Some lizards and turtles | Omnivore
Omnivores (from Latin: omne all, everything; vorare to devour) are species that eat both plants and animals as their primary food source. They are opportunistic, general feeders not specifically adapted to eat and digest either meat or plant material exclusively.[1]
Pigs are one well-known example of an omnivore.[2]
Crows are another example of an omnivore that many people see every day.[3] Humans themselves are omnivores.
Although there are reported cases of herbivores eating meat matter as well as examples of carnivores eating plants, the classification refers to the adaptations and main food source of the species in general so these exceptions do not make either individual animals nor the species as a whole omnivores.
Most bear species are considered omnivores, but individuals' diets can range from almost exclusively herbivorous to almost exclusively carnivorous depending on what food sources are available locally and seasonally. Polar bears can be classified as carnivores while pandas almost exclusively eat bamboo and are therefore herbivores.
# Species considered omnivorous
- Various mammals
Bears
Coatis
Canines like gray wolves or dingos eat meat and some vegetable manner
Hedgehogs
Opossums
Pigs
Some primates including chimpanzees and humans
Raccoons
Rodents, including Chipmunks, Mice, Rats and Squirrels
Skunks
Sloths
- Bears
- Coatis
- Canines like gray wolves or dingos eat meat and some vegetable manner
- Hedgehogs
- Opossums
- Pigs
- Some primates including chimpanzees and humans
- Raccoons
- Rodents, including Chipmunks, Mice, Rats and Squirrels
- Skunks
- Sloths
- Various birds (whose prey can consist of berries and nectar to insects, worms, fish, small rodents and snakes)
Cassowarys
Chickens
Corvids, including Crows, Magpies, Ravens and Rooks
Keas
Rails
Rheas
- Cassowarys
- Chickens
- Corvids, including Crows, Magpies, Ravens and Rooks
- Keas
- Rails
- Rheas
- Some fish such as Piranhas
- Some lizards and turtles | https://www.wikidoc.org/index.php/Omnivore | |
5d916e4953bf0716d3b136c0d2ea96fa6c965f9a | wikidoc | Oogonium | Oogonium
# Overview
An oogonium (plural oogonia) is an immature ovum. It is a female gametogonium. They are formed in large numbers by mitosis early in fetal life from primordial germ cells, which are present in the fetus between weeks 4 and 8.
Oogonia are present in the fetus between weeks 5 and 30.
Oogonia are also the female reproductive structures in certain thallophytes, and are usually rounded cells or sacs containing one or more oospheres.
# Further development
Once the primordial germ cells have gotten to the ovary, they develop into oogonia. During week 6 of development, oogonia migrate from the yolk sac to the genital ridge ( site of the future gonads-ovaries in this case) located on the posterior abdominal wall.
Oogonia develop by mitosis. However, some of them become primary oocytes, which begin meiosis which is halted in prophase I. When they have entered Prophase I of meiosis they become primary oocytes; it is important to note that this process is complete before birth, in contrast to spermatogenesis. Primary oocytes are present from week 10 until menopause at ~53 years
# Oogamy
Oogamy may be spelt oögamy with a diaresis (or umlaut). The link with other articles may depend on this symbol.
# Oogonia
## Algae
This term is used in (the study of algae) to refer to the union of the male (motile or non-motile) with the female gamete.The female oogonium is usually enlarged and develops a single ovum. The male (antheridium) usually produces many cells with flagella except in the Rhodophyta which have no flagella. There is no evidence that the red algae ever had flagella, or cilia and it is suggested that they are the most primitive eukaryotes.
## Fungi
Oogonia also occur in the fungi. | Oogonium
Template:Infobox Anatomy
# Overview
An oogonium (plural oogonia) is an immature ovum. It is a female gametogonium. They are formed in large numbers by mitosis early in fetal life from primordial germ cells, which are present in the fetus between weeks 4 and 8.
Oogonia are present in the fetus between weeks 5 and 30.
Oogonia are also the female reproductive structures in certain thallophytes, and are usually rounded cells or sacs containing one or more oospheres.
# Further development
Once the primordial germ cells have gotten to the ovary, they develop into oogonia. During week 6 of development, oogonia migrate from the yolk sac to the genital ridge ( site of the future gonads-ovaries in this case) located on the posterior abdominal wall.
Oogonia develop by mitosis. However, some of them become primary oocytes, which begin meiosis which is halted in prophase I. When they have entered Prophase I of meiosis they become primary oocytes; it is important to note that this process is complete before birth, in contrast to spermatogenesis. Primary oocytes are present from week 10 until menopause at ~53 years
# Oogamy
Oogamy may be spelt oögamy with a diaresis (or umlaut). The link with other articles may depend on this symbol.
# Oogonia
## Algae
This term is used in [phycology] (the study of algae) to refer to the union of the male (motile or non-motile) with the female gamete.[1]The female oogonium is usually enlarged and develops a single ovum. The male (antheridium) usually produces many cells with flagella except in the Rhodophyta which have no flagella. [2] There is no evidence that the red algae ever had flagella, or cilia and it is suggested that they are the most primitive eukaryotes.[3]
## Fungi
Oogonia also occur in the fungi.[4] | https://www.wikidoc.org/index.php/Oogonia | |
1c30ab92ca180332ada328fab7cc3c33f28264b6 | wikidoc | Ophiasis | Ophiasis
Ophiasis is a form of alopecia areata characterized by the the loss of hair in the shape of a wave at the circumference of the head.
It gets its name from "ophis", which is the Greek word for snake, because of the apparent similarity to a snake-shape and the pattern of hair loss.
The term "sisaipho" is used to characterize the inverse pattern. Sisaipho is the reverse spelling of ophiasis. It is also called "ophiasis inversus". | Ophiasis
Ophiasis is a form of alopecia areata characterized by the the loss of hair in the shape of a wave at the circumference of the head. [1]
It gets its name from "ophis", which is the Greek word for snake, because of the apparent similarity to a snake-shape and the pattern of hair loss.[2]
The term "sisaipho" is used to characterize the inverse pattern. Sisaipho is the reverse spelling of ophiasis.[3] It is also called "ophiasis inversus".[4] | https://www.wikidoc.org/index.php/Ophiasis | |
52070fa0c55261f13f454c44e6f4419641af0154 | wikidoc | Orlistat | Orlistat
# 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
Orlistat is an antiobesity drug that is FDA approved for the treatment of obesity including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet. Common adverse reactions include oily spotting, flatus with discharge,fecal urgency,fatty/oily stool,oily evacuation,
increased defecation, fecal incontinence, abdominal pain/discomfort, nausea, influenza, back pain, rash.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Orlistat is indicated for obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet. Orlistat is also indicated to reduce the risk for weight regain after prior weight loss. Orlistat is indicated for obese patients with an initial body mass index (BMI) ≥30 kg/m2 or ≥27 kg/m2 in the presence of other risk factors (e.g., hypertension, diabetes, dyslipidemia).
- TABLE 1 illustrates body mass index (BMI) according to a variety of weights and heights. The BMI is calculated by dividing weight in kilograms by height in meters squared. For example, a person who weighs 180 lbs and is 5'5" would have a BMI of 30.
# Dosing
- The recommended dose of Orlistat is one 120-mg capsule three times a day with each main meal containing fat (during or up to 1 hour after the meal).
- The patient should be on a nutritionally balanced, reduced-calorie diet that contains approximately 30% of calories from fat. The daily intake of fat, carbohydrate, and protein should be distributed over three main meals. If a meal is occasionally missed or contains no fat, the dose of orlistat can be omitted.
- Because orlistat has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene, patients should be counseled to take a multivitamin containing fat-soluble vitamins to ensure adequate nutrition. The vitamin supplement should be taken at least 2 hours before or after the administration of orlistat, such as at bedtime.
- For patients receiving both orlistat and cyclosporine therapy, administer cyclosporine 3 hours after orlistat.
- For patients receiving both orlistat and levothyroxine therapy, administer levothyroxine and orlistat at least 4 hours apart. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
- Doses above 120 mg three times a day have not been shown to provide additional benefit.
- Based on fecal fat measurements, the effect of orlistat is seen as soon as 24 to 48 hours after dosing. Upon discontinuation of therapy, fecal fat content usually returns to pretreatment levels within 48 to 72 hours.
# DOSAGE FORMS AND STRENGTHS
- Orlistat 120 mg turquoise capsules imprinted with ROCHE and orlistat 120 in black ink.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
# Indications and Dosing
- Concomitant nutritionally-balanced meal with 30% calories from fat is recommended
- Concomitant daily multivitamin supplement is recommended
- Obesity: 120 mg orally 3 times daily during or within 1 hour of each fat-containing meal
- Obesity: over-the-counter dose: 60 mg ORALLY 3 times daily during or within 1 hour of each fat-containing meal
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Orlistat in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Orlistat FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
# Indications and Dosing
- Concomitant nutritionally-balanced meal with 30% calories from fat is recommended.
- Concomitant daily multivitamin supplement is recommended.
- Obesity: (12 to 16 years) 120 mg ORALLY 3 times daily during or within 1 hour of each fat-containing meal.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Orlistat in pediatric patients.
# Contraindications
- Pregnancy
- Patients with chronic malabsorption syndrome
- Patients with cholestasis
- Patients with known hypersensitivity to orlistat or to any component of this product
# Warnings
# Concomitant Drug and Vitamin Use
- Data from a orlistat and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when orlistat was coadministered with cyclosporine. Therefore, orlistat and cyclosporine should not be simultaneously coadministered. To reduce the chance of a drug-drug interaction, cyclosporine should be taken at least 3 hours before or after orlistat in patients taking both drugs. In addition, in those patients whose cyclosporine levels are being measured, more frequent monitoring should be considered.
- Patients should be strongly encouraged to take a multivitamin supplement that contains fat-soluble vitamins to ensure adequate nutrition because orlistat has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene. In addition, the levels of vitamin D and beta-carotene may be low in obese patients compared with non-obese subjects. The supplement should be taken once a day at least 2 hours before or after the administration of orlistat, such as at bedtime.
- TABLE 2 illustrates the percentage of adult patients on orlistat and placebo who developed a low vitamin level on two or more consecutive visits during 1 and 2 years of therapy in studies in which patients were not previously receiving vitamin supplementation.
- TABLE 3 illustrates the percentage of adolescent patients on orlistat and placebo who developed a low vitamin level on two or more consecutive visits during the 1-year study.
- Weight-loss may affect glycemic control in patients with diabetes mellitus. A reduction in dose of oral hypoglycemic medication (e.g., sulfonylureas) or insulin may be required in some patients
# Liver Injury
- There have been rare postmarketing reports of severe liver injury with hepatocellular necrosis or acute hepatic failure in patients treated with orlistat, with some of these cases resulting in liver transplant or death. Patients should be instructed to report any symptoms of hepatic dysfunction (anorexia, pruritus, jaundice, dark urine, light-colored stools, or right upper quadrant pain) while taking orlistat. When these symptoms occur, orlistat and other suspect medications should be discontinued immediately and liver function tests and ALT and AST levels obtained.
# Increases in Urinary Oxalate
- Some patients may develop increased levels of urinary oxalate following treatment with orlistat. Cases of oxalate nephrolithiasis and oxalate nephropathy with renal failure have been reported. Monitor renal function when prescribing orlistat to patients at risk for renal impairment and use with caution in those with a history of hyperoxaluria or calcium oxalate nephrolithiasis.
# Cholelithiasis
Substantial weight loss can increase the risk of cholelithiasis. In a clinical trial of orlistat for the prevention of type 2 diabetes, the rates of cholelithiasis as an adverse event were 2.9% (47/1649) for patients randomized to orlistat and 1.8% (30/1655) for patients randomized to placebo.
# Miscellaneous
- Organic causes of obesity (e.g., hypothyroidism) should be excluded before prescribing orlistat.
- Patients should be advised to adhere to dietary guidelines. Gastrointestinal events may increase when orlistat is taken with a diet high in fat (>30% total daily calories from fat). The daily intake of fat should be distributed over three main meals. If orlistat is taken with any one meal very high in fat, the possibility of gastrointestinal effects increases.
# Adverse Reactions
## Clinical Trials Experience
# Clinical Trials
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in patients.
- Commonly Observed (based on first year and second year data)
- Gastrointestinal (GI) symptoms were the most commonly observed treatment-emergent adverse events associated with the use of orlistat in the seven double-blind, placebo-controlled clinical trials and are primarily a manifestation of the mechanism of action. (Commonly observed is defined as an incidence of ≥5% and an incidence in the orlistat 120 mg group that is at least twice that of placebo.)
In general, the first occurrence of these events was within 3 months of starting therapy. Overall, approximately 50% of all episodes of GI adverse events associated with orlistat treatment lasted for less than 1 week, and a majority lasted for no more than 4 weeks. However, GI adverse events may occur in some individuals over a period of 6 months or longer.
Discontinuation of Treatment
In controlled clinical trials, 8.8% of patients treated with orlistat discontinued treatment due to adverse events, compared with 5.0% of placebo-treated patients. For orlistat, the most common adverse events resulting in discontinuation of treatment were gastrointestinal.
Other Adverse Clinical Events
The following table lists other treatment-emergent adverse events from seven multicenter, double-blind, placebo-controlled clinical trials that occurred at a frequency of ≥2% among patients treated with orlistat 120 mg three times a day and with an incidence that was greater than placebo during year 1 and year 2, regardless of relationship to study medication.
In the 4-year XENDOS study, the general pattern of adverse events was similar to that reported for the 1- and 2-year studies with the total incidence of gastrointestinal-related adverse events occurring in year 1 decreasing each year over the 4-year period.
In clinical trials in obese diabetic patients, hypoglycemia and abdominal distension were also observed.
Pediatric Patients
In clinical trials with orlistat in adolescent patients ages 12 to 16 years, the profile of adverse reactions was generally similar to that observed in adults.
## Postmarketing Experience
The following adverse reactions have been identified during postapproval use of orlistat. 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 orlistat exposure.
- Rare cases of increase in transaminases and in alkaline phosphatase and hepatitis that may be serious have been reported. There have been reports of hepatic failure observed with the use of orlistat in postmarketing surveillance, with some of these cases resulting in liver transplant or death.
- Cases of reduced concentrations of cyclosporine have been reported when cyclosporine was co-administered with orlistat.
- Rare cases of hypersensitivity have been reported with the use of orlistat. Signs and symptoms have included pruritus, rash, urticaria, angioedema, bronchospasm and anaphylaxis. Very rare cases of bullous eruption have been reported.
- Reports of decreased prothrombin, increased INR and unbalanced anticoagulant treatment resulting in change of hemostatic parameters have been reported in patients treated concomitantly with orlistat and anticoagulants.
- Hypothyroidism has been reported in patients treated concomitantly with orlistat and levothyroxine.
- Acute oxalate nephropathy after treatment with orlistat has been reported in patients with or at risk for renal disease.
- Pancreatitis has been reported with the use of orlistat in postmarketing surveillance. No causal relationship or physiopathological mechanism between pancreatitis and obesity therapy has been definitively established.
- Lower gastrointestinal bleeding has been reported in patients treated with orlistat. Most reports are non serious; severe or persistent cases should be investigated further.
- Convulsions have been reported in patients treated concomitantly with orlistat and antiepileptic drugs.
# Drug Interactions
Cyclosporine
Data from a orlistat and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when orlistat was coadministered with cyclosporine. Orlistat and cyclosporine should not be simultaneously coadministered. Cyclosporine should be administered 3 hours after the administration of orlistat.
Fat-soluble Vitamin Supplements and Analogues
Data from a pharmacokinetic interaction study showed that the absorption of beta-carotene supplement is reduced when concomitantly administered with orlistat. Orlistat inhibited absorption of a vitamin E acetate supplement. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time
Levothyroxine
Hypothyroidism has been reported in patients treated concomitantly with orlistat and levothyroxine postmarketing . Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. Administer levothyroxine and orlistat at least 4 hours apart .
Warfarin
Vitamin K absorption may be decreased with orlistat. Patients on chronic stable doses of warfarin who are prescribed orlistat should be monitored closely for changes in coagulation parameters.
Antiepileptic Drugs
Convulsions have been reported in patients treated concomitantly with orlistat and antiepileptic drugs. Patients should be monitored for possible changes in the frequency and/or severity of convulsions
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category X
Orlistat is contraindicated during pregnancy, because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. A minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy. No embryotoxicity or teratogenicity was seen in animals that received orlistat at doses much higher than the recommended human dose. 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 of maternal weight loss to the fetus.
Animal Data
Reproduction studies were conducted in rats and rabbits at doses up to 800 mg/kg/day. Neither study showed embryotoxicity or teratogenicity. This dose is 23 and 47 times the daily human dose calculated on a body surface area (mg/m2) basis for rats and rabbits, respectively.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Orlistat in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Orlistat during labor and delivery.
### Nursing Mothers
It is not known if orlistat is present in human milk. Caution should be exercised when orlistat is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 12 have not been established.
- The safety and efficacy of orlistat have been evaluated in obese adolescent patients aged 12 to 16 years. Use of orlistat in this age group is supported by evidence from adequate and well-controlled studies of orlistat in adults with additional data from a 54-week efficacy and safety study and a 21-day mineral balance study in obese adolescent patients aged 12 to 16 years. Patients treated with orlistat in the 54-week efficacy and safety study (64.8% female, 75% Caucasians, 18.8% Blacks, and 6.3% Other) had a mean reduction in BMI of 0.55 kg/m2 compared with an average increase of 0.31 kg/m2 in placebo-treated patients (p=0.001). In both adolescent studies, adverse effects were generally similar to those described in adults and included fatty/oily stool, oily spotting, and oily evacuation. In a subgroup of 152 orlistat and 77 placebo patients from the 54-week study, changes in body composition measured by DEXA were similar in both treatment groups with the exception of fat mass, which was significantly reduced in patients treated with orlistat compared to patients treated with placebo (-2.5 kg vs -0.6 kg, p=0.033). Because orlistat can interfere with the absorption of fat-soluble vitamins, all patients should take a daily multivitamin that contains vitamins A, D, E, K, and beta-carotene. The vitamin supplement should be taken at least 2 hours before or after orlistat .
- Plasma concentrations of orlistat and its metabolites M1 and M3 were similar to those found in adults at the same dose level. Daily fecal fat excretions were 27% and 7% of dietary intake in orlistat and placebo treatment groups, respectively.
### Geriatic Use
Clinical studies of orlistat did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.
### Gender
There is no FDA guidance on the use of Orlistat with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Orlistat with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Orlistat in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Orlistat in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Orlistat in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Orlistat in patients who are immunocompromised.
### Others
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Orlistat Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Orlistat and IV administrations.
# Overdosage
Single doses of 800 mg orlistat and multiple doses of up to 600 mg three times a day for 15 days have been studied in normal weight and obese subjects without significant adverse findings.
Should a significant overdose of orlistat occur, it is recommended that the patient be observed for 24 hours. Based on human and animal studies, systemic effects attributable to the lipase-inhibiting properties of orlistat should be rapidly reversible.
# Pharmacology
## Mechanism of Action
- Orlistat is a reversible inhibitor of gastrointestinal lipases. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine residue site of gastric and pancreatic lipases. The inactivated enzymes are thus unavailable to hydrolyze dietary fat in the form of triglycerides into absorbable free fatty acids and monoglycerides. As undigested triglycerides are not absorbed, the resulting caloric deficit may have a positive effect on weight control.
## Structure
- Orlistat (orlistat) is a gastrointestinal lipase inhibitor for obesity management that acts by inhibiting the absorption of dietary fats.
- Orlistat is (S)-2-formylamino-4-methyl-pentanoic acid (S)-1-(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl methyl-dodecyl ester. Its empirical formula is C29H53NO5, and its molecular weight is 495.7. It is a single diastereomeric molecule that contains four chiral centers, with a negative optical rotation in ethanol at 529 nm. The structure is:
- Orlistat is a white to off-white crystalline powder. Orlistat is practically insoluble in water, freely soluble in chloroform, and very soluble in methanol and ethanol. Orlistat has no pKa within the physiological pH range.
- Orlistat is available for oral administration as a turquoise hard-gelatin capsule. The capsule is imprinted with black. Each capsule contains a pellet formulation consisting of 120 mg of the active ingredient, orlistat, as well as the inactive ingredients microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, povidone, and talc. The capsule shell contains gelatin, titanium dioxide, and FD&C Blue No. 2 with black printing ink containing pharmaceutical grade shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonium solution, potassium hydroxide and black iron oxide.
## Pharmacodynamics
'Dose-response Relationship'
The dose-response relationship for orlistat in human volunteers is shown in FIGURE 1. The effect is the percentage of ingested fat excreted, referred to as fecal fat excretion percentage. Both individual data (open circles) and the curve predicted for the population with the maximum-effect model (continuous line) are shown in FIGURE 1.
At the recommended therapeutic dose of 120 mg three times a day, orlistat inhibits dietary fat absorption by approximately 30%.
Ethanol does not affect orlistat's effect on preventing the absorption of fat.
'Other Short-term Studies'
- Adults
In several studies of up to 6-weeks duration, the effects of therapeutic doses of orlistat on gastrointestinal and systemic physiological processes were assessed in normal weight and obese subjects. Postprandial cholecystokinin plasma concentrations were lowered after multiple doses of orlistat in two studies but not significantly different from placebo in two other experiments. There were no clinically significant changes observed in gallbladder motility, bile composition or lithogenicity, or colonic cell proliferation rate, and no clinically significant reduction of gastric emptying time or gastric acidity. In addition, no effects on plasma triglyceride levels or systemic lipases were observed with the administration of orlistat in these studies. In a 3-week study of 28 healthy male volunteers, orlistat (120 mg three times a day) did not significantly affect the balance of calcium, magnesium, phosphorus, zinc, copper, and iron.
- Pediatrics
In a 3-week study of 32 obese adolescents aged 12 to 16 years, orlistat (120 mg three times a day) did not significantly affect the balance of calcium, magnesium, phosphorus, zinc, or copper. The iron balance was decreased by 64.7 µmole/24 hours and 40.4 µmole/24 hours in orlistat and placebo treatment groups, respectively.
## Pharmacokinetics
Absorption
Systemic exposure to orlistat is minimal. Following oral dosing with 360 mg 14C-orlistat, plasma radioactivity peaked at approximately 8 hours; plasma concentrations of intact orlistat were near the limits of detection (<5 ng/mL). In therapeutic studies involving monitoring of plasma samples, detection of intact orlistat in plasma was sporadic and concentrations were low (<10 ng/mL or 0.02 µM), without evidence of accumulation, and consistent with minimal absorption.
Distribution
In vitro orlistat was >99% bound to plasma proteins (lipoproteins and albumin were major binding proteins). Orlistat minimally partitioned into erythrocytes.
Metabolism
Based on an oral 14C-orlistat mass balance study in obese patients, two metabolites, M1 ((the hydrolyzed β-lactone ring product of orlistat) and M3 (sequential metabolite after M1's cleavage of the N-formyl leucine side-chain), accounted for approximately 42% of total radioactivity in plasma. M1 and M3 have an open β-lactone ring and extremely weak lipase inhibitory activity (1000- and 2500-fold less than orlistat, respectively). In view of this low inhibitory activity and the low plasma levels at the therapeutic dose (average of 26 ng/mL and 108 ng/mL for M1 and M3, respectively, 2 to 4 hours after a dose), these metabolites are considered pharmacologically inconsequential. The primary metabolite M1 had a short half-life (approximately 3 hours) whereas the secondary metabolite M3 eliminated at a slower rate (half-life approximately 13.5 hours).
Elimination
Following a single oral dose of 360 mg 14C-orlistat in both normal weight and obese subjects, fecal excretion of the unabsorbed drug was found to be the major route of elimination. Orlistat and its M1 and M3 metabolites were also subject to biliary excretion. Approximately 97% of the administered radioactivity was excreted in feces; 83% of that was found to be unchanged orlistat. The cumulative renal excretion of total radioactivity was <2% of the given dose of 360 mg 14C-orlistat. The time to reach complete excretion (fecal plus urinary) was 3 to 5 days. The disposition of orlistat appeared to be similar between normal weight and obese subjects. Based on limited data, the half-life of the absorbed orlistat is in the range of 1 to 2 hours.
Specific Populations
No pharmacokinetic study was conducted for specific populations such as geriatric, different races, and patients with renal and hepatic impairment.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenicity studies in rats and mice did not show a carcinogenic potential for orlistat at doses up to 1000 mg/kg/day and 1500 mg/kg/day, respectively. For mice and rats, these doses are 38 and 46 times the daily human dose calculated on an area under concentration vs time curve basis of total drug-related material.
- Orlistat had no detectable mutagenic or genotoxic activity as determined by the Ames test, a mammalian forward mutation assay (V79/HPRT), an in vitro clastogenesis assay in peripheral human lymphocytes, an unscheduled DNA synthesis assay (UDS) in rat hepatocytes in culture, and an in vivo mouse micronucleus test.
- When given to rats at a dose of 400 mg/kg/day in a fertility and reproduction study, orlistat had no observable adverse effects. This dose is 12 times the daily human dose calculated on a body surface area (mg/m2) basis.
# Clinical Studies
- The long-term effects of XENICAL on morbidity and mortality associated with obesity have not been established.
- The effects of orlistat on weight loss, weight maintenance, and weight regain and on a number of comorbidities (eg, type 2 diabetes, lipids, blood pressure) were assessed in the 4-year XENDOS study and in seven long-term (1- to 2-years duration) multicenter, double-blind, placebo-controlled clinical trials. During the first year of therapy, the studies of 2-year duration assessed weight loss and weight maintenance. During the second year of therapy, some studies assessed continued weight loss and weight maintenance and others assessed the effect of orlistat on weight regain. These studies included over 2800 patients treated with orlistat and 1400 patients treated with placebo (age range 17-78 years, 80.2% women, 91.0% Caucasians, 5.7% Blacks, 2.3% Hispanics, 0.1% Other). The majority of these patients had obesity-related risk factors and comorbidities. In the XENDOS study, which included 3304 patients (age range 30-58 years, 55% women, 99% Caucasians, 1% other), the time to onset of type 2 diabetes was assessed in addition to weight management. In all these studies, treatment with orlistat and placebo designates treatment with orlistat plus diet and placebo plus diet, respectively.
- During the weight loss and weight maintenance period, a well-balanced, reduced-calorie diet that was intended to result in an approximate 20% decrease in caloric intake and provide 30% of calories from fat was recommended to all patients. In addition, all patients were offered nutritional counseling.
## One-year Results: Weight Loss, Weight Maintenance, and Risk Factors
Pooled data from five clinical trials indicated that the overall mean weight loss from randomization to the end of 1 year of treatment in the intent-to-treat population was 13.4 lbs in the patients treated with orlistat and 5.8 lbs in the placebo-treated patients. After 1 year of treatment, the mean percent weight loss difference between orlistat-treated patients and placebo-treated patients was 3%. One thousand seventy two (69%) patients treated with orlistat and 701 (63%) patients treated with placebo completed 1 year of treatment. Of the patients who completed 1 year of treatment, 57% of the patients treated with orlistat (120 mg three times a day) and 31% of the placebo-treated patients lost at least 5% of their baseline body weight.
The percentages of patients achieving ≥5% and ≥10% weight loss after 1 year in five large multicenter studies for the intent-to-treat populations are presented in TABLE 6.
The relative changes in risk factors associated with obesity following 1 year of therapy with orlistat and placebo are presented for the population as a whole and for the population with abnormal values at randomization.
Population as a Whole
The changes in metabolic, cardiovascular and anthropometric risk factors associated with obesity based on pooled data for five clinical studies, regardless of the patient's risk factor status at randomization, are presented in TABLE 7. One year of therapy with orlistat resulted in relative improvement in several risk factors.
Population With Abnormal Risk Factors at Randomization
The changes from randomization following 1-year treatment in the population with abnormal lipid levels (LDL ≥130 mg/dL, LDL/HDL ≥3.5, HDL <35 mg/dL) were greater for orlistat compared to placebo with respect to LDL-cholesterol (-7.83% vs +1.14%) and the LDL/HDL ratio (-0.64 vs -0.46). HDL increased in the placebo group by 20.1% and in the orlistat group by 18.8%. In the population with abnormal blood pressure at baseline (systolic BP ≥140 mm Hg), the change in SBP from randomization to 1 year was greater for orlistat (-10.89 mm Hg) than placebo (-5.07 mm Hg). For patients with a diastolic blood pressure ≥90 mm Hg, orlistat patients decreased by -7.9 mm Hg while the placebo patients decreased by -5.5 mm Hg. Fasting insulin decreased more for orlistat than placebo (-39 vs -16 pmol/L) from randomization to 1 year in the population with abnormal baseline values (≥120 pmol/L). A greater reduction in waist circumference for orlistat vs placebo (-7.29 vs -4.53 cm) was observed in the population with abnormal baseline values (≥100 cm).
## Effect on Weight Regain
- Three studies were designed to evaluate the effects of orlistat compared to placebo in reducing weight regain after a previous weight loss achieved following either diet alone (one study, 14302) or prior treatment with orlistat (two studies, 14119C and 14185). The diet utilized during the 1-year weight regain portion of the studies was a weight-maintenance diet, rather than a weight-loss diet, and patients received less nutritional counseling than patients in weight-loss studies. For studies 14119C and 14185, patients' previous weight loss was due to 1 year of treatment with orlistat in conjunction with a mildly hypocaloric diet. Study 14302 was conducted to evaluate the effects of 1 year of treatment with orlistat on weight regain in patients who had lost 8% or more of their body weight in the previous 6 months on diet alone.
- In study 14119C, patients treated with placebo regained 52% of the weight they had previously lost while the patients treated with orlistat regained 26% of the weight they had previously lost (p<0.001). In study 14185, patients treated with placebo regained 63% of the weight they had previously lost while the patients treated with orlistat regained 35% of the weight they had lost (p<0.001). In study 14302, patients treated with placebo regained 53% of the weight they had previously lost while the patients treated with orlistat regained 32% of the weight that they had lost (p<0.001)
## Two-year Results: Long-term Weight Control and Risk Factors
- The treatment effects of orlistat were examined for 2 years in four of the five 1-year weight management clinical studies previously discussed (see TABLE 6). At the end of year 1, the patients' diets were reviewed and changed where necessary. The diet prescribed in the second year was designed to maintain patient's current weight. Orlistat was shown to be more effective than placebo in long-term weight control in four large, multicenter, 2-year double-blind, placebo-controlled studies.
- Pooled data from four clinical studies indicate that 74% of all patients treated with 120 mg three times a day of orlistat and 76% of patients treated with placebo completed 2 years of the same therapy. Pooled data from four clinical studies indicate that the mean weight loss difference between orlistat 120 mg three times a day and placebo treatment groups at year 2 in those patients who completed 1 year of treatment (ITT LOCF) was 3%. In the same studies cited in the One-year Results (see TABLE 6), the percentages of patients achieving a ≥5% and ≥10% weight loss after 2 years are shown in TABLE 8.
The relative changes in risk factors associated with obesity following 2 years of therapy were also assessed in the population as a whole and the population with abnormal risk factors at randomization.
Population as a Whole
The relative differences in risk factors between treatment with orlistat and placebo were similar to the results following 1 year of therapy for total cholesterol, LDL-cholesterol, LDL/HDL ratio, triglycerides, fasting glucose, fasting insulin, diastolic blood pressure, waist circumference, and hip circumference. The relative differences between treatment groups for HDL cholesterol and systolic blood pressure were less than that observed in the year one results.
Population With Abnormal Risk Factors at Randomization
The relative differences in risk factors between treatment with orlistat and placebo were similar to the results following 1 year of therapy for LDL- and HDL-cholesterol, triglycerides, fasting insulin, diastolic blood pressure, and waist circumference. The relative differences between treatment groups for LDL/HDL ratio and isolated systolic blood pressure were less than that observed in the year one results.
## Four-year Results: Long-term Weight Control and Risk Factors
- In the 4-year double-blind, placebo-controlled XENDOS study, the effects of orlistat in delaying the onset of type 2 diabetes and on body weight were compared to placebo in 3304 obese patients who had either normal or impaired glucose tolerance at baseline. Thirty-four percent of the 1655 patients who were randomized to the placebo group and 52% of the 1649 patients who were randomized to the orlistat group completed the 4-year study.
- At the end of the study, the mean percent weight loss in the placebo group was -2.75% compared with -5.17% in the orlistat group (p<0.001) (see FIGURE 2). Forty-five percent of the placebo patients and 73% of the orlistat patients lost ≥5% of their baseline body weight, and 21% of the placebo patients and 41% of the orlistat patients lost ≥10% of their baseline body weight following the first year of treatment. Following 4 years of treatment, 28% of the placebo patients and 45% of the orlistat patients lost ≥5% of their baseline body weight and 10% of the placebo patients and 21% of the orlistat patients lost ≥10% of their baseline body weight. After 4 years of treatment, the mean % difference in weight loss between orlistat treated patients and placebo was 2.5%.
- ITT LOCF study population
- The relative changes from baseline in risk factors associated with obesity following 4 years of therapy were assessed in the XENDOS study population (see TABLE 9).
Onset of Type 2 Diabetes in Obese Patients
- In the XENDOS trial, in the overall population, orlistat delayed the onset of type 2 diabetes such that at the end of four years of treatment the cumulative incidence rate of diabetes was 8.3% for the placebo group compared to 5.5% for the orlistat group, p=0.01 (see TABLE 10). This finding was driven by a statistically-significant reduction in the incidence of developing type 2 diabetes in those patients who had impaired glucose tolerance at baseline (TABLE 10 and FIGURE 3). Orlistat did not reduce the risk for the development of diabetes in patients with normal glucose tolerance at baseline.
- The effect of orlistat to delay the onset of type 2 diabetes in obese patients with IGT is presumably due to weight loss, and not to any independent effects of the drug on glucose or insulin metabolism. The effect of orlistat on weight loss is adjunctive to diet and exercise.
## Study of Patients With Type 2 Diabetes
- A 1-year double-blind, placebo-controlled study in type 2 diabetics (N=321) stabilized on sulfonylureas was conducted. Thirty percent of patients treated with XENICAL achieved at least a 5% or greater reduction in body weight from randomization compared to 13% of the placebo-treated patients (p<0.001). TABLE 11 describes the changes over 1 year of treatment with orlistat compared to placebo, in sulfonylurea usage and dose reduction as well as in hemoglobin HbA1c, fasting glucose, and insulin.
- In addition, orlistat (n=162) compared to placebo (n=159) was associated with significant lowering for total cholesterol (-1.0% vs +9.0%, p≤0.05), LDL-cholesterol (-3.0% vs +10.0%, p≤0.05), LDL/HDL ratio (-0.26 vs -0.02, p≤0.05) and triglycerides (+2.54% vs +16.2%, p≤0.05), respectively. For HDL cholesterol, there was a +6.49% increase on orlistat and +8.6% increase on placebo, p>0.05. Systolic blood pressure increased by +0.61 mm Hg on orlistat and increased by +4.33 mm Hg on placebo, p>0.05. Diastolic blood pressure decreased by -0.47 mm Hg for orlistat and by -0.5 mm Hg for placebo, p>0.05
## Glucose Tolerance in Obese Patients
- Two-year studies that included oral glucose tolerance tests were conducted in obese patients not previously diagnosed or treated for type 2 diabetes and whose baseline oral glucose tolerance test (OGTT) status at randomization was either normal, impaired, or diabetic.
- The progression from a normal OGTT at randomization to a diabetic or impaired OGTT following 2 years of treatment with orlistat (n=251) or placebo (n=207) were compared. Following treatment with orlistat, 0.0% and 7.2% of the patients progressed from normal to diabetic and normal to impaired, respectively, compared to 1.9% and 12.6% of the placebo treatment group, respectively.
- In patients found to have an impaired OGTT at randomization, the percent of patients improving to normal or deteriorating to diabetic status following 1 and 2 years of treatment with orlistat compared to placebo are presented. After 1 year of treatment, 45.8% of the placebo patients and 73% of the orlistat patients had a normal oral glucose tolerance test while 10.4% of the placebo patients and 2.6% of the orlistat patients became diabetic. After 2 years of treatment, 50% of the placebo patients and 71.7% of the orlistat patients had a normal oral glucose tolerance test while 7.5% of placebo patients were found to be diabetic and 1.7% of orlistat patients were found to be diabetic after treatment.
## Pediatric Clinical Studies
- The effects of orlistat on body mass index (BMI) and weight loss were assessed in a 54-week multicenter, double-blind, placebo-controlled study in 539 obese adolescents (357 receiving orlistat 120 mg three times a day, 182 receiving placebo), aged 12 to 16 years. All study participants had a baseline BMI that was 2 units greater than the US weighted mean for the 95th percentile based on age and gender. Body mass index was the primary efficacy parameter because it takes into account changes in height and body weight, which occur in growing children.
- During the study, all patients were instructed to take a multivitamin containing fat-soluble vitamins at least 2 hours before or after ingestion of orlistat. Patients were also maintained on a well-balanced, reduced-calorie diet that was intended to provide 30% of calories from fat. In addition, all patients were placed on a behavior modification program and offered exercise counseling.
- Approximately 65% of patients in each treatment group completed the study.
- Following one year of treatment, BMI decreased by an average of 0.55 kg/m2 in the orlistat-treated patients and increased by an average of 0.31 kg/m2 in the placebo-treated patients (p=0.001).
- The percentages of patients achieving ≥5% and ≥10% reduction in BMI and body weight after 52 weeks of treatment for the intent-to-treat population are presented in TABLE 12.
# How Supplied
XENICAL is a turquoise, hard-gelatin capsule containing pellets of powder.
Orlistat 120 mg Capsules: Turquoise, two-piece, No. 1 opaque hard-gelatin capsule imprinted with ROCHE and XENICAL 120 in black ink — bottle of 90 (NDC 0004-0257-52).
## Storage
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) . Keep bottle tightly closed.
Orlistat should not be used after the given expiration date.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
Alcohol-Orlistat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
-rlistat
# Look-Alike Drug Names
There is limited information regarding Orlistat Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Orlistat
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
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# Overview
Orlistat is an antiobesity drug that is FDA approved for the treatment of obesity including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet. Common adverse reactions include oily spotting, flatus with discharge,fecal urgency,fatty/oily stool,oily evacuation,
increased defecation, fecal incontinence, abdominal pain/discomfort, nausea, influenza, back pain, rash.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Orlistat is indicated for obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet. Orlistat is also indicated to reduce the risk for weight regain after prior weight loss. Orlistat is indicated for obese patients with an initial body mass index (BMI) ≥30 kg/m2 or ≥27 kg/m2 in the presence of other risk factors (e.g., hypertension, diabetes, dyslipidemia).
- TABLE 1 illustrates body mass index (BMI) according to a variety of weights and heights. The BMI is calculated by dividing weight in kilograms by height in meters squared. For example, a person who weighs 180 lbs and is 5'5" would have a BMI of 30.
# Dosing
- The recommended dose of Orlistat is one 120-mg capsule three times a day with each main meal containing fat (during or up to 1 hour after the meal).
- The patient should be on a nutritionally balanced, reduced-calorie diet that contains approximately 30% of calories from fat. The daily intake of fat, carbohydrate, and protein should be distributed over three main meals. If a meal is occasionally missed or contains no fat, the dose of orlistat can be omitted.
- Because orlistat has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene, patients should be counseled to take a multivitamin containing fat-soluble vitamins to ensure adequate nutrition. The vitamin supplement should be taken at least 2 hours before or after the administration of orlistat, such as at bedtime.
- For patients receiving both orlistat and cyclosporine therapy, administer cyclosporine 3 hours after orlistat.
- For patients receiving both orlistat and levothyroxine therapy, administer levothyroxine and orlistat at least 4 hours apart. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
- Doses above 120 mg three times a day have not been shown to provide additional benefit.
- Based on fecal fat measurements, the effect of orlistat is seen as soon as 24 to 48 hours after dosing. Upon discontinuation of therapy, fecal fat content usually returns to pretreatment levels within 48 to 72 hours.
# DOSAGE FORMS AND STRENGTHS
- Orlistat 120 mg turquoise capsules imprinted with ROCHE and orlistat 120 in black ink.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
# Indications and Dosing
- Concomitant nutritionally-balanced meal with 30% calories from fat is recommended
- Concomitant daily multivitamin supplement is recommended
- Obesity: 120 mg orally 3 times daily during or within 1 hour of each fat-containing meal
- Obesity: over-the-counter dose: 60 mg ORALLY 3 times daily during or within 1 hour of each fat-containing meal[1]
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Orlistat in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Orlistat FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
# Indications and Dosing
- Concomitant nutritionally-balanced meal with 30% calories from fat is recommended.
- Concomitant daily multivitamin supplement is recommended.
- Obesity: (12 to 16 years) 120 mg ORALLY 3 times daily during or within 1 hour of each fat-containing meal.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Orlistat in pediatric patients.
# Contraindications
- Pregnancy
- Patients with chronic malabsorption syndrome
- Patients with cholestasis
- Patients with known hypersensitivity to orlistat or to any component of this product
# Warnings
# Concomitant Drug and Vitamin Use
- Data from a orlistat and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when orlistat was coadministered with cyclosporine. Therefore, orlistat and cyclosporine should not be simultaneously coadministered. To reduce the chance of a drug-drug interaction, cyclosporine should be taken at least 3 hours before or after orlistat in patients taking both drugs. In addition, in those patients whose cyclosporine levels are being measured, more frequent monitoring should be considered.
- Patients should be strongly encouraged to take a multivitamin supplement that contains fat-soluble vitamins to ensure adequate nutrition because orlistat has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene. In addition, the levels of vitamin D and beta-carotene may be low in obese patients compared with non-obese subjects. The supplement should be taken once a day at least 2 hours before or after the administration of orlistat, such as at bedtime.
- TABLE 2 illustrates the percentage of adult patients on orlistat and placebo who developed a low vitamin level on two or more consecutive visits during 1 and 2 years of therapy in studies in which patients were not previously receiving vitamin supplementation.
- TABLE 3 illustrates the percentage of adolescent patients on orlistat and placebo who developed a low vitamin level on two or more consecutive visits during the 1-year study.
- Weight-loss may affect glycemic control in patients with diabetes mellitus. A reduction in dose of oral hypoglycemic medication (e.g., sulfonylureas) or insulin may be required in some patients
# Liver Injury
- There have been rare postmarketing reports of severe liver injury with hepatocellular necrosis or acute hepatic failure in patients treated with orlistat, with some of these cases resulting in liver transplant or death. Patients should be instructed to report any symptoms of hepatic dysfunction (anorexia, pruritus, jaundice, dark urine, light-colored stools, or right upper quadrant pain) while taking orlistat. When these symptoms occur, orlistat and other suspect medications should be discontinued immediately and liver function tests and ALT and AST levels obtained.
# Increases in Urinary Oxalate
- Some patients may develop increased levels of urinary oxalate following treatment with orlistat. Cases of oxalate nephrolithiasis and oxalate nephropathy with renal failure have been reported. Monitor renal function when prescribing orlistat to patients at risk for renal impairment and use with caution in those with a history of hyperoxaluria or calcium oxalate nephrolithiasis.
# Cholelithiasis
Substantial weight loss can increase the risk of cholelithiasis. In a clinical trial of orlistat for the prevention of type 2 diabetes, the rates of cholelithiasis as an adverse event were 2.9% (47/1649) for patients randomized to orlistat and 1.8% (30/1655) for patients randomized to placebo.
# Miscellaneous
- Organic causes of obesity (e.g., hypothyroidism) should be excluded before prescribing orlistat.
- Patients should be advised to adhere to dietary guidelines. Gastrointestinal events may increase when orlistat is taken with a diet high in fat (>30% total daily calories from fat). The daily intake of fat should be distributed over three main meals. If orlistat is taken with any one meal very high in fat, the possibility of gastrointestinal effects increases.
# Adverse Reactions
## Clinical Trials Experience
# Clinical Trials
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in patients.
- Commonly Observed (based on first year and second year data)
- Gastrointestinal (GI) symptoms were the most commonly observed treatment-emergent adverse events associated with the use of orlistat in the seven double-blind, placebo-controlled clinical trials and are primarily a manifestation of the mechanism of action. (Commonly observed is defined as an incidence of ≥5% and an incidence in the orlistat 120 mg group that is at least twice that of placebo.)
In general, the first occurrence of these events was within 3 months of starting therapy. Overall, approximately 50% of all episodes of GI adverse events associated with orlistat treatment lasted for less than 1 week, and a majority lasted for no more than 4 weeks. However, GI adverse events may occur in some individuals over a period of 6 months or longer.
Discontinuation of Treatment
In controlled clinical trials, 8.8% of patients treated with orlistat discontinued treatment due to adverse events, compared with 5.0% of placebo-treated patients. For orlistat, the most common adverse events resulting in discontinuation of treatment were gastrointestinal.
Other Adverse Clinical Events
The following table lists other treatment-emergent adverse events from seven multicenter, double-blind, placebo-controlled clinical trials that occurred at a frequency of ≥2% among patients treated with orlistat 120 mg three times a day and with an incidence that was greater than placebo during year 1 and year 2, regardless of relationship to study medication.
In the 4-year XENDOS study, the general pattern of adverse events was similar to that reported for the 1- and 2-year studies with the total incidence of gastrointestinal-related adverse events occurring in year 1 decreasing each year over the 4-year period.
In clinical trials in obese diabetic patients, hypoglycemia and abdominal distension were also observed.
Pediatric Patients
In clinical trials with orlistat in adolescent patients ages 12 to 16 years, the profile of adverse reactions was generally similar to that observed in adults.
## Postmarketing Experience
The following adverse reactions have been identified during postapproval use of orlistat. 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 orlistat exposure.
- Rare cases of increase in transaminases and in alkaline phosphatase and hepatitis that may be serious have been reported. There have been reports of hepatic failure observed with the use of orlistat in postmarketing surveillance, with some of these cases resulting in liver transplant or death.
- Cases of reduced concentrations of cyclosporine have been reported when cyclosporine was co-administered with orlistat.
- Rare cases of hypersensitivity have been reported with the use of orlistat. Signs and symptoms have included pruritus, rash, urticaria, angioedema, bronchospasm and anaphylaxis. Very rare cases of bullous eruption have been reported.
- Reports of decreased prothrombin, increased INR and unbalanced anticoagulant treatment resulting in change of hemostatic parameters have been reported in patients treated concomitantly with orlistat and anticoagulants.
- Hypothyroidism has been reported in patients treated concomitantly with orlistat and levothyroxine.
- Acute oxalate nephropathy after treatment with orlistat has been reported in patients with or at risk for renal disease.
- Pancreatitis has been reported with the use of orlistat in postmarketing surveillance. No causal relationship or physiopathological mechanism between pancreatitis and obesity therapy has been definitively established.
- Lower gastrointestinal bleeding has been reported in patients treated with orlistat. Most reports are non serious; severe or persistent cases should be investigated further.
- Convulsions have been reported in patients treated concomitantly with orlistat and antiepileptic drugs.
# Drug Interactions
Cyclosporine
Data from a orlistat and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when orlistat was coadministered with cyclosporine. Orlistat and cyclosporine should not be simultaneously coadministered. Cyclosporine should be administered 3 hours after the administration of orlistat.
Fat-soluble Vitamin Supplements and Analogues
Data from a pharmacokinetic interaction study showed that the absorption of beta-carotene supplement is reduced when concomitantly administered with orlistat. Orlistat inhibited absorption of a vitamin E acetate supplement. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time
Levothyroxine
Hypothyroidism has been reported in patients treated concomitantly with orlistat and levothyroxine postmarketing . Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. Administer levothyroxine and orlistat at least 4 hours apart .
Warfarin
Vitamin K absorption may be decreased with orlistat. Patients on chronic stable doses of warfarin who are prescribed orlistat should be monitored closely for changes in coagulation parameters.
Antiepileptic Drugs
Convulsions have been reported in patients treated concomitantly with orlistat and antiepileptic drugs. Patients should be monitored for possible changes in the frequency and/or severity of convulsions
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category X
Orlistat is contraindicated during pregnancy, because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. A minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy. No embryotoxicity or teratogenicity was seen in animals that received orlistat at doses much higher than the recommended human dose. 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 of maternal weight loss to the fetus.
Animal Data
Reproduction studies were conducted in rats and rabbits at doses up to 800 mg/kg/day. Neither study showed embryotoxicity or teratogenicity. This dose is 23 and 47 times the daily human dose calculated on a body surface area (mg/m2) basis for rats and rabbits, respectively.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Orlistat in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Orlistat during labor and delivery.
### Nursing Mothers
It is not known if orlistat is present in human milk. Caution should be exercised when orlistat is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 12 have not been established.
- The safety and efficacy of orlistat have been evaluated in obese adolescent patients aged 12 to 16 years. Use of orlistat in this age group is supported by evidence from adequate and well-controlled studies of orlistat in adults with additional data from a 54-week efficacy and safety study and a 21-day mineral balance study in obese adolescent patients aged 12 to 16 years. Patients treated with orlistat in the 54-week efficacy and safety study (64.8% female, 75% Caucasians, 18.8% Blacks, and 6.3% Other) had a mean reduction in BMI of 0.55 kg/m2 compared with an average increase of 0.31 kg/m2 in placebo-treated patients (p=0.001). In both adolescent studies, adverse effects were generally similar to those described in adults and included fatty/oily stool, oily spotting, and oily evacuation. In a subgroup of 152 orlistat and 77 placebo patients from the 54-week study, changes in body composition measured by DEXA were similar in both treatment groups with the exception of fat mass, which was significantly reduced in patients treated with orlistat compared to patients treated with placebo (-2.5 kg vs -0.6 kg, p=0.033). Because orlistat can interfere with the absorption of fat-soluble vitamins, all patients should take a daily multivitamin that contains vitamins A, D, E, K, and beta-carotene. The vitamin supplement should be taken at least 2 hours before or after orlistat .
- Plasma concentrations of orlistat and its metabolites M1 and M3 were similar to those found in adults at the same dose level. Daily fecal fat excretions were 27% and 7% of dietary intake in orlistat and placebo treatment groups, respectively.
### Geriatic Use
Clinical studies of orlistat did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.
### Gender
There is no FDA guidance on the use of Orlistat with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Orlistat with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Orlistat in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Orlistat in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Orlistat in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Orlistat in patients who are immunocompromised.
### Others
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Orlistat Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Orlistat and IV administrations.
# Overdosage
Single doses of 800 mg orlistat and multiple doses of up to 600 mg three times a day for 15 days have been studied in normal weight and obese subjects without significant adverse findings.
Should a significant overdose of orlistat occur, it is recommended that the patient be observed for 24 hours. Based on human and animal studies, systemic effects attributable to the lipase-inhibiting properties of orlistat should be rapidly reversible.
# Pharmacology
## Mechanism of Action
- Orlistat is a reversible inhibitor of gastrointestinal lipases. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine residue site of gastric and pancreatic lipases. The inactivated enzymes are thus unavailable to hydrolyze dietary fat in the form of triglycerides into absorbable free fatty acids and monoglycerides. As undigested triglycerides are not absorbed, the resulting caloric deficit may have a positive effect on weight control.
## Structure
- Orlistat (orlistat) is a gastrointestinal lipase inhibitor for obesity management that acts by inhibiting the absorption of dietary fats.
- Orlistat is (S)-2-formylamino-4-methyl-pentanoic acid (S)-1-(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl methyl-dodecyl ester. Its empirical formula is C29H53NO5, and its molecular weight is 495.7. It is a single diastereomeric molecule that contains four chiral centers, with a negative optical rotation in ethanol at 529 nm. The structure is:
- Orlistat is a white to off-white crystalline powder. Orlistat is practically insoluble in water, freely soluble in chloroform, and very soluble in methanol and ethanol. Orlistat has no pKa within the physiological pH range.
- Orlistat is available for oral administration as a turquoise hard-gelatin capsule. The capsule is imprinted with black. Each capsule contains a pellet formulation consisting of 120 mg of the active ingredient, orlistat, as well as the inactive ingredients microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, povidone, and talc. The capsule shell contains gelatin, titanium dioxide, and FD&C Blue No. 2 with black printing ink containing pharmaceutical grade shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonium solution, potassium hydroxide and black iron oxide.
## Pharmacodynamics
'Dose-response Relationship'
The dose-response relationship for orlistat in human volunteers is shown in FIGURE 1. The effect is the percentage of ingested fat excreted, referred to as fecal fat excretion percentage. Both individual data (open circles) and the curve predicted for the population with the maximum-effect model (continuous line) are shown in FIGURE 1.
At the recommended therapeutic dose of 120 mg three times a day, orlistat inhibits dietary fat absorption by approximately 30%.
Ethanol does not affect orlistat's effect on preventing the absorption of fat.
'Other Short-term Studies'
- Adults
In several studies of up to 6-weeks duration, the effects of therapeutic doses of orlistat on gastrointestinal and systemic physiological processes were assessed in normal weight and obese subjects. Postprandial cholecystokinin plasma concentrations were lowered after multiple doses of orlistat in two studies but not significantly different from placebo in two other experiments. There were no clinically significant changes observed in gallbladder motility, bile composition or lithogenicity, or colonic cell proliferation rate, and no clinically significant reduction of gastric emptying time or gastric acidity. In addition, no effects on plasma triglyceride levels or systemic lipases were observed with the administration of orlistat in these studies. In a 3-week study of 28 healthy male volunteers, orlistat (120 mg three times a day) did not significantly affect the balance of calcium, magnesium, phosphorus, zinc, copper, and iron.
- Pediatrics
In a 3-week study of 32 obese adolescents aged 12 to 16 years, orlistat (120 mg three times a day) did not significantly affect the balance of calcium, magnesium, phosphorus, zinc, or copper. The iron balance was decreased by 64.7 µmole/24 hours and 40.4 µmole/24 hours in orlistat and placebo treatment groups, respectively.
## Pharmacokinetics
Absorption
Systemic exposure to orlistat is minimal. Following oral dosing with 360 mg 14C-orlistat, plasma radioactivity peaked at approximately 8 hours; plasma concentrations of intact orlistat were near the limits of detection (<5 ng/mL). In therapeutic studies involving monitoring of plasma samples, detection of intact orlistat in plasma was sporadic and concentrations were low (<10 ng/mL or 0.02 µM), without evidence of accumulation, and consistent with minimal absorption.
Distribution
In vitro orlistat was >99% bound to plasma proteins (lipoproteins and albumin were major binding proteins). Orlistat minimally partitioned into erythrocytes.
Metabolism
Based on an oral 14C-orlistat mass balance study in obese patients, two metabolites, M1 ((the hydrolyzed β-lactone ring product of orlistat) and M3 (sequential metabolite after M1's cleavage of the N-formyl leucine side-chain), accounted for approximately 42% of total radioactivity in plasma. M1 and M3 have an open β-lactone ring and extremely weak lipase inhibitory activity (1000- and 2500-fold less than orlistat, respectively). In view of this low inhibitory activity and the low plasma levels at the therapeutic dose (average of 26 ng/mL and 108 ng/mL for M1 and M3, respectively, 2 to 4 hours after a dose), these metabolites are considered pharmacologically inconsequential. The primary metabolite M1 had a short half-life (approximately 3 hours) whereas the secondary metabolite M3 eliminated at a slower rate (half-life approximately 13.5 hours).
Elimination
Following a single oral dose of 360 mg 14C-orlistat in both normal weight and obese subjects, fecal excretion of the unabsorbed drug was found to be the major route of elimination. Orlistat and its M1 and M3 metabolites were also subject to biliary excretion. Approximately 97% of the administered radioactivity was excreted in feces; 83% of that was found to be unchanged orlistat. The cumulative renal excretion of total radioactivity was <2% of the given dose of 360 mg 14C-orlistat. The time to reach complete excretion (fecal plus urinary) was 3 to 5 days. The disposition of orlistat appeared to be similar between normal weight and obese subjects. Based on limited data, the half-life of the absorbed orlistat is in the range of 1 to 2 hours.
Specific Populations
No pharmacokinetic study was conducted for specific populations such as geriatric, different races, and patients with renal and hepatic impairment.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenicity studies in rats and mice did not show a carcinogenic potential for orlistat at doses up to 1000 mg/kg/day and 1500 mg/kg/day, respectively. For mice and rats, these doses are 38 and 46 times the daily human dose calculated on an area under concentration vs time curve basis of total drug-related material.
- Orlistat had no detectable mutagenic or genotoxic activity as determined by the Ames test, a mammalian forward mutation assay (V79/HPRT), an in vitro clastogenesis assay in peripheral human lymphocytes, an unscheduled DNA synthesis assay (UDS) in rat hepatocytes in culture, and an in vivo mouse micronucleus test.
- When given to rats at a dose of 400 mg/kg/day in a fertility and reproduction study, orlistat had no observable adverse effects. This dose is 12 times the daily human dose calculated on a body surface area (mg/m2) basis.
# Clinical Studies
- The long-term effects of XENICAL on morbidity and mortality associated with obesity have not been established.
- The effects of orlistat on weight loss, weight maintenance, and weight regain and on a number of comorbidities (eg, type 2 diabetes, lipids, blood pressure) were assessed in the 4-year XENDOS study and in seven long-term (1- to 2-years duration) multicenter, double-blind, placebo-controlled clinical trials. During the first year of therapy, the studies of 2-year duration assessed weight loss and weight maintenance. During the second year of therapy, some studies assessed continued weight loss and weight maintenance and others assessed the effect of orlistat on weight regain. These studies included over 2800 patients treated with orlistat and 1400 patients treated with placebo (age range 17-78 years, 80.2% women, 91.0% Caucasians, 5.7% Blacks, 2.3% Hispanics, 0.1% Other). The majority of these patients had obesity-related risk factors and comorbidities. In the XENDOS study, which included 3304 patients (age range 30-58 years, 55% women, 99% Caucasians, 1% other), the time to onset of type 2 diabetes was assessed in addition to weight management. In all these studies, treatment with orlistat and placebo designates treatment with orlistat plus diet and placebo plus diet, respectively.
- During the weight loss and weight maintenance period, a well-balanced, reduced-calorie diet that was intended to result in an approximate 20% decrease in caloric intake and provide 30% of calories from fat was recommended to all patients. In addition, all patients were offered nutritional counseling.
## One-year Results: Weight Loss, Weight Maintenance, and Risk Factors
Pooled data from five clinical trials indicated that the overall mean weight loss from randomization to the end of 1 year of treatment in the intent-to-treat population was 13.4 lbs in the patients treated with orlistat and 5.8 lbs in the placebo-treated patients. After 1 year of treatment, the mean percent weight loss difference between orlistat-treated patients and placebo-treated patients was 3%. One thousand seventy two (69%) patients treated with orlistat and 701 (63%) patients treated with placebo completed 1 year of treatment. Of the patients who completed 1 year of treatment, 57% of the patients treated with orlistat (120 mg three times a day) and 31% of the placebo-treated patients lost at least 5% of their baseline body weight.
The percentages of patients achieving ≥5% and ≥10% weight loss after 1 year in five large multicenter studies for the intent-to-treat populations are presented in TABLE 6.
The relative changes in risk factors associated with obesity following 1 year of therapy with orlistat and placebo are presented for the population as a whole and for the population with abnormal values at randomization.
Population as a Whole
The changes in metabolic, cardiovascular and anthropometric risk factors associated with obesity based on pooled data for five clinical studies, regardless of the patient's risk factor status at randomization, are presented in TABLE 7. One year of therapy with orlistat resulted in relative improvement in several risk factors.
Population With Abnormal Risk Factors at Randomization
The changes from randomization following 1-year treatment in the population with abnormal lipid levels (LDL ≥130 mg/dL, LDL/HDL ≥3.5, HDL <35 mg/dL) were greater for orlistat compared to placebo with respect to LDL-cholesterol (-7.83% vs +1.14%) and the LDL/HDL ratio (-0.64 vs -0.46). HDL increased in the placebo group by 20.1% and in the orlistat group by 18.8%. In the population with abnormal blood pressure at baseline (systolic BP ≥140 mm Hg), the change in SBP from randomization to 1 year was greater for orlistat (-10.89 mm Hg) than placebo (-5.07 mm Hg). For patients with a diastolic blood pressure ≥90 mm Hg, orlistat patients decreased by -7.9 mm Hg while the placebo patients decreased by -5.5 mm Hg. Fasting insulin decreased more for orlistat than placebo (-39 vs -16 pmol/L) from randomization to 1 year in the population with abnormal baseline values (≥120 pmol/L). A greater reduction in waist circumference for orlistat vs placebo (-7.29 vs -4.53 cm) was observed in the population with abnormal baseline values (≥100 cm).
## Effect on Weight Regain
- Three studies were designed to evaluate the effects of orlistat compared to placebo in reducing weight regain after a previous weight loss achieved following either diet alone (one study, 14302) or prior treatment with orlistat (two studies, 14119C and 14185). The diet utilized during the 1-year weight regain portion of the studies was a weight-maintenance diet, rather than a weight-loss diet, and patients received less nutritional counseling than patients in weight-loss studies. For studies 14119C and 14185, patients' previous weight loss was due to 1 year of treatment with orlistat in conjunction with a mildly hypocaloric diet. Study 14302 was conducted to evaluate the effects of 1 year of treatment with orlistat on weight regain in patients who had lost 8% or more of their body weight in the previous 6 months on diet alone.
- In study 14119C, patients treated with placebo regained 52% of the weight they had previously lost while the patients treated with orlistat regained 26% of the weight they had previously lost (p<0.001). In study 14185, patients treated with placebo regained 63% of the weight they had previously lost while the patients treated with orlistat regained 35% of the weight they had lost (p<0.001). In study 14302, patients treated with placebo regained 53% of the weight they had previously lost while the patients treated with orlistat regained 32% of the weight that they had lost (p<0.001)
## Two-year Results: Long-term Weight Control and Risk Factors
- The treatment effects of orlistat were examined for 2 years in four of the five 1-year weight management clinical studies previously discussed (see TABLE 6). At the end of year 1, the patients' diets were reviewed and changed where necessary. The diet prescribed in the second year was designed to maintain patient's current weight. Orlistat was shown to be more effective than placebo in long-term weight control in four large, multicenter, 2-year double-blind, placebo-controlled studies.
- Pooled data from four clinical studies indicate that 74% of all patients treated with 120 mg three times a day of orlistat and 76% of patients treated with placebo completed 2 years of the same therapy. Pooled data from four clinical studies indicate that the mean weight loss difference between orlistat 120 mg three times a day and placebo treatment groups at year 2 in those patients who completed 1 year of treatment (ITT LOCF) was 3%. In the same studies cited in the One-year Results (see TABLE 6), the percentages of patients achieving a ≥5% and ≥10% weight loss after 2 years are shown in TABLE 8.
The relative changes in risk factors associated with obesity following 2 years of therapy were also assessed in the population as a whole and the population with abnormal risk factors at randomization.
Population as a Whole
The relative differences in risk factors between treatment with orlistat and placebo were similar to the results following 1 year of therapy for total cholesterol, LDL-cholesterol, LDL/HDL ratio, triglycerides, fasting glucose, fasting insulin, diastolic blood pressure, waist circumference, and hip circumference. The relative differences between treatment groups for HDL cholesterol and systolic blood pressure were less than that observed in the year one results.
Population With Abnormal Risk Factors at Randomization
The relative differences in risk factors between treatment with orlistat and placebo were similar to the results following 1 year of therapy for LDL- and HDL-cholesterol, triglycerides, fasting insulin, diastolic blood pressure, and waist circumference. The relative differences between treatment groups for LDL/HDL ratio and isolated systolic blood pressure were less than that observed in the year one results.
## Four-year Results: Long-term Weight Control and Risk Factors
- In the 4-year double-blind, placebo-controlled XENDOS study, the effects of orlistat in delaying the onset of type 2 diabetes and on body weight were compared to placebo in 3304 obese patients who had either normal or impaired glucose tolerance at baseline. Thirty-four percent of the 1655 patients who were randomized to the placebo group and 52% of the 1649 patients who were randomized to the orlistat group completed the 4-year study.
- At the end of the study, the mean percent weight loss in the placebo group was -2.75% compared with -5.17% in the orlistat group (p<0.001) (see FIGURE 2). Forty-five percent of the placebo patients and 73% of the orlistat patients lost ≥5% of their baseline body weight, and 21% of the placebo patients and 41% of the orlistat patients lost ≥10% of their baseline body weight following the first year of treatment. Following 4 years of treatment, 28% of the placebo patients and 45% of the orlistat patients lost ≥5% of their baseline body weight and 10% of the placebo patients and 21% of the orlistat patients lost ≥10% of their baseline body weight. After 4 years of treatment, the mean % difference in weight loss between orlistat treated patients and placebo was 2.5%.
- ITT LOCF study population
- The relative changes from baseline in risk factors associated with obesity following 4 years of therapy were assessed in the XENDOS study population (see TABLE 9).
Onset of Type 2 Diabetes in Obese Patients
- In the XENDOS trial, in the overall population, orlistat delayed the onset of type 2 diabetes such that at the end of four years of treatment the cumulative incidence rate of diabetes was 8.3% for the placebo group compared to 5.5% for the orlistat group, p=0.01 (see TABLE 10). This finding was driven by a statistically-significant reduction in the incidence of developing type 2 diabetes in those patients who had impaired glucose tolerance at baseline (TABLE 10 and FIGURE 3). Orlistat did not reduce the risk for the development of diabetes in patients with normal glucose tolerance at baseline.
- The effect of orlistat to delay the onset of type 2 diabetes in obese patients with IGT is presumably due to weight loss, and not to any independent effects of the drug on glucose or insulin metabolism. The effect of orlistat on weight loss is adjunctive to diet and exercise.
## Study of Patients With Type 2 Diabetes
- A 1-year double-blind, placebo-controlled study in type 2 diabetics (N=321) stabilized on sulfonylureas was conducted. Thirty percent of patients treated with XENICAL achieved at least a 5% or greater reduction in body weight from randomization compared to 13% of the placebo-treated patients (p<0.001). TABLE 11 describes the changes over 1 year of treatment with orlistat compared to placebo, in sulfonylurea usage and dose reduction as well as in hemoglobin HbA1c, fasting glucose, and insulin.
- In addition, orlistat (n=162) compared to placebo (n=159) was associated with significant lowering for total cholesterol (-1.0% vs +9.0%, p≤0.05), LDL-cholesterol (-3.0% vs +10.0%, p≤0.05), LDL/HDL ratio (-0.26 vs -0.02, p≤0.05) and triglycerides (+2.54% vs +16.2%, p≤0.05), respectively. For HDL cholesterol, there was a +6.49% increase on orlistat and +8.6% increase on placebo, p>0.05. Systolic blood pressure increased by +0.61 mm Hg on orlistat and increased by +4.33 mm Hg on placebo, p>0.05. Diastolic blood pressure decreased by -0.47 mm Hg for orlistat and by -0.5 mm Hg for placebo, p>0.05
## Glucose Tolerance in Obese Patients
- Two-year studies that included oral glucose tolerance tests were conducted in obese patients not previously diagnosed or treated for type 2 diabetes and whose baseline oral glucose tolerance test (OGTT) status at randomization was either normal, impaired, or diabetic.
- The progression from a normal OGTT at randomization to a diabetic or impaired OGTT following 2 years of treatment with orlistat (n=251) or placebo (n=207) were compared. Following treatment with orlistat, 0.0% and 7.2% of the patients progressed from normal to diabetic and normal to impaired, respectively, compared to 1.9% and 12.6% of the placebo treatment group, respectively.
- In patients found to have an impaired OGTT at randomization, the percent of patients improving to normal or deteriorating to diabetic status following 1 and 2 years of treatment with orlistat compared to placebo are presented. After 1 year of treatment, 45.8% of the placebo patients and 73% of the orlistat patients had a normal oral glucose tolerance test while 10.4% of the placebo patients and 2.6% of the orlistat patients became diabetic. After 2 years of treatment, 50% of the placebo patients and 71.7% of the orlistat patients had a normal oral glucose tolerance test while 7.5% of placebo patients were found to be diabetic and 1.7% of orlistat patients were found to be diabetic after treatment.
## Pediatric Clinical Studies
- The effects of orlistat on body mass index (BMI) and weight loss were assessed in a 54-week multicenter, double-blind, placebo-controlled study in 539 obese adolescents (357 receiving orlistat 120 mg three times a day, 182 receiving placebo), aged 12 to 16 years. All study participants had a baseline BMI that was 2 units greater than the US weighted mean for the 95th percentile based on age and gender. Body mass index was the primary efficacy parameter because it takes into account changes in height and body weight, which occur in growing children.
- During the study, all patients were instructed to take a multivitamin containing fat-soluble vitamins at least 2 hours before or after ingestion of orlistat. Patients were also maintained on a well-balanced, reduced-calorie diet that was intended to provide 30% of calories from fat. In addition, all patients were placed on a behavior modification program and offered exercise counseling.
- Approximately 65% of patients in each treatment group completed the study.
- Following one year of treatment, BMI decreased by an average of 0.55 kg/m2 in the orlistat-treated patients and increased by an average of 0.31 kg/m2 in the placebo-treated patients (p=0.001).
- The percentages of patients achieving ≥5% and ≥10% reduction in BMI and body weight after 52 weeks of treatment for the intent-to-treat population are presented in TABLE 12.
# How Supplied
XENICAL is a turquoise, hard-gelatin capsule containing pellets of powder.
Orlistat 120 mg Capsules: Turquoise, two-piece, No. 1 opaque hard-gelatin capsule imprinted with ROCHE and XENICAL 120 in black ink — bottle of 90 (NDC 0004-0257-52).
## Storage
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep bottle tightly closed.
Orlistat should not be used after the given expiration date.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
Alcohol-Orlistat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
orlistat
# Look-Alike Drug Names
There is limited information regarding Orlistat Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Orlistat | |
56c2453db6d63f00b0926f7a6d205d8a82e7c898 | wikidoc | Orvietan | Orvietan
Orvietan or orviétan was a medical concoction popular during the 17th and 18th century. It was used as a panacea against poisonings with criminal intent, as well as against mushroom poisonings, snakebite, scorpion stings, bites by rabid animals and against the plague.
Orvietan was probably named after a certain Lupi da Orvieto, native from the city of Orvieto, though there is no certain information on this.
# Origins
Gerolamo Ferranti started producing and selling orviétan in early 17th century Paris. He was a fairground attraction, asking onlookers to give him unknown poisons to swallow and watch him cure himself with the remedy. Other charlatans in the business were Jean Vitrario, Desiderio Descombes, and Cristoforo Contugi. Though most physicians and pharmacists were skeptical, the reputed medical doctor Johann Schröder published his own recipe in Pharmacopeia Medico-Chymica in 1655. The first pharmacist to include orviétan in his compendium was Moyse Charas in Pharmacopée Royale Galénique et Chymique, 1676.
# Ingredients
Orvietan was a concoction of partially toxic herbs, wine and dissolved honey, but existed in powdered form too (sold in lead boxes). Patrizia Catellani and Renzo Console analyzed 35 different recipes for mixing orvietan, published between 1655 and 1857. The number of ingredients varies from 9 to 57. The most frequent 26 ingredients are: Garden Angelica, Healing Wolfsbane, Birthwort, Bistort, Sweet Flag, Carline Thistle, Dittany, Gentian, Masterwort, Black Salsify, Tormentil, Valerian, Blessed Thistle, Dittany of Crete, Rue, Germander, Laurel berries, Juniper berries, cinnamon, cloves, viper meat, the two concoctions mithridate and theriac, as well as white wine, and honey.
# Literary references
Literary works mentioning orvietan include Tabarin's Inventaire Universel des Œuvres de Tabarin (1622), Molière's L'Amour médecin (1665), Voltaire's Pot-pourri (1765), Mme de Sevigne's correspondence, and Walter Scott's Kenilworth (1821), though Scott translates it as Venice treacle. | Orvietan
Orvietan or orviétan was a medical concoction popular during the 17th and 18th century. It was used as a panacea against poisonings with criminal intent, as well as against mushroom poisonings, snakebite, scorpion stings, bites by rabid animals and against the plague.
Orvietan was probably named after a certain Lupi da Orvieto, native from the city of Orvieto, though there is no certain information on this.
# Origins
Gerolamo Ferranti started producing and selling orviétan in early 17th century Paris. He was a fairground attraction, asking onlookers to give him unknown poisons to swallow and watch him cure himself with the remedy. Other charlatans in the business were Jean Vitrario, Desiderio Descombes, and Cristoforo Contugi. Though most physicians and pharmacists were skeptical, the reputed medical doctor Johann Schröder published his own recipe in Pharmacopeia Medico-Chymica in 1655. The first pharmacist to include orviétan in his compendium was Moyse Charas in Pharmacopée Royale Galénique et Chymique, 1676.
# Ingredients
Orvietan was a concoction of partially toxic herbs, wine and dissolved honey, but existed in powdered form too (sold in lead boxes). Patrizia Catellani and Renzo Console analyzed 35 different recipes for mixing orvietan, published between 1655 and 1857. The number of ingredients varies from 9 to 57. The most frequent 26 ingredients are: Garden Angelica, Healing Wolfsbane, Birthwort, Bistort, Sweet Flag, Carline Thistle, Dittany, Gentian, Masterwort, Black Salsify, Tormentil, Valerian, Blessed Thistle, Dittany of Crete, Rue, Germander, Laurel berries, Juniper berries, cinnamon, cloves, viper meat, the two concoctions mithridate and theriac, as well as white wine, and honey.
# Literary references
Literary works mentioning orvietan include Tabarin's Inventaire Universel des Œuvres de Tabarin (1622), Molière's L'Amour médecin (1665), Voltaire's Pot-pourri (1765), Mme de Sevigne's correspondence, and Walter Scott's Kenilworth (1821), though Scott translates it as Venice treacle.
# External links
- L’Orvietano, una Panacea Popolare e Controversa
de:Orvietan
sv:Orvietan
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Orvietan | |
e65c8f8279a7f7e0e8bee6185dca336bed9a9f3d | wikidoc | Otoscope | Otoscope
An Otoscope or auriscope is a medical device which is used to look into the ears. Health care providers use otoscopes to screen for illness during regular check-ups and also to investigate when a symptom involves the ears. With an otoscope, it is possible to visualize the outer ear and middle ear.
Otoscopes consist of a handle and a head. The head contains an electric light source and a low power magnifying lens. The front end of the otoscope has an attachment for disposable plastic ear speculums. The examiner first straightens the ear canal by pulling on the pinna and then inserts the ear speculum side of the otoscope into the external ear. The examiner can then look through a lens on the rear of the instrument and see inside the ear canal. Many models have a detachable sliding rear window which allows the examiner to insert instruments through the otoscope into the ear canal, such as for removing earwax (cerumen). Most models also have an insertion point for a bulb capable of pushing air through the speculum. This puff of air allows an examiner to test the mobility of the tympanic membrane.
Many otoscopes used in doctors offices are wall-mounted, while others are portable. Wall-mounted otoscopes are attached by a flexible power cord to a base, which serves to hold the otoscope when it's not in use and also serves as a source of electric power, being plugged into an electric outlet. Portable models are powered by batteries in the handle; these batteries are usually rechargeable and can be recharged from a base unit. Otoscopes are often sold with ophthalmoscopes as a diagnostic set.
Diseases which may be diagnosed by an otoscope include otitis media and otitis externa, infection of the middle and outer parts of the ear, respectively.
Otoscopes are also frequently used for examining patients' noses (avoiding the need for a separate nasal speculum) and (with the speculum removed) upper throats. | Otoscope
An Otoscope or auriscope is a medical device which is used to look into the ears. Health care providers use otoscopes to screen for illness during regular check-ups and also to investigate when a symptom involves the ears. With an otoscope, it is possible to visualize the outer ear and middle ear.
Otoscopes consist of a handle and a head. The head contains an electric light source and a low power magnifying lens. The front end of the otoscope has an attachment for disposable plastic ear speculums. The examiner first straightens the ear canal by pulling on the pinna and then inserts the ear speculum side of the otoscope into the external ear. The examiner can then look through a lens on the rear of the instrument and see inside the ear canal. Many models have a detachable sliding rear window which allows the examiner to insert instruments through the otoscope into the ear canal, such as for removing earwax (cerumen). Most models also have an insertion point for a bulb capable of pushing air through the speculum. This puff of air allows an examiner to test the mobility of the tympanic membrane.
Many otoscopes used in doctors offices are wall-mounted, while others are portable. Wall-mounted otoscopes are attached by a flexible power cord to a base, which serves to hold the otoscope when it's not in use and also serves as a source of electric power, being plugged into an electric outlet. Portable models are powered by batteries in the handle; these batteries are usually rechargeable and can be recharged from a base unit. Otoscopes are often sold with ophthalmoscopes as a diagnostic set.
Diseases which may be diagnosed by an otoscope include otitis media and otitis externa, infection of the middle and outer parts of the ear, respectively.
Otoscopes are also frequently used for examining patients' noses (avoiding the need for a separate nasal speculum) and (with the speculum removed) upper throats.
# External links
- Overview at wisc.edu
- Overview at indstate.edu
de:Otoskop
nl:Otoscoop
no:Otoskop
nn:Otoskop
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Otoscope | |
a601bea757c202f989bbce6a9da04faece4ca7aa | wikidoc | Outbreak | Outbreak
Outbreak is a classification used in epidemiology to describe a small, localized group of people or organisms infected with a disease. Such groups are often confined to a village or a small area. Outbreaks may also refer to epidemics, which affect a region in a country or a group of countries, or pandemics, which describe global disease outbreaks.
# Outbreak Investigation
When investigating disease outbreaks, the epidemiology profession has developed a number of widely accepted steps. As described by the Centers for Disease Control and Prevention, these include the following:
- Identify the existence of the outbreak: is the group of ill persons normal for the time of year, geographic area, etc.?
- Verify the diagnosis related to the outbreak
- Create a case definition to define who/what is included as a case
- Complete descriptive epidemiology: describe outbreak with respect to time, place, and people
- Develop a hypothesis: what appears to be causing the outbreak?
- Study hypothesis: collect data and perform analysis
- Refine hypothesis and carry out further study
- Develop and implement control and prevention systems
- Release findings to greater community
# Types
- Common source (Point source)
- Propagated
- Continuous source
- Zoonotic
# Notes | Outbreak
Outbreak is a classification used in epidemiology to describe a small, localized group of people or organisms infected with a disease. Such groups are often confined to a village or a small area. Outbreaks may also refer to epidemics, which affect a region in a country or a group of countries, or pandemics, which describe global disease outbreaks.
# Outbreak Investigation
When investigating disease outbreaks, the epidemiology profession has developed a number of widely accepted steps. As described by the Centers for Disease Control and Prevention, these include the following[1]:
- Identify the existence of the outbreak: is the group of ill persons normal for the time of year, geographic area, etc.?
- Verify the diagnosis related to the outbreak
- Create a case definition to define who/what is included as a case
- Complete descriptive epidemiology: describe outbreak with respect to time, place, and people
- Develop a hypothesis: what appears to be causing the outbreak?
- Study hypothesis: collect data and perform analysis
- Refine hypothesis and carry out further study
- Develop and implement control and prevention systems
- Release findings to greater community
# Types
- Common source (Point source)
- Propagated
- Continuous source
- Zoonotic
# Notes
- ↑ http://www.cdc.gov/excite/classroom/outbreak/steps.htm
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Outbreak | |
36787a8cc3b0eefd08f476b76c97cb83b363b4d5 | wikidoc | Oxazepam | Oxazepam
# 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
Oxazepam is a Benzodiazepine that is FDA approved for the treatment of anxiety disorders and anxiety with alcohol withdrawal syndrome. Common adverse reactions include drowsiness, Dizziness, Headache, Somnolence, Vertigo.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Anxiety
Because of the flexibility of this product and the range of emotional disturbances responsive to it, dosage should be individualized for maximum beneficial effects.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oxazepam in adult patients.
### Non–Guideline-Supported Use
### Insomnia
- Insomnia: 15 mg before bedtime.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
This product is not indicated in pediatric patients under 6 years of age. Absolute dosage for pediatric patients 6 to 12 years of age is not established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oxazepam in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxazepam in pediatric patients.
# Contraindications
- History of previous hypersensitivity reaction to oxazepam.
- Oxazepam is not indicated in psychoses.
# Warnings
- As with other CNS-acting drugs, patients should be cautioned against driving automobiles or operating dangerous machinery until it is known that they do not become drowsy or dizzy on oxazepam therapy.
- Patients should be warned that the effects of alcohol or other CNS-depressant drugs may be additive to those of oxazepam, possibly requiring adjustment of dosage or elimination of such agents.
### Physical and Psychological Dependence
- Withdrawal symptoms (Benzodiazepine withdrawal syndrome), similar in character to those noted with barbiturates and alcohol (convulsions, tremor, abdominal and muscle cramps, vomiting, and sweating), have occurred following abrupt discontinuance of oxazepam.
- The more severe withdrawal symptoms have usually been limited to those patients who received excessive doses over an extended period of time.
- Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months.
- Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage-tapering schedule followed.
- Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving oxazepam or other psychotropic agents because of the predisposition of such patients to habituation and dependence.
# Adverse Reactions
## Clinical Trials Experience
The necessity for discontinuation of therapy due to undesirable effects has been rare. Transient, mild drowsiness is commonly seen in the first few days of therapy. If it persists, the dosage should be reduced. In few instances, dizziness, vertigo, headache, and rarely syncope have occurred either alone or together with drowsiness. Mild paradoxical reactions, i.e., excitement, stimulation of affect, have been reported in psychiatric patients; these reactions may be secondary to relief of anxiety and usually appear in the first two weeks of therapy.
Other side effects occurring during oxazepam therapy include rare instances of minor diffuse skin rashes-morbilliform, urticarial, and maculopapular, nausea, lethargy, edema, slurred speech, tremor, and altered libido. Such side effects have been infrequent and are generally controlled with reduction of dosage. A case of an extensive fixed drug eruption also has been reported.
Although rare, leukopenia and hepatic dysfunction including jaundice have been reported during therapy. Periodic blood counts and liver-function tests are advisable. Ataxia with oxazepam has been reported in rare instances and does not appear to be specifically related to dose or age.
Although the following side reactions have not as yet been reported with oxazepam, they have occurred with related compounds (chlordiazepoxide and diazepam): paradoxical excitation with severe rage reactions, hallucinations, menstrual irregularities, change in EEG pattern, blood dyscrasias including agranulocytosis, blurred vision, diplopia, incontinence, stupor, disorientation, fever, and euphoria.
Transient amnesia or memory impairment has been reported in association with the use of benzodiazepines.
## Postmarketing Experience
There is limited information regarding Oxazepam Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Oxazepam Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
An increased risk of congenital malformations associated with the use of minor tranquilizers (chlordiazepoxide, diazepam, and meprobamate) during the first trimester of pregnancy has been suggested in several studies. Oxazepam, a benzodiazepine derivative, has not been studied adequately to determine whether it, too, may be associated with an increased risk of fetal abnormality. Because use of these drugs is rarely a matter of urgency, their use during this period should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug.
Pregnancy Category (AUS): C
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oxazepam in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Oxazepam during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Oxazepam in women who are nursing.
### Pediatric Use
Safety and effectiveness in pediatric patients under 6 years of age have not been established. Absolute dosage for pediatric patients 6 to 12 years of age is not established.
### Geriatic Use
- Clinical studies of oxazepam were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects.
- Age (<80 years old) does not appear to have a clinically significant effect on oxazepam kinetics.
- Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered.
- Greater sensitivity of some older individuals to the effects of oxazepam (e.g., sedation, hypotension, paradoxical excitation) cannot be ruled out.
- In general, dose selection for oxazepam for elderly patients should be cautious, usually starting at the lower end of the dosing range.
### Gender
There is no FDA guidance on the use of Oxazepam with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Oxazepam with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Oxazepam in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Oxazepam in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Oxazepam in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Oxazepam in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
Although rare, leukopenia and hepatic dysfunction including jaundice have been reported during therapy. Periodic blood counts and liver-function tests are advisable.
# IV Compatibility
There is limited information regarding the compatibility of Oxazepam and IV administrations.
# Overdosage
In the management of overdosage with any drug, it should be born in mind that multiple agents may have been taken.
### Symptoms
Overdosage of benzodiazepines is usually manifested by varying degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion and lethargy. In more serious cases, and especially when other drugs or alcohol were ingested, symptoms may include ataxia, hypotonia, hypotension, hypnotic state, stage one (1) to three (3) coma, and very rarely, death.
### Management
Induced vomiting and/or gastric lavage should be undertaken, followed by general supportive care, monitoring of vital signs, and close observation of the patient. Hypotension, though unlikely, usually may be controlled with norepinephrine bitartrate injection. The value of dialysis has not been adequately determined for oxazepam.
The benzodiazepine antagonist flumazenil may be used in hospitalized patients as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS should be consulted prior to use.
# Pharmacology
## Mechanism of Action
There is limited information regarding mechanism of action of oxazepam in the drug label.
## Structure
- Oxazepam is the first of a chemical series of compounds, the 3-hydroxybenzodiazepinones.
- Oxazepam is 7 chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one, and has the following structural formula:
- Oxazepam is a white crystalline powder.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of oxazepam in the drug label.
## Pharmacokinetics
- Pharmacokinetic testing in 12 volunteers demonstrated that a single 30 mg dose of a capsule, tablet or suspension will result in an equivalent extent of absorption.
- For the capsule and tablet, peak plasma levels averaged 450 mg/mL and were observed to occur about 3 hours after dosing.
- The mean elimination half-life for oxazepam was approximately 8.2 hours (range 5.7 to 10.9 hours).
- This product has a single, major inactive metabolite in man, a glucuronide excreted in urine.
Age (80 years old) does not appear to have a clinically significant effect on oxazepam kinetics.
- A statistically significant increase in elimination half-life in the very elderly (80 years of age) as compared to younger subjects has been reported, due to a 30% increase in volume of distribution, as well as a 50% reduction in unbound clearance ofoxazepam in the very elderly.
## Nonclinical Toxicology
There is limited information regarding nonclinical toxicology of oxazepam in the drug label.
# Clinical Studies
There is limited information regarding Oxazepam Clinical Studies in the drug label.
# How Supplied
Oxazepam capsules are available as follows:
- 10 mg — Each pink opaque gelatin #4 capsule printed withand 067 in black ink on both cap and body contains 10 mg of Oxazepam, USP. Capsules are supplied in bottles of 100 (NDC 0228-2067-10) and 500 (NDC 0228-2067-50).
- 15 mg — Each red opaque gelatin #4 capsule printed withand 069 in black ink on both cap and body contains 15 mg of Oxazepam, USP. Capsules are supplied in bottles of 100 (NDC 0228-2069-10) and 500 (NDC 0228-2069-50).
- 30 mg — Each maroon opaque gelatin #4 capsule printed with and 073 in blue ink on both cap and body contains 30 mg of Oxazepam, USP. Capsules are supplied in bottles of 100 (NDC 0228-2073-10).
## Storage
- Store at 25(C (77(F); excursions permitted to 15( to 30(C (59( to 86(F).
- Keep tightly closed.
- Dispense in a tight, light-resistant container as defined in the USP.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Oxazepam Patient Counseling Information in the drug label.
# Precautions with Alcohol
Patients should be warned that the effects of alcohol or other CNS-depressant drugs may be additive to those of oxazepam, possibly requiring adjustment of dosage or elimination of such agents.
# Brand Names
- Serax
# Look-Alike Drug Names
There is limited information regarding Oxazepam Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Oxazepam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Oxazepam is a Benzodiazepine that is FDA approved for the treatment of anxiety disorders and anxiety with alcohol withdrawal syndrome. Common adverse reactions include drowsiness, Dizziness, Headache, Somnolence, Vertigo.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Anxiety
Because of the flexibility of this product and the range of emotional disturbances responsive to it, dosage should be individualized for maximum beneficial effects.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oxazepam in adult patients.
### Non–Guideline-Supported Use
### Insomnia
- Insomnia: 15 mg before bedtime. [1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
This product is not indicated in pediatric patients under 6 years of age. Absolute dosage for pediatric patients 6 to 12 years of age is not established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oxazepam in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxazepam in pediatric patients.
# Contraindications
- History of previous hypersensitivity reaction to oxazepam.
- Oxazepam is not indicated in psychoses.
# Warnings
- As with other CNS-acting drugs, patients should be cautioned against driving automobiles or operating dangerous machinery until it is known that they do not become drowsy or dizzy on oxazepam therapy.
- Patients should be warned that the effects of alcohol or other CNS-depressant drugs may be additive to those of oxazepam, possibly requiring adjustment of dosage or elimination of such agents.
### Physical and Psychological Dependence
- Withdrawal symptoms (Benzodiazepine withdrawal syndrome), similar in character to those noted with barbiturates and alcohol (convulsions, tremor, abdominal and muscle cramps, vomiting, and sweating), have occurred following abrupt discontinuance of oxazepam.
- The more severe withdrawal symptoms have usually been limited to those patients who received excessive doses over an extended period of time.
- Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months.
- Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage-tapering schedule followed.
- Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving oxazepam or other psychotropic agents because of the predisposition of such patients to habituation and dependence.
# Adverse Reactions
## Clinical Trials Experience
The necessity for discontinuation of therapy due to undesirable effects has been rare. Transient, mild drowsiness is commonly seen in the first few days of therapy. If it persists, the dosage should be reduced. In few instances, dizziness, vertigo, headache, and rarely syncope have occurred either alone or together with drowsiness. Mild paradoxical reactions, i.e., excitement, stimulation of affect, have been reported in psychiatric patients; these reactions may be secondary to relief of anxiety and usually appear in the first two weeks of therapy.
Other side effects occurring during oxazepam therapy include rare instances of minor diffuse skin rashes-morbilliform, urticarial, and maculopapular, nausea, lethargy, edema, slurred speech, tremor, and altered libido. Such side effects have been infrequent and are generally controlled with reduction of dosage. A case of an extensive fixed drug eruption also has been reported.
Although rare, leukopenia and hepatic dysfunction including jaundice have been reported during therapy. Periodic blood counts and liver-function tests are advisable. Ataxia with oxazepam has been reported in rare instances and does not appear to be specifically related to dose or age.
Although the following side reactions have not as yet been reported with oxazepam, they have occurred with related compounds (chlordiazepoxide and diazepam): paradoxical excitation with severe rage reactions, hallucinations, menstrual irregularities, change in EEG pattern, blood dyscrasias including agranulocytosis, blurred vision, diplopia, incontinence, stupor, disorientation, fever, and euphoria.
Transient amnesia or memory impairment has been reported in association with the use of benzodiazepines.
## Postmarketing Experience
There is limited information regarding Oxazepam Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Oxazepam Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
An increased risk of congenital malformations associated with the use of minor tranquilizers (chlordiazepoxide, diazepam, and meprobamate) during the first trimester of pregnancy has been suggested in several studies. Oxazepam, a benzodiazepine derivative, has not been studied adequately to determine whether it, too, may be associated with an increased risk of fetal abnormality. Because use of these drugs is rarely a matter of urgency, their use during this period should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug.
Pregnancy Category (AUS): C
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oxazepam in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Oxazepam during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Oxazepam in women who are nursing.
### Pediatric Use
Safety and effectiveness in pediatric patients under 6 years of age have not been established. Absolute dosage for pediatric patients 6 to 12 years of age is not established.
### Geriatic Use
- Clinical studies of oxazepam were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects.
- Age (<80 years old) does not appear to have a clinically significant effect on oxazepam kinetics.
- Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered.
- Greater sensitivity of some older individuals to the effects of oxazepam (e.g., sedation, hypotension, paradoxical excitation) cannot be ruled out.
- In general, dose selection for oxazepam for elderly patients should be cautious, usually starting at the lower end of the dosing range.
### Gender
There is no FDA guidance on the use of Oxazepam with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Oxazepam with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Oxazepam in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Oxazepam in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Oxazepam in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Oxazepam in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
Although rare, leukopenia and hepatic dysfunction including jaundice have been reported during therapy. Periodic blood counts and liver-function tests are advisable.
# IV Compatibility
There is limited information regarding the compatibility of Oxazepam and IV administrations.
# Overdosage
In the management of overdosage with any drug, it should be born in mind that multiple agents may have been taken.
### Symptoms
Overdosage of benzodiazepines is usually manifested by varying degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion and lethargy. In more serious cases, and especially when other drugs or alcohol were ingested, symptoms may include ataxia, hypotonia, hypotension, hypnotic state, stage one (1) to three (3) coma, and very rarely, death.
### Management
Induced vomiting and/or gastric lavage should be undertaken, followed by general supportive care, monitoring of vital signs, and close observation of the patient. Hypotension, though unlikely, usually may be controlled with norepinephrine bitartrate injection. The value of dialysis has not been adequately determined for oxazepam.
The benzodiazepine antagonist flumazenil may be used in hospitalized patients as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS should be consulted prior to use.
# Pharmacology
## Mechanism of Action
There is limited information regarding mechanism of action of oxazepam in the drug label.
## Structure
- Oxazepam is the first of a chemical series of compounds, the 3-hydroxybenzodiazepinones.
- Oxazepam is 7 chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one, and has the following structural formula:
- Oxazepam is a white crystalline powder.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of oxazepam in the drug label.
## Pharmacokinetics
- Pharmacokinetic testing in 12 volunteers demonstrated that a single 30 mg dose of a capsule, tablet or suspension will result in an equivalent extent of absorption.
- For the capsule and tablet, peak plasma levels averaged 450 mg/mL and were observed to occur about 3 hours after dosing.
- The mean elimination half-life for oxazepam was approximately 8.2 hours (range 5.7 to 10.9 hours).
- This product has a single, major inactive metabolite in man, a glucuronide excreted in urine.
Age (80 years old) does not appear to have a clinically significant effect on oxazepam kinetics.
- A statistically significant increase in elimination half-life in the very elderly (80 years of age) as compared to younger subjects has been reported, due to a 30% increase in volume of distribution, as well as a 50% reduction in unbound clearance ofoxazepam in the very elderly.
## Nonclinical Toxicology
There is limited information regarding nonclinical toxicology of oxazepam in the drug label.
# Clinical Studies
There is limited information regarding Oxazepam Clinical Studies in the drug label.
# How Supplied
Oxazepam capsules are available as follows:
- 10 mg — Each pink opaque gelatin #4 capsule printed withand 067 in black ink on both cap and body contains 10 mg of Oxazepam, USP. Capsules are supplied in bottles of 100 (NDC 0228-2067-10) and 500 (NDC 0228-2067-50).
- 15 mg — Each red opaque gelatin #4 capsule printed withand 069 in black ink on both cap and body contains 15 mg of Oxazepam, USP. Capsules are supplied in bottles of 100 (NDC 0228-2069-10) and 500 (NDC 0228-2069-50).
- 30 mg — Each maroon opaque gelatin #4 capsule printed with and 073 in blue ink on both cap and body contains 30 mg of Oxazepam, USP. Capsules are supplied in bottles of 100 (NDC 0228-2073-10).
## Storage
- Store at 25(C (77(F); excursions permitted to 15( to 30(C (59( to 86(F).
- Keep tightly closed.
- Dispense in a tight, light-resistant container as defined in the USP.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Oxazepam Patient Counseling Information in the drug label.
# Precautions with Alcohol
Patients should be warned that the effects of alcohol or other CNS-depressant drugs may be additive to those of oxazepam, possibly requiring adjustment of dosage or elimination of such agents.
# Brand Names
- Serax[4]
# Look-Alike Drug Names
There is limited information regarding Oxazepam Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Oxazepam | |
eaf2fbbbd94cdf9afa1c09c76c978c199f63cf4e | wikidoc | Oxeladin | Oxeladin
# Overview
Oxeladin is a cough suppressant. It is a highly potent and effective drug used to treat all types of cough of various etiologies. It is not related to opium or its derivatives, so treatment with oxeladin is free of risk of dependence or addiction. Oxeladin has none of the side effects (such as hypnosis, respiratory depression, tolerance, constipation and analgesia) which are present when common antitussives, such as codeine and its derivatives, are used. It may be used at every age, as well as in patients with heart disease, since it has a high level of safety and a great selectivity to act on the bulbar centre of cough.
# Indications
Oxeladin is indicated in all types of cough. Besides its antitussive action, it helps to clear the respiratory tract, since it increases the quantity of secretion and thins bronchial secretion.
- Irritative cough
- Allergic cough
- Psychogenic cough
- Treatment of cough in patients with heart disease (it has no action upon the cardiovascular system)
- Infectious cough: tracheitis, bronchitis, pneumonia
- Treatment of cough in pre- and post-operative treatment for bronchoscopy
# Contraindications
Although fetal malformations have not been reported, oxeladin should not be used during the first trimester of pregnancy. Oxeladin is contraindicated in patients with MAOI therapy.
# Side effects
Rarely, some patients have reported rash, dizziness, sedation or mild digestive disturbances. These usually disappear on reducing the dosage or interrupting the treatment.
# Addiction
Oxeladin differs from common antitussives that cause addiction (such as etilmorphin, codeine or its derivatives) in that there is no evidence of risk of addiction or dependence.
# Composition and packaging
Oxeladin is available as drops, syrup and tablets, providing easier ways of management which will be chosen depending on the age and clinical stage.
## Drops
Each 1ml (33 drops) contains oxeladin citrate 20 mg. The bottle contains 20ml of solution.
## Syrup
Each 100ml contains oxeladin citrate 200 mg. The bottle contains 100ml of syrup.
## Tablets
Each tablet contains oxeladin citrate 20 mg. The box contains 20 tablets in blister packs
# Dosage
- Children 2-5yrs: 2.5ml-5ml (17 drops) every 4-6 hours
- Children 6-12 yrs: 10ml (33 drops), or 1 tablet, every 4-6 hours
- Children 12 yrs and over and adults: 15ml (50 drops), or 2 tablets, every 4-6 hours
# Restrictions in use and availability
The Drug and Medical Technology Agency of Armenia rejected the registration of oxeladin in July 2000 since studies in[[Germany have shown potential carcinogenicity of the drug. | Oxeladin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Oxeladin is a cough suppressant. It is a highly potent and effective drug used to treat all types of cough of various etiologies. It is not related to opium or its derivatives, so treatment with oxeladin is free of risk of dependence or addiction. Oxeladin has none of the side effects (such as hypnosis, respiratory depression, tolerance, constipation and analgesia) which are present when common antitussives, such as codeine and its derivatives, are used. It may be used at every age, as well as in patients with heart disease, since it has a high level of safety and a great selectivity to act on the bulbar centre of cough.
# Indications
Oxeladin is indicated in all types of cough. Besides its antitussive action, it helps to clear the respiratory tract, since it increases the quantity of secretion and thins bronchial secretion.
- Irritative cough
- Allergic cough
- Psychogenic cough
- Treatment of cough in patients with heart disease (it has no action upon the cardiovascular system)
- Infectious cough: tracheitis, bronchitis, pneumonia
- Treatment of cough in pre- and post-operative treatment for bronchoscopy
# Contraindications
Although fetal malformations have not been reported, oxeladin should not be used during the first trimester of pregnancy. Oxeladin is contraindicated in patients with MAOI therapy.
# Side effects
Rarely, some patients have reported rash, dizziness, sedation or mild digestive disturbances. These usually disappear on reducing the dosage or interrupting the treatment.
# Addiction
Oxeladin differs from common antitussives that cause addiction (such as etilmorphin, codeine or its derivatives) in that there is no evidence of risk of addiction or dependence.
# Composition and packaging
Oxeladin is available as drops, syrup and tablets, providing easier ways of management which will be chosen depending on the age and clinical stage.
## Drops
Each 1ml (33 drops) contains oxeladin citrate 20 mg. The bottle contains 20ml of solution.
## Syrup
Each 100ml contains oxeladin citrate 200 mg. The bottle contains 100ml of syrup.
## Tablets
Each tablet contains oxeladin citrate 20 mg. The box contains 20 tablets in blister packs
# Dosage
- Children 2-5yrs: 2.5ml-5ml (17 drops) every 4-6 hours
- Children 6-12 yrs: 10ml (33 drops), or 1 tablet, every 4-6 hours
- Children 12 yrs and over and adults: 15ml (50 drops), or 2 tablets, every 4-6 hours
# Restrictions in use and availability
The Drug and Medical Technology Agency of Armenia rejected the registration of oxeladin in July 2000 since studies in[[Germany have shown potential carcinogenicity of the drug. | https://www.wikidoc.org/index.php/Oxeladin | |
76816695b14b7d3d63877ba7f2c31c7249741172 | wikidoc | Oxytocin | Oxytocin
Oxytocin (Oxt) is a peptide hormone and neuropeptide. Oxytocin is normally produced by the paraventricular nucleus of the hypothalamus and released by the posterior pituitary. It plays a role in social bonding, sexual reproduction, childbirth, and the period after childbirth. Oxytocin is released into the bloodstream as a hormone in response to stretching of the cervix and uterus during labor and with stimulation of the nipples from breastfeeding. This helps with birth, bonding with the baby, and milk production. Oxytocin was discovered by Henry Dale in 1906. Its molecular structure was determined in 1952. Oxytocin is also used as a medication to facilitate childbirth.
# Biochemistry
Estrogen has been found to increase the secretion of oxytocin and to increase the expression of its receptor, the oxytocin receptor, in the brain. In women, a single dose of estradiol has been found to be sufficient to increase circulating oxytocin concentrations.
## Biosynthesis
The oxytocin peptide is synthesized as an inactive precursor protein from the OXT gene. This precursor protein also includes the oxytocin carrier protein neurophysin I. The inactive precursor protein is progressively hydrolyzed into smaller fragments (one of which is neurophysin I) via a series of enzymes. The last hydrolysis that releases the active oxytocin nonapeptide is catalyzed by peptidylglycine alpha-amidating monooxygenase (PAM).
The activity of the PAM enzyme system is dependent upon vitamin C (ascorbate), which is a necessary vitamin cofactor. By chance, sodium ascorbate by itself was found to stimulate the production of oxytocin from ovarian tissue over a range of concentrations in a dose-dependent manner. Many of the same tissues (e.g. ovaries, testes, eyes, adrenals, placenta, thymus, pancreas) where PAM (and oxytocin by default) is found are also known to store higher concentrations of vitamin C.
Oxytocin is known to be metabolized by the oxytocinase, leucyl/cystinyl aminopeptidase. Other oxytocinases are also known to exist. Amastatin, bestatin (ubenimex), leupeptin, and puromycin have been found to inhibit the enzymatic degradation of oxytocin, though they also inhibit the degradation of various other peptides, such as vasopressin, met-enkephalin, and dynorphin A.
## Neural sources
In the hypothalamus, oxytocin is made in magnocellular neurosecretory cells of the supraoptic and paraventricular nuclei, and is stored in Herring bodies at the axon terminals in the posterior pituitary. It is then released into the blood from the posterior lobe (neurohypophysis) of the pituitary gland. These axons (likely, but dendrites have not been ruled out) have collaterals that innervate neurons in the nucleus accumbens, a brain structure where oxytocin receptors are expressed. The endocrine effects of hormonal oxytocin and the cognitive or behavioral effects of oxytocin neuropeptides are thought to be coordinated through its common release through these collaterals. Oxytocin is also produced by some neurons in the paraventricular nucleus that project to other parts of the brain and to the spinal cord. Depending on the species, oxytocin receptor-expressing cells are located in other areas, including the amygdala and bed nucleus of the stria terminalis.
In the pituitary gland, oxytocin is packaged in large, dense-core vesicles, where it is bound to neurophysin I as shown in the inset of the figure; neurophysin is a large peptide fragment of the larger precursor protein molecule from which oxytocin is derived by enzymatic cleavage.
Secretion of oxytocin from the neurosecretory nerve endings is regulated by the electrical activity of the oxytocin cells in the hypothalamus. These cells generate action potentials that propagate down axons to the nerve endings in the pituitary; the endings contain large numbers of oxytocin-containing vesicles, which are released by exocytosis when the nerve terminals are depolarised.
## Non-neural sources
Endogenous oxytocin concentrations in the brain have been found to be as much as 1000-fold higher than peripheral levels.
Outside the brain, oxytocin-containing cells have been identified in several diverse tissues, including in females in the corpus luteum and the placenta; in males in the testicles' interstitial cells of Leydig; and in both sexes in the retina, the adrenal medulla, the thymus and the pancreas. The finding of significant amounts of this classically "neurohypophysial" hormone outside the central nervous system raises many questions regarding its possible importance in these different tissues.
### Male
The Leydig cells in some species have been shown to possess the biosynthetic machinery to manufacture testicular oxytocin de novo, to be specific, in rats (which can synthesize vitamin C endogenously), and in guinea pigs, which, like humans, require an exogenous source of vitamin C (ascorbate) in their diets.
### Female
Oxytocin is synthesized by corpora lutea of several species, including ruminants and primates. Along with estrogen, it is involved in inducing the endometrial synthesis of prostaglandin F2α to cause regression of the corpus luteum.
## Evolution
Virtually all vertebrates have an oxytocin-like nonapeptide hormone that supports reproductive functions and a vasopressin-like nonapeptide hormone involved in water regulation. The two genes are usually located close to each other (less than 15,000 bases apart) on the same chromosome, and are transcribed in opposite directions (however, in fugu, the homologs are further apart and transcribed in the same direction).
The two genes are believed to result from a gene duplication event; the ancestral gene is estimated to be about 500 million years old and is found in cyclostomata (modern members of the Agnatha).
# Biological function
Oxytocin has peripheral (hormonal) actions, and also has actions in the brain. Its actions are mediated by specific, oxytocin receptors. The oxytocin receptor is a G-protein-coupled receptor that requires magnesium and cholesterol. It belongs to the rhodopsin-type (class I) group of G-protein-coupled receptors.
Studies have looked at oxytocin's role in various behaviors, including orgasm, social recognition, pair bonding, anxiety, and maternal behaviors.
## Physiological
The peripheral actions of oxytocin mainly reflect secretion from the pituitary gland. The behavioral effects of oxytocin are thought to reflect release from centrally projecting oxytocin neurons, different from those that project to the pituitary gland, or that are collaterals from them. Oxytocin receptors are expressed by neurons in many parts of the brain and spinal cord, including the amygdala, ventromedial hypothalamus, septum, nucleus accumbens, and brainstem.
- Milk ejection reflex/Letdown reflex: in lactating (breastfeeding) mothers, oxytocin acts at the mammary glands, causing milk to be 'let down' into lactiferous ducts, from where it can be excreted via the nipple. Suckling by the infant at the nipple is relayed by spinal nerves to the hypothalamus. The stimulation causes neurons that make oxytocin to fire action potentials in intermittent bursts; these bursts result in the secretion of pulses of oxytocin from the neurosecretory nerve terminals of the pituitary gland.
- Uterine contraction: important for cervical dilation before birth, oxytocin causes contractions during the second and third stages of labor. Oxytocin release during breastfeeding causes mild but often painful contractions during the first few weeks of lactation. This also serves to assist the uterus in clotting the placental attachment point postpartum. However, in knockout mice lacking the oxytocin receptor, reproductive behavior and parturition are normal.
- Due to its similarity to vasopressin, it can reduce the excretion of urine slightly. In several species, oxytocin can stimulate sodium excretion from the kidneys (natriuresis), and, in humans, high doses can result in low sodium levels (hyponatremia).
- Cardiac effects: oxytocin and oxytocin receptors are also found in the heart in some rodents, and the hormone may play a role in the embryonal development of the heart by promoting cardiomyocyte differentiation. However, the absence of either oxytocin or its receptor in knockout mice has not been reported to produce cardiac insufficiencies.
- Modulation of hypothalamic-pituitary-adrenal axis activity: oxytocin, under certain circumstances, indirectly inhibits release of adrenocorticotropic hormone and cortisol and, in those situations, may be considered an antagonist of vasopressin.
- Preparing fetal neurons for delivery: crossing the placenta, maternal oxytocin reaches the fetal brain and induces a switch in the action of neurotransmitter GABA from excitatory to inhibitory on fetal cortical neurons. This silences the fetal brain for the period of delivery and reduces its vulnerability to hypoxic damage.
- Feeding: a 2012 paper suggested that oxytocin neurons in the para-ventricular hypothalamus in the brain may play a key role in suppressing appetite under normal conditions and that other hypothalamic neurons may trigger eating via inhibition of these oxytocin neurons. This population of oxytocin neurons is absent in Prader-Willi syndrome, a genetic disorder that leads to uncontrollable feeding and obesity, and may play a key role in its pathophysiology.
## Psychological
- Autism: Oxytocin has been implicated in the etiology of autism, with one report suggesting autism is correlated with genomic deletion of the chromosome containing the oxytocin receptor gene (OXTR). Studies involving Caucasian and Finnish samples and Chinese Han families provide support for the relationship of OXTR with autism. Autism may also be associated with an aberrant methylation of OXTR.
### Bonding
In the prairie vole, oxytocin released into the brain of the female during sexual activity is important for forming a pair bond with her sexual partner. Vasopressin appears to have a similar effect in males. Oxytocin has a role in social behaviors in many species, so it likely also does in humans. In a 2003 study, both humans and dog oxytocin levels in the blood rose after five to 24 minutes of a petting session. This possibly plays a role in the emotional bonding between humans and dogs.
- Maternal behavior: Female rats given oxytocin antagonists after giving birth do not exhibit typical maternal behavior. By contrast, virgin female sheep show maternal behavior toward foreign lambs upon cerebrospinal fluid infusion of oxytocin, which they would not do otherwise. Oxytocin is involved in the initiation of maternal behavior, not its maintenance; for example, it is higher in mothers after they interact with unfamiliar children rather than their own.
- Ingroup bonding: Oxytocin can increase positive attitudes, such as bonding, toward individuals with similar characteristics, who then become classified as "in-group" members, whereas individuals who are dissimilar become classified as "out-group" members. Race can be used as an example of in-group and out-group tendencies because society often categorizes individuals into groups based on race (Caucasian, African American, Latino, etc.). One study that examined race and empathy found that participants receiving nasally administered oxytocin had stronger reactions to pictures of in-group members making pained faces than to pictures of out-group members with the same expression. This shows that oxytocin may be implicated in our ability to empathize with individuals of different races and could potentially translate into willingness to help individuals in pain or stressful situations. Moreover, individuals of one race may be more inclined to help individuals of the same race than individuals of another race when they are experiencing pain. Oxytocin has also been implicated in lying when lying would prove beneficial to other in-group members. In a study where such a relationship was examined, it was found that when individuals were administered oxytocin, rates of dishonesty in the participants' responses increased for their in-group members when a beneficial outcome for their group was expected. Both of these examples show the tendency of individuals to act in ways that benefit those considered to be members of their social group, or in-group.
Oxytocin is not only correlated with the preferences of individuals to associate with members of their own group, but it is also evident during conflicts between members of different groups. During conflict, individuals receiving nasally administered oxytocin demonstrate more frequent defense-motivated responses toward in-group members than out-group members. Further, oxytocin was correlated with participant desire to protect vulnerable in-group members, despite that individual's attachment to the conflict. Similarly, it has been demonstrated that when oxytocin is administered, individuals alter their subjective preferences in order to align with in-group ideals over out-group ideals. These studies demonstrate that oxytocin is associated with intergroup dynamics. Further, oxytocin influences the responses of individuals in a particular group to those of another group. The in-group bias is evident in smaller groups; however, it can also be extended to groups as large as one's entire country leading toward a tendency of strong national zeal. A study done in the Netherlands showed that oxytocin increased the in-group favoritism of their nation while decreasing acceptance of members of other ethnicities and foreigners. People also show more affection for their country's flag while remaining indifferent to other cultural objects when exposed to oxytocin. It has thus been hypothesized that this hormone may be a factor in xenophobic tendencies secondary to this effect. Thus, oxytocin appears to affect individuals at an international level where the in-group becomes a specific "home" country and the out-group grows to include all other countries.
### Drugs
- Drug interaction: Impact on effects of alcohol and other drugs: According to several studies in animals, oxytocin inhibits the development of tolerance to various addictive drugs (opiates, cocaine, alcohol), and reduces withdrawal symptoms. MDMA (ecstasy) may increase feelings of love, empathy, and connection to others by stimulating oxytocin activity primarily via activation of serotonin 5-HT1A receptors, if initial studies in animals apply to humans. The anxiolytic Buspar (buspirone) may produce some of its effects via 5-HT1A receptor-induced oxytocin stimulation as well.
- Addiction vulnerability: Concentrations of endogenous oxytocin can impact the effects of various drugs and one's susceptibility to substance use disorders. Additionally, bilateral interactions with numerous systems, including the dopamine system, Hypothalamic–pituitary–adrenal axis and immune system, can impact development of dependence. The status of the endogenous oxytocin system might enhance or reduce susceptibility to addiction through its interaction with these systems. Individual differences in the endogenous oxytocin system based on genetic predisposition, gender and environmental influences, may therefore affect addiction vulnerability. Oxytocin may be related to the place conditioning behaviors observed in habitual drug abusers.
### Fear and anxiety
Oxytocin is typically remembered for the effect it has on prosocial behaviors, such as its role in facilitating trust and attachment between individuals. Consequently, oxytocin is often referred to as the “love hormone". However, oxytocin has a more complex role than solely enhancing prosocial behaviors. There is consensus that oxytocin modulates fear and anxiety; that is, it does not directly elicit fear or anxiety. Two dominant theories explain the role of oxytocin in fear and anxiety. One theory states that oxytocin increases approach/avoidance to certain social stimuli and the second theory states that oxytocin increases the salience of certain social stimuli, causing the animal or human to pay closer attention to socially relevant stimuli.
Nasally administered oxytocin has been reported to reduce fear, possibly by inhibiting the amygdala (which is thought to be responsible for fear responses). Indeed, studies in rodents have shown oxytocin can efficiently inhibit fear responses by activating an inhibitory circuit within the amygdala. Some researchers have argued oxytocin has a general enhancing effect on all social emotions, since intranasal administration of oxytocin also increases envy and Schadenfreude. Individuals who receive an intranasal dose of oxytocin identify facial expressions of disgust more quickly than individuals who do not receive oxytocin. Facial expressions of disgust are evolutionarily linked to the idea of contagion. Thus, oxytocin increases the salience of cues that imply contamination, which leads to a faster response because these cues are especially relevant for survival. In another study, after administration of oxytocin, individuals displayed an enhanced ability to recognize expressions of fear compared to the individuals who received the placebo. Oxytocin modulates fear responses by enhancing the maintenance of social memories. Rats that are genetically modified to have a surplus of oxytocin receptors display a greater fear response to a previously conditioned stressor. Oxytocin enhances the aversive social memory, leading the rat to display a greater fear response when the aversive stimulus is encountered again.
### Mood and depression
Oxytocin produces antidepressant-like effects in animal models of depression, and a deficit of it may be involved in the pathophysiology of depression in humans. The antidepressant-like effects of oxytocin are not blocked by a selective antagonist of the oxytocin receptor, suggesting that these effects are not mediated by the oxytocin receptor. In accordance, unlike oxytocin, the selective non-peptide oxytocin receptor agonist WAY-267,464 does not produce antidepressant-like effects, at least in the tail suspension test. In contrast to WAY-267,464, carbetocin, a close analogue of oxytocin and peptide oxytocin receptor agonist, notably does produce antidepressant-like effects in animals. As such, the antidepressant-like effects of oxytocin may be mediated by modulation of a different target, perhaps the vasopressin V1A receptor where oxytocin is known to weakly bind as an agonist.
Sildenafil has been found to enhance electrically evoked oxytocin release from the pituitary gland. In accordance, the drug shows oxytocin-dependent antidepressant-like effects in animals, and it has proposed that sildenafil may hold promise as a potential antidepressant in humans.
### Sex differences
It has been shown that oxytocin differentially affects males and females. Females who are administered oxytocin are overall faster in responding to socially relevant stimuli than males who received oxytocin. Additionally, after the administration of oxytocin, females show increased amygdala activity in response to threatening scenes; however, males do not show increased amygdala activation. This phenomenon can be explained by looking at the role of gonadal hormones, specifically estrogen, which modulate the enhanced threat processing seen in females. Estrogen has been shown to stimulate the release of oxytocin from the hypothalamus and promote receptor binding in the amygdala.
It has also been shown that testosterone directly suppresses oxytocin in mice. This has been hypothesized to have evolutionary significance. With oxytocin suppressed, activities such as hunting and attacking invaders would be less mentally difficult as oxytocin is strongly associated with empathy.
### Social
- Affecting generosity by increasing empathy during perspective taking: In a neuroeconomics experiment, intranasal oxytocin increased generosity in the Ultimatum Game by 80%, but had no effect in the Dictator Game that measures altruism. Perspective-taking is not required in the Dictator Game, but the researchers in this experiment explicitly induced perspective-taking in the Ultimatum Game by not identifying to participants into which role they would be placed. Serious methodological questions have arisen, however, with regard to the role of oxytocin in trust and generosity. Empathy in healthy males has been shown to be increased after intranasal oxytocin This is most likely due to the effect of oxytocin in enhancing eye gaze. There is some discussion about which aspect of empathy oxytocin might alter – for example, cognitive vs. emotional empathy. While studying wild chimpanzees, it was noted that after a chimpanzee shared food with a non-kin related chimpanzee, the subjects' levels of oxytocin increased, as measured through their urine. In comparison to other cooperative activities between chimpanzees that were monitored including grooming, food sharing generated higher levels of oxytocin. This comparatively higher level of oxytocin after food sharing parallels the increased level of oxytocin in nursing mothers, sharing nutrients with their kin.
- Trust is increased by oxytocin. Disclosure of emotional events is a sign of trust in humans. When recounting a negative event, humans who receive intranasal oxytocin share more emotional details and stories with more emotional significance. Humans also find faces more trustworthy after receiving intranasal oxytocin. In a study, participants who received intranasal oxytocin viewed photographs of human faces with neutral expressions and found them to be more trustworthy than those who did not receive oxytocin. This may be because oxytocin reduces the fear of social betrayal in humans. Even after experiencing social alienation by being excluded from a conversation, humans who received oxytocin scored higher in trust on the Revised NEO Personality Inventory. Moreover, in a risky investment game, experimental subjects given nasally administered oxytocin displayed "the highest level of trust" twice as often as the control group. Subjects who were told they were interacting with a computer showed no such reaction, leading to the conclusion that oxytocin was not merely affecting risk aversion. When there is a reason to be distrustful, such as experiencing betrayal, differing reactions are associated with oxytocin receptor gene (OXTR) differences. Those with the CT haplotype experience a stronger reaction, in the form of anger, to betrayal.
- Romantic attachment: In some studies, high levels of plasma oxytocin have been correlated with romantic attachment. For example, if a couple is separated for a long period of time, anxiety can increase due to the lack of physical affection. Oxytocin may aid romantically attached couples by decreasing their feelings of anxiety when they are separated.
- Group-serving dishonesty/deception: In a carefully controlled study exploring the biological roots of immoral behavior, oxytocin was shown to promote dishonesty when the outcome favored the group to which an individual belonged instead of just the individual.
- Sexual activity: The relationship between oxytocin and human sexual response is unclear. At least two uncontrolled studies have found increases in plasma oxytocin at orgasm – in both men and women. Plasma oxytocin levels are notably increased around the time of self-stimulated orgasm and are still higher than baseline when measured five minutes after self arousal. The authors of one of these studies speculated that oxytocin's effects on muscle contractibility may facilitate sperm and egg transport.
- Oxytocin affects social distance between adult males and females, and may be responsible at least in part for romantic attraction and subsequent monogamous pair bonding. An oxytocin nasal spray caused men in a monogamous relationship, but not single men, to increase the distance between themselves and an attractive woman during a first encounter by 10 to 15 centimeters. The researchers suggested that oxytocin may help promote fidelity within monogamous relationships. For this reason, it is sometimes referred to as the "bonding hormone". There is some evidence that oxytocin promotes ethnocentric behavior, incorporating the trust and empathy of in-groups with their suspicion and rejection of outsiders. Furthermore, genetic differences in the oxytocin receptor gene (OXTR) have been associated with maladaptive social traits such as aggressive behavior.
- Social behavior and wound healing: Oxytocin is also thought to modulate inflammation by decreasing certain cytokines. Thus, the increased release in oxytocin following positive social interactions has the potential to improve wound healing. A study by Marazziti and colleagues used heterosexual couples to investigate this possibility. They found increases in plasma oxytocin following a social interaction were correlated with faster wound healing. They hypothesized this was due to oxytocin reducing inflammation, thus allowing the wound to heal more quickly. This study provides preliminary evidence that positive social interactions may directly influence aspects of health. According to a study published in 2014, silencing of oxytocin receptor interneurons in the medial prefrontal cortex (mPFC) of female mice resulted in loss of social interest in male mice during the sexually receptive phase of the estrous cycle. Oxytocin evokes feelings of contentment, reductions in anxiety, and feelings of calmness and security when in the company of the mate. This suggests oxytocin may be important for the inhibition of the brain regions associated with behavioral control, fear, and anxiety, thus allowing orgasm to occur. Research has also demonstrated that oxytocin can decrease anxiety and protect against stress, particularly in combination with social support. It is found, that endocannabinoid signaling mediates oxytocin-driven social reward.
# Chemistry
Oxytocin is a peptide of nine amino acids (a nonapeptide) in the sequence cysteine-tyrosine-isoleucine-glutamine-asparagine-cysteine-proline-leucine-glycine-amide (Cys – Tyr – Ile – Gln – Asn – Cys – Pro – Leu – Gly – NH2, or CYIQNCPLG-NH2); its C-terminus has been converted to a primary amide and a disulfide bridge joins the cysteine moieties. Oxytocin has a molecular mass of 1007 Da, and one international unit (IU) of oxytocin is the equivalent of 1.68 μg of pure peptide.
While the structure of oxytocin is highly conserved in placental mammals, a novel structure of oxytocin was recently reported in marmosets, tamarins, and other new world primates. Genomic sequencing of the gene for oxytocin revealed a single in-frame mutation (thymine for cytosine) which results in a single amino acid substitution at the 8-position (proline for leucine). Since this original Lee et al. paper, two other laboratories have confirmed Pro8-OT and documented additional oxytocin structural variants in this primate taxon. Vargas-Pinilla et al. sequenced the coding regions of the OXT gene in other genera in new world primates and identified the following variants in addition to Leu8- and Pro8-OT: Ala8-OT, Thr8-OT, and Val3/Pro8-OT. Ren et al. identified a variant further, Phe2-OT in howler monkeys.
The biologically active form of oxytocin, commonly measured by RIA and/or HPLC techniques, is also known as the octapeptide "oxytocin disulfide" (oxidized form), but oxytocin also exists as a reduced straight-chain (non-cyclic) dithiol nonapeptide called oxytoceine. It has been theorized that oxytoceine may act as a free radical scavenger, as donating an electron to a free radical allows oxytoceine to be re-oxidized to oxytocin via the dehydroascorbate / ascorbate redox couple.
The structure of oxytocin is very similar to that of vasopressin. Both are nonapeptides with a single disulfide bridge, differing only by two substitutions in the amino acid sequence (differences from oxytocin bolded for clarity): Cys – Tyr – Phe – Gln – Asn – Cys – Pro – Arg – Gly – NH2. A table showing the sequences of members of the vasopressin/oxytocin superfamily and the species expressing them is present in the vasopressin article. Oxytocin and vasopressin were isolated and their total synthesis reported in 1954, work for which Vincent du Vigneaud was awarded the 1955 Nobel Prize in Chemistry with the citation: "for his work on biochemically important sulphur compounds, especially for the first synthesis of a polypeptide hormone."
Oxytocin and vasopressin are the only known hormones released by the human posterior pituitary gland to act at a distance. However, oxytocin neurons make other peptides, including corticotropin-releasing hormone and dynorphin, for example, that act locally. The magnocellular neurosecretory cells that make oxytocin are adjacent to magnocellular neurosecretory cells that make vasopressin. These are large neuroendocrine neurons which are excitable and can generate action potentials.
# History
The uterine-contracting properties of the principle that would later be named oxytocin were discovered by British pharmacologist Sir Henry Hallett Dale in 1906, and its milk ejection property was described by Ott and Scott in 1910 and by Schafer and Mackenzie in 1911. In the 1920s, oxytocin and vasopressin were isolated from pituitary tissue and given their current names. The word oxytocin was coined from the term oxytocic, Greek ὀξύς, oxys, and τοκετός , toketos, meaning "quick birth".
Oxytocin became the first polypeptide hormone to be sequenced or synthesized. Du Vigneaud was awarded the Nobel Prize in 1955 for his work. | Oxytocin
Oxytocin (Oxt) is a peptide hormone and neuropeptide. Oxytocin is normally produced by the paraventricular nucleus of the hypothalamus and released by the posterior pituitary.[3] It plays a role in social bonding, sexual reproduction, childbirth, and the period after childbirth.[4] Oxytocin is released into the bloodstream as a hormone in response to stretching of the cervix and uterus during labor and with stimulation of the nipples from breastfeeding.[5] This helps with birth, bonding with the baby, and milk production.[5][6] Oxytocin was discovered by Henry Dale in 1906.[7] Its molecular structure was determined in 1952.[8] Oxytocin is also used as a medication to facilitate childbirth.[9][10][11]
# Biochemistry
Estrogen has been found to increase the secretion of oxytocin and to increase the expression of its receptor, the oxytocin receptor, in the brain.[12] In women, a single dose of estradiol has been found to be sufficient to increase circulating oxytocin concentrations.[13]
## Biosynthesis
The oxytocin peptide is synthesized as an inactive precursor protein from the OXT gene.[14][15][16] This precursor protein also includes the oxytocin carrier protein neurophysin I.[17] The inactive precursor protein is progressively hydrolyzed into smaller fragments (one of which is neurophysin I) via a series of enzymes. The last hydrolysis that releases the active oxytocin nonapeptide is catalyzed by peptidylglycine alpha-amidating monooxygenase (PAM).[18]
The activity of the PAM enzyme system is dependent upon vitamin C (ascorbate), which is a necessary vitamin cofactor. By chance, sodium ascorbate by itself was found to stimulate the production of oxytocin from ovarian tissue over a range of concentrations in a dose-dependent manner.[19] Many of the same tissues (e.g. ovaries, testes, eyes, adrenals, placenta, thymus, pancreas) where PAM (and oxytocin by default) is found are also known to store higher concentrations of vitamin C.[20]
Oxytocin is known to be metabolized by the oxytocinase, leucyl/cystinyl aminopeptidase.[21][22] Other oxytocinases are also known to exist.[21][23] Amastatin, bestatin (ubenimex), leupeptin, and puromycin have been found to inhibit the enzymatic degradation of oxytocin, though they also inhibit the degradation of various other peptides, such as vasopressin, met-enkephalin, and dynorphin A.[23][24][25][26]
## Neural sources
In the hypothalamus, oxytocin is made in magnocellular neurosecretory cells of the supraoptic and paraventricular nuclei, and is stored in Herring bodies at the axon terminals in the posterior pituitary. It is then released into the blood from the posterior lobe (neurohypophysis) of the pituitary gland. These axons (likely, but dendrites have not been ruled out) have collaterals that innervate neurons in the nucleus accumbens, a brain structure where oxytocin receptors are expressed.[27] The endocrine effects of hormonal oxytocin and the cognitive or behavioral effects of oxytocin neuropeptides are thought to be coordinated through its common release through these collaterals.[27] Oxytocin is also produced by some neurons in the paraventricular nucleus that project to other parts of the brain and to the spinal cord.[28] Depending on the species, oxytocin receptor-expressing cells are located in other areas, including the amygdala and bed nucleus of the stria terminalis.
In the pituitary gland, oxytocin is packaged in large, dense-core vesicles, where it is bound to neurophysin I as shown in the inset of the figure; neurophysin is a large peptide fragment of the larger precursor protein molecule from which oxytocin is derived by enzymatic cleavage.
Secretion of oxytocin from the neurosecretory nerve endings is regulated by the electrical activity of the oxytocin cells in the hypothalamus. These cells generate action potentials that propagate down axons to the nerve endings in the pituitary; the endings contain large numbers of oxytocin-containing vesicles, which are released by exocytosis when the nerve terminals are depolarised.
## Non-neural sources
Endogenous oxytocin concentrations in the brain have been found to be as much as 1000-fold higher than peripheral levels.[29]
Outside the brain, oxytocin-containing cells have been identified in several diverse tissues, including in females in the corpus luteum[30][31] and the placenta;[32] in males in the testicles' interstitial cells of Leydig;[33] and in both sexes in the retina,[34] the adrenal medulla,[35] the thymus[36] and the pancreas.[37] The finding of significant amounts of this classically "neurohypophysial" hormone outside the central nervous system raises many questions regarding its possible importance in these different tissues.
### Male
The Leydig cells in some species have been shown to possess the biosynthetic machinery to manufacture testicular oxytocin de novo, to be specific, in rats (which can synthesize vitamin C endogenously), and in guinea pigs, which, like humans, require an exogenous source of vitamin C (ascorbate) in their diets.[38]
### Female
Oxytocin is synthesized by corpora lutea of several species, including ruminants and primates. Along with estrogen, it is involved in inducing the endometrial synthesis of prostaglandin F2α to cause regression of the corpus luteum.[39]
## Evolution
Virtually all vertebrates have an oxytocin-like nonapeptide hormone that supports reproductive functions and a vasopressin-like nonapeptide hormone involved in water regulation. The two genes are usually located close to each other (less than 15,000 bases apart) on the same chromosome, and are transcribed in opposite directions (however, in fugu,[40] the homologs are further apart and transcribed in the same direction).
The two genes are believed to result from a gene duplication event; the ancestral gene is estimated to be about 500 million years old and is found in cyclostomata (modern members of the Agnatha).[41]
# Biological function
Oxytocin has peripheral (hormonal) actions, and also has actions in the brain. Its actions are mediated by specific, oxytocin receptors. The oxytocin receptor is a G-protein-coupled receptor that requires magnesium and cholesterol. It belongs to the rhodopsin-type (class I) group of G-protein-coupled receptors.[citation needed]
Studies have looked at oxytocin's role in various behaviors, including orgasm, social recognition, pair bonding, anxiety, and maternal behaviors.[42]
## Physiological
The peripheral actions of oxytocin mainly reflect secretion from the pituitary gland. The behavioral effects of oxytocin are thought to reflect release from centrally projecting oxytocin neurons, different from those that project to the pituitary gland, or that are collaterals from them.[27] Oxytocin receptors are expressed by neurons in many parts of the brain and spinal cord, including the amygdala, ventromedial hypothalamus, septum, nucleus accumbens, and brainstem.[citation needed]
- Milk ejection reflex/Letdown reflex: in lactating (breastfeeding) mothers, oxytocin acts at the mammary glands, causing milk to be 'let down' into lactiferous ducts, from where it can be excreted via the nipple.[43] Suckling by the infant at the nipple is relayed by spinal nerves to the hypothalamus. The stimulation causes neurons that make oxytocin to fire action potentials in intermittent bursts; these bursts result in the secretion of pulses of oxytocin from the neurosecretory nerve terminals of the pituitary gland.
- Uterine contraction: important for cervical dilation before birth, oxytocin causes contractions during the second and third stages of labor.[44] Oxytocin release during breastfeeding causes mild but often painful contractions during the first few weeks of lactation. This also serves to assist the uterus in clotting the placental attachment point postpartum. However, in knockout mice lacking the oxytocin receptor, reproductive behavior and parturition are normal.[45]
- Due to its similarity to vasopressin, it can reduce the excretion of urine slightly. In several species, oxytocin can stimulate sodium excretion from the kidneys (natriuresis), and, in humans, high doses can result in low sodium levels (hyponatremia).
- Cardiac effects: oxytocin and oxytocin receptors are also found in the heart in some rodents, and the hormone may play a role in the embryonal development of the heart by promoting cardiomyocyte differentiation.[46][47] However, the absence of either oxytocin or its receptor in knockout mice has not been reported to produce cardiac insufficiencies.[45]
- Modulation of hypothalamic-pituitary-adrenal axis activity: oxytocin, under certain circumstances, indirectly inhibits release of adrenocorticotropic hormone and cortisol and, in those situations, may be considered an antagonist of vasopressin.[48]
- Preparing fetal neurons for delivery: crossing the placenta, maternal oxytocin reaches the fetal brain and induces a switch in the action of neurotransmitter GABA from excitatory to inhibitory on fetal cortical neurons. This silences the fetal brain for the period of delivery and reduces its vulnerability to hypoxic damage.[49]
- Feeding: a 2012 paper suggested that oxytocin neurons in the para-ventricular hypothalamus in the brain may play a key role in suppressing appetite under normal conditions and that other hypothalamic neurons may trigger eating via inhibition of these oxytocin neurons. This population of oxytocin neurons is absent in Prader-Willi syndrome, a genetic disorder that leads to uncontrollable feeding and obesity, and may play a key role in its pathophysiology.[50]
## Psychological
- Autism: Oxytocin has been implicated in the etiology of autism, with one report suggesting autism is correlated with genomic deletion of the chromosome containing the oxytocin receptor gene (OXTR). Studies involving Caucasian and Finnish samples and Chinese Han families provide support for the relationship of OXTR with autism.[51][52] Autism may also be associated with an aberrant methylation of OXTR.[51]
### Bonding
In the prairie vole, oxytocin released into the brain of the female during sexual activity is important for forming a pair bond with her sexual partner. Vasopressin appears to have a similar effect in males.[53] Oxytocin has a role in social behaviors in many species, so it likely also does in humans. In a 2003 study, both humans and dog oxytocin levels in the blood rose after five to 24 minutes of a petting session. This possibly plays a role in the emotional bonding between humans and dogs.[54]
- Maternal behavior: Female rats given oxytocin antagonists after giving birth do not exhibit typical maternal behavior.[55] By contrast, virgin female sheep show maternal behavior toward foreign lambs upon cerebrospinal fluid infusion of oxytocin, which they would not do otherwise.[56] Oxytocin is involved in the initiation of maternal behavior, not its maintenance; for example, it is higher in mothers after they interact with unfamiliar children rather than their own.[57]
- Ingroup bonding: Oxytocin can increase positive attitudes, such as bonding, toward individuals with similar characteristics, who then become classified as "in-group" members, whereas individuals who are dissimilar become classified as "out-group" members. Race can be used as an example of in-group and out-group tendencies because society often categorizes individuals into groups based on race (Caucasian, African American, Latino, etc.). One study that examined race and empathy found that participants receiving nasally administered oxytocin had stronger reactions to pictures of in-group members making pained faces than to pictures of out-group members with the same expression.[58] This shows that oxytocin may be implicated in our ability to empathize with individuals of different races and could potentially translate into willingness to help individuals in pain or stressful situations. Moreover, individuals of one race may be more inclined to help individuals of the same race than individuals of another race when they are experiencing pain. Oxytocin has also been implicated in lying when lying would prove beneficial to other in-group members. In a study where such a relationship was examined, it was found that when individuals were administered oxytocin, rates of dishonesty in the participants' responses increased for their in-group members when a beneficial outcome for their group was expected.[59] Both of these examples show the tendency of individuals to act in ways that benefit those considered to be members of their social group, or in-group.
Oxytocin is not only correlated with the preferences of individuals to associate with members of their own group, but it is also evident during conflicts between members of different groups. During conflict, individuals receiving nasally administered oxytocin demonstrate more frequent defense-motivated responses toward in-group members than out-group members. Further, oxytocin was correlated with participant desire to protect vulnerable in-group members, despite that individual's attachment to the conflict.[60] Similarly, it has been demonstrated that when oxytocin is administered, individuals alter their subjective preferences in order to align with in-group ideals over out-group ideals.[61] These studies demonstrate that oxytocin is associated with intergroup dynamics. Further, oxytocin influences the responses of individuals in a particular group to those of another group. The in-group bias is evident in smaller groups; however, it can also be extended to groups as large as one's entire country leading toward a tendency of strong national zeal. A study done in the Netherlands showed that oxytocin increased the in-group favoritism of their nation while decreasing acceptance of members of other ethnicities and foreigners.[62] People also show more affection for their country's flag while remaining indifferent to other cultural objects when exposed to oxytocin.[63] It has thus been hypothesized that this hormone may be a factor in xenophobic tendencies secondary to this effect. Thus, oxytocin appears to affect individuals at an international level where the in-group becomes a specific "home" country and the out-group grows to include all other countries.
### Drugs
- Drug interaction: Impact on effects of alcohol and other drugs: According to several studies in animals, oxytocin inhibits the development of tolerance to various addictive drugs (opiates, cocaine, alcohol), and reduces withdrawal symptoms.[64] MDMA (ecstasy) may increase feelings of love, empathy, and connection to others by stimulating oxytocin activity primarily via activation of serotonin 5-HT1A receptors, if initial studies in animals apply to humans.[65] The anxiolytic Buspar (buspirone) may produce some of its effects via 5-HT1A receptor-induced oxytocin stimulation as well.[66][67]
- Addiction vulnerability: Concentrations of endogenous oxytocin can impact the effects of various drugs and one's susceptibility to substance use disorders. Additionally, bilateral interactions with numerous systems, including the dopamine system, Hypothalamic–pituitary–adrenal axis and immune system, can impact development of dependence. The status of the endogenous oxytocin system might enhance or reduce susceptibility to addiction through its interaction with these systems. Individual differences in the endogenous oxytocin system based on genetic predisposition, gender and environmental influences, may therefore affect addiction vulnerability.[68] Oxytocin may be related to the place conditioning behaviors observed in habitual drug abusers.
### Fear and anxiety
Oxytocin is typically remembered for the effect it has on prosocial behaviors, such as its role in facilitating trust and attachment between individuals. Consequently, oxytocin is often referred to as the “love hormone".[69][qualify evidence] However, oxytocin has a more complex role than solely enhancing prosocial behaviors. There is consensus that oxytocin modulates fear and anxiety; that is, it does not directly elicit fear or anxiety.[70] Two dominant theories explain the role of oxytocin in fear and anxiety. One theory states that oxytocin increases approach/avoidance to certain social stimuli and the second theory states that oxytocin increases the salience of certain social stimuli, causing the animal or human to pay closer attention to socially relevant stimuli.[71]
Nasally administered oxytocin has been reported to reduce fear, possibly by inhibiting the amygdala (which is thought to be responsible for fear responses).[72] Indeed, studies in rodents have shown oxytocin can efficiently inhibit fear responses by activating an inhibitory circuit within the amygdala.[73][74] Some researchers have argued oxytocin has a general enhancing effect on all social emotions, since intranasal administration of oxytocin also increases envy and Schadenfreude.[75] Individuals who receive an intranasal dose of oxytocin identify facial expressions of disgust more quickly than individuals who do not receive oxytocin.[71][qualify evidence] Facial expressions of disgust are evolutionarily linked to the idea of contagion. Thus, oxytocin increases the salience of cues that imply contamination, which leads to a faster response because these cues are especially relevant for survival. In another study, after administration of oxytocin, individuals displayed an enhanced ability to recognize expressions of fear compared to the individuals who received the placebo.[76] Oxytocin modulates fear responses by enhancing the maintenance of social memories. Rats that are genetically modified to have a surplus of oxytocin receptors display a greater fear response to a previously conditioned stressor. Oxytocin enhances the aversive social memory, leading the rat to display a greater fear response when the aversive stimulus is encountered again.[70]
### Mood and depression
Oxytocin produces antidepressant-like effects in animal models of depression,[77] and a deficit of it may be involved in the pathophysiology of depression in humans.[78] The antidepressant-like effects of oxytocin are not blocked by a selective antagonist of the oxytocin receptor, suggesting that these effects are not mediated by the oxytocin receptor.[13] In accordance, unlike oxytocin, the selective non-peptide oxytocin receptor agonist WAY-267,464 does not produce antidepressant-like effects, at least in the tail suspension test.[79] In contrast to WAY-267,464, carbetocin, a close analogue of oxytocin and peptide oxytocin receptor agonist, notably does produce antidepressant-like effects in animals.[79] As such, the antidepressant-like effects of oxytocin may be mediated by modulation of a different target, perhaps the vasopressin V1A receptor where oxytocin is known to weakly bind as an agonist.[80][81]
Sildenafil has been found to enhance electrically evoked oxytocin release from the pituitary gland.[77][qualify evidence] In accordance, the drug shows oxytocin-dependent antidepressant-like effects in animals, and it has proposed that sildenafil may hold promise as a potential antidepressant in humans.[77]
### Sex differences
It has been shown that oxytocin differentially affects males and females. Females who are administered oxytocin are overall faster in responding to socially relevant stimuli than males who received oxytocin.[71][82] Additionally, after the administration of oxytocin, females show increased amygdala activity in response to threatening scenes; however, males do not show increased amygdala activation. This phenomenon can be explained by looking at the role of gonadal hormones, specifically estrogen, which modulate the enhanced threat processing seen in females. Estrogen has been shown to stimulate the release of oxytocin from the hypothalamus and promote receptor binding in the amygdala.[82]
It has also been shown that testosterone directly suppresses oxytocin in mice.[83] This has been hypothesized to have evolutionary significance. With oxytocin suppressed, activities such as hunting and attacking invaders would be less mentally difficult as oxytocin is strongly associated with empathy.[84]
### Social
- Affecting generosity by increasing empathy during perspective taking: In a neuroeconomics experiment, intranasal oxytocin increased generosity in the Ultimatum Game by 80%, but had no effect in the Dictator Game that measures altruism. Perspective-taking is not required in the Dictator Game, but the researchers in this experiment explicitly induced perspective-taking in the Ultimatum Game by not identifying to participants into which role they would be placed.[85] Serious methodological questions have arisen, however, with regard to the role of oxytocin in trust and generosity.[86] Empathy in healthy males has been shown to be increased after intranasal oxytocin[84][87] This is most likely due to the effect of oxytocin in enhancing eye gaze.[88] There is some discussion about which aspect of empathy oxytocin might alter – for example, cognitive vs. emotional empathy.[89] While studying wild chimpanzees, it was noted that after a chimpanzee shared food with a non-kin related chimpanzee, the subjects' levels of oxytocin increased, as measured through their urine. In comparison to other cooperative activities between chimpanzees that were monitored including grooming, food sharing generated higher levels of oxytocin. This comparatively higher level of oxytocin after food sharing parallels the increased level of oxytocin in nursing mothers, sharing nutrients with their kin.[90]
- Trust is increased by oxytocin.[91][92][93] Disclosure of emotional events is a sign of trust in humans. When recounting a negative event, humans who receive intranasal oxytocin share more emotional details and stories with more emotional significance.[92] Humans also find faces more trustworthy after receiving intranasal oxytocin. In a study, participants who received intranasal oxytocin viewed photographs of human faces with neutral expressions and found them to be more trustworthy than those who did not receive oxytocin.[91] This may be because oxytocin reduces the fear of social betrayal in humans.[94] Even after experiencing social alienation by being excluded from a conversation, humans who received oxytocin scored higher in trust on the Revised NEO Personality Inventory.[93] Moreover, in a risky investment game, experimental subjects given nasally administered oxytocin displayed "the highest level of trust" twice as often as the control group. Subjects who were told they were interacting with a computer showed no such reaction, leading to the conclusion that oxytocin was not merely affecting risk aversion.[95] When there is a reason to be distrustful, such as experiencing betrayal, differing reactions are associated with oxytocin receptor gene (OXTR) differences. Those with the CT haplotype experience a stronger reaction, in the form of anger, to betrayal.[96]
- Romantic attachment: In some studies, high levels of plasma oxytocin have been correlated with romantic attachment. For example, if a couple is separated for a long period of time, anxiety can increase due to the lack of physical affection. Oxytocin may aid romantically attached couples by decreasing their feelings of anxiety when they are separated.[97]
- Group-serving dishonesty/deception: In a carefully controlled study exploring the biological roots of immoral behavior, oxytocin was shown to promote dishonesty when the outcome favored the group to which an individual belonged instead of just the individual.[98]
- Sexual activity: The relationship between oxytocin and human sexual response is unclear. At least two uncontrolled studies have found increases in plasma oxytocin at orgasm – in both men and women.[99][100] Plasma oxytocin levels are notably increased around the time of self-stimulated orgasm and are still higher than baseline when measured five minutes after self arousal.[99] The authors of one of these studies speculated that oxytocin's effects on muscle contractibility may facilitate sperm and egg transport.[99]
- Oxytocin affects social distance between adult males and females, and may be responsible at least in part for romantic attraction and subsequent monogamous pair bonding. An oxytocin nasal spray caused men in a monogamous relationship, but not single men, to increase the distance between themselves and an attractive woman during a first encounter by 10 to 15 centimeters. The researchers suggested that oxytocin may help promote fidelity within monogamous relationships.[105] For this reason, it is sometimes referred to as the "bonding hormone". There is some evidence that oxytocin promotes ethnocentric behavior, incorporating the trust and empathy of in-groups with their suspicion and rejection of outsiders.[62] Furthermore, genetic differences in the oxytocin receptor gene (OXTR) have been associated with maladaptive social traits such as aggressive behavior.[106]
- Social behavior[62][107] and wound healing: Oxytocin is also thought to modulate inflammation by decreasing certain cytokines. Thus, the increased release in oxytocin following positive social interactions has the potential to improve wound healing. A study by Marazziti and colleagues used heterosexual couples to investigate this possibility. They found increases in plasma oxytocin following a social interaction were correlated with faster wound healing. They hypothesized this was due to oxytocin reducing inflammation, thus allowing the wound to heal more quickly. This study provides preliminary evidence that positive social interactions may directly influence aspects of health.[108] According to a study published in 2014, silencing of oxytocin receptor interneurons in the medial prefrontal cortex (mPFC) of female mice resulted in loss of social interest in male mice during the sexually receptive phase of the estrous cycle.[109] Oxytocin evokes feelings of contentment, reductions in anxiety, and feelings of calmness and security when in the company of the mate.[97] This suggests oxytocin may be important for the inhibition of the brain regions associated with behavioral control, fear, and anxiety, thus allowing orgasm to occur. Research has also demonstrated that oxytocin can decrease anxiety and protect against stress, particularly in combination with social support.[110] It is found, that endocannabinoid signaling mediates oxytocin-driven social reward.[111]
# Chemistry
Oxytocin is a peptide of nine amino acids (a nonapeptide) in the sequence cysteine-tyrosine-isoleucine-glutamine-asparagine-cysteine-proline-leucine-glycine-amide (Cys – Tyr – Ile – Gln – Asn – Cys – Pro – Leu – Gly – NH2, or CYIQNCPLG-NH2); its C-terminus has been converted to a primary amide and a disulfide bridge joins the cysteine moieties.[112] Oxytocin has a molecular mass of 1007 Da, and one international unit (IU) of oxytocin is the equivalent of 1.68 μg of pure peptide.[113]
While the structure of oxytocin is highly conserved in placental mammals, a novel structure of oxytocin was recently reported in marmosets, tamarins, and other new world primates. Genomic sequencing of the gene for oxytocin revealed a single in-frame mutation (thymine for cytosine) which results in a single amino acid substitution at the 8-position (proline for leucine).[114] Since this original Lee et al. paper, two other laboratories have confirmed Pro8-OT and documented additional oxytocin structural variants in this primate taxon. Vargas-Pinilla et al. sequenced the coding regions of the OXT gene in other genera in new world primates and identified the following variants in addition to Leu8- and Pro8-OT: Ala8-OT, Thr8-OT, and Val3/Pro8-OT.[115] Ren et al. identified a variant further, Phe2-OT in howler monkeys.[116]
The biologically active form of oxytocin, commonly measured by RIA and/or HPLC techniques, is also known as the octapeptide "oxytocin disulfide" (oxidized form), but oxytocin also exists as a reduced straight-chain (non-cyclic) dithiol nonapeptide called oxytoceine.[117] It has been theorized that oxytoceine may act as a free radical scavenger, as donating an electron to a free radical allows oxytoceine to be re-oxidized to oxytocin via the dehydroascorbate / ascorbate redox couple.[118]
The structure of oxytocin is very similar to that of vasopressin. Both are nonapeptides with a single disulfide bridge, differing only by two substitutions in the amino acid sequence (differences from oxytocin bolded for clarity): Cys – Tyr – Phe – Gln – Asn – Cys – Pro – Arg – Gly – NH2.[112] A table showing the sequences of members of the vasopressin/oxytocin superfamily and the species expressing them is present in the vasopressin article. Oxytocin and vasopressin were isolated and their total synthesis reported in 1954,[119] work for which Vincent du Vigneaud was awarded the 1955 Nobel Prize in Chemistry with the citation: "for his work on biochemically important sulphur compounds, especially for the first synthesis of a polypeptide hormone."[120]
Oxytocin and vasopressin are the only known hormones released by the human posterior pituitary gland to act at a distance. However, oxytocin neurons make other peptides, including corticotropin-releasing hormone and dynorphin, for example, that act locally. The magnocellular neurosecretory cells that make oxytocin are adjacent to magnocellular neurosecretory cells that make vasopressin. These are large neuroendocrine neurons which are excitable and can generate action potentials.[121]
# History
The uterine-contracting properties of the principle that would later be named oxytocin were discovered by British pharmacologist Sir Henry Hallett Dale in 1906,[122][42] and its milk ejection property was described by Ott and Scott in 1910[123] and by Schafer and Mackenzie in 1911.[124] In the 1920s, oxytocin and vasopressin were isolated from pituitary tissue and given their current names. The word oxytocin was coined from the term oxytocic, Greek ὀξύς, oxys, and τοκετός , toketos, meaning "quick birth".
Oxytocin became the first polypeptide hormone to be sequenced[125] or synthesized.[126][127][128] Du Vigneaud was awarded the Nobel Prize in 1955 for his work.[129] | https://www.wikidoc.org/index.php/Oxytocic | |
a961055cf24c5bab7600853ec9eb4ee7dc1bd70a | wikidoc | pH meter | pH meter
# Overview
A pH meter is an electronic instrument used to measure the pH (acidity or alkalinity) of a liquid (though special probes are sometimes used to measure the pH of semi-solid substances). A typical pH meter consists of a special measuring probe (a glass electrode) connected to an electronic meter that measures and displays the pH reading.
# The probe
The pH probe measures pH as the activity of hydrogen ions surrounding a thin-walled glass bulb at its tip. The probe produces a small voltage (about 0.06 volt per pH unit) that is measured and displayed as pH units by the meter. For more information about pH probes, see glass electrode.
# The meter
The meter circuit is fundamentally no more than a voltmeter that displays measurements in pH units instead of volts. The input impedance of the meter must be very high because of the high resistance — approximately 20 to 1000 MΩ — of the glass electrode probes typically used with pH meters. The circuit of a simple pH meter usually consists of operational amplifiers in an inverting configuration, with a total voltage gain of about -17. The inverting amplifier converts the small voltage produced by the probe (-0.059 volt/pH in basic solutions, +0.059 volt/pH in acid solutions) into pH units, which are then offset by seven volts to give a reading on the pH scale. For example:
- At neutral pH (pH 7) the voltage at the probe's output is 0 volts. 0 - 17 + 7 = 7.
- At alkaline pH, the voltage at the probe's output ranges from > 0 to +0.41 volts (7 - 0.059 = 0.41). So for a sample of pH 10 (3 pH units from neutral), 3 - 0.059 = 0.18 volts), the output of the meter's amplifier is 0.18 - 17 + 7 = 10.
- At acid pH, the voltage at the probe's output ranges from -0.7 volts to < 0. So for a sample of pH 4 (also 3 pH units from neutral, but in the other direction), 3 - +0.059 = +0.18 volts, the output of the meter's amplifier is -0.18 - 17 + 7 = 4.
The two basic adjustments performed at calibration (see below) set the gain and offset of the inverting amplifier.
# Calibration and use
Calibration with at least two, but preferably three, buffer solution standards is usually performed every time a pH meter is used, though modern instruments will hold their calibration for around a month. One of the buffers has a pH of 7.01 (almost neutral pH) and the second buffer solution is selected to match the pH range in which the measurements are to be taken: usually pH 10.01 for basic solutions and pH 4.01 for acidic solutions (It should be noted that the pH of the calibration solutions is only valid at 25°C). The gain and offset settings of the meter are adjusted repeatedly as the probe is alternately placed in the two calibration standards until accurate readings are obtained in both solutions. Modern instruments have completely automated this process and only require immersing in each solution once, or at worst, twice.
The calibration process correlates the voltage produced by the probe (approximately 0.06 volts per pH unit) with the pH scale. After calibration, the probe is rinsed in distilled, deionized water to remove any traces of the buffer solution, blotted with a clean tissue to absorb any remaining water which could dilute the sample and thus alter the reading, and then quickly immersed in the sample. Between uses, the probe tip, which must be kept wet at all times, is typically kept immersed in a small volume of storage solution, which is an acidic solution of around pH 3.0. Alternatively, the pH 7.01 calibration solution can be used, but this results in a need for more frequent calibration. In an emergency, tap water can be used, but distilled or deionised water must never be used for longer-term probe storage as the relatively ionless water 'sucks' ions out of the probe, which degrades it.
Occasionally (about once a month), the probe should be cleaned using pH-electrode cleaning solution; generally a 0.1 M solution of Hydrochloric Acid (HCl) is used , having a pH of about one.
# Types of pH meters
pH meters range from simple and inexpensive pen-like devices to complex and expensive laboratory instruments with computer interfaces and several inputs for indicator (ion-sensitive, redox), reference electrodes, and temperature sensors such as thermoresistors or thermocouples. Cheaper models sometimes require that temperature measurements be entered to adjust for the slight variation in pH caused by temperature. Specialty meters and probes are available for use in special applications, harsh environments, etc. Pocket pH meter are readily available today for a few tens of dollars that automatically compensate for temperature (ATC, Automatic Temperature Compensation)
# History
The first commercial pH meters were built around 1936 by Radiometer in Denmark and by Dr. Arnold Orville Beckman in the United States. While Beckman was an assistant professor of chemistry at the California Institute of Technology, he was asked to devise a quick and accurate method for measuring the acidity of lemon juice for the California Fruit Growers Exchange (Sunkist). Beckman's invention helped him to launch the Beckman Instruments company (now Beckman Coulter). In 2004 the Beckman pH meter was designated an ACS National Historical Chemical Landmark in recognition of its significance as the first commercially successful electronic pH meter.
# Building a pH meter
Because the circuitry of a basic pH meter is quite simple, it is possible to build a serviceable pH meter or pH controller with parts available at a neighborhood electronics retailer. (pH probes, however, are not so easily acquired and must usually be ordered from a scientific instrument supplier.) For a walkthrough of how to build the simplest possible pH meteror a detailed description of how to build a pH meter/pH controller, see The pH Pages. The application note for the LM6001chip at the National Semiconductor web site also has a very simple demonstration circuit. Although the application note is for a specialty IC, serviceable pH meters can be built from any operational amplifier with a high input impedance, such as the common and inexpensive National Semiconductor TL082 or its equivalent. | pH meter
# Overview
A pH meter is an electronic instrument used to measure the pH (acidity or alkalinity) of a liquid (though special probes are sometimes used to measure the pH of semi-solid substances). A typical pH meter consists of a special measuring probe (a glass electrode) connected to an electronic meter that measures and displays the pH reading.
# The probe
The pH probe measures pH as the activity of hydrogen ions surrounding a thin-walled glass bulb at its tip. The probe produces a small voltage (about 0.06 volt per pH unit) that is measured and displayed as pH units by the meter. For more information about pH probes, see glass electrode.
# The meter
The meter circuit is fundamentally no more than a voltmeter that displays measurements in pH units instead of volts. The input impedance of the meter must be very high because of the high resistance — approximately 20 to 1000 MΩ — of the glass electrode probes typically used with pH meters. The circuit of a simple pH meter usually consists of operational amplifiers in an inverting configuration, with a total voltage gain of about -17. The inverting amplifier converts the small voltage produced by the probe (-0.059 volt/pH in basic solutions, +0.059 volt/pH in acid solutions) into pH units, which are then offset by seven volts to give a reading on the pH scale. For example:
- At neutral pH (pH 7) the voltage at the probe's output is 0 volts. 0 * 17 + 7 = 7.
- At alkaline pH, the voltage at the probe's output ranges from > 0 to +0.41 volts (7 * 0.059 = 0.41). So for a sample of pH 10 (3 pH units from neutral), 3 * 0.059 = 0.18 volts), the output of the meter's amplifier is 0.18 * 17 + 7 = 10.
- At acid pH, the voltage at the probe's output ranges from -0.7 volts to < 0. So for a sample of pH 4 (also 3 pH units from neutral, but in the other direction), 3 * +0.059 = +0.18 volts, the output of the meter's amplifier is -0.18 * 17 + 7 = 4.
The two basic adjustments performed at calibration (see below) set the gain and offset of the inverting amplifier.
# Calibration and use
Calibration with at least two, but preferably three, buffer solution standards is usually performed every time a pH meter is used, though modern instruments will hold their calibration for around a month. One of the buffers has a pH of 7.01 (almost neutral pH) and the second buffer solution is selected to match the pH range in which the measurements are to be taken: usually pH 10.01 for basic solutions and pH 4.01 for acidic solutions (It should be noted that the pH of the calibration solutions is only valid at 25°C). The gain and offset settings of the meter are adjusted repeatedly as the probe is alternately placed in the two calibration standards until accurate readings are obtained in both solutions. Modern instruments have completely automated this process and only require immersing in each solution once, or at worst, twice.
The calibration process correlates the voltage produced by the probe (approximately 0.06 volts per pH unit) with the pH scale. After calibration, the probe is rinsed in distilled, deionized water to remove any traces of the buffer solution, blotted with a clean tissue to absorb any remaining water which could dilute the sample and thus alter the reading, and then quickly immersed in the sample. Between uses, the probe tip, which must be kept wet at all times, is typically kept immersed in a small volume of storage solution, which is an acidic solution of around pH 3.0. Alternatively, the pH 7.01 calibration solution can be used, but this results in a need for more frequent calibration. In an emergency, tap water can be used, but distilled or deionised water must never be used for longer-term probe storage as the relatively ionless water 'sucks' ions out of the probe, which degrades it.
Occasionally (about once a month), the probe should be cleaned using pH-electrode cleaning solution; generally a 0.1 M solution of Hydrochloric Acid (HCl) is used [1], having a pH of about one.
# Types of pH meters
pH meters range from simple and inexpensive pen-like devices to complex and expensive laboratory instruments with computer interfaces and several inputs for indicator (ion-sensitive, redox), reference electrodes, and temperature sensors such as thermoresistors or thermocouples. Cheaper models sometimes require that temperature measurements be entered to adjust for the slight variation in pH caused by temperature. Specialty meters and probes are available for use in special applications, harsh environments, etc. Pocket pH meter are readily available today for a few tens of dollars that automatically compensate for temperature (ATC, Automatic Temperature Compensation)
# History
The first commercial pH meters were built around 1936 by Radiometer in Denmark and by Dr. Arnold Orville Beckman in the United States. While Beckman was an assistant professor of chemistry at the California Institute of Technology, he was asked to devise a quick and accurate method for measuring the acidity of lemon juice for the California Fruit Growers Exchange (Sunkist). Beckman's invention helped him to launch the Beckman Instruments company (now Beckman Coulter). In 2004 the Beckman pH meter was designated an ACS National Historical Chemical Landmark in recognition of its significance as the first commercially successful electronic pH meter.[2]
# Building a pH meter
Because the circuitry of a basic pH meter is quite simple, it is possible to build a serviceable pH meter or pH controller with parts available at a neighborhood electronics retailer. (pH probes, however, are not so easily acquired and must usually be ordered from a scientific instrument supplier.) For a walkthrough of how to build the simplest possible pH meteror a detailed description of how to build a pH meter/pH controller, see The pH Pages. The application note for the LM6001chip at the National Semiconductor web site also has a very simple demonstration circuit. Although the application note is for a specialty IC, serviceable pH meters can be built from any operational amplifier with a high input impedance, such as the common and inexpensive National Semiconductor TL082 or its equivalent. | https://www.wikidoc.org/index.php/PH_meter | |
0dbe56f8869391f7396cea442d59145aa45b4e0e | wikidoc | PPP1R14A | PPP1R14A
Protein phosphatase 1 regulatory subunit 14A also known as CPI-17 (C-kinase potentiated Protein phosphatase-1 Inhibitor Mr = 17 kDa) is a protein that in humans is encoded by the PPP1R14A gene.
# Function
CPI-17 is a phosphorylation-dependent inhibitor protein of smooth muscle myosin phosphatase, discovered in pig aortic homogenetes. Phosphorylation of the Thr-38 residue converts the protein into a potent inhibitor for myosin phosphatase. A single phosphorylation of CPI-17 at Thr-38 triggers a global conformational change that causes re-alignment of four helices. Multiple kinases are identified to phosphorylate CPI-17, such as PKC, ROCK, PKN, ZIPK, ILK, and PAK. Agonist stimulation of smooth muscle enhances CPI-17 phosphorylation mainly through PKC and ROCK. Myosin phosphatase inhibition increases myosin phosphorylation and smooth muscle contraction in the absence of increased intracellular Ca2+ concentration. This phenomenon is known as Ca2+ sensitization, which occurs in response to agonist stimulation of smooth muscle. In Purkinje neuron, CPI-17 is involved in long-term synaptic depression.
There are three homologues of CPI-17:
- Phosphatase Holoenzyme Inhibitor (PHI: PPP1R14B),
- Kinase Enhanced Phosphatase Inhibitor (KEPI: PPP1R14C), and
- Gastric-Brain Phosphatase Inhibitor (GBPI: PPP1R14D).
# Clinical significance
CPI-17 is up-regulated some cancer cells, and causes hyperphosphorylation of tumor suppressor merlin/NF2. | PPP1R14A
Protein phosphatase 1 regulatory subunit 14A also known as CPI-17 (C-kinase potentiated Protein phosphatase-1 Inhibitor Mr = 17 kDa) is a protein that in humans is encoded by the PPP1R14A gene.[1][2][3]
# Function
CPI-17 is a phosphorylation-dependent inhibitor protein of smooth muscle myosin phosphatase, discovered in pig aortic homogenetes. Phosphorylation of the Thr-38 residue converts the protein into a potent inhibitor for myosin phosphatase. A single phosphorylation of CPI-17 at Thr-38 triggers a global conformational change that causes re-alignment of four helices. Multiple kinases are identified to phosphorylate CPI-17, such as PKC, ROCK, PKN, ZIPK, ILK, and PAK. Agonist stimulation of smooth muscle enhances CPI-17 phosphorylation mainly through PKC and ROCK. Myosin phosphatase inhibition increases myosin phosphorylation and smooth muscle contraction in the absence of increased intracellular Ca2+ concentration. This phenomenon is known as Ca2+ sensitization, which occurs in response to agonist stimulation of smooth muscle. In Purkinje neuron, CPI-17 is involved in long-term synaptic depression.
There are three homologues of CPI-17:
- Phosphatase Holoenzyme Inhibitor (PHI: PPP1R14B),
- Kinase Enhanced Phosphatase Inhibitor (KEPI: PPP1R14C), and
- Gastric-Brain Phosphatase Inhibitor (GBPI: PPP1R14D).
# Clinical significance
CPI-17 is up-regulated some cancer cells, and causes hyperphosphorylation of tumor suppressor merlin/NF2.[4][3] | https://www.wikidoc.org/index.php/PPP1R14A | |
1c1ce61c3119581f3efae7234e03176ff6bee110 | wikidoc | PPP1R15A | PPP1R15A
Protein phosphatase 1 regulatory subunit 15A also known as growth arrest and DNA damage-inducible protein GADD34 is a protein that in humans is encoded by the PPP1R15A gene.
The Gadd34/MyD116 gene was originally discovered as a member in a set of gadd and MyD mammalian genes encoding acidic proteins that synergistically suppress cell growth. Later on it has been characterized as a gene playing a role in ER stress-induced cell death, being a target of ATF4 that plays a role in ER-mediated cell death via promoting protein dephosphorylation of eIF2α and reversing translational inhibition.
# Function
This gene is a member of a group of genes whose transcript levels are increased following stressful growth arrest conditions and treatment with DNA-damaging agents. The induction of this gene by ionizing radiation occurs in certain cell lines regardless of p53 status, and its protein response is correlated with apoptosis following ionizing radiation.
# Interactions
PPP1R15A has been shown to interact with:
- BAG1
- LYN,
- MLL,
- PPP1CA,
- PPP1CB,
- PPP1CC,
- SMARCB1, and
- TSN. | PPP1R15A
Protein phosphatase 1 regulatory subunit 15A also known as growth arrest and DNA damage-inducible protein GADD34 is a protein that in humans is encoded by the PPP1R15A gene.[1][2][3]
The Gadd34/MyD116 gene was originally discovered as a member in a set of gadd and MyD mammalian genes encoding acidic proteins that synergistically suppress cell growth.[4] Later on it has been characterized as a gene playing a role in ER stress-induced cell death, being a target of ATF4 that plays a role in ER-mediated cell death via promoting protein dephosphorylation of eIF2α and reversing translational inhibition.[5]
# Function
This gene is a member of a group of genes whose transcript levels are increased following stressful growth arrest conditions and treatment with DNA-damaging agents. The induction of this gene by ionizing radiation occurs in certain cell lines regardless of p53 status, and its protein response is correlated with apoptosis following ionizing radiation.[3]
# Interactions
PPP1R15A has been shown to interact with:
- BAG1[6]
- LYN,[7]
- MLL,[8]
- PPP1CA,[6][9][10]
- PPP1CB,[9][10]
- PPP1CC,[9][10]
- SMARCB1,[8][9] and
- TSN.[11] | https://www.wikidoc.org/index.php/PPP1R15A | |
60397a8771533fecce1623acd495c4c8d2a17412 | wikidoc | Perforin | Perforin
Perforin-1 is a protein that in humans is encoded by the PRF1 gene and the Prf1 gene in mice.
# Function
Perforin is a pore forming cytolytic protein found in the granules of cytotoxic T lymphocytes (CTLs) and Natural Killer cells (NK cells). Upon degranulation, perforin binds to the target cell's plasma membrane, and oligomerises in a Ca2+ dependent manner to form pores on the target cell. The pore formed allows for the passive diffusion of a family of pro-apoptotic proteases, known as the granzymes, into the target cell. The lytic membrane-inserting part of perforin is the MACPF domain. This region shares homology with cholesterol-dependent cytolysins from Gram-positive bacteria.
Perforin has structural and functional similarities to complement component 9 (C9). Like C9, this protein creates transmembrane tubules and is capable of lysing non-specifically a variety of target cells. This protein is one of the main cytolytic proteins of cytolytic granules, and it is known to be a key effector molecule for T-cell- and natural killer-cell-mediated cytolysis. Perforin is thought to act by creating holes in the plasma membrane which triggers an influx of calcium and initiates membrane repair mechanisms. These repair mechanisms bring perforin and granzymes into early endosomes.
# Clinical significance
Homozygous inheritance of defective PRF1 alleles result in the development of familial hemophagocytic lymphohistiocytosis type 2 (FHL2), a rare and lethal autosomal recessive disorder of infancy.
# Interactions
Perforin has been shown to interact with calreticulin. | Perforin
Perforin-1 is a protein that in humans is encoded by the PRF1 gene and the Prf1 gene in mice.[1][2][3]
# Function
Perforin is a pore forming cytolytic protein found in the granules of cytotoxic T lymphocytes (CTLs) and Natural Killer cells (NK cells). Upon degranulation, perforin binds to the target cell's plasma membrane, and oligomerises in a Ca2+ dependent manner to form pores on the target cell. The pore formed allows for the passive diffusion of a family of pro-apoptotic proteases, known as the granzymes, into the target cell.[4] The lytic membrane-inserting part of perforin is the MACPF domain.[5] This region shares homology with cholesterol-dependent cytolysins from Gram-positive bacteria.[6]
Perforin has structural and functional similarities to complement component 9 (C9). Like C9, this protein creates transmembrane tubules and is capable of lysing non-specifically a variety of target cells. This protein is one of the main cytolytic proteins of cytolytic granules, and it is known to be a key effector molecule for T-cell- and natural killer-cell-mediated cytolysis.[3] Perforin is thought to act by creating holes in the plasma membrane which triggers an influx of calcium and initiates membrane repair mechanisms. These repair mechanisms bring perforin and granzymes into early endosomes.[7]
# Clinical significance
Homozygous inheritance of defective PRF1 alleles result in the development of familial hemophagocytic lymphohistiocytosis type 2 (FHL2), a rare and lethal autosomal recessive disorder of infancy.[3]
# Interactions
Perforin has been shown to interact with calreticulin.[8] | https://www.wikidoc.org/index.php/PRF1 | |
58ccfc432ef3b9414c0b6d10263c0aa21090bbbe | wikidoc | Palladin | Palladin
Palladin is a protein that in humans is encoded by the PALLD gene. Palladin is a component of actin-containing microfilaments that control cell shape, adhesion, and contraction.
# Discovery
Palladin was characterised independently by two research groups, first in the lab of Carol Otey (in 2000) and then in the lab of Olli Carpén (in 2001). It is a part of the myotilin-myopalladin-palladin family and may play an important role in modulating the actin cytoskeleton. Palladin, in contrast to myotilin and myopalladin, which are expressed only in striated muscle, is expressed ubiquitously in cells of mesenchymal origin.
Palladin was named after the Renaissance architect Andrea Palladio, reflecting its localization to architectural elements of the cell.
# Isoforms
In humans, it appears that seven different isoforms exist, some of which arise through alternative splicing. In mice, three major isoforms of palladin arise from a single gene. These isoforms contain between three and five copies (depending on the isoform) of an Ig-like domain and between one and two copies of a polyproline domain.
# Function
Palladin's precise biological role is poorly understood, but it has been shown to play a role in cytoskeletal organization, embryonic development, cell motility, scar formation in the skin, and nerve cell development.
# Disease linkage
Recently, it has been demonstrated that palladin RNA is overexpressed in patients with pancreatic neoplasia, and that palladin is both overexpressed and mutated in an inherited form of pancreatic cancer. The palladin mutation identified in familial pancreatic cancer may be unique to a single North American family, as this same mutation has not been found in any other European or North American populations, respectively, in two other genetic studies.
Further, Salaria et al. have shown that palladin is overexpressed in the non-neoplastic stroma of pancreatic cancer, but only rarely in the cancer cells per se, suggesting that palladin's role in this disease may involve changes in the tumor microenvironmment. More research is clearly required before this protein and its role in neoplasia can be fully understood.
Disease-causing mutations have also been identified in the two other members of this gene family. Myotilin mutations cause a form of limb-girdle muscular dystrophy, and mutations in myopalladin cause an inherited form of heart disease (dilated cardiomyopathy).
# Interactions
PALLD has been shown to interact with EZR. | Palladin
Palladin is a protein that in humans is encoded by the PALLD gene.[1][2][3][4] Palladin is a component of actin-containing microfilaments that control cell shape, adhesion, and contraction.[4]
# Discovery
Palladin was characterised independently by two research groups, first in the lab of Carol Otey (in 2000)[2] and then in the lab of Olli Carpén (in 2001).[5] It is a part of the myotilin-myopalladin-palladin family and may play an important role in modulating the actin cytoskeleton.[6] Palladin, in contrast to myotilin and myopalladin, which are expressed only in striated muscle, is expressed ubiquitously in cells of mesenchymal origin.
Palladin was named after the Renaissance architect Andrea Palladio, reflecting its localization to architectural elements of the cell.[2]
# Isoforms
In humans, it appears that seven different isoforms exist, some of which arise through alternative splicing.[7] In mice, three major isoforms of palladin arise from a single gene. These isoforms contain between three and five copies (depending on the isoform) of an Ig-like domain and between one and two copies of a polyproline domain.[2]
# Function
Palladin's precise biological role is poorly understood, but it has been shown to play a role in cytoskeletal organization, embryonic development, cell motility, scar formation in the skin, and nerve cell development.[6]
# Disease linkage
Recently, it has been demonstrated that palladin RNA is overexpressed in patients with pancreatic neoplasia, and that palladin is both overexpressed and mutated in an inherited form of pancreatic cancer.[8] The palladin mutation identified in familial pancreatic cancer may be unique to a single North American family, as this same mutation has not been found in any other European or North American populations, respectively, in two other genetic studies.[9][10]
Further, Salaria et al. have shown that palladin is overexpressed in the non-neoplastic stroma of pancreatic cancer, but only rarely in the cancer cells per se,[11] suggesting that palladin's role in this disease may involve changes in the tumor microenvironmment. More research is clearly required before this protein and its role in neoplasia can be fully understood.
Disease-causing mutations have also been identified in the two other members of this gene family. Myotilin mutations cause a form of limb-girdle muscular dystrophy, and mutations in myopalladin cause an inherited form of heart disease (dilated cardiomyopathy).
# Interactions
PALLD has been shown to interact with EZR.[5] | https://www.wikidoc.org/index.php/Palladin | |
7cf78e84d48824ee10d22c578b2ee439e97a67b2 | wikidoc | Pancreas | Pancreas
# Overview
The pancreas is a gland organ in the digestive and endocrine systems of vertebrates. It is both exocrine (secreting pancreatic juice containing digestive enzymes) and endocrine (producing several important hormones, including insulin, glucagon, and somatostatin).
# Function
Under a microscope, when properly stained, it is easy to distinguish two different tissue types in the pancreas. These regions correspond to the main pancreatic functions:
## Endocrine
There are four main types of cells in the islets of Langerhans. They are relatively difficult to distinguish using standard staining techniques, but they can be classified by their secretion:
The islets are a compact collection of endocrine cells arranged in clusters and cords and are crisscrossed by a dense network of capillaries. The capillaries of the islets are lined by layers of endocrine cells in direct contact with vessels, and most endocrine cells are in direct contact with blood vessels, by either cytoplasmic processes or by direct apposition. According to the volume The Body, by Alan E. Nourse, in the Time-Life Science Library Series, the islets are "busily manufacturing their hormone and generally disregarding the pancreatic cells all around them, as though they were located in some completely different part of the body." (op. cit., p. 171.)
## Exocrine
There are two main types of exocrine pancreatic cells, responsible for two main classes of secretions:
# Diseases of the pancreas
Due to the importance of its enzyme contents, injury to the pancreas is potentially very dangerous. A puncture of the pancreas generally requires prompt and experienced medical intervention.
Diseases associated with the pancreas include:
## Diabetes mellitus
Diabetes mellitus is a metabolic disorder characterized by hyperglycemia. All three forms of the disease are due to the inability of the beta cells of the pancreas to produce sufficient insulin.
Researchers at the Toronto Hospital for Sick Children injected capsaicin into NOD mice (Non-obese diabetic mice, a strain that is genetically predisposed to develop the equivalent of diabetes mellitus type 1) to kill the pancreatic sensory nerves. This treatment reduced the development of diabetes mellitus in these mice by 80%, suggesting a link between neuropeptides and the development of diabetes. When the researchers injected the pancreas of the diabetic mice with sensory neuropeptide (sP), they were cured of the diabetes for as long as 4 months. Also, insulin resistance (characteristic of diabetes mellitus type 2) was reduced.
## Benign tumours
Like any other organ, the pancreas is susceptible to the growth of benign tumors. Benign tumors do not invade neighboring tissues, do not cause metastases, and usually do not return after surgical removal.
It is also possible to get cancer of the pancreas which is a cancer with a particularly poor prognosis, rarely detected in its early stages.
## Cystic fibrosis
Cystic fibrosis, also known as mucoviscidosis, is a hereditary disease that affects the entire body, causing progressive disability and early death. There is no cure for cystic fibrosis, and most affected individuals die young from lung failure. Cystic fibrosis is caused by a mutation in a gene called the cystic fibrosis transmembrane conductance regulator (CFTR). The product of this gene helps create sweat, digestive juices, and mucus. Although most people without CF have two working copies of the CFTR gene, only one is needed to prevent cystic fibrosis. Cystic fibrosis develops when neither gene works normally. Therefore, it is considered an autosomal recessive disease. The name cystic fibrosis refers to the characteristic 'fibrosis' (tissue scarring) and cyst formation within the pancreas. Cystic fibrosis causes irreversible damage to the pancreas, which often results in painful inflammation (pancreatitis).
## Exocrine pancreatic insufficiency
Exocrine pancreatic insufficiency (EPI) is the inability to properly digest food due to a lack of digestive enzymes made by the pancreas. EPI is found in humans afflicted with cystic fibrosis. It is caused by a progressive loss of the pancreatic cells that make digestive enzymes. Chronic pancreatitis is the most common cause of EPI in humans. Loss of digestive enzymes leads to maldigestion and malabsorption of nutrients.
## Hemosuccus pancreaticus
Hemosuccus pancreaticus, also known as pseudohematobilia or Wirsungorrhage, is a rare cause of hemorrhage in the gastrointestinal tract. It is caused by a bleeding source in the pancreas, pancreatic duct, or structures adjacent to the pancreas, such as the splenic artery, that bleed into the pancreatic duct. Patients with hemosuccus may develop symptoms of gastrointestinal hemorrhage, such as blood in the stools, maroon stools, or melena. They may also develop abdominal pain. Hemosuccus pancreaticus is associated with pancreatitis, pancreatic cancer and aneurysms of the splenic artery. Angiography may be used to treat hemosuccus pancreaticus, where the celiac axis is injected to determine the blood vessel that is bleeding, because embolization of the end vessel may terminate the hemorrhage. Alternatively, a distal pancreatectomy may be required to stop the hemorrhage.
## Pancreatitis
Pancreatitis is inflammation of the pancreas. There are two forms of pancreatitis, which are different in causes and symptoms, and require different treatment:
- Acute pancreatitis: A rapidly-onset inflammation of the pancreas.
- Chronic pancreatitis: A long-standing inflammation of the pancreas.
## Pancreatic pseudocyst
A pancreatic pseudocyst is a circumscribed collection of fluid rich in amylase and other pancreatic enzymes, blood and necrotic tissue, typically located in the lesser sac.
# History
The pancreas was first identified by Herophilus (335-280 BC), a Greek anatomist and surgeon. Only a few hundred years later, Ruphos, another Greek anatomist, gave the pancreas its name. The term "pancreas" is derived from the Greek pan, "all", and kreas, "flesh", probably referring to the organ's homogeneous appearance.
# Pancreas as a food
Pancreases (specifically calf and lamb pancreases) are eaten in meals like Sweetbread, often going by the name stomach.
# Development
The pancreas forms from the endoderm. The endoderm is responsible for the production of the tissue within the pancreas, lungs, and thyroids. The pancreas starts to form in the tenth week in fetal development. In the twelfth week the islets of Langerhan start to show. The pancreas is fully matured by the age of two. Therefore, infants show digestive problems due to the fact that their pancreas is unable to secrete all of the proper digestive enzymes.
# Additional images
- Accessory digestive system.
- Digestive organs.
- The celiac artery and its branches; the stomach has been raised and the peritoneum removed.
- Lymphatics of stomach, etc. The stomach has been turned upward.
- Transverse section through the middle of the first lumbar vertebra, showing the relations of the pancreas.
- The duodenum and pancreas.
- The pancreatic duct.
- Pancreas of a human embryo of five weeks.
- Pancreas of a human embryo at end of sixth week.
- Front of abdomen, showing surface markings for duodenum, pancreas, and kidneys. | Pancreas
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The pancreas is a gland organ in the digestive and endocrine systems of vertebrates. It is both exocrine (secreting pancreatic juice containing digestive enzymes) and endocrine (producing several important hormones, including insulin, glucagon, and somatostatin).
# Function
Under a microscope, when properly stained, it is easy to distinguish two different tissue types in the pancreas.[1] These regions correspond to the main pancreatic functions:
## Endocrine
There are four main types of cells in the islets of Langerhans. They are relatively difficult to distinguish using standard staining techniques, but they can be classified by their secretion:
The islets are a compact collection of endocrine cells arranged in clusters and cords and are crisscrossed by a dense network of capillaries. The capillaries of the islets are lined by layers of endocrine cells in direct contact with vessels, and most endocrine cells are in direct contact with blood vessels, by either cytoplasmic processes or by direct apposition. According to the volume The Body, by Alan E. Nourse, in the Time-Life Science Library Series, the islets are "busily manufacturing their hormone and generally disregarding the pancreatic cells all around them, as though they were located in some completely different part of the body." (op. cit., p. 171.)
## Exocrine
There are two main types of exocrine pancreatic cells, responsible for two main classes of secretions:
# Diseases of the pancreas
Due to the importance of its enzyme contents, injury to the pancreas is potentially very dangerous. A puncture of the pancreas generally requires prompt and experienced medical intervention.
Diseases associated with the pancreas include:
## Diabetes mellitus
Diabetes mellitus is a metabolic disorder characterized by hyperglycemia. All three forms of the disease are due to the inability of the beta cells of the pancreas to produce sufficient insulin.
Researchers at the Toronto Hospital for Sick Children injected capsaicin into NOD mice (Non-obese diabetic mice, a strain that is genetically predisposed to develop the equivalent of diabetes mellitus type 1) to kill the pancreatic sensory nerves. This treatment reduced the development of diabetes mellitus in these mice by 80%, suggesting a link between neuropeptides and the development of diabetes. When the researchers injected the pancreas of the diabetic mice with sensory neuropeptide (sP), they were cured of the diabetes for as long as 4 months. Also, insulin resistance (characteristic of diabetes mellitus type 2) was reduced.
## Benign tumours
Like any other organ, the pancreas is susceptible to the growth of benign tumors. Benign tumors do not invade neighboring tissues, do not cause metastases, and usually do not return after surgical removal.
It is also possible to get cancer of the pancreas which is a cancer with a particularly poor prognosis, rarely detected in its early stages.
## Cystic fibrosis
Cystic fibrosis, also known as mucoviscidosis, is a hereditary disease that affects the entire body, causing progressive disability and early death. There is no cure for cystic fibrosis, and most affected individuals die young from lung failure. Cystic fibrosis is caused by a mutation in a gene called the cystic fibrosis transmembrane conductance regulator (CFTR). The product of this gene helps create sweat, digestive juices, and mucus. Although most people without CF have two working copies of the CFTR gene, only one is needed to prevent cystic fibrosis. Cystic fibrosis develops when neither gene works normally. Therefore, it is considered an autosomal recessive disease. The name cystic fibrosis refers to the characteristic 'fibrosis' (tissue scarring) and cyst formation within the pancreas. Cystic fibrosis causes irreversible damage to the pancreas, which often results in painful inflammation (pancreatitis).
## Exocrine pancreatic insufficiency
Exocrine pancreatic insufficiency (EPI) is the inability to properly digest food due to a lack of digestive enzymes made by the pancreas. EPI is found in humans afflicted with cystic fibrosis. It is caused by a progressive loss of the pancreatic cells that make digestive enzymes. Chronic pancreatitis is the most common cause of EPI in humans. Loss of digestive enzymes leads to maldigestion and malabsorption of nutrients.
## Hemosuccus pancreaticus
Hemosuccus pancreaticus, also known as pseudohematobilia or Wirsungorrhage, is a rare cause of hemorrhage in the gastrointestinal tract. It is caused by a bleeding source in the pancreas, pancreatic duct, or structures adjacent to the pancreas, such as the splenic artery, that bleed into the pancreatic duct. Patients with hemosuccus may develop symptoms of gastrointestinal hemorrhage, such as blood in the stools, maroon stools, or melena. They may also develop abdominal pain. Hemosuccus pancreaticus is associated with pancreatitis, pancreatic cancer and aneurysms of the splenic artery. Angiography may be used to treat hemosuccus pancreaticus, where the celiac axis is injected to determine the blood vessel that is bleeding, because embolization of the end vessel may terminate the hemorrhage. Alternatively, a distal pancreatectomy may be required to stop the hemorrhage.
## Pancreatitis
Pancreatitis is inflammation of the pancreas. There are two forms of pancreatitis, which are different in causes and symptoms, and require different treatment:
- Acute pancreatitis: A rapidly-onset inflammation of the pancreas.
- Chronic pancreatitis: A long-standing inflammation of the pancreas.
## Pancreatic pseudocyst
A pancreatic pseudocyst is a circumscribed collection of fluid rich in amylase and other pancreatic enzymes, blood and necrotic tissue, typically located in the lesser sac.
# History
The pancreas was first identified by Herophilus (335-280 BC), a Greek anatomist and surgeon. Only a few hundred years later, Ruphos, another Greek anatomist, gave the pancreas its name. The term "pancreas" is derived from the Greek pan, "all", and kreas, "flesh", probably referring to the organ's homogeneous appearance.[2]
# Pancreas as a food
Pancreases (specifically calf and lamb pancreases) are eaten in meals like Sweetbread, often going by the name stomach.
# Development
The pancreas forms from the endoderm. The endoderm is responsible for the production of the tissue within the pancreas, lungs, and thyroids. The pancreas starts to form in the tenth week in fetal development. In the twelfth week the islets of Langerhan start to show. The pancreas is fully matured by the age of two. Therefore, infants show digestive problems due to the fact that their pancreas is unable to secrete all of the proper digestive enzymes.
# Additional images
- Accessory digestive system.
- Digestive organs.
- The celiac artery and its branches; the stomach has been raised and the peritoneum removed.
- Lymphatics of stomach, etc. The stomach has been turned upward.
- Transverse section through the middle of the first lumbar vertebra, showing the relations of the pancreas.
- The duodenum and pancreas.
- The pancreatic duct.
- Pancreas of a human embryo of five weeks.
- Pancreas of a human embryo at end of sixth week.
- Front of abdomen, showing surface markings for duodenum, pancreas, and kidneys. | https://www.wikidoc.org/index.php/Pancreas | |
1240e3889395c3f3d5c4587ab298dfaa7f75247f | wikidoc | Pandemic | Pandemic
# Overview
A pandemic (from Greek παν pan all + δήμος demos people) is an epidemic that spreads through human populations across a large region (for example a continent), or even worldwide.
# Definition
According to the World Health Organization (WHO), a pandemic can start when three conditions have been met:
- the emergence of a disease new to the population.
- the agent infects humans, causing serious illness.
- the agent spreads easily and sustainably among humans.
A disease or condition is not a pandemic merely because it is widespread or kills many people; it must also be infectious. For example cancer is responsible for many deaths but is not considered a pandemic because the disease is not infectious or contagious (although certain causes of some types of cancer might be).
# WHO pandemic influenza phases
The WHO global influenza preparedness plan defines the stages of pandemic influenza, outlines the role of WHO and makes recommendations for national measures before and during a pandemic. The phases are:
Interpandemic period:
- Phase 1: No new influenza virus subtypes have been detected in humans.
- Phase 2: No new influenza virus subtypes have been detected in humans, but an animal variant threatens human disease.
Pandemic alert period:
- Phase 3: Human infection(s) with a new subtype but no human-to-human spread.
- Phase 4: Small cluster(s) with limited localized human-to-human transmission
- Phase 5: Larger cluster(s) but human-to-human spread still localized.
Pandemic period:
- Phase 6: Pandemic: increased and sustained transmission in general population.
# Pandemics and notable epidemics through history
There have been a number of significant pandemics recorded in human history, generally zoonoses that came about with domestication of animals — such as influenza and tuberculosis. There have been a number of particularly significant epidemics that deserve mention above the "mere" destruction of cities:
- Peloponnesian War, 430 BC. Typhoid fever killed a quarter of the Athenian troops and a quarter of the population over four years. This disease fatally weakened the dominance of Athens, but the sheer virulence of the disease prevented its wider spread; i.e. it killed off its hosts at a rate faster than they could spread it. The exact cause of the plague was unknown for many years; in January 2006, researchers from the University of Athens analyzed teeth recovered from a mass grave underneath the city, and confirmed the presence of bacteria responsible for typhoid.
- Antonine Plague, 165–180. Possibly smallpox brought back from the Near East; killed a quarter of those infected and up to five million in all. At the height of a second outbreak (251–266) 5,000 people a day were said to be dying in Rome.
- Plague of Justinian, from 541 to 750, was the first recorded outbreak of the bubonic plague. It started in Egypt and reached Constantinople the following spring, killing (according to the Byzantine chronicler Procopius) 10,000 a day at its height and perhaps 40 percent of the city's inhabitants. It went on to eliminate a quarter to a half of the human population that it struck throughout the known world.
- The Black Death, started 1300s. Eight hundred years after the last outbreak, the bubonic plague returned to Europe. Starting in Asia, the disease reached Mediterranean and western Europe in 1348 (possibly from Italian merchants fleeing fighting in the Crimea), and killed twenty million Europeans in six years, a quarter of the total population and up to a half in the worst-affected urban areas.
- Cholera
first pandemic 1816–1826. Previously restricted to the Indian subcontinent, the pandemic began in Bengal, then spread across India by 1820. It extended as far as China and the Caspian Sea before receding.
The second pandemic (1829–1851) reached Europe, London in 1832, Ontario Canada and New York in the same year, and the Pacific coast of North America by 1834.
The third pandemic (1852–1860) mainly affected Russia, with over a million deaths.
The fourth pandemic (1863–1875) spread mostly in Europe and Africa.
In 1866 there was an outbreak in North America.
In 1892 cholera contaminated the water supply of Hamburg, Germany, and caused 8,606 deaths.
The seventh pandemic (1899–1923) had little effect in Europe because of advances in public health, but Russia was badly affected again.
The eighth pandemic began in Indonesia in 1961, called El Tor after the strain, and reached Bangladesh in 1963, India in 1964, and the USSR in 1966.
- first pandemic 1816–1826. Previously restricted to the Indian subcontinent, the pandemic began in Bengal, then spread across India by 1820. It extended as far as China and the Caspian Sea before receding.
- The second pandemic (1829–1851) reached Europe, London in 1832, Ontario Canada and New York in the same year, and the Pacific coast of North America by 1834.
- The third pandemic (1852–1860) mainly affected Russia, with over a million deaths.
- The fourth pandemic (1863–1875) spread mostly in Europe and Africa.
- In 1866 there was an outbreak in North America.
- In 1892 cholera contaminated the water supply of Hamburg, Germany, and caused 8,606 deaths.
- The seventh pandemic (1899–1923) had little effect in Europe because of advances in public health, but Russia was badly affected again.
- The eighth pandemic began in Indonesia in 1961, called El Tor after the strain, and reached Bangladesh in 1963, India in 1964, and the USSR in 1966.
- Influenza
The "first" pandemic of 1510 travelled from Africa and spread across Europe.
The "Asiatic Flu", 1889–1890. Was first reported in May of 1889 in Bukhara, Russia. By October, it had reached Tomsk and the Caucasus. It rapidly spread west and hit North America in December 1889, South America in February–April 1890, India in February-March 1890, and Australia in March–April 1890. It was purportedly caused by the H2N8 type of flu virus and had a very high attack and mortality rate.
The "Spanish flu", 1918–1919. First identified early March 1918 in US troops training at Camp Funston, Kansas, by October 1918 it had spread to become a world-wide pandemic on all continents. Unusually deadly and virulent, it ended nearly as quickly as it began, vanishing completely within 18 months. In six months, 25 million were dead; some estimates put the total of those killed worldwide at over twice that number. An estimated 17 million died in India, 500,000 in the United States and 200,000 in the UK. The virus was recently reconstructed by scientists at the CDC studying remains preserved by the Alaskan permafrost. They identified it as a type of H1N1 virus.
The "Asian Flu", 1957–58. An H2N2 caused about 70,000 deaths in the United States. First identified in China in late February 1957, the Asian flu spread to the United States by June 1957.
The "Hong Kong Flu", 1968–69. An H3N2 caused about 34,000 deaths in the United States. This virus was first detected in Hong Kong in early 1968 and spread to the United States later that year. Influenza A (H3N2) viruses still circulate today.
- The "first" pandemic of 1510 travelled from Africa and spread across Europe.
- The "Asiatic Flu", 1889–1890. Was first reported in May of 1889 in Bukhara, Russia. By October, it had reached Tomsk and the Caucasus. It rapidly spread west and hit North America in December 1889, South America in February–April 1890, India in February-March 1890, and Australia in March–April 1890. It was purportedly caused by the H2N8 type of flu virus and had a very high attack and mortality rate.
- The "Spanish flu", 1918–1919. First identified early March 1918 in US troops training at Camp Funston, Kansas, by October 1918 it had spread to become a world-wide pandemic on all continents. Unusually deadly and virulent, it ended nearly as quickly as it began, vanishing completely within 18 months. In six months, 25 million were dead; some estimates put the total of those killed worldwide at over twice that number. An estimated 17 million died in India, 500,000 in the United States and 200,000 in the UK. The virus was recently reconstructed by scientists at the CDC studying remains preserved by the Alaskan permafrost. They identified it as a type of H1N1 virus.
- The "Asian Flu", 1957–58. An H2N2 caused about 70,000 deaths in the United States. First identified in China in late February 1957, the Asian flu spread to the United States by June 1957.
- The "Hong Kong Flu", 1968–69. An H3N2 caused about 34,000 deaths in the United States. This virus was first detected in Hong Kong in early 1968 and spread to the United States later that year. Influenza A (H3N2) viruses still circulate today.
- Typhus, sometimes called "camp fever" because of its pattern of flaring up in times of strife. (It is also known as "gaol fever" and "ship fever", for its habits of spreading wildly in cramped quarters, such as jails and ships.) Emerging during the Crusades, it had its first impact in Europe in 1489 in Spain. During fighting between the Christian Spaniards and the Muslims in Granada, the Spanish lost 3,000 to war casualties and 20,000 to typhus. In 1528 the French lost 18,000 troops in Italy and lost supremacy in Italy to the Spanish. In 1542, 30,000 people died of typhus while fighting the Ottomans in the Balkans. The disease also played a major role in the destruction of Napoleon's Grande Armée in Russia in 1812. Typhus also killed numerous prisoners in the Nazi concentration camps during World War II.
- Effects of Colonization. Encounters between European explorers and populations in the rest of the world often introduced local epidemics of extraordinary virulence. Disease killed the entire native (Guanches) population of the Canary Islands in the 16th century. Half the native population of Hispaniola in 1518 was killed by smallpox. Smallpox also ravaged Mexico in the 1520s, killing 150,000 in Tenochtitlán alone, including the emperor, and Peru in the 1530s, aiding the European conquerors. Measles killed a further two million Mexican natives in the 1600s. Some believe that the death of 90 to 95 percent of the Native American population of the New World was caused by Old World diseases. As late as 1848–49, as many as 40,000 out of 150,000 Hawaiians are estimated to have died of measles, whooping cough and influenza.
There are also a number of unknown diseases that were extremely serious but have now vanished, so the etiology of these diseases cannot be established. The cause of English Sweat in 16th-century England, which struck people down in an instant and was more greatly feared even than the bubonic plague, is still unknown.
# Concern about possible future pandemics
## Ebola virus and other quickly lethal diseases
Lassa fever, Rift Valley fever, Marburg virus, Ebola virus and Bolivian hemorrhagic fever are highly contagious and deadly diseases with the theoretical potential to become pandemics. Their ability to spread efficiently enough to cause a pandemic is limited, however, as transmission of these viruses requires close contact with the infected vector. Furthermore, the short time between a vector becoming infectious and the onset of symptoms allows medical professionals to quickly quarantine vectors and prevent them from carrying the pathogen elsewhere. Genetic mutations could occur which could elevate their potential for causing widespread harm, thus close observation by contagious disease specialists is merited.
## Antibiotic resistance
Antibiotic-resistant "superbugs" may also revive diseases previously regarded as "conquered." Cases of tuberculosis resistant to all traditionally effective treatments have emerged to the great concern of health professionals.
Such common bacteria as Staphylococcus aureus, Serratia marcescens and species of Enterococcus that have developed resistance to the strongest available antibiotics such as vancomycin emerged in the past 20 years as an important cause of hospital-acquired nosocomial infections, and are now colonizing and causing disease in the general population.
In the U.S., 2,000,000 people per year are catching hospital-acquired infections after having been admitted to hospitals to receive medical care for unrelated reasons. The latest number of infections are startling, (2006) equating to 4 new cases per minute. Of those, 90,000+ people die. Organizations like the Center for Disease Control, WHO and Safe Care Campaign are leading the effort to eradicate these avoidable, yet deadly infections.
## HIV infection
HIV — the virus that causes AIDS — is now considered a global pandemic with infection rates as high as 25% in southern and eastern Africa. Effective education about safer sexual practices and bloodborne infection precautions training have helped to slow down infection rates in several African countries sponsoring national education programs. Infection rates are rising again in Asia and the Americas.
## SARS
In 2003, there were concerns that SARS, a new, highly contagious form of atypical pneumonia caused by a coronavirus dubbed SARS-CoV, might become pandemic. Rapid action by national and international health authorities such as the World Health Organization helped slow transmission and eventually broke the chain of transmission, ending the localized epidemics before they could become a pandemic. The disease has not been eradicated, however, and could re-emerge unexpectedly, warranting monitoring and case reporting of suspicious cases of atypical pneumonia.
## Avian flu
Wild aquatic birds are the natural hosts for a range of influenza A viruses. Occasionally viruses are transmitted from these species to other species and may then cause outbreaks in domestic poultry or (rarely) give rise to a human pandemic.
In February 2004, avian influenza virus was detected in birds in Vietnam, increasing fears of the emergence of new variant strains. It is feared that if the avian influenza virus combines with a human influenza virus (in a bird or a human), the new subtype created could be both highly contagious and highly lethal in humans. Such a subtype could cause a global influenza pandemic, similar to the Spanish Flu, or the lower mortality pandemics such as the Asian Flu and the Hong Kong Flu.
From October 2004 to February 2005, some 3,700 test kits of the 1957 Asian Flu virus were accidentally spread around the world from a lab in the US.
In May 2005, scientists urgently call nations to prepare for a global influenza pandemic that could strike as much as 20% of the world's population.
In October 2005, cases of the avian flu (the deadly strain H5N1) were identified in Turkey. EU Health Commissioner Markos Kyprianou said: "We have received now confirmation that the virus found in Turkey is an avian flu H5N1 virus. There is a direct relationship with viruses found in Russia, Mongolia and China." Cases of bird flu were also identified shortly thereafter in Romania, and then Greece. Possible cases of the virus have also been found in Croatia, Bulgaria and in the United Kingdom.. However, by the end of October only 67 people had died as a result of H5N1 which was atypical of previous influenza pandemics.
Despite sensational media reporting, avian flu cannot yet be categorized as a "pandemic" because the virus cannot yet cause sustained and efficient human-to-human transmission. Cases so far are recognized to have been transmitted from bird to human, but as of December 2006 there have been very few (if any) cases of proven human-to-human transmission. Regular influenza viruses establish infection by attaching to receptors in the throat and lungs, but the avian influenza virus can only attach to receptors located deep in the lungs of humans, requiring close, prolonged contact with infected patients and thus limiting person-to-person transmission. The current WHO phase of pandemic alert is level 3, described as "no or very limited human-to-human transmission." | Pandemic
# Overview
A pandemic (from Greek παν pan all + δήμος demos people) is an epidemic that spreads through human populations across a large region (for example a continent), or even worldwide.
# Definition
According to the World Health Organization (WHO), a pandemic can start when three conditions have been met:
- the emergence of a disease new to the population.
- the agent infects humans, causing serious illness.
- the agent spreads easily and sustainably among humans.
A disease or condition is not a pandemic merely because it is widespread or kills many people; it must also be infectious. For example cancer is responsible for many deaths but is not considered a pandemic because the disease is not infectious or contagious (although certain causes of some types of cancer might be).
# WHO pandemic influenza phases
The WHO global influenza preparedness plan defines the stages of pandemic influenza, outlines the role of WHO and makes recommendations for national measures before and during a pandemic. The phases are:
Interpandemic period:
- Phase 1: No new influenza virus subtypes have been detected in humans.
- Phase 2: No new influenza virus subtypes have been detected in humans, but an animal variant threatens human disease.
Pandemic alert period:
- Phase 3: Human infection(s) with a new subtype but no human-to-human spread.
- Phase 4: Small cluster(s) with limited localized human-to-human transmission
- Phase 5: Larger cluster(s) but human-to-human spread still localized.
Pandemic period:
- Phase 6: Pandemic: increased and sustained transmission in general population.
# Pandemics and notable epidemics through history
There have been a number of significant pandemics recorded in human history, generally zoonoses that came about with domestication of animals — such as influenza and tuberculosis. There have been a number of particularly significant epidemics that deserve mention above the "mere" destruction of cities:
- Peloponnesian War, 430 BC. Typhoid fever killed a quarter of the Athenian troops and a quarter of the population over four years. This disease fatally weakened the dominance of Athens, but the sheer virulence of the disease prevented its wider spread; i.e. it killed off its hosts at a rate faster than they could spread it. The exact cause of the plague was unknown for many years; in January 2006, researchers from the University of Athens analyzed teeth recovered from a mass grave underneath the city, and confirmed the presence of bacteria responsible for typhoid. [1]
- Antonine Plague, 165–180. Possibly smallpox brought back from the Near East; killed a quarter of those infected and up to five million in all. At the height of a second outbreak (251–266) 5,000 people a day were said to be dying in Rome.
- Plague of Justinian, from 541 to 750, was the first recorded outbreak of the bubonic plague. It started in Egypt and reached Constantinople the following spring, killing (according to the Byzantine chronicler Procopius) 10,000 a day at its height and perhaps 40 percent of the city's inhabitants. It went on to eliminate a quarter to a half of the human population that it struck throughout the known world. [1]
- The Black Death, started 1300s. Eight hundred years after the last outbreak, the bubonic plague returned to Europe. Starting in Asia, the disease reached Mediterranean and western Europe in 1348 (possibly from Italian merchants fleeing fighting in the Crimea), and killed twenty million Europeans in six years, a quarter of the total population and up to a half in the worst-affected urban areas.[2]
- Cholera
first pandemic 1816–1826. Previously restricted to the Indian subcontinent, the pandemic began in Bengal, then spread across India by 1820. It extended as far as China and the Caspian Sea before receding.
The second pandemic (1829–1851) reached Europe, London in 1832, Ontario Canada and New York in the same year, and the Pacific coast of North America by 1834.
The third pandemic (1852–1860) mainly affected Russia, with over a million deaths.
The fourth pandemic (1863–1875) spread mostly in Europe and Africa.
In 1866 there was an outbreak in North America.
In 1892 cholera contaminated the water supply of Hamburg, Germany, and caused 8,606 deaths.[3]
The seventh pandemic (1899–1923) had little effect in Europe because of advances in public health, but Russia was badly affected again.
The eighth pandemic began in Indonesia in 1961, called El Tor after the strain, and reached Bangladesh in 1963, India in 1964, and the USSR in 1966.
- first pandemic 1816–1826. Previously restricted to the Indian subcontinent, the pandemic began in Bengal, then spread across India by 1820. It extended as far as China and the Caspian Sea before receding.
- The second pandemic (1829–1851) reached Europe, London in 1832, Ontario Canada and New York in the same year, and the Pacific coast of North America by 1834.
- The third pandemic (1852–1860) mainly affected Russia, with over a million deaths.
- The fourth pandemic (1863–1875) spread mostly in Europe and Africa.
- In 1866 there was an outbreak in North America.
- In 1892 cholera contaminated the water supply of Hamburg, Germany, and caused 8,606 deaths.[3]
- The seventh pandemic (1899–1923) had little effect in Europe because of advances in public health, but Russia was badly affected again.
- The eighth pandemic began in Indonesia in 1961, called El Tor after the strain, and reached Bangladesh in 1963, India in 1964, and the USSR in 1966.
- Influenza
The "first" pandemic of 1510 travelled from Africa and spread across Europe.[4][5]
The "Asiatic Flu", 1889–1890. Was first reported in May of 1889 in Bukhara, Russia. By October, it had reached Tomsk and the Caucasus. It rapidly spread west and hit North America in December 1889, South America in February–April 1890, India in February-March 1890, and Australia in March–April 1890. It was purportedly caused by the H2N8 type of flu virus and had a very high attack and mortality rate.
The "Spanish flu", 1918–1919. First identified early March 1918 in US troops training at Camp Funston, Kansas, by October 1918 it had spread to become a world-wide pandemic on all continents. Unusually deadly and virulent, it ended nearly as quickly as it began, vanishing completely within 18 months. In six months, 25 million were dead; some estimates put the total of those killed worldwide at over twice that number. An estimated 17 million died in India, 500,000 in the United States and 200,000 in the UK. The virus was recently reconstructed by scientists at the CDC studying remains preserved by the Alaskan permafrost. They identified it as a type of H1N1 virus.
The "Asian Flu", 1957–58. An H2N2 caused about 70,000 deaths in the United States. First identified in China in late February 1957, the Asian flu spread to the United States by June 1957.
The "Hong Kong Flu", 1968–69. An H3N2 caused about 34,000 deaths in the United States. This virus was first detected in Hong Kong in early 1968 and spread to the United States later that year. Influenza A (H3N2) viruses still circulate today.
- The "first" pandemic of 1510 travelled from Africa and spread across Europe.[4][5]
- The "Asiatic Flu", 1889–1890. Was first reported in May of 1889 in Bukhara, Russia. By October, it had reached Tomsk and the Caucasus. It rapidly spread west and hit North America in December 1889, South America in February–April 1890, India in February-March 1890, and Australia in March–April 1890. It was purportedly caused by the H2N8 type of flu virus and had a very high attack and mortality rate.
- The "Spanish flu", 1918–1919. First identified early March 1918 in US troops training at Camp Funston, Kansas, by October 1918 it had spread to become a world-wide pandemic on all continents. Unusually deadly and virulent, it ended nearly as quickly as it began, vanishing completely within 18 months. In six months, 25 million were dead; some estimates put the total of those killed worldwide at over twice that number. An estimated 17 million died in India, 500,000 in the United States and 200,000 in the UK. The virus was recently reconstructed by scientists at the CDC studying remains preserved by the Alaskan permafrost. They identified it as a type of H1N1 virus.
- The "Asian Flu", 1957–58. An H2N2 caused about 70,000 deaths in the United States. First identified in China in late February 1957, the Asian flu spread to the United States by June 1957.
- The "Hong Kong Flu", 1968–69. An H3N2 caused about 34,000 deaths in the United States. This virus was first detected in Hong Kong in early 1968 and spread to the United States later that year. Influenza A (H3N2) viruses still circulate today.
- Typhus, sometimes called "camp fever" because of its pattern of flaring up in times of strife. (It is also known as "gaol fever" and "ship fever", for its habits of spreading wildly in cramped quarters, such as jails and ships.) Emerging during the Crusades, it had its first impact in Europe in 1489 in Spain. During fighting between the Christian Spaniards and the Muslims in Granada, the Spanish lost 3,000 to war casualties and 20,000 to typhus. In 1528 the French lost 18,000 troops in Italy and lost supremacy in Italy to the Spanish. In 1542, 30,000 people died of typhus while fighting the Ottomans in the Balkans. The disease also played a major role in the destruction of Napoleon's Grande Armée in Russia in 1812. Typhus also killed numerous prisoners in the Nazi concentration camps during World War II.
- Effects of Colonization. Encounters between European explorers and populations in the rest of the world often introduced local epidemics of extraordinary virulence. Disease killed the entire native (Guanches) population of the Canary Islands in the 16th century. Half the native population of Hispaniola in 1518 was killed by smallpox. Smallpox also ravaged Mexico in the 1520s, killing 150,000 in Tenochtitlán alone, including the emperor, and Peru in the 1530s, aiding the European conquerors. Measles killed a further two million Mexican natives in the 1600s. Some believe that the death of 90 to 95 percent of the Native American population of the New World was caused by Old World diseases. As late as 1848–49, as many as 40,000 out of 150,000 Hawaiians are estimated to have died of measles, whooping cough and influenza.[6][7]
There are also a number of unknown diseases that were extremely serious but have now vanished, so the etiology of these diseases cannot be established. The cause of English Sweat in 16th-century England, which struck people down in an instant and was more greatly feared even than the bubonic plague, is still unknown.
# Concern about possible future pandemics
## Ebola virus and other quickly lethal diseases
Lassa fever, Rift Valley fever, Marburg virus, Ebola virus and Bolivian hemorrhagic fever are highly contagious and deadly diseases with the theoretical potential to become pandemics. Their ability to spread efficiently enough to cause a pandemic is limited, however, as transmission of these viruses requires close contact with the infected vector. Furthermore, the short time between a vector becoming infectious and the onset of symptoms allows medical professionals to quickly quarantine vectors and prevent them from carrying the pathogen elsewhere. Genetic mutations could occur which could elevate their potential for causing widespread harm, thus close observation by contagious disease specialists is merited.
## Antibiotic resistance
Antibiotic-resistant "superbugs" may also revive diseases previously regarded as "conquered." Cases of tuberculosis resistant to all traditionally effective treatments have emerged to the great concern of health professionals.
Such common bacteria as Staphylococcus aureus, Serratia marcescens and species of Enterococcus that have developed resistance to the strongest available antibiotics such as vancomycin emerged in the past 20 years as an important cause of hospital-acquired nosocomial infections, and are now colonizing and causing disease in the general population.
In the U.S., 2,000,000 people per year are catching hospital-acquired infections after having been admitted to hospitals to receive medical care for unrelated reasons. The latest number of infections are startling, (2006) equating to 4 new cases per minute. Of those, 90,000+ people die. Organizations like the Center for Disease Control, WHO and Safe Care Campaign are leading the effort to eradicate these avoidable, yet deadly infections.
## HIV infection
HIV — the virus that causes AIDS — is now considered a global pandemic with infection rates as high as 25% in southern and eastern Africa. Effective education about safer sexual practices and bloodborne infection precautions training have helped to slow down infection rates in several African countries sponsoring national education programs. Infection rates are rising again in Asia and the Americas.
## SARS
In 2003, there were concerns that SARS, a new, highly contagious form of atypical pneumonia caused by a coronavirus dubbed SARS-CoV, might become pandemic. Rapid action by national and international health authorities such as the World Health Organization helped slow transmission and eventually broke the chain of transmission, ending the localized epidemics before they could become a pandemic. The disease has not been eradicated, however, and could re-emerge unexpectedly, warranting monitoring and case reporting of suspicious cases of atypical pneumonia.
## Avian flu
Wild aquatic birds are the natural hosts for a range of influenza A viruses. Occasionally viruses are transmitted from these species to other species and may then cause outbreaks in domestic poultry or (rarely) give rise to a human pandemic. [8] [9]
In February 2004, avian influenza virus was detected in birds in Vietnam, increasing fears of the emergence of new variant strains. It is feared that if the avian influenza virus combines with a human influenza virus (in a bird or a human), the new subtype created could be both highly contagious and highly lethal in humans. Such a subtype could cause a global influenza pandemic, similar to the Spanish Flu, or the lower mortality pandemics such as the Asian Flu and the Hong Kong Flu.
From October 2004 to February 2005, some 3,700 test kits of the 1957 Asian Flu virus were accidentally spread around the world from a lab in the US[2].
In May 2005, scientists urgently call nations to prepare for a global influenza pandemic that could strike as much as 20% of the world's population.
In October 2005, cases of the avian flu (the deadly strain H5N1) were identified in Turkey. EU Health Commissioner Markos Kyprianou said: "We have received now confirmation that the virus found in Turkey is an avian flu H5N1 virus. There is a direct relationship with viruses found in Russia, Mongolia and China." Cases of bird flu were also identified shortly thereafter in Romania, and then Greece. Possible cases of the virus have also been found in Croatia, Bulgaria and in the United Kingdom.[3]. However, by the end of October only 67 people had died as a result of H5N1 which was atypical of previous influenza pandemics.
Despite sensational media reporting, avian flu cannot yet be categorized as a "pandemic" because the virus cannot yet cause sustained and efficient human-to-human transmission. Cases so far are recognized to have been transmitted from bird to human, but as of December 2006 there have been very few (if any) cases of proven human-to-human transmission. Regular influenza viruses establish infection by attaching to receptors in the throat and lungs, but the avian influenza virus can only attach to receptors located deep in the lungs of humans, requiring close, prolonged contact with infected patients and thus limiting person-to-person transmission. The current WHO phase of pandemic alert is level 3, described as "no or very limited human-to-human transmission." | https://www.wikidoc.org/index.php/Pandemic | |
c607c7fca74cc9462d3e13b9b9a6e4393427ba4e | wikidoc | Pangolin | Pangolin
Pangolins (Template:PronEng) or scaly anteaters are mammals in the order Pholidota. There is only one extant family (Manidae) and one genus (Manis) of pangolins, comprising eight species. There are also a number of extinct taxa. Pangolins have large keratin scales covering their skin and are the only mammals with this adaptation. They are found in tropical regions of Africa and Asia. The name "pangolin" derives from the Malay word pengguling ("something that rolls up"). Pangolins are nocturnal animals, using their well-developed sense of smell to find insects. The long-tailed pangolin is also active by day. Pangolins spend most of the daytime sleeping, curled up into a ball.
Pangolins were classified with various other orders, for example Xenarthra, which includes the ordinary anteaters, sloths, and the similar-looking armadillos. But newer genetic evidence, indicates that their closest living relatives are the Carnivora, with which they form a clade, the Ferae. Some paleontologists have classified the pangolins in the order Cimolesta, together with several extinct groups.
# Physical description and behavior
The physical appearance of pangolins is marked by large, hardened, plate-like scales. The scales, which are soft on newborn pangolins but harden as the animal matures, are made of keratin, the same material of which human fingernails and tetrapod claws are made. The pangolin is often compared to a walking pine cone or globe artichoke. It can curl up into a ball when threatened, with its overlapping scales acting as armour and its face tucked under its tail. The scales are razor-sharp, and provide extra defense for this reason. The front claws are so long that they are unsuited for walking, and so the animal walks with its fore paws curled over to protect them. Pangolins can also emit a noxious smelling acid from glands near the anus, similar to the spray of a skunk. Pangolins have short legs, with sharp claws which they use for burrowing into termite and ant mounds, as well as climbing.
The size of pangolins varies by species, ranging from 30 cm to 100 cm (12 to 39 inches). Females are generally smaller than males.
The tongues of pangolins are extremely elongated and extend into the abdominal cavity. By convergent evolution pangolins, the giant anteater, and the tube-lipped nectar bat, all have tongues which are unattached from their hyoid bone and extend past their pharynx deep into the thorax. This extension lies between the sternum and the trachea. Large pangolins can extend their tongues as much as 40 cm (16 inches), with a diameter of only 0.5 cm (1/4 inch).
In pangolins, the section of the brain that relates to problem solving is highly developed. Although their problem solving ability is primarily used to find food in obscure locations, when kept in captivity pangolins are remarkable escape artists..
Arboreal pangolins live in hollow trees, whereas the ground dwelling species dig tunnels underground, up to a depth of 3.5 meters (11 feet). Pangolins are also good swimmers.
# Diet
Pangolins lack teeth and the ability to chew. Instead, they tear open anthills or termite mounds with their powerful front claws and probe deep into them with their very long tongues. Pangolins have an enormous salivary gland in their chests to lubricate the tongue with sticky, ant-catching saliva.
Some species, such as the Tree Pangolin, use their strong tails to hang from tree branches and strip away bark from the trunk, exposing insect nests inside.
# Reproduction
Gestation is 120-150 days. African pangolin females usually give birth to a single offspring at a time, but the Asiatic species can give birth from one to three. Weight at birth is 80-450 g (3-18 ounces), and the scales are initially soft. The young cling to the mother's tail as she moves about, although, in burrowing species, they remain in the burrow for the first 2-4 weeks of life. Weaning takes place at around three months of age, and pangolins becomes sexually mature at two years.
# Threats
Pangolin are hunted and eaten in many parts of Africa and it is one of the more popular types of bush meat. Pangolins are also in great demand in China because their meat is considered a delicacy and some Chinese believe pangolin scales reduce swelling, promote blood circulation and help breast-feeding women produce milk. This, coupled with deforestation, has led to a large decrease in the numbers of Giant Pangolins.
Pangolin populations have suffered from illegal trafficking. In May 2007, for example, Guardian Unlimited reported that 31 pangolins were found aboard an abandoned vessel off the coast of China. The boat contained some 5,000 endangered animals.
The Guardian recently provided a description of the killing and eating of pangolins: "A Guangdong chef interviewed last year in the Beijing Science and Technology Daily described how to cook a pangolin: 'We keep them alive in cages until the customer makes an order. Then we hammer them unconscious, cut their throats and drain the blood. It is a slow death. We then boil them to remove the scales. We cut the meat into small pieces and use it to make a number of dishes, including braised meat and soup. Usually the customers take the blood home with them afterwards.'"
On November 10, 2007, Thai customs officers announced that they had rescued over 100 pangolins as the animals were being smuggled out of the country, en route to China, where they were to be sold for cooking.
# Taxonomy
- ORDER PHOLIDOTA
Family †Epoicotheriidae
Family †Metacheiromyidae
Family Manidae
Subfamily †Eurotamanduidae
Genus †Eurotamandua
Subfamily Maninae
Genus †Cryptomanis
Genus †Eomanis
Genus †Necromanis
Genus †Patriomanis
Genus Manis
Subgenus Manis
Indian Pangolin (M. crassicaudata)
Chinese Pangolin (M. pentadactyla)
Subgenus Paramanis
Sunda Pangolin (M. javanica)
Philippine Pangolin (M. culionensis)
Subgenus Smutsia
Giant Pangolin (M. gigantea)
Ground Pangolin (M. temmincki)
Subgenus Phataginus
Tree Pangolin (M. tricuspis)
Subgenus Uromanis
Long-tailed Pangolin (M. tetradactyla)
- Family †Epoicotheriidae
- Family †Metacheiromyidae
- Family Manidae
Subfamily †Eurotamanduidae
Genus †Eurotamandua
Subfamily Maninae
Genus †Cryptomanis
Genus †Eomanis
Genus †Necromanis
Genus †Patriomanis
Genus Manis
Subgenus Manis
Indian Pangolin (M. crassicaudata)
Chinese Pangolin (M. pentadactyla)
Subgenus Paramanis
Sunda Pangolin (M. javanica)
Philippine Pangolin (M. culionensis)
Subgenus Smutsia
Giant Pangolin (M. gigantea)
Ground Pangolin (M. temmincki)
Subgenus Phataginus
Tree Pangolin (M. tricuspis)
Subgenus Uromanis
Long-tailed Pangolin (M. tetradactyla)
- Subfamily †Eurotamanduidae
Genus †Eurotamandua
- Genus †Eurotamandua
- Subfamily Maninae
Genus †Cryptomanis
Genus †Eomanis
Genus †Necromanis
Genus †Patriomanis
Genus Manis
Subgenus Manis
Indian Pangolin (M. crassicaudata)
Chinese Pangolin (M. pentadactyla)
Subgenus Paramanis
Sunda Pangolin (M. javanica)
Philippine Pangolin (M. culionensis)
Subgenus Smutsia
Giant Pangolin (M. gigantea)
Ground Pangolin (M. temmincki)
Subgenus Phataginus
Tree Pangolin (M. tricuspis)
Subgenus Uromanis
Long-tailed Pangolin (M. tetradactyla)
- Genus †Cryptomanis
- Genus †Eomanis
- Genus †Necromanis
- Genus †Patriomanis
- Genus Manis
Subgenus Manis
Indian Pangolin (M. crassicaudata)
Chinese Pangolin (M. pentadactyla)
Subgenus Paramanis
Sunda Pangolin (M. javanica)
Philippine Pangolin (M. culionensis)
Subgenus Smutsia
Giant Pangolin (M. gigantea)
Ground Pangolin (M. temmincki)
Subgenus Phataginus
Tree Pangolin (M. tricuspis)
Subgenus Uromanis
Long-tailed Pangolin (M. tetradactyla)
- Subgenus Manis
Indian Pangolin (M. crassicaudata)
Chinese Pangolin (M. pentadactyla)
- Indian Pangolin (M. crassicaudata)
- Chinese Pangolin (M. pentadactyla)
- Subgenus Paramanis
Sunda Pangolin (M. javanica)
Philippine Pangolin (M. culionensis)
- Sunda Pangolin (M. javanica)
- Philippine Pangolin (M. culionensis)
- Subgenus Smutsia
Giant Pangolin (M. gigantea)
Ground Pangolin (M. temmincki)
- Giant Pangolin (M. gigantea)
- Ground Pangolin (M. temmincki)
- Subgenus Phataginus
Tree Pangolin (M. tricuspis)
- Tree Pangolin (M. tricuspis)
- Subgenus Uromanis
Long-tailed Pangolin (M. tetradactyla)
- Long-tailed Pangolin (M. tetradactyla) | Pangolin
Pangolins (Template:PronEng) or scaly anteaters are mammals in the order Pholidota. There is only one extant family (Manidae) and one genus (Manis) of pangolins, comprising eight species. There are also a number of extinct taxa. Pangolins have large keratin scales covering their skin and are the only mammals with this adaptation.[2] They are found in tropical regions of Africa and Asia. The name "pangolin" derives from the Malay word pengguling ("something that rolls up"). Pangolins are nocturnal animals, using their well-developed sense of smell to find insects. The long-tailed pangolin is also active by day. Pangolins spend most of the daytime sleeping, curled up into a ball.[3]
Pangolins were classified with various other orders, for example Xenarthra, which includes the ordinary anteaters, sloths, and the similar-looking armadillos. But newer genetic evidence,[4] indicates that their closest living relatives are the Carnivora, with which they form a clade, the Ferae.[5] Some paleontologists have classified the pangolins in the order Cimolesta, together with several extinct groups.
# Physical description and behavior
The physical appearance of pangolins is marked by large, hardened, plate-like scales. The scales, which are soft on newborn pangolins but harden as the animal matures, are made of keratin, the same material of which human fingernails and tetrapod claws are made. The pangolin is often compared to a walking pine cone or globe artichoke. It can curl up into a ball when threatened, with its overlapping scales acting as armour and its face tucked under its tail. The scales are razor-sharp, and provide extra defense for this reason. The front claws are so long that they are unsuited for walking, and so the animal walks with its fore paws curled over to protect them. Pangolins can also emit a noxious smelling acid from glands near the anus, similar to the spray of a skunk. Pangolins have short legs, with sharp claws which they use for burrowing into termite and ant mounds, as well as climbing.
The size of pangolins varies by species, ranging from 30 cm to 100 cm (12 to 39 inches). Females are generally smaller than males.
The tongues of pangolins are extremely elongated and extend into the abdominal cavity. By convergent evolution pangolins, the giant anteater, and the tube-lipped nectar bat, all have tongues which are unattached from their hyoid bone and extend past their pharynx deep into the thorax.[6] This extension lies between the sternum and the trachea. Large pangolins can extend their tongues as much as 40 cm (16 inches), with a diameter of only 0.5 cm (1/4 inch).[3]
In pangolins, the section of the brain that relates to problem solving is highly developed. Although their problem solving ability is primarily used to find food in obscure locations, when kept in captivity pangolins are remarkable escape artists.[citation needed].
Arboreal pangolins live in hollow trees, whereas the ground dwelling species dig tunnels underground, up to a depth of 3.5 meters (11 feet).[3] Pangolins are also good swimmers.[3]
# Diet
Pangolins lack teeth and the ability to chew. Instead, they tear open anthills or termite mounds with their powerful front claws and probe deep into them with their very long tongues. Pangolins have an enormous salivary gland in their chests to lubricate the tongue with sticky, ant-catching saliva.
Some species, such as the Tree Pangolin, use their strong tails to hang from tree branches and strip away bark from the trunk, exposing insect nests inside.
# Reproduction
Gestation is 120-150 days. African pangolin females usually give birth to a single offspring at a time, but the Asiatic species can give birth from one to three.[3] Weight at birth is 80-450 g (3-18 ounces), and the scales are initially soft. The young cling to the mother's tail as she moves about, although, in burrowing species, they remain in the burrow for the first 2-4 weeks of life. Weaning takes place at around three months of age, and pangolins becomes sexually mature at two years.[7]
# Threats
Pangolin are hunted and eaten in many parts of Africa and it is one of the more popular types of bush meat. Pangolins are also in great demand in China because their meat is considered a delicacy and some Chinese believe pangolin scales reduce swelling, promote blood circulation and help breast-feeding women produce milk. This, coupled with deforestation, has led to a large decrease in the numbers of Giant Pangolins.
Pangolin populations have suffered from illegal trafficking. In May 2007, for example, Guardian Unlimited reported that 31 pangolins were found aboard an abandoned vessel off the coast of China. The boat contained some 5,000 endangered animals.
The Guardian recently provided a description of the killing and eating of pangolins: "A Guangdong chef interviewed last year in the Beijing Science and Technology Daily described how to cook a pangolin: 'We keep them alive in cages until the customer makes an order. Then we hammer them unconscious, cut their throats and drain the blood. It is a slow death. We then boil them to remove the scales. We cut the meat into small pieces and use it to make a number of dishes, including braised meat and soup. Usually the customers take the blood home with them afterwards.'" [8]
On November 10, 2007, Thai customs officers announced that they had rescued over 100 pangolins as the animals were being smuggled out of the country, en route to China, where they were to be sold for cooking. [9]
# Taxonomy
- ORDER PHOLIDOTA
Family †Epoicotheriidae
Family †Metacheiromyidae
Family Manidae
Subfamily †Eurotamanduidae
Genus †Eurotamandua
Subfamily Maninae
Genus †Cryptomanis
Genus †Eomanis
Genus †Necromanis
Genus †Patriomanis
Genus Manis
Subgenus Manis
Indian Pangolin (M. crassicaudata)
Chinese Pangolin (M. pentadactyla)
Subgenus Paramanis
Sunda Pangolin (M. javanica)
Philippine Pangolin (M. culionensis)
Subgenus Smutsia
Giant Pangolin (M. gigantea)
Ground Pangolin (M. temmincki)
Subgenus Phataginus
Tree Pangolin (M. tricuspis)
Subgenus Uromanis
Long-tailed Pangolin (M. tetradactyla)
- Family †Epoicotheriidae
- Family †Metacheiromyidae
- Family Manidae
Subfamily †Eurotamanduidae
Genus †Eurotamandua
Subfamily Maninae
Genus †Cryptomanis
Genus †Eomanis
Genus †Necromanis
Genus †Patriomanis
Genus Manis
Subgenus Manis
Indian Pangolin (M. crassicaudata)
Chinese Pangolin (M. pentadactyla)
Subgenus Paramanis
Sunda Pangolin (M. javanica)
Philippine Pangolin (M. culionensis)
Subgenus Smutsia
Giant Pangolin (M. gigantea)
Ground Pangolin (M. temmincki)
Subgenus Phataginus
Tree Pangolin (M. tricuspis)
Subgenus Uromanis
Long-tailed Pangolin (M. tetradactyla)
- Subfamily †Eurotamanduidae
Genus †Eurotamandua
- Genus †Eurotamandua
- Subfamily Maninae
Genus †Cryptomanis
Genus †Eomanis
Genus †Necromanis
Genus †Patriomanis
Genus Manis
Subgenus Manis
Indian Pangolin (M. crassicaudata)
Chinese Pangolin (M. pentadactyla)
Subgenus Paramanis
Sunda Pangolin (M. javanica)
Philippine Pangolin (M. culionensis)
Subgenus Smutsia
Giant Pangolin (M. gigantea)
Ground Pangolin (M. temmincki)
Subgenus Phataginus
Tree Pangolin (M. tricuspis)
Subgenus Uromanis
Long-tailed Pangolin (M. tetradactyla)
- Genus †Cryptomanis
- Genus †Eomanis
- Genus †Necromanis
- Genus †Patriomanis
- Genus Manis
Subgenus Manis
Indian Pangolin (M. crassicaudata)
Chinese Pangolin (M. pentadactyla)
Subgenus Paramanis
Sunda Pangolin (M. javanica)
Philippine Pangolin (M. culionensis)
Subgenus Smutsia
Giant Pangolin (M. gigantea)
Ground Pangolin (M. temmincki)
Subgenus Phataginus
Tree Pangolin (M. tricuspis)
Subgenus Uromanis
Long-tailed Pangolin (M. tetradactyla)
- Subgenus Manis
Indian Pangolin (M. crassicaudata)
Chinese Pangolin (M. pentadactyla)
- Indian Pangolin (M. crassicaudata)
- Chinese Pangolin (M. pentadactyla)
- Subgenus Paramanis
Sunda Pangolin (M. javanica)
Philippine Pangolin (M. culionensis)
- Sunda Pangolin (M. javanica)
- Philippine Pangolin (M. culionensis)
- Subgenus Smutsia
Giant Pangolin (M. gigantea)
Ground Pangolin (M. temmincki)
- Giant Pangolin (M. gigantea)
- Ground Pangolin (M. temmincki)
- Subgenus Phataginus
Tree Pangolin (M. tricuspis)
- Tree Pangolin (M. tricuspis)
- Subgenus Uromanis
Long-tailed Pangolin (M. tetradactyla)
- Long-tailed Pangolin (M. tetradactyla) | https://www.wikidoc.org/index.php/Pangolin | |
960385be9fa2546f29df03e6a7ce17eae4938df6 | wikidoc | Pannexin | Pannexin
Pannexins (from Greek 'παν' — all, and from Latin 'nexus' — connection) are a family of vertebrate proteins identified by their homology to the invertebrate innexins. While innexins are responsible for forming gap junctions in invertebrates, the pannexins have been shown to predominantly exist as large transmembrane channels connecting the intracellular and extracellular space, allowing the passage of ions and small molecules between these compartments (such as ATP and sulforhodamine B).
Three pannexins have been described in Chordates: Panx1, Panx2 and Panx3.
# Function
Pannexin 1 has been shown to be involved in early stages of innate immunity through an interaction with the P2X7 purinergic receptor. Activation of the pannexin channel through binding of ATP to P2X7 receptor leads to the release of interleukin-1β.
Hypothetical roles of pannexins in the nervous system include participating in sensory processing, synchronization between hippocampus and cortex, hippocampal plasticity, and propagation of calcium waves. Calcium waves are supported by glial cells, which help maintain and modulate neuronal metabolism. According to one of the hypotheses, pannexins also may participate in pathological reactions, including the neural damage after ischemia and subsequent cell death.
Pannexin 1 channels are pathways for release of ATP from cells.
# Relationship to connexins
Intercellular gap junctions in vertebrates, including humans, are formed by the connexin family of proteins. Structurally, pannexins and connexins are very similar, consisting of 4 transmembrane domains, 2 extracellular and 1 intracellular loop, along with intracellular N- and C-terminal tails. Despite this shared topology, the protein families do not share enough sequence similarity to confidently infer common ancestry.
# Clinical significance
Truncating mutations in pannexin 1 have been shown to promote breast and colon cancer metastasis to the lungs by allowing cancer cells to survive mechanical stretch in the microcirculation through the release of ATP.
Pannexins may be involved in the process of tumor development. Particularly, PANX2 expression levels predict post diagnosis survival for patients with glial tumors.
Probenecid, a well-established drug for the treatment of gout, allows for discrimination between channels formed by connexins and pannexins. Probenecid did not affect channels formed by connexins. | Pannexin
Pannexins (from Greek 'παν' — all, and from Latin 'nexus' — connection) are a family of vertebrate proteins identified by their homology to the invertebrate innexins.[1] While innexins are responsible for forming gap junctions in invertebrates, the pannexins have been shown to predominantly exist as large transmembrane channels connecting the intracellular and extracellular space, allowing the passage of ions and small molecules between these compartments (such as ATP and sulforhodamine B).
Three pannexins have been described in Chordates: Panx1, Panx2 and Panx3.[2]
# Function
Pannexin 1 has been shown to be involved in early stages of innate immunity through an interaction with the P2X7 purinergic receptor. Activation of the pannexin channel through binding of ATP to P2X7 receptor leads to the release of interleukin-1β.[3]
Hypothetical roles of pannexins in the nervous system include participating in sensory processing, synchronization between hippocampus and cortex, hippocampal plasticity, and propagation of calcium waves. Calcium waves are supported by glial cells, which help maintain and modulate neuronal metabolism. According to one of the hypotheses, pannexins also may participate in pathological reactions, including the neural damage after ischemia and subsequent cell death.[4]
Pannexin 1 channels are pathways for release of ATP from cells.[5]
# Relationship to connexins
Intercellular gap junctions in vertebrates, including humans, are formed by the connexin family of proteins.[6] Structurally, pannexins and connexins are very similar, consisting of 4 transmembrane domains, 2 extracellular and 1 intracellular loop, along with intracellular N- and C-terminal tails. Despite this shared topology, the protein families do not share enough sequence similarity to confidently infer common ancestry.
# Clinical significance
Truncating mutations in pannexin 1 have been shown to promote breast and colon cancer metastasis to the lungs by allowing cancer cells to survive mechanical stretch in the microcirculation through the release of ATP.[7]
Pannexins may be involved in the process of tumor development. Particularly, PANX2 expression levels predict post diagnosis survival for patients with glial tumors.
Probenecid, a well-established drug for the treatment of gout, allows for discrimination between channels formed by connexins and pannexins. Probenecid did not affect channels formed by connexins.[8] | https://www.wikidoc.org/index.php/Pannexin | |
85124dafb122a64f3158ebf4220d95a4654baafe | wikidoc | Pap test | Pap test
# Overview
In gynecology, the Papanikolaou test or Papanicolaou test (also called Pap smear, Pap test, cervical smear, or smear test) is a medical screening method, invented independently by Aurel Babeş and Georgios Papanikolaou, primarily designed to detect premalignant and malignant processes in the ectocervix. It may also detect infections and abnormalities in the endocervix and endometrium.
The endocervix may be partially sampled with the device used to obtain the ectocervical sample, but due to the anatomy of this area, consistent and reliable sampling cannot be guaranteed. As abnormal endocervical cells may be sampled, those examining them are taught to recognize them.
The endometrium is not directly sampled with the device used to sample the ectocervix. Cells may exfoliate onto the cervix and be collected from there, so as with endocervical cells, abnormal cells can be recognised if present but the Pap Test should not be used as a screening tool for endometrial malignancy.
The potentially pre-cancerous changes (called dysplasias or cervical or endocervical intraepithelial neoplasia) are usually caused by sexually transmitted human papillomaviruses (HPVs). The test aims to detect and prevent the progression of HPV-induced cervical cancer and other abnormalities in the female genital tract by sampling cells from the outer opening of the cervix (Latin for "neck") of the uterus and the endocervix. The sampling technique changed very little since its invention by Georgios Papanikolaou (1883–1962) to detect cyclic hormonal changes in vaginal cells in the early 20th century until the development of liquid based cell thinlayer technology. The test remains an effective, widely used method for early detection of cervical cancer and pre-cancer.
The UK's call and recall system is among the best; estimates of its effectiveness vary widely but it may prevent about 700 deaths per year in the UK.
It is not a perfect test. "A nurse performing 200 tests each year would prevent a death once in 38 years. During this time she or he would care for over 152 women with abnormal results, over 79 women would be referred for investigation, over 53 would have abnormal biopsy results, and over 17 would have persisting abnormalities for more than two years. At least one woman during the 38 years would die from cervical cancer despite being screened."
HPV vaccine may offer better prospects in the long term.
It is generally recommended that females who have had sex seek regular Pap smear testing. Guidelines on frequency vary, from annually to every five years. If results are abnormal, and depending on the nature of the abnormality, the test may need to be repeated in three to twelve months. If the abnormality requires closer scrutiny, the patient may be referred for detailed inspection of the cervix by colposcopy. The patient may also be referred for HPV DNA testing, which can serve as an adjunct to Pap testing.
About 5% to 7% of pap smears produce abnormal results, such as dysplasia, possibly indicating a pre-cancerous condition. Although many low grade cervical dysplasias spontaneously regress without ever leading to cervical cancer, dysplasia can serve as an indication that increased vigilance is needed. Endocervical and endometrial abnormalities can also be detected, as can a number of infectious processes, including yeast and Trichomonas vaginalis. A small proportion of abnormalities are reported as of "uncertain significance".
# Technical aspects
Samples are collected from the outer opening or os of the cervix using an Aylesbury spatula and an endocervical brush, or (more frequently with the advent of liquid-based cytology) a plastic-fronded broom. The broom is not as good a collection device, since it is much less effective at collecting endocervical material as the spatula and brush. The cells are placed on a glass slide and checked for abnormalities in the laboratory.
The sample is stained using the Papanicolaou technique, in which tinctorial dyes and acids are selectively retained by cells. Unstained cells cannot be visualized with light microscopy. The stains chosen by Papanicolau were selected to highlight cytoplasmic keratinization, which actually has almost nothing to do with the nuclear features used to make diagnoses now.
The sample is then screened by a specially trained and qualified cytotechnologist using a light microscope. The terminology for who screens the sample varies according the country; in the UK, the personnel are known as Cytoscreeners, Biomedical scientists (BMS), Advanced Practitioners and Pathologists. The latter two take responsibility for reporting the abnormal sample which may require further investigation.
Studies of the accuracy of conventional cytology report:
- sensitivity 72%
- specificity 94%
In the United States, physicians who fail to diagnose cervical cancer from a pap smear have been convicted of negligent homicide. In 1988 and 1989, Karen Smith had received pap smears which were argued to have "unequivocally" shown that she had cancer; yet the lab had not made the diagnosis. She died on March 8 1995. Later, a physician and a laboratory technician were convicted of negligent homicide. These events have led to even more rigorous quality assurance programs, and to emphasizing that this is a screening, not a diagnostic, test, associated with a small irreducible error rate.
## Liquid based monolayer cytology
Since the mid-1990s, techniques based around placing the sample into a vial containing a liquid medium which preserves the cells have been increasingly used. The media are primarily ethanol based. Two of the types are Sure-Path (TriPath Imaging) and Thin-Prep (Cytyc Corp).
Once placed into the vial, the sample is processed at the laboratory into a cell thin-layer, stained, and examined by light microscopy. The liquid sample has the advantage of being suitable for low and high risk HPV testing and reduced unsatisfactory specimens from 4.1% to 2.6%. Proper sample acquisition is crucial to the accuracy of the test; clearly, a cell that is not in the sample cannot be evaluated.
Studies of the accuracy of liquid based monolayer cytology report:
- sensitivity 61% to 66%
- specificity 82% to 91%
Some, but not all studies, report increased sensitivity from the liquid based smears.
## Human papillomavirus testing
The presence of HPV indicates that the person has been infected, the majority of women who get infected will successfully clear the infection within 18 months. It is those who have an infection of prolonged duration with high risk types (e.g. types 16,18,31,45) that are more likely to develop Cervical Intraepithelial Neoplasia due to the effects that HPV has on DNA.
Studies of the accuracy of HPV testing report:
- sensitivity 88% to 91% (for detecting CIN 3 or higher) to 97% (for detecting CIN2+)
- specificity 73% to 79% (for detecting CIN 3 or higher) to 93% (for detecting CIN 3 or higher)
By adding the more sensitive HPV Test, the specificity may decline. However, the drop in specificity is not definite. If the specificity does decline, this results in increased numbers of false positive tests and many women who did not have disease having colposcopy and treatment. A worthwhile screening test requires a balance between the sensitivity and specificity to ensure that those having a disease are correctly identified as having it and equally importantly those not identifying those without the disease as having it. Due to the liquid based pap smears having a false negative rate of 15-35%, the American College of Obstetricians and Gynecologists and American Society for Colposcopy and Cervical Pathology have recommended the use of HPV testing in addition to the pap smear in all women over the age of 30.
Regarding the role of HPV testing, randomized controlled trials have compared HPV to colposcopy. HPV testing appears as sensitive as immediate colposcopy while reducing the number of colposcopies needed. Randomized controlled trial have suggested that HPV testing could follow abnormal cytology or could precede cervical cytology examination.
A study published in April 2007 suggested the act of performing a Pap smear produces an inflammatory cytokine response, which may initiate immunologic clearance of HPV, therefore reducing the risk of cervical cancer. Women who had even a single Pap smear in their history had a lower incidence of cancer. "A statistically significant decline in the HPV positivity rate correlated with the lifetime number of Pap smears received."
## Automated analysis
In the last decade there have been successful attempts to develop automated, computer image analysis systems for screening. Automation may improve sensitivity and reduce unsatisfactory specimens. One of these has been FDA approved and functions in high volume reference laboratories, with human oversight.
# Practical aspects
The physician or operator collecting a sample for the test inserts a speculum into the patient's vagina, to obtain a cell sample from the cervix. A pap smear appointment is normally not scheduled during menstruation. The procedure is usually painful, because of the neuroanatomy of the cervix. However, this can depend on the patient's anatomy, the skill of the practitioner, psychological factors, and other conditions. Results usually take about 3 weeks. Slight bleeding, cramps, and other discomfort can occur afterwards.
Other tests, including the TruTest, an endometrial biopsy used for early detection of uterine cancer, can be performed during the same visit. | Pap test
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
In gynecology, the Papanikolaou test or Papanicolaou test (also called Pap smear, Pap test, cervical smear, or smear test) is a medical screening method, invented independently by Aurel Babeş[1] and Georgios Papanikolaou, primarily designed to detect premalignant and malignant processes in the ectocervix. It may also detect infections and abnormalities in the endocervix and endometrium.
The endocervix may be partially sampled with the device used to obtain the ectocervical sample, but due to the anatomy of this area, consistent and reliable sampling cannot be guaranteed. As abnormal endocervical cells may be sampled, those examining them are taught to recognize them.
The endometrium is not directly sampled with the device used to sample the ectocervix. Cells may exfoliate onto the cervix and be collected from there, so as with endocervical cells, abnormal cells can be recognised if present but the Pap Test should not be used as a screening tool for endometrial malignancy.
The potentially pre-cancerous changes (called dysplasias or cervical or endocervical intraepithelial neoplasia) are usually caused by sexually transmitted human papillomaviruses (HPVs). The test aims to detect and prevent the progression of HPV-induced cervical cancer and other abnormalities in the female genital tract by sampling cells from the outer opening of the cervix (Latin for "neck") of the uterus and the endocervix. The sampling technique changed very little since its invention by Georgios Papanikolaou (1883–1962) to detect cyclic hormonal changes in vaginal cells in the early 20th century until the development of liquid based cell thinlayer technology. The test remains an effective, widely used method for early detection of cervical cancer and pre-cancer.
The UK's call and recall system is among the best;[citation needed] estimates of its effectiveness vary widely but it may prevent about 700 deaths per year in the UK.
It is not a perfect test. "A nurse performing 200 tests each year would prevent a death once in 38 years. During this time she or he would care for over 152 women with abnormal results, over 79 women would be referred for investigation, over 53 would have abnormal biopsy results, and over 17 would have persisting abnormalities for more than two years. At least one woman during the 38 years would die from cervical cancer despite being screened."[2]
HPV vaccine may offer better prospects in the long term.
It is generally recommended that females who have had sex seek regular Pap smear testing. Guidelines on frequency vary, from annually to every five years. If results are abnormal, and depending on the nature of the abnormality, the test may need to be repeated in three to twelve months. If the abnormality requires closer scrutiny, the patient may be referred for detailed inspection of the cervix by colposcopy. The patient may also be referred for HPV DNA testing, which can serve as an adjunct to Pap testing.
About 5% to 7% of pap smears produce abnormal results,[citation needed] such as dysplasia, possibly indicating a pre-cancerous condition. Although many low grade cervical dysplasias spontaneously regress without ever leading to cervical cancer, dysplasia can serve as an indication that increased vigilance is needed. Endocervical and endometrial abnormalities can also be detected, as can a number of infectious processes, including yeast and Trichomonas vaginalis. A small proportion of abnormalities are reported as of "uncertain significance".
# Technical aspects
Samples are collected from the outer opening or os of the cervix using an Aylesbury spatula and an endocervical brush, or (more frequently with the advent of liquid-based cytology) a plastic-fronded broom. The broom is not as good a collection device, since it is much less effective at collecting endocervical material as the spatula and brush.[3] The cells are placed on a glass slide and checked for abnormalities in the laboratory.
The sample is stained using the Papanicolaou technique, in which tinctorial dyes and acids are selectively retained by cells. Unstained cells cannot be visualized with light microscopy. The stains chosen by Papanicolau were selected to highlight cytoplasmic keratinization, which actually has almost nothing to do with the nuclear features used to make diagnoses now.
The sample is then screened by a specially trained and qualified cytotechnologist using a light microscope. The terminology for who screens the sample varies according the country; in the UK, the personnel are known as Cytoscreeners, Biomedical scientists (BMS), Advanced Practitioners and Pathologists. The latter two take responsibility for reporting the abnormal sample which may require further investigation.
Studies of the accuracy of conventional cytology report:[4]
- sensitivity 72%
- specificity 94%
In the United States, physicians who fail to diagnose cervical cancer from a pap smear have been convicted of negligent homicide. In 1988 and 1989, Karen Smith had received pap smears which were argued to have "unequivocally" shown that she had cancer; yet the lab had not made the diagnosis. She died on March 8 1995. Later, a physician and a laboratory technician were convicted of negligent homicide.[citation needed] These events have led to even more rigorous quality assurance programs, and to emphasizing that this is a screening, not a diagnostic, test, associated with a small irreducible error rate.
## Liquid based monolayer cytology
Since the mid-1990s, techniques based around placing the sample into a vial containing a liquid medium which preserves the cells have been increasingly used. The media are primarily ethanol based. Two of the types are Sure-Path (TriPath Imaging) and Thin-Prep (Cytyc Corp).
Once placed into the vial, the sample is processed at the laboratory into a cell thin-layer, stained, and examined by light microscopy. The liquid sample has the advantage of being suitable for low and high risk HPV testing and reduced unsatisfactory specimens from 4.1% to 2.6%.[5] Proper sample acquisition is crucial to the accuracy of the test; clearly, a cell that is not in the sample cannot be evaluated.
Studies of the accuracy of liquid based monolayer cytology report:
- sensitivity 61%[6] to 66%[4]
- specificity 82%[6] to 91%[4]
Some[5], but not all studies[4][6], report increased sensitivity from the liquid based smears.
## Human papillomavirus testing
The presence of HPV indicates that the person has been infected, the majority of women who get infected will successfully clear the infection within 18 months. It is those who have an infection of prolonged duration with high risk types[7] (e.g. types 16,18,31,45) that are more likely to develop Cervical Intraepithelial Neoplasia due to the effects that HPV has on DNA.
Studies of the accuracy of HPV testing report:
- sensitivity 88% to 91% (for detecting CIN 3 or higher)[6] to 97% (for detecting CIN2+)[8]
- specificity 73% to 79% (for detecting CIN 3 or higher)[6] to 93% (for detecting CIN 3 or higher)[8]
By adding the more sensitive HPV Test, the specificity may decline. However, the drop in specificity is not definite. [9] If the specificity does decline, this results in increased numbers of false positive tests and many women who did not have disease having colposcopy[10] and treatment. A worthwhile screening test requires a balance between the sensitivity and specificity to ensure that those having a disease are correctly identified as having it and equally importantly those not identifying those without the disease as having it. Due to the liquid based pap smears having a false negative rate of 15-35%, the American College of Obstetricians and Gynecologists[citation needed] and American Society for Colposcopy and Cervical Pathology[11] have recommended the use of HPV testing in addition to the pap smear in all women over the age of 30.
Regarding the role of HPV testing, randomized controlled trials have compared HPV to colposcopy. HPV testing appears as sensitive as immediate colposcopy while reducing the number of colposcopies needed.[12] Randomized controlled trial have suggested that HPV testing could follow abnormal cytology[6] or could precede cervical cytology examination.[8]
A study published in April 2007 suggested the act of performing a Pap smear produces an inflammatory cytokine response, which may initiate immunologic clearance of HPV, therefore reducing the risk of cervical cancer. Women who had even a single Pap smear in their history had a lower incidence of cancer. "A statistically significant decline in the HPV positivity rate correlated with the lifetime number of Pap smears received."[13]
## Automated analysis
In the last decade there have been successful attempts to develop automated, computer image analysis systems for screening.[14] Automation may improve sensitivity and reduce unsatisfactory specimens.[15] One of these has been FDA approved and functions in high volume reference laboratories, with human oversight.[citation needed]
# Practical aspects
The physician or operator collecting a sample for the test inserts a speculum into the patient's vagina, to obtain a cell sample from the cervix. A pap smear appointment is normally not scheduled during menstruation. The procedure is usually painful, because of the neuroanatomy of the cervix. However, this can depend on the patient's anatomy, the skill of the practitioner, psychological factors, and other conditions. Results usually take about 3 weeks. Slight bleeding, cramps, and other discomfort can occur afterwards.
Other tests, including the TruTest, an endometrial biopsy used for early detection of uterine cancer, can be performed during the same visit. | https://www.wikidoc.org/index.php/Pap_test | |
3295702c3ba09ae74b2df41f582b6fb7e51f22d1 | wikidoc | Paradigm | Paradigm
# Overview
Since the late 1960s, the word paradigm (Template:IPAEng) has referred to thought pattern in any scientific discipline or other epistemological context. Initially, the word was specific to grammar: the 1900 Merriam-Webster dictionary defines its technical use only in the context of grammar or, in rhetoric, as a term for an illustrative parable or fable.
In linguistics, Ferdinand de Saussure used paradigm to refer to a class of elements with similarities. The Merriam-Webster Online dictionary defines it as "a philosophical and theoretical framework of a scientific school or discipline within which theories, laws, and generalizations and the experiments performed in support of them are formulated; broadly : a philosophical or theoretical framework of any kind.
# Scientific paradigm
Historian of science Thomas Kuhn gave this word its contemporary meaning when he adopted it to refer to the set of practices that define a scientific discipline during a particular period of time. Kuhn himself came to prefer the terms exemplar and normal science, which have more exact philosophical meanings. However, in his book The Structure of Scientific Revolutions Kuhn defines a scientific paradigm as:
- what is to be observed and scrutinized
- the kind of questions that are supposed to be asked and probed for answers in relation to this subject
- how these questions are to be structured
- how the results of scientific investigations should be interpreted
Alternatively, the Oxford English Dictionary defines paradigm as "a pattern or model, an exemplar." Thus an additional component of Kuhn's definition of paradigm is:
- how is an experiment to be conducted, and what equipment is available to conduct the experiment.
Thus, within normal science, the paradigm is the set of exemplary experiments that are likely to be copied or emulated. The prevailing paradigm often represents a more specific way of viewing reality, or limitations on acceptable programs for future research, than the much more general scientific method.
An example of a currently accepted paradigm would be the standard model of physics. The scientific method would allow for orthodox scientific investigations of many phenomena which might contradict or disprove the standard model; however grant funding would be more difficult to obtain for such experiments, in proportion to the amount of departure from accepted standard model theory which the experiment would test for. For example, an experiment to test for the mass of the neutrino or decay of the proton (small departures from the model) would be more likely to receive money than experiments to look for the violation of the conservation of momentum, or ways to engineer reverse time travel.
One important aspect of Kuhn's paradigms is that the paradigms are incommensurable, which means that two paradigms can not be compared to each other. A new paradigm which replaces an old paradigm is not necessarily better, because the criteria of judgement depend on the paradigm.
A more disparaging term groupthink, and the term mindset, have very similar meanings that apply to smaller and larger scale examples of disciplined thought. Michel Foucault used the terms episteme and discourse, mathesis and taxinomia, for aspects of a "paradigm" in Kuhn's original sense.
Simple common analogy: A simplified analogy for paradigm is a habit of reasoning or, the box in the commonly used phrase "thinking outside the box". Thinking inside the box is analogous with normal science. The box encompasses the thinking of normal science and thus the box is analogous with paradigm. "Thinking outside the box" would be what Kuhn calls revolutionary science. Revolutionary science is usually unsuccessful, and only rarely leads to new paradigms. When they are successful they lead to large scale changes in the scientific worldview.
# Paradigm shifts
Paradigm shifts tend to be most dramatic in sciences that appear to be stable and mature, as in physics at the end of the 19th century. At that time, physics seemed to be a discipline filling in the last few details of a largely worked-out system. In 1900, Lord Kelvin famously stated, "There is nothing new to be discovered in physics now. All that remains is more and more precise measurement." Five years later, Albert Einstein published his paper on special relativity, which challenged the very simple set of rules laid down by Newtonian mechanics, which had been used to describe force and motion for over two hundred years. In this case, the new paradigm reduces the old to a special case In the sense that Newtonian mechanics is still a good model for approximation for speeds that are slow compared to the speed of light.
In The Structure of Scientific Revolutions, Kuhn wrote that "Successive transition from one paradigm to another via revolution is the usual developmental pattern of mature science." (p.12)
Kuhn's idea was itself revolutionary in its time, as it caused a major change in the way that academics talk about science. Thus, it caused or was itself part of a "paradigm shift" in the history and sociology of science.
Philosophers and historians of science, including Kuhn himself, ultimately accepted a modified version of Kuhn's model, which synthesizes his original view with the gradualist model that preceded it. Kuhn's original model is now generally seen as too limited.
Kuhn himself did not consider the concept of paradigm as appropriate for the social sciences. He explains in his preface to "The Structure of Scientific Revolutions" that he concocted the concept of paradigm precisely in order to distinguish the social from the natural sciences (p.x). He wrote this book at the Palo Alto Center for Scholars, surrounded by social scientists, when he observed that they were never in agreement on theories or concepts. He explains that he wrote this book precisely to show that there are no, nor can be, any paradigms in the social sciences. Mattei Dogan, a French sociologist, in his article "Paradigms in the Social Sciences," develops Kuhn's original thesis that there are no paradigms at all in the social sciences since the concepts are polysemic, the deliberate mutual ignorance between scholars and the proliferation of schools in these disciplines. Dogan provides many examples of the inexistance of paradigms in the social sciences in his essay, particularly in sociology, political science and political anthropology.
## Paradigm Paralysis
Perhaps the greatest barrier to a paradigm shift, in some cases, is the reality of paradigm paralysis, the inability to see beyond the current models of thinking.
Examples include Galileo's theory of a heliocentric universe, the discovery of electrostatic photography, xerography, and the quartz clock.
# Paradigm as the "Gestalt of a Weltanschauung"
Another perspective to the concept of what a paradigm is, is that a Paradigm is the Gestalt (organized whole) of the three main branches of philosophy that forms a "Weltanschauung" (German for 'Worldview')
Uses of the concept paradigm in the understanding of Kuhn and others, are mostly unclear and ambiguous analogies — ignotum per ignotius (the unknown explained by means of the more unknown), or obscurum per obscurius (the unclear explained by means of the more unclear) — to other concepts like the model.
Kuhn defines a paradigm as: “an entire constellation of beliefs, values and techniques, and so on, shared by the members of a given community”(Kuhn). This definition by Kuhn appears in the 1969 postscript to his original book, because originally the use of the term paradigm was not clearly defined. Besides this definition Kuhn mentioned another sense of use he had: a Paradigm also “denotes one sort of element in that constellation, the concrete puzzle-solutions which, employed as models or examples, can replace explicit rules as a basis for the solution of the remaining puzzles of normal science” . The term remains imprecise due to the different uses it is given.
Paradigms could be described from a structural perspective. Paradigms operate on different levels; the macro, meso and micro levels of the paradigm's structure. The levels address the fundamental structure of the paradigms, rather than its chronological-historical categorization or the etymological use, as used by most disciplines. The levels of paradigms are always present and not limited to these categories. They assist in an understanding of the functioning of a paradigm.
In the macro' level, a cognizance of the basic assumption to the question: ‘what can be understood’ is required. The question is: "Can it in reality be assumed that the essences of ideal things could be known at all, as in Plato's and Aristotle's use of the theory of ideas? Besides the essentialistic approaches of these two philosophers, is it not possible that "the things themselves reveal themselves as they are", analysed in Heidegger's fundamental ontology? The assumption we make in answering these questions will predispose the perception that determines the way we ask the question about how we come to knowledge.
In the meso level, the question is how the macro level influences and forms the resulting theory of knowledge. “Is only deductive-delimited knowledge of human perception available to man, or is man open to an inductive-comprehensive understanding of the world?”. If man is open to inductive knowledge, where does it originate? The assumption on the macro level is the basis for this assumption. All philosophical efforts since the pre-socratics are essentialistic. An ontological approach seeks to evade the essences of things, requiring the things themselves to reveal them as they are.
In the micro level, the consequent perception of the two preceding levels, answering the questions of what is in the world and how the world is understood, is used in a practical way of doing. Is the praxis built on multiple ‘laws of conduct’ (ethic), or is it a fundamental and constant encounter with the open world as a different way of perception? Such a different perception is an 'affective awareness'. Previous and current understanding of perception is limited to essentialistic categories of limitation. 'Affective awareness' is by nature open and unlimited, inductive and not limited to 'sense perception'.
So a paradigm is a view of reality that is a 'Gestalt' resulting from the three branches of philosophy; metaphysics, epistemology and ethics (see Encyclopædia Britannica: Branches of Philosophy):
(1) a metaphysical assumption of what could be known (refer to the pre-Socratics Parmenides and Heraclitus). It forms the basis for:
(2) a conception of epistemological knowledge acquisition. This is the essentialistic line of thinking essentialism from Plato, Aristotle and Popper vs. the ontological line of thinking (ontology) opened up by the 'uncertainty principle' of Heisenberg's quantum theories to Heidegger's 'Fundamental Ontology'. This in turn is the basis for the:
(3) praxis in an ethic for living.
It is obvious that the three branches of philosophy describe the structure of a paradigm. None of the branches of Metaphysics, Epistemology and Ethics can be left out for understanding paradigms. Together they describe a 'Gestalt', akin to a spiral (not a mere circular) movement, forming Hermeneutical understanding.
The result is that Hermeneutics can not be reduced to an interpretation of something in context of the text itself in a mere 'hermeneutic circle'; it is a developmental cycle that involves:
(a) "Wahrnehmung" as an 'affective awareness', which is more than mere sense perception. The method toward an affective awareness is through 'ontological understanding'. It forms the principles behind a paradigm, conceived as either the Heraclitean 'flux' (Heraclitus) or the Parmenidean 'one' (Parmenides). This principle is perceived as the relation of the limited to the unlimited. Meta-ethical 'principles', like the golden ethical rule of “Do unto others as you would like them to do unto you”, are formed here.
(b) "Verstehen" as the analysis of 'being' to reach understanding of the 'self'. Here the building of, or coming to, a theory of knowledge is achieved, determined by the assumptions in my metaphysical 'belief' of the nature of reality in (a). These assumptions necessarily tend to a predominantly inductive or mainly deductive theory of knowledge acquisition, which is reflected in my epistemology. Messo-ethical 'norms', like the sanctity of human life and freedom, are formulated at this level.
(c) "Ethos" is the attempt to form the world we live in, by growing an 'attitude' or participation in a mutually structured reality. All those who choose to participate in this reality, do it by 'taking responsibility for personal actions' in a social environment. More concrete micro-ethical 'codes of conduct', like monogamy and what we consider to be 'true and correct behaviour', is systematised into our 'dogma' at this level.
(d) "Praxis" is doing the 'right' thing. It is the behaviour resulting from systematising (a), (b) and (c) into a Gestalt, where the whole is more than the sum of the parts. This behavioural level is again the basis for "Wahrnemung", repeating the cycle on a new level. Most important is to understand that this cycle does not now start from the previous position of departure. There is a 'new awareness' of the praxis due to the previous stages in the cycle. The next cycle of "Wahrnemung" is elevated from the previous level of affective awareness to a deeper understanding. This is the basis for a new understanding of development. Development is far more than a 'mechanistic' process, by definition mechanistic processes all function and are 'essentially' closed systems. Development is by definition dependent on an inductive element. Another important point is that there is no start or end point in the cycle, every stage is on an elevated level from its previous position. Contrasted to that, a circle has a start and an end, which has actually no development; it is only a reaffirmation of what was before in a stagnant fundamentalism.
Thus, a Paradigm can only be understood in the context of a Hermeneutical cycle (rather than a Hermeneutical circle) within the Structure of the Paradigms. It supersedes mere interpretation or just bringing understanding. It implies that Paradigms are developmental by nature, moving in a hermeneutical cycle instead of a process of recurring mechanistic circles. Describing a paradigm as an era, epic, model, weltanschauung, or any other term is hardly more than merely renaming the concept of a paradigm to some other known concept, risking to be a tautological swapping of terms.
Secondary source: '"Paradigm Development in Systematic Theology"', Dissertation at the University of South Africa (UNISA) by Lando L Lehmann, Nov 2004. Description: - Direct Download when Description does not work: Template:PDFlink
# Other uses
Handa, M.L. (1986) introduced the idea of "social paradigm" in the context of social sciences. He identified the basic components of a social paradigm. Like Kuhn, Handa addressed the issue of changing paradigm; the process popularly known as "paradigm shift". In this respect, he focused on social circumstances that precipitate such a shift and the effects of the shift on the social institutions, including the institution of education. This broad shift in the social arena, in turn, changes the way the individual perceives reality.
Another use of the word paradigm is in the sense of Weltanschauung (German for world view). For example, in social science, the term is used to describe the set of experiences, beliefs and values that affect the way an individual perceives reality and responds to that perception. Social scientists have adopted the Kuhnian phrase "paradigm shift" to denote a change in how a given society goes about organizing and understanding reality. A “dominant paradigm” refers to the values, or system of thought, in a society that are most standard and widely held at a given time. Dominant paradigms are shaped both by the community’s cultural background and by the context of the historical moment. The following are conditions that facilitate a system of thought to become an accepted dominant paradigm:
- Professional organizations that give legitimacy to the paradigm
- Dynamic leaders who introduce and purport the paradigm
- Journals and editors who write about the system of thought. They both disseminate the information essential to the paradigm and give the paradigm legitimacy
- Government agencies who give credence to the paradigm
- Educators who propagate the paradigm’s ideas by teaching it to students
- Conferences conducted that are devoted to discussing ideas central to the paradigm
- Media coverage
- Lay groups, or groups based around the concerns of lay persons, that embrace the beliefs central to the paradigm
- Sources of funding to further research on the paradigm
The word paradigm is also still used to indicate a pattern or model or an outstandingly clear or typical example or archetype. The term is frequently used in this sense in the design professions. Design Paradigms or archetypes, comprise functional precedents for design solutions. The best known references on design paradigms are Design Paradigms: A Sourcebook for Creative Visualization, by Wake, and Design Paradigms by Petroski.
This term is also used in cybernetics. Here it means (in a very wide sense) a (conceptual) protoprogramme for reducing the chaotic mass to some form of order. Note the similarities to the concept of entropy in chemistry and physics. A paradigm there would be a sort of prohibition to proceed with any action that would increase the total entropy of the system. In order to create a paradigm, a closed system which would accept any changes is required. Thus a paradigm can be only applied to a system that is not in its final stage.
# Notes
- ↑ paradigm - Definition from the Merriam-Webster Online Dictionary
- ↑ Do you suffer from paradigm paralysis ? | Paradigm
# Overview
Since the late 1960s, the word paradigm (Template:IPAEng) has referred to thought pattern in any scientific discipline or other epistemological context. Initially, the word was specific to grammar: the 1900 Merriam-Webster dictionary defines its technical use only in the context of grammar or, in rhetoric, as a term for an illustrative parable or fable.
In linguistics, Ferdinand de Saussure used paradigm to refer to a class of elements with similarities. The Merriam-Webster Online dictionary defines it as "a philosophical and theoretical framework of a scientific school or discipline within which theories, laws, and generalizations and the experiments performed in support of them are formulated; broadly : a philosophical or theoretical framework of any kind.[1]
# Scientific paradigm
Historian of science Thomas Kuhn gave this word its contemporary meaning when he adopted it to refer to the set of practices that define a scientific discipline during a particular period of time. Kuhn himself came to prefer the terms exemplar and normal science, which have more exact philosophical meanings. However, in his book The Structure of Scientific Revolutions Kuhn defines a scientific paradigm as:
- what is to be observed and scrutinized
- the kind of questions that are supposed to be asked and probed for answers in relation to this subject
- how these questions are to be structured
- how the results of scientific investigations should be interpreted
Alternatively, the Oxford English Dictionary defines paradigm as "a pattern or model, an exemplar." Thus an additional component of Kuhn's definition of paradigm is:
- how is an experiment to be conducted, and what equipment is available to conduct the experiment.
Thus, within normal science, the paradigm is the set of exemplary experiments that are likely to be copied or emulated. The prevailing paradigm often represents a more specific way of viewing reality, or limitations on acceptable programs for future research, than the much more general scientific method.
An example of a currently accepted paradigm would be the standard model of physics. The scientific method would allow for orthodox scientific investigations of many phenomena which might contradict or disprove the standard model; however grant funding would be more difficult to obtain for such experiments, in proportion to the amount of departure from accepted standard model theory which the experiment would test for. For example, an experiment to test for the mass of the neutrino or decay of the proton (small departures from the model) would be more likely to receive money than experiments to look for the violation of the conservation of momentum, or ways to engineer reverse time travel.
One important aspect of Kuhn's paradigms is that the paradigms are incommensurable, which means that two paradigms can not be compared to each other. A new paradigm which replaces an old paradigm is not necessarily better, because the criteria of judgement depend on the paradigm.
A more disparaging term groupthink, and the term mindset, have very similar meanings that apply to smaller and larger scale examples of disciplined thought. Michel Foucault used the terms episteme and discourse, mathesis and taxinomia, for aspects of a "paradigm" in Kuhn's original sense.
Simple common analogy: A simplified analogy for paradigm is a habit of reasoning or, the box in the commonly used phrase "thinking outside the box". Thinking inside the box is analogous with normal science. The box encompasses the thinking of normal science and thus the box is analogous with paradigm. "Thinking outside the box" would be what Kuhn calls revolutionary science. Revolutionary science is usually unsuccessful, and only rarely leads to new paradigms. When they are successful they lead to large scale changes in the scientific worldview.[citation needed]
# Paradigm shifts
Paradigm shifts tend to be most dramatic in sciences that appear to be stable and mature, as in physics at the end of the 19th century. At that time, physics seemed to be a discipline filling in the last few details of a largely worked-out system. In 1900, Lord Kelvin famously stated, "There is nothing new to be discovered in physics now. All that remains is more and more precise measurement." Five years later, Albert Einstein published his paper on special relativity, which challenged the very simple set of rules laid down by Newtonian mechanics, which had been used to describe force and motion for over two hundred years. In this case, the new paradigm reduces the old to a special case In the sense that Newtonian mechanics is still a good model for approximation for speeds that are slow compared to the speed of light.
In The Structure of Scientific Revolutions, Kuhn wrote that "Successive transition from one paradigm to another via revolution is the usual developmental pattern of mature science." (p.12)
Kuhn's idea was itself revolutionary in its time, as it caused a major change in the way that academics talk about science. Thus, it caused or was itself part of a "paradigm shift" in the history and sociology of science.
Philosophers and historians of science, including Kuhn himself, ultimately accepted a modified version of Kuhn's model, which synthesizes his original view with the gradualist model that preceded it. Kuhn's original model is now generally seen as too limited.
Kuhn himself did not consider the concept of paradigm as appropriate for the social sciences. He explains in his preface to "The Structure of Scientific Revolutions" that he concocted the concept of paradigm precisely in order to distinguish the social from the natural sciences (p.x). He wrote this book at the Palo Alto Center for Scholars, surrounded by social scientists, when he observed that they were never in agreement on theories or concepts. He explains that he wrote this book precisely to show that there are no, nor can be, any paradigms in the social sciences. Mattei Dogan, a French sociologist, in his article "Paradigms in the Social Sciences," develops Kuhn's original thesis that there are no paradigms at all in the social sciences since the concepts are polysemic, the deliberate mutual ignorance between scholars and the proliferation of schools in these disciplines. Dogan provides many examples of the inexistance of paradigms in the social sciences in his essay, particularly in sociology, political science and political anthropology.
## Paradigm Paralysis
Perhaps the greatest barrier to a paradigm shift, in some cases, is the reality of paradigm paralysis, the inability to see beyond the current models of thinking.[2]
Examples include Galileo's theory of a heliocentric universe, the discovery of electrostatic photography, xerography, and the quartz clock.
# Paradigm as the "Gestalt of a Weltanschauung"
Another perspective to the concept of what a paradigm is, is that a Paradigm is the Gestalt (organized whole) of the three main branches of philosophy that forms a "Weltanschauung" (German for 'Worldview')
Uses of the concept paradigm in the understanding of Kuhn and others, are mostly unclear and ambiguous analogies — ignotum per ignotius (the unknown explained by means of the more unknown), or obscurum per obscurius (the unclear explained by means of the more unclear) — to other concepts like the model.
Kuhn defines a paradigm as: “an entire constellation of beliefs, values and techniques, and so on, shared by the members of a given community”(Kuhn). This definition by Kuhn appears in the 1969 postscript to his original book, because originally the use of the term paradigm was not clearly defined. Besides this definition Kuhn mentioned another sense of use he had: a Paradigm also “denotes one sort of element in that constellation, the concrete puzzle-solutions which, employed as models or examples, can replace explicit rules as a basis for the solution of the remaining puzzles of normal science” [Ibid]. The term remains imprecise due to the different uses it is given.
Paradigms could be described from a structural perspective. Paradigms operate on different levels; the macro, meso and micro levels of the paradigm's structure. The levels address the fundamental structure of the paradigms, rather than its chronological-historical categorization or the etymological use, as used by most disciplines. The levels of paradigms are always present and not limited to these categories. They assist in an understanding of the functioning of a paradigm.
In the macro' level, a cognizance of the basic assumption to the question: ‘what can be understood’ is required. The question is: "Can it in reality be assumed that the essences of ideal things could be known at all, as in Plato's and Aristotle's use of the theory of ideas? Besides the essentialistic approaches of these two philosophers, is it not possible that "the things themselves reveal themselves as they are", analysed in Heidegger's fundamental ontology? The assumption we make in answering these questions will predispose the perception that determines the way we ask the question about how we come to knowledge.
In the meso level, the question is how the macro level influences and forms the resulting theory of knowledge. “Is only deductive-delimited knowledge of human perception available to man, or is man open to an inductive-comprehensive understanding of the world?”. If man is open to inductive knowledge, where does it originate? The assumption on the macro level is the basis for this assumption. All philosophical efforts since the pre-socratics are essentialistic. An ontological approach seeks to evade the essences of things, requiring the things themselves to reveal them as they are.
In the micro level, the consequent perception of the two preceding levels, answering the questions of what is in the world and how the world is understood, is used in a practical way of doing. Is the praxis built on multiple ‘laws of conduct’ (ethic), or is it a fundamental and constant encounter with the open world as a different way of perception? Such a different perception is an 'affective awareness'. Previous and current understanding of perception is limited to essentialistic categories of limitation. 'Affective awareness' is by nature open and unlimited, inductive and not limited to 'sense perception'.
So a paradigm is a view of reality that is a 'Gestalt' resulting from the three branches of philosophy; metaphysics, epistemology and ethics (see Encyclopædia Britannica: Branches of Philosophy):
(1) a metaphysical assumption of what could be known (refer to the pre-Socratics Parmenides and Heraclitus). It forms the basis for:
(2) a conception of epistemological knowledge acquisition. This is the essentialistic line of thinking essentialism from Plato, Aristotle and Popper vs. the ontological line of thinking (ontology) opened up by the 'uncertainty principle' of Heisenberg's quantum theories to Heidegger's 'Fundamental Ontology'. This in turn is the basis for the:
(3) praxis in an ethic for living.
It is obvious that the three branches of philosophy describe the structure of a paradigm. None of the branches of Metaphysics, Epistemology and Ethics can be left out for understanding paradigms. Together they describe a 'Gestalt', akin to a spiral (not a mere circular) movement, forming Hermeneutical understanding.
The result is that Hermeneutics can not be reduced to an interpretation of something in context of the text itself in a mere 'hermeneutic circle'; it is a developmental cycle that involves:
(a) "Wahrnehmung" as an 'affective awareness', which is more than mere sense perception. The method toward an affective awareness is through 'ontological understanding'. It forms the principles behind a paradigm, conceived as either the Heraclitean 'flux' (Heraclitus) or the Parmenidean 'one' (Parmenides). This principle is perceived as the relation of the limited to the unlimited. Meta-ethical 'principles', like the golden ethical rule of “Do unto others as you would like them to do unto you”, are formed here.
(b) "Verstehen" as the analysis of 'being' to reach understanding of the 'self'. Here the building of, or coming to, a theory of knowledge is achieved, determined by the assumptions in my metaphysical 'belief' of the nature of reality in (a). These assumptions necessarily tend to a predominantly inductive or mainly deductive theory of knowledge acquisition, which is reflected in my epistemology. Messo-ethical 'norms', like the sanctity of human life and freedom, are formulated at this level.
(c) "Ethos" is the attempt to form the world we live in, by growing an 'attitude' or participation in a mutually structured reality. All those who choose to participate in this reality, do it by 'taking responsibility for personal actions' in a social environment. More concrete micro-ethical 'codes of conduct', like monogamy and what we consider to be 'true and correct behaviour', is systematised into our 'dogma' at this level.
(d) "Praxis" is doing the 'right' thing. It is the behaviour resulting from systematising (a), (b) and (c) into a Gestalt, where the whole is more than the sum of the parts. This behavioural level is again the basis for "Wahrnemung", repeating the cycle on a new level. Most important is to understand that this cycle does not now start from the previous position of departure. There is a 'new awareness' of the praxis due to the previous stages in the cycle. The next cycle of "Wahrnemung" is elevated from the previous level of affective awareness to a deeper understanding. This is the basis for a new understanding of development. Development is far more than a 'mechanistic' process, by definition mechanistic processes all function and are 'essentially' closed systems. Development is by definition dependent on an inductive element. Another important point is that there is no start or end point in the cycle, every stage is on an elevated level from its previous position. Contrasted to that, a circle has a start and an end, which has actually no development; it is only a reaffirmation of what was before in a stagnant fundamentalism.
Thus, a Paradigm can only be understood in the context of a Hermeneutical cycle (rather than a Hermeneutical circle) within the Structure of the Paradigms. It supersedes mere interpretation or just bringing understanding. It implies that Paradigms are developmental by nature, moving in a hermeneutical cycle instead of a process of recurring mechanistic circles. Describing a paradigm as an era, epic, model, weltanschauung, or any other term is hardly more than merely renaming the concept of a paradigm to some other known concept, risking to be a tautological swapping of terms.
Secondary source: '"Paradigm Development in Systematic Theology"', Dissertation at the University of South Africa (UNISA) by Lando L Lehmann, Nov 2004. Description:[1] - Direct Download when Description does not work: Template:PDFlink
# Other uses
Handa, M.L. (1986) introduced the idea of "social paradigm" in the context of social sciences. He identified the basic components of a social paradigm. Like Kuhn, Handa addressed the issue of changing paradigm; the process popularly known as "paradigm shift". In this respect, he focused on social circumstances that precipitate such a shift and the effects of the shift on the social institutions, including the institution of education. This broad shift in the social arena, in turn, changes the way the individual perceives reality.
Another use of the word paradigm is in the sense of Weltanschauung (German for world view). For example, in social science, the term is used to describe the set of experiences, beliefs and values that affect the way an individual perceives reality and responds to that perception. Social scientists have adopted the Kuhnian phrase "paradigm shift" to denote a change in how a given society goes about organizing and understanding reality. A “dominant paradigm” refers to the values, or system of thought, in a society that are most standard and widely held at a given time. Dominant paradigms are shaped both by the community’s cultural background and by the context of the historical moment. The following are conditions that facilitate a system of thought to become an accepted dominant paradigm:
- Professional organizations that give legitimacy to the paradigm
- Dynamic leaders who introduce and purport the paradigm
- Journals and editors who write about the system of thought. They both disseminate the information essential to the paradigm and give the paradigm legitimacy
- Government agencies who give credence to the paradigm
- Educators who propagate the paradigm’s ideas by teaching it to students
- Conferences conducted that are devoted to discussing ideas central to the paradigm
- Media coverage
- Lay groups, or groups based around the concerns of lay persons, that embrace the beliefs central to the paradigm
- Sources of funding to further research on the paradigm
The word paradigm is also still used to indicate a pattern or model or an outstandingly clear or typical example or archetype. The term is frequently used in this sense in the design professions. Design Paradigms or archetypes, comprise functional precedents for design solutions. The best known references on design paradigms are Design Paradigms: A Sourcebook for Creative Visualization, by Wake, and Design Paradigms by Petroski.
This term is also used in cybernetics. Here it means (in a very wide sense) a (conceptual) protoprogramme for reducing the chaotic mass to some form of order. Note the similarities to the concept of entropy in chemistry and physics. A paradigm there would be a sort of prohibition to proceed with any action that would increase the total entropy of the system. In order to create a paradigm, a closed system which would accept any changes is required. Thus a paradigm can be only applied to a system that is not in its final stage.
# Notes
- ↑ paradigm - Definition from the Merriam-Webster Online Dictionary
- ↑ Do you suffer from paradigm paralysis ? | https://www.wikidoc.org/index.php/Paradigm | |
c56675076c805b55562f99c260e4cebf2b93931e | wikidoc | Paraffin | Paraffin
# Overview
In chemistry, paraffin is the common name for the alkane hydrocarbons with the general formula CnH2n+2. Paraffin wax refers to the solids with n=20–40.
The simplest paraffin molecule is that of methane, CH4, a gas at room temperature. Heavier members of the series, such as that of octane C8H18, appear as liquids at room temperature. The solid forms of paraffin, called paraffin wax, are from the heaviest molecules from C20 to C40. Paraffin wax was identified by Carl Reichenbach in 1830.
Paraffin, or paraffin hydrocarbon, is also the technical name for an alkane in general, but in most cases it refers specifically to a linear, or normal alkane — whereas branched, or isoalkanes are also called isoparaffins. It is distinct from the fuel known in Britain and South Africa as paraffin oil or just paraffin, which is called kerosene in much of the U.S., Australia and New Zealand.
The name is derived from the Latin parum (= barely) + affinis with the meaning here of "lacking affinity", or "lacking reactivity". This is because alkanes, being non-polar and lacking in functional groups, are very unreactive.
# Wax
Paraffin wax (or simply "paraffin", but see alternative name for kerosene, above) is mostly found as a white, odorless, tasteless, waxy solid, with a typical melting point between about 47 °C to 64 °C, and having a density of around 0.9 g/cm3. It is insoluble in water, but soluble in ether, benzene, and certain esters. Paraffin is unaffected by most common chemical reagents, but burns readily.
Pure paraffin wax is an excellent electrical insulator, with an electrical resistivity of between 10^{13} and 10^{17} ohm metre. This is better than nearly all other materials except some plastics (notably teflon). It is an effective neutron moderator and was used in James Chadwick's 1932 experiments to identify the neutron.
Paraffin wax (C25H52) is an excellent material to store heat, having a specific heat capacity of 2.14–2.9 J g–1 K–1 (joule per gram per kelvin) and a heat of fusion of 200–220 J g–1. This property is exploited in modified sheetrock for home building material: it is infused in the sheetrock during manufacture so as, when installed, it melts during the day, absorbing heat, and solidifies again at night, releasing the heat. Wax expands considerably when it melts and this allows its use in thermostats for industrial, domestic and, particularly, automobile purposes.
Pure paraffin wax is rarely used for carving original models for casting metal and other materials in the lost wax process, as it is relatively brittle at room temperature and presents the risks of chipping and breakage when worked. Soft and pliable waxes, like beeswax, may be preferred for such sculpture, but "investment casting waxes," often paraffin-based, are expressly formulated for the purpose.
In industrial applications, it is often useful to modify the crystal properties of the paraffin wax, typically by adding branching to the existing carbon backbone chain. The modification is usually done with additives, such as EVA copolymers, microcrystalline wax, or forms of polyethylene. The branched properties result in a modified paraffin with a higher viscosity, smaller crystalline structure, and modified functional properties.
# Mineral oil
Liquid paraffin, or mineral oil, is a mixture of heavier alkanes, and has a number of names, including nujol, adepsine oil, alboline, glymol, medicinal paraffin, saxol, or USP mineral oil. It has a density of around 0.8 g/cm3. Liquid paraffin (medicinal) is used to aid bowel movement in persons suffering chronic constipation; it passes through the alimentary canal without itself being taken into the body, but it limits the amount of water removed from the stool. In the food industry, where it may be called "wax", it can be used as a lubricant in mechanical mixing, applied to baking tins to ensure that loaves are easily released when cooked and as a coating for fruit or other items requiring a "shiny" appearance for sale. It is often used in infrared spectroscopy, as it has a relatively uncomplicated IR spectrum. When the sample to be tested is made into a mull (a very thick paste), liquid paraffin is added so it can be spread on the transparent (to infrared) mounting plates to be tested.
# Uses
## Gaseous
- Fuels
## Liquids
- Fuels
- Medicine (Laxative)
- Culinary
- Fire breathing
- Used in toiletries and cosmetics as a moisturiser or emollient.
## Paraffin wax
- Candle-making
- Coatings for waxed paper or cloth
- Food-grade paraffin wax:
Shiny coating used in candy-making; although edible, it is nondigestible, passing right through the body without being broken down
Coating for many kinds of hard cheese, like Edam cheese.
Sealant for jars, cans, and bottles
Chewing gum additive
- Shiny coating used in candy-making; although edible, it is nondigestible, passing right through the body without being broken down
- Coating for many kinds of hard cheese, like Edam cheese.
- Sealant for jars, cans, and bottles
- Chewing gum additive
- Investment casting
- Anti-caking agent, moisture repellent, and dustbinding coatings for fertilizers
- Agent for preparation of specimens for histology
- Bullet lubricant - with other ingredients, such as olive oil and beeswax
- Solid propellant for hybrid rocket motors
- Component of surfwax, used for grip on surfboards in surfing
- Component of glide wax, used on skis and snowboards.
- Friction-reducer, for use on handrails and cement ledges, commonly used in skateboarding
- Microwax: food additive, a glazing agent with E number E905
- Forensics aid: the nitrate test uses paraffin wax to detect nitrates and nitrites on the hand of a shooting suspect
- Anti-ozonant agent: blends of paraffin and micro waxes are used in rubber compounds to prevent cracking of the rubber; the antiozonant waxes can be produced from synthetic waxes, FT wax, and Fischer Tropsch wax
- Mechanical thermostats and actuators, as an expansion medium for activating such devices.
- "Potting" guitar pickups, which reduce microphonic feedback caused from the subtle movements of the pole pieces
- Wax baths for beauty and therapy purposes
- Thickening agent in many Paintballs, as used by Crayola
- An effective, although comedogenic, moisturiser in toiletries and cosmetics such as Vaseline.
- Prevents oxidation on the surface of polished steel and iron | Paraffin
# Overview
In chemistry, paraffin is the common name for the alkane hydrocarbons with the general formula CnH2n+2. Paraffin wax refers to the solids with n=20–40.
The simplest paraffin molecule is that of methane, CH4, a gas at room temperature. Heavier members of the series, such as that of octane C8H18, appear as liquids at room temperature. The solid forms of paraffin, called paraffin wax, are from the heaviest molecules from C20 to C40. Paraffin wax was identified by Carl Reichenbach in 1830.[1]
Paraffin, or paraffin hydrocarbon, is also the technical name for an alkane in general, but in most cases it refers specifically to a linear, or normal alkane — whereas branched, or isoalkanes are also called isoparaffins. It is distinct from the fuel known in Britain and South Africa as paraffin oil or just paraffin, which is called kerosene in much of the U.S., Australia and New Zealand.
The name is derived from the Latin parum (= barely) + affinis with the meaning here of "lacking affinity", or "lacking reactivity". This is because alkanes, being non-polar and lacking in functional groups, are very unreactive.
# Wax
Paraffin wax (or simply "paraffin", but see alternative name for kerosene, above) is mostly found as a white, odorless, tasteless, waxy solid, with a typical melting point between about 47 °C to 64 °C, and having a density of around 0.9 g/cm3.[2] It is insoluble in water, but soluble in ether, benzene, and certain esters. Paraffin is unaffected by most common chemical reagents, but burns readily.
Pure paraffin wax is an excellent electrical insulator, with an electrical resistivity of between <math>10^{13}</math> and <math>10^{17}</math> ohm metre.[3] This is better than nearly all other materials except some plastics (notably teflon). It is an effective neutron moderator and was used in James Chadwick's 1932 experiments to identify the neutron.[4][5]
Paraffin wax (C25H52) is an excellent material to store heat, having a specific heat capacity of 2.14–2.9 J g–1 K–1 (joule per gram per kelvin) and a heat of fusion of 200–220 J g–1.[6] This property is exploited in modified sheetrock for home building material: it is infused in the sheetrock during manufacture so as, when installed, it melts during the day, absorbing heat, and solidifies again at night, releasing the heat. Wax expands considerably when it melts and this allows its use in thermostats for industrial, domestic and, particularly, automobile purposes.[7]
Pure paraffin wax is rarely used for carving original models for casting metal and other materials in the lost wax process, as it is relatively brittle at room temperature and presents the risks of chipping and breakage when worked. Soft and pliable waxes, like beeswax, may be preferred for such sculpture, but "investment casting waxes," often paraffin-based, are expressly formulated for the purpose.
In industrial applications, it is often useful to modify the crystal properties of the paraffin wax, typically by adding branching to the existing carbon backbone chain. The modification is usually done with additives, such as EVA copolymers, microcrystalline wax, or forms of polyethylene. The branched properties result in a modified paraffin with a higher viscosity, smaller crystalline structure, and modified functional properties.
# Mineral oil
Liquid paraffin, or mineral oil, is a mixture of heavier alkanes, and has a number of names, including nujol, adepsine oil, alboline, glymol, medicinal paraffin, saxol, or USP mineral oil. It has a density of around 0.8 g/cm3.[2] Liquid paraffin (medicinal) is used to aid bowel movement in persons suffering chronic constipation; it passes through the alimentary canal without itself being taken into the body, but it limits the amount of water removed from the stool. In the food industry, where it may be called "wax", it can be used as a lubricant in mechanical mixing, applied to baking tins to ensure that loaves are easily released when cooked and as a coating for fruit or other items requiring a "shiny" appearance for sale.[8] It is often used in infrared spectroscopy, as it has a relatively uncomplicated IR spectrum. When the sample to be tested is made into a mull (a very thick paste), liquid paraffin is added so it can be spread on the transparent (to infrared) mounting plates to be tested.
# Uses
## Gaseous
- Fuels
## Liquids
- Fuels
- Medicine (Laxative)
- Culinary
- Fire breathing
- Used in toiletries and cosmetics as a moisturiser or emollient.
## Paraffin wax
- Candle-making
- Coatings for waxed paper or cloth
- Food-grade paraffin wax:
Shiny coating used in candy-making; although edible, it is nondigestible, passing right through the body without being broken down
Coating for many kinds of hard cheese, like Edam cheese.
Sealant for jars, cans, and bottles
Chewing gum additive
- Shiny coating used in candy-making; although edible, it is nondigestible, passing right through the body without being broken down
- Coating for many kinds of hard cheese, like Edam cheese.
- Sealant for jars, cans, and bottles
- Chewing gum additive
- Investment casting
- Anti-caking agent, moisture repellent, and dustbinding coatings for fertilizers
- Agent for preparation of specimens for histology
- Bullet lubricant - with other ingredients, such as olive oil and beeswax
- Solid propellant for hybrid rocket motors
- Component of surfwax, used for grip on surfboards in surfing
- Component of glide wax, used on skis and snowboards.
- Friction-reducer, for use on handrails and cement ledges, commonly used in skateboarding
- Microwax[1]: food additive, a glazing agent with E number E905
- Forensics aid: the nitrate test uses paraffin wax to detect nitrates and nitrites on the hand of a shooting suspect
- Anti-ozonant agent: blends of paraffin and micro waxes are used in rubber compounds to prevent cracking of the rubber; the antiozonant waxes can be produced from synthetic waxes, FT wax, and Fischer Tropsch wax
- Mechanical thermostats and actuators, as an expansion medium for activating such devices.[9]
- "Potting" guitar pickups, which reduce microphonic feedback caused from the subtle movements of the pole pieces
- Wax baths for beauty and therapy purposes
- Thickening agent in many Paintballs, as used by Crayola
- An effective, although comedogenic, moisturiser in toiletries and cosmetics such as Vaseline.
- Prevents oxidation on the surface of polished steel and iron[10] | https://www.wikidoc.org/index.php/Paraffin | |
a230020571406c35ce97f3be031b6d88c5c445e8 | wikidoc | Paragard | Paragard
The ParaGard T-380A is a copper-T IUD manufactured and marketed in the United States by Duramed Pharmaceuticals. It is the only copper-containing intrauterine device approved for use in the U.S. (a hormonal uterine device, the Mirena, also approved). The ParaGard consists of a T-shaped polyethylene frame wound with copper wire, along with two monofilament threads to aid in removal of the IUD. The ParaGard is typically inserted and removed under local anesthesia in a gynecologist's office. The ParaGard is currently approved for 10 years use, however the newest data shows it actually remains effective for at least 12 years, and perhaps beyond, after which it should be removed and replaced if desired. The ParaGard can be used as a form of emergency contraception if inserted within three to five days after unprotected intercourse, and it can be inserted directly after childbirth or abortion.
Like all (non-hormonal) IUDs, the ParaGard prompts the release of leukocytes and prostaglandins by the endometrium. These substances are hostile to both sperm and eggs; the presence of copper increases this spermicidal effect. Although the only experimentally demonstrated effect is spermicidal/ovicidal, it is possible the IUD may rarely prevent the development of embryos.
The ParaGard's perfect and typical use effectiveness rate is 99.4%. First year expulsion rate is 5.7%, with expulsion rates dropping off sharply after the first year. There is a higher risk of expulsion for women who have never given birth. Side effects can include heavier or longer periods, worsening cramps and may include a slightly increased risk of PID.
The ParaGard T 380A was developed in the 1970s by the Population Council and Finishing Enterprises Inc. (FEI). The Population Council's ParaGard NDA was approved by the FDA and FEI began manufacturing it for distribution outside the United States in 1984. GynoPharma (original name GynoMed) began marketing it in the U.S. in May 1988. On August 2, 1995, Ortho-McNeil acquired GynoPharma and began marketing ParaGard in the U.S. On January 1, 2004, FEI Women's Health acquired the patent from the Population Council and U.S. marketing rights from Ortho-McNeil. On November 10, 2005, Durmaed Pharmaceuticals, a subsidiary of Barr Pharmaceuticals, acquired FEI Women's Health and ParaGard.
The original FDA approval of ParaGard in 1984 was for 4 years continuous use, this was later extended to 6 years in 1989, then 8 years in 1991, then 10 years in 1994. | Paragard
The ParaGard T-380A is a copper-T IUD manufactured and marketed in the United States by Duramed Pharmaceuticals. It is the only copper-containing intrauterine device approved for use in the U.S. (a hormonal uterine device, the Mirena, also approved). The ParaGard consists of a T-shaped polyethylene frame wound with copper wire, along with two monofilament threads to aid in removal of the IUD. The ParaGard is typically inserted and removed under local anesthesia in a gynecologist's office. The ParaGard is currently approved for 10 years use, however the newest data shows it actually remains effective for at least 12 years, and perhaps beyond, after which it should be removed and replaced if desired. The ParaGard can be used as a form of emergency contraception if inserted within three to five days after unprotected intercourse, and it can be inserted directly after childbirth or abortion.
Like all (non-hormonal) IUDs, the ParaGard prompts the release of leukocytes and prostaglandins by the endometrium. These substances are hostile to both sperm and eggs; the presence of copper increases this spermicidal effect. Although the only experimentally demonstrated effect is spermicidal/ovicidal, it is possible the IUD may rarely prevent the development of embryos.[1][2]
The ParaGard's perfect and typical use effectiveness rate is 99.4%. First year expulsion rate is 5.7%, with expulsion rates dropping off sharply after the first year. There is a higher risk of expulsion for women who have never given birth. Side effects can include heavier or longer periods, worsening cramps and may include a slightly increased risk of PID.
The ParaGard T 380A was developed in the 1970s by the Population Council and Finishing Enterprises Inc. (FEI). The Population Council's ParaGard NDA was approved by the FDA and FEI began manufacturing it for distribution outside the United States in 1984. GynoPharma (original name GynoMed) began marketing it in the U.S. in May 1988. On August 2, 1995, Ortho-McNeil acquired GynoPharma and began marketing ParaGard in the U.S. On January 1, 2004, FEI Women's Health acquired the patent from the Population Council and U.S. marketing rights from Ortho-McNeil. On November 10, 2005, Durmaed Pharmaceuticals, a subsidiary of Barr Pharmaceuticals, acquired FEI Women's Health and ParaGard.
The original FDA approval of ParaGard in 1984 was for 4 years continuous use, this was later extended to 6 years in 1989, then 8 years in 1991, then 10 years in 1994.
# External links
- ParaGard T 380A Intrauterine Copper Contraceptive]
- ParaGard T 380A Patient Package Insert
- FEI Women's Health ParaGard T 380A Timeline | https://www.wikidoc.org/index.php/Paragard | |
1744f0667dbb13d95d367b4bea55ef785910a950 | wikidoc | Parallax | Parallax
Parallax, more accurately motion parallax, is the change of angular position of two observations of a single object relative to each other as seen by an observer, caused by the motion of the observer. Simply put, it is the apparent shift of an object against the background that is caused by a change in the observer's position. The term is derived from the Greek παραλλαγή (parallagé), meaning "alteration".
Parallax is often thought of as the 'apparent motion' of an object against a distant background because of a perspective shift, as seen in Figure 1. When viewed from Viewpoint A, the object appears to be closer to the blue square. When the viewpoint is changed to Viewpoint B, the object appears to have moved in front of the red square.
In astronomy, parallax is the only direct method by which distances to objects beyond the Solar System can be measured. The Hipparcos satellite has used the technique for over 100,000 nearby stars. This provides the basis for all other distance measurements in astronomy, the cosmic distance ladder.
# Use in distance measurement
By observing parallax, measuring angles and using geometry, one can determine the distance to various objects. When the object in question is a star, the effect is known as stellar parallax. The first successful measurements of stellar parallax were made by Friedrich Bessel in 1838, for the star 61 Cygni.
Distance measurement by parallax is a special case of the principle of triangulation, which states that one can solve for all the sides and angles in a network of triangles if, in addition to all the angles in the network, the length of at least one side has been measured. Thus, the careful measurement of the length of one baseline can fix the scale of an entire triangulation network. In parallax, the triangle is extremely long and narrow, and by measuring both its shortest side (the motion of the observer) and the small top angle (the other two being close to 90 degrees), the length of the long sides (in practice considered to be equal) can be determined.
## Parallax error
Precise parallax measurements of distance usually have an associated error. Thus a parallax may be described as some angle ± some angle-error. However this "± angle-error" does not translate directly into a ± error for the range, except for relatively small errors. The reason for this is that an error toward a smaller angle results in a greater error in distance than an error toward a larger angle.
However, an approximation of the distance error can be computed by means of the following:
where d is the distance and p is the parallax. The approximation is far more accurate for parallax errors that are small relative to the parallax than for relatively large errors.
## Parallax error in photography
Parallax error can be seen when taking photos with many types of cameras, such as twin-lens reflex cameras and those including viewfinders (such as rangefinder cameras). In such cameras, the eye sees the subject through different optics (the viewfinder, or a second lens) than the one through which the photo is taken. As the viewfinder is often found above the lens of the camera, photos with parallax error are often slightly lower than intended, the classic example being the image of person with his or her head cropped off. This problem is addressed in single-lens reflex cameras, in which the viewfinder sees through the same lens through which the photo is taken (with the aid of a movable mirror), thus avoiding parallax error.
# Parallax and measurement instruments
If an optical instrument — e.g., a telescope, microscope, or theodolite — is imprecisely focused, its cross-hairs will appear to move with respect to the object focused on if one moves one's head horizontally in front of the eyepiece. This is why it is important, especially when performing measurements, to focus carefully in order to eliminate the parallax, and to check by moving one's head.
Also, in non-optical measurements the thickness of a ruler can create parallax in fine measurements. One is always cautioned in science classes to "avoid parallax." This means that one should always take measurements with one's eye on a line directly perpendicular to the ruler, so that the thickness of the ruler does not create error in positioning for fine measurements. A similar error can occur when reading the position of a pointer against a scale in an instrument such as a galvanometer. To help the user avoid this problem, the scale is sometimes printed above a narrow strip of mirror, and the user positions his eye so that the pointer obscures its own reflection. This guarantees that the user's line of sight is perpendicular to the mirror and therefore to the scale.
# Photogrammetric parallax
Aerial picture pairs, when viewed through a stereo viewer, offer a pronounced stereo effect of landscape and buildings. High buildings appear to 'keel over' in the direction away from the centre of the photograph. Measurements of this parallax are used to deduce the height of the buildings, provided that flying height and baseline distances are known. This is a key component to the process of photogrammetry.
# Lunar parallax
Lunar parallax involves the arithmetic of parallel stars between two inverted axes which rotate in angles that are only visible by the moon.
Jules Verne, in From the Earth to the Moon, wrote:
"Up till then, many people had no idea how one could calculate the distance separating the Moon from the Earth. The circumstance was exploited to teach them that this distance was obtained by measuring the parallax of the Moon. If the word parallax appeared to amaze them, they were told that it was the angle subtended by two straight lines running from both ends of the Earth's radius to the Moon. If they had doubts on the perfection of this method, they were immediately shown that not only did this mean distance amount to a whole two hundred thirty-four thousand three hundred and forty-seven miles (94,330 leagues), but also that the astronomers were not in error by more than seventy miles (≈ 30 leagues)."
A primitive way to determine the lunar parallax from one location is by using a lunar eclipse. The full shadow of the Earth on the Moon has an apparent radius of curvature equal to the difference between the apparent radii of the Earth and the Sun as seen from the Moon. This radius can be seen to be equal to 0.75 degree, from which (with the solar apparent radius 0.25 degree) we get an Earth apparent radius of 1 degree. This yields for the Earth-Moon distance 60 Earth radii or 384,000 km. This procedure was first used by Aristarchus of Samos and Hipparchus, and later found its way into the work of Ptolemy.
Another way to use parallax to determine the distance to the Moon would be to take two pictures of the Moon at exactly the same time from two locations on Earth, and compare the position of the Moon relative to the visible stars. Using the orientation of the Earth, and those two points, and a perpendicular displacement, a distance to the Moon can be triangulated.
# Solar parallax
After Copernicus proposed his heliocentric system, with the Earth in revolution around the Sun, it was possible to build a scale model of the whole solar system, but without the scale. To ascertain the scale, it is necessary only to measure one distance within the solar system, e.g., the mean distance from the Earth to the Sun (now called an astronomical unit, or AU). When found by triangulation, this is referred to as the solar parallax, the difference in position of the Sun as seen from the Earth's centre and a point one Earth radius away, i.e., the angle subtended at the Sun by the Earth's mean radius. Knowing the solar parallax and the mean Earth radius allows one to calculate the AU, the first, small step on the long road of establishing the size — and thus, according to Big Bang theory, the minimum age — of the visible Universe.
A primitive way to determine the distance to the Sun in terms of the distance to the Moon was already proposed by Aristarchus of Samos in his book On the Sizes and Distances of the Sun and Moon. He argued that the Sun, Moon, and Earth form a right triangle (right angle at the Moon) at the moment of first or last quarter moon. He then estimated that the Moon, Earth, Sun angle was 87°. Using correct geometry but inaccurate observational data, Aristarchus concluded that the Sun was slightly less than 20 times farther away than the Moon. The true value of this angle is close to 89° 50', and the Sun is actually about 390 times farther away. He pointed out that the Moon and Sun have nearly equal apparent angular sizes and therefore their diameters must be in proportion to their distances from Earth. He thus concluded that the Sun was around 20 times larger than the Moon; this conclusion, although incorrect, follows logically from his incorrect data. It does suggest that the Sun is clearly larger than the Earth, which could be taken to support the heliocentric model. Although these results were incorrect due to observational errors, they were based on correct geometric principles of parallax, and became the basis for estimates of the size of the solar system for almost 2000 years, until the transit of Venus was correctly observed in 1761 and 1769.
This method was proposed by Edmond Halley in 1716 , although he did not live to see the results.
The use of Venus transits was less successful than had been hoped due to the black drop effect, but the resulting estimate, 153 million kilometers, is just 2% over the currently accepted value, 149.6 million kilometers.
Much later, the solar system was 'scaled' using the parallax of asteroids, some of which, like Eros, pass much
closer to Earth than Venus. In a favourable opposition, Eros can approach the Earth to within 22 million kilometres. Both the
-pposition of 1901 and that of 1930/1931 were used for this purpose, the calculations of the latter determination being completed by
Astronomer Royal Sir Harold Spencer Jones.
Also radar reflections, both off Venus (1958) and off asteroids, like Icarus, have been used for solar parallax
determination. Today, use of spacecraft telemetry links has solved this old problem completely.
# Stellar parallax
On an interstellar scale, parallax created by the different orbital positions of the Earth causes nearby stars to appear to move relative to more distant stars. However, this effect is so small it is undetectable without extremely precise measurements.
The annual parallax is defined as the difference in position of a star as seen from the Earth and Sun, i.e. the angle subtended at a star by the mean radius of the Earth's orbit around the Sun. Given two points on opposite sides of the orbit, the parallax is half the maximum parallactic shift evident from the star viewed from the two points. The parsec is defined the distance for which the annual parallax is 1 arcsecond. A parsec equals 3.26 light years.
The distance of an object (in parsecs) can be roughly computed as the reciprocal of the parallax. For instance, the Hipparcos satellite measured the parallax of the nearest star, Proxima Centauri, as 0.77233 seconds of arc (±.00242"). Therefore, the distance is 1/0.772=1.29 parsecs or about 4.22 light years (±.01 ly).
The angles involved in these calculations are very small. For example, 0.772 arcseconds is approximately the angle subtended by an object about 2 centimeters in diameter (roughly the size of a U.S. quarter dollar) located about 5.3 kilometers away.
## Computation
The parallax p = \frac {1 AU} {d} \cdot 180 \cdot \frac {3600} {\pi} in arc seconds
where
Picking a good unit of measure will cancel the constants.
Derivation:
The fact that stellar parallax was so small that it was unobservable at the time was used as the main scientific argument against heliocentrism during the early modern age. It is clear from Euclid's geometry that the effect would be undetectable if the stars were far enough away; but for various reasons such a gigantic size seemed entirely implausible.
Measurement of the annual parallax as the earth goes through its orbit was the first reliable way to determine the distances to the closest stars. This method was first successfully used by Friedrich Wilhelm Bessel in 1838 when he measured the distance to 61 Cygni with a heliometer, and it remains the standard for calibrating other measurement methods (after the size of the orbit of the earth is measured by radar reflection of other planets).
In 1989, the satellite 'Hipparcos' was launched primarily for obtaining parallaxes and proper motions of nearby stars, increasing the reach of the method tenfold. Even so, Hipparcos is only able to measure parallax angles for stars up to about 1,600 light-years away — a little more than one percent of the diameter of our galaxy.
# Dynamic or moving-cluster parallax
The open stellar cluster Hyades in Taurus extends over such a large part of the sky, 20 degrees, that the proper motions as derived from astrometry appear to converge with some precision to a perspective point north of Orion. Combining the observed apparent (angular) proper motion in seconds of arc with the also observed true (absolute) receding motion as witnessed by the Doppler redshift of the stellar spectral lines, allows estimation of the distance to the cluster (151 light years) and its member stars in much the same way as using annual parallax.
Dynamic parallax has sometimes also been used to determine the distance to a supernova, when the optical wave front of the outburst is seen to propagate through the surrounding dust clouds at an apparent angular velocity, while its true propagation velocity is known be the speed of light.
# In computer graphics
In many early graphical applications, such as video games, the scene was constructed of independent layers that were scrolled at different speeds when the player/cursor moved. Some hardware had explicit support for such layers, such as the Super Nintendo Entertainment System. This gave some layers the appearance of being farther away than others and was useful for creating an illusion of depth, but only worked when the player was moving. Now, most games are based on much more comprehensive three-dimensional graphic models, although portable game (DS, PSP) systems still often use parallax.
# As a metaphor
In a philosophic/geometric sense: An apparent change in the direction of an object, caused by a change in observational position that
provides a new line of sight. The apparent displacement, or difference of position, of an object, as seen from two different stations, or points of view. In contemporary writing parallax can also be the same story, or a similar story from approximately the same time line, from one book told from a different perspective in another book. The word and concept feature prominently in James Joyce's 1922 novel, Ulysses. Orson Scott Card also used the term when referring to Ender's Shadow as compared to Ender's Game.
The metaphor is also invoked in the magnum opus of Slovenian philosopher Slavoj Žižek in his work 'The Parallax View'. "The philosophical twist to be added ((to parallax)), of course, is that the observed distance is not simply subjective, since the same object which exists 'out there' is seen from two different stances, or points of view. It is rather that, as Hegel would have put it, subject and object are inherently mediated so that an 'epistemological' shift in the subject's point of view always reflects an ontological shift in the object itself. Or -to put it in Lacanese- the subject's gaze is always-already inscribed into the perceived object itself, in the guise of its 'blind spot,' that which is 'in the object more than object itself', the point from which the object itself returns the gaze. Sure the picture is in my eye, but I am also in the picture." | Parallax
Parallax, more accurately motion parallax, is the change of angular position of two observations of a single object relative to each other as seen by an observer, caused by the motion of the observer. Simply put, it is the apparent shift of an object against the background that is caused by a change in the observer's position. The term is derived from the Greek παραλλαγή (parallagé), meaning "alteration".
Parallax is often thought of as the 'apparent motion' of an object against a distant background because of a perspective shift, as seen in Figure 1. When viewed from Viewpoint A, the object appears to be closer to the blue square. When the viewpoint is changed to Viewpoint B, the object appears to have moved in front of the red square.
In astronomy, parallax is the only direct method by which distances to objects beyond the Solar System can be measured. The Hipparcos satellite has used the technique for over 100,000 nearby stars. This provides the basis for all other distance measurements in astronomy, the cosmic distance ladder.
# Use in distance measurement
By observing parallax, measuring angles and using geometry, one can determine the distance to various objects. When the object in question is a star, the effect is known as stellar parallax. The first successful measurements of stellar parallax were made by Friedrich Bessel in 1838, for the star 61 Cygni.
Distance measurement by parallax is a special case of the principle of triangulation, which states that one can solve for all the sides and angles in a network of triangles if, in addition to all the angles in the network, the length of at least one side has been measured. Thus, the careful measurement of the length of one baseline can fix the scale of an entire triangulation network. In parallax, the triangle is extremely long and narrow, and by measuring both its shortest side (the motion of the observer) and the small top angle (the other two being close to 90 degrees), the length of the long sides (in practice considered to be equal) can be determined.
## Parallax error
Precise parallax measurements of distance usually have an associated error. Thus a parallax may be described as some angle ± some angle-error. However this "± angle-error" does not translate directly into a ± error for the range, except for relatively small errors. The reason for this is that an error toward a smaller angle results in a greater error in distance than an error toward a larger angle.
However, an approximation of the distance error can be computed by means of the following:
where d is the distance and p is the parallax. The approximation is far more accurate for parallax errors that are small relative to the parallax than for relatively large errors.
## Parallax error in photography
Parallax error can be seen when taking photos with many types of cameras, such as twin-lens reflex cameras and those including viewfinders (such as rangefinder cameras). In such cameras, the eye sees the subject through different optics (the viewfinder, or a second lens) than the one through which the photo is taken. As the viewfinder is often found above the lens of the camera, photos with parallax error are often slightly lower than intended, the classic example being the image of person with his or her head cropped off. This problem is addressed in single-lens reflex cameras, in which the viewfinder sees through the same lens through which the photo is taken (with the aid of a movable mirror), thus avoiding parallax error.
# Parallax and measurement instruments
If an optical instrument — e.g., a telescope, microscope, or theodolite — is imprecisely focused, its cross-hairs will appear to move with respect to the object focused on if one moves one's head horizontally in front of the eyepiece. This is why it is important, especially when performing measurements, to focus carefully in order to eliminate the parallax, and to check by moving one's head.
Also, in non-optical measurements the thickness of a ruler can create parallax in fine measurements. One is always cautioned in science classes to "avoid parallax." This means that one should always take measurements with one's eye on a line directly perpendicular to the ruler, so that the thickness of the ruler does not create error in positioning for fine measurements. A similar error can occur when reading the position of a pointer against a scale in an instrument such as a galvanometer. To help the user avoid this problem, the scale is sometimes printed above a narrow strip of mirror, and the user positions his eye so that the pointer obscures its own reflection. This guarantees that the user's line of sight is perpendicular to the mirror and therefore to the scale.
# Photogrammetric parallax
Aerial picture pairs, when viewed through a stereo viewer, offer a pronounced stereo effect of landscape and buildings. High buildings appear to 'keel over' in the direction away from the centre of the photograph. Measurements of this parallax are used to deduce the height of the buildings, provided that flying height and baseline distances are known. This is a key component to the process of photogrammetry.
# Lunar parallax
Lunar parallax involves the arithmetic of parallel stars between two inverted axes which rotate in angles that are only visible by the moon.
Jules Verne, in From the Earth to the Moon, wrote:
"Up till then, many people had no idea how one could calculate the distance separating the Moon from the Earth. The circumstance was exploited to teach them that this distance was obtained by measuring the parallax of the Moon. If the word parallax appeared to amaze them, they were told that it was the angle subtended by two straight lines running from both ends of the Earth's radius to the Moon. If they had doubts on the perfection of this method, they were immediately shown that not only did this mean distance amount to a whole two hundred thirty-four thousand three hundred and forty-seven miles (94,330 leagues), but also that the astronomers were not in error by more than seventy miles (≈ 30 leagues)."
A primitive way to determine the lunar parallax from one location is by using a lunar eclipse. The full shadow of the Earth on the Moon has an apparent radius of curvature equal to the difference between the apparent radii of the Earth and the Sun as seen from the Moon. This radius can be seen to be equal to 0.75 degree, from which (with the solar apparent radius 0.25 degree) we get an Earth apparent radius of 1 degree. This yields for the Earth-Moon distance 60 Earth radii or 384,000 km. This procedure was first used by Aristarchus of Samos and Hipparchus, and later found its way into the work of Ptolemy.
Another way to use parallax to determine the distance to the Moon would be to take two pictures of the Moon at exactly the same time from two locations on Earth, and compare the position of the Moon relative to the visible stars. Using the orientation of the Earth, and those two points, and a perpendicular displacement, a distance to the Moon can be triangulated.
# Solar parallax
After Copernicus proposed his heliocentric system, with the Earth in revolution around the Sun, it was possible to build a scale model of the whole solar system, but without the scale. To ascertain the scale, it is necessary only to measure one distance within the solar system, e.g., the mean distance from the Earth to the Sun (now called an astronomical unit, or AU). When found by triangulation, this is referred to as the solar parallax, the difference in position of the Sun as seen from the Earth's centre and a point one Earth radius away, i.e., the angle subtended at the Sun by the Earth's mean radius. Knowing the solar parallax and the mean Earth radius allows one to calculate the AU, the first, small step on the long road of establishing the size — and thus, according to Big Bang theory, the minimum age — of the visible Universe.
A primitive way to determine the distance to the Sun in terms of the distance to the Moon was already proposed by Aristarchus of Samos in his book On the Sizes and Distances of the Sun and Moon. He argued that the Sun, Moon, and Earth form a right triangle (right angle at the Moon) at the moment of first or last quarter moon. He then estimated that the Moon, Earth, Sun angle was 87°. Using correct geometry but inaccurate observational data, Aristarchus concluded that the Sun was slightly less than 20 times farther away than the Moon. The true value of this angle is close to 89° 50', and the Sun is actually about 390 times farther away. He pointed out that the Moon and Sun have nearly equal apparent angular sizes and therefore their diameters must be in proportion to their distances from Earth. He thus concluded that the Sun was around 20 times larger than the Moon; this conclusion, although incorrect, follows logically from his incorrect data. It does suggest that the Sun is clearly larger than the Earth, which could be taken to support the heliocentric model. Although these results were incorrect due to observational errors, they were based on correct geometric principles of parallax, and became the basis for estimates of the size of the solar system for almost 2000 years, until the transit of Venus was correctly observed in 1761 and 1769.
This method was proposed by Edmond Halley in 1716 , although he did not live to see the results.
The use of Venus transits was less successful than had been hoped due to the black drop effect, but the resulting estimate, 153 million kilometers, is just 2% over the currently accepted value, 149.6 million kilometers.
Much later, the solar system was 'scaled' using the parallax of asteroids, some of which, like Eros, pass much
closer to Earth than Venus. In a favourable opposition, Eros can approach the Earth to within 22 million kilometres. Both the
opposition of 1901 and that of 1930/1931 were used for this purpose, the calculations of the latter determination being completed by
Astronomer Royal Sir Harold Spencer Jones.
Also radar reflections, both off Venus (1958) and off asteroids, like Icarus, have been used for solar parallax
determination. Today, use of spacecraft telemetry links has solved this old problem completely.
# Stellar parallax
On an interstellar scale, parallax created by the different orbital positions of the Earth causes nearby stars to appear to move relative to more distant stars. However, this effect is so small it is undetectable without extremely precise measurements.
The annual parallax is defined as the difference in position of a star as seen from the Earth and Sun, i.e. the angle subtended at a star by the mean radius of the Earth's orbit around the Sun. Given two points on opposite sides of the orbit, the parallax is half the maximum parallactic shift evident from the star viewed from the two points. The parsec is defined the distance for which the annual parallax is 1 arcsecond. A parsec equals 3.26 light years.
The distance of an object (in parsecs) can be roughly computed as the reciprocal of the parallax. For instance, the Hipparcos satellite measured the parallax of the nearest star, Proxima Centauri, as 0.77233 seconds of arc (±.00242"). Therefore, the distance is 1/0.772=1.29 parsecs or about 4.22 light years (±.01 ly).
The angles involved in these calculations are very small. For example, 0.772 arcseconds is approximately the angle subtended by an object about 2 centimeters in diameter (roughly the size of a U.S. quarter dollar) located about 5.3 kilometers away.
## Computation
The parallax <math>p = \frac {1 AU} {d} \cdot 180 \cdot \frac {3600} {\pi} </math> in arc seconds
where
Picking a good unit of measure will cancel the constants.
Derivation:
The fact that stellar parallax was so small that it was unobservable at the time was used as the main scientific argument against heliocentrism during the early modern age. It is clear from Euclid's geometry that the effect would be undetectable if the stars were far enough away; but for various reasons such a gigantic size seemed entirely implausible.
Measurement of the annual parallax as the earth goes through its orbit was the first reliable way to determine the distances to the closest stars. This method was first successfully used by Friedrich Wilhelm Bessel in 1838 when he measured the distance to 61 Cygni with a heliometer, and it remains the standard for calibrating other measurement methods (after the size of the orbit of the earth is measured by radar reflection of other planets).
In 1989, the satellite 'Hipparcos' was launched primarily for obtaining parallaxes and proper motions of nearby stars, increasing the reach of the method tenfold. Even so, Hipparcos is only able to measure parallax angles for stars up to about 1,600 light-years away — a little more than one percent of the diameter of our galaxy.
# Dynamic or moving-cluster parallax
The open stellar cluster Hyades in Taurus extends over such a large part of the sky, 20 degrees, that the proper motions as derived from astrometry appear to converge with some precision to a perspective point north of Orion. Combining the observed apparent (angular) proper motion in seconds of arc with the also observed true (absolute) receding motion as witnessed by the Doppler redshift of the stellar spectral lines, allows estimation of the distance to the cluster (151 light years) and its member stars in much the same way as using annual parallax.
Dynamic parallax has sometimes also been used to determine the distance to a supernova, when the optical wave front of the outburst is seen to propagate through the surrounding dust clouds at an apparent angular velocity, while its true propagation velocity is known be the speed of light.
# In computer graphics
In many early graphical applications, such as video games, the scene was constructed of independent layers that were scrolled at different speeds when the player/cursor moved. Some hardware had explicit support for such layers, such as the Super Nintendo Entertainment System. This gave some layers the appearance of being farther away than others and was useful for creating an illusion of depth, but only worked when the player was moving. Now, most games are based on much more comprehensive three-dimensional graphic models, although portable game (DS, PSP) systems still often use parallax.
# As a metaphor
In a philosophic/geometric sense: An apparent change in the direction of an object, caused by a change in observational position that
provides a new line of sight. The apparent displacement, or difference of position, of an object, as seen from two different stations, or points of view. In contemporary writing parallax can also be the same story, or a similar story from approximately the same time line, from one book told from a different perspective in another book. The word and concept feature prominently in James Joyce's 1922 novel, Ulysses. Orson Scott Card also used the term when referring to Ender's Shadow as compared to Ender's Game.
The metaphor is also invoked in the magnum opus of Slovenian philosopher Slavoj Žižek in his work 'The Parallax View'. "The philosophical twist to be added ((to parallax)), of course, is that the observed distance is not simply subjective, since the same object which exists 'out there' is seen from two different stances, or points of view. It is rather that, as Hegel would have put it, subject and object are inherently mediated so that an 'epistemological' shift in the subject's point of view always reflects an ontological shift in the object itself. Or -to put it in Lacanese- the subject's gaze is always-already inscribed into the perceived object itself, in the guise of its 'blind spot,' that which is 'in the object more than object itself', the point from which the object itself returns the gaze. Sure the picture is in my eye, but I am also in the picture."
[1] | https://www.wikidoc.org/index.php/Parallax | |
b27e5f94834452ddc72569e1d29b30cabae4d78a | wikidoc | Paroxysm | Paroxysm
Paroxysm
- a sudden outburst of a violent emotion or action (laughter, rage)
- a seizure, spasm, cramp, sudden attack of pain
- an increase of symptoms or periodic attacks of a disease (such as malaria, asthma, migraine, trigeminal neuralgia, tachycardia, whooping cough, and epilepsy.)
- In geology a volcanic eruption with a Volcanic Explosivity Index of 5 (on a scale of 0-8) is called 'paroxysmal.'
For medical meanings see also paroxysmal attacks. | Paroxysm
Paroxysm
- a sudden outburst of a violent emotion or action (laughter, rage)
- a seizure, spasm, cramp, sudden attack of pain
- an increase of symptoms or periodic attacks of a disease (such as malaria, asthma, migraine, trigeminal neuralgia, tachycardia, whooping cough, and epilepsy.)
- In geology a volcanic eruption with a Volcanic Explosivity Index of 5 (on a scale of 0-8) is called 'paroxysmal.'
For medical meanings see also paroxysmal attacks.
# External links
- Bronchial Asthma as Paroxysmal Disease Common mechanisms of asthma with other neurogenic paroxysmal diseases.
Template:Disease-stub
sv:Paroxysm
de:Paroxysmus
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Paroxysm | |
a540920416a830e8dd3b7392c44598c812dc6364 | wikidoc | Parvulin | Parvulin
Parvulin, a 92-amino acid protein discovered in E. coli in 1994, is the smallest known protein with prolyl isomerase activity, which catalyzes the cis-trans isomerization of proline peptide bonds. Although parvulin has no homology with larger prolyl isomerases such as cyclophilin and FKBP, it does share structural features with subdomains of other proteins involved in preparing secreted proteins for export from the cell.
Although parvulin is as active as the larger prolyl isomerases against a short proline-containing test peptide, it has lower relative activity against biological substrates, possibly because the larger molecules have a higher ability to bind the substrate peptide. Parvulin itself contains proline residues and its folding can be accelerated by the presence of cyclophilin; parvulin folding can also be autocatalytic.
A eukaryotic homolog of parvulin known as Pin1 is required to execute the transition from G2 phase to M phase in the cell cycle. Absence of Pin1 activity in humans has also been implicated in the folding and processing of the amyloid precursor protein, whose degradation product is the cytotoxic peptide amyloid beta implicated in Alzheimer's disease. | Parvulin
Parvulin, a 92-amino acid protein discovered in E. coli in 1994,[1] is the smallest known protein with prolyl isomerase activity, which catalyzes the cis-trans isomerization of proline peptide bonds. Although parvulin has no homology with larger prolyl isomerases such as cyclophilin and FKBP, it does share structural features with subdomains of other proteins involved in preparing secreted proteins for export from the cell. [2]
Although parvulin is as active as the larger prolyl isomerases against a short proline-containing test peptide, it has lower relative activity against biological substrates, possibly because the larger molecules have a higher ability to bind the substrate peptide.[3] Parvulin itself contains proline residues and its folding can be accelerated by the presence of cyclophilin; parvulin folding can also be autocatalytic.
A eukaryotic homolog of parvulin known as Pin1 is required to execute the transition from G2 phase to M phase in the cell cycle.[4] Absence of Pin1 activity in humans has also been implicated in the folding and processing of the amyloid precursor protein, whose degradation product is the cytotoxic peptide amyloid beta implicated in Alzheimer's disease.[5] | https://www.wikidoc.org/index.php/Parvulin | |
37996372a9554eee082d0090d438c424e18c4b1b | wikidoc | Paxillin | Paxillin
Paxillin is a protein that in humans is encoded by the PXN gene. Paxillin is expressed at focal adhesions of non-striated cells and at costameres of striated muscle cells, and it functions to adhere cells to the extracellular matrix. Mutations in PXN as well as abnormal expression of paxillin protein has been implicated in the progression of various cancers.
# Structure
Human paxillin is 64.5 kDa in molecular weight and 591 amino acids in length.
The C-terminal region of paxillin is composed of four tandem double zinc finger LIM domains that are cysteine/histidine-rich with conserved repeats; these serve as binding sites for the protein tyrosine phosphatase-PEST, tubulin and serves as the targeting motif for focal adhesions.
The N-terminal region of paxillin has five highly conserved leucine-rich sequences termed LD motifs, which mediate several interactions, including that with pp125FAK and vinculin. The LD motifs are predicted to form amphipathic alpha helices, with each leucine residue positioned on one face of the alpha helix to form a hydrophobic protein-binding interface. The N-terminal region also has a proline-rich domain that has potential for Src-SH3 binding. Three N-terminal YXXP motifs may serve as binding sites for talin or v-Crk SH2.
# Function
Paxillin is a signal transduction adaptor protein discovered in 1990 in the laboratory of Keith Burridge The C-terminal region of paxillin contains four LIM domains that target paxillin to focal adhesions. It is presumed through a direct association with the cytoplasmic tail of beta-integrin. The N-terminal region of paxillin is rich in protein–protein interaction sites. The proteins that bind to paxillin are diverse and include protein tyrosine kinases, such as Src and focal adhesion kinase (FAK), structural proteins, such as vinculin and actopaxin, and regulators of actin organization, such as COOL/PIX and PKL/GIT. Paxillin is tyrosine-phosphorylated by FAK and Src upon integrin engagement or growth factor stimulation, creating binding sites for the adapter protein Crk.
In striated muscle cells, paxillin is important in costamerogenesis, or the formation of costameres, which are specialized focal adhesion-like structures in muscle cells that tether Z-disc structures across the sarcolemma to the extracellular matrix. The current working model of costamerogenesis is that in cultured, undifferentiated myoblasts, alpha-5 integrin, vinculin and paxillin are in complex and located primarily at focal adhesions. During early differentiation, premyofibril formation through sarcomerogenesis occurs, and premyofibrils assemble at structures that are typical of focal adhesions in non-muscle cells; a similar phenomenon is observed in cultured cardiomyocytes. Premyofibrils become nascent myofibrils, which progressively align to form mature myofibrils and nascent costamere structures appear. Costameric proteins redistribute to form mature costameres. While the precise functions of paxillin in this process are still being unveiled, studies investigating binding partners of paxillin have provided mechanistic understanding of its function. The proline-rich region of paxillin specifically binds to the second SH3 domain of ponsin, which occurs after the onset of the myogenic differentiation and with expression restricted to costameres. We also know that the binding of paxillin to focal adhesion kinase (FAK) is critical for directing paxillin function. The phosphorylation of FAK at serine-910 regulates the interaction of FAK with paxillin, and controls the stability of paxillin at costameres in cardiomyocytes, with phosphorylation reducing the half-life of paxillin. This is important to understand because the stability of the FAK-paxillin interaction is likely inversely related to the stability of the vinculin-paxillin interaction, which would likely indicate the strength of the costamere interaction as well as sarcomere reorganization; processes which have been linked to dilated cardiomyopathy. Additional studies have shown that paxillin itself is phosphorylated, and this participates in hypertrophic signaling pathways in cardiomyocytes. Treatment of cardiomyocytes with the hypertrophic agonist, phenylephrine stimulated a rapid increase in tyrosine phosphorylation paxillin, which was mediated by protein tyrosine kinases.
The structural reorganization of paxillin in cardiomyocytes has also been detected in mouse models of dilated cardiomyopathy. In a mouse model of tropomodulin overexpression, paxillin distribution was revamped coordinate with increased phosphorylation and cleavage of paxillin. Similarly, paxillin was shown to have altered localization in cardiomyocytes from transgenic mice expressing a constitutively-active rac1. These data show that alterations in costameric organization, in part via paxillin redistribution, may be a pathogenic mechanism in dilated cardiomyopathy. In addition, in mice subjected to pressure overload-induced cardiac hypertrophy, inducing hypertrophic cardiomyopathy, paxillin expression levels increased, suggesting a role for paxillin in both types of cardiomyopathy.
# Clinical significance
Paxillin has been shown to have a clinically-significant role in patients with several cancer types. Enhanced expression of paxillin has been detected in premalignant areas of hyperplasia, squamous metaplasia and goblet cell metaplasia, as well as dysplastic lesions and carcinoma in high-risk patients with lung adenocarcinoma. Mutations in PXN have been associated with enhanced tumor growth, cell proliferation, and invasion in lung cancer tissues.
During tumor transformation, a consistent finding is that paxillin protein is recruited and phosphorylated. Paxillin plays a role in the MET tyrosine kinase signaling pathway, which is upregulated in many cancers.
# Interactions
Paxillin has been shown to interact with:
- PTP-PEST,
- tubulin,
- VCL,
- pp125FAK.
- SRC
- SORBS1.
- PARVA and
- ILK | Paxillin
Paxillin is a protein that in humans is encoded by the PXN gene. Paxillin is expressed at focal adhesions of non-striated cells and at costameres of striated muscle cells, and it functions to adhere cells to the extracellular matrix. Mutations in PXN as well as abnormal expression of paxillin protein has been implicated in the progression of various cancers.
# Structure
Human paxillin is 64.5 kDa in molecular weight and 591 amino acids in length.[1]
The C-terminal region of paxillin is composed of four tandem double zinc finger LIM domains that are cysteine/histidine-rich with conserved repeats; these serve as binding sites for the protein tyrosine phosphatase-PEST,[2] tubulin[3] and serves as the targeting motif for focal adhesions.[4]
The N-terminal region of paxillin has five highly conserved leucine-rich sequences termed LD motifs, which mediate several interactions, including that with pp125FAK and vinculin.[5][6] The LD motifs are predicted to form amphipathic alpha helices, with each leucine residue positioned on one face of the alpha helix to form a hydrophobic protein-binding interface. The N-terminal region also has a proline-rich domain that has potential for Src-SH3 binding. Three N-terminal YXXP motifs may serve as binding sites for talin or v-Crk SH2.[7][8]
# Function
Paxillin is a signal transduction adaptor protein discovered in 1990 in the laboratory of Keith Burridge[9] The C-terminal region of paxillin contains four LIM domains that target paxillin to focal adhesions. It is presumed through a direct association with the cytoplasmic tail of beta-integrin. The N-terminal region of paxillin is rich in protein–protein interaction sites. The proteins that bind to paxillin are diverse and include protein tyrosine kinases, such as Src and focal adhesion kinase (FAK), structural proteins, such as vinculin and actopaxin, and regulators of actin organization, such as COOL/PIX and PKL/GIT. Paxillin is tyrosine-phosphorylated by FAK and Src upon integrin engagement or growth factor stimulation,[10] creating binding sites for the adapter protein Crk.
In striated muscle cells, paxillin is important in costamerogenesis, or the formation of costameres, which are specialized focal adhesion-like structures in muscle cells that tether Z-disc structures across the sarcolemma to the extracellular matrix. The current working model of costamerogenesis is that in cultured, undifferentiated myoblasts, alpha-5 integrin, vinculin and paxillin are in complex and located primarily at focal adhesions. During early differentiation, premyofibril formation through sarcomerogenesis occurs, and premyofibrils assemble at structures that are typical of focal adhesions in non-muscle cells; a similar phenomenon is observed in cultured cardiomyocytes.[11] Premyofibrils become nascent myofibrils, which progressively align to form mature myofibrils and nascent costamere structures appear. Costameric proteins redistribute to form mature costameres.[12] While the precise functions of paxillin in this process are still being unveiled, studies investigating binding partners of paxillin have provided mechanistic understanding of its function. The proline-rich region of paxillin specifically binds to the second SH3 domain of ponsin, which occurs after the onset of the myogenic differentiation and with expression restricted to costameres.[13] We also know that the binding of paxillin to focal adhesion kinase (FAK) is critical for directing paxillin function. The phosphorylation of FAK at serine-910 regulates the interaction of FAK with paxillin, and controls the stability of paxillin at costameres in cardiomyocytes, with phosphorylation reducing the half-life of paxillin.[14] This is important to understand because the stability of the FAK-paxillin interaction is likely inversely related to the stability of the vinculin-paxillin interaction, which would likely indicate the strength of the costamere interaction as well as sarcomere reorganization; processes which have been linked to dilated cardiomyopathy.[15] Additional studies have shown that paxillin itself is phosphorylated, and this participates in hypertrophic signaling pathways in cardiomyocytes. Treatment of cardiomyocytes with the hypertrophic agonist, phenylephrine stimulated a rapid increase in tyrosine phosphorylation paxillin, which was mediated by protein tyrosine kinases.[16]
The structural reorganization of paxillin in cardiomyocytes has also been detected in mouse models of dilated cardiomyopathy. In a mouse model of tropomodulin overexpression, paxillin distribution was revamped coordinate with increased phosphorylation and cleavage of paxillin.[17] Similarly, paxillin was shown to have altered localization in cardiomyocytes from transgenic mice expressing a constitutively-active rac1.[18] These data show that alterations in costameric organization, in part via paxillin redistribution, may be a pathogenic mechanism in dilated cardiomyopathy. In addition, in mice subjected to pressure overload-induced cardiac hypertrophy, inducing hypertrophic cardiomyopathy, paxillin expression levels increased, suggesting a role for paxillin in both types of cardiomyopathy.[19]
# Clinical significance
Paxillin has been shown to have a clinically-significant role in patients with several cancer types. Enhanced expression of paxillin has been detected in premalignant areas of hyperplasia, squamous metaplasia and goblet cell metaplasia, as well as dysplastic lesions and carcinoma in high-risk patients with lung adenocarcinoma.[20] Mutations in PXN have been associated with enhanced tumor growth, cell proliferation, and invasion in lung cancer tissues.[21]
During tumor transformation, a consistent finding is that paxillin protein is recruited and phosphorylated.[22] Paxillin plays a role in the MET tyrosine kinase signaling pathway, which is upregulated in many cancers.[23]
# Interactions
Paxillin has been shown to interact with:
- PTP-PEST,[2]
- tubulin,[3]
- VCL,[9][24]
- pp125FAK.[25][26][27]
- SRC[28][29]
- SORBS1.[13]
- PARVA[30] and
- ILK[31] | https://www.wikidoc.org/index.php/Paxillin | |
2a9ea51606970afac2c2f79b41b3131825b757ea | wikidoc | Pennales | Pennales
Order Pennales is a traditional subdivision of the heterokont algae known as diatoms. The order is named for the shape of the cell walls (or valves or frustules) of pennate diatoms, which are elongated in valve view. The valves may be linear or oval in shape, and usually bear bilaterally symmetrical ornamental patterns. These patterns are composed of a series of transverse lines (known as striae) that can appear as rows of dots when viewed with an optical microscope. Some pennate diatoms also exhibit a fissure along their longitudinal axis. This is known as a raphe, and is involved in gliding movements made by diatom cells.
In terms of cell cycle, vegetative cells are diploid and undergo mitosis during normal cell division. Periodically, meiosis produces morphologically-identical haploid gametes (isogametes), which fuse to produce a (sometimes binucleate) zygote that develops into an auxospore (from which full-size vegetative cells are produced).
In some taxonomic schemes, the pennate diatoms are divided into two groups: pennate diatoms without a raphe (Order Fragilariophyceae), and pennate diatoms with a raphe (Order Bacillariophyceae). | Pennales
Order Pennales is a traditional subdivision of the heterokont algae known as diatoms[1][2]. The order is named for the shape of the cell walls (or valves or frustules) of pennate diatoms, which are elongated in valve view. The valves may be linear or oval in shape, and usually bear bilaterally symmetrical ornamental patterns. These patterns are composed of a series of transverse lines (known as striae) that can appear as rows of dots when viewed with an optical microscope. Some pennate diatoms also exhibit a fissure along their longitudinal axis. This is known as a raphe, and is involved in gliding movements made by diatom cells.
In terms of cell cycle, vegetative cells are diploid and undergo mitosis during normal cell division. Periodically, meiosis produces morphologically-identical haploid gametes (isogametes), which fuse to produce a (sometimes binucleate) zygote that develops into an auxospore (from which full-size vegetative cells are produced).
In some taxonomic schemes[2], the pennate diatoms are divided into two groups: pennate diatoms without a raphe (Order Fragilariophyceae), and pennate diatoms with a raphe (Order Bacillariophyceae). | https://www.wikidoc.org/index.php/Pennales | |
bccb05029b2f18fe6396f4c52e37220c5018909c | wikidoc | Peonidin | Peonidin
Peonidin is an anthocyanidin, and a primary plant pigment. Peonidin gives purplish-red hues to flowers such as the peony, from which it takes its name, and roses. It is also present in some blue flowers, such as the morning glory.
Like most anthocyanidins it is pH sensitive, and changes from red to blue as pH rises. This happens because anthocynaidins are highly conjugated chromophores. When the pH is changed, the extent of the conjugation (of the double bonds) is altered, which alters the wavelength of light energy absorbed by the molecule. (Natural anthocyanidins are most stable in a very low pH environment; at pH 8.0, most become colorless.) At pH 2.0, peonidin is cherry red; at 3.0 a strong yellowish pink; at 5.0 it is grape red-purple; and at 8.0 it becomes deep blue; unlike many anthocyanidins, however, it is stable at higher pH, and has in fact been isolated as a blue colorant from the brilliant "Heavenly Blue" morning glory (Ipomoea tricolor Cav cv).
Because of its unusual color stability,a cafeyl-acylated buffered formulation of it has been patented for use as food coloring.
Peonidin, like many anthodcyanidins, has show potent inhibitory and apoptotic effects on cancer cells in vitro, notably metastatic human breast cancer cells.
A very large question, however, has been raised about anthocyanidins' penetration and retention in human cells in vivo, due to their rapid elimination from the human body.
By far the greatest dietary source of peonidin is raw cranberries, which contain 42 mg. per 100 g. of fruit. Blueberries, plums, grapes, and cherries also contain significant amounts, ranging from 5 to 12 mg/100g. Only fresh fruit has been shown to contain significant peonidin; frozen blueberries have been shown to contain almost none.
It has also been isolated from raw black rice and black bananas.
The higher levels of peonidin in fresh fruit corresponds to the rule of thumb that more natural fruit is healthier. Specifically, the amount of phenolic compounds in cranberries have been found to be inversely correlated with fruit size and crop yield.
-References-
- ↑ JUNG YEON KWON, KI WON LEE, HAENG JEON HUR, HYONG JOO LEE (2007)
Peonidin Inhibits Phorbol-Ester-Induced COX-2 Expression and Transformation in JB6 P+ Cells by Blocking Phosphorylation of ERK-1 and -2,Annals of the New York Academy of Sciences 1095 (1), 513–520 (January, 2007).
- ↑ Nutrient Search - Peonidin
- ↑ ISHS | Peonidin
Peonidin is an anthocyanidin, and a primary plant pigment. Peonidin gives purplish-red hues to flowers such as the peony, from which it takes its name, and roses. It is also present in some blue flowers, such as the morning glory.
Like most anthocyanidins it is pH sensitive, and changes from red to blue as pH rises. This happens because anthocynaidins are highly conjugated chromophores. When the pH is changed, the extent of the conjugation (of the double bonds) is altered, which alters the wavelength of light energy absorbed by the molecule. (Natural anthocyanidins are most stable in a very low pH environment; at pH 8.0, most become colorless.) At pH 2.0, peonidin is cherry red; at 3.0 a strong yellowish pink; at 5.0 it is grape red-purple; and at 8.0 it becomes deep blue; unlike many anthocyanidins, however, it is stable at higher pH, and has in fact been isolated as a blue colorant from the brilliant "Heavenly Blue" morning glory (Ipomoea tricolor Cav cv).
Because of its unusual color stability,a cafeyl-acylated buffered formulation of it has been patented for use as food coloring.
Peonidin, like many anthodcyanidins, has show potent inhibitory and apoptotic effects on cancer cells in vitro, notably metastatic human breast cancer cells. [1]
A very large question, however, has been raised about anthocyanidins' penetration and retention in human cells in vivo, due to their rapid elimination from the human body.
By far the greatest dietary source of peonidin is raw cranberries, which contain 42 mg. per 100 g. of fruit. Blueberries, plums, grapes, and cherries also contain significant amounts, ranging from 5 to 12 mg/100g. Only fresh fruit has been shown to contain significant peonidin; frozen blueberries have been shown to contain almost none. [2]
It has also been isolated from raw black rice and black bananas.
The higher levels of peonidin in fresh fruit corresponds to the rule of thumb that more natural fruit is healthier. Specifically, the amount of phenolic compounds in cranberries have been found to be inversely correlated with fruit size and crop yield. [3]
-References-
- ↑ JUNG YEON KWON, KI WON LEE, HAENG JEON HUR, HYONG JOO LEE (2007)
Peonidin Inhibits Phorbol-Ester-Induced COX-2 Expression and Transformation in JB6 P+ Cells by Blocking Phosphorylation of ERK-1 and -2,Annals of the New York Academy of Sciences 1095 (1), 513–520 (January, 2007).
- ↑ Nutrient Search - Peonidin
- ↑ ISHS
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Peonidin | |
6389f44f7f5b4421f0c201489f65c6623cd37934 | wikidoc | Percodan | Percodan
Percodan is a potent compound painkiller used to treat moderately severe to severe acute (short-term) pain. Percodan contains aspirin and oxycodone, a potent opioid agonist. Percodan was first marketed by DuPont Pharmaceuticals and prescribed in the United States in 1950. At one time one of the most widely prescribed painkillers, Percodan has largely been replaced by alternative oxycodone compounds containing acetaminophen (Tylenol) instead of aspirin, such as Percocet.
# Pharmacology
Each Percodan tablet contains the following active ingredients:
- 4.5 mg of oxycodone hydrochloride
- 0.38 mg of oxycodone terephthalate
- 325 mg of aspirin.
Each tablet also contains the following inactive ingredients:
- FD&C Yellow 10
- FD&C Yellow 6
- microcrystalline cellulose
- starch.
The oxycodone component in Percodan is technically 14-hydroxy-7,8-dihydrocodein-6-one, a white odorless, crystalline powder which is synthesized from the opium alkaloid thebaine. Thebaine by itself has no therapeutic value. Oxycodone is metabolized into oxymorphone. Unlike morphine and like codeine, oxycodone has a good oral potency. Prior to the introduction of acetaminophen (paracetamol), Percodan was the mainstay in post-operative oral pain treatment due to the potency and long half-life of oxycodone. Percodan originally contained a small amount of caffeine.
The usual dose is one tablet every six hours as needed for pain. The maximum daily dose should not exceed 12 tablets.
# Decline of use
Percodan has largely been replaced by Percocet (which is a compound of oxycodone and acetaminophen, instead of Percodan's aspirin) and other oxycodone-containing compounds for post-operative pain, since aspirin and other anti-inflammatory drugs increase prothrombin time and thus inhibit the blood from clotting, which can result in post-operative complications, such as excessive bleeding. Norco and Vicodin, which contain hydrocodone and acetaminophen, have also gained favor over Percodan for post-operative pain because hydrocodone is nearly as potent as oxycodone, and it is not as highly regulated as Percodan. In the United States, Percodan is regulated as a Schedule II controlled substance under the Uniform Controlled Substances Act of 1970, along with cocaine, morphine and raw (unprocessed) opium. Schedule II prescriptions may not be filled by telephone (except in an emergency), and no refills are allowed. By contrast, Vicodin, Norco, and other hydrocodone-containing compounds are in Schedule III. Percodan is becoming something of a relic in the United States, at least, as the number of prescriptions has fallen precipitously since the 1960s in light of the alternate drugs available containing oxycodone (Percocet, Tylox, OxyContin, Roxicodone).
# Miscellaneous
Percodan is also sold under the brand name Endodan. All products containing oxycodone (including Percodan, Percocet, OxyContin) have the potential to be habit-forming. Oxycodone can produce drug dependence of the morphine type and, therefore, has the potential for being abused. It is a favorite of and eagerly sought after by opiate addicts; many addicts, however, prefer OxyContin because it does not contain any other active ingredients besides oxycodone, unlike Percodan and Percocet, which each contain aspirin and Tylenol, respectively.
As of 2008, Percodan and Percocet are manufactured by Endo Pharmaceuticals. | Percodan
Percodan is a potent compound painkiller used to treat moderately severe to severe acute (short-term) pain. Percodan contains aspirin and oxycodone, a potent opioid agonist. Percodan was first marketed by DuPont Pharmaceuticals and prescribed in the United States in 1950. At one time one of the most widely prescribed painkillers, Percodan has largely been replaced by alternative oxycodone compounds containing acetaminophen (Tylenol) instead of aspirin, such as Percocet.
# Pharmacology
Each Percodan tablet contains the following active ingredients:
- 4.5 mg of oxycodone hydrochloride
- 0.38 mg of oxycodone terephthalate
- 325 mg of aspirin.
Each tablet also contains the following inactive ingredients:
- FD&C Yellow 10
- FD&C Yellow 6
- microcrystalline cellulose
- starch.
The oxycodone component in Percodan is technically 14-hydroxy-7,8-dihydrocodein-6-one, a white odorless, crystalline powder which is synthesized from the opium alkaloid thebaine. Thebaine by itself has no therapeutic value. Oxycodone is metabolized into oxymorphone. Unlike morphine and like codeine, oxycodone has a good oral potency. Prior to the introduction of acetaminophen (paracetamol), Percodan was the mainstay in post-operative oral pain treatment due to the potency and long half-life of oxycodone. Percodan originally contained a small amount of caffeine.
The usual dose is one tablet every six hours as needed for pain. The maximum daily dose should not exceed 12 tablets.
# Decline of use
Percodan has largely been replaced by Percocet (which is a compound of oxycodone and acetaminophen, instead of Percodan's aspirin) and other oxycodone-containing compounds for post-operative pain, since aspirin and other anti-inflammatory drugs increase prothrombin time and thus inhibit the blood from clotting, which can result in post-operative complications, such as excessive bleeding. Norco and Vicodin, which contain hydrocodone and acetaminophen, have also gained favor over Percodan for post-operative pain because hydrocodone is nearly as potent as oxycodone, and it is not as highly regulated as Percodan. In the United States, Percodan is regulated as a Schedule II controlled substance under the Uniform Controlled Substances Act of 1970, along with cocaine, morphine and raw (unprocessed) opium. Schedule II prescriptions may not be filled by telephone (except in an emergency), and no refills are allowed. By contrast, Vicodin, Norco, and other hydrocodone-containing compounds are in Schedule III. Percodan is becoming something of a relic in the United States, at least, as the number of prescriptions has fallen precipitously since the 1960s in light of the alternate drugs available containing oxycodone (Percocet, Tylox, OxyContin, Roxicodone).
# Miscellaneous
Percodan is also sold under the brand name Endodan. All products containing oxycodone (including Percodan, Percocet, OxyContin) have the potential to be habit-forming. Oxycodone can produce drug dependence of the morphine type and, therefore, has the potential for being abused. It is a favorite of and eagerly sought after by opiate addicts; many addicts, however, prefer OxyContin because it does not contain any other active ingredients besides oxycodone, unlike Percodan and Percocet, which each contain aspirin and Tylenol, respectively.
As of 2008, Percodan and Percocet are manufactured by Endo Pharmaceuticals.
# External links
- Percodan Prescribing Information from Endo Pharmaceuticals.
- Search "Percodan" in FDA Archives; shows approval in 1950.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Percodan | |
6777a927de3c7c069317710307c75cdf0ae133e9 | wikidoc | Perlecan | Perlecan
Perlecan (PLC) also known as basement membrane-specific heparan sulfate proteoglycan core protein (HSPG) or heparan sulfate proteoglycan 2 (HSPG2), is a protein that in humans is encoded by the HSPG2 gene.
Perlecan is a large multidomain (five domains, labeled I-V) proteoglycan that binds to and cross-links many extracellular matrix (ECM) components and cell-surface molecules. Perlecan is synthesized by both vascular endothelial and smooth muscle cells and deposited in the extracellular matrix. Perlecan is highly conserved across species and the available data indicate that it has evolved from ancient ancestors by gene duplication and exon shuffling.
# Structure
Perlecan consists of a core protein of molecular weight 470 kDa to which three long chains (each approximately 70-100 kDa) of glycosaminoglycans (often heparan sulfate, HS, but can be chondroitin sulfate, CS) are attached. The core protein consists of five distinct structural domains. The N-terminal domain I (aa ~1-195) contains attachment sites for HS chains. Although HS chains are not required for correct folding and secretion of the protein, lack of HS or decreased sulfation can decrease perlecan's ability to interact with matrix proteins. Removal of HS chains may affect matrix organization and endothelial barrier function. Domain II comprises four repeats homologous to the ligand-binding portion of the LDL receptor with six conserved cysteine residues and a pentapeptide, DGSDE, which mediates ligand binding by the LDL receptor. Domain III has homology to the domain IVa and IVb of laminin. Domain IV consists of a series of IG modules. The C-terminal Domain V, which has homology to the G domain of the long arm of laminin, is responsible for self-assembly and may be important for basement membrane formation in vivo. Thus, perlecan core protein and HS chains could modulate matrix assembly, cell proliferation, lipoprotein binding and cell adhesion.
A diagram showing the domain structure of perlecan is available here
# Function
Perlecan is a key component of the vascular extracellular matrix, where it interacts with a variety of other matrix components and helps to maintain the endothelial barrier function. Perlecan is a potent inhibitor of smooth muscle cell proliferation and is thus thought to help maintain vascular homeostasis. Perlecan can also promote growth factor (e.g., FGF2) activity and thus stimulate endothelial growth and re-generation.
# Modification of glycosaminoglycan chains
Modifications of the heparan sulfate chains on C- and N-terminal domains are the best-studied differences in the secretory pathway of perlecan. Chondroitin sulfate can be substituted for heparan sulfate, and sulfate incorporation or the sugar composition of the chains can change. Loss of enzymes involved in the heparan sulfate synthetic pathway lead to a number of conditions.
Differential heparan sulfate chain modification can occur through a number of regulatory signals. Perlecan in the growth plate of mouse long bones shows glycosylation changes in the chondrocyte progression from the resting zone to the proliferating zone. Although initially the glycosaminoglycan (GAG) chains of perlecan were thought to be exclusively heparan sulfate, chondroitin sulfate chains can be substituted during specific regulatory cues. By expressing a recombinant form of the N-terminal domain I of the protein and demonstrating that digestion of the peptide with either heparanase or chondroitinase did not lead to complete loss of the peptide's activity, it was shown that chondroitin sulfate chains can be added to human perlecan. This was in agreement with previous data showing chondroitin sulfate GAG chains attached to bovine perlecan produced by chondrocytes and that recombinant human domain I protein was glycosylated with both heparan and chondroitin sulfate chains when expressed in Chinese Hamster Ovary cells. The preferential addition of heparan sulfate or chondroitin sulfate chains to domains I and V could have an effect on the differentiation of mesenchymal tissues into cartilage, bone or any number of tissues, but the regulatory mechanism of changing from heparan sulfate to chondroitin sulfate addition are not well understood.
While studying the effect of proteoglycan composition on nephritic permselectivity, it was noted that puromycin treatment of human glomerular endothelial cells (HGEC) altered the sulfation level of GAG chains on proteoglycans such as perlecan, which in turn caused a decrease in the stability of the GAG chains. The core protein mRNA levels of proteoglycans were not affected, thus the decrease in GAG chains was as a result of some other factor, which in this case turned out to be a decrease in expression of sulfate transferase enzymes, which play a key role in GAG biosynthesis. It seems that there may be some overlap in diseases stemming from loss of heparan sulfate proteoglycan expression and loss of enzymes involved in heparan sulfate biosynthesis.
# Degradation
Cells can modify their extracellular matrix and basement membranes in response to signals or stress. Specific proteases act on the protein in the extracellular environment when cells have a reason to move or change their surroundings. Cathepsin S is a cysteine protease that moderately attenuates binding of FGF-positive cells to a perlecan-positive substrate. Cathepsin S is a potential protease that acts on the core protein of perlecan in the basement membrane or stroma.
The heparan sulfate chains of perlecan bind growth factors in the ECM, and serve as co-ligands or ligand enhancers when bound to receptors. Another study showed that release of HS-bound basic FGF in culture could be achieved through treatment with stromelysin, heparitinase I, rat collagenase and plasmin, and these proteolysis sites are illustrated in figure 1. This was proposed as a non-exhaustive list of the proteases that could mediate release of growth factors from the heparan sulfate chains of perlecan. Although Whitelock et al. suggested that thrombin cleavage consensus sequences exist in the core protein of perlecan, they also postulate that any thrombin activation of perlecan actually comes from cleavage of other ECM constituents. This article states that heparanase is responsible for cleavage of the heparan sulfate chains of perlecan in matrix. This releases growth factors bound to the heparan sulfate, specifically FGF-10. Addition of heparanase to cell culture of epithelia in basement membrane caused an increase in epithelial cell proliferation due to FGF-10 release.
In a model of explant growth in vitro using corneal epithelium, Matrix Metalloproteinase (MMP) 2 expression correlates with an initial degradation of the original basement membrane. Reformation of basement membrane in culture was dependent on an initial upregulation followed by a downregulation of MMP-9, in contrast to the constant expression of MMP-2. This is not evidence that MMP-2 and MMP-9 directly cleave perlecan protein in vivo but shows that the proteins clearly modulate some factor in maturation of basement membrane. Another family of metalloproteases, the Bone Morphogenetic Protein 1/Tolloid-like family, releases the c-terminal endorepellin domain of the perlecan core protein. The laminin-like globular domain contains the active motif of endorepellin, and is unable to be cleaved by cells expressing mutant and inactive forms of the BMP-1 proteins. Furthermore, the critical residue necessary for this cleavage to take place was localized to Asp4197. This proteolytic process may have significance in disease as a corresponding fragment was found in the urine of patients suffering end-stage renal failure and in the amniotic fluid of pregnant women who have undergone premature rupture of the membrane.
# Expression
## Expression during development
Timing of gene expression during development varies from tissue to tissue. Basement membranes are often the driving force behind separating epithelia from stroma and connective tissue. Perlecan is of particular importance in cardiovascular, neural and cartilaginous development.
Pre-implantation blastocyst development is a controlled cascade of gene regulation and intercellular signaling. Extracellular perlecan has been observed at the blastocyst stage of mouse embryonic development, specifically upregulated at the point when the embryo reaches “attachment competence”. This finding was upheld at both the mRNA level and the protein level, shown by RT-PCR and immunostaining. Later embryonic development is just as precisely regulated as pre-implantation development, and is more complicated due to differentiation of all tissues. The first study of perlecan expression during embryonal development found that the protein was first expressed during development of the cardiovascular system, and later correlates with maturation of the majority of tissues in the body, i.e. separation of epithelial layers from endothelia and stroma by basement membranes. Again, this upregulation during cardiovascular development is concomitant with the role of perlecan's C-terminus as endorepellin.
Spatio-temporal specificity in trans-activation of the perlecan gene during development is key to the maturation of basement membranes and thus to the complete separation of epithelia from endothelia and stroma. A thorough study of perlecan expression during chick embryo development has shown that perlecan is present at the morula stage and for the rest of development, although expression can be transient and precisely timed in certain tissue predecessors. In the rat embryo, perlecan expression has been shown to increase in vascular smooth muscle cells (VSMCs) post e19 in fetal development. This correlates perfectly with the ceasing of proliferation of VSMCs at e18 and a change in their phenotype. The theory put forward in this study is that perlecan plays an anti-proliferative role for VSMCs once a certain developmental point is reached, much like confluence-dependent expression of perlecan in culture. These findings were corroborated by similar results from studies of rat pulmonary artery and lung epithelia. These tissues also were found to begin perlecan production once cell division had ceased, around fetal day 19.
The development of the nervous system and extension of axons is precisely directed by cues from extracellular matrix molecules. Olfactory neurite outgrowth in mouse development is guided at least in part by an ECM laid down by olfactory epithelial cells (OECs). Perlecan and laminin-1 appear to be important in this guidance pathway, although perlecan induction occurs slightly later than laminin-1. This data is supported by earlier data showing that OECs express FGF-1 during olfactory development, and that perlecan can stimulate olfactory sensory neurite outgrowth in culture in the presence of FGF-1. Perlecan also showed nerve adhesive properties in a previous study, further suggesting that it may act in an attractive role in combination with laminin rather than a repulsive one.
Cartilage and bone development have proven to be dependent upon perlecan expression. The protein becomes visible by immunostaining on day 15 during mouse development, independently from other basement membrane proteins, suggesting that it is simply a part of the ECM of developing chondrocytes, in addition to collagen II and other cartilage markers that are expressed starting on day 12. Taken with the data, that mice lacking the pln gene cannot maintain stable cartilage, it is apparent that perlecan is essential to the maturation and stability of cartilaginous structure. This is supported by a study showing that knockdown of perlecan production inhibits the final stages of chondrogenic differentiation in C3H10T1/2 fibroblasts in culture. Bone development, i.e. mineralization of cartilaginous tissue, correlates with loss of perlecan and heparan sulfate at the chondro-osseous junction (COJ). In an effort to understand how heparan sulfate and perlecan direct mesenchymal stem cells into the osteogenic pathway, human mesenchymal stem cells were treated with heparanase and chondroitinase in culture. This led to increased mineralization and expression of osteocyte markers, supporting the data showing that loss of heparan sulfate at the COJ is a key factor in osteogenesis. It is thought that the driving force behind heparanase and chondroitinase activation of osteogenesis is release of bone morphogenetic protein bound in the heparan sulfate chains.
### Animal models
Perlecan knockdown in embryonic zebrafish has been achieved through the use of Morpholinos targeted to the perlecan transcript. Morpholinos were used to block translation of the perlecan mRNA in zebrafish embryos, as part of an investigation into perlecan function in skeletal and vascular development. The Morpholino targets the five prime untranslated region of the perlecan mRNA thus blocking translation of the message. Loss of the perlecan protein in these fish led to serious myopathies and circulation problems. As shown in a later study from the same laboratory, this phenotype could be rescued through the addition of exogenous VEGF-A.
The importance of perlecan to mammalian development is demonstrated by perlecan gene knockout experiments. Nearly half of all mice in which the perlecan gene has been knocked out (perlecan null mice) die at embryonic day 10.5, when the perlecan gene normally starts to be expressed. Others die just after birth with severe defects such as abnormal basement membrane formation, defective cephalic and long bone development and achondroplasia. The knockout strategy employed for the first perlecan knockout mouse was a floxing of exon 6 by insertion of a neomycin cassette, and subsequent CRE expression for removal of exon 6 from the genome. This resulted in the cartilage-compromised phenotype previously discussed and loss of basement membrane integrity in a variety of tissues. The fetal mortality rate is high and the mouse that survive die soon after birth. A separately developed perlecan knockout mouse model was created by insertion of a neomycin cassette into exon 7 of the pln gene. These knockout mice were also 40% embryonic lethal, with the rest of the mice dying soon after birth due to severe skeletal abnormalities. In yet another mouse knock-in model, the perlecan gene was mutated by homologous recombination of the endogenous perlecan gene with a construct containing 2 and 5 kb arms of homology surrounding a deleted exon 3, which is only 45 base pairs in length. This deletion abolished heparan sulfate chain attachment to the resulting core protein in vivo. The ensuing study showed that mice lacking heparan sulfate additions on perlecan had collapse of lens capsule integrity by postnatal week 3, indicating a role for heparan sulfate in maintaining lens capsule basement membrane integrity, similar to the TGF-β knockout mouse model. Exon 3 knockout mice also showed decreased wound healing and angiogenesis capabilities when challenged by either epidermal injury or FGF-2 addition to the cornea. In the epidermal injury study, a wound spanning the depth of the epidermis was created in exon 3-negative mice and control mice, and in the knockout mice angiogenesis and the hallmarks of wound healing were slow to develop possibly due to decreased growth factor sequestration by the heparan sulfate-negative perlecan. A similar result was produced in the corneal micropocket assay, where FGF-2 is implanted into the cornea of mice and in normal mice angiogenesis is induced. In the knockout mice this angiogenic effect was impaired, although not completely.
Studies from gene knockout mice and human diseases have also revealed critical in vivo roles for perlecan in cartilage development and neuromuscular junction activity.
## Signaling pathways and their effect on expression
Signaling pathways function to elevate or decrease levels of transcription of genes, which in turn cause cells to change their gene expression profile. The end effect of signaling pathways is exerted on the promoter of genes, which can include elements upstream or downstream of the transcriptional start site, some of which can exist inside of the transcribed gene itself. A number of signaling molecules can effect changes in perlecan expression including the transforming growth factor-Beta (TGF-β), interleukin(IL) and vascular endothelial growth factor (VEGF) families of molecules.
### Transcriptional activation
The upstream 2.5 kilobases of the perlecan promoter region were studied by CAT activation in cell lines of various histological origins. This study concluded that there existed a TGF-β responsive element in the promoter just 285 base pairs upstream of the transcriptional start site. This result has been corroborated in such tissues as human colon carcinoma cells. and murine uterine epithelium by in vitro addition of the cytokine to cell culture medium. In vitro studies of TGF-β1 signaling and its effects on perlecan expression can have varying results in different cell types. In human coronary smooth muscle cells in culture, TGF-β1 signaling showed no effect on perlecan expression although it did upregulate other matrix constituents. In vivo demonstration of the dynamic regulation of perlecan and its control by extracellular signaling pathways is critical to our understanding of the protein's role in development. To this end, a transgenic mouse line was created expressing porcine TGF-β1 under the lens-specific αA-crystallin promoter and then another similar line was created but with the gene driven by the βb-crystallin promoter, corresponding to another lens-specific gene. This developmentally dynamic tissue showed a serious misregulation of extracellular matrix components including perlecan with TGF-β1 over expression. Corneal opacification occurred in both transgenic lines early in development due to greatly increased expression of perlecan, fibronectin and thrombospondin-1 in the corneal mesenchyme. The effect was more pronounced in the βB-1 Crystallin promoter-driven line.
The IL family of inflammatory cytokines also upregulates the pln transcript. In a mouse model of Alzheimer's plaque formation, IL-1-alpha effects an increase in perlecan expression in response to brain injury. IL-4 treatment of human gingival fibroblasts in culture led to increased production of various heparan sulfate proteoglycans including perlecan. Treatment of human lung fibroblasts in vitro with IL-1-beta did not lead to any significant increase in perlecan production.
Another signaling pathway shown to augment pln transcription is the VEGF pathway. VEGF165 treatment of human brain microvascular endothelial cells in culture stimulates increased pln transcription. This molecule is a ligand of VEGF Receptor-2 (VGFR2), and it seems that this VEGF165 response is specific for perlecan upregulation, leading to a positive feedback loop involving fibroblastic growth factor (FGF), FGF Receptor (FGFR) and VEGFR2 in response to endothelial damage. This microvascular-specific regulation by VEGF165 raises the possibility that the anti-coagulant function of perlecan is a part of the damage-control process in brain endothelia.
Protein Kinase C signaling is putatively responsible for upregulating transcription and translation of certain proteoglycans including perlecan. When the endocytic pathway of HeLa cells is inhibited by overexpression of a mutant dynamin, Protein Kinase C is activated and perlecan message and protein are subsequently increased. In contrast, the usual downregulation of perlecan in response to hyperglycemia is lost in mice negative for PKC-α.
### Transcriptional downregulation
Interferon-γ signaling mediates transcriptional repression of the perlecan gene. This was first shown in colon cancer cell lines, and subsequently in cell lines of other tissue origins, but in each case intact STAT1 transcription factor was required for the signal to take effect. This led the investigators to believe that the transcription factor STAT1 was interacting with the Pln promoter in the distal region, localized to 660 base pairs upstream of the transcription start site. Interferon- γ treatment of blastocyst-stage murine embryos leads to a loss of perlecan expression on the trophectoderm, and thus an embryonic morphology and phenotype in cell culture, which is suggestive that these interferon-γ treated blastocysts would be defective in implantation. Presumably the loss of perlecan expression stems from downregulation of transcription via STAT1 transcription factor activity as shown previously. These in vitro results are not necessarily representative of normal physiological interferon- γ concentrations, nor are the cytokine normally expressed widely but instead at very specific developmental timepoints. Important to note is that perlecan expression can be decreased by treatment with an exogenous cytokine such as interferon- γ, and if there were a physiologically abnormal increase in expression of the cytokine it could interfere with implantation.
## Cell stressors and their effect on expression
Mechanical and chemical stress can damage basement membranes or the cells they support. This could influence the gene expression profile of the cells, especially in their extracellular matrix, which often provides physical support and a chemical barrier for the cells. Hypoxia, inflammation, mechanical and chemical stress have been examined as to how they relate to perlecan expression.
Hypoxia is a condition found in disease states and during injury and often results in a lack of endothelial cell proliferation. This and perlecan's role as endorepellin prompted one study into the nature of perlecan expression regulation by endothelial cells during hypoxic conditions. Under hypoxic conditions, this study found that perlecan expression by rat cardiac microvascular endothelial cells was decreased sixty-one percent compared to normal controls. The contention of this paper is that perlecan downregulation leads to a loss of FAK activation and thus less ERK signaling, leading to decreased cell proliferation. It does seem counterintuitive that endothelial cells would proliferate less quickly due to loss of perlecan and its endorepellin subunit. It could be that these endothelial cells merely downregulated transcription of many genes in response to hypoxic conditions. In another study, hypoxia led to induction of genes associated with apoptosis and cell death, but repression of genes was not limited to proteins associated with a specific pathway. When T84 intestinal epithelial cells are exposed to hypoxic conditions for 24 hours a significant increase in perlecan mRNA and protein production occurs. They relate this to the fact that many genes elevated in response to hypoxia contain a cAMP response element (CRE) in their promoter, as does pln. This difference between endothelial cells from the study in 2007 and the epithelial cell studied in these experiments is indicative of how varied the regulatory mechanisms of perlecan may be in different cell types.
The development of beta-amyloid plaques on the brain is associated with onset of Alzheimer's disease. These plaques induce a constant state of inflammation in areas of accumulation, leading to expression of certain inflammation-related gene products, some of which perpetuate the inflammation in the brain context. As previously mentioned, to investigate the effect of brain inflammation on expression levels of perlecan, needle stab wounds were created in mice brains, and after inflammation and variable periods of recovery, mRNA and protein levels were assessed via in situ hybridization and immunostaining. Perlecan levels were increased in the hippocampus but not in the striatum during the healing period, along with IL 1-alpha expression. Perlecan expression was traced to microglial cells in the hippocampus and astrocytes. This role for perlecan in beta-amyloid plaque generation is supported by an earlier study showing that perlecan and beta-amyloid treatment of rat brains led to formation of senile plaques, whereas treatment with beta-amyloid alone did not have the same effect.
At the organismic level, mechanical stress has a profound impact on extracellular matrix integrity and probably causes induction of a number of ECM genes for repair and remodeling of ECM in tissue stroma and basement membranes. One study examined the in vitro effects of pressure on global gene transcription using a microarray approach and a cell stretching system meant to simulate intraocular pressure in the lamina cribosa (connective tissue) of the optic nerve head. Their findings were that perlecan and several other proteoglycans were upregulated in response to the stretching stimulus. TGF-β2 and VEGF were induced as well, possibly contributing to the upregulation of the perlecan transcript and protein. It has been shown that autocrine TGF-β signaling is a compensatory result of mechanical stress in vitro in endothelial cells. Using a similar cell stretching mechanism to mimic arterial pressure, this investigation showed that perlecan production increased in response to mechanical strain. This is contingent upon TGF-β autocrine signaling in a positive feedback loop with p38 and ERK. This endothelial cell increase in production of VSMC growth inhibitors (i.e. heparin) is reversed in VSMCs, where mechanical stress induces proliferation. Deformation of VSMC cells in culture leads to perlecan upregulation, with a significant increase in sulfation of the heparan sulfate chains. This is not in contrast to the data shown where perlecan expression is constant beyond e19 in rat VSMC, which suggested that perlecan plays an antiproliferative role for VSMCs. In this case, it seems that the molecule's signaling function is the operative upregulated factor, especially due to the increase in sulfation of the heparan sulfate chains.
Chemical damage to organs can affect not only the cell's genetic and mechanical integrity but the extracellular matrix of the tissue. To study the effect of chemical damage on liver cells, wistar rats were treated with carbon tetrachloride for 48 hours prior to sacrificing. Prior to treatment with CCl4, perlecan staining was limited to the bile duct and sinusoidal blood vessels of the liver. After treatment, perlecan staining was intense in areas of necrosis. This could have been due to the increase in capillarization of the liver as an attempt to regenerate damaged tissue. A similar finding was shown in acetamenophin treatment of mice, where perlecan and other matrix components were heavily expressed in necrotic lesions of the liver.
## Expression in cell culture
One of the resounding arguments against the validity of in vitro results of cell culture on 2D plastic plates is that the environment does not accurately reflect that of the cells in the organism. This problem is being dealt with by developing 3D cell cultures using a wide variety of substrates as the scaffolds or environments for the cells. In this kind of setting the expression of ECM genes has the potential to more closely resemble that of the native expression profile. 3D scaffolds, the structures on which the cultured cells grow, can be composed of other cells, i.e. cocultures, synthetic polymers mimicking the cells natural environment or purified ECM such as matrigel, and any mixture of these three components.
One such system has been developed to study skin development and basal membrane formation between keratinocytes and the stroma. This system is used to delineate the development of basement membrane between fibroblasts in the stroma (in this case fibroblasts in a type-I collagen gel) and keratinocytes grown on top of the gel. Perlecan expression and thus basement membrane maturation is dependent on nidogen crosslinking of collagen IV and laminin γ1 chain in this system. This effect also led to a lack of hemidesmosomes in the developing tissue. Another system using a disorganized hydrated collagen I gel has been used to demonstrate that primary human corneal fibroblasts will eventually invade the gel and create a matrix consisting of collagen type I and perlecan, as well as several other sulfated matrix glycoproteins. This mimics the in vivo corneal fibroblast's developmental program and response to injury.
One of the long-term goals of creating 3D cell culture systems is to engineer tissues that can be used as replacements for patients with many types of disease. In tissue engineered heart valves created by seeding myofibroblasts onto collagen type I followed by endothelial cells, heparan sulfate proteoglycan expression has been verified, although no distinction between syndecan and perlecan has been made in these tissues. Another procedure that could be made possible by tissue engineering is keratoepithelioplasty. Transplanted tissue must remain intact, which requires a pre-formed basement membrane. Collagen gels have promoted formation of a complete basement membrane by corneal epithelial cells in culture.
Perlecan also holds promise to serve as a scaffold for plating cells in culture. Human salivary gland ductal and acinar cells have been successfully grown on a bioactive peptide containing a sequence repeated in domain IV of the perlecan protein. These cells reproduce acini-like structures similar to those found in the native gland and tight junctions, along with complete basement membranes in culture.
# Disease association
## Cancer
While Perlecan suppression causes substantial inhibition of tumor growth and neovascularization in null mice, in contrast, when perlecan-null cells are injected into nude mice enhanced tumor growth is observed when compared to controls.
Cancer progression and pathogenesis is intimately linked to extracellular matrix composition and the role of perlecan and other ECM molecules in cancer is being studied by a large number of laboratories. Since the basement membrane is the first obstacle in the way of extravasating carcinoma cells, the functions of perlecan in this process are multiple. One model system used to study perlecan expression in carcinoma cell lines is that of the MeWo/70W melanoma metastatic progression cell lines. MeWo cells are characteristically less invasive than their clonal variant cell line 70W. One lab studied perlecan expression in 27 invasive melanomas and 26 of the 27 samples showed a significant increase in perlecan message when compared to normal tissue from the same patients. They then used the MeWo and 70W cell lines to study if perlecan expression changed during treatment with neurotrophins, which can stimulate cell invasion through matrigel in vitro. The more invasive 70W cells began expressing perlecan message ten minutes after stimulation with the neurotrophins, and the MeWo cells did not produce any pln message regardless of treatment. This study took special note of the fact that perlecan upregulation occurred even before that of heparanase, an essential protein involved in the process of extravasation.
In ovarian cancer as in other cancers, perlecan expression occurs differently throughout progression of the disease. Perlecan staining is lost in ovarian basement membrane that has been breached by an invasive adenocarcinoma, which is in contrast to perlecan staining in the basement membranes of normal ovaries and those with benign tumors, where basement membrane is homogeneous and very similar in composition to that in other normal tissues. This is consistent with other results showing loss of perlecan in basement membranes affected by invasive cervical cancer spreading to the pelvic lymph nodes, which comes as no surprise due to the correlation of elevated levels of heparanase mRNA expression with invasion of similar cervical carcinoma. By contrast, tumor formation of the immortalized mouse epithelial cell line RT101 injected into rats was dependent on perlecan expression by the mouse cells and not on the presence of endogenous rat perlecan. RT101 cells with perlecan knocked down by antisense did not show tumor formation in this system, however cells expressing the antisense perlecan and a recombinant construct encoding domains I, II, and III of mouse perlecan did indeed show tumor formation. Thus in this system it does appear that tumor cell expression of perlecan is necessary for tumor aggregation. More research into GAG chain or core protein modification by invasive tumor cells as compared to benign tumor cells and normal tissue would be informative to better understand perlecans role in cancer migration.
Several laboratories have studied in vitro tumor cell angiogenesis using antisense constructs to the perlecan message. The full-length reverse complement cDNA, driven by a strong promoter, is transfected into various cell types to completely eliminate perlecan expression. Antisense in colon carcinoma cells blocks perlecan translation, leading to decreased tumor growth and angiogenesis. A similar in vitro decrease in proliferation occurred in NIH 3T3 cells and a human melanoma cell line expressing antisense perlecan mRNA. Findings in vitro with Kaposi's sarcoma cell lines showed that loss of perlecan via transfection with an antisense construct led to decreased proliferation and migration of this highly metastatic cell type. These results are in contrast to in vivo results with the same Kaposi Sarcoma lines, which show that decreased perlecan leads to increased angiogenesis, which facilitates migration and thus is associated with increase in tumor grade. Antisense knockdown of perlecan in fibrosarcoma cell lines led to increased growth and migration both in vitro and in vivo. These findings of greater tumorigenesis in vivo are supported by data showing that the C-terminus of the perlecan protein acts as an endostatic module now known as endorepellin.
A ribozyme construct was created for use in knocking down perlecan translation levels. This ribozyme was targeted at a sequence coding domain I of the perlecan protein. It reduced expression of perlecan up to 80% in the prostate cancer cell line C42B. In contrast to previously discussed studies these cells produced smaller tumors than their parental cells when injected into athymic mice. What this disparity in results means for invasion is unknown, although it is true that perlecan is part of the extracellular matrix in mesenchymal tissue, and cells undergoing epithelial-mesenchymal transition (EMT) may upregulate perlecan expression as part of their EMT programming.
## Diabetes and cardiovascular disease
Perlecan levels are decreased in many disease states - e.g., diabetes, atherosclerosis and arthritis. Perlecan has an important role in the maintenance of the glomerular filtration barrier. Decreased perlecan in the glomerular basement membrane has a central role in the development of diabetic albuminuria. Perlecan expression is down regulated by many atherogenic stimuli and thus Perlecan is thought to play a protective role in atherosclerosis. Diabetes and atherosclerosis are commonly associated syndromes. 80% of diabetes-associated deaths involve some form of atherosclerotic complication, and the basement membrane of endothelia has been implicated in the atherogenic process. Synthesis of heparan sulfate was shown to decrease in the arteries of diabetics and in arteries developing atherosclerotic lesions.
The mechanism by which heparan sulfate was downregulated in these lesions remained unknown for some time. One theory states that high glucose in circulation could lead to a decrease in GAG chain attachment to perlecan, but not necessarily a change in the synthetic pathway of the GAG chains or that of the core protein. After treatment of human aortic endothelial cells with high glucose medium, secreted perlecan contained less sulfate incorporation accompanied by less overall GAG chain incorporation. Although no signaling pathway is identified leading to this decrease in GAG chain incorporation, it is suggested that the 30% loss in overall glycosylation of the protein could mean loss of one of the three HS chains on perlecan in this model of diabetes-associated hyperglycemia. It is also noted that similar decreases in extracellular HS without a change in staining for the core protein chains occur in diabetic kidneys and in kidney cells in culture treated with high glucose.
Atherosclerosis is most often the culprit in coronary heart disease and other cardiovascular conditions, and a large aggregation of perlecan protein is symptomatic of advanced atherosclerotic plaques. VSMCs are the producers of the perlecan in this condition, meaning that a good deal of research has been focused on understanding the means of perlecan upregulation in this condition. In a test of the effect of circulating nonesterified fatty acids (symptomatic of diabetes and atherogenesis) on perlecan expression by VSMCs, expression did not change when compared to control cells. This was in contrast to a 2-10-fold increase in expression of other basement membrane proteoglycans. Thrombin is another marker associated with atherogenesis and procoagulation, and it selectively upregulates production of perlecan but not other proteoglycans in human VSMCs in culture. It is suggested that this effect is only seen when VSMCs reach confluence, but not prior to confluence. This concept is similar to previously mentioned studies showing that perlecan is only produced by VSMCs once they have ceased proliferation during development. Another marker in the atherosclerotic pathway is angiotensin II, which also upregulates perlecan expression in VSMCs in culture. Given the prominence of perlecan expression in atherosclerosis there is potential for therapy based upon perlecan expression and research may eventually proceed in that direction.
## Genetic disease
Mutations in the HSPG2 gene, which encodes perlecan, cause Schwartz–Jampel syndrome.
# Interactions
Perlecan has been shown to interact with
- FBLN2,
- FGF7,
- FGFBP1, and
- Transthyretin. | Perlecan
Perlecan (PLC) also known as basement membrane-specific heparan sulfate proteoglycan core protein (HSPG) or heparan sulfate proteoglycan 2 (HSPG2), is a protein that in humans is encoded by the HSPG2 gene.[1][2][3]
Perlecan is a large multidomain (five domains, labeled I-V) proteoglycan that binds to and cross-links many extracellular matrix (ECM) components and cell-surface molecules.[4] Perlecan is synthesized by both vascular endothelial and smooth muscle cells and deposited in the extracellular matrix. Perlecan is highly conserved across species and the available data indicate that it has evolved from ancient ancestors by gene duplication and exon shuffling.[4]
# Structure
Perlecan consists of a core protein of molecular weight 470 kDa to which three long chains (each approximately 70-100 kDa) of glycosaminoglycans (often heparan sulfate, HS, but can be chondroitin sulfate, CS) are attached. The core protein consists of five distinct structural domains. The N-terminal domain I (aa ~1-195) contains attachment sites for HS chains. Although HS chains are not required for correct folding and secretion of the protein, lack of HS or decreased sulfation can decrease perlecan's ability to interact with matrix proteins. Removal of HS chains may affect matrix organization and endothelial barrier function. Domain II comprises four repeats homologous to the ligand-binding portion of the LDL receptor with six conserved cysteine residues and a pentapeptide, DGSDE, which mediates ligand binding by the LDL receptor. Domain III has homology to the domain IVa and IVb of laminin. Domain IV consists of a series of IG modules. The C-terminal Domain V, which has homology to the G domain of the long arm of laminin, is responsible for self-assembly and may be important for basement membrane formation in vivo. Thus, perlecan core protein and HS chains could modulate matrix assembly, cell proliferation, lipoprotein binding and cell adhesion.
A diagram showing the domain structure of perlecan is available here
# Function
Perlecan is a key component of the vascular extracellular matrix, where it interacts with a variety of other matrix components and helps to maintain the endothelial barrier function. Perlecan is a potent inhibitor of smooth muscle cell proliferation and is thus thought to help maintain vascular homeostasis. Perlecan can also promote growth factor (e.g., FGF2) activity and thus stimulate endothelial growth and re-generation.
# Modification of glycosaminoglycan chains
Modifications of the heparan sulfate chains on C- and N-terminal domains are the best-studied differences in the secretory pathway of perlecan. Chondroitin sulfate can be substituted for heparan sulfate, and sulfate incorporation or the sugar composition of the chains can change. Loss of enzymes involved in the heparan sulfate synthetic pathway lead to a number of conditions.
Differential heparan sulfate chain modification can occur through a number of regulatory signals. Perlecan in the growth plate of mouse long bones shows glycosylation changes in the chondrocyte progression from the resting zone to the proliferating zone.[5] Although initially the glycosaminoglycan (GAG) chains of perlecan were thought to be exclusively heparan sulfate, chondroitin sulfate chains can be substituted during specific regulatory cues. By expressing a recombinant form of the N-terminal domain I of the protein and demonstrating that digestion of the peptide with either heparanase or chondroitinase did not lead to complete loss of the peptide's activity, it was shown that chondroitin sulfate chains can be added to human perlecan.[6] This was in agreement with previous data showing chondroitin sulfate GAG chains attached to bovine perlecan produced by chondrocytes[7] and that recombinant human domain I protein was glycosylated with both heparan and chondroitin sulfate chains when expressed in Chinese Hamster Ovary cells.[8] The preferential addition of heparan sulfate or chondroitin sulfate chains to domains I and V could have an effect on the differentiation of mesenchymal tissues into cartilage, bone or any number of tissues, but the regulatory mechanism of changing from heparan sulfate to chondroitin sulfate addition are not well understood.
While studying the effect of proteoglycan composition on nephritic permselectivity, it was noted that puromycin treatment of human glomerular endothelial cells (HGEC) altered the sulfation level of GAG chains on proteoglycans such as perlecan, which in turn caused a decrease in the stability of the GAG chains. The core protein mRNA levels of proteoglycans were not affected, thus the decrease in GAG chains was as a result of some other factor, which in this case turned out to be a decrease in expression of sulfate transferase enzymes, which play a key role in GAG biosynthesis.[9] It seems that there may be some overlap in diseases stemming from loss of heparan sulfate proteoglycan expression and loss of enzymes involved in heparan sulfate biosynthesis.
# Degradation
Cells can modify their extracellular matrix and basement membranes in response to signals or stress. Specific proteases act on the protein in the extracellular environment when cells have a reason to move or change their surroundings. Cathepsin S is a cysteine protease that moderately attenuates binding of FGF-positive cells to a perlecan-positive substrate. Cathepsin S is a potential protease that acts on the core protein of perlecan in the basement membrane or stroma.[10]
The heparan sulfate chains of perlecan bind growth factors in the ECM, and serve as co-ligands or ligand enhancers when bound to receptors. Another study showed that release of HS-bound basic FGF in culture could be achieved through treatment with stromelysin, heparitinase I, rat collagenase and plasmin,[11] and these proteolysis sites are illustrated in figure 1. This was proposed as a non-exhaustive list of the proteases that could mediate release of growth factors from the heparan sulfate chains of perlecan. Although Whitelock et al. suggested that thrombin cleavage consensus sequences exist in the core protein of perlecan, they also postulate that any thrombin activation of perlecan actually comes from cleavage of other ECM constituents. This article states that heparanase is responsible for cleavage of the heparan sulfate chains of perlecan in matrix. This releases growth factors bound to the heparan sulfate, specifically FGF-10. Addition of heparanase to cell culture of epithelia in basement membrane caused an increase in epithelial cell proliferation due to FGF-10 release.[12]
In a model of explant growth in vitro using corneal epithelium, Matrix Metalloproteinase (MMP) 2 expression correlates with an initial degradation of the original basement membrane. Reformation of basement membrane in culture was dependent on an initial upregulation followed by a downregulation of MMP-9, in contrast to the constant expression of MMP-2. This is not evidence that MMP-2 and MMP-9 directly cleave perlecan protein in vivo but shows that the proteins clearly modulate some factor in maturation of basement membrane.[13] Another family of metalloproteases, the Bone Morphogenetic Protein 1/Tolloid-like family, releases the c-terminal endorepellin domain of the perlecan core protein. The laminin-like globular domain contains the active motif of endorepellin, and is unable to be cleaved by cells expressing mutant and inactive forms of the BMP-1 proteins. Furthermore, the critical residue necessary for this cleavage to take place was localized to Asp4197.[14] This proteolytic process may have significance in disease as a corresponding fragment was found in the urine of patients suffering end-stage renal failure[15] and in the amniotic fluid of pregnant women who have undergone premature rupture of the membrane.[16]
# Expression
## Expression during development
Timing of gene expression during development varies from tissue to tissue. Basement membranes are often the driving force behind separating epithelia from stroma and connective tissue. Perlecan is of particular importance in cardiovascular, neural and cartilaginous development.
Pre-implantation blastocyst development is a controlled cascade of gene regulation and intercellular signaling. Extracellular perlecan has been observed at the blastocyst stage of mouse embryonic development, specifically upregulated at the point when the embryo reaches “attachment competence”.[17] This finding was upheld at both the mRNA level and the protein level, shown by RT-PCR and immunostaining. Later embryonic development is just as precisely regulated as pre-implantation development, and is more complicated due to differentiation of all tissues. The first study of perlecan expression during embryonal development found that the protein was first expressed during development of the cardiovascular system, and later correlates with maturation of the majority of tissues in the body, i.e. separation of epithelial layers from endothelia and stroma by basement membranes.[18] Again, this upregulation during cardiovascular development is concomitant with the role of perlecan's C-terminus as endorepellin.
Spatio-temporal specificity in trans-activation of the perlecan gene during development is key to the maturation of basement membranes and thus to the complete separation of epithelia from endothelia and stroma. A thorough study of perlecan expression during chick embryo development has shown that perlecan is present at the morula stage and for the rest of development, although expression can be transient and precisely timed in certain tissue predecessors.[19] In the rat embryo, perlecan expression has been shown to increase in vascular smooth muscle cells (VSMCs) post e19 in fetal development. This correlates perfectly with the ceasing of proliferation of VSMCs at e18 and a change in their phenotype. The theory put forward in this study is that perlecan plays an anti-proliferative role for VSMCs once a certain developmental point is reached, much like confluence-dependent expression of perlecan in culture.[20] These findings were corroborated by similar results from studies of rat pulmonary artery and lung epithelia. These tissues also were found to begin perlecan production once cell division had ceased, around fetal day 19.[21]
The development of the nervous system and extension of axons is precisely directed by cues from extracellular matrix molecules. Olfactory neurite outgrowth in mouse development is guided at least in part by an ECM laid down by olfactory epithelial cells (OECs). Perlecan and laminin-1 appear to be important in this guidance pathway, although perlecan induction occurs slightly later than laminin-1.[22] This data is supported by earlier data showing that OECs express FGF-1 during olfactory development, and that perlecan can stimulate olfactory sensory neurite outgrowth in culture in the presence of FGF-1.[23] Perlecan also showed nerve adhesive properties in a previous study, further suggesting that it may act in an attractive role in combination with laminin rather than a repulsive one.[24]
Cartilage and bone development have proven to be dependent upon perlecan expression. The protein becomes visible by immunostaining on day 15 during mouse development, independently from other basement membrane proteins, suggesting that it is simply a part of the ECM of developing chondrocytes, in addition to collagen II and other cartilage markers that are expressed starting on day 12.[25] Taken with the data,[26] that mice lacking the pln gene cannot maintain stable cartilage, it is apparent that perlecan is essential to the maturation and stability of cartilaginous structure. This is supported by a study showing that knockdown of perlecan production inhibits the final stages of chondrogenic differentiation in C3H10T1/2 fibroblasts in culture.[27] Bone development, i.e. mineralization of cartilaginous tissue, correlates with loss of perlecan and heparan sulfate at the chondro-osseous junction (COJ).[28][29] In an effort to understand how heparan sulfate and perlecan direct mesenchymal stem cells into the osteogenic pathway, human mesenchymal stem cells were treated with heparanase and chondroitinase in culture. This led to increased mineralization and expression of osteocyte markers, supporting the data showing that loss of heparan sulfate at the COJ is a key factor in osteogenesis.[30] It is thought that the driving force behind heparanase and chondroitinase activation of osteogenesis is release of bone morphogenetic protein bound in the heparan sulfate chains.
### Animal models
Perlecan knockdown in embryonic zebrafish has been achieved through the use of Morpholinos targeted to the perlecan transcript. Morpholinos were used to block translation of the perlecan mRNA in zebrafish embryos, as part of an investigation into perlecan function in skeletal and vascular development. The Morpholino targets the five prime untranslated region of the perlecan mRNA thus blocking translation of the message.[31] Loss of the perlecan protein in these fish led to serious myopathies and circulation problems. As shown in a later study from the same laboratory, this phenotype could be rescued through the addition of exogenous VEGF-A.[32]
The importance of perlecan to mammalian development is demonstrated by perlecan gene knockout experiments. Nearly half of all mice in which the perlecan gene has been knocked out (perlecan null mice) die at embryonic day 10.5, when the perlecan gene normally starts to be expressed.[33] Others die just after birth with severe defects such as abnormal basement membrane formation, defective cephalic and long bone development and achondroplasia.[26][34] The knockout strategy employed for the first perlecan knockout mouse[25] was a floxing of exon 6 by insertion of a neomycin cassette, and subsequent CRE expression for removal of exon 6 from the genome. This resulted in the cartilage-compromised phenotype previously discussed and loss of basement membrane integrity in a variety of tissues. The fetal mortality rate is high and the mouse that survive die soon after birth. A separately developed perlecan knockout mouse model was created by insertion of a neomycin cassette into exon 7 of the pln gene.[34] These knockout mice were also 40% embryonic lethal, with the rest of the mice dying soon after birth due to severe skeletal abnormalities. In yet another mouse knock-in model, the perlecan gene was mutated by homologous recombination of the endogenous perlecan gene with a construct containing 2 and 5 kb arms of homology surrounding a deleted exon 3, which is only 45 base pairs in length. This deletion abolished heparan sulfate chain attachment to the resulting core protein in vivo. The ensuing study showed that mice lacking heparan sulfate additions on perlecan had collapse of lens capsule integrity by postnatal week 3, indicating a role for heparan sulfate in maintaining lens capsule basement membrane integrity,[35] similar to the TGF-β knockout mouse model.[36][37] Exon 3 knockout mice also showed decreased wound healing and angiogenesis capabilities when challenged by either epidermal injury or FGF-2 addition to the cornea.[38] In the epidermal injury study, a wound spanning the depth of the epidermis was created in exon 3-negative mice and control mice, and in the knockout mice angiogenesis and the hallmarks of wound healing were slow to develop possibly due to decreased growth factor sequestration by the heparan sulfate-negative perlecan. A similar result was produced in the corneal micropocket assay, where FGF-2 is implanted into the cornea of mice and in normal mice angiogenesis is induced. In the knockout mice this angiogenic effect was impaired, although not completely.
Studies from gene knockout mice and human diseases have also revealed critical in vivo roles for perlecan in cartilage development[39] and neuromuscular junction activity.[40]
## Signaling pathways and their effect on expression
Signaling pathways function to elevate or decrease levels of transcription of genes, which in turn cause cells to change their gene expression profile. The end effect of signaling pathways is exerted on the promoter of genes, which can include elements upstream or downstream of the transcriptional start site, some of which can exist inside of the transcribed gene itself. A number of signaling molecules can effect changes in perlecan expression including the transforming growth factor-Beta (TGF-β), interleukin(IL) and vascular endothelial growth factor (VEGF) families of molecules.
### Transcriptional activation
The upstream 2.5 kilobases of the perlecan promoter region were studied by CAT activation in cell lines of various histological origins.[41] This study concluded that there existed a TGF-β responsive element in the promoter just 285 base pairs upstream of the transcriptional start site. This result has been corroborated in such tissues as human colon carcinoma cells.[42] and murine uterine epithelium[43] by in vitro addition of the cytokine to cell culture medium. In vitro studies of TGF-β1 signaling and its effects on perlecan expression can have varying results in different cell types. In human coronary smooth muscle cells in culture, TGF-β1 signaling showed no effect on perlecan expression although it did upregulate other matrix constituents.[44] In vivo demonstration of the dynamic regulation of perlecan and its control by extracellular signaling pathways is critical to our understanding of the protein's role in development. To this end, a transgenic mouse line was created expressing porcine TGF-β1 under the lens-specific αA-crystallin promoter[36] and then another similar line was created but with the gene driven by the βb-crystallin promoter, corresponding to another lens-specific gene.[37] This developmentally dynamic tissue showed a serious misregulation of extracellular matrix components including perlecan with TGF-β1 over expression. Corneal opacification occurred in both transgenic lines early in development due to greatly increased expression of perlecan, fibronectin and thrombospondin-1 in the corneal mesenchyme. The effect was more pronounced in the βB-1 Crystallin promoter-driven line.
The IL family of inflammatory cytokines also upregulates the pln transcript. In a mouse model of Alzheimer's plaque formation, IL-1-alpha effects an increase in perlecan expression in response to brain injury.[45] IL-4 treatment of human gingival fibroblasts in culture led to increased production of various heparan sulfate proteoglycans including perlecan.[46] Treatment of human lung fibroblasts in vitro with IL-1-beta did not lead to any significant increase in perlecan production.[47]
Another signaling pathway shown to augment pln transcription is the VEGF pathway. VEGF165 treatment of human brain microvascular endothelial cells in culture stimulates increased pln transcription. This molecule is a ligand of VEGF Receptor-2 (VGFR2), and it seems that this VEGF165 response is specific for perlecan upregulation, leading to a positive feedback loop involving fibroblastic growth factor (FGF), FGF Receptor (FGFR) and VEGFR2 in response to endothelial damage. This microvascular-specific regulation by VEGF165 raises the possibility that the anti-coagulant function of perlecan is a part of the damage-control process in brain endothelia.[48]
Protein Kinase C signaling is putatively responsible for upregulating transcription and translation of certain proteoglycans including perlecan. When the endocytic pathway of HeLa cells is inhibited by overexpression of a mutant dynamin, Protein Kinase C is activated and perlecan message and protein are subsequently increased.[49] In contrast, the usual downregulation of perlecan in response to hyperglycemia is lost in mice negative for PKC-α.[50]
### Transcriptional downregulation
Interferon-γ signaling mediates transcriptional repression of the perlecan gene.[51] This was first shown in colon cancer cell lines, and subsequently in cell lines of other tissue origins, but in each case intact STAT1 transcription factor was required for the signal to take effect. This led the investigators to believe that the transcription factor STAT1 was interacting with the Pln promoter in the distal region, localized to 660 base pairs upstream of the transcription start site.[51] Interferon- γ treatment of blastocyst-stage murine embryos leads to a loss of perlecan expression on the trophectoderm, and thus an embryonic morphology and phenotype in cell culture, which is suggestive that these interferon-γ treated blastocysts would be defective in implantation.[52] Presumably the loss of perlecan expression stems from downregulation of transcription via STAT1 transcription factor activity as shown previously. These in vitro results are not necessarily representative of normal physiological interferon- γ concentrations, nor are the cytokine normally expressed widely but instead at very specific developmental timepoints. Important to note is that perlecan expression can be decreased by treatment with an exogenous cytokine such as interferon- γ, and if there were a physiologically abnormal increase in expression of the cytokine it could interfere with implantation.
## Cell stressors and their effect on expression
Mechanical and chemical stress can damage basement membranes or the cells they support. This could influence the gene expression profile of the cells, especially in their extracellular matrix, which often provides physical support and a chemical barrier for the cells. Hypoxia, inflammation, mechanical and chemical stress have been examined as to how they relate to perlecan expression.
Hypoxia is a condition found in disease states and during injury and often results in a lack of endothelial cell proliferation. This and perlecan's role as endorepellin prompted one study into the nature of perlecan expression regulation by endothelial cells during hypoxic conditions.[53] Under hypoxic conditions, this study found that perlecan expression by rat cardiac microvascular endothelial cells was decreased sixty-one percent compared to normal controls. The contention of this paper is that perlecan downregulation leads to a loss of FAK activation and thus less ERK signaling, leading to decreased cell proliferation. It does seem counterintuitive that endothelial cells would proliferate less quickly due to loss of perlecan and its endorepellin subunit. It could be that these endothelial cells merely downregulated transcription of many genes in response to hypoxic conditions. In another study, hypoxia led to induction of genes associated with apoptosis and cell death, but repression of genes was not limited to proteins associated with a specific pathway.[54] When T84 intestinal epithelial cells are exposed to hypoxic conditions for 24 hours a significant increase in perlecan mRNA and protein production occurs.[55] They relate this to the fact that many genes elevated in response to hypoxia contain a cAMP response element (CRE) in their promoter, as does pln. This difference between endothelial cells from the study in 2007 and the epithelial cell studied in these experiments is indicative of how varied the regulatory mechanisms of perlecan may be in different cell types.
The development of beta-amyloid plaques on the brain is associated with onset of Alzheimer's disease. These plaques induce a constant state of inflammation in areas of accumulation, leading to expression of certain inflammation-related gene products, some of which perpetuate the inflammation in the brain context. As previously mentioned, to investigate the effect of brain inflammation on expression levels of perlecan, needle stab wounds were created in mice brains, and after inflammation and variable periods of recovery, mRNA and protein levels were assessed via in situ hybridization and immunostaining. Perlecan levels were increased in the hippocampus but not in the striatum during the healing period, along with IL 1-alpha expression.[45] Perlecan expression was traced to microglial cells in the hippocampus and astrocytes. This role for perlecan in beta-amyloid plaque generation is supported by an earlier study showing that perlecan and beta-amyloid treatment of rat brains led to formation of senile plaques, whereas treatment with beta-amyloid alone did not have the same effect.[56]
At the organismic level, mechanical stress has a profound impact on extracellular matrix integrity and probably causes induction of a number of ECM genes for repair and remodeling of ECM in tissue stroma and basement membranes. One study examined the in vitro effects of pressure on global gene transcription using a microarray approach and a cell stretching system meant to simulate intraocular pressure in the lamina cribosa (connective tissue) of the optic nerve head. Their findings were that perlecan and several other proteoglycans were upregulated in response to the stretching stimulus. TGF-β2 and VEGF were induced as well, possibly contributing to the upregulation of the perlecan transcript and protein.[57] It has been shown that autocrine TGF-β signaling is a compensatory result of mechanical stress in vitro in endothelial cells. Using a similar cell stretching mechanism to mimic arterial pressure, this investigation showed that perlecan production increased in response to mechanical strain. This is contingent upon TGF-β autocrine signaling in a positive feedback loop with p38 and ERK.[58] This endothelial cell increase in production of VSMC growth inhibitors (i.e. heparin) is reversed in VSMCs, where mechanical stress induces proliferation.[59] Deformation of VSMC cells in culture leads to perlecan upregulation, with a significant increase in sulfation of the heparan sulfate chains.[60] This is not in contrast to the data shown where perlecan expression is constant beyond e19 in rat VSMC, which suggested that perlecan plays an antiproliferative role for VSMCs. In this case, it seems that the molecule's signaling function is the operative upregulated factor, especially due to the increase in sulfation of the heparan sulfate chains.
Chemical damage to organs can affect not only the cell's genetic and mechanical integrity but the extracellular matrix of the tissue. To study the effect of chemical damage on liver cells, wistar rats were treated with carbon tetrachloride for 48 hours prior to sacrificing. Prior to treatment with CCl4, perlecan staining was limited to the bile duct and sinusoidal blood vessels of the liver. After treatment, perlecan staining was intense in areas of necrosis. This could have been due to the increase in capillarization of the liver as an attempt to regenerate damaged tissue.[61] A similar finding was shown in acetamenophin treatment of mice, where perlecan and other matrix components were heavily expressed in necrotic lesions of the liver.[62]
## Expression in cell culture
One of the resounding arguments against the validity of in vitro results of cell culture on 2D plastic plates is that the environment does not accurately reflect that of the cells in the organism. This problem is being dealt with by developing 3D cell cultures using a wide variety of substrates as the scaffolds or environments for the cells. In this kind of setting the expression of ECM genes has the potential to more closely resemble that of the native expression profile. 3D scaffolds, the structures on which the cultured cells grow, can be composed of other cells, i.e. cocultures, synthetic polymers mimicking the cells natural environment or purified ECM such as matrigel, and any mixture of these three components.
One such system has been developed to study skin development and basal membrane formation between keratinocytes and the stroma.[63] This system is used to delineate the development of basement membrane between fibroblasts in the stroma (in this case fibroblasts in a type-I collagen gel) and keratinocytes grown on top of the gel. Perlecan expression and thus basement membrane maturation is dependent on nidogen crosslinking of collagen IV and laminin γ1 chain in this system.[64] This effect also led to a lack of hemidesmosomes in the developing tissue. Another system using a disorganized hydrated collagen I gel has been used to demonstrate that primary human corneal fibroblasts will eventually invade the gel and create a matrix consisting of collagen type I and perlecan, as well as several other sulfated matrix glycoproteins. This mimics the in vivo corneal fibroblast's developmental program and response to injury.[65]
One of the long-term goals of creating 3D cell culture systems is to engineer tissues that can be used as replacements for patients with many types of disease. In tissue engineered heart valves created by seeding myofibroblasts onto collagen type I followed by endothelial cells, heparan sulfate proteoglycan expression has been verified, although no distinction between syndecan and perlecan has been made in these tissues.[66] Another procedure that could be made possible by tissue engineering is keratoepithelioplasty. Transplanted tissue must remain intact, which requires a pre-formed basement membrane. Collagen gels have promoted formation of a complete basement membrane by corneal epithelial cells in culture.[67]
Perlecan also holds promise to serve as a scaffold for plating cells in culture. Human salivary gland ductal and acinar cells have been successfully grown on a bioactive peptide containing a sequence repeated in domain IV of the perlecan protein. These cells reproduce acini-like structures similar to those found in the native gland and tight junctions, along with complete basement membranes in culture.[68]
# Disease association
## Cancer
While Perlecan suppression causes substantial inhibition of tumor growth and neovascularization in null mice, in contrast, when perlecan-null cells are injected into nude mice enhanced tumor growth is observed when compared to controls.
Cancer progression and pathogenesis is intimately linked to extracellular matrix composition and the role of perlecan and other ECM molecules in cancer is being studied by a large number of laboratories. Since the basement membrane is the first obstacle in the way of extravasating carcinoma cells, the functions of perlecan in this process are multiple. One model system used to study perlecan expression in carcinoma cell lines is that of the MeWo/70W melanoma metastatic progression cell lines. MeWo cells are characteristically less invasive than their clonal variant cell line 70W. One lab studied perlecan expression in 27 invasive melanomas and 26 of the 27 samples showed a significant increase in perlecan message when compared to normal tissue from the same patients. They then used the MeWo and 70W cell lines to study if perlecan expression changed during treatment with neurotrophins, which can stimulate cell invasion through matrigel in vitro. The more invasive 70W cells began expressing perlecan message ten minutes after stimulation with the neurotrophins, and the MeWo cells did not produce any pln message regardless of treatment. This study took special note of the fact that perlecan upregulation occurred even before that of heparanase, an essential protein involved in the process of extravasation.[69][70]
In ovarian cancer as in other cancers, perlecan expression occurs differently throughout progression of the disease. Perlecan staining is lost in ovarian basement membrane that has been breached by an invasive adenocarcinoma, which is in contrast to perlecan staining in the basement membranes of normal ovaries and those with benign tumors, where basement membrane is homogeneous and very similar in composition to that in other normal tissues.[71] This is consistent with other results showing loss of perlecan in basement membranes affected by invasive cervical cancer spreading to the pelvic lymph nodes, which comes as no surprise due to the correlation of elevated levels of heparanase mRNA expression with invasion of similar cervical carcinoma.[72] By contrast, tumor formation of the immortalized mouse epithelial cell line RT101 injected into rats was dependent on perlecan expression by the mouse cells and not on the presence of endogenous rat perlecan. RT101 cells with perlecan knocked down by antisense did not show tumor formation in this system, however cells expressing the antisense perlecan and a recombinant construct encoding domains I, II, and III of mouse perlecan did indeed show tumor formation. Thus in this system it does appear that tumor cell expression of perlecan is necessary for tumor aggregation.[73] More research into GAG chain or core protein modification by invasive tumor cells as compared to benign tumor cells and normal tissue would be informative to better understand perlecans role in cancer migration.
Several laboratories have studied in vitro tumor cell angiogenesis using antisense constructs to the perlecan message. The full-length reverse complement cDNA, driven by a strong promoter, is transfected into various cell types to completely eliminate perlecan expression. Antisense in colon carcinoma cells blocks perlecan translation, leading to decreased tumor growth and angiogenesis.[74] A similar in vitro decrease in proliferation occurred in NIH 3T3 cells and a human melanoma cell line expressing antisense perlecan mRNA.[75] Findings in vitro with Kaposi's sarcoma cell lines showed that loss of perlecan via transfection with an antisense construct led to decreased proliferation and migration of this highly metastatic cell type.[76] These results are in contrast to in vivo results with the same Kaposi Sarcoma lines, which show that decreased perlecan leads to increased angiogenesis, which facilitates migration and thus is associated with increase in tumor grade.[76] Antisense knockdown of perlecan in fibrosarcoma cell lines led to increased growth and migration both in vitro and in vivo.[77] These findings of greater tumorigenesis in vivo are supported by data showing that the C-terminus of the perlecan protein acts as an endostatic module now known as endorepellin.[31][32][78]
A ribozyme construct was created for use in knocking down perlecan translation levels. This ribozyme was targeted at a sequence coding domain I of the perlecan protein. It reduced expression of perlecan up to 80% in the prostate cancer cell line C42B.[79] In contrast to previously discussed studies these cells produced smaller tumors than their parental cells when injected into athymic mice. What this disparity in results means for invasion is unknown, although it is true that perlecan is part of the extracellular matrix in mesenchymal tissue, and cells undergoing epithelial-mesenchymal transition (EMT) may upregulate perlecan expression as part of their EMT programming.
## Diabetes and cardiovascular disease
Perlecan levels are decreased in many disease states - e.g., diabetes, atherosclerosis and arthritis. Perlecan has an important role in the maintenance of the glomerular filtration barrier.[80] Decreased perlecan in the glomerular basement membrane has a central role in the development of diabetic albuminuria. Perlecan expression is down regulated by many atherogenic stimuli and thus Perlecan is thought to play a protective role in atherosclerosis.[81][82] Diabetes and atherosclerosis are commonly associated syndromes. 80% of diabetes-associated deaths involve some form of atherosclerotic complication, and the basement membrane of endothelia has been implicated in the atherogenic process. Synthesis of heparan sulfate was shown to decrease in the arteries of diabetics and in arteries developing atherosclerotic lesions.[83]
The mechanism by which heparan sulfate was downregulated in these lesions remained unknown for some time. One theory states that high glucose in circulation could lead to a decrease in GAG chain attachment to perlecan, but not necessarily a change in the synthetic pathway of the GAG chains or that of the core protein. After treatment of human aortic endothelial cells with high glucose medium, secreted perlecan contained less sulfate incorporation accompanied by less overall GAG chain incorporation.[84] Although no signaling pathway is identified leading to this decrease in GAG chain incorporation, it is suggested that the 30% loss in overall glycosylation of the protein could mean loss of one of the three HS chains on perlecan in this model of diabetes-associated hyperglycemia. It is also noted that similar decreases in extracellular HS without a change in staining for the core protein chains occur in diabetic kidneys and in kidney cells in culture treated with high glucose.[85][86]
Atherosclerosis is most often the culprit in coronary heart disease and other cardiovascular conditions, and a large aggregation of perlecan protein is symptomatic of advanced atherosclerotic plaques. VSMCs are the producers of the perlecan in this condition, meaning that a good deal of research has been focused on understanding the means of perlecan upregulation in this condition. In a test of the effect of circulating nonesterified fatty acids (symptomatic of diabetes and atherogenesis) on perlecan expression by VSMCs, expression did not change when compared to control cells. This was in contrast to a 2-10-fold increase in expression of other basement membrane proteoglycans.[87] Thrombin is another marker associated with atherogenesis and procoagulation, and it selectively upregulates production of perlecan but not other proteoglycans in human VSMCs in culture.[88] It is suggested that this effect is only seen when VSMCs reach confluence, but not prior to confluence. This concept is similar to previously mentioned studies showing that perlecan is only produced by VSMCs once they have ceased proliferation during development.[20][21] Another marker in the atherosclerotic pathway is angiotensin II, which also upregulates perlecan expression in VSMCs in culture.[89] Given the prominence of perlecan expression in atherosclerosis there is potential for therapy based upon perlecan expression and research may eventually proceed in that direction.
## Genetic disease
Mutations in the HSPG2 gene, which encodes perlecan, cause Schwartz–Jampel syndrome.[3]
# Interactions
Perlecan has been shown to interact with
- FBLN2,[90][91]
- FGF7,[92]
- FGFBP1,[93] and
- Transthyretin.[94] | https://www.wikidoc.org/index.php/Perlecan | |
e61e9b9ea996e680863426848d9fe2d026b40733 | wikidoc | Peroxide | Peroxide
# Overview
A peroxide is a compound containing an oxygen-oxygen single bond. The simplest stable peroxide is hydrogen peroxide. Superoxides, dioxygenyls, ozones and ozonides compound are considered separately.
# Organic chemistry
In organic chemistry, peroxide is a specific functional group or a molecule containing an oxygen-oxygen single bond (R-O-O-R'). When the other oxygen bears a hydrogen, it is called a hydroperoxide (R-O-O-H). The radical HOO· is known as hydroperoxide radical, and is thought to be involved in combustion of hydrocarbons in air.
Organic peroxides tend to decompose easily to free radicals of the form:
This makes them useful as catalysts for some types of polymerisation, such as the polyester resins used in glass-reinforced plastics. MEKP (methyl ethyl ketone peroxide) is commonly used for this purpose.
However, the same property also means that organic peroxides can accidentally initiate explosive polymerization in materials with unsaturated chemical bonds. Since peroxides can form spontaneously in some materials, some caution must be exercised with such "peroxide-forming materials." Triacetone triperoxide (TATP) and hexamethylene triperoxide diamine are explosive organic peroxide compounds; TATP may be formed accidentally as a waste product in some reactions. In addition, many liquid ethers in the presence of air, light, and metal slowly (over a period of months) form ether peroxides (e.g., diethyl ether peroxide), which are extremely unstable. As a consequence, it is recommended that ether be stored over potassium hydroxide, which not only destroys peroxides but also acts as a powerful desiccant. Extreme care must be taken with samples showing signs of crystal growth or precipitates.
TATP is an easily synthesized, inexpensive, explosive compound that is difficult to detect by normal screening methods. Consequently, it is an explosive favored by terrorists. TATP was used in the 2005 London Underground bombings and the 2001 "shoe bomber." In 2002, a simple mass spectroscopy screening method was developed.
# Inorganic chemistry
In inorganic chemistry, peroxide is the anion O22−. It is highly basic, and present in ionic compounds. Pure peroxides (containing only cations and the peroxide anions) are usually formed by burning alkali metals or alkaline earth metals in air or oxygen. Sodium peroxide Na2O2 is a typical example.
The peroxide ion contains two electrons more than the oxygen molecule. These two electrons, according to the molecular orbital theory, complete the two π- antibonding orbitals. This has as result a weakening of the bond strength of the peroxide ion and a greater length for the bond O-O : Li2O2 130 pm to BaO2 147 pm. Furthermore, the peroxide ion is diamagnetic.
The peroxides of the alkali metals and Ca, Sr and Ba are ionic. The peroxides of a number of electropositive metals such as Mg, the lanthanides and the uranyl-ion show an intermediary character, between ionic and covalent. The peroxides of metals such as Zn, Cd and Hg are mainly covalent.
Peroxides are powerful oxidizers, and usually fairly unstable. Ionic peroxides react with water and diluted acids to form hydrogen peroxide. Organic compounds are oxidized to carbonates, even at normal temperatures. Sodium peroxide is a powerful oxidator of metals, such as iron.
The oxides, peroxides and superoxides are closely related, forming a chain of oxygen ions of progressively higher oxidation number.
Barium peroxide is used in pyrotechnics and tracer ammunition, and was once used in the manufacture of hydrogen peroxide. Sodium peroxide is used as a carbon dioxide absorber and oxygen regenerator (e.g. in some submarines), through the reaction: | Peroxide
# Overview
A peroxide is a compound containing an oxygen-oxygen single bond. The simplest stable peroxide is hydrogen peroxide. Superoxides, dioxygenyls, ozones and ozonides compound are considered separately.
# Organic chemistry
In organic chemistry, peroxide is a specific functional group or a molecule containing an oxygen-oxygen single bond (R-O-O-R'). When the other oxygen bears a hydrogen, it is called a hydroperoxide (R-O-O-H). The radical HOO· is known as hydroperoxide radical, and is thought to be involved in combustion of hydrocarbons in air.
Organic peroxides tend to decompose easily to free radicals of the form:
This makes them useful as catalysts for some types of polymerisation, such as the polyester resins used in glass-reinforced plastics. MEKP (methyl ethyl ketone peroxide) is commonly used for this purpose.
However, the same property also means that organic peroxides can accidentally initiate explosive polymerization in materials with unsaturated chemical bonds. Since peroxides can form spontaneously in some materials, some caution must be exercised with such "peroxide-forming materials." Triacetone triperoxide (TATP) and hexamethylene triperoxide diamine are explosive organic peroxide compounds; TATP may be formed accidentally as a waste product in some reactions. In addition, many liquid ethers in the presence of air, light, and metal slowly (over a period of months) form ether peroxides (e.g., diethyl ether peroxide), which are extremely unstable. As a consequence, it is recommended that ether be stored over potassium hydroxide, which not only destroys peroxides but also acts as a powerful desiccant. Extreme care must be taken with samples showing signs of crystal growth or precipitates.
TATP is an easily synthesized, inexpensive, explosive compound that is difficult to detect by normal screening methods. Consequently, it is an explosive favored by terrorists. TATP was used in the 2005 London Underground bombings and the 2001 "shoe bomber." In 2002, a simple mass spectroscopy screening method was developed.[1]
# Inorganic chemistry
In inorganic chemistry, peroxide is the anion O22−. It is highly basic, and present in ionic compounds. Pure peroxides (containing only cations and the peroxide anions) are usually formed by burning alkali metals or alkaline earth metals in air or oxygen. Sodium peroxide Na2O2 is a typical example.
The peroxide ion contains two electrons more than the oxygen molecule. These two electrons, according to the molecular orbital theory, complete the two π* antibonding orbitals. This has as result a weakening of the bond strength of the peroxide ion and a greater length for the bond O-O : Li2O2 130 pm to BaO2 147 pm. Furthermore, the peroxide ion is diamagnetic.
The peroxides of the alkali metals and Ca, Sr and Ba are ionic. The peroxides of a number of electropositive metals such as Mg, the lanthanides and the uranyl-ion show an intermediary character, between ionic and covalent. The peroxides of metals such as Zn, Cd and Hg are mainly covalent.
Peroxides are powerful oxidizers, and usually fairly unstable. Ionic peroxides react with water and diluted acids to form hydrogen peroxide. Organic compounds are oxidized to carbonates, even at normal temperatures. Sodium peroxide is a powerful oxidator of metals, such as iron.
The oxides, peroxides and superoxides are closely related, forming a chain of oxygen ions of progressively higher oxidation number.
Barium peroxide is used in pyrotechnics and tracer ammunition, and was once used in the manufacture of hydrogen peroxide. Sodium peroxide is used as a carbon dioxide absorber and oxygen regenerator (e.g. in some submarines), through the reaction: | https://www.wikidoc.org/index.php/Peroxide | |
bc863dd0340ddcdd3cff7fa5523943d408faff5c | wikidoc | Perylene | Perylene
# Overview
Perylene or perilene is a polycyclic aromatic hydrocarbon with chemical formula Template:Carbon20Template:Hydrogen12 and CAS number Template:CASREF, occurring as a brown solid. It or its derivatives may be carcinogenic, and it is considered to be a hazardous pollutant. In cell membrane cytochemistry, perylene is used as a fluorescent lipid probe.
# Emission
Perylene displays blue fluorescence. It is used as a blue-emitting dopant material in OLEDs, either pure or substituted. Perylene can be also used as an organic photoconductor. It has an absorption maximum at 434nm, and as with all polycyclic aromatic compounds, low water solubility (1.2 x 10-5 mmol/l). Perylene has a molar extinction coefficient of 38,500 M-1cm-1 at 435.75 nm.
# Structure
The perylene molecule consists of two naphthalene molecules connected by a carbon-carbon bond at the 1 and 8 positions on both molecules. All of the carbon atoms in perylene are sp2 hybridized. When drawing the structure of perylene, it is important not to represent the center ring as a fifth benzene ring. By doing so, this would cause two of the carbons to become sp3 hybridized causing part of the molecule to lose its aromaticity, and therefore its ability to fluoresce. The structure of perylene has been extensively studied by X-ray crystallography. | Perylene
Template:Chembox new
# Overview
Perylene or perilene is a polycyclic aromatic hydrocarbon with chemical formula Template:Carbon20Template:Hydrogen12 and CAS number Template:CASREF, occurring as a brown solid. It or its derivatives may be carcinogenic, and it is considered to be a hazardous pollutant. In cell membrane cytochemistry, perylene is used as a fluorescent lipid probe.
# Emission
Perylene displays blue fluorescence. It is used as a blue-emitting dopant material in OLEDs, either pure or substituted. Perylene can be also used as an organic photoconductor. It has an absorption maximum at 434nm, and as with all polycyclic aromatic compounds, low water solubility (1.2 x 10-5 mmol/l). Perylene has a molar extinction coefficient of 38,500 M-1cm-1 at 435.75 nm.
# Structure
The perylene molecule consists of two naphthalene molecules connected by a carbon-carbon bond at the 1 and 8 positions on both molecules. All of the carbon atoms in perylene are sp2 hybridized. When drawing the structure of perylene, it is important not to represent the center ring as a fifth benzene ring. By doing so, this would cause two of the carbons to become sp3 hybridized causing part of the molecule to lose its aromaticity, and therefore its ability to fluoresce. The structure of perylene has been extensively studied by X-ray crystallography.[1] | https://www.wikidoc.org/index.php/Perylene | |
37e3ed2cd2ab945395bfa14b7ce6951c21b9c27d | wikidoc | Phagemid | Phagemid
A phagemid or phasmid is a type of cloning vector developed as a co-infection of the M13 helper phage and plasmids to produce a smaller version of the virus.
an example is PRS314 which is of 4.78 kb size. Phagemids contain an ori for double stranded replication as well as an ori for single stranded replication, mostly not comprising the entire phagemid (i.e., only a small part of the phagemid is copied as a single strand).
They find their application at phage displays.
A phagemid is different from a closely related cloning vector called a cosmid. While a cosmid can enter a host cell very effectively, almost all of the viral genes have been removed to make room for exogenous DNA, therefore the virus cannot replicate itself. In a phagemid, however, an origin of replication is present. This means that in the presence of a 'helper' virus such as f1, the rest of the genes to replicate viral proteins are present, therefore more virus particles can be created using the host cell's resources. | Phagemid
A phagemid or phasmid is a type of cloning vector developed as a co-infection of the M13 helper phage and plasmids to produce a smaller version of the virus.
an example is PRS314 which is of 4.78 kb size. Phagemids contain an ori for double stranded replication as well as an ori for single stranded replication, mostly not comprising the entire phagemid (i.e., only a small part of the phagemid is copied as a single strand).
They find their application at phage displays.
A phagemid is different from a closely related cloning vector called a cosmid. While a cosmid can enter a host cell very effectively, almost all of the viral genes have been removed to make room for exogenous DNA, therefore the virus cannot replicate itself. In a phagemid, however, an origin of replication is present. This means that in the presence of a 'helper' virus such as f1, the rest of the genes to replicate viral proteins are present, therefore more virus particles can be created using the host cell's resources. | https://www.wikidoc.org/index.php/Phagemid | |
0241f1206d532aa9534b79e57f13450d36ff596f | wikidoc | Philtrum | Philtrum
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
The philtrum (Greek philtron, from philein, "to love; to kiss"), also known as the infranasal depression, is the vertical groove in the upper lip, formed where the nasomedial and maxillary processes meet during embryonic development.
The philtrum allows humans to express a much larger range of lip motions than would otherwise be possible, which enhances vocal and non-verbal communication.
# Pathology
When these processes fail to fuse fully, a cleft lip (sometimes called a "hare lip") can result.
A flattened or smooth philtrum can be a symptom of Fetal alcohol syndrome.
# Etymology
The ancient Greeks used to believe that the philtrum was one of the most erogenous spots on the human body, hence the etymology.
# Folklore
According to the Jewish Talmud (Niddah 30b), God sends an angel to each womb and teaches a baby all the wisdom that can be obtained. Just before the unborn baby comes out, the angel touches it between the upper lip and the nose and all that it has taught the baby is forgotten.
Commentries on this particular story can be found in "What the Angel Taught you" by Rabbi Noah Weinberg and Yaakov Salomon (ISBN 1-57819-134-3).
Similarly, in other folksayings, it is said that an angel "shushes" the baby in the womb, to stop it from talking about heaven, or to forget. Other stories say that it is an indent left by the finger of God. Still more say that it is the spot where the angel put his finger to "shush" the child after having told it a secret. (This was memorably referenced in the film The Prophecy by the arch-angel Gabriel (Christopher Walken).) | Philtrum
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
The philtrum (Greek philtron, from philein, "to love; to kiss"), also known as the infranasal depression, is the vertical groove in the upper lip, formed where the nasomedial and maxillary processes meet during embryonic development.
The philtrum allows humans to express a much larger range of lip motions than would otherwise be possible, which enhances vocal and non-verbal communication.
# Pathology
When these processes fail to fuse fully, a cleft lip (sometimes called a "hare lip") can result.
A flattened or smooth philtrum can be a symptom of Fetal alcohol syndrome.[1]
# Etymology
The ancient Greeks used to believe that the philtrum was one of the most erogenous spots on the human body, hence the etymology.[2]
# Folklore
According to the Jewish Talmud (Niddah 30b), God sends an angel to each womb and teaches a baby all the wisdom that can be obtained. Just before the unborn baby comes out, the angel touches it between the upper lip and the nose and all that it has taught the baby is forgotten.
Commentries on this particular story can be found in "What the Angel Taught you" by Rabbi Noah Weinberg and Yaakov Salomon (ISBN 1-57819-134-3).
Similarly, in other folksayings, it is said that an angel "shushes" the baby in the womb, to stop it from talking about heaven, or to forget. Other stories say that it is an indent left by the finger of God. Still more say that it is the spot where the angel put his finger to "shush" the child after having told it a secret. (This was memorably referenced in the film The Prophecy by the arch-angel Gabriel (Christopher Walken).) | https://www.wikidoc.org/index.php/Philtrum | |
d6a05aa43679fd2882880610cfcd4c47ace68e5b | wikidoc | Porfimer | Porfimer
# Disclaimer
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# Overview
Porfimer is a photosensitizing agent that is FDA approved for the treatment of obstructive esophageal cancer, completely or partially obstructing endobronchial non-small-cell lung cancer (NSCLC), Barrett's esophagus. Common adverse reactions include constipation, dysphagia, esophageal stricture, anemia, backache, insomnia, bronchitis, dyspnea, obstruction of bronchus, pharyngitis, stenosis of bronchus, fever, pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Barrett's esophagus, Ablation of high-grade dysplasia in patients not undergoing surgery: 2 mg/kg IV over 3 to 5 minutes followed by local application of laser light (630 nanometers wavelength) to the tumor 40 to 50 hours later; a second laser light application may be given 96 to 120 hours after administration of porfimer; patients may receive an additional course a minimum of 90 days after therapy; MAX number of courses is 3 (each separated by 90 days).
- Barrett's esophagus, Ablation of high-grade dysplasia in patients not undergoing surgery: The manufacturer recommends a light dose of 130 Joules/centimeter; acceptable light intensity for the balloon/diffuser combinations are 200 to 270 milliwatts/centimeter of diffuser. If repeated, use a light dose of 50 Joules/centimeter of fiber optic diffuser length 96 to 120 hours after initial injection.
- Carcinoma of esophagus, Completely or partially obstructed disease in patients ineligible for Nd/YAG laser therapy (palliative): 2 mg/kg IV over 3-5 minutes followed by local application of laser light (630 nanometers wavelength) to the tumor 40 to 50 hours later. A second laser light application may be given 96 to 120 hours after administration of porfimer, preceded by careful debridement of residual tumor; patients may receive an additional course a minimum of 30 days after therapy; max. number of courses is 3 (each separated by 30 days).
- Carcinoma of esophagus, Completely or partially obstructed disease in patients ineligible for Nd/YAG laser therapy (palliative): The manufacturer recommends 300 Joules/centimeter (J/cm) of tumor length with the fiber tip set to deliver the light dose using exposure times of 12 minutes and 30 seconds.
- Cholangiocarcinoma of biliary tract, Unresectable, after double stenting: 2 mg/kg IV administered 48 hours before laser activation was used in a clinical trial; photoactivation was performed at 630 nanometers using a light dose of 180 joules/cm(2).
- Non-small cell lung cancer, Completely or partially obstructing endobronchial disease: 2 mg/kg IV over 3 to 5 minutes followed by local application of laser light (630 nanometers wavelength) to the tumor 40 to 50 hours later; a second laser light application may be given 96 to 120 hours after administration of porfimer, preceded by careful debridement of residual tumor; patients may receive an additional course a minimum of 30 days after therapy; MAX number of courses is 3 (each separated by 30 days).
- Non-small cell lung cancer, Microinvasive endobronchial disease; in patients ineligible for surgery or radiotherapy: 2 mg/kg IV over 3 to 5 minutes followed by local application of laser light (630 nanometers wavelength) to the tumor 40 to 50 hours later; a second laser light application may be given 96 to 120 hours after administration of porfimer, preceded by careful debridement of residual tumor; patients may receive an additional course a minimum of 30 days after therapy; MAX number of courses is 3 (each separated by 30 days)
- Non-small cell lung cancer, Microinvasive endobronchial disease; in patients ineligible for surgery or radiotherapy: The manufacturer recommends 200 Joules/centimeter (J/cm) of tumor length for both palliation and treatment; with the fiber tip set to deliver the light dose using exposure times of 8 minutes and 20 seconds.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Porfimer in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Porfimer in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in children have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Porfimer in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Porfimer in pediatric patients.
# Contraindications
PHOTOFRIN® is contraindicated in patients with porphyria or in patients with known allergies to porphyrins.
Photodynamic therapy is contraindicated in patients with an existing tracheoesophageal or bronchoesophageal fistula.
Photodynamic therapy is contraindicated in patients with tumors eroding into a major blood vessel.
Photodynamic therapy is not suitable for emergency treatment of patients with severe acute respiratory distress caused by an obstructing endobronchial lesion because 40 to 50 hours are required between injection with PHOTOFRIN® and laser light treatment.
Photodynamic therapy is not suitable for patients with esophageal or gastric varices, or patients with esophageal ulcers >1 cm in diameter.
# Warnings
Following injection with PHOTOFRIN® precautions must be taken to avoid exposure of skin and eyes to direct sunlight or bright indoor light (see PRECAUTIONS, GENERAL PRECAUTIONS AND INFORMATION FOR PATIENTS).
## Esophageal Cancer
If the esophageal tumor is eroding into the trachea or bronchial tree, the likelihood of tracheoesophageal or bronchoesophageal fistula resulting from treatment is sufficiently high that PDT is not recommended.
Patients with esophageal varices should be treated with extreme caution. Light should not be given directly to the variceal area because of the high risk of bleeding.
## Endobronchial Cancer
Patients should be assessed for the possibility that a tumor may be eroding into a pulmonary blood vessel (see CONTRAINDICATIONS). Patients at high risk for fatal massive hemoptysis (FMH) include those with large, centrally located tumors, those with cavitating tumors or those with extensive tumor extrinsic to the bronchus.
If the endobronchial tumor invades deeply into the bronchial wall, the possibility exists for fistula formation upon resolution of tumor.
Photodynamic therapy should be used with extreme caution for endobronchial tumors in locations where treatment-induced inflammation could obstruct the main airway, e.g., long or circumferential tumors of the trachea, tumors of the carina that involve both mainstem bronchi circumferentially, or circumferential tumors in the mainstem bronchus in patients with prior pneumonectomy.
## High-Grade Dysplasia (HGD) in Barrett’s Esophagus (BE)
The long-term effect of PDT on HGD in BE is unknown. There is always a risk of cancer or abnormal epithelium that is invisible to the endoscopist beneath the new squamous cell epithelium; these facts emphasize the risk of overlooking cancer in such patients and the need for rigorous continuing surveillance despite the endoscopic appearance of complete squamous cell reepithelialization. It is recommended that endoscopic biopsy surveillance be conducted every three months, until four consecutive negative evaluations for HGD have been recorded; further follow-up may be scheduled every 6 to 12 months, as per judgment of physicians. The follow-up period of the pivotal study at the time of analysis was a minimum of two years (ranging from 2 to 3.6 years).
# Adverse Reactions
## Clinical Trials Experience
Systemically induced effects associated with PDT with PHOTOFRIN® consist of photosensitivity and mild constipation. All patients who receive PHOTOFRIN® will be photosensitive and must observe precautions to avoid sunlight and bright indoor light. Photosensitivity reactions occurred in approximately 20% of cancer patients and in 68% of high-grade dysplasia (HGD) in Barrett’s esophagus (BE) patients treated with PHOTOFRIN®. Typically these reactions were mostly mild to moderate erythema but they also included swelling, itching, burning sensation, feeling hot, or blisters. In a single study of 24 healthy subjects, some evidence of photosensitivity reactions occurred in all subjects. Other less common skin manifestations were also reported in areas where photosensitivity reactions had occurred, such as increased hair growth, skin discoloration, skin nodules, increased wrinkles and increased skin fragility. These manifestations may be attributable to a pseudoporphyria state (temporary drug-induced cutaneous porphyria).
Most toxicities associated with this therapy are local effects seen in the region of illumination and occasionally in surrounding tissues. The local adverse reactions are characteristic of an inflammatory response induced by the photodynamic effect.
A few cases of fluid imbalance have been reported following the use of PDT with PHOTOFRIN® in patients with overtly disseminated intraperitoneal malignancies. Fluid imbalance is an expected PDT treatment-related event.
A case of cataracts has been reported in a 51 year-old obese man treated with PHOTOFRIN® PDT for HGD in BE. The patient suffered from a PDT response with development of a deep esophageal ulcer. Within two months post PDT, the patient noted difficulty with his distant vision. A thorough eye examination revealed a change in the refractive error that later progressed to cataracts in both eyes. Both of his parents had a history of cataracts in their 70s. Whether PHOTOFRIN® directly caused or accelerated a familial underlying condition is unknown.
## Esophageal Carcinoma
The following adverse events were reported over the entire follow-up period in at least 5% of patients treated with PHOTOFRIN® PDT, who had completely or partially obstructing esophageal cancer. Table 7 presents data from 88 patients who received the currently marketed formulation. The relationship of many of these adverse events to PDT with PHOTOFRIN® is uncertain.
Location of the tumor was a prognostic factor for three adverse events: upper-third of the esophagus (esophageal edema), middle-third (atrial fibrillation), and lower-third, the most vascular region (anemia). Also, patients with large tumors (>10 cm) were more likely to experience anemia. Two of 17 patients with complete esophageal obstruction from tumor experienced esophageal perforations, which were considered to be possibly treatment associated; these perforations occurred during subsequent endoscopies.
Serious and other notable adverse events observed in less than 5% of PDT-treated patients with obstructing esophageal cancer in the clinical studies include the following; their relationship to therapy is uncertain. In the gastrointestinal system, esophageal perforation, gastric ulcer, ileus, jaundice, and peritonitis have occurred. Sepsis has been reported occasionally. Cardiovascular events have included angina pectoris, bradycardia, myocardial infarction, sick sinus syndrome, and supraventricular tachycardia. Respiratory events of bronchitis, bronchospasm, laryngotracheal edema, pneumonitis, pulmonary hemorrhage, pulmonary edema, respiratory failure, and stridor have occurred. The temporal relationship of some gastrointestinal, cardiovascular and respiratory events to the administration of light was suggestive of mediastinal inflammation in some patients. Vision-related events of abnormal vision, diplopia, eye pain and photophobia have been reported.
## Obstructing Endobronchial Cancer
Table 8 presents adverse events that were reported over the entire follow-up period in at least 5% of patients with obstructing endobronchial cancer treated with PHOTOFRIN® PDT or Nd:YAG. These data are based on the 86 patients who received the currently marketed formulation. Since it seems likely that most adverse events caused by these acute acting therapies would occur within 30 days of treatment, Table 8 presents those events occurring within 30 days of a treatment procedure, as well as those occurring over the entire follow-up period. It should be noted that follow-up was 33% longer for the PDT group than for the Nd:YAG group, thereby introducing a bias against PDT when adverse event rates are compared for the entire follow-up period. The extent of follow-up in the 30-day period following treatment was comparable between groups (only 9% more for PDT).
Transient inflammatory reactions in PDT-treated patients occur in about 10% of patients and manifest as fever, bronchitis, chest pain, and dyspnea. The incidences of bronchitis and dyspnea were higher with PDT than with Nd:YAG. Most cases of bronchitis occurred within 1 week of treatment and all but one were mild or moderate in intensity. The events usually resolved within 10 days with antibiotic therapy. Treatment-related worsening of dyspnea is generally transient and self-limiting. Debridement of the treated area is mandatory to remove exudate and necrotic tissue. Life-threatening respiratory insufficiency likely due to therapy occurred in 3% of PDT-treated patients and 2% of Nd:YAG-treated patients.
There was a trend toward a higher rate of fatal massive hemoptysis (FMH) occurring on the PDT arm (10%) versus the Nd:YAG arm (5%), however, the rate of FMH occurring within 30 days of treatment was the same for PDT and Nd:YAG (4% total events, 3% treatment-associated events). Patients who have received radiation therapy have a higher incidence of FMH after treatment with PDT and after other forms of local therapy than patients who have not received radiation therapy, but analyses suggest that this increased risk may be due to associated prognostic factors such as having a centrally located tumor. The incidence of FMH in patients previously treated with radiotherapy was 21% (6/29) in the PDT group and 10% (3/29) in the Nd:YAG group. In patients with no prior radiotherapy, the overall incidence of FMH was less than 1%.
Other serious or notable adverse events were observed in less than 5% of PDT-treated patients with endobronchial cancer; their relationship to therapy is uncertain. In the respiratory system, pulmonary thrombosis, pulmonary embolism, and lung abscess have occurred. Cardiac failure, sepsis, and possible cerebrovascular accident have also been reported in one patient each.
## Superficial Endobronchial Tumors
The following adverse events were reported over the entire follow-up period in at least 5% of patients with superficial tumors (microinvasive or carcinoma in situ) who received the currently marketed formulation.
In patients with superficial endobronchial tumors, 44 of 90 patients (49%) experienced an adverse event, two-thirds of which were related to the respiratory system. The most common reaction to therapy was a mucositis reaction in one-fifth of the patients, which manifested as edema, exudate, and obstruction. The obstruction (mucus plug) is easily removed with suction or forceps. Mucositis can be minimized by avoiding exposure of normal tissue to excessive light (see PRECAUTIONS). Three patients experienced life-threatening dyspnea: one was given a double dose of light, one was treated concurrently in both mainstem bronchi and the other had had prior pneumonectomy and was treated in the sole remaining main airway. Stent placement was required in 3% of the patients due to endobronchial stricture. Fatal massive hemoptysis occurred within 30 days of treatment in one patient with superficial tumors (1%).
## High-Grade Dysplasia (HGD) in Barrett’s Esophagus (BE)
Table 10 presents adverse events that were reported, regardless of the relationship to treatment, over the follow-up period in at least 5% of patients with HGD in BE in either controlled or uncontrolled clinical trials.
In the PHOTOFRIN® PDT + OM group, severe treatment-associated adverse events included chest pain of non-cardiac origin, dysphagia, nausea, vomiting, regurgitation, and heartburn. The severity of these symptoms decreased within 4 to 6 weeks following treatment.
The majority of the photosensitivity reactions occurred within 90 days following PHOTOFRIN® injection and was of mild (69%) or moderate (24%) intensity. Almost all (98%) of the photosensitivity reactions were considered to be associated with treatment. Fourteen (10%) patients reported severe reactions, all of which resolved. The typical reaction was described as skin disorder, sunburn or rash, and affected mostly the face, hands, and neck. Associated symptoms and signs were swelling, pruritis, erythema, blisters, itching, burning sensation, and feeling of heat.
The majority of esophageal stenosis and strictures reported in the PHOTOFRIN® PDT + OM group were of mild (55%) or moderate (37%) intensity, while approximately 8% were of severe intensity. The majority of esophageal strictures were reported during Course 2 of treatment. All esophageal strictures were considered to be associated with treatment. Most esophageal strictures were manageable through dilations (see PRECAUTIONS).
Laboratory Abnormalities
In patients with esophageal cancer, PDT with PHOTOFRIN® may result in anemia due to tumor bleeding. No significant effects were observed for other parameters in patients with endobronchial carcinoma or with HGD in BE.
## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Photofrin with PDT. 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.
Infusion reactions: Infusion reactions including urticaria, bradycardia, hypotension, dizziness, and hypertension.
# Drug Interactions
## Other Photosensitizing Agents
There have been no formal interaction studies of PHOTOFRIN and any other drugs. However, it is possible that concomitant use of other photosensitizing agents (e.g., tetracyclines, sulfonamides, phenothiazines, sulfonylurea hypoglycemic agents, thiazide diuretics, griseofulvin, and fluoroquinolones) could increase the risk of photosensitivity reaction.
## Concomitant Therapy
Photodynamic therapy (PDT) with PHOTOFRIN causes direct intracellular damage by initiating radical chain reactions that damage intracellular membranes and mitochondria. Tissue damage also results from ischemia secondary to vasoconstriction, platelet activation and aggregation and clotting. Research in animals and in cell culture has suggested that many drugs could influence the effects of PDT, possible examples of which are described below. There are no human data that support or rebut these possibilities.
Compounds that quench active oxygen species or scavenge radicals, such as dimethyl sulfoxide, β-carotene, ethanol, formate and mannitol would be expected to decrease PDT activity. Preclinical data also suggest that tissue ischemia, allopurinol, calcium channel blockers and some prostaglandin synthesis inhibitors could interfere with PHOTOFRIN PDT. Drugs that decrease clotting, vasoconstriction or platelet aggregation, e.g., thromboxane A2 inhibitors, could decrease the efficacy of PDT. Glucocorticoid hormones given before or concomitant with PDT may decrease the efficacy of the treatment.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled studies in pregnant women. PHOTOFRIN® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
PHOTOFRIN® given to rat dams during fetal organogenesis intravenously at 8 mg/kg/d (0.64 times the clinical dose on a mg/m2 basis) for 10 days caused no major malformations or developmental changes. This dose caused maternal and fetal toxicity resulting in increased resorptions, decreased litter size, delayed ossification, and reduced fetal weight. PHOTOFRIN® caused no major malformations when given to rabbits intravenously during organogenesis at 4 mg/kg/d (0.65 times the clinical dose on a mg/m2 basis) for 13 days. This dose caused maternal toxicity resulting in increased resorptions, decreased litter size, and reduced fetal body weight.
PHOTOFRIN® given to rats during late pregnancy through lactation intravenously at 4 mg/kg/d (0.32 times the clinical dose on a mg/m2 basis) for at least 42 days caused a reversible decrease in growth of offspring. Parturition was unaffected.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Porfimer in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Porfimer during labor and delivery.
### Nursing Mothers
- It is not known whether PHOTOFRIN is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from PHOTOFRIN, a decision should be made whether not to treat or to discontinue breastfeeding, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in children have not been established.
### Geriatic Use
- Approximately 70% of the patients treated with PDT using PHOTOFRIN in clinical trials were over 60 years of age. There was no apparent difference in effectiveness or safety in these patients compared to younger people. Dose modification based upon age is not required.
### Gender
There is no FDA guidance on the use of Porfimer with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Porfimer with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Porfimer in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Porfimer in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Porfimer in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Porfimer in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Porfimer in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Porfimer in the drug label.
# Overdosage
PHOTOFRIN Overdose
- There is no information on overdosage situations involving PHOTOFRIN. Higher than recommended drug doses of two 2 mg/kg doses given two days apart (10 patients) and three 2 mg/kg doses given within two weeks (one patient), were tolerated without notable adverse reactions. Effects of overdosage on the duration of photosensitivity are unknown. Laser treatment should not be given if an overdose of PHOTOFRIN is administered. In the event of an overdose, patients should protect their eyes and skin from direct sunlight or bright indoor lights for 30 days. At this time, patients should test for residual photosensitivity. PHOTOFRIN is not dialyzable.
Overdose of Laser Light Following PHOTOFRIN Injection
- Light doses of two to three times the recommended dose have been administered to a few patients with superficial endobronchial tumors. One patient experienced life-threatening dyspnoea and the others had no notable complications. Increased symptoms and damage to normal tissue might be expected following an overdose of light. There is no information on overdose of laser light following PHOTOFRIN injection in patients with esophageal cancer or in patients with high-grade dysplasia in Barrett's esophagus.
# Pharmacology
## Mechanism of Action
- Cellular damage caused by photodynamic therapy (PDT) with PHOTOFRIN is a consequence of the propagation of radical reactions. Radical initiation may occur after porfimer sodium absorbs light to form a porphyrin excited state. Spin transfer from porfimer sodium to molecular oxygen may then generate singlet oxygen. Subsequent radical reactions can form superoxide and hydroxyl radicals. Tumor death also occurs through ischemic necrosis secondary to vascular occlusion that appears to be partly mediated by thromboxane A2 release. As opposed to a thermal effect, the laser treatment with porfimer sodium induces a photochemical effect. The necrotic reaction and associated inflammatory responses may evolve over several days.
## Structure
- PHOTOFRIN (porfimer sodium) for Injection is a photosensitizing agent used in the photodynamic therapy (PDT) of tumors and of high-grade dysplasia (HGD) in Barrett’s esophagus (BE). Following reconstitution of the freeze-dried product with 5% Dextrose Injection (USP) or 0.9% Sodium Chloride Injection (USP), it is injected intravenously. This is followed 40–50 hours later by illumination of the tumor or the esophageal segment with HGD in BE with laser light (630 nm wavelength). PHOTOFRIN is not a single chemical entity; it is a mixture of oligomers formed by ether and ester linkages of up to eight porphyrin units. It is a dark red to reddish brown cake or powder. Each vial of PHOTOFRIN contains 75 mg of porfimer sodium as a sterile freeze-dried cake or powder. Hydrochloric Acid and/or Sodium Hydroxide may be added during manufacture to adjust the pH to within 7.2-7.9. There are no preservatives or other additives. The structural formula below is representative of the components present in PHOTOFRIN.
## Pharmacodynamics
- The cytotoxic and antitumor actions of PHOTOFRIN are light and oxygen dependent. PDT with PHOTOFRIN is a two-stage process. The first stage is the intravenous injection of PHOTOFRIN. Clearance from a variety of tissues occurs over 40-72 hours, but tumors, skin, and organs of the reticuloendothelial system (including liver and spleen) retain PHOTOFRIN for a longer period. Illumination with 630 nm wavelength laser light constitutes the second stage of therapy. Tumor selectivity in treatment occurs through a combination of selective retention of PHOTOFRIN and selective delivery of light.
## Pharmacokinetics
- The pharmacokinetics of PHOTOFRIN were studied in 18 cancer patients who received two doses of PHOTOFRIN, 2 mg/kg each, administered 30 to 45 days appart as slow IV injection over 3 to 5 mintues. The mean Cmax values were comparable after the first and second administrations (43.1 ± 10.5 mcg/mL and 41.3 ± 8.7 mcg/mL, respectively). However, the mean AUC0-inf of porfimer was about 34% higher after the second administration than that after the first administration (3937 ± 1034 mcg.h/mL and 2937 ± 627 mcg.hour/mL, respectively), indicating some accumulation upon repeated administration. The elimination half-life of porfimer increased from 410 to 725 hours after the first and second administrations, respectively.
- PHOTOFRIN was approximately 90% protein bound in human serum, studied in vitro. The binding was independent of concentration over the concentration range of 20–100 mcg/mL.
Effect of Gender:
- The effect of gender was determined in 18 patients (8 males and 10 females) who received two administrations of PHOTOFRIN 2 mg/kg within 30-45 days apart as slow IV injection over 3 to 5 minutes. The mean Cmax value and AUC values were comparable between males and females following either the first of the second administrations.
Effect of Hepatic Renal Impairment:
- The effect of hepatic and renal impairment has not been studied.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- No long-term studies have been conducted to evaluate the carcinogenic potential of porfimer sodium.
- In the presence of light, in vitro, porfimer sodium PDT did not cause mutations in the Ames test, nor did it cause chromosome aberrations or mutations (HGPRT locus) in Chinese hamster ovary (CHO) cells. Porfimer sodium PDT caused <2-fold, but significant, increases in sister chromatid exchange in CHO cells irradiated with visible light and a 3-fold increase in Chinese hamster lung fibroblasts irradiated with near UV light. Porfimer sodium PDT caused an increase in thymidine kinase mutants and DNA-protein cross-links in mouse L5178Y cells, but not mouse LYR83 cells. Porfimer sodium PDT caused a light-dose dependant increase in DNA-strand breaks in malignant human cervical carcinoma cells, but not in normal cells. In the absence of light, porfimer sodium was negative in a Chinese hamster ovarian cells (CHO/HGPRT) mutation test. In vivo, porfimer sodium did not cause chromosomal aberrations in the mouse micronucleus test.
- Porfimer sodium given to male and female rats intravenously, at 4 mg/kg/d (0.32 times the clinical dose on a mg/m2 basis) before conception and through Day 7 of pregnancy caused no impairment of fertility. In this study, long-term dosing with porfimer sodium caused discoloration of testes and ovaries and hypertrophy of the testes. Porfimer sodium also caused decreased body weight in the parent rats.
# Clinical Studies
- Clinical studies of photodynamic therapy (PDT) with PHOTOFRIN were conducted in patients with obstructing esophageal and endobronchial non-small-cell lung cancers, in patients with early-stage radiologically occult endobronchial cancer, and in patients with high-grade dysplasia (HGD) in Barrett's esophagus (BE). In all clinical studies, the method of PDT administration was essentially identical. A course of therapy consisted of one injection of PHOTOFRIN (2 mg/kg administered as a slow intravenous injection over 3–5 minutes) followed by up to two non-thermal applications of 630 nm laser light. Light doses of 300 J/cm of diffuser length were used in esophageal cancer. Light doses of 200 J/cm of diffuser length were used in endobronchial cancer for both palliation of obstructing cancer and treatment of superficial lesions. For the ablation of HGD in BE, the light dose administered was 130 J/cm of diffuser length using a centering balloon for the first application and 50 J/cm of diffuser length without a centering balloon for the second application. In all cases, the first application of light occurred 40–50 hours after PHOTOFRIN injection.
- For treatment of esophageal cancer debridement of residua via endoscopy is optional 96–120 hours after injection, after which any residual tumor could be retreated with a second laser light application at the same light dose used for the initial treatment. Additional courses of PDT with PHOTOFRIN were allowed after one month, up to a maximum of three courses.
- For treatment of endobronchial cancer, debridement of residua was performed via bronchoscopy 96–120 hours after injection, after which any residual tumor could be retreated with a second laser light application at the same light dose used for the initial treatment. Additional courses of PDT with PHOTOFRIN-were allowed after one month, up to a maximum of three courses.
- For ablation of HGD in BE, a second laser light application of 50 J/cm of diffuser length without a centering balloon could be given 96-120 hours after the PHOTOFRIN injection for untreated areas ("skip" areas). Additional courses of PDT with PHOTOFRIN were allowed after three months, up to a maximum of three courses.
Esophageal Cancer
- PDT with PHOTOFRIN was utilized in a multicenter, single-arm study in 17 patients with completely obstructing esophageal carcinoma. Assessments were made at 1 week and 1 month after the last treatment procedure. As shown in TABLE 10, after a single course of therapy, 94% of patients obtained an objective tumor response and 76% of patients experienced some palliation of their dysphagia. On average, before treatment these patients had difficulty swallowing liquids, even saliva. After one course of therapy, there was a statistically significant improvement in mean dysphagia grade (1.5 units, p <0.05) and 13 of 17 patients could swallow liquids without difficulty 1 week and/or 1 month after treatment. Based on all courses, three patients achieved a complete tumor response (CR). In two of these patients, the CR was documented only at Week 1 as they had no further assessments. The third patient achieved a CR after a second course of therapy, which was supported by negative histopathology and maintained for the entire follow-up of 6 months.
- Of the 17 treated patients, 11 (65%) received clinically important benefit from PDT. Clinically important benefit was defined hierarchically as a complete tumor response (3 patients), achievement of normal swallowing (2 patients went from Grade 5 dysphagia to Grade 1), or achievement of a marked improvement of two or more grades of dysphagia with minimal adverse reactions (6 patients). The median duration of benefit in these patients was 69 days. Duration of benefit was calculated only for the period with documented evidence of improvement. All of these patients were still in response at their last assessment and, therefore, the estimate of 69 days is conservative. The median survival for these 11 patients was 115 days.
Endobronchial Cancer
- Two randomized multicenter Phase III studies were conducted to compare the safety and efficacy of PHOTOFRIN PDT versus Nd:YAG laser therapy for reduction of obstruction and palliation of symptomatic patients with partially or completely obstructing endobronchial non-small-cell lung cancer. Assessments were made at 1 week and at monthly intervals after treatment. TABLE 11 shows the results from all randomized patients in the two studies combined. Objective tumor response rates (CR + PR), which demonstrate reduction of obstruction, were 59% for PDT and 58% for Nd:YAG at Week 1. The response rate at 1 month or later was 60% for PDT and 41% for Nd:YAG.
- Patient symptoms were evaluated using a 5- or 6-grade pulmonary symptom severity rating scale for dyspnoea, cough, and hemoptysis. Patients with moderate to severe symptoms are those most in need of palliation. Improvements of 2 or more grades are considered to be clinically significant. TABLE 12 shows the percentages of patients with moderate to severe symptoms at baseline who demonstrated a 2-grade improvement at any time during the interval evaluated.
- In a separate retrospective analysis, patients were individually evaluated to identify those patients whose benefit to risk ratio was most favorable, i.e., those who obtained clinically important benefit with minimal adverse reactions. Clinically important benefit was defined as one of the following:
- A substantial improvement in pulmonary symptoms at Month 1 or later (dyspnoea ≥2 grades, hemoptysis ≥3 grades, cough ≥3 grades or increase in FEV1 ≥40%);
A moderate improvement in symptoms at Month 2 or later (dyspnoea 1 grade, cough 2 grades, hemoptysis 2 grades or increase in FEV1 ≥20%); or
A durable objective tumor response (CR or PR maintained to Month 2 or longer).
Thirty-six (36) of the 99 PDT-treated patients (36%) and 23 of the 99 Nd:YAG-treated patients (23%) received clinically important benefit with only minimal or moderate toxicities of short duration. Thirty-four of 99 PDT-treated patients demonstrated improvements in 2 or more efficacy endpoints (dyspnoea, cough, hemoptysis, sputum, atelectasis, pulmonary function tests of FEV1 or FVC, Karnofsky Performance Score or tumor response) and 29 patients had improvements in 3 or more.
- The median duration of documented benefit in the 36 patients was 63 days. In these patients with late-stage obstructing lung cancer, median survival was 174 days in PDT-treated patients and 161 days in Nd:YAG-treated patients.
- The efficacy of PHOTOFRIN PDT was also evaluated in the treatment of microinvasive endobronchial tumors in 62 inoperable patients in three noncomparative studies. Microinvasive lung cancer is defined histologically as disease, which invades beyond the basement membrane but not through or into the cartilage. For 11 of the 62 patients, it was clearly documented that surgery and radiotherapy were not indicated. These 11 patients were all inoperable for medical or technical reasons. Radiotherapy was not indicated due to prior high-dose radiotherapy (7 patients), poor pulmonary function (2 patients), multifocal multilobar disease (1 patient), and poor medical condition (1 patient). As shown in TABLE 13, the complete tumor response rate, biopsy-proven at least 3 months after treatment, was 50%, median time to tumor recurrence was more than 2.7 years, median survival was 2.9 years and disease-specific survival was 4.1 years.
High-Grade Dysplasia in Barrett's Esophagus
- The safety and efficacy of PDT with PHOTOFRIN in ablation of HGD in patients with BE was assessed in one controlled randomized clinical study and two supportive studies.
Controlled Randomized Study
- A multicenter, pathology blinded, randomized, controlled study was conducted in North America and Europe to assess the efficacy of PDT with PHOTOFRIN for Injection plus omeprazole (PHOTOFRIN PDT + OM) in producing complete ablation of HGD in patients with BE compared to control patients receiving omeprazole alone (OM Only). A total of 485 patients with the diagnosis of HGD were screened for the study; 208 (43%) were randomized to treatment, 237 (49%) were excluded because the diagnosis of HGD was not confirmed and 40 (8%) did not meet other screening criteria or declined to participate in the study. The high patient exclusion rate re-enforces the recommendation by the American College of Gastroenterology that the diagnosis of HGD in BE should be confirmed by an expert GI pathologist. Patients were centrally randomized in a 2:1 proportion to receive PHOTOFRIN PDT + OM (138 patients) or OM Only (70 patients). All patients underwent rigorous systematic quarterly endoscopic biopsy surveillance. Four-quadrant jumbo biopsies at every 2 cm of the entire Barrett’s mucosa were obtained at each follow-up visit (every three months or six months if four consecutive quarterly follow-up endoscopic biopsy results were negative for HGD). All histological assessments were carried out at a central pathology laboratory and read by pathologists blinded to the treatment administered.
- A total of 208 patients who had biopsy-proven HGD in BE were enrolled in the initial 2-year phase of the study. Of those, 199 patients were considered evaluable: 130 of 138 (94%) patients randomized to the PHOTOFRIN PDT + OM group and 69 of 70 (99%) randomized to the OM Only group had no esophageal invasive cancer, suspicion of esophageal invasive cancer, lymph node involvement, or metastases, and had received at least one PHOTOFRIN PDT course or one week of OM treatment, respectively. A disproportionate percentage of patients were discontinued from the OM Only group during the initial 2-year phase leaving 81 (59%) patients in the PHOTOFRIN PDT + OM group and 21 (30%) patients in the OM Only group at the end of the 2-year phase. Consequently, a total of 102 patients who completed the initial 2-year phase were eligible for continuation into the long-term phase until completion of 5 years; of those, 48 (59%) patients from the PHOTOFRIN PDT + OM group and 13 (62%) patients from the OM Only group consented to pursue the long-term phase until completion of 5 years. The mean age was 66 years (38 to 89 years) in the PHOTOFRIN PDT + OM group, and 67 (36 to 88 years) in the OM Only group. The patients in both treatment groups were predominantly male (85%), Caucasian (99%), and former smokers (64%). These characteristics are typical of patients with HGD in BE. Patients randomized to the PHOTOFRIN PDT + OM treatment received up to three courses of treatment separated by at least 90 days. Each course consisted of intravenous administration of 2.0 mg/kg of PHOTOFRIN followed 40-50 hours later by a 630 nm laser light dose of 130 J/cm of diffuser length delivered using a centering balloon. A second laser light dose of 50 J/cm of diffuser length could be administered without a centering balloon 96-120 hours after the injection of PHOTOFRIN for treatment of "skip" areas. Since centering balloons are up to 7 cm in length, patients with more extensive HGD were treated with two or three courses. Both the PHOTOFRIN PDT treatment group and the control group received 20 mg of omeprazole BID to decrease reflux esophagitis. The mean duration of the follow-up period was 34 months (0-67 months) for the PHOTOFRIN PDT + OM group and 25 months (0-65 months) for the OM Only group.
- The primary efficacy endpoint was the Complete Response rate (CR3 or better) at any one of the endoscopic assessment time points. The CR3 or better response was defined as the complete ablation of HGD and referred to as a composite of the following three response levels.
- CR1 – Complete replacement of all Barrett’s metaplasia and dysplasia with normal squamous cell epithelium;
- CR2 – Ablation of all histological grades of dysplasia, including patients with indefinite grade of dysplasia, but some areas of Barrett’s epithelium still remain; and
- CR3 – Ablation of all areas of HGD but with some areas of low-grade dysplasia with or without areas which are indefinite for dysplasia, or areas of Barrett’s metaplastic epithelium.
- Additional efficacy endpoints included:
- Quality of Complete Response, which consisted of CR1 and CR2 or better.
- Duration of CR;
- Time to Progression to Cancer.
- TABLE 14 presents the overall clinical response for both treatment groups in the intent-to-treat (ITT) population whose response was CR3 or better at any one of the evaluation time points. Overall, PHOTOFRIN PDT + OM was effective in eliminating HGD in patients with BE. The proportion of responders was significantly higher in the PHOTOFRIN PDT + OM group than in the OM Only group (77% vs. 39%, respectively; p<0.0001).
- The quality of response in the PHOTOFRIN PDT + OM group was significantly better than that measured in the OM Only group at all response levels (p<0.0001). Seventy-two (52%) patients in the PHOTOFRIN PDT + OM group achieved a CR1 response as compared to only five (7%) patients in the OM Only group. Eighty-one (59%) patients in the PHOTOFRIN PDT + OM group achieved a CR2 or better response as compared to ten (14%) patients in the OM Only group.
NOTE: Six patients in the PHOTOFRIN PDT + OM group and three patients in the OM Only group without post-baseline biopsy data are considered as non-responders.
- At the end of the long-term phase, the median response duration was 44.6 months (95% CI: 15.0-not reached, months) in the PHOTOFRIN PDT + OM group compared to 3.2 months (95% CI: 3.0-3.4, months) in the OM Only group.
- At the end of the initial 2 year phase, the time to progression to cancer was significantly longer in the PHOTOFRIN PDT + OM group compared to the OM Only group (HR=0.36 (95% CI: 0.19-0.69), a hazard ratio less than 1 favors the PHOTOFRIN PDT + OM group). The proportion of patients' progression to cancer was lower in the PHOTOFRIN PDT + OM group than in the OM Only group: 13% (18 of 138 patients) vs. 28% (20 of 70 patients).
- Complete response was influenced by the following factors: treatment with PHOTOFRIN PDT + OM (vs. OM Only), single focus of HGD (vs. multiple foci), and prior omeprazole intake of at least 3 months (yes vs. no). Complete response was not influenced by the duration of HGD, length of BE, nodular conditions, gender, age, smoking history, and study center’s size.
Supportive Studies
- Two uncontrolled, supportive studies were conducted that were physician-sponsored, single center Phase II trials. Both studies included patients that had low-grade dysplasia (LGD), HGD and early adenocarcinoma. All HGD in BE patients were treated with PHOTOFRIN PDT and omeprazole.
- The first study enrolled 99 patients (44 with HGD); the purpose of this study was to determine the required light dose to produce effective results. The second study enrolled 86 patients (42 with HGD), who were randomized to receive either PHOTOFRIN PDT with prednisone or PHOTOFRIN PDT without prednisone to determine whether steroid treatment would reduce the incidence and severity of esophageal strictures.
- A CR3 or better response was demonstrated in 93% of 44 patients with HGD in the first study and in 95% of 42 patients with HGD in the second study after a minimum follow-up of 12 months. A CR2 or better response was achieved in 82% of patients in the first study and in 91% of patients in the second study. A CR1 response occurred in 57% of patients in the first study and in 60% of the second study. Progression to cancer during the above follow-up period occurred in 18% of patients in the first study and in 7% of patients in the second study. No reduction in the incidence or severity of esophageal strictures was found in the prednisone group in the second study.
# How Supplied
- PHOTOFRIN (porfimer sodium) for Injection is supplied as a freeze-dried cake or powder as follows:
NDC 76128-155-75, 75 mg vial
## Storage
- PHOTOFRIN freeze-dried cake or powder should be stored at Controlled Room Temperature 20-25°C (68-77°F) .
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Photosensitivity
- Patients should be warned to avoid exposure of skin and eyes to direct sunlight or bright indoor light for at least 30 days following injection with PHOTOFRIN.
- Patients should be informed that photosensitivity might last for more than 90 days if patients suffer from liver impairment.
- Patients should be instructed to wear protective clothing and dark sunglasses when outdoors, which have an average white light transmittance of < 4%.
- Patients should be encouraged to expose their skin to ambient indoor light to facilitate elimination of PHOTOFRIN from their skin.
Common Adverse Reactions
- Patients should be informed that treatment with photodynamic therapy might lead to adverse reactions which include ocular sensitivity, chest pain, respiratory distress or esophageal strictures. In such cases, patients should call their physicians.
# Precautions with Alcohol
- Alcohol-Porfimer interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PHOTOFRIN
# Look-Alike Drug Names
There is limited information regarding Porfimer Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Porfimer
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Steven Bellm, M.D. [2]
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# Overview
Porfimer is a photosensitizing agent that is FDA approved for the treatment of obstructive esophageal cancer, completely or partially obstructing endobronchial non-small-cell lung cancer (NSCLC), Barrett's esophagus. Common adverse reactions include constipation, dysphagia, esophageal stricture, anemia, backache, insomnia, bronchitis, dyspnea, obstruction of bronchus, pharyngitis, stenosis of bronchus, fever, pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Barrett's esophagus, Ablation of high-grade dysplasia in patients not undergoing surgery: 2 mg/kg IV over 3 to 5 minutes followed by local application of laser light (630 nanometers wavelength) to the tumor 40 to 50 hours later; a second laser light application may be given 96 to 120 hours after administration of porfimer; patients may receive an additional course a minimum of 90 days after therapy; MAX number of courses is 3 (each separated by 90 days).
- Barrett's esophagus, Ablation of high-grade dysplasia in patients not undergoing surgery: The manufacturer recommends a light dose of 130 Joules/centimeter; acceptable light intensity for the balloon/diffuser combinations are 200 to 270 milliwatts/centimeter of diffuser. If repeated, use a light dose of 50 Joules/centimeter of fiber optic diffuser length 96 to 120 hours after initial injection.
- Carcinoma of esophagus, Completely or partially obstructed disease in patients ineligible for Nd/YAG laser therapy (palliative): 2 mg/kg IV over 3-5 minutes followed by local application of laser light (630 nanometers wavelength) to the tumor 40 to 50 hours later. A second laser light application may be given 96 to 120 hours after administration of porfimer, preceded by careful debridement of residual tumor; patients may receive an additional course a minimum of 30 days after therapy; max. number of courses is 3 (each separated by 30 days).
- Carcinoma of esophagus, Completely or partially obstructed disease in patients ineligible for Nd/YAG laser therapy (palliative): The manufacturer recommends 300 Joules/centimeter (J/cm) of tumor length with the fiber tip set to deliver the light dose using exposure times of 12 minutes and 30 seconds.
- Cholangiocarcinoma of biliary tract, Unresectable, after double stenting: 2 mg/kg IV administered 48 hours before laser activation was used in a clinical trial; photoactivation was performed at 630 nanometers using a light dose of 180 joules/cm(2).
- Non-small cell lung cancer, Completely or partially obstructing endobronchial disease: 2 mg/kg IV over 3 to 5 minutes followed by local application of laser light (630 nanometers wavelength) to the tumor 40 to 50 hours later; a second laser light application may be given 96 to 120 hours after administration of porfimer, preceded by careful debridement of residual tumor; patients may receive an additional course a minimum of 30 days after therapy; MAX number of courses is 3 (each separated by 30 days).
- Non-small cell lung cancer, Microinvasive endobronchial disease; in patients ineligible for surgery or radiotherapy: 2 mg/kg IV over 3 to 5 minutes followed by local application of laser light (630 nanometers wavelength) to the tumor 40 to 50 hours later; a second laser light application may be given 96 to 120 hours after administration of porfimer, preceded by careful debridement of residual tumor; patients may receive an additional course a minimum of 30 days after therapy; MAX number of courses is 3 (each separated by 30 days)
- Non-small cell lung cancer, Microinvasive endobronchial disease; in patients ineligible for surgery or radiotherapy: The manufacturer recommends 200 Joules/centimeter (J/cm) of tumor length for both palliation and treatment; with the fiber tip set to deliver the light dose using exposure times of 8 minutes and 20 seconds.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Porfimer in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Porfimer in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in children have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Porfimer in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Porfimer in pediatric patients.
# Contraindications
PHOTOFRIN® is contraindicated in patients with porphyria or in patients with known allergies to porphyrins.
Photodynamic therapy is contraindicated in patients with an existing tracheoesophageal or bronchoesophageal fistula.
Photodynamic therapy is contraindicated in patients with tumors eroding into a major blood vessel.
Photodynamic therapy is not suitable for emergency treatment of patients with severe acute respiratory distress caused by an obstructing endobronchial lesion because 40 to 50 hours are required between injection with PHOTOFRIN® and laser light treatment.
Photodynamic therapy is not suitable for patients with esophageal or gastric varices, or patients with esophageal ulcers >1 cm in diameter.
# Warnings
Following injection with PHOTOFRIN® precautions must be taken to avoid exposure of skin and eyes to direct sunlight or bright indoor light (see PRECAUTIONS, GENERAL PRECAUTIONS AND INFORMATION FOR PATIENTS).
## Esophageal Cancer
If the esophageal tumor is eroding into the trachea or bronchial tree, the likelihood of tracheoesophageal or bronchoesophageal fistula resulting from treatment is sufficiently high that PDT is not recommended.
Patients with esophageal varices should be treated with extreme caution. Light should not be given directly to the variceal area because of the high risk of bleeding.
## Endobronchial Cancer
Patients should be assessed for the possibility that a tumor may be eroding into a pulmonary blood vessel (see CONTRAINDICATIONS). Patients at high risk for fatal massive hemoptysis (FMH) include those with large, centrally located tumors, those with cavitating tumors or those with extensive tumor extrinsic to the bronchus.
If the endobronchial tumor invades deeply into the bronchial wall, the possibility exists for fistula formation upon resolution of tumor.
Photodynamic therapy should be used with extreme caution for endobronchial tumors in locations where treatment-induced inflammation could obstruct the main airway, e.g., long or circumferential tumors of the trachea, tumors of the carina that involve both mainstem bronchi circumferentially, or circumferential tumors in the mainstem bronchus in patients with prior pneumonectomy.
## High-Grade Dysplasia (HGD) in Barrett’s Esophagus (BE)
The long-term effect of PDT on HGD in BE is unknown. There is always a risk of cancer or abnormal epithelium that is invisible to the endoscopist beneath the new squamous cell epithelium; these facts emphasize the risk of overlooking cancer in such patients and the need for rigorous continuing surveillance despite the endoscopic appearance of complete squamous cell reepithelialization. It is recommended that endoscopic biopsy surveillance be conducted every three months, until four consecutive negative evaluations for HGD have been recorded; further follow-up may be scheduled every 6 to 12 months, as per judgment of physicians. The follow-up period of the pivotal study at the time of analysis was a minimum of two years (ranging from 2 to 3.6 years).
# Adverse Reactions
## Clinical Trials Experience
Systemically induced effects associated with PDT with PHOTOFRIN® consist of photosensitivity and mild constipation. All patients who receive PHOTOFRIN® will be photosensitive and must observe precautions to avoid sunlight and bright indoor light. Photosensitivity reactions occurred in approximately 20% of cancer patients and in 68% of high-grade dysplasia (HGD) in Barrett’s esophagus (BE) patients treated with PHOTOFRIN®. Typically these reactions were mostly mild to moderate erythema but they also included swelling, itching, burning sensation, feeling hot, or blisters. In a single study of 24 healthy subjects, some evidence of photosensitivity reactions occurred in all subjects. Other less common skin manifestations were also reported in areas where photosensitivity reactions had occurred, such as increased hair growth, skin discoloration, skin nodules, increased wrinkles and increased skin fragility. These manifestations may be attributable to a pseudoporphyria state (temporary drug-induced cutaneous porphyria).
Most toxicities associated with this therapy are local effects seen in the region of illumination and occasionally in surrounding tissues. The local adverse reactions are characteristic of an inflammatory response induced by the photodynamic effect.
A few cases of fluid imbalance have been reported following the use of PDT with PHOTOFRIN® in patients with overtly disseminated intraperitoneal malignancies. Fluid imbalance is an expected PDT treatment-related event.
A case of cataracts has been reported in a 51 year-old obese man treated with PHOTOFRIN® PDT for HGD in BE. The patient suffered from a PDT response with development of a deep esophageal ulcer. Within two months post PDT, the patient noted difficulty with his distant vision. A thorough eye examination revealed a change in the refractive error that later progressed to cataracts in both eyes. Both of his parents had a history of cataracts in their 70s. Whether PHOTOFRIN® directly caused or accelerated a familial underlying condition is unknown.
## Esophageal Carcinoma
The following adverse events were reported over the entire follow-up period in at least 5% of patients treated with PHOTOFRIN® PDT, who had completely or partially obstructing esophageal cancer. Table 7 presents data from 88 patients who received the currently marketed formulation. The relationship of many of these adverse events to PDT with PHOTOFRIN® is uncertain.
Location of the tumor was a prognostic factor for three adverse events: upper-third of the esophagus (esophageal edema), middle-third (atrial fibrillation), and lower-third, the most vascular region (anemia). Also, patients with large tumors (>10 cm) were more likely to experience anemia. Two of 17 patients with complete esophageal obstruction from tumor experienced esophageal perforations, which were considered to be possibly treatment associated; these perforations occurred during subsequent endoscopies.
Serious and other notable adverse events observed in less than 5% of PDT-treated patients with obstructing esophageal cancer in the clinical studies include the following; their relationship to therapy is uncertain. In the gastrointestinal system, esophageal perforation, gastric ulcer, ileus, jaundice, and peritonitis have occurred. Sepsis has been reported occasionally. Cardiovascular events have included angina pectoris, bradycardia, myocardial infarction, sick sinus syndrome, and supraventricular tachycardia. Respiratory events of bronchitis, bronchospasm, laryngotracheal edema, pneumonitis, pulmonary hemorrhage, pulmonary edema, respiratory failure, and stridor have occurred. The temporal relationship of some gastrointestinal, cardiovascular and respiratory events to the administration of light was suggestive of mediastinal inflammation in some patients. Vision-related events of abnormal vision, diplopia, eye pain and photophobia have been reported.
## Obstructing Endobronchial Cancer
Table 8 presents adverse events that were reported over the entire follow-up period in at least 5% of patients with obstructing endobronchial cancer treated with PHOTOFRIN® PDT or Nd:YAG. These data are based on the 86 patients who received the currently marketed formulation. Since it seems likely that most adverse events caused by these acute acting therapies would occur within 30 days of treatment, Table 8 presents those events occurring within 30 days of a treatment procedure, as well as those occurring over the entire follow-up period. It should be noted that follow-up was 33% longer for the PDT group than for the Nd:YAG group, thereby introducing a bias against PDT when adverse event rates are compared for the entire follow-up period. The extent of follow-up in the 30-day period following treatment was comparable between groups (only 9% more for PDT).
Transient inflammatory reactions in PDT-treated patients occur in about 10% of patients and manifest as fever, bronchitis, chest pain, and dyspnea. The incidences of bronchitis and dyspnea were higher with PDT than with Nd:YAG. Most cases of bronchitis occurred within 1 week of treatment and all but one were mild or moderate in intensity. The events usually resolved within 10 days with antibiotic therapy. Treatment-related worsening of dyspnea is generally transient and self-limiting. Debridement of the treated area is mandatory to remove exudate and necrotic tissue. Life-threatening respiratory insufficiency likely due to therapy occurred in 3% of PDT-treated patients and 2% of Nd:YAG-treated patients.
There was a trend toward a higher rate of fatal massive hemoptysis (FMH) occurring on the PDT arm (10%) versus the Nd:YAG arm (5%), however, the rate of FMH occurring within 30 days of treatment was the same for PDT and Nd:YAG (4% total events, 3% treatment-associated events). Patients who have received radiation therapy have a higher incidence of FMH after treatment with PDT and after other forms of local therapy than patients who have not received radiation therapy, but analyses suggest that this increased risk may be due to associated prognostic factors such as having a centrally located tumor. The incidence of FMH in patients previously treated with radiotherapy was 21% (6/29) in the PDT group and 10% (3/29) in the Nd:YAG group. In patients with no prior radiotherapy, the overall incidence of FMH was less than 1%.
Other serious or notable adverse events were observed in less than 5% of PDT-treated patients with endobronchial cancer; their relationship to therapy is uncertain. In the respiratory system, pulmonary thrombosis, pulmonary embolism, and lung abscess have occurred. Cardiac failure, sepsis, and possible cerebrovascular accident have also been reported in one patient each.
## Superficial Endobronchial Tumors
The following adverse events were reported over the entire follow-up period in at least 5% of patients with superficial tumors (microinvasive or carcinoma in situ) who received the currently marketed formulation.
In patients with superficial endobronchial tumors, 44 of 90 patients (49%) experienced an adverse event, two-thirds of which were related to the respiratory system. The most common reaction to therapy was a mucositis reaction in one-fifth of the patients, which manifested as edema, exudate, and obstruction. The obstruction (mucus plug) is easily removed with suction or forceps. Mucositis can be minimized by avoiding exposure of normal tissue to excessive light (see PRECAUTIONS). Three patients experienced life-threatening dyspnea: one was given a double dose of light, one was treated concurrently in both mainstem bronchi and the other had had prior pneumonectomy and was treated in the sole remaining main airway. Stent placement was required in 3% of the patients due to endobronchial stricture. Fatal massive hemoptysis occurred within 30 days of treatment in one patient with superficial tumors (1%).
## High-Grade Dysplasia (HGD) in Barrett’s Esophagus (BE)
Table 10 presents adverse events that were reported, regardless of the relationship to treatment, over the follow-up period in at least 5% of patients with HGD in BE in either controlled or uncontrolled clinical trials.
In the PHOTOFRIN® PDT + OM group, severe treatment-associated adverse events included chest pain of non-cardiac origin, dysphagia, nausea, vomiting, regurgitation, and heartburn. The severity of these symptoms decreased within 4 to 6 weeks following treatment.
The majority of the photosensitivity reactions occurred within 90 days following PHOTOFRIN® injection and was of mild (69%) or moderate (24%) intensity. Almost all (98%) of the photosensitivity reactions were considered to be associated with treatment. Fourteen (10%) patients reported severe reactions, all of which resolved. The typical reaction was described as skin disorder, sunburn or rash, and affected mostly the face, hands, and neck. Associated symptoms and signs were swelling, pruritis, erythema, blisters, itching, burning sensation, and feeling of heat.
The majority of esophageal stenosis and strictures reported in the PHOTOFRIN® PDT + OM group were of mild (55%) or moderate (37%) intensity, while approximately 8% were of severe intensity. The majority of esophageal strictures were reported during Course 2 of treatment. All esophageal strictures were considered to be associated with treatment. Most esophageal strictures were manageable through dilations (see PRECAUTIONS).
Laboratory Abnormalities
In patients with esophageal cancer, PDT with PHOTOFRIN® may result in anemia due to tumor bleeding. No significant effects were observed for other parameters in patients with endobronchial carcinoma or with HGD in BE.
## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Photofrin with PDT. 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.
Infusion reactions: Infusion reactions including urticaria, bradycardia, hypotension, dizziness, and hypertension.
# Drug Interactions
## Other Photosensitizing Agents
There have been no formal interaction studies of PHOTOFRIN and any other drugs. However, it is possible that concomitant use of other photosensitizing agents (e.g., tetracyclines, sulfonamides, phenothiazines, sulfonylurea hypoglycemic agents, thiazide diuretics, griseofulvin, and fluoroquinolones) could increase the risk of photosensitivity reaction.
## Concomitant Therapy
Photodynamic therapy (PDT) with PHOTOFRIN causes direct intracellular damage by initiating radical chain reactions that damage intracellular membranes and mitochondria. Tissue damage also results from ischemia secondary to vasoconstriction, platelet activation and aggregation and clotting. Research in animals and in cell culture has suggested that many drugs could influence the effects of PDT, possible examples of which are described below. There are no human data that support or rebut these possibilities.
Compounds that quench active oxygen species or scavenge radicals, such as dimethyl sulfoxide, β-carotene, ethanol, formate and mannitol would be expected to decrease PDT activity. Preclinical data also suggest that tissue ischemia, allopurinol, calcium channel blockers and some prostaglandin synthesis inhibitors could interfere with PHOTOFRIN PDT. Drugs that decrease clotting, vasoconstriction or platelet aggregation, e.g., thromboxane A2 inhibitors, could decrease the efficacy of PDT. Glucocorticoid hormones given before or concomitant with PDT may decrease the efficacy of the treatment.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled studies in pregnant women. PHOTOFRIN® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
PHOTOFRIN® given to rat dams during fetal organogenesis intravenously at 8 mg/kg/d (0.64 times the clinical dose on a mg/m2 basis) for 10 days caused no major malformations or developmental changes. This dose caused maternal and fetal toxicity resulting in increased resorptions, decreased litter size, delayed ossification, and reduced fetal weight. PHOTOFRIN® caused no major malformations when given to rabbits intravenously during organogenesis at 4 mg/kg/d (0.65 times the clinical dose on a mg/m2 basis) for 13 days. This dose caused maternal toxicity resulting in increased resorptions, decreased litter size, and reduced fetal body weight.
PHOTOFRIN® given to rats during late pregnancy through lactation intravenously at 4 mg/kg/d (0.32 times the clinical dose on a mg/m2 basis) for at least 42 days caused a reversible decrease in growth of offspring. Parturition was unaffected.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Porfimer in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Porfimer during labor and delivery.
### Nursing Mothers
- It is not known whether PHOTOFRIN is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from PHOTOFRIN, a decision should be made whether not to treat or to discontinue breastfeeding, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in children have not been established.
### Geriatic Use
- Approximately 70% of the patients treated with PDT using PHOTOFRIN in clinical trials were over 60 years of age. There was no apparent difference in effectiveness or safety in these patients compared to younger people. Dose modification based upon age is not required.
### Gender
There is no FDA guidance on the use of Porfimer with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Porfimer with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Porfimer in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Porfimer in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Porfimer in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Porfimer in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Porfimer in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Porfimer in the drug label.
# Overdosage
PHOTOFRIN Overdose
- There is no information on overdosage situations involving PHOTOFRIN. Higher than recommended drug doses of two 2 mg/kg doses given two days apart (10 patients) and three 2 mg/kg doses given within two weeks (one patient), were tolerated without notable adverse reactions. Effects of overdosage on the duration of photosensitivity are unknown. Laser treatment should not be given if an overdose of PHOTOFRIN is administered. In the event of an overdose, patients should protect their eyes and skin from direct sunlight or bright indoor lights for 30 days. At this time, patients should test for residual photosensitivity. PHOTOFRIN is not dialyzable.
Overdose of Laser Light Following PHOTOFRIN Injection
- Light doses of two to three times the recommended dose have been administered to a few patients with superficial endobronchial tumors. One patient experienced life-threatening dyspnoea and the others had no notable complications. Increased symptoms and damage to normal tissue might be expected following an overdose of light. There is no information on overdose of laser light following PHOTOFRIN injection in patients with esophageal cancer or in patients with high-grade dysplasia in Barrett's esophagus.
# Pharmacology
## Mechanism of Action
- Cellular damage caused by photodynamic therapy (PDT) with PHOTOFRIN is a consequence of the propagation of radical reactions. Radical initiation may occur after porfimer sodium absorbs light to form a porphyrin excited state. Spin transfer from porfimer sodium to molecular oxygen may then generate singlet oxygen. Subsequent radical reactions can form superoxide and hydroxyl radicals. Tumor death also occurs through ischemic necrosis secondary to vascular occlusion that appears to be partly mediated by thromboxane A2 release. As opposed to a thermal effect, the laser treatment with porfimer sodium induces a photochemical effect. The necrotic reaction and associated inflammatory responses may evolve over several days.
## Structure
- PHOTOFRIN (porfimer sodium) for Injection is a photosensitizing agent used in the photodynamic therapy (PDT) of tumors and of high-grade dysplasia (HGD) in Barrett’s esophagus (BE). Following reconstitution of the freeze-dried product with 5% Dextrose Injection (USP) or 0.9% Sodium Chloride Injection (USP), it is injected intravenously. This is followed 40–50 hours later by illumination of the tumor or the esophageal segment with HGD in BE with laser light (630 nm wavelength). PHOTOFRIN is not a single chemical entity; it is a mixture of oligomers formed by ether and ester linkages of up to eight porphyrin units. It is a dark red to reddish brown cake or powder. Each vial of PHOTOFRIN contains 75 mg of porfimer sodium as a sterile freeze-dried cake or powder. Hydrochloric Acid and/or Sodium Hydroxide may be added during manufacture to adjust the pH to within 7.2-7.9. There are no preservatives or other additives. The structural formula below is representative of the components present in PHOTOFRIN.
## Pharmacodynamics
- The cytotoxic and antitumor actions of PHOTOFRIN are light and oxygen dependent. PDT with PHOTOFRIN is a two-stage process. The first stage is the intravenous injection of PHOTOFRIN. Clearance from a variety of tissues occurs over 40-72 hours, but tumors, skin, and organs of the reticuloendothelial system (including liver and spleen) retain PHOTOFRIN for a longer period. Illumination with 630 nm wavelength laser light constitutes the second stage of therapy. Tumor selectivity in treatment occurs through a combination of selective retention of PHOTOFRIN and selective delivery of light.
## Pharmacokinetics
- The pharmacokinetics of PHOTOFRIN were studied in 18 cancer patients who received two doses of PHOTOFRIN, 2 mg/kg each, administered 30 to 45 days appart as slow IV injection over 3 to 5 mintues. The mean Cmax values were comparable after the first and second administrations (43.1 ± 10.5 mcg/mL and 41.3 ± 8.7 mcg/mL, respectively). However, the mean AUC0-inf of porfimer was about 34% higher after the second administration than that after the first administration (3937 ± 1034 mcg.h/mL and 2937 ± 627 mcg.hour/mL, respectively), indicating some accumulation upon repeated administration. The elimination half-life of porfimer increased from 410 to 725 hours after the first and second administrations, respectively.
- PHOTOFRIN was approximately 90% protein bound in human serum, studied in vitro. The binding was independent of concentration over the concentration range of 20–100 mcg/mL.
Effect of Gender:
- The effect of gender was determined in 18 patients (8 males and 10 females) who received two administrations of PHOTOFRIN 2 mg/kg within 30-45 days apart as slow IV injection over 3 to 5 minutes. The mean Cmax value and AUC values were comparable between males and females following either the first of the second administrations.
Effect of Hepatic Renal Impairment:
- The effect of hepatic and renal impairment has not been studied.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- No long-term studies have been conducted to evaluate the carcinogenic potential of porfimer sodium.
- In the presence of light, in vitro, porfimer sodium PDT did not cause mutations in the Ames test, nor did it cause chromosome aberrations or mutations (HGPRT locus) in Chinese hamster ovary (CHO) cells. Porfimer sodium PDT caused <2-fold, but significant, increases in sister chromatid exchange in CHO cells irradiated with visible light and a 3-fold increase in Chinese hamster lung fibroblasts irradiated with near UV light. Porfimer sodium PDT caused an increase in thymidine kinase mutants and DNA-protein cross-links in mouse L5178Y cells, but not mouse LYR83 cells. Porfimer sodium PDT caused a light-dose dependant increase in DNA-strand breaks in malignant human cervical carcinoma cells, but not in normal cells. In the absence of light, porfimer sodium was negative in a Chinese hamster ovarian cells (CHO/HGPRT) mutation test. In vivo, porfimer sodium did not cause chromosomal aberrations in the mouse micronucleus test.
- Porfimer sodium given to male and female rats intravenously, at 4 mg/kg/d (0.32 times the clinical dose on a mg/m2 basis) before conception and through Day 7 of pregnancy caused no impairment of fertility. In this study, long-term dosing with porfimer sodium caused discoloration of testes and ovaries and hypertrophy of the testes. Porfimer sodium also caused decreased body weight in the parent rats.
# Clinical Studies
- Clinical studies of photodynamic therapy (PDT) with PHOTOFRIN were conducted in patients with obstructing esophageal and endobronchial non-small-cell lung cancers, in patients with early-stage radiologically occult endobronchial cancer, and in patients with high-grade dysplasia (HGD) in Barrett's esophagus (BE). In all clinical studies, the method of PDT administration was essentially identical. A course of therapy consisted of one injection of PHOTOFRIN (2 mg/kg administered as a slow intravenous injection over 3–5 minutes) followed by up to two non-thermal applications of 630 nm laser light. Light doses of 300 J/cm of diffuser length were used in esophageal cancer. Light doses of 200 J/cm of diffuser length were used in endobronchial cancer for both palliation of obstructing cancer and treatment of superficial lesions. For the ablation of HGD in BE, the light dose administered was 130 J/cm of diffuser length using a centering balloon for the first application and 50 J/cm of diffuser length without a centering balloon for the second application. In all cases, the first application of light occurred 40–50 hours after PHOTOFRIN injection.
- For treatment of esophageal cancer debridement of residua via endoscopy is optional 96–120 hours after injection, after which any residual tumor could be retreated with a second laser light application at the same light dose used for the initial treatment. Additional courses of PDT with PHOTOFRIN were allowed after one month, up to a maximum of three courses.
- For treatment of endobronchial cancer, debridement of residua was performed via bronchoscopy 96–120 hours after injection, after which any residual tumor could be retreated with a second laser light application at the same light dose used for the initial treatment. Additional courses of PDT with PHOTOFRIN-were allowed after one month, up to a maximum of three courses.
- For ablation of HGD in BE, a second laser light application of 50 J/cm of diffuser length without a centering balloon could be given 96-120 hours after the PHOTOFRIN injection for untreated areas ("skip" areas). Additional courses of PDT with PHOTOFRIN were allowed after three months, up to a maximum of three courses.
Esophageal Cancer
- PDT with PHOTOFRIN was utilized in a multicenter, single-arm study in 17 patients with completely obstructing esophageal carcinoma. Assessments were made at 1 week and 1 month after the last treatment procedure. As shown in TABLE 10, after a single course of therapy, 94% of patients obtained an objective tumor response and 76% of patients experienced some palliation of their dysphagia. On average, before treatment these patients had difficulty swallowing liquids, even saliva. After one course of therapy, there was a statistically significant improvement in mean dysphagia grade (1.5 units, p <0.05) and 13 of 17 patients could swallow liquids without difficulty 1 week and/or 1 month after treatment. Based on all courses, three patients achieved a complete tumor response (CR). In two of these patients, the CR was documented only at Week 1 as they had no further assessments. The third patient achieved a CR after a second course of therapy, which was supported by negative histopathology and maintained for the entire follow-up of 6 months.
- Of the 17 treated patients, 11 (65%) received clinically important benefit from PDT. Clinically important benefit was defined hierarchically as a complete tumor response (3 patients), achievement of normal swallowing (2 patients went from Grade 5 dysphagia to Grade 1), or achievement of a marked improvement of two or more grades of dysphagia with minimal adverse reactions (6 patients). The median duration of benefit in these patients was 69 days. Duration of benefit was calculated only for the period with documented evidence of improvement. All of these patients were still in response at their last assessment and, therefore, the estimate of 69 days is conservative. The median survival for these 11 patients was 115 days.
Endobronchial Cancer
- Two randomized multicenter Phase III studies were conducted to compare the safety and efficacy of PHOTOFRIN PDT versus Nd:YAG laser therapy for reduction of obstruction and palliation of symptomatic patients with partially or completely obstructing endobronchial non-small-cell lung cancer. Assessments were made at 1 week and at monthly intervals after treatment. TABLE 11 shows the results from all randomized patients in the two studies combined. Objective tumor response rates (CR + PR), which demonstrate reduction of obstruction, were 59% for PDT and 58% for Nd:YAG at Week 1. The response rate at 1 month or later was 60% for PDT and 41% for Nd:YAG.
- Patient symptoms were evaluated using a 5- or 6-grade pulmonary symptom severity rating scale for dyspnoea, cough, and hemoptysis. Patients with moderate to severe symptoms are those most in need of palliation. Improvements of 2 or more grades are considered to be clinically significant. TABLE 12 shows the percentages of patients with moderate to severe symptoms at baseline who demonstrated a 2-grade improvement at any time during the interval evaluated.
- In a separate retrospective analysis, patients were individually evaluated to identify those patients whose benefit to risk ratio was most favorable, i.e., those who obtained clinically important benefit with minimal adverse reactions. Clinically important benefit was defined as one of the following:
- A substantial improvement in pulmonary symptoms at Month 1 or later (dyspnoea ≥2 grades, hemoptysis ≥3 grades, cough ≥3 grades or increase in FEV1 ≥40%);
A moderate improvement in symptoms at Month 2 or later (dyspnoea 1 grade, cough 2 grades, hemoptysis 2 grades or increase in FEV1 ≥20%); or
A durable objective tumor response (CR or PR maintained to Month 2 or longer).
Thirty-six (36) of the 99 PDT-treated patients (36%) and 23 of the 99 Nd:YAG-treated patients (23%) received clinically important benefit with only minimal or moderate toxicities of short duration. Thirty-four of 99 PDT-treated patients demonstrated improvements in 2 or more efficacy endpoints (dyspnoea, cough, hemoptysis, sputum, atelectasis, pulmonary function tests of FEV1 or FVC, Karnofsky Performance Score or tumor response) and 29 patients had improvements in 3 or more.
- The median duration of documented benefit in the 36 patients was 63 days. In these patients with late-stage obstructing lung cancer, median survival was 174 days in PDT-treated patients and 161 days in Nd:YAG-treated patients.
- The efficacy of PHOTOFRIN PDT was also evaluated in the treatment of microinvasive endobronchial tumors in 62 inoperable patients in three noncomparative studies. Microinvasive lung cancer is defined histologically as disease, which invades beyond the basement membrane but not through or into the cartilage. For 11 of the 62 patients, it was clearly documented that surgery and radiotherapy were not indicated. These 11 patients were all inoperable for medical or technical reasons. Radiotherapy was not indicated due to prior high-dose radiotherapy (7 patients), poor pulmonary function (2 patients), multifocal multilobar disease (1 patient), and poor medical condition (1 patient). As shown in TABLE 13, the complete tumor response rate, biopsy-proven at least 3 months after treatment, was 50%, median time to tumor recurrence was more than 2.7 years, median survival was 2.9 years and disease-specific survival was 4.1 years.
High-Grade Dysplasia in Barrett's Esophagus
- The safety and efficacy of PDT with PHOTOFRIN in ablation of HGD in patients with BE was assessed in one controlled randomized clinical study and two supportive studies.
Controlled Randomized Study
- A multicenter, pathology blinded, randomized, controlled study was conducted in North America and Europe to assess the efficacy of PDT with PHOTOFRIN for Injection plus omeprazole (PHOTOFRIN PDT + OM) in producing complete ablation of HGD in patients with BE compared to control patients receiving omeprazole alone (OM Only). A total of 485 patients with the diagnosis of HGD were screened for the study; 208 (43%) were randomized to treatment, 237 (49%) were excluded because the diagnosis of HGD was not confirmed and 40 (8%) did not meet other screening criteria or declined to participate in the study. The high patient exclusion rate re-enforces the recommendation by the American College of Gastroenterology that the diagnosis of HGD in BE should be confirmed by an expert GI pathologist. Patients were centrally randomized in a 2:1 proportion to receive PHOTOFRIN PDT + OM (138 patients) or OM Only (70 patients). All patients underwent rigorous systematic quarterly endoscopic biopsy surveillance. Four-quadrant jumbo biopsies at every 2 cm of the entire Barrett’s mucosa were obtained at each follow-up visit (every three months or six months if four consecutive quarterly follow-up endoscopic biopsy results were negative for HGD). All histological assessments were carried out at a central pathology laboratory and read by pathologists blinded to the treatment administered.
- A total of 208 patients who had biopsy-proven HGD in BE were enrolled in the initial 2-year phase of the study. Of those, 199 patients were considered evaluable: 130 of 138 (94%) patients randomized to the PHOTOFRIN PDT + OM group and 69 of 70 (99%) randomized to the OM Only group had no esophageal invasive cancer, suspicion of esophageal invasive cancer, lymph node involvement, or metastases, and had received at least one PHOTOFRIN PDT course or one week of OM treatment, respectively. A disproportionate percentage of patients were discontinued from the OM Only group during the initial 2-year phase leaving 81 (59%) patients in the PHOTOFRIN PDT + OM group and 21 (30%) patients in the OM Only group at the end of the 2-year phase. Consequently, a total of 102 patients who completed the initial 2-year phase were eligible for continuation into the long-term phase until completion of 5 years; of those, 48 (59%) patients from the PHOTOFRIN PDT + OM group and 13 (62%) patients from the OM Only group consented to pursue the long-term phase until completion of 5 years. The mean age was 66 years (38 to 89 years) in the PHOTOFRIN PDT + OM group, and 67 (36 to 88 years) in the OM Only group. The patients in both treatment groups were predominantly male (85%), Caucasian (99%), and former smokers (64%). These characteristics are typical of patients with HGD in BE. Patients randomized to the PHOTOFRIN PDT + OM treatment received up to three courses of treatment separated by at least 90 days. Each course consisted of intravenous administration of 2.0 mg/kg of PHOTOFRIN followed 40-50 hours later by a 630 nm laser light dose of 130 J/cm of diffuser length delivered using a centering balloon. A second laser light dose of 50 J/cm of diffuser length could be administered without a centering balloon 96-120 hours after the injection of PHOTOFRIN for treatment of "skip" areas. Since centering balloons are up to 7 cm in length, patients with more extensive HGD were treated with two or three courses. Both the PHOTOFRIN PDT treatment group and the control group received 20 mg of omeprazole BID to decrease reflux esophagitis. The mean duration of the follow-up period was 34 months (0-67 months) for the PHOTOFRIN PDT + OM group and 25 months (0-65 months) for the OM Only group.
- The primary efficacy endpoint was the Complete Response rate (CR3 or better) at any one of the endoscopic assessment time points. The CR3 or better response was defined as the complete ablation of HGD and referred to as a composite of the following three response levels.
- CR1 – Complete replacement of all Barrett’s metaplasia and dysplasia with normal squamous cell epithelium;
- CR2 – Ablation of all histological grades of dysplasia, including patients with indefinite grade of dysplasia, but some areas of Barrett’s epithelium still remain; and
- CR3 – Ablation of all areas of HGD but with some areas of low-grade dysplasia with or without areas which are indefinite for dysplasia, or areas of Barrett’s metaplastic epithelium.
- Additional efficacy endpoints included:
- Quality of Complete Response, which consisted of CR1 and CR2 or better.
- Duration of CR;
- Time to Progression to Cancer.
- TABLE 14 presents the overall clinical response for both treatment groups in the intent-to-treat (ITT) population whose response was CR3 or better at any one of the evaluation time points. Overall, PHOTOFRIN PDT + OM was effective in eliminating HGD in patients with BE. The proportion of responders was significantly higher in the PHOTOFRIN PDT + OM group than in the OM Only group (77% vs. 39%, respectively; p<0.0001).
- The quality of response in the PHOTOFRIN PDT + OM group was significantly better than that measured in the OM Only group at all response levels (p<0.0001). Seventy-two (52%) patients in the PHOTOFRIN PDT + OM group achieved a CR1 response as compared to only five (7%) patients in the OM Only group. Eighty-one (59%) patients in the PHOTOFRIN PDT + OM group achieved a CR2 or better response as compared to ten (14%) patients in the OM Only group.
NOTE: Six patients in the PHOTOFRIN PDT + OM group and three patients in the OM Only group without post-baseline biopsy data are considered as non-responders.
- At the end of the long-term phase, the median response duration was 44.6 months (95% CI: 15.0-not reached, months) in the PHOTOFRIN PDT + OM group compared to 3.2 months (95% CI: 3.0-3.4, months) in the OM Only group.
- At the end of the initial 2 year phase, the time to progression to cancer was significantly longer in the PHOTOFRIN PDT + OM group compared to the OM Only group (HR=0.36 (95% CI: 0.19-0.69), a hazard ratio less than 1 favors the PHOTOFRIN PDT + OM group). The proportion of patients' progression to cancer was lower in the PHOTOFRIN PDT + OM group than in the OM Only group: 13% (18 of 138 patients) vs. 28% (20 of 70 patients).
- Complete response was influenced by the following factors: treatment with PHOTOFRIN PDT + OM (vs. OM Only), single focus of HGD (vs. multiple foci), and prior omeprazole intake of at least 3 months (yes vs. no). Complete response was not influenced by the duration of HGD, length of BE, nodular conditions, gender, age, smoking history, and study center’s size.
Supportive Studies
- Two uncontrolled, supportive studies were conducted that were physician-sponsored, single center Phase II trials. Both studies included patients that had low-grade dysplasia (LGD), HGD and early adenocarcinoma. All HGD in BE patients were treated with PHOTOFRIN PDT and omeprazole.
- The first study enrolled 99 patients (44 with HGD); the purpose of this study was to determine the required light dose to produce effective results. The second study enrolled 86 patients (42 with HGD), who were randomized to receive either PHOTOFRIN PDT with prednisone or PHOTOFRIN PDT without prednisone to determine whether steroid treatment would reduce the incidence and severity of esophageal strictures.
- A CR3 or better response was demonstrated in 93% of 44 patients with HGD in the first study and in 95% of 42 patients with HGD in the second study after a minimum follow-up of 12 months. A CR2 or better response was achieved in 82% of patients in the first study and in 91% of patients in the second study. A CR1 response occurred in 57% of patients in the first study and in 60% of the second study. Progression to cancer during the above follow-up period occurred in 18% of patients in the first study and in 7% of patients in the second study. No reduction in the incidence or severity of esophageal strictures was found in the prednisone group in the second study.
# How Supplied
- PHOTOFRIN (porfimer sodium) for Injection is supplied as a freeze-dried cake or powder as follows:
NDC 76128-155-75, 75 mg vial
## Storage
- PHOTOFRIN freeze-dried cake or powder should be stored at Controlled Room Temperature 20-25°C (68-77°F) [see USP].
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Photosensitivity
- Patients should be warned to avoid exposure of skin and eyes to direct sunlight or bright indoor light for at least 30 days following injection with PHOTOFRIN.
- Patients should be informed that photosensitivity might last for more than 90 days if patients suffer from liver impairment.
- Patients should be instructed to wear protective clothing and dark sunglasses when outdoors, which have an average white light transmittance of < 4%.
- Patients should be encouraged to expose their skin to ambient indoor light to facilitate elimination of PHOTOFRIN from their skin.
Common Adverse Reactions
- Patients should be informed that treatment with photodynamic therapy might lead to adverse reactions which include ocular sensitivity, chest pain, respiratory distress or esophageal strictures. In such cases, patients should call their physicians.
# Precautions with Alcohol
- Alcohol-Porfimer interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PHOTOFRIN
# Look-Alike Drug Names
There is limited information regarding Porfimer Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Photofrin | |
891b05cb196640adcb0a6da7551270ff964ee977 | wikidoc | Pickling | Pickling
Pickling, also known as brining or corning, is the process of preserving food by anaerobic fermentation in brine (a solution of salt in water), to produce lactic acid, or marinating and storing it in an acid solution, usually vinegar (acetic acid). The resulting food is called a pickle. This procedure gives the food a salty or sour taste.
The distinguishing feature is a pH less than 4.6, which is sufficient to kill most necrobacteria. Pickling can preserve perishable foods for months. Antimicrobial herbs and spices, such as mustard, garlic, cinnamon or cloves, are often added.
If the food contains sufficient moisture, a pickling brine may be produced simply by adding dry salt. For example, sauerkraut and Korean kimchi are produced by salting the vegetables to draw out excess water. Natural fermentation at room temperature, by lactic acid bacteria, produces the required acidity. Other pickles are made by placing vegetables in vinegar. Unlike the canning process, pickling (which includes fermentation) does not require that the food be completely sterile before it is sealed. The acidity or salinity of the solution, the temperature of fermentation, and the exclusion of oxygen determine which microorganisms dominate, and determine the flavor of the end product. Template:Ref harvard
When both salt concentration and temperature are low, Leuconostoc mesenteroides dominates, producing a mix of acids, alcohol, and aroma compounds. At higher temperatures Lactobacillus plantarum dominates, which produces primarily lactic acid. Many pickles start with Leuconostoc, and change to Lactobacillus with higher acidity. Template:Ref harvard
Pickling began as a way to preserve food for out-of-season use and for long journeys, especially by sea. Salt pork and salt beef were common staples for sailors before the days of steam engines. Although the process was invented to preserve foods, pickles are also made and eaten because people enjoy the resulting flavors. Pickling may also improve the nutritious value of food by introducing B vitamins produced by bacteria.
# Popularity of pickles around the world
## Asia
### East Asia
China is home to a huge variety of pickled vegetables, including radish, baicai (Chinese cabbage, notably suan cai, la bai cai, pao cai, and Tianjin preserved vegetable), zha cai, chili pepper and cucumber, among many others.
Japanese tsukemono (pickled foods) include takuan (daikon), umeboshi (ume plum), gari & beni shoga (ginger), turnip, cucumber, and Chinese cabbage.
Korean kimchi is usually made from pickled Chinese cabbage.
### South Asia
In Sri Lanka, they traditionally prepare pickles called achcharu which is made from slices of carrots, onions, ground dates, mustard ground with pepper, crushed ginger with garlic and vinegar seasoned in a clay pot.
### Southeast Asia
Indonesian acar is usually made from sliced or diced cucumber, carrot, bird's eye chilies, shallots and seasoned with vinegar, sugar and salt. Sometimes Indonesians added other kinds of fruits, such as sliced/diced papaya and pineapple.
In the Philippines, they also have pickles called "achara" which are made from slices of green papaya, shallots, cloves of garlic and vinegar.
In Vietnam, pickles are called cải chua (literally "sour vegetables"), and are often made from mustard greens.
## Europe
In Turkey, pickles are called turşu. Turkish people make turşu with several vegetables, roots, and fruits such as peppers, cucumber, Armenian cucumber (acur), cabbage, tomato, eggplant (aubergine), carrot, turnip, beetroot, green almond, green plum, etc. Also, they use several spices to flavour their pickles.
In Albania, Bulgaria and Serbia, mixed pickles are known as turshi. They are a very popular traditional appetizer for raki. Pickled green tomatoes, cucumbers, carrots, bell peppers, peppers, eggplants, and sauerkraut, are also very popular.
In Romania, common pickles are beetroot, cucumbers, green tomatoes (gogonele), carrots, cabbage, bell peppers, melons, mushrooms and cauliflowers.
In Russia, popular pickled foods include beets, mushrooms, various types of tomatoes, cabbage, cucumbers, ramsons, garlic, eggplant (typically stuffed with julienned carrots), custard squash, and even watermelon.
Pickled herring and rollmops are pickled fish dishes popular typically in Scandinavia. Salmon may be brine-pickled.
In Britain, pickled onions and pickled eggs are often sold in pubs and fish and chip shops. Pickled beetroot, walnuts, and gherkins, and condiments such as Branston Pickle and piccalilli are typically eaten as an accompaniment to pork pies and cold meats or a ploughman's lunch.
In Ukraine common garden produce is usually dilled to be consumed in winter. Salt, dill, currant leaves and garlic are used and, after storage in a cool, dark place, give tomatoes and cucumbers a distinctive flavour.
In Italy, giardiniera is a popular dish of pickled vegetables including onions, carrots, celery and cauliflower. Italian giardiniera is different from the American condiment called giardiniera.
## Middle East
In Iran and many Arab countries like Lebanon and Egypt, pickles (called mekhallel in Arabic, hamutzim in Hebrew, or torshi in Persian) are served at almost every meal. They vary, but the most common are made from turnips, peppers, green olives, cucumbers, beetroot, cabbage, lemons and cauliflower.
## North America
The United States and Canada pickle market is dominated by pickled cucumbers (which are commonly referred to as simply pickles), olives, and sauerkraut, although many pickles popular in other nations are also available (such as the pickled tomato common in New York City delicatessens). Giardiniera, a mixture of pickled peppers, celery and olives, is a popular condiment in Chicago, often served with Italian beef sandwiches. Pickled eggs are common in the Upper Peninsula of Michigan. In the southern United States, pickled okra is popular. In Mexico, chile peppers, particularly of the Jalapeño and serrano varieties, pickled with onions, carrots and herbs are common condiments.
# Other foods that are commonly pickled
- Vegetables: ginger, lotus root, garlic, asparagus, onion, radish, green beans, eggplant
- Capers and olives are usually served pickled in the West (unlike the salt-cured versions favored in the Orient).
- Fruit: mango, kumquat, lemon, peach, watermelon rind
- Peppers and chiles: banana peppers, jalapeños, etc.,
- Meat: beef (to make corned beef and pastrami), pork, ham
- Fish see also ceviche
- Eggs
- Okra | Pickling
Pickling, also known as brining or corning, is the process of preserving food by anaerobic fermentation in brine (a solution of salt in water), to produce lactic acid, or marinating and storing it in an acid solution, usually vinegar (acetic acid). The resulting food is called a pickle. This procedure gives the food a salty or sour taste.
The distinguishing feature is a pH less than 4.6[1], which is sufficient to kill most necrobacteria. Pickling can preserve perishable foods for months. Antimicrobial herbs and spices, such as mustard, garlic, cinnamon or cloves, are often added.[2]
If the food contains sufficient moisture, a pickling brine may be produced simply by adding dry salt. For example, sauerkraut and Korean kimchi are produced by salting the vegetables to draw out excess water. Natural fermentation at room temperature, by lactic acid bacteria, produces the required acidity. Other pickles are made by placing vegetables in vinegar. Unlike the canning process, pickling (which includes fermentation) does not require that the food be completely sterile before it is sealed. The acidity or salinity of the solution, the temperature of fermentation, and the exclusion of oxygen determine which microorganisms dominate, and determine the flavor of the end product. Template:Ref harvard
When both salt concentration and temperature are low, Leuconostoc mesenteroides dominates, producing a mix of acids, alcohol, and aroma compounds. At higher temperatures Lactobacillus plantarum dominates, which produces primarily lactic acid. Many pickles start with Leuconostoc, and change to Lactobacillus with higher acidity. Template:Ref harvard
Pickling began as a way to preserve food for out-of-season use and for long journeys, especially by sea. Salt pork and salt beef were common staples for sailors before the days of steam engines. Although the process was invented to preserve foods, pickles are also made and eaten because people enjoy the resulting flavors. Pickling may also improve the nutritious value of food by introducing B vitamins produced by bacteria.[citation needed]
# Popularity of pickles around the world
## Asia
### East Asia
China is home to a huge variety of pickled vegetables, including radish, baicai (Chinese cabbage, notably suan cai, la bai cai, pao cai, and Tianjin preserved vegetable), zha cai, chili pepper and cucumber, among many others.
Japanese tsukemono (pickled foods) include takuan (daikon), umeboshi (ume plum), gari & beni shoga (ginger), turnip, cucumber, and Chinese cabbage.
Korean kimchi is usually made from pickled Chinese cabbage.
### South Asia
In Sri Lanka, they traditionally prepare pickles called achcharu which is made from slices of carrots, onions, ground dates, mustard ground with pepper, crushed ginger with garlic and vinegar seasoned in a clay pot.
### Southeast Asia
Indonesian acar is usually made from sliced or diced cucumber, carrot, bird's eye chilies, shallots and seasoned with vinegar, sugar and salt. Sometimes Indonesians added other kinds of fruits, such as sliced/diced papaya and pineapple.
In the Philippines, they also have pickles called "achara" which are made from slices of green papaya, shallots, cloves of garlic and vinegar.
In Vietnam, pickles are called cải chua (literally "sour vegetables"), and are often made from mustard greens.
## Europe
In Turkey, pickles are called turşu. Turkish people make turşu with several vegetables, roots, and fruits such as peppers, cucumber, Armenian cucumber (acur), cabbage, tomato, eggplant (aubergine), carrot, turnip, beetroot, green almond, green plum, etc. Also, they use several spices to flavour their pickles.
In Albania, Bulgaria and Serbia, mixed pickles are known as turshi. They are a very popular traditional appetizer for raki. Pickled green tomatoes, cucumbers, carrots, bell peppers, peppers, eggplants, and sauerkraut, are also very popular.
In Romania, common pickles are beetroot, cucumbers, green tomatoes (gogonele), carrots, cabbage, bell peppers, melons, mushrooms and cauliflowers.
In Russia, popular pickled foods include beets, mushrooms, various types of tomatoes, cabbage, cucumbers, ramsons, garlic, eggplant (typically stuffed with julienned carrots), custard squash, and even watermelon.
Pickled herring and rollmops are pickled fish dishes popular typically in Scandinavia. Salmon may be brine-pickled.
In Britain, pickled onions and pickled eggs are often sold in pubs and fish and chip shops. Pickled beetroot, walnuts, and gherkins, and condiments such as Branston Pickle and piccalilli are typically eaten as an accompaniment to pork pies and cold meats or a ploughman's lunch.
In Ukraine common garden produce is usually dilled to be consumed in winter. Salt, dill, currant leaves and garlic are used and, after storage in a cool, dark place, give tomatoes and cucumbers a distinctive flavour.
In Italy, giardiniera is a popular dish of pickled vegetables including onions, carrots, celery and cauliflower. Italian giardiniera is different from the American condiment called giardiniera.
## Middle East
In Iran and many Arab countries like Lebanon and Egypt, pickles (called mekhallel in Arabic, hamutzim in Hebrew, or torshi in Persian) are served at almost every meal. They vary, but the most common are made from turnips, peppers, green olives, cucumbers, beetroot, cabbage, lemons and cauliflower.
## North America
The United States and Canada pickle market is dominated by pickled cucumbers (which are commonly referred to as simply pickles), olives, and sauerkraut, although many pickles popular in other nations are also available (such as the pickled tomato common in New York City delicatessens). Giardiniera, a mixture of pickled peppers, celery and olives, is a popular condiment in Chicago, often served with Italian beef sandwiches. Pickled eggs are common in the Upper Peninsula of Michigan. In the southern United States, pickled okra is popular. In Mexico, chile peppers, particularly of the Jalapeño and serrano varieties, pickled with onions, carrots and herbs are common condiments.
# Other foods that are commonly pickled
- Vegetables: ginger, lotus root, garlic, asparagus, onion, radish, green beans, eggplant
- Capers and olives are usually served pickled in the West (unlike the salt-cured versions favored in the Orient).
- Fruit: mango, kumquat, lemon, peach, watermelon rind
- Peppers and chiles: banana peppers, jalapeños, etc.,
- Meat: beef (to make corned beef and pastrami), pork, ham
- Fish see also ceviche
- Eggs
- Okra
Template:Cooking Techniques | https://www.wikidoc.org/index.php/Pickling | |
58d460517dc334dd50e7e2704c4e3592f2ef3643 | wikidoc | Pimozide | Pimozide
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# Overview
Pimozide is an antipsychotic that is FDA approved for the treatment of Tourette's Disorder in patients who have failed to respond satisfactorily to standard treatment. Common adverse reactions include sedation, akathisia, akinesia, adverse behavior effect and visual disturbance.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Pimozide is indicated for the suppression of motor and phonic tics in patients with Tourette's Disorder who have failed to respond satisfactorily to standard treatment.
- Pimozide is not intended as a treatment of first choice nor is it intended for the treatment of tics that are merely annoying or cosmetically troublesome.
- Pimozide should be reserved for use in Tourette's Disorder patients whose development and/or daily life function is severely compromised by the presence of motor and phonic tics.
- Dosage:
- Should be initiated with a dose of 1 to 2 mg a day in divided doses.
- The dose may be increased thereafter every other day.
- Most patients are maintained at less than 0.2 mg/kg/day, or 10 mg/day, whichever is less.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pimozide in adult patients.
### Non–Guideline-Supported Use
- Chronic schizophrenia
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Pimozide is indicated for the suppression of motor and phonic tics in patients with Tourette's Disorder who have failed to respond satisfactorily to standard treatment.
- Pimozide is not intended as a treatment of first choice nor is it intended for the treatment of tics that are merely annoying or cosmetically troublesome.
- Pimozide should be reserved for use in Tourette's Disorder patients whose development and/or daily life function is severely compromised by the presence of motor and phonic tics.
- Dosage:
- Should be initiated at a dose of 0.05 mg/kg preferably taken once at bedtime.
- The dose may be increased every third day to a maximum of 0.2 mg/kg not to exceed 10 mg/day.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pimozide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pimozide in pediatric patients.
# Contraindications
- Pimozide is contraindicated in the treatment of simple tics or tics other than those associated with Tourette's Disorder.
- Pimozide should not be used in patients taking drugs that may, themselves, cause motor and phonic tics (e.g., pemoline, methylphenidate and amphetamines) until such patients have been withdrawn from these drugs to determine whether or not the drugs, rather than Tourette's Disorder, are responsible for the tics.
- Because pimozide prolongs the QT interval of the electrocardiogram it is contraindicated in patients with congenital long QT syndrome, patients with a history of cardiac arrhythmias, patients taking other drugs which prolong the QT interval of the electrocardiogram or patients with known hypokalemia or hypomagnesemia.
- Pimozide is contraindicated in patients with severe toxic central nervous system depression or comatose states from any cause.
- Pimozide is contraindicated in patients with hypersensitivity to it. As it is not known whether cross-sensitivity exists among the antipsychotics, pimozide should be used with appropriate caution in patients who have demonstrated hypersensitivity to other antipsychotic drugs.
- Ventricular arrhythmias have been rarely associated with the use of macrolide antibiotics in patients with prolonged QT intervals, as might be produced by pimozide. Specifically, two sudden deaths have been reported when clarithromycin was added to ongoing pimozide therapy. Furthermore, some evidence suggests that pimozide is metabolized partly by the enzyme system cytochrome P450 3A4 (CYP 3A4). Macrolide antibiotics are inhibitors of CYP 3A4, and thus could potentially impede pimozide metabolism. For these reasons, pimozide is contraindicated in patients receiving the macrolide antibiotics clarithromycin, erythromycin, azithromycin, dirithromycin, and troleandomycin.
- Concomitant use in patients taking Celexa or Lexapro is contraindicated.
- Clinical drug interaction studies have demonstrated that pimozide is also metabolized by CYP 2D6. Concomitant use of pimozide with paroxetine and other strong CYP 2D6 inhibitors is contraindicated.
- Concomitant use of pimozide in patients taking sertraline is contraindicated.
Because azole antifungal agents are also inhibitors of the CYP 3A4 enzymes and thus may likewise impair pimozide metabolism, pimozide is contraindicated in patients receiving the azole antifungal agents itraconazole and ketoconazole.
Similarly, protease inhibitor drugs are also inhibitors of CYP 3A4, and thus pimozide is contraindicated in patients receiving protease inhibitors such as ritonavir, saquinovir, indinavir, and nelfinavir.
Nefazodone is a potent inhibitor of CYP 3A4, and its concomitant use with pimozide is also contraindicated.
Other drugs that are relatively less potent inhibitors of CYP 3A4 should also be avoided, in view of the risks: e.g. zileuton, fluvoxamine.
# Warnings
The use of pimozide in the treatment of Tourette's Disorder involves different risk/benefit considerations than when antipsychotic drugs are used to treat other conditions. Consequently, a decision to use pimozide should take into consideration the following.
A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, antipsychotic drugs should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
The management of NMS should include:
- immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy,
- intensive symptomatic treatment and medical monitoring, and
- treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
Hyperpyrexia, not associated with the above symptom complex, has been reported with other antipsychotic drugs.
Sudden, unexpected deaths have occurred in experimental studies of conditions other than Tourette's Disorder. These deaths occurred while patients were receiving dosages in the range of 1 mg per kg. One possible mechanism for such deaths is prolongation of the QT interval predisposing patients to ventricular arrhythmia. An electrocardiogram should be performed before pimozide treatment is initiated and periodically thereafter, especially during the period of dose adjustment.
pimozide may have a tumorigenic potential. Based on studies conducted in mice, it is known that pimozide can produce a dose-related increase in pituitary tumors. The full significance of this finding is not known, but should be taken into consideration in the physician's and patient's decisions to use this drug product. This finding should be given special consideration when the patient is young and chronic use of pimozide is anticipated.
In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents.
Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of pimozide should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue pimozide and have their WBC followed until recovery.
# Adverse Reactions
## Clinical Trials Experience
Neuromuscular (extrapyramidal) reactions during the administration of pimozide® (pimozide) have been reported frequently, often during the first few days of treatment. In most patients, these reactions involved Parkinson-like symptoms which, when first observed, were usually mild to moderately severe and usually reversible.
Other types of neuromuscular reactions (motor restlessness, dystonia, akathisia, hyperreflexia, opisthotonos, oculogyric crises) have been reported far less frequently. Severe extrapyramidal reactions have been reported to occur at relatively low doses. Generally the occurrence and severity of most extrapyramidal symptoms are dose-related since they occur at relatively high doses and have been shown to disappear or become less severe when the dose is reduced. Administration of antiparkinson drugs such as benztropine mesylate or trihexyphenidyl hydrochloride may be required for control of such reactions. It should be noted that persistent extrapyramidal reactions have been reported and that the drug may have to be discontinued in such cases.
Generally, patients receiving short term therapy experience no problems with abrupt discontinuation of antipsychotic drugs. However, some patients on maintenance treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of these cases the dyskinetic movements are indistinguishable from the syndrome described below under "Tardive Dyskinesia" except for duration. It is not known whether gradual withdrawal of antipsychotic drugs will reduce the rate of occurrence of withdrawal emergent neurological signs, but until further evidence becomes available, it seems reasonable to gradually withdraw use of pimozide.
pimozide may be associated with persistent dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may appear in some patients on long-term therapy or may occur after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear irreversible. The syndrome is characterized by rhythmical involuntary movements of tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities and the trunk.
There is no known effective treatment for tardive dyskinesia; antiparkinson agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, this syndrome may be masked.
It has been reported that fine vermicular movement of the tongue may be an early sign of tardive dyskinesia and if the medication is stopped at that time the syndrome may not develop.
Electrocardiographic changes have been observed in clinical trials of pimozide in Tourette's Disorder and schizophrenia. These have included prolongation of the QT interval, flattening, notching and inversion of the T wave and the appearance of U waves. Sudden, unexpected deaths and grand mal seizure have occurred at doses above 20 mg/day.
Neuroleptic malignant syndrome (NMS) has been reported with pimozide. (See WARNINGS for further information concerning NMS.)
Hyperpyrexia has been reported with other antipsychotic drugs.
The following adverse reaction tabulation was derived from 20 patients in a 6-week long placebo-controlled clinical trial of pimozide in Tourette's Disorder.
The following adverse event tabulation was derived from 36 children (age 2 to 12) in a 24-week open trial of pimozide in Tourette's Disorder.
Because clinical investigational experience with pimozide in Tourette's Disorder is limited, uncommon adverse reactions may not have been detected. The physician should consider that other adverse reactions associated with antipsychotics may occur.
In addition to the adverse reactions listed above, those listed below have been reported in U.S. clinical trials of pimozide in conditions other than Tourette's Disorder.
- Body as a Whole: Asthenia, chest pain, periorbital edema
- Cardiovascular/Respiratory: Postural hypotension, hypotension, hypertension, tachycardia, palpitations
- Gastrointestinal: Increased salivation, nausea, vomiting, anorexia, GI distress
- Endocrine: Loss of libido
- Metabolic/Nutritional: Weight gain, weight loss
- Central Nervous System: Dizziness, tremor, parkinsonism, fainting, dyskinesia
- Psychiatric: Excitement
- Skin: Rash, sweating, skin irritation
- Special Senses: Blurred vision, cataracts
- Urogenital: Nocturia, urinary frequency
## Postmarketing Experience
The following experiences were described in spontaneous postmarketing reports. These reports do not provide sufficient information to establish a clear causal relationship with the use of pimozide.
- Gastrointestinal: Gingival hyperplasia in one patient
- Hematologic: Hemolytic anemia
- Metabolic/Nutritional: Hyponatremia
- Other: Seizure
# Drug Interactions
Because pimozide prolongs the QT interval of the electrocardiogram, an additive effect on QT interval would be anticipated if administered with other drugs, such as phenothiazines, tricyclic antidepressants or antiarrhythmic agents, which prolong the QT interval. Accordingly, pimozide should not be given with dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol, tacrolimus, ziprasidone, or other drugs that have demonstrated QT prolongation as one of their pharmacodynamic effects. Also, the use of macrolide antibiotics in patients with prolonged QT intervals has been rarely associated with ventricular arrhythmias. Such concomitant administration should not be undertaken.
Since pimozide is partly metabolized via CYP 3A4, it should not be administered concomitantly with inhibitors of this metabolic system, such as azole antifungal agents and protease inhibitor drugs.
In a controlled study, a single dose of pimozide 2 mg co-administered with racemic citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Racemic citalopram did not alter the mean AUC or Cmax of pimozide. The mechanism of this pharmacodynamic interaction is not known. Concomitant use of pimozide and Celexa or Lexapro is contraindicated.
CYP 2D6 inhibitors: In healthy subjects, co-administration of pimozide 2 mg (single dose) and paroxetine 60 mg resulted in a 151% increase in pimozide AUC and a 62% increase in pimozide Cmax compared to pimozide administered alone. The increase in pimozide AUC and Cmax is related to the CYP 2D6 inhibitory properties of paroxetine. Concomitant use of pimozide and paroxetine or other strong CYP 2D6 inhibitors are contraindicated.
As CYP 1A2 may also contribute to the metabolism of pimozide, prescribers should be aware of the theoretical potential for drug interactions with inhibitors of this enzymatic system.
pimozide may be capable of potentiating CNS depressants, including analgesics, sedatives, anxiolytics, and alcohol.
Rare case reports have suggested possible additive effects of pimozide and fluoxetine leading to bradycardia.
Concomitant administration of pimozide and sertraline should be contraindicated.
Patients should avoid grapefruit juice because it may inhibit the metabolism of pimozide by CYP 3A4.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Reproduction studies performed in rats and rabbits at oral doses up to 8 times the maximum human dose did not reveal evidence of teratogenicity. In the rat, however, this multiple of the human dose resulted in decreased pregnancies and in the retarded development of fetuses. These effects are thought to be due to an inhibition or delay in implantation which is also observed in rodents administered other antipsychotic drugs. In the rabbit, maternal toxicity, mortality, decreased weight gain, and embryotoxicity including increased resorptions were dose-related. Because animal reproduction studies are not always predictive of human response, pimozide should be given to a pregnant woman only if the potential benefits of treatment clearly outweigh the potential risks.
Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
Pimozide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS): B1
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pimozide in women who are pregnant.
### Labor and Delivery
This drug has no recognized use in labor or delivery.
### Nursing Mothers
It is not known whether pimozide is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity and unknown cardiovascular effects in the infant, 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
Although Tourette's Disorder most often has its onset between the ages of 2 and 15 years, information on the use and efficacy of pimozide in patients less than 12 years of age is limited. A 24-week open label study in 36 children between the ages of 2 and 12 demonstrated that pimozide has a similar safety profile in this age group as in older patients and there were no safety findings that would preclude its use in this age group.
Because its use and safety have not been evaluated in other childhood disorders, pimozide is not recommended for use in any condition other than Tourette's Disorder.
### Geriatic Use
There is no FDA guidance on the use of Pimozide in geriatric settings.
### Gender
There is no FDA guidance on the use of Pimozide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pimozide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pimozide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pimozide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
Reproduction studies in animals were not adequate to assess all aspects of fertility. Nevertheless, female rats administered pimozide had prolonged estrus cycles, an effect also produced by other antipsychotic drugs.
### Immunocompromised Patients
There is no FDA guidance one the use of Pimozide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
- An ECG should be done at baseline and periodically thereafter throughout the period of dose adjustment. Any indication of prolongation of QTc interval beyond an absolute limit of 0.47 seconds (children) or 0.52 seconds (adults), or more than 25% above the patient's original baseline should be considered a basis for stopping further dose increase and considering a lower dose.
- Since hypokalemia has been associated with ventricular arrhythmias, potassium insufficiency, secondary to diuretics, diarrhea, or other cause, should be corrected before pimozide therapy is initiated and normal potassium maintained during therapy.
# IV Compatibility
There is limited information regarding the compatibility of Pimozide and IV administrations.
# Overdosage
In general, the signs and symptoms of overdosage with pimozide (pimozide) would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would be:
- electrocardiographic abnormalities
- severe extrapyramidal reactions
- hypotension
- a comatose state with respiratory depression
In the event of overdosage, gastric lavage, establishment of a patent airway and, if necessary, mechanically-assisted respiration are advised. Electrocardiographic monitoring should commence immediately and continue until the ECG parameters are within the normal range. Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine and norepinephrine.
Epinephrine should not be used. In case of severe extrapyramidal reactions, antiparkinson medication should be administered. Because of the long half-life of pimozide, patients who take an overdose should be observed for at least 4 days. As with all drugs, the physician should consider contacting a poison control center for additional information on the treatment of overdose.
# Pharmacology
## Mechanism of Action
- The exact mechanism of action has not been established; however, pimozide blocks dopamine receptors in the central nervous system (CNS).
- The efficacy of pimozide in suppressing the tics of Tourette's syndrome is thought to be due to dopaminergic blockade.
## Structure
The structural formula of pimozide, 1--4-piperidinyl]-1,3-dihydro-2H-benzimidazole-2-one is:
## Pharmacodynamics
Pimozide is an orally active antipsychotic drug product which shares with other antipsychotics the ability to blockade dopaminergic receptors on neurons in the central nervous system. Although its exact mode of action has not been established, the ability of pimozide to suppress motor and phonic tics in Tourette's Disorder is thought to be a function of its dopaminergic blocking activity. However, receptor blockade is often accompanied by a series of secondary alterations in central dopamine metabolism and function which may contribute to both pimozide's therapeutic and untoward effects. In addition, pimozide, in common with other antipsychotic drugs, has various effects on other central nervous system receptor systems which are not fully characterized.
## Pharmacokinetics
More than 50% of a dose of pimozide is absorbed after oral administration. Based on the pharmacokinetic and metabolic profile, pimozide appears to undergo significant first pass metabolism. Peak serum levels occur generally six to eight hours (range 4-12 hours) after dosing.
Pimozide is extensively metabolized, primarily by N-dealkylation in the liver. This metabolism is catalyzed mainly by the cytochrome P450 3A4 (CYP 3A4) enzymatic system and to a lesser extent, by cytochrome P450 1A2 (CYP 1A2) and cytochrome P450 2D6 (CYP 2D6). Two major metabolites have been identified, 1-(4-piperidyl)-2-benzimidazolinone and 4,4-bis(4-fluorophenyl) butyric acid. The antipsychotic activity of these metabolites is undetermined. The major route of elimination of pimozide and its metabolites is through the kidney.
The mean serum elimination half-life of pimozide in schizophrenic patients was approximately 55 hours. There was a 13-fold interindividual difference in the area under the serum pimozide level-time curve and an equivalent degree of variation in peak serum levels among patients studied. The significance of this is unclear since there are few correlations between plasma levels and clinical findings.
Effects of food and disease upon the absorption, distribution, metabolism and elimination of pimozide are not known.
## Nonclinical Toxicology
Carcinogenicity studies were conducted in mice and rats. In mice, pimozide causes a dose-related increase in pituitary and mammary tumors.
When mice were treated for up to 18 months with pimozide, pituitary gland changes developed in females only. These changes were characterized as hyperplasia at doses approximating the human dose and adenoma at doses about fifteen times the maximum recommended human dose on a mg per kg basis. The mechanism for the induction of pituitary tumors in mice is not known.
Mammary gland tumors in female mice were also increased, but these tumors are expected in rodents treated with antipsychotic drugs which elevate prolactin levels. Chronic administration of an antipsychotic also causes elevated prolactin levels in humans. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with antipsychotic drugs, the clinical significance of elevated serum prolactin levels is unknown for most patients. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of these drugs and mammary tumorigenesis. The available evidence, however, is considered too limited to be conclusive at this time.
In a 24-month carcinogenicity study in rats, animals received up to 50 times the maximum recommended human dose. No increased incidence of overall tumors or tumors at any site was observed in either sex. Because of the limited number of animals surviving this study, the meaning of these results is unclear.
Pimozide did not have mutagenic activity in the Ames test with four bacterial test strains, in the mouse dominant lethal test or in the micronucleus test in rats.
# Clinical Studies
There is limited information regarding Pimozide Clinical Studies in the drug label.
# How Supplied
- Pimozide 1 mg tablets
- Available in bottles of 100 (NDC 57844-151-01).
- Pimozide 2 mg tablets
- Available in bottles of 100 (NDC 57844-187-01).
## Storage
Store at 25°C (77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Treatment with pimozide exposes the patient to serious risks. A decision to use pimozide chronically in Tourette's Disorder is one that deserves full consideration by the patient (or patient's family) as well as by the treating physician. Because the goal of treatment is symptomatic improvement, the patient's view of the need for treatment and assessment of response are critical in evaluating the impact of therapy and weighing its benefits against the risks. Since the physician is the primary source of information about the use of a drug in any disease, it is recommended that the following information be discussed with patients and/or their families.
pimozide is intended only for use in patients with Tourette's Disorder whose symptoms are severe and who cannot tolerate, or who do not respond to HALDOL® (haloperidol).
Given the likelihood that a proportion of patients exposed chronically to antipsychotics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided.
There is limited information available on the use of pimozide in children under 12 years of age.
The information available on pimozide from foreign marketing experience and from U.S. clinical trials indicates that pimozide has a side effect profile similar to that of other antipsychotic drugs. Patients should be informed that all types of side effects associated with the use of antipsychotics may be associated with the use of pimozide.
In addition, sudden, unexpected deaths have occurred in patients taking high doses of pimozide for conditions other than Tourette's Disorder. These deaths may have been the result of an effect of pimozide upon the heart. Therefore, patients should be instructed not to exceed the prescribed dose of pimozide and they should realize the need for the initial ECG and for follow-up ECGs during treatment.
Also, pimozide, at a dose about 15 times that given humans, caused an increase in the number of benign tumors of the pituitary gland in female mice. It is not possible to say how important this is. Similar tumors were not seen in rats given pimozide, nor at lower doses in mice, which is reassuring. However, any such finding must be considered to suggest a possible risk of long term use of the drug.
Because substances in grapefruit juice may inhibit the metabolism of pimozide by CYP 3A4, patients should be advised to avoid grapefruit juice.
# Precautions with Alcohol
Alcohol-Pimozide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Orap
# Look-Alike Drug Names
There is limited information regarding Pimozide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Pimozide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]
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# Overview
Pimozide is an antipsychotic that is FDA approved for the treatment of Tourette's Disorder in patients who have failed to respond satisfactorily to standard treatment. Common adverse reactions include sedation, akathisia, akinesia, adverse behavior effect and visual disturbance.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Pimozide is indicated for the suppression of motor and phonic tics in patients with Tourette's Disorder who have failed to respond satisfactorily to standard treatment.
- Pimozide is not intended as a treatment of first choice nor is it intended for the treatment of tics that are merely annoying or cosmetically troublesome.
- Pimozide should be reserved for use in Tourette's Disorder patients whose development and/or daily life function is severely compromised by the presence of motor and phonic tics.
- Dosage:
- Should be initiated with a dose of 1 to 2 mg a day in divided doses.
- The dose may be increased thereafter every other day.
- Most patients are maintained at less than 0.2 mg/kg/day, or 10 mg/day, whichever is less.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pimozide in adult patients.
### Non–Guideline-Supported Use
- Chronic schizophrenia
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Pimozide is indicated for the suppression of motor and phonic tics in patients with Tourette's Disorder who have failed to respond satisfactorily to standard treatment.
- Pimozide is not intended as a treatment of first choice nor is it intended for the treatment of tics that are merely annoying or cosmetically troublesome.
- Pimozide should be reserved for use in Tourette's Disorder patients whose development and/or daily life function is severely compromised by the presence of motor and phonic tics.
- Dosage:
- Should be initiated at a dose of 0.05 mg/kg preferably taken once at bedtime.
- The dose may be increased every third day to a maximum of 0.2 mg/kg not to exceed 10 mg/day.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pimozide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pimozide in pediatric patients.
# Contraindications
- Pimozide is contraindicated in the treatment of simple tics or tics other than those associated with Tourette's Disorder.
- Pimozide should not be used in patients taking drugs that may, themselves, cause motor and phonic tics (e.g., pemoline, methylphenidate and amphetamines) until such patients have been withdrawn from these drugs to determine whether or not the drugs, rather than Tourette's Disorder, are responsible for the tics.
- Because pimozide prolongs the QT interval of the electrocardiogram it is contraindicated in patients with congenital long QT syndrome, patients with a history of cardiac arrhythmias, patients taking other drugs which prolong the QT interval of the electrocardiogram or patients with known hypokalemia or hypomagnesemia.
- Pimozide is contraindicated in patients with severe toxic central nervous system depression or comatose states from any cause.
- Pimozide is contraindicated in patients with hypersensitivity to it. As it is not known whether cross-sensitivity exists among the antipsychotics, pimozide should be used with appropriate caution in patients who have demonstrated hypersensitivity to other antipsychotic drugs.
- Ventricular arrhythmias have been rarely associated with the use of macrolide antibiotics in patients with prolonged QT intervals, as might be produced by pimozide. Specifically, two sudden deaths have been reported when clarithromycin was added to ongoing pimozide therapy. Furthermore, some evidence suggests that pimozide is metabolized partly by the enzyme system cytochrome P450 3A4 (CYP 3A4). Macrolide antibiotics are inhibitors of CYP 3A4, and thus could potentially impede pimozide metabolism. For these reasons, pimozide is contraindicated in patients receiving the macrolide antibiotics clarithromycin, erythromycin, azithromycin, dirithromycin, and troleandomycin.
- Concomitant use in patients taking Celexa or Lexapro is contraindicated.
- Clinical drug interaction studies have demonstrated that pimozide is also metabolized by CYP 2D6. Concomitant use of pimozide with paroxetine and other strong CYP 2D6 inhibitors is contraindicated.
- Concomitant use of pimozide in patients taking sertraline is contraindicated.
Because azole antifungal agents are also inhibitors of the CYP 3A4 enzymes and thus may likewise impair pimozide metabolism, pimozide is contraindicated in patients receiving the azole antifungal agents itraconazole and ketoconazole.
Similarly, protease inhibitor drugs are also inhibitors of CYP 3A4, and thus pimozide is contraindicated in patients receiving protease inhibitors such as ritonavir, saquinovir, indinavir, and nelfinavir.
Nefazodone is a potent inhibitor of CYP 3A4, and its concomitant use with pimozide is also contraindicated.
Other drugs that are relatively less potent inhibitors of CYP 3A4 should also be avoided, in view of the risks: e.g. zileuton, fluvoxamine.
# Warnings
The use of pimozide in the treatment of Tourette's Disorder involves different risk/benefit considerations than when antipsychotic drugs are used to treat other conditions. Consequently, a decision to use pimozide should take into consideration the following.
A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, antipsychotic drugs should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
The management of NMS should include:
- immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy,
- intensive symptomatic treatment and medical monitoring, and
- treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
Hyperpyrexia, not associated with the above symptom complex, has been reported with other antipsychotic drugs.
Sudden, unexpected deaths have occurred in experimental studies of conditions other than Tourette's Disorder. These deaths occurred while patients were receiving dosages in the range of 1 mg per kg. One possible mechanism for such deaths is prolongation of the QT interval predisposing patients to ventricular arrhythmia. An electrocardiogram should be performed before pimozide treatment is initiated and periodically thereafter, especially during the period of dose adjustment.
pimozide may have a tumorigenic potential. Based on studies conducted in mice, it is known that pimozide can produce a dose-related increase in pituitary tumors. The full significance of this finding is not known, but should be taken into consideration in the physician's and patient's decisions to use this drug product. This finding should be given special consideration when the patient is young and chronic use of pimozide is anticipated.
In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents.
Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of pimozide should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue pimozide and have their WBC followed until recovery.
# Adverse Reactions
## Clinical Trials Experience
Neuromuscular (extrapyramidal) reactions during the administration of pimozide® (pimozide) have been reported frequently, often during the first few days of treatment. In most patients, these reactions involved Parkinson-like symptoms which, when first observed, were usually mild to moderately severe and usually reversible.
Other types of neuromuscular reactions (motor restlessness, dystonia, akathisia, hyperreflexia, opisthotonos, oculogyric crises) have been reported far less frequently. Severe extrapyramidal reactions have been reported to occur at relatively low doses. Generally the occurrence and severity of most extrapyramidal symptoms are dose-related since they occur at relatively high doses and have been shown to disappear or become less severe when the dose is reduced. Administration of antiparkinson drugs such as benztropine mesylate or trihexyphenidyl hydrochloride may be required for control of such reactions. It should be noted that persistent extrapyramidal reactions have been reported and that the drug may have to be discontinued in such cases.
Generally, patients receiving short term therapy experience no problems with abrupt discontinuation of antipsychotic drugs. However, some patients on maintenance treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of these cases the dyskinetic movements are indistinguishable from the syndrome described below under "Tardive Dyskinesia" except for duration. It is not known whether gradual withdrawal of antipsychotic drugs will reduce the rate of occurrence of withdrawal emergent neurological signs, but until further evidence becomes available, it seems reasonable to gradually withdraw use of pimozide.
pimozide may be associated with persistent dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may appear in some patients on long-term therapy or may occur after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear irreversible. The syndrome is characterized by rhythmical involuntary movements of tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities and the trunk.
There is no known effective treatment for tardive dyskinesia; antiparkinson agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, this syndrome may be masked.
It has been reported that fine vermicular movement of the tongue may be an early sign of tardive dyskinesia and if the medication is stopped at that time the syndrome may not develop.
Electrocardiographic changes have been observed in clinical trials of pimozide in Tourette's Disorder and schizophrenia. These have included prolongation of the QT interval, flattening, notching and inversion of the T wave and the appearance of U waves. Sudden, unexpected deaths and grand mal seizure have occurred at doses above 20 mg/day.
Neuroleptic malignant syndrome (NMS) has been reported with pimozide. (See WARNINGS for further information concerning NMS.)
Hyperpyrexia has been reported with other antipsychotic drugs.
The following adverse reaction tabulation was derived from 20 patients in a 6-week long placebo-controlled clinical trial of pimozide in Tourette's Disorder.
The following adverse event tabulation was derived from 36 children (age 2 to 12) in a 24-week open trial of pimozide in Tourette's Disorder.
Because clinical investigational experience with pimozide in Tourette's Disorder is limited, uncommon adverse reactions may not have been detected. The physician should consider that other adverse reactions associated with antipsychotics may occur.
In addition to the adverse reactions listed above, those listed below have been reported in U.S. clinical trials of pimozide in conditions other than Tourette's Disorder.
- Body as a Whole: Asthenia, chest pain, periorbital edema
- Cardiovascular/Respiratory: Postural hypotension, hypotension, hypertension, tachycardia, palpitations
- Gastrointestinal: Increased salivation, nausea, vomiting, anorexia, GI distress
- Endocrine: Loss of libido
- Metabolic/Nutritional: Weight gain, weight loss
- Central Nervous System: Dizziness, tremor, parkinsonism, fainting, dyskinesia
- Psychiatric: Excitement
- Skin: Rash, sweating, skin irritation
- Special Senses: Blurred vision, cataracts
- Urogenital: Nocturia, urinary frequency
## Postmarketing Experience
The following experiences were described in spontaneous postmarketing reports. These reports do not provide sufficient information to establish a clear causal relationship with the use of pimozide.
- Gastrointestinal: Gingival hyperplasia in one patient
- Hematologic: Hemolytic anemia
- Metabolic/Nutritional: Hyponatremia
- Other: Seizure
# Drug Interactions
Because pimozide prolongs the QT interval of the electrocardiogram, an additive effect on QT interval would be anticipated if administered with other drugs, such as phenothiazines, tricyclic antidepressants or antiarrhythmic agents, which prolong the QT interval. Accordingly, pimozide should not be given with dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol, tacrolimus, ziprasidone, or other drugs that have demonstrated QT prolongation as one of their pharmacodynamic effects. Also, the use of macrolide antibiotics in patients with prolonged QT intervals has been rarely associated with ventricular arrhythmias. Such concomitant administration should not be undertaken.
Since pimozide is partly metabolized via CYP 3A4, it should not be administered concomitantly with inhibitors of this metabolic system, such as azole antifungal agents and protease inhibitor drugs.
In a controlled study, a single dose of pimozide 2 mg co-administered with racemic citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Racemic citalopram did not alter the mean AUC or Cmax of pimozide. The mechanism of this pharmacodynamic interaction is not known. Concomitant use of pimozide and Celexa or Lexapro is contraindicated.
CYP 2D6 inhibitors: In healthy subjects, co-administration of pimozide 2 mg (single dose) and paroxetine 60 mg resulted in a 151% increase in pimozide AUC and a 62% increase in pimozide Cmax compared to pimozide administered alone. The increase in pimozide AUC and Cmax is related to the CYP 2D6 inhibitory properties of paroxetine. Concomitant use of pimozide and paroxetine or other strong CYP 2D6 inhibitors are contraindicated.
As CYP 1A2 may also contribute to the metabolism of pimozide, prescribers should be aware of the theoretical potential for drug interactions with inhibitors of this enzymatic system.
pimozide may be capable of potentiating CNS depressants, including analgesics, sedatives, anxiolytics, and alcohol.
Rare case reports have suggested possible additive effects of pimozide and fluoxetine leading to bradycardia.
Concomitant administration of pimozide and sertraline should be contraindicated.
Patients should avoid grapefruit juice because it may inhibit the metabolism of pimozide by CYP 3A4.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Reproduction studies performed in rats and rabbits at oral doses up to 8 times the maximum human dose did not reveal evidence of teratogenicity. In the rat, however, this multiple of the human dose resulted in decreased pregnancies and in the retarded development of fetuses. These effects are thought to be due to an inhibition or delay in implantation which is also observed in rodents administered other antipsychotic drugs. In the rabbit, maternal toxicity, mortality, decreased weight gain, and embryotoxicity including increased resorptions were dose-related. Because animal reproduction studies are not always predictive of human response, pimozide should be given to a pregnant woman only if the potential benefits of treatment clearly outweigh the potential risks.
Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
Pimozide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS): B1
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pimozide in women who are pregnant.
### Labor and Delivery
This drug has no recognized use in labor or delivery.
### Nursing Mothers
It is not known whether pimozide is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity and unknown cardiovascular effects in the infant, 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
Although Tourette's Disorder most often has its onset between the ages of 2 and 15 years, information on the use and efficacy of pimozide in patients less than 12 years of age is limited. A 24-week open label study in 36 children between the ages of 2 and 12 demonstrated that pimozide has a similar safety profile in this age group as in older patients and there were no safety findings that would preclude its use in this age group.
Because its use and safety have not been evaluated in other childhood disorders, pimozide is not recommended for use in any condition other than Tourette's Disorder.
### Geriatic Use
There is no FDA guidance on the use of Pimozide in geriatric settings.
### Gender
There is no FDA guidance on the use of Pimozide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pimozide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pimozide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pimozide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
Reproduction studies in animals were not adequate to assess all aspects of fertility. Nevertheless, female rats administered pimozide had prolonged estrus cycles, an effect also produced by other antipsychotic drugs.
### Immunocompromised Patients
There is no FDA guidance one the use of Pimozide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
- An ECG should be done at baseline and periodically thereafter throughout the period of dose adjustment. Any indication of prolongation of QTc interval beyond an absolute limit of 0.47 seconds (children) or 0.52 seconds (adults), or more than 25% above the patient's original baseline should be considered a basis for stopping further dose increase and considering a lower dose.
- Since hypokalemia has been associated with ventricular arrhythmias, potassium insufficiency, secondary to diuretics, diarrhea, or other cause, should be corrected before pimozide therapy is initiated and normal potassium maintained during therapy.
# IV Compatibility
There is limited information regarding the compatibility of Pimozide and IV administrations.
# Overdosage
In general, the signs and symptoms of overdosage with pimozide (pimozide) would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would be:
- electrocardiographic abnormalities
- severe extrapyramidal reactions
- hypotension
- a comatose state with respiratory depression
In the event of overdosage, gastric lavage, establishment of a patent airway and, if necessary, mechanically-assisted respiration are advised. Electrocardiographic monitoring should commence immediately and continue until the ECG parameters are within the normal range. Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine and norepinephrine.
Epinephrine should not be used. In case of severe extrapyramidal reactions, antiparkinson medication should be administered. Because of the long half-life of pimozide, patients who take an overdose should be observed for at least 4 days. As with all drugs, the physician should consider contacting a poison control center for additional information on the treatment of overdose.
# Pharmacology
## Mechanism of Action
- The exact mechanism of action has not been established; however, pimozide blocks dopamine receptors in the central nervous system (CNS).
- The efficacy of pimozide in suppressing the tics of Tourette's syndrome is thought to be due to dopaminergic blockade.
## Structure
The structural formula of pimozide, 1-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazole-2-one is:
## Pharmacodynamics
Pimozide is an orally active antipsychotic drug product which shares with other antipsychotics the ability to blockade dopaminergic receptors on neurons in the central nervous system. Although its exact mode of action has not been established, the ability of pimozide to suppress motor and phonic tics in Tourette's Disorder is thought to be a function of its dopaminergic blocking activity. However, receptor blockade is often accompanied by a series of secondary alterations in central dopamine metabolism and function which may contribute to both pimozide's therapeutic and untoward effects. In addition, pimozide, in common with other antipsychotic drugs, has various effects on other central nervous system receptor systems which are not fully characterized.
## Pharmacokinetics
More than 50% of a dose of pimozide is absorbed after oral administration. Based on the pharmacokinetic and metabolic profile, pimozide appears to undergo significant first pass metabolism. Peak serum levels occur generally six to eight hours (range 4-12 hours) after dosing.
Pimozide is extensively metabolized, primarily by N-dealkylation in the liver. This metabolism is catalyzed mainly by the cytochrome P450 3A4 (CYP 3A4) enzymatic system and to a lesser extent, by cytochrome P450 1A2 (CYP 1A2) and cytochrome P450 2D6 (CYP 2D6). Two major metabolites have been identified, 1-(4-piperidyl)-2-benzimidazolinone and 4,4-bis(4-fluorophenyl) butyric acid. The antipsychotic activity of these metabolites is undetermined. The major route of elimination of pimozide and its metabolites is through the kidney.
The mean serum elimination half-life of pimozide in schizophrenic patients was approximately 55 hours. There was a 13-fold interindividual difference in the area under the serum pimozide level-time curve and an equivalent degree of variation in peak serum levels among patients studied. The significance of this is unclear since there are few correlations between plasma levels and clinical findings.
Effects of food and disease upon the absorption, distribution, metabolism and elimination of pimozide are not known.
## Nonclinical Toxicology
Carcinogenicity studies were conducted in mice and rats. In mice, pimozide causes a dose-related increase in pituitary and mammary tumors.
When mice were treated for up to 18 months with pimozide, pituitary gland changes developed in females only. These changes were characterized as hyperplasia at doses approximating the human dose and adenoma at doses about fifteen times the maximum recommended human dose on a mg per kg basis. The mechanism for the induction of pituitary tumors in mice is not known.
Mammary gland tumors in female mice were also increased, but these tumors are expected in rodents treated with antipsychotic drugs which elevate prolactin levels. Chronic administration of an antipsychotic also causes elevated prolactin levels in humans. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with antipsychotic drugs, the clinical significance of elevated serum prolactin levels is unknown for most patients. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of these drugs and mammary tumorigenesis. The available evidence, however, is considered too limited to be conclusive at this time.
In a 24-month carcinogenicity study in rats, animals received up to 50 times the maximum recommended human dose. No increased incidence of overall tumors or tumors at any site was observed in either sex. Because of the limited number of animals surviving this study, the meaning of these results is unclear.
Pimozide did not have mutagenic activity in the Ames test with four bacterial test strains, in the mouse dominant lethal test or in the micronucleus test in rats.
# Clinical Studies
There is limited information regarding Pimozide Clinical Studies in the drug label.
# How Supplied
- Pimozide 1 mg tablets
- Available in bottles of 100 (NDC 57844-151-01).
- Pimozide 2 mg tablets
- Available in bottles of 100 (NDC 57844-187-01).
## Storage
Store at 25°C (77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Treatment with pimozide exposes the patient to serious risks. A decision to use pimozide chronically in Tourette's Disorder is one that deserves full consideration by the patient (or patient's family) as well as by the treating physician. Because the goal of treatment is symptomatic improvement, the patient's view of the need for treatment and assessment of response are critical in evaluating the impact of therapy and weighing its benefits against the risks. Since the physician is the primary source of information about the use of a drug in any disease, it is recommended that the following information be discussed with patients and/or their families.
pimozide is intended only for use in patients with Tourette's Disorder whose symptoms are severe and who cannot tolerate, or who do not respond to HALDOL® (haloperidol).
Given the likelihood that a proportion of patients exposed chronically to antipsychotics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided.
There is limited information available on the use of pimozide in children under 12 years of age.
The information available on pimozide from foreign marketing experience and from U.S. clinical trials indicates that pimozide has a side effect profile similar to that of other antipsychotic drugs. Patients should be informed that all types of side effects associated with the use of antipsychotics may be associated with the use of pimozide.
In addition, sudden, unexpected deaths have occurred in patients taking high doses of pimozide for conditions other than Tourette's Disorder. These deaths may have been the result of an effect of pimozide upon the heart. Therefore, patients should be instructed not to exceed the prescribed dose of pimozide and they should realize the need for the initial ECG and for follow-up ECGs during treatment.
Also, pimozide, at a dose about 15 times that given humans, caused an increase in the number of benign tumors of the pituitary gland in female mice. It is not possible to say how important this is. Similar tumors were not seen in rats given pimozide, nor at lower doses in mice, which is reassuring. However, any such finding must be considered to suggest a possible risk of long term use of the drug.
Because substances in grapefruit juice may inhibit the metabolism of pimozide by CYP 3A4, patients should be advised to avoid grapefruit juice.
# Precautions with Alcohol
Alcohol-Pimozide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Orap [1]
# Look-Alike Drug Names
There is limited information regarding Pimozide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Pimozide | |
079c55e2502b3fbd8ce69f306c5bf9157ea559c9 | wikidoc | Pindolol | Pindolol
# 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
Pindolol is a beta-adrenergic blocker that is FDA approved for the treatment of hypertension. Common adverse reactions include edema, arthralgia, myalgia, dizziness, nervouseness, insomnia, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Dosing Information
- The dosage of pindolol tablets should be individualized. The recommended initial dose of pindolol tablets is 5 mg b.i.d. alone or in combination with other antihypertensive agents. An antihypertensive response usually occurs within the first week of treatment. Maximal response, however, may take as long as or occasionally longer than 2 weeks. If a satisfactory reduction in blood pressure does not occur within 3 to 4 weeks, the dose may be adjusted in increments of 10 mg/day at these intervals up to a maximum of 60 mg/day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pindolol in adult patients.
### Non–Guideline-Supported Use
Dosing Information
- 10 to 40 mg/day.
Dosing Information
- Monotherapy: 2.5 to 10 mg q6h.
- Combination therapy: pindolol 15 mg bid + digoxin 0.125 to 0.5 mg/day.
Dosing Information
- 5 to 30 mg daily.
Dosing information
- 2.5 mg daily to 15 mg bid.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Pindolol 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 Pindolol in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Pindolol in pediatric patients.
# Contraindications
- Bronchial asthma
- Overt cardiac failure
- Cardiogenic shock
- Second degree AV heart block
- Third degree AV heart block
- Severe bradycardia
# Warnings
### Cardiac Failure
- Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by beta-blockade may precipitate more severe failure. Although beta-blockers should be avoided in overt congestive heart failure, if necessary, pindolol can be used with caution in patients with a history of failure who are well-compensated, usually with digitalis and diuretics. Beta-blockes do not abolish the inotropic action of digitalis on heart muscle.
### In Patients Without History of Cardiac Failure
- In patients with latent cardiac insufficiency, continued depression of the myocardium with beta-blockers over a period of time can in some cases lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or be given a diuretic, and the response observed closely. If cardiac failure continues, despite adequate digitalization and diuretic, pindolol therapy should be withdrawn (gradually if possible).
### Exacerbation of Ischemic Heart Disease Following Abrupt Withdrawal
- Hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy; exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such therapy. When discontinuing chronically administered pindolol, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1-2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, pindolol administration should be reinstituted promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician’s advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue pindolol therapy abruptly even in patients treated only for hypertension.
### Nonallergic Bronchospasm (e.g., chronic bronchitis, emphysema) - Patients with Bronchospastic Diseases Should in General Not Receive Beta-Blockers
- Pindolol should be administered with caution since it may block bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta2 receptors.
### Major Surgery
- Because beta-blockade impairs the ability of the heart to respond to reflex stimuli and may increase the risks of general anesthesia and surgical procedures, resulting in protracted hypotension or low cardiac output, it has generally been suggested that such therapy should be gradually withdrawn several days prior to surgery. Recognition of the increased sensitivity to catecholamines of patients recently withdrawn from beta-blocker therapy, however, has made this recommendation controversial. If possible, beta-blockers should be withdrawn well before surgery takes place. In the event of emergency surgery, the anesthesiologist should be informed that the patient is on beta-blocker therapy.
- The effects of pindolol can be reversed by administration of beta-receptor agonists such as isoproterenol, dopamine, dobutamine, or levarterenol. Difficulty in restarting and maintaining the heart beat has also been reported with beta-adrenergic receptor blocking agents.
### Diabetes and Hypoglycemia
- Beta-blockade may prevent the appearance of premonitory signs and symptoms (e.g., tachycardia and blood pressure changes) of acute hypoglycemia. This is especially important with labile diabetics. Beta-blockade also reduces the release of insulin in response to hyperglycemia; therefore, it may be necessary to adjust the dose of antidiabetic drugs.
### Thyrotoxicosis
- Beta-blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-blockade which might precipitate a thyroid crisis.
# Adverse Reactions
## Clinical Trials Experience
- Most adverse reactions have been mild. The incidences listed in the following table are derived from 12-week comparative double-blind, parallel design trials in hypertensive patients given pindolol as monotherapy, given various active control drugs as monotherapy, or given placebo. Data for pindolol and the positive controls were pooled from several trials because no striking differences were seen in the individual studies, with one exception. When considering all adverse reactions reported, the frequency of edema was noticeably higher in positive control trials (16% pindolol vs. 9% positive control) than in placebo controlled trials (6% pindolol vs. 3% placebo). The table includes adverse reactions either volunteered or elicited, and at least possibly drug-related, which were reported in greater than 2% of pindolol patients and other selected important reactions.
- The following selected (potentially important) adverse reactions were seen in 2% or fewer patients and their relationship to pindolol is uncertain:
- Central nervous system: Anxiety, lethargy.
- Autonomic nervous system: Visual disturbances, hyperhidrosis.
- Cardiovascular: Bradycardia, claudication, cold extremities, heart block, hypotension, syncope, tachycardia, weight gain.
- Gastrointestinal: Diarrhea, vomiting.
- Respiratory: Wheezing.
- Urogenital: Impotence, pollakiuria.
- Miscellaneous: Eye discomfort or burning eyes.
### Potential Adverse Effects
- In addition, other adverse effects not aforementioned have been reported with other beta-blockers and should be considered potential adverse effects of pindolol:
- Central Nervous System: Reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics.
- Cardiovascular: Intensification of AV block.
- Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm, respiratory distress. While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.
- Hematologic: Agranulocytosis, thrombocytopenic purpura and nonthrombocytopenic purpura.
- Gastrointestinal: Mesenteric arterial thrombosis, ischemic colitis.
- Miscellaneous: Reversible alopecia, Peyronie’s disease.
- The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with pindolol during investigational use and extensive foreign experience amounting to over 4 million patient-years.
### Clinical Laboratory
- Minor persistent elevations in serum transaminases (SGOT, SGPT) have been noted in 7% of patients during pindolol administration, but progressive elevations were not observed. These elevations were not associated with any other abnormalities that would suggest hepatic impairment, such as decreased serum albumin and total proteins. During more than a decade of worldwide marketing, there have been no reports in the medical literature of overt hepatic injury. Alkaline phosphatase, lactic acid dehydrogenase (LDH), and uric acid are also elevated on rare occasions. The significance of these findings is unknown.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Pindolol in the drug label.
# Drug Interactions
- Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blockers. Patients receiving pindolol plus a catecholamine-depleting agent should, therefore, be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope, or orthostatic hypotension.
- Pindolol has been used with a variety of antihypertensive agents, including hydrochlorothiazide, hydralazine, and guanethidine without unexpected adverse interactions.
- Pindolol has been shown to increase serum thioridazine levels when both drugs are coadministered. Pindolol levels may also be increased with this combination.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Studies in rats and rabbits exceeding 100 times the maximum recommended human doses, revealed no embryotoxicity or teratogenicity. Since there are no adequate and well controlled studies in pregnant women, and since animal reproduction studies are not always predictive of human response, pindolol, as with any drug, should be employed during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pindolol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pindolol during labor and delivery.
### Nursing Mothers
Since pindolol is secreted in human milk, nursing should not be undertaken by mothers receiving the drug.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
There is no FDA guidance on the use of Pindolol in geriatric settings.
### Gender
There is no FDA guidance on the use of Pindolol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pindolol with respect to specific racial populations.
### Renal Impairment
Beta-blockers should be used with caution in patients with renal function. Poor renal function has only minor effects on pindolol clearance.
### Hepatic Impairment
Beta-blockers should be used with caution in patients with hepatic impairment. Poor hepatic function may cause blood levels of pindolol to increase substantially.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pindolol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pindolol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding the monitorization of Pindolol in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Pindolol and IV administrations.
# Overdosage
No specific information on emergency treatment of overdosage is available. Therefore, on the basis of the pharmacologic actions of pindolol, the following general measures should be employed as appropriate in addition to gastric lavage:
- Excessive Bradycardia: Administer atropine; if there is no response to vagal blockade, administer isoproterenol cautiously.
- Cardiac Failure: Digitalize the patient and/or administer diuretic. It has been reported that glucagon may be useful in this situation.
- Hypotension: Administer vasopressors, e.g., epinephrine or norepinephrine, with serial monitoring of blood pressure. (There is evidence that epinephrine may be the drug of choice.)
- Bronchospasm: Administer a beta2 stimulating agent such as isoproterenol and/or a theophylline derivative.
- A case of an acute overdosage has been reported with an intake of 500 mg of pindolol by a hypertensive patient. Blood pressure increased and heart rate was ≥ 80 beats/min. Recovery was uneventful. In another case, 250 mg of pindolol was taken with 150 mg diazepam and 50 mg nitrazepam, producing coma and hypotension. The patient recovered in 24 hours.
# Pharmacology
## Mechanism of Action
- The mechanism of the antihypertensive effects of beta-blockers has not been established, but several mechanisms have been postulated:
- An effect on the central nervous system resulting in a reduced sympathetic outflow to the periphery
- Competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic receptor sites, leading to decreased cardiac output
- An inhibition of renin release.
- These mechanisms appear less likely for pindolol than other beta-blockers in view of the modest effect on resting cardiac output and renin.
## Structure
- Pindolol, a synthetic beta-adrenergic receptor blocking agent with intrinsic sympathomimetic activity is 1-(Indol-4-yloxy)-3-(isopropylamino)-2-propanol.
- Pindolol, USP is a white to off-white, crystalline powder having a faint odor which is practically insoluble in water; slightly soluble in methanol; and very slightly soluble in chloroform.
- Each tablet for oral administration contains pindolol and the following inactive ingredients: crospovidone, lactose, magnesium stearate, microcrystalline cellulose, and pregelatinized starch.
## Pharmacodynamics
- In standard pharmacologic tests in man and animals, pindolol attenuates increases in heart rate, systolic blood pressure, and cardiac output resulting from exercise and isoproterenol administration, thus confirming its beta-blocking properties. The ISA or partial agonist activity of pindolol is mediated directly at the adrenergic receptor sites and may be blocked by other beta-blockers. In catecholamine depleted animal experiments, ISA is manifested as an increase in the inotropic and chronotropic activity of the myocardium. In man, ISA is manifested by a smaller reduction in the resting heart rate (4 to 8 beats/min) than is seen with drugs lacking ISA. There is also a smaller reduction in resting cardiac output. The clinical significance of this observation has not been evaluated and there is no evidence, or reason to believe, that exercise cardiac output is less affected by pindolol.
- Pindolol has been shown in controlled, double-blind clinical studies to be an effective antihypertensive agent when used as monotherapy, or when added to therapy with thiazide-type diuretics. Divided dosages in the range of 10 mg to 60 mg daily have been shown to be effective. As monotherapy, pindolol is as effective as propranolol, α-methyldopa, hydrochlorothiazide, and chlorthalidone in reducing systolic and diastolic blood pressure. The effect on blood pressure is not orthostatic, i.e., pindolol was equally effective in reducing the supine and standing blood pressure.
- In open, long-term studies up to 4 years, no evidence of diminution of the blood pressure lowering response was observed.
- An average 3-pound increase in body weight has been noted in patients treated with pindolol alone, a larger increase than was observed with propranolol or placebo. The weight gain appeared unrelated to blood pressure response and was not associated with an increased risk of heart failure, although edema was more common than in control patients. Pindolol does not have a consistent effect on plasma renin activity.
- Beta-blockade therapy is useful when it is necessary to suppress the effects of beta-adrenergic agonists in order to achieve therapeutic goals. However, in certain clinical situations, (e.g., cardiac failure, heart block, bronchospasm), the preservation of an adequate sympathetic tone may be necessary to maintain vital functions. Although a beta-antagonist with ISA such as pindolol does not eliminate sympathetic tone entirely, there is no controlled evidence that it is safer than other beta-blockers in such conditions as heart failure, heart block, or bronchospasm or is less likely to cause those conditions. In single-dose studies of the effects of beta-blockers on FEV1, pindolol was indistinguishable from other non-cardioselective agents in its reduction of FEV1, and its reduction in the effectiveness of an exogenous beta-agonist.
- Exacerbation of angina and, in some cases, myocardial infarction and ventricular dysrhythmias have been reported after abrupt discontinuation of therapy with beta-adrenergic blocking agents in patients with coronary artery disease. Abrupt withdrawal of these agents in patients without coronary artery disease has resulted in transient symptoms, including tremulousness, sweating, palpitation, headache, and malaise. Several mechanisms have been proposed to explain these phenomena, among them increased sensitivity to catecholamines because of increased numbers of beta receptors.
## Pharmacokinetics
- Pindolol is rapidly and reproducibly absorbed (greater than 95%), achieving peak plasma concentrations within 1 hour of drug administration. Pindolol has no significant first-pass effect. The blood concentrations are proportional in a linear manner to the administered dose in the range of 5 mg to 20 mg. Upon repeated administration to the same subject, variation is minimal.
- After a single dose, intersubject variation for peak plasma concentrations was about 4-fold (e.g., 45 to 167 ng/mL for a 20 mg dose). Upon multiple dosing, intersubject variation decreased to 2- to 2.5-fold. Pindolol is only 40% bound to plasma proteins and is evenly distributed between plasma and red cells. The volume of distribution in healthy subjects is about 2 L/kg.
- Pindolol undergoes extensive metabolism in animals and man. In man, 35% to 40% is excreted unchanged in the urine and 60% to 65% is metabolized primarily to hydroxy-metabolites which are excreted as glucuronides and ethereal sulfates. The polar metabolites are excreted with a half-life of approximately 8 hours and thus multiple dosing therapy (q.8H) results in a less than 50% accumulation in plasma. About 6% to 9% of an administered intravenous dose is excreted by the bile into the feces.
- The disposition of pindolol after oral administration is monophasic with a half-life in healthy subjects or hypertensive patients with normal renal function of approximately 3 to 4 hours. Following t.i.d. administration (q.8H), no significant accumulation of pindolol is observed.
- In elderly hypertensive patients with normal renal function, the half-life of pindolol is more variable, averaging about 7 hours, but with values as high as 15 hours.
- In hypertensive patients with renal diseases, the half-life is within the range expected for healthy subjects. However, a significant decrease (50%) in volume of distribution (VD) is observed in uremic patients and VD appears to be directly correlated to creatinine clearance. Therefore, renal drug clearance is significantly reduced in uremic patients, resulting in a significant decrease in urinary excretion of unchanged drug. Uremic patients with a creatinine clearance of less than 20 mL/min generally excreted less than 15% of the administered dose unchanged in the urine.
- In patients with histologically diagnosed cirrhosis of the liver, the elimination of pindolol was more variable in rate and generally significantly slower than in healthy subjects. The total body clearance of pindolol in cirrhotic patients ranged from about 50 to 300 mL/min and was directly correlated to antipyrine clearance. The half-life ranges from 2.5 hours to greater than 30 hours. These findings strongly suggest that caution should be exercised in dosage adjustments of pindolol in such patients.
- The bioavailability of pindolol is not significantly affected by coadministration of food, hydralazine, hydrochlorothiazide or aspirin. Pindolol has no effect on warfarin activity or the clinical effectiveness of digoxin, although small transient decreases in plasma digoxin concentrations were noted.
## Nonclinical Toxicology
- In chronic oral toxicologic studies (1 to 2 years) in mice, rats, and dogs, pindolol did not produce any significant toxic effects. In 2-year oral carcinogenicity studies in rats and mice in doses as high as 59 mg/kg/day and 124 mg/kg/day (50 and 100 times the maximum recommended human dose), respectively, pindolol did not produce any neoplastic, preneoplastic, or nonneoplastic pathologic lesions. In fertility and general reproductive performance studies in rats, pindolol caused no adverse effects at a dose of 10 mg/kg.
- In the male fertility and general reproductive performance test in rats, definite toxicity characterized by mortality and decreased weight gain was observed in the group given 100 mg/kg/day. At 30 mg/kg/day, decreased mating was associated with testicular atrophy and/or decreased spermatogenesis. This response is not clearly drug-related, however, as there was no dose-response relationship within this experiment and no similar effect on testes of rats administered pindolol as a dietary admixture for 104 weeks. There appeared to be an increase in prenatal mortality in males given 100 mg/kg but development of offspring was not impaired. In females administered pindolol prior to mating through day 21 of lactation, mating behavior was decreased at 100 mg/kg and 30 mg/kg. At these dosages there also was increased mortality of offspring. Prenatal mortality was increased at 10 mg/kg but there was not a clear dose-response relationship in this experiment. There was an increased resorption rate at 100 mg/kg observed in females necropsied on the 15th day of gestation.
# Clinical Studies
- Pindolol has been shown in controlled, double-blind clinical studies to be an effective antihypertensive agent when used as monotherapy, or when added to therapy with thiazide-type diuretics. Divided dosages in the range of 10 mg to 60 mg daily have been shown to be effective. As monotherapy, pindolol is as effective as propranolol, α-methyldopa, hydrochlorothiazide, and chlorthalidone in reducing systolic and diastolic blood pressure. The effect on blood pressure is not orthostatic, i.e., pindolol was equally effective in reducing the supine and standing blood pressure.
# How Supplied
- Pindolol Tablets, USP are available as 5 mg and 10 mg tablets.
- The 5 mg tablets are round white tablets, debossed "MP 178" bisected on one side and blank on the other side. Bottles of 100 CRC NDC 57664-655-88
- The 10 mg tablets are round white tablets, debossed "MP 183" bisected on one side and blank on the other side. Bottles of 100 CRC NDC 57664-656-88
## Storage
- Store at 20° to 25°C (68° to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients, especially those with evidence of coronary artery insufficiency, should be warned against interruption or discontinuation of pindolol therapy without the physician's advice. Although cardiac failure rarely occurs in properly selected patients, patients being treated with beta-blockers should be advised to consult the physician at the first sign or symptom of impending failure.
# Precautions with Alcohol
- Alcohol-Pindolol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Visken
# Look-Alike Drug Names
There is limited information regarding Pindolol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Pindolol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2], Sheng Shi, 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
Pindolol is a beta-adrenergic blocker that is FDA approved for the treatment of hypertension. Common adverse reactions include edema, arthralgia, myalgia, dizziness, nervouseness, insomnia, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Dosing Information
- The dosage of pindolol tablets should be individualized. The recommended initial dose of pindolol tablets is 5 mg b.i.d. alone or in combination with other antihypertensive agents. An antihypertensive response usually occurs within the first week of treatment. Maximal response, however, may take as long as or occasionally longer than 2 weeks. If a satisfactory reduction in blood pressure does not occur within 3 to 4 weeks, the dose may be adjusted in increments of 10 mg/day at these intervals up to a maximum of 60 mg/day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pindolol in adult patients.
### Non–Guideline-Supported Use
Dosing Information
- 10 to 40 mg/day.[1]
Dosing Information
- Monotherapy: 2.5 to 10 mg q6h.[2]
- Combination therapy: pindolol 15 mg bid + digoxin 0.125 to 0.5 mg/day.[3]
Dosing Information
- 5 to 30 mg daily.[4]
Dosing information
- 2.5 mg daily to 15 mg bid.[5]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Pindolol 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 Pindolol in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Pindolol in pediatric patients.
# Contraindications
- Bronchial asthma
- Overt cardiac failure
- Cardiogenic shock
- Second degree AV heart block
- Third degree AV heart block
- Severe bradycardia
# Warnings
### Cardiac Failure
- Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by beta-blockade may precipitate more severe failure. Although beta-blockers should be avoided in overt congestive heart failure, if necessary, pindolol can be used with caution in patients with a history of failure who are well-compensated, usually with digitalis and diuretics. Beta-blockes do not abolish the inotropic action of digitalis on heart muscle.
### In Patients Without History of Cardiac Failure
- In patients with latent cardiac insufficiency, continued depression of the myocardium with beta-blockers over a period of time can in some cases lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or be given a diuretic, and the response observed closely. If cardiac failure continues, despite adequate digitalization and diuretic, pindolol therapy should be withdrawn (gradually if possible).
### Exacerbation of Ischemic Heart Disease Following Abrupt Withdrawal
- Hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy; exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such therapy. When discontinuing chronically administered pindolol, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1-2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, pindolol administration should be reinstituted promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician’s advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue pindolol therapy abruptly even in patients treated only for hypertension.
### Nonallergic Bronchospasm (e.g., chronic bronchitis, emphysema) - Patients with Bronchospastic Diseases Should in General Not Receive Beta-Blockers
- Pindolol should be administered with caution since it may block bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta2 receptors.
### Major Surgery
- Because beta-blockade impairs the ability of the heart to respond to reflex stimuli and may increase the risks of general anesthesia and surgical procedures, resulting in protracted hypotension or low cardiac output, it has generally been suggested that such therapy should be gradually withdrawn several days prior to surgery. Recognition of the increased sensitivity to catecholamines of patients recently withdrawn from beta-blocker therapy, however, has made this recommendation controversial. If possible, beta-blockers should be withdrawn well before surgery takes place. In the event of emergency surgery, the anesthesiologist should be informed that the patient is on beta-blocker therapy.
- The effects of pindolol can be reversed by administration of beta-receptor agonists such as isoproterenol, dopamine, dobutamine, or levarterenol. Difficulty in restarting and maintaining the heart beat has also been reported with beta-adrenergic receptor blocking agents.
### Diabetes and Hypoglycemia
- Beta-blockade may prevent the appearance of premonitory signs and symptoms (e.g., tachycardia and blood pressure changes) of acute hypoglycemia. This is especially important with labile diabetics. Beta-blockade also reduces the release of insulin in response to hyperglycemia; therefore, it may be necessary to adjust the dose of antidiabetic drugs.
### Thyrotoxicosis
- Beta-blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-blockade which might precipitate a thyroid crisis.
# Adverse Reactions
## Clinical Trials Experience
- Most adverse reactions have been mild. The incidences listed in the following table are derived from 12-week comparative double-blind, parallel design trials in hypertensive patients given pindolol as monotherapy, given various active control drugs as monotherapy, or given placebo. Data for pindolol and the positive controls were pooled from several trials because no striking differences were seen in the individual studies, with one exception. When considering all adverse reactions reported, the frequency of edema was noticeably higher in positive control trials (16% pindolol vs. 9% positive control) than in placebo controlled trials (6% pindolol vs. 3% placebo). The table includes adverse reactions either volunteered or elicited, and at least possibly drug-related, which were reported in greater than 2% of pindolol patients and other selected important reactions.
- The following selected (potentially important) adverse reactions were seen in 2% or fewer patients and their relationship to pindolol is uncertain:
- Central nervous system: Anxiety, lethargy.
- Autonomic nervous system: Visual disturbances, hyperhidrosis.
- Cardiovascular: Bradycardia, claudication, cold extremities, heart block, hypotension, syncope, tachycardia, weight gain.
- Gastrointestinal: Diarrhea, vomiting.
- Respiratory: Wheezing.
- Urogenital: Impotence, pollakiuria.
- Miscellaneous: Eye discomfort or burning eyes.
### Potential Adverse Effects
- In addition, other adverse effects not aforementioned have been reported with other beta-blockers and should be considered potential adverse effects of pindolol:
- Central Nervous System: Reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics.
- Cardiovascular: Intensification of AV block.
- Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm, respiratory distress. While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.
- Hematologic: Agranulocytosis, thrombocytopenic purpura and nonthrombocytopenic purpura.
- Gastrointestinal: Mesenteric arterial thrombosis, ischemic colitis.
- Miscellaneous: Reversible alopecia, Peyronie’s disease.
- The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with pindolol during investigational use and extensive foreign experience amounting to over 4 million patient-years.
### Clinical Laboratory
- Minor persistent elevations in serum transaminases (SGOT, SGPT) have been noted in 7% of patients during pindolol administration, but progressive elevations were not observed. These elevations were not associated with any other abnormalities that would suggest hepatic impairment, such as decreased serum albumin and total proteins. During more than a decade of worldwide marketing, there have been no reports in the medical literature of overt hepatic injury. Alkaline phosphatase, lactic acid dehydrogenase (LDH), and uric acid are also elevated on rare occasions. The significance of these findings is unknown.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Pindolol in the drug label.
# Drug Interactions
- Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blockers. Patients receiving pindolol plus a catecholamine-depleting agent should, therefore, be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope, or orthostatic hypotension.
- Pindolol has been used with a variety of antihypertensive agents, including hydrochlorothiazide, hydralazine, and guanethidine without unexpected adverse interactions.
- Pindolol has been shown to increase serum thioridazine levels when both drugs are coadministered. Pindolol levels may also be increased with this combination.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Studies in rats and rabbits exceeding 100 times the maximum recommended human doses, revealed no embryotoxicity or teratogenicity. Since there are no adequate and well controlled studies in pregnant women, and since animal reproduction studies are not always predictive of human response, pindolol, as with any drug, should be employed during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pindolol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pindolol during labor and delivery.
### Nursing Mothers
Since pindolol is secreted in human milk, nursing should not be undertaken by mothers receiving the drug.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
There is no FDA guidance on the use of Pindolol in geriatric settings.
### Gender
There is no FDA guidance on the use of Pindolol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pindolol with respect to specific racial populations.
### Renal Impairment
Beta-blockers should be used with caution in patients with renal function. Poor renal function has only minor effects on pindolol clearance.
### Hepatic Impairment
Beta-blockers should be used with caution in patients with hepatic impairment. Poor hepatic function may cause blood levels of pindolol to increase substantially.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pindolol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pindolol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding the monitorization of Pindolol in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Pindolol and IV administrations.
# Overdosage
No specific information on emergency treatment of overdosage is available. Therefore, on the basis of the pharmacologic actions of pindolol, the following general measures should be employed as appropriate in addition to gastric lavage:
- Excessive Bradycardia: Administer atropine; if there is no response to vagal blockade, administer isoproterenol cautiously.
- Cardiac Failure: Digitalize the patient and/or administer diuretic. It has been reported that glucagon may be useful in this situation.
- Hypotension: Administer vasopressors, e.g., epinephrine or norepinephrine, with serial monitoring of blood pressure. (There is evidence that epinephrine may be the drug of choice.)
- Bronchospasm: Administer a beta2 stimulating agent such as isoproterenol and/or a theophylline derivative.
- A case of an acute overdosage has been reported with an intake of 500 mg of pindolol by a hypertensive patient. Blood pressure increased and heart rate was ≥ 80 beats/min. Recovery was uneventful. In another case, 250 mg of pindolol was taken with 150 mg diazepam and 50 mg nitrazepam, producing coma and hypotension. The patient recovered in 24 hours.
# Pharmacology
## Mechanism of Action
- The mechanism of the antihypertensive effects of beta-blockers has not been established, but several mechanisms have been postulated:
- An effect on the central nervous system resulting in a reduced sympathetic outflow to the periphery
- Competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic receptor sites, leading to decreased cardiac output
- An inhibition of renin release.
- These mechanisms appear less likely for pindolol than other beta-blockers in view of the modest effect on resting cardiac output and renin.
## Structure
- Pindolol, a synthetic beta-adrenergic receptor blocking agent with intrinsic sympathomimetic activity is 1-(Indol-4-yloxy)-3-(isopropylamino)-2-propanol.
- Pindolol, USP is a white to off-white, crystalline powder having a faint odor which is practically insoluble in water; slightly soluble in methanol; and very slightly soluble in chloroform.
- Each tablet for oral administration contains pindolol and the following inactive ingredients: crospovidone, lactose, magnesium stearate, microcrystalline cellulose, and pregelatinized starch.
## Pharmacodynamics
- In standard pharmacologic tests in man and animals, pindolol attenuates increases in heart rate, systolic blood pressure, and cardiac output resulting from exercise and isoproterenol administration, thus confirming its beta-blocking properties. The ISA or partial agonist activity of pindolol is mediated directly at the adrenergic receptor sites and may be blocked by other beta-blockers. In catecholamine depleted animal experiments, ISA is manifested as an increase in the inotropic and chronotropic activity of the myocardium. In man, ISA is manifested by a smaller reduction in the resting heart rate (4 to 8 beats/min) than is seen with drugs lacking ISA. There is also a smaller reduction in resting cardiac output. The clinical significance of this observation has not been evaluated and there is no evidence, or reason to believe, that exercise cardiac output is less affected by pindolol.
- Pindolol has been shown in controlled, double-blind clinical studies to be an effective antihypertensive agent when used as monotherapy, or when added to therapy with thiazide-type diuretics. Divided dosages in the range of 10 mg to 60 mg daily have been shown to be effective. As monotherapy, pindolol is as effective as propranolol, α-methyldopa, hydrochlorothiazide, and chlorthalidone in reducing systolic and diastolic blood pressure. The effect on blood pressure is not orthostatic, i.e., pindolol was equally effective in reducing the supine and standing blood pressure.
- In open, long-term studies up to 4 years, no evidence of diminution of the blood pressure lowering response was observed.
- An average 3-pound increase in body weight has been noted in patients treated with pindolol alone, a larger increase than was observed with propranolol or placebo. The weight gain appeared unrelated to blood pressure response and was not associated with an increased risk of heart failure, although edema was more common than in control patients. Pindolol does not have a consistent effect on plasma renin activity.
- Beta-blockade therapy is useful when it is necessary to suppress the effects of beta-adrenergic agonists in order to achieve therapeutic goals. However, in certain clinical situations, (e.g., cardiac failure, heart block, bronchospasm), the preservation of an adequate sympathetic tone may be necessary to maintain vital functions. Although a beta-antagonist with ISA such as pindolol does not eliminate sympathetic tone entirely, there is no controlled evidence that it is safer than other beta-blockers in such conditions as heart failure, heart block, or bronchospasm or is less likely to cause those conditions. In single-dose studies of the effects of beta-blockers on FEV1, pindolol was indistinguishable from other non-cardioselective agents in its reduction of FEV1, and its reduction in the effectiveness of an exogenous beta-agonist.
- Exacerbation of angina and, in some cases, myocardial infarction and ventricular dysrhythmias have been reported after abrupt discontinuation of therapy with beta-adrenergic blocking agents in patients with coronary artery disease. Abrupt withdrawal of these agents in patients without coronary artery disease has resulted in transient symptoms, including tremulousness, sweating, palpitation, headache, and malaise. Several mechanisms have been proposed to explain these phenomena, among them increased sensitivity to catecholamines because of increased numbers of beta receptors.
## Pharmacokinetics
- Pindolol is rapidly and reproducibly absorbed (greater than 95%), achieving peak plasma concentrations within 1 hour of drug administration. Pindolol has no significant first-pass effect. The blood concentrations are proportional in a linear manner to the administered dose in the range of 5 mg to 20 mg. Upon repeated administration to the same subject, variation is minimal.
- After a single dose, intersubject variation for peak plasma concentrations was about 4-fold (e.g., 45 to 167 ng/mL for a 20 mg dose). Upon multiple dosing, intersubject variation decreased to 2- to 2.5-fold. Pindolol is only 40% bound to plasma proteins and is evenly distributed between plasma and red cells. The volume of distribution in healthy subjects is about 2 L/kg.
- Pindolol undergoes extensive metabolism in animals and man. In man, 35% to 40% is excreted unchanged in the urine and 60% to 65% is metabolized primarily to hydroxy-metabolites which are excreted as glucuronides and ethereal sulfates. The polar metabolites are excreted with a half-life of approximately 8 hours and thus multiple dosing therapy (q.8H) results in a less than 50% accumulation in plasma. About 6% to 9% of an administered intravenous dose is excreted by the bile into the feces.
- The disposition of pindolol after oral administration is monophasic with a half-life in healthy subjects or hypertensive patients with normal renal function of approximately 3 to 4 hours. Following t.i.d. administration (q.8H), no significant accumulation of pindolol is observed.
- In elderly hypertensive patients with normal renal function, the half-life of pindolol is more variable, averaging about 7 hours, but with values as high as 15 hours.
- In hypertensive patients with renal diseases, the half-life is within the range expected for healthy subjects. However, a significant decrease (50%) in volume of distribution (VD) is observed in uremic patients and VD appears to be directly correlated to creatinine clearance. Therefore, renal drug clearance is significantly reduced in uremic patients, resulting in a significant decrease in urinary excretion of unchanged drug. Uremic patients with a creatinine clearance of less than 20 mL/min generally excreted less than 15% of the administered dose unchanged in the urine.
- In patients with histologically diagnosed cirrhosis of the liver, the elimination of pindolol was more variable in rate and generally significantly slower than in healthy subjects. The total body clearance of pindolol in cirrhotic patients ranged from about 50 to 300 mL/min and was directly correlated to antipyrine clearance. The half-life ranges from 2.5 hours to greater than 30 hours. These findings strongly suggest that caution should be exercised in dosage adjustments of pindolol in such patients.
- The bioavailability of pindolol is not significantly affected by coadministration of food, hydralazine, hydrochlorothiazide or aspirin. Pindolol has no effect on warfarin activity or the clinical effectiveness of digoxin, although small transient decreases in plasma digoxin concentrations were noted.
## Nonclinical Toxicology
- In chronic oral toxicologic studies (1 to 2 years) in mice, rats, and dogs, pindolol did not produce any significant toxic effects. In 2-year oral carcinogenicity studies in rats and mice in doses as high as 59 mg/kg/day and 124 mg/kg/day (50 and 100 times the maximum recommended human dose), respectively, pindolol did not produce any neoplastic, preneoplastic, or nonneoplastic pathologic lesions. In fertility and general reproductive performance studies in rats, pindolol caused no adverse effects at a dose of 10 mg/kg.
- In the male fertility and general reproductive performance test in rats, definite toxicity characterized by mortality and decreased weight gain was observed in the group given 100 mg/kg/day. At 30 mg/kg/day, decreased mating was associated with testicular atrophy and/or decreased spermatogenesis. This response is not clearly drug-related, however, as there was no dose-response relationship within this experiment and no similar effect on testes of rats administered pindolol as a dietary admixture for 104 weeks. There appeared to be an increase in prenatal mortality in males given 100 mg/kg but development of offspring was not impaired. In females administered pindolol prior to mating through day 21 of lactation, mating behavior was decreased at 100 mg/kg and 30 mg/kg. At these dosages there also was increased mortality of offspring. Prenatal mortality was increased at 10 mg/kg but there was not a clear dose-response relationship in this experiment. There was an increased resorption rate at 100 mg/kg observed in females necropsied on the 15th day of gestation.
# Clinical Studies
- Pindolol has been shown in controlled, double-blind clinical studies to be an effective antihypertensive agent when used as monotherapy, or when added to therapy with thiazide-type diuretics. Divided dosages in the range of 10 mg to 60 mg daily have been shown to be effective. As monotherapy, pindolol is as effective as propranolol, α-methyldopa, hydrochlorothiazide, and chlorthalidone in reducing systolic and diastolic blood pressure. The effect on blood pressure is not orthostatic, i.e., pindolol was equally effective in reducing the supine and standing blood pressure.
# How Supplied
- Pindolol Tablets, USP are available as 5 mg and 10 mg tablets.
- The 5 mg tablets are round white tablets, debossed "MP 178" bisected on one side and blank on the other side. Bottles of 100 CRC NDC 57664-655-88
- The 10 mg tablets are round white tablets, debossed "MP 183" bisected on one side and blank on the other side. Bottles of 100 CRC NDC 57664-656-88
## Storage
- Store at 20° to 25°C (68° to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients, especially those with evidence of coronary artery insufficiency, should be warned against interruption or discontinuation of pindolol therapy without the physician's advice. Although cardiac failure rarely occurs in properly selected patients, patients being treated with beta-blockers should be advised to consult the physician at the first sign or symptom of impending failure.
# Precautions with Alcohol
- Alcohol-Pindolol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Visken
# Look-Alike Drug Names
There is limited information regarding Pindolol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Pindolol | |
88e458901f6d680ff8b7e5380415990e4dd3a947 | wikidoc | Pine oil | Pine oil
Pine oil is an essential oil obtained by the steam distillation of needles, twigs and cones from a variety of species of pine, particularly Pinus sylvestris.
It is used in aromatherapy, as a scent in bath oils, as a cleaning product, and as a lubricant in small and expensive clockwork instruments. It is naturally deodorizing, and antibacterial. It may also be used varyingly as a disinfectant, massage oil and an antiseptic in homeopathic medicine.
Pine oil is distiguished from other products from pine such as turpentine, the low-boiling fraction from the distillation of pine sap, and rosin, the thick tar remaining after turpentine is distilled.
Chemically, pine oil consists mainly of cyclic terpene alcohols. It may also contain terpene hydrocarbons, ethers, and esters. The exact composition depends on various factors such as the variety of pine it is produced from and the parts of the tree used.
Industrially, pine oil is used in metal extraction from ores. For example, in copper extraction pine oil is used to soak all copper sulfide ores for froth flotation.
# Properties as a disinfectant
Pine oil is a phenolic disinfectant that is mildly antiseptic. Pine oil disinfectants are relatively inexpensive and widely available. They are effective against some bacterial strains and enveloped viruses, but not generally effective against non-enveloped viruses or spores.
It will kill the causative agents of typhoid, gastroenteritis, rabies, enteric fever, cholera, several forms of meningitis, whooping cough, gonorrhea and several types of dysentery. It is also effective against several of the leading causes of food poisoning. It is not effective against spore related illneses such as tetanus or anthrax or against non-enveloped viruses such as poliovirus, rhinovirus, hepatitis B or hepatitis C.
Pine oil has a relatively low human toxicity level, a low corrosion level and limited persistence; however, it irritates the skin and mucous membranes and has been known to cause breathing problems. Large doses may cause central nervous system depression. | Pine oil
Template:Chembox new
Pine oil is an essential oil obtained by the steam distillation of needles, twigs and cones from a variety of species of pine, particularly Pinus sylvestris.
It is used in aromatherapy, as a scent in bath oils, as a cleaning product, and as a lubricant in small and expensive clockwork instruments. It is naturally deodorizing, and antibacterial. It may also be used varyingly as a disinfectant, massage oil and an antiseptic in homeopathic medicine.
Pine oil is distiguished from other products from pine such as turpentine, the low-boiling fraction from the distillation of pine sap, and rosin, the thick tar remaining after turpentine is distilled.
Chemically, pine oil consists mainly of cyclic terpene alcohols.[1] It may also contain terpene hydrocarbons, ethers, and esters. The exact composition depends on various factors such as the variety of pine it is produced from and the parts of the tree used.
Industrially, pine oil is used in metal extraction from ores.[1] For example, in copper extraction pine oil is used to soak all copper sulfide ores for froth flotation.
## Properties as a disinfectant
Pine oil is a phenolic disinfectant that is mildly antiseptic.[2] Pine oil disinfectants are relatively inexpensive and widely available. They are effective against some bacterial strains and enveloped viruses, but not generally effective against non-enveloped viruses or spores.
It will kill the causative agents of typhoid, gastroenteritis, rabies, enteric fever, cholera, several forms of meningitis, whooping cough, gonorrhea and several types of dysentery.[3] It is also effective against several of the leading causes of food poisoning.[citation needed] It is not effective against spore related illneses such as tetanus or anthrax or against non-enveloped viruses such as poliovirus, rhinovirus, hepatitis B or hepatitis C.[3]
Pine oil has a relatively low human toxicity level, a low corrosion level and limited persistence; however, it irritates the skin and mucous membranes and has been known to cause breathing problems.[2] Large doses may cause central nervous system depression.[1] | https://www.wikidoc.org/index.php/Pine_oil | |
8a7550191c7a709063dbbc765782f0983146d52f | wikidoc | Placenta | Placenta
Please Join in Editing This Page and Apply to be an Editor-In-Chief for this topic:
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The placenta is a sack of fat present in placental vertebrates, such as some mammals and sharks during gestation (pregnancy).
The placenta develops from the same sperm and egg cells that form the fetus, and functions as a fetomaternal organ with two components, the fetal part (Chorion Frondosum), and the maternal part (Decidua Basailis).
# Structure
## In humans
By the beginning of fourth month, the placenta has two components:
- Maternal Portion: Decidua Basalis
- Fetal Portion: Chorion Frondosum.
Placenta is bordered on the fetal side by Chorionic plate, and on the maternal side by Decidual plate (decidua basailis). Between the chorionic and decidual plates are intervillous spaces, which are filled with maternal blood.
During the fourth and fifth months, the decidua forms a number of decidual septa, which project into intervillous spaces, but do not reach the chorionic plate. As a result of this septum formation, the placenta is divided into a number of compartments or cotyledons. Since the decidual septa do not reach the chorionic plate, contact between cotyledons is maintained.
## In non-human mammals
The major group mammals referred to as "placental mammals" belong to eutheria. In actuality, marsupials (metatheria) all have placentae, as well. Egg-laying monotremes do not. Aside from the bandicoot, most of the placenta in marsupials is not considered true-placenta, as it does not invasively implant into the uterine wall, and tends to function for only a fraction of the time (see below).
The shape and exchanging surfaces of eutherian mammals varies according to family:
- Ruminants have cotyledonary placenta, which is really many small placentas where the fetus' cotyledons interface with the dams' caruncle, forming a placentome.
- Carnivores have a zonary placenta.
- Perissodactyles have a micro-cotyledonary that grossly resembles diffuse placentas.
- Primates have discoid placentas.
# Functions
## Filtration and transfer
The placenta receives nutrients, oxygen, antibodies, and hormones from the mother's blood, and passes out waste. It forms a barrier, the placental barrier, which filters out some substances that could harm the fetus. The placental barrier does not allow the two bloods from the mother and embryo to mix, because, if the blood types do not match, then the baby will be destroyed. Many substances are not filtered out, however, including alcohol, all anesthesia drugs used in medical childbirth (opioids and cocaine derivatives), and some chemicals associated with smoking cigarettes. Several types of virus, such as Human Cytomegalovirus, may also cross this barrier; this often leads to various degrees of birth defects in the infant.
# Placental circulation
## Maternal placental circulation
The maternal blood enters the intervillous space through endometrial arteries (spiral arteries), 80 to 100 in number. They pierce the decidual plate and then pass through the gaps in cytotrophoblastic shell. As the artery enters, it is under high pressure because it enters through the small gap; this pressure forces the blood deep into intervillous spaces and bathes the villi. Exchange of gases takes place. As the pressure decreases, the deoxygenated blood flows backwards to the decidua and enters the endometrial veins.
## Fetoplacental circulation
Deoxygenated fetal blood passes through umbilical arteries to placenta. At the junction of umbilical cord and placenta, the umbilical arteries branch radially to form chorionic arteries. Chorionic arteries also branch before they enter into the villi. In the villi, they form an extensive arteriocapillary venous system, bringing the fetal blood extremely close to the maternal blood; but normally no intermingling of fetal and maternal blood occurs.
## Metabolic and endocrine activity
In addition to the transfer of gases and nutrients, the placenta also has metabolic and endocrine activity. It produces, among other hormones, progesterone, which is important in maintaining the pregnancy; somatomammotropin (also known as placental lactogen), which acts to increase the amount of glucose and lipids in the maternal blood; estrogen; relaxin, and human chorionic gonadotrophin (hCG). This results in increased transfer of these nutrients to the fetus and is also the main cause of the increased blood sugar levels seen in pregnancy. The hormone HCG (human chorionic gonadotrophin) ensures that progesterone and oestrogen is still being secreted as these hormones make sure the uterus lining is developing and is a good environment for the foetus. However, after about two months the placenta takes on the role of producing progesterone and therefore HCG os no longer needed. HCG is excreted in urine and this is how pregnancy tests work.
Materno-foetal circulation passes through the duct of Smith-Bessant before crossing the laura-brain barrier.
## Parasitic cloaking from immune system of mother
To hide itself from the mother's immune system the placenta secretes Neurokinin B containing Phosphocholine molecules. This is the same mechanism used by the parasitic Nematode worm, to avoid detection by the immune system of its host.
# Birth
When the fetus is born, its placenta begins a physiological separation for spontaneous expulsion afterwards (and for this reason is often called the afterbirth). The umbilical cord is routinely clamped and severed prior to the delivery of the placenta, often within seconds or minutes of birth, a medical protocol known as 'active management of third stage' which has been called into question by advocates of natural birth and 'passive management of third stage' The site of the former umbilical cord attachment in the center of the front of the abdomen is known as the umbilicus, navel, or belly-button.
Modern obstetric practice has decreased maternal death rates enormously. The addition of active management of the third stage of labour is a major contributor towards this. It involves giving oxytocin via IM injection, followed by cord traction to assist in delivering the placenta. The BMJ summaised the Cochrane group metanalysis (2000) of the benefits of active third stage as follows "One systematic review found that active management of the third stage of labour, consisting of controlled cord traction, early cord clamping plus drainage, and a prophylactic oxytocic agent, reduced postpartum haemorrhage of 500 or 1000 mL or greater and related morbidities including mean blood loss, postpartum haemoglobin less than 9 g/dL, blood transfusion, need for supplemental iron postpartum, and length of third stage of labour. Although active management increased adverse effects such as nausea, vomiting, and headache, one RCT identified by the review found that women were less likely to be dissatisfied when their third stage of labour was actively managed."
Risks of retained placenta include hemorrhage and infection. If the placenta fails to deliver in 30 minutes in a hospital environment, manual extraction may be required if heavy ongoing bleeding occurs, and very rarely a curettage is necessary to ensure that no remnants of the placenta remain (in rare conditions with very adherant placenta (placenta accreta)). However, in birth centers and attended home birth environments, it is common for licensed care providers to wait for the placenta's birth up to 2 hours in some instances.
## Non-humans
In most mammalian species, the mother bites through the cord and consumes the placenta, primarily for the benefit of prostaglandin on the uterus after birth. This is known as placentophagy. However, it has been observed in zoology that chimpanzees, with which humans share 99% of genetic material, apply themselves to nurturing their offspring, and keep the fetus, cord, and placenta intact until the cord dries and detaches the next day.
# Pathology
See:
- Placenta accreta
- Placenta praevia
- Placental abruption
# Additional images
- Fetus of about eight weeks, enclosed in the amnion. Magnified a little over two diameters.
# See Also
- Embryo
- Partuition
- Uterus | Placenta
Template:Infobox Embryology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Please Join in Editing This Page and Apply to be an 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.
The placenta is a sack of fat present in placental vertebrates, such as some mammals and sharks during gestation (pregnancy).
The placenta develops from the same sperm and egg cells that form the fetus, and functions as a fetomaternal organ with two components, the fetal part (Chorion Frondosum), and the maternal part (Decidua Basailis).
# Structure
## In humans
By the beginning of fourth month, the placenta has two components:
- Maternal Portion: Decidua Basalis
- Fetal Portion: Chorion Frondosum.
Placenta is bordered on the fetal side by Chorionic plate, and on the maternal side by Decidual plate (decidua basailis). Between the chorionic and decidual plates are intervillous spaces, which are filled with maternal blood.
During the fourth and fifth months, the decidua forms a number of decidual septa, which project into intervillous spaces, but do not reach the chorionic plate. As a result of this septum formation, the placenta is divided into a number of compartments or cotyledons. Since the decidual septa do not reach the chorionic plate, contact between cotyledons is maintained.
## In non-human mammals
The major group mammals referred to as "placental mammals" belong to eutheria. In actuality, marsupials (metatheria) all have placentae, as well. Egg-laying monotremes do not. Aside from the bandicoot,[1] most of the placenta in marsupials is not considered true-placenta, as it does not invasively implant into the uterine wall, and tends to function for only a fraction of the time (see below).
The shape and exchanging surfaces of eutherian mammals varies according to family:
- Ruminants have cotyledonary placenta, which is really many small placentas where the fetus' cotyledons interface with the dams' caruncle, forming a placentome.
- Carnivores have a zonary placenta.
- Perissodactyles have a micro-cotyledonary that grossly resembles diffuse placentas.
- Primates have discoid placentas.
# Functions
## Filtration and transfer
The placenta receives nutrients, oxygen, antibodies, and hormones from the mother's blood, and passes out waste. It forms a barrier, the placental barrier, which filters out some substances that could harm the fetus. The placental barrier does not allow the two bloods from the mother and embryo to mix, because, if the blood types do not match, then the baby will be destroyed. Many substances are not filtered out, however, including alcohol, all anesthesia drugs used in medical childbirth (opioids and cocaine derivatives), and some chemicals associated with smoking cigarettes. Several types of virus, such as Human Cytomegalovirus, may also cross this barrier; this often leads to various degrees of birth defects in the infant.
# Placental circulation
## Maternal placental circulation
The maternal blood enters the intervillous space through endometrial arteries (spiral arteries), 80 to 100 in number. They pierce the decidual plate and then pass through the gaps in cytotrophoblastic shell. As the artery enters, it is under high pressure because it enters through the small gap; this pressure forces the blood deep into intervillous spaces and bathes the villi. Exchange of gases takes place. As the pressure decreases, the deoxygenated blood flows backwards to the decidua and enters the endometrial veins.
## Fetoplacental circulation
Deoxygenated fetal blood passes through umbilical arteries to placenta. At the junction of umbilical cord and placenta, the umbilical arteries branch radially to form chorionic arteries. Chorionic arteries also branch before they enter into the villi. In the villi, they form an extensive arteriocapillary venous system, bringing the fetal blood extremely close to the maternal blood; but normally no intermingling of fetal and maternal blood occurs.
## Metabolic and endocrine activity
In addition to the transfer of gases and nutrients, the placenta also has metabolic and endocrine activity. It produces, among other hormones, progesterone, which is important in maintaining the pregnancy; somatomammotropin (also known as placental lactogen), which acts to increase the amount of glucose and lipids in the maternal blood; estrogen; relaxin, and human chorionic gonadotrophin (hCG). This results in increased transfer of these nutrients to the fetus and is also the main cause of the increased blood sugar levels seen in pregnancy. The hormone HCG (human chorionic gonadotrophin) ensures that progesterone and oestrogen is still being secreted as these hormones make sure the uterus lining is developing and is a good environment for the foetus. However, after about two months the placenta takes on the role of producing progesterone and therefore HCG os no longer needed. HCG is excreted in urine and this is how pregnancy tests work.
Materno-foetal circulation passes through the duct of Smith-Bessant before crossing the laura-brain barrier.
## Parasitic cloaking from immune system of mother
To hide itself from the mother's immune system the placenta secretes Neurokinin B containing Phosphocholine molecules. This is the same mechanism used by the parasitic Nematode worm, to avoid detection by the immune system of its host.[2]
# Birth
When the fetus is born, its placenta begins a physiological separation for spontaneous expulsion afterwards (and for this reason is often called the afterbirth). The umbilical cord is routinely clamped and severed prior to the delivery of the placenta, often within seconds or minutes of birth, a medical protocol known as 'active management of third stage' which has been called into question by advocates of natural birth and 'passive management of third stage'[3] The site of the former umbilical cord attachment in the center of the front of the abdomen is known as the umbilicus, navel, or belly-button.
Modern obstetric practice has decreased maternal death rates enormously. The addition of active management of the third stage of labour is a major contributor towards this. It involves giving oxytocin via IM injection, followed by cord traction to assist in delivering the placenta. The BMJ summaised the Cochrane group metanalysis (2000) of the benefits of active third stage as follows "One systematic review found that active management of the third stage of labour, consisting of controlled cord traction, early cord clamping plus drainage, and a prophylactic oxytocic agent, reduced postpartum haemorrhage of 500 or 1000 mL or greater and related morbidities including mean blood loss, postpartum haemoglobin less than 9 g/dL, blood transfusion, need for supplemental iron postpartum, and length of third stage of labour. Although active management increased adverse effects such as nausea, vomiting, and headache, one RCT identified by the review found that women were less likely to be dissatisfied when their third stage of labour was actively managed."[3]
Risks of retained placenta include hemorrhage and infection. If the placenta fails to deliver in 30 minutes in a hospital environment, manual extraction may be required if heavy ongoing bleeding occurs, and very rarely a curettage is necessary to ensure that no remnants of the placenta remain (in rare conditions with very adherant placenta (placenta accreta)). However, in birth centers and attended home birth environments, it is common for licensed care providers to wait for the placenta's birth up to 2 hours in some instances.
## Non-humans
In most mammalian species, the mother bites through the cord and consumes the placenta, primarily for the benefit of prostaglandin on the uterus after birth. This is known as placentophagy. However, it has been observed in zoology that chimpanzees, with which humans share 99% of genetic material, apply themselves to nurturing their offspring, and keep the fetus, cord, and placenta intact until the cord dries and detaches the next day.
# Pathology
See:
- Placenta accreta
- Placenta praevia
- Placental abruption
# Additional images
- Fetus of about eight weeks, enclosed in the amnion. Magnified a little over two diameters.
# See Also
- Embryo
- Partuition
- Uterus | https://www.wikidoc.org/index.php/Placenta | |
c7416715c73d1b4868717f639887b06161ce5bc8 | wikidoc | Platanus | Platanus
# Overview
Platanus (/ˈplætənəs/)Template:Sfn is a genus comprising a small number of tree species native to the Northern Hemisphere. They are the sole living members of the family Platanaceae.
All members of Platanus are tall, reaching 30 to 50 meters in height. All except for P. kerrii are deciduous, and most are found in riparian or other wetland habitats in the wild, though proving drought-tolerant in cultivation. The hybrid London Plane has proved particularly tolerant of urban conditions.
They are often known in English as planes or plane trees. Some North American species are called sycamores (especially Platanus occidentalisTemplate:Sfn), although that term also refers to either the fig Ficus sycomorus, the plant originally so named, or the Great, or Sycamore Maple, Acer pseudoplatanus.Template:Sfn
# Botany
The flowers are reduced and are borne in balls (globose heads); 3–7 hairy sepals may be fused at the base, and the petals are 3–7 and are spatulate. Male and female flowers are separate, but borne on the same plant (monoecious). The number of heads in one cluster (inflorescence) is indicative of the species (see table below). The male flower has 3–8 stamens; the female has a superior ovary with 3–7 carpels. Plane trees are wind-pollinated. Male flower-heads fall off after shedding their pollen.
After being pollinated, the female flowers become achenes that form an aggregate ball. Typically, the core of the ball is 1 cm in diameter and is covered with a net of mesh 1 mm, which can be peeled off. The ball is 2.5–4 cm in diameter and contains several hundred achenes, each of which has a single seed and is conical, with the point attached downward to the net at the surface of the ball. There is also a tuft of many thin stiff yellow-green bristle fibers attached to the base of each achene. These bristles help in wind dispersion of the fruits as in the dandelion.
The leaves are simple. In the subgenus Platanus they have a palmate outline. The base of the leaf stalk (petiole) is enlarged and completely wraps around the young stem bud in its axil. The axillary bud is exposed only after the leaf falls off.
The mature bark peels off or exfoliates easily in irregularly shaped patches, producing a mottled, scaly appearance. On old trunks, bark may not flake off, but thickens and cracks instead.
# Phylogeny
There are two subgenera, subgenus Castaneophyllum containing the anomalous P. kerrii, and subgenus Platanus, with all the others; recent studies in MexicoTemplate:Sfn have increased the number of accepted species in this subgenus. Within subgenus Platanus, genetic evidence suggests that P. racemosa is more closely related to P. orientalis than it is to the other North American species.Template:Sfn There are fossil records of plane trees as early as 115 million years (the Lower Cretaceous). Despite the geographic separation between North America and Old World, species from these continents will cross readily resulting in fertile hybrids such as the London Plane.
# Species
The following are recognized species of plane trees:
# Diseases
Planes are susceptible to Plane Anthracnose (Apiognomonia veneta), a fungal disease that can defoliate the trees in some years. The worst infections are associated with cold, wet spring weather. P. occidentalis and the other American species are the most susceptible, with P. orientalis the most resistant. The hybrid London Plane is intermediate in resistance.
Ceratocystis platani, a wilt disease, has become a significant problem in recent years in much of Europe.Template:Sfn
Other diseases such as powdery mildew occur frequently, but are of lesser importance.
Platanus species are used as food plants by the larvae of some Lepidoptera species including Phyllonorycter platani and Setaceous Hebrew Character.
# Uses
The principal use of these trees is as ornamental trees, especially in urban areas and by roadsides. The London plane is particularly popular for this purpose. The American plane is cultivated sometimes for timber and investigations have been made into its use as a biomass crop. The oriental plane is widely used as an ornamental and also has a number of minor medicinal uses.
# Cultural history
Most significant aspects of cultural history apply to Platanus orientalis in the Old World.
# Footnotes | Platanus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Platanus (/[invalid input: 'icon']ˈplætənəs/)Template:Sfn is a genus comprising a small number of tree species native to the Northern Hemisphere. They are the sole living members of the family Platanaceae.
All members of Platanus are tall, reaching 30 to 50 meters in height. All except for P. kerrii are deciduous, and most are found in riparian or other wetland habitats in the wild, though proving drought-tolerant in cultivation. The hybrid London Plane has proved particularly tolerant of urban conditions.
They are often known in English as planes or plane trees. Some North American species are called sycamores (especially Platanus occidentalisTemplate:Sfn), although that term also refers to either the fig Ficus sycomorus, the plant originally so named, or the Great, or Sycamore Maple, Acer pseudoplatanus.Template:Sfn
# Botany
The flowers are reduced and are borne in balls (globose heads); 3–7 hairy sepals may be fused at the base, and the petals are 3–7 and are spatulate. Male and female flowers are separate, but borne on the same plant (monoecious). The number of heads in one cluster (inflorescence) is indicative of the species (see table below). The male flower has 3–8 stamens; the female has a superior ovary with 3–7 carpels. Plane trees are wind-pollinated. Male flower-heads fall off after shedding their pollen.
After being pollinated, the female flowers become achenes that form an aggregate ball. Typically, the core of the ball is 1 cm in diameter and is covered with a net of mesh 1 mm, which can be peeled off. The ball is 2.5–4 cm in diameter and contains several hundred achenes, each of which has a single seed and is conical, with the point attached downward to the net at the surface of the ball. There is also a tuft of many thin stiff yellow-green bristle fibers attached to the base of each achene. These bristles help in wind dispersion of the fruits as in the dandelion.
The leaves are simple. In the subgenus Platanus they have a palmate outline. The base of the leaf stalk (petiole) is enlarged and completely wraps around the young stem bud in its axil. The axillary bud is exposed only after the leaf falls off.
The mature bark peels off or exfoliates easily in irregularly shaped patches, producing a mottled, scaly appearance. On old trunks, bark may not flake off, but thickens and cracks instead.
# Phylogeny
There are two subgenera, subgenus Castaneophyllum containing the anomalous P. kerrii, and subgenus Platanus, with all the others; recent studies in MexicoTemplate:Sfn have increased the number of accepted species in this subgenus. Within subgenus Platanus, genetic evidence suggests that P. racemosa is more closely related to P. orientalis than it is to the other North American species.Template:Sfn There are fossil records of plane trees as early as 115 million years (the Lower Cretaceous). Despite the geographic separation between North America and Old World, species from these continents will cross readily resulting in fertile hybrids such as the London Plane.
# Species
The following are recognized species of plane trees:
# Diseases
Planes are susceptible to Plane Anthracnose (Apiognomonia veneta), a fungal disease that can defoliate the trees in some years. The worst infections are associated with cold, wet spring weather. P. occidentalis and the other American species are the most susceptible, with P. orientalis the most resistant. The hybrid London Plane is intermediate in resistance.
Ceratocystis platani, a wilt disease, has become a significant problem in recent years in much of Europe.Template:Sfn
Other diseases such as powdery mildew occur frequently, but are of lesser importance.
Platanus species are used as food plants by the larvae of some Lepidoptera species including Phyllonorycter platani and Setaceous Hebrew Character.
# Uses
The principal use of these trees is as ornamental trees, especially in urban areas and by roadsides. The London plane is particularly popular for this purpose. The American plane is cultivated sometimes for timber and investigations have been made into its use as a biomass crop. The oriental plane is widely used as an ornamental and also has a number of minor medicinal uses.
# Cultural history
Most significant aspects of cultural history apply to Platanus orientalis in the Old World.
# Footnotes | https://www.wikidoc.org/index.php/Plane_tree | |
86dd2de4e0d42fafce34a2dd575778cac73365cb | wikidoc | Plankton | Plankton
Plankton consist of any drifting organisms (animals, plants, or bacteria) that inhabit the pelagic zone of oceans, seas, or bodies of fresh water. Plankton are defined by their ecological niche rather than their genetic classification. They provide a crucial source of food to aquatic life.
# Definitions
The name plankton is derived from the Greek word πλανκτος ("planktos"), meaning "wanderer" or "drifter". While some forms of plankton are capable of independent movement and can swim up to several hundreds of meters vertically in a single day (a behavior called diel vertical migration), their horizontal position is primarily determined by currents in the body of water they inhabit. By definition, organisms classified as plankton are unable to resist ocean currents. This is in contrast to nekton organisms that can swim against the ambient flow of the water environment and control their position (e.g. squid, fish, and marine mammals).
Within the plankton, itself, holoplankton are those organisms that spend their entire life cycle as part of the plankton (e.g. most algae, copepods, salps, and some jellyfish). By contrast, meroplankton are those organisms that are only planktonic for part of their lives (usually the larval stage), and then graduate to either the nekton or a benthic (sea floor) existence. Examples of meroplankton include the larvae of sea urchins, starfish, crustaceans, marine worms, and most fish.
Plankton abundance and distribution are strongly dependent on factors such as ambient nutrients concentrations, the physical state of the water column, and the abundance of other plankton.
The study of plankton is termed planktology. Individual plankton are referred to as plankters.
# Functional groups
Plankton are primarily divided into broad functional (or trophic level) groups:
- Phytoplankton (from Greek phyton, or plant), autotrophic, prokaryotic or eukaryotic algae that live near the water surface where there is sufficient light to support photosynthesis. Among the more important groups are the diatoms, cyanobacteria and dinoflagellates.
- Zooplankton (from Greek zoon, or animal), small protozoans or metazoans (e.g. crustaceans and other animals) that feed on other plankton and telonemia. Some of the eggs and larvae of larger animals, such as fish, crustaceans, and annelids, are included here.
- Bacterioplankton, bacteria and archaea, which play an important role in remineralising organic material down the water column (note that the prokaryotic phytoplankton are also bacterioplankton).
This scheme divides the plankton community into broad producer, consumer and recycler groups. In reality, the trophic level of some plankton is not straightforward. For example, although most dinoflagellates are either photosynthetic producers or heterotrophic consumers, many species are mixotrophic depending upon their circumstances.
# Size groups
Plankton are also often described in terms of size. Usually the following divisions are used:
However, some of these terms may be used with very different boundaries, especially on the larger end of the scale. The existence and importance of nano- and even smaller plankton was only discovered during the 1980s, but they are thought to make up the largest proportion of all plankton in number and diversity.
# Distribution
Plankton are found throughout the oceans, seas and lakes of Earth. However, the local abundance of plankton varies horizontally, vertically and seasonally. The primary source of this variability is the availability of light. All plankton ecosystems are driven by the input of solar energy (but see chemosynthesis), and this confines primary production to surface waters, and to geographical regions and seasons when light is abundant.
A secondary source of variability is that of nutrient availability. Although large areas of the tropical and sub-tropical oceans have abundant light, they experience relatively low primary production because of the poor availability of nutrients such as nitrate, phosphate and silicate. This is a product of large-scale ocean circulation and stratification of the water column. In such regions, primary production, still usually occurs at greater depth, although at a reduced level (because of reduced light).
Despite significant concentrations of macronutrients, some regions of the ocean are unproductive (so-called HNLC regions). Field studies have found that the mineral micronutrient iron is deficient in these regions, and that adding it can lead to the formation of blooms of many (though not all) kinds of phytoplankton. Iron primarily reaches the ocean through the deposition of atmospheric dust on the sea surface. Paradoxically, oceanic areas adjacent to unproductive, arid regions of continents thus typically have abundant phytoplankton (e.g., the western Atlantic Ocean, where trade winds bring dust from the Sahara Desert in north Africa). It has been suggested that large-scale "seeding" of the world's oceans with iron could generate blooms of phytoplankton large enough to draw down enough carbon dioxide out of the atmosphere to offset its anthropogenic emissions (responsible for global warming), although other researchers have disputed the scale of this effect.
While plankton are found in the greatest abundance in surface waters, they occur throughout the water column. At depths where no primary production occurs, zooplankton and bacterioplankton instead make use of organic material sinking from the more productive surface waters above. This flux of sinking material can be especially high following the termination of spring blooms.
# Biogeochemical significance
Aside from representing the bottom few levels of a food chain that leads up to commercially important fisheries, plankton ecosystems play a role in the biogeochemical cycles of many important chemical elements. Of particular contemporary significance is their role in the ocean's carbon cycle.
As stated, phytoplankton fix carbon in sunlit surface waters via photosynthesis. Through (primarily) zooplankton grazing, this carbon enters the planktonic foodweb, where it is either respired to provide metabolic energy, or accumulates as biomass or detritus. As living or dead organic material is typically more dense than seawater it tends to sink, and in open ocean ecosystems away from the coasts this leads to the transport of carbon from surface waters to the deep. This process is known as the biological pump, and is one of the reasons that the oceans constitute the largest (active) pool of carbon on Earth.
Some researchers have even proposed that it might be possible to increase the ocean's uptake of carbon dioxide generated through human activities by increasing the production of plankton through fertilization, primarily with the micronutrient iron. However, it is debatable whether this technique is practical at a large scale, and some researchers have drawn attention to possible drawbacks such as ocean anoxia and resultant methanogenesis (caused by the excess production remineralising at depth).
# Importance to fish
Zooplankton are initially the sole prey item for almost all fish larvae as they use up their yolk sacs and switch to external feeding for nutrition. Fish species rely on the density and distribution of zooplankton to coincide with first-feeding larvae for good survival of larvae, which can otherwise starve. Natural factors (e.g. variations in oceanic currents) and man-made factors (e.g. dams on rivers) can strongly affect zooplankton density and distribution, which can in turn strongly affect the larval survival, and therefore breeding success and stock strength, of fish species. | Plankton
Plankton consist of any drifting organisms (animals, plants, or bacteria) that inhabit the pelagic zone of oceans, seas, or bodies of fresh water. Plankton are defined by their ecological niche rather than their genetic classification. They provide a crucial source of food to aquatic life.
# Definitions
The name plankton is derived from the Greek word πλανκτος ("planktos"), meaning "wanderer" or "drifter".[1] While some forms of plankton are capable of independent movement and can swim up to several hundreds of meters vertically in a single day (a behavior called diel vertical migration), their horizontal position is primarily determined by currents in the body of water they inhabit. By definition, organisms classified as plankton are unable to resist ocean currents. This is in contrast to nekton organisms that can swim against the ambient flow of the water environment and control their position (e.g. squid, fish, and marine mammals).
Within the plankton, itself, holoplankton are those organisms that spend their entire life cycle as part of the plankton (e.g. most algae, copepods, salps, and some jellyfish). By contrast, meroplankton are those organisms that are only planktonic for part of their lives (usually the larval stage), and then graduate to either the nekton or a benthic (sea floor) existence. Examples of meroplankton include the larvae of sea urchins, starfish, crustaceans, marine worms, and most fish.
Plankton abundance and distribution are strongly dependent on factors such as ambient nutrients concentrations, the physical state of the water column, and the abundance of other plankton.
The study of plankton is termed planktology. Individual plankton are referred to as plankters.
# Functional groups
Plankton are primarily divided into broad functional (or trophic level) groups:
- Phytoplankton (from Greek phyton, or plant), autotrophic, prokaryotic or eukaryotic algae that live near the water surface where there is sufficient light to support photosynthesis. Among the more important groups are the diatoms, cyanobacteria and dinoflagellates.
- Zooplankton (from Greek zoon, or animal), small protozoans or metazoans (e.g. crustaceans and other animals) that feed on other plankton and telonemia. Some of the eggs and larvae of larger animals, such as fish, crustaceans, and annelids, are included here.
- Bacterioplankton, bacteria and archaea, which play an important role in remineralising organic material down the water column (note that the prokaryotic phytoplankton are also bacterioplankton).
This scheme divides the plankton community into broad producer, consumer and recycler groups. In reality, the trophic level of some plankton is not straightforward. For example, although most dinoflagellates are either photosynthetic producers or heterotrophic consumers, many species are mixotrophic depending upon their circumstances.
# Size groups
Plankton are also often described in terms of size.[2] Usually the following divisions are used:
However, some of these terms may be used with very different boundaries, especially on the larger end of the scale. The existence and importance of nano- and even smaller plankton was only discovered during the 1980s, but they are thought to make up the largest proportion of all plankton in number and diversity.
# Distribution
Plankton are found throughout the oceans, seas and lakes of Earth. However, the local abundance of plankton varies horizontally, vertically and seasonally. The primary source of this variability is the availability of light. All plankton ecosystems are driven by the input of solar energy (but see chemosynthesis), and this confines primary production to surface waters, and to geographical regions and seasons when light is abundant.
A secondary source of variability is that of nutrient availability. Although large areas of the tropical and sub-tropical oceans have abundant light, they experience relatively low primary production because of the poor availability of nutrients such as nitrate, phosphate and silicate. This is a product of large-scale ocean circulation and stratification of the water column. In such regions, primary production, still usually occurs at greater depth, although at a reduced level (because of reduced light).
Despite significant concentrations of macronutrients, some regions of the ocean are unproductive (so-called HNLC regions)[3]. Field studies have found that the mineral micronutrient iron is deficient in these regions, and that adding it can lead to the formation of blooms of many (though not all) kinds of phytoplankton[4]. Iron primarily reaches the ocean through the deposition of atmospheric dust on the sea surface. Paradoxically, oceanic areas adjacent to unproductive, arid regions of continents thus typically have abundant phytoplankton (e.g., the western Atlantic Ocean, where trade winds bring dust from the Sahara Desert in north Africa). It has been suggested that large-scale "seeding" of the world's oceans with iron could generate blooms of phytoplankton large enough to draw down enough carbon dioxide out of the atmosphere to offset its anthropogenic emissions (responsible for global warming), although other researchers have disputed the scale of this effect[5].
While plankton are found in the greatest abundance in surface waters, they occur throughout the water column. At depths where no primary production occurs, zooplankton and bacterioplankton instead make use of organic material sinking from the more productive surface waters above. This flux of sinking material can be especially high following the termination of spring blooms.
# Biogeochemical significance
Aside from representing the bottom few levels of a food chain that leads up to commercially important fisheries, plankton ecosystems play a role in the biogeochemical cycles of many important chemical elements. Of particular contemporary significance is their role in the ocean's carbon cycle.
As stated, phytoplankton fix carbon in sunlit surface waters via photosynthesis. Through (primarily) zooplankton grazing, this carbon enters the planktonic foodweb, where it is either respired to provide metabolic energy, or accumulates as biomass or detritus. As living or dead organic material is typically more dense than seawater it tends to sink, and in open ocean ecosystems away from the coasts this leads to the transport of carbon from surface waters to the deep. This process is known as the biological pump, and is one of the reasons that the oceans constitute the largest (active) pool of carbon on Earth.
Some researchers have even proposed that it might be possible to increase the ocean's uptake of carbon dioxide generated through human activities by increasing the production of plankton through fertilization, primarily with the micronutrient iron. However, it is debatable whether this technique is practical at a large scale, and some researchers have drawn attention to possible drawbacks such as ocean anoxia and resultant methanogenesis (caused by the excess production remineralising at depth).[6]
# Importance to fish
Zooplankton are initially the sole prey item for almost all fish larvae as they use up their yolk sacs and switch to external feeding for nutrition. Fish species rely on the density and distribution of zooplankton to coincide with first-feeding larvae for good survival of larvae, which can otherwise starve. Natural factors (e.g. variations in oceanic currents) and man-made factors (e.g. dams on rivers) can strongly affect zooplankton density and distribution, which can in turn strongly affect the larval survival, and therefore breeding success and stock strength, of fish species. | https://www.wikidoc.org/index.php/Plankton | |
4e1482c06a435039ab946b7efb676576876a6351 | wikidoc | Plantago | Plantago
Plantago is a genus of about 200 species of small, inconspicuous plants commonly called plantains. They share this name with the very dissimilar plantain, a kind of banana. Most are herbaceous plants, though a few are subshrubs growing to 60 cm (23.5 in) tall. The leaves are sessile, but have a narrow part near the stem which is a pseudo-petiole. They have three or five parallel veins that diverge in the wider part of the leaf. Leaves are broad or narrow, depending on the species. The inflorescences are borne on stalks typically 5-40 cm (2.25-15.75 in) tall, and can be a short cone or a long spike, with numerous tiny wind-pollinated flowers.
Plantains are used as food plants by the larvae of some species of Lepidoptera - see list of Lepidoptera which feed on Plantago.
They are found all over the world, including America, Asia, Australia, New Zealand, Africa and Europe. Many species in the genus are cosmopolitan weeds.
# Uses
Plantago species are often used as herbal remedies. The herb is astringent, anti-toxic, antimicrobial, anti-inflammatory, as well as demulcent, expectorant, styptic and diuretic. Externally, a poultice of the leaves is useful for insect bites, poison-ivy rashes, minor sores, and boils. In folklore it is even claimed to be able to cure snakebite. Internally, it is used for coughs and bronchitis, as a tea, tincture, or syrup. The broad-leaved varieties are sometimes used as a leaf vegetable for salads, green sauce, et cetera.
Plantain seed husks expand and become mucilaginous when wet, especially those of P. psyllium, which is used in common over-the-counter bulk laxative and fiber supplement products such as Metamucil. P. psyllium seed is useful for constipation, irritable bowel syndrome, dietary fiber supplementation, and diverticular disease. Recent research is also showing it to be promising in lowering cholesterol and controlling diabetes.
Psyllium supplements are typically used in powder form, along with adequate amounts of fluids. A dose of at least 7 grams daily taken with adequate amounts of fluid (water, juice) is used by some for management of elevated cholesterol. There are a number of psyllium products used for constipation. The usual dose is about 3.5 grams twice a day. Psyllium is also a component of several ready-to-eat cereals.
In India, mucilage from (Plantago ovata) is obtained by grinding off the husk. The mucilage is sold as Isabgol, a laxative which is used to control irregular bowel syndrome and constipation. It is also used in cereals as a treatment of mild to moderate hypercholesterolemia and for reducing blood glucose. It has been used as an indigenous Ayurvedic and Unani medicine for a whole range of bowel problems including chronic constipation, amoebic dysentry and diarrhoea.
In Romania and Bulgaria, leaves from Plantago major are used as a folk remedy to preventing infection on cuts and scratches because of its antiseptic properties.
# Species
There are about 200 species of Plantago, including:
# Gallery
- Plantago alpina
Plantago alpina
- Ribwort plantain (Plantago lanceolata)
Ribwort plantain (Plantago lanceolata)
- Ribwort Plantain (Plantago lanceolata)
Ribwort Plantain (Plantago lanceolata)
- Plantago nivalis
Plantago nivalis
- Ribwort Plantain flower spike
Ribwort Plantain flower spike
- Buckshorn Plantain (Plantago coronopus)
Buckshorn Plantain (Plantago coronopus)
- Plantago media stepposa
Plantago media stepposa
- Plantago maritima
Plantago maritima | Plantago
Plantago is a genus of about 200 species of small, inconspicuous plants commonly called plantains. They share this name with the very dissimilar plantain, a kind of banana. Most are herbaceous plants, though a few are subshrubs growing to 60 cm (23.5 in) tall. The leaves are sessile, but have a narrow part near the stem which is a pseudo-petiole. They have three or five parallel veins that diverge in the wider part of the leaf. Leaves are broad or narrow, depending on the species. The inflorescences are borne on stalks typically 5-40 cm (2.25-15.75 in) tall, and can be a short cone or a long spike, with numerous tiny wind-pollinated flowers.
Plantains are used as food plants by the larvae of some species of Lepidoptera - see list of Lepidoptera which feed on Plantago.
They are found all over the world, including America, Asia, Australia, New Zealand, Africa and Europe. Many species in the genus are cosmopolitan weeds.
# Uses
Plantago species are often used as herbal remedies. The herb is astringent, anti-toxic, antimicrobial, anti-inflammatory, as well as demulcent, expectorant, styptic and diuretic. Externally, a poultice of the leaves is useful for insect bites, poison-ivy rashes, minor sores, and boils. In folklore it is even claimed to be able to cure snakebite. Internally, it is used for coughs and bronchitis, as a tea, tincture, or syrup. The broad-leaved varieties are sometimes used as a leaf vegetable for salads, green sauce, et cetera.
Plantain seed husks expand and become mucilaginous when wet, especially those of P. psyllium, which is used in common over-the-counter bulk laxative and fiber supplement products such as Metamucil. P. psyllium seed is useful for constipation, irritable bowel syndrome, dietary fiber supplementation, and diverticular disease. Recent research is also showing it to be promising in lowering cholesterol and controlling diabetes.
Psyllium supplements are typically used in powder form, along with adequate amounts of fluids. A dose of at least 7 grams daily taken with adequate amounts of fluid (water, juice) is used by some for management of elevated cholesterol. There are a number of psyllium products used for constipation. The usual dose is about 3.5 grams twice a day. Psyllium is also a component of several ready-to-eat cereals.
In India, mucilage from (Plantago ovata) is obtained by grinding off the husk. The mucilage is sold as Isabgol, a laxative which is used to control irregular bowel syndrome and constipation. It is also used in cereals as a treatment of mild to moderate hypercholesterolemia and for reducing blood glucose. It has been used as an indigenous Ayurvedic and Unani medicine for a whole range of bowel problems including chronic constipation, amoebic dysentry and diarrhoea.
In Romania and Bulgaria, leaves from Plantago major are used as a folk remedy to preventing infection on cuts and scratches because of its antiseptic properties.
# Species
There are about 200 species of Plantago, including:
# Gallery
- Plantago alpina
Plantago alpina
- Ribwort plantain (Plantago lanceolata)
Ribwort plantain (Plantago lanceolata)
- Ribwort Plantain (Plantago lanceolata)
Ribwort Plantain (Plantago lanceolata)
- Plantago nivalis
Plantago nivalis
- Ribwort Plantain flower spike
Ribwort Plantain flower spike
- Buckshorn Plantain (Plantago coronopus)
Buckshorn Plantain (Plantago coronopus)
- Plantago media stepposa
Plantago media stepposa
- Plantago maritima
Plantago maritima | https://www.wikidoc.org/index.php/Plantago | |
5b0ff573d753aa73530ce6cd44f025bc618982d4 | wikidoc | Pleonasm | Pleonasm
Pleonasm is the use of more words (or even word-parts) than necessary to express an idea clearly. The word comes originally from Greek Template:Polytonic ("excess"). A closely related, narrower concept (some would say a subset of pleonasm) is rhetorical tautology, in which essentially the same thing is said more than once in different words (e.g "black darkness", "cold ice", "burning fire"). Regardless, both are a form of redundancy. Pleonasm and tautology each refer to different forms of redundancy in speech and the written word.
# Pleonasm usage
Often, pleonasm is understood to mean a word or phrase which is useless, clichéd, or repetitive, but a pleonasm can also be simply an unremarkable use of idiom. It can even aid in achieving a particular linguistic effect, be it social, poetic, or literary. In other words, pleonasm sometimes serves the same function as rhetorical repetition — it reinforces a point, rendering writing clearer and easier to understand. Further, pleonasm can serve as a redundancy check: If a word is unknown, misunderstood, or misheard, or the medium of communication is poor — a wireless telephone connection or sloppy handwriting — pleonastic phrases can help ensure that the entire meaning gets across even if some of the words get lost.
## Idiomatic expressions
Some pleonastic phrases are part of a language's idiom, like "safe haven" and "tuna fish" in English. They are so common that their use is unremarkable, although in many cases the redundancy can be dropped with no loss of meaning.
Pleonastic phrases like "off of" are common in spoken or informal written American English, such as when used in a phrase like "keep the cat off of the couch". In a satellite-framed language like English, verb phrases containing particles that denote direction of motion are so frequent that even when such a particle is pleonastic, it seems natural to include it.
## Professional and scholarly use
Some pleonastic phrases, when used in professional or scholarly writing, may reflect a standardized usage that has evolved over time; or a precise meaning familiar to specialists, but not necessarily to those outside that discipline. One such example is legally operative language ("null and void", "terms and conditions", "each and all") often drafted into legal documents. Although such usage may be favoured in certain contexts, it may also be disfavoured when used gratuitously to portray false erudition, obfuscate, or otherwise introduce unnecessary verbiage. This is especially so in disciplines (such as the natural sciences) where such imprecision may introduce critical ambiguities.
## Stylistic preference
In addition, pleonasms can serve purposes external to meaning. For example, a speaker who is too terse often is interpreted as lacking ease or grace, because, in spoken and signed language, sentences are spontaneously created without the benefit of editing. The restriction on the ability to plan often creates much redundancy. In written language, removing words not strictly necessary sometimes makes writing seem stilted or awkward, especially if the words are cut from an idiomatic expression.
On the other hand, as is the case with any literary or rhetorical effect, excessive use of pleonasm weakens writing and speech; too many words distract from the content. Writers wanting to conceal a thought or a purpose obscure their meaning with verbiage. William Strunk Jr. advocated concision in The Elements of Style, (1918):
Yet, one has only to look at Baroque, Mannerist, and Victorian sources for different opinions.
## Literary uses
- "This was the most unkindest cut of all."—William Shakespeare, Julius Caesar.
- "O LORD, how many are my foes! Many are rising against me;"—Psalm 3:1, New Revised Standard Version of the Bible. (The Psalms contain numerous similar examples.)
- "From that day mortal, and this happie State/ Shalt loose, expell'd from hence into a World/ Of woe and sorrow"—John Milton, Paradise Lost. (See also Shakespeare's "Sonnet 81".)
- "Beyond the garage were some decorative trees trimmed as carefully as poodle dogs."—Raymond Chandler, The Big Sleep. (When Chandler wrote this line, poodles may not have been as widely known as now. He may have chosen the redundancy to assure his simile would be understood.)
# Pleonasm types
There are two kinds of pleonasm: syntactic pleonasm and semantic pleonasm.
# Syntactic pleonasm
Syntactic pleonasm occurs when the grammar of a language makes certain function words optional. For example, consider the following English sentences:
In this construction, the conjunction that is optional when joining a sentence to a verb phrase with know. Both sentences are grammatically correct, but the word that is considered pleonastic in this case.
The same phenomenon occurs in Spanish with subject pronouns. Since Spanish is a null subject language, which allows subject pronouns to be deleted when understood, the following sentences mean the same:-
In this case, the pronoun yo ("I") is grammatically optional; both sentences mean "I love you" (however, they may not have the same tone or intention—this depends on pragmatics rather than grammar). Such differing but syntactically equivalent constructions, in many language, may also indicate a difference in register.
The process of deleting pronouns is called pro-dropping, and it also happens in many other languages, such as Portuguese, some Slavic languages, and Lao.
The pleonastic ne (ne pléonastique) expressing uncertainty in formal French works as follows:
Two more striking examples of French pleonastic construction are the word "aujourd'hui" translated as "today", but originally meaning "on the day of today", and the phrase "Qu'est-ce que c'est?" meaning "What's that?" or "What is it?", while literally it means "What is it that it is?".
When Robert South said, "It is a pleonasam , a figure usual in Scripture, by a multiplicity of expressions to signify one notable thing," he was observing the Biblical Hebrew poetic propensity to repeat thoughts in different words, a result of the fact that written Biblical Hebrew was a comparatively early form of written language and was written using oral patterning, which has lots of pleonasms. In particular, very many verses of the Psalms are split into two halves, each of which says much the same thing in different words. The complex rules and forms of written language as distinct from spoken language were not as well developed as they are today when the books making up the Judeo-Christian Old Testament were written. See also parallelism (rhetoric).
This same pleonastic style remains very common in modern poetry and songwriting (e.g., "Anne, with her father / is out in the boat / riding the water / riding the waves / on the sea", from Peter Gabriel's "Mercy Street").
# Semantic pleonasm
Semantic pleonasm is more a question of style and usage than grammar. Linguists usually call this redundancy to avoid confusion with syntactic pleonasm, a more important phenomenon for theoretical linguistics. It can take various forms, including:
- Overlap: One word's semantic component is subsumed by the other:
- Prolixity: A phrase may have words which add nothing, or nothing logical or relevant, to the meaning.
See List of redundant expressions for more examples.
An expression like "tuna fish", however, might elicit one of many possible responses, such as:
- It will simply be accepted as synonymous with "tuna".
- It will be perceived as redundant (and thus perhaps silly, illogical, ignorant, inefficient, dialectal, odd, and/or intentionally humorous).
- It will imply a distinction. A reader of "tuna fish" could properly wonder: "Is there a kind of tuna which is not a fish? There is, after all, a dolphin mammal and a dolphin fish." This assumption turns out to be correct, as a "tuna" can also mean a prickly pear ; and "tuner" is pronounced the same in some dialects of English.
- It will be perceived as a verbal clarification, since the word "tuna" is quite short, and may be misheard as "tune" followed by an aspiration, for example.
This is a good reason for careful speakers and writers to be aware of pleonasms, especially with cases such as "tuna fish", which is normally used only in some dialects of American English, and would sound strange in other variants of the language, and even odder in translation into other languages.
Note that not all constructions that are typically pleonasms are so in all cases, nor are all constructions derived from pleonasms themselves pleonastic:
Morphemes, not just words, can enter the realm of pleonasm: Some word-parts are simply optional in various languages and dialects. A familiar example to American English speakers would be the allegedly optional "-al-", probably most commonly seen in "publically" vs. "publicly"—both spellings are considered correct/acceptable in American English, and both pronounced the same, in this dialect, rendering the "publically" spelling pleonastic in US English; in other dialects it is "required", while it is quite conceivable that in another generation or so of American English it will be "forbidden". This treatment of words ending in "-ic", "-ac", etc., is quite inconsistent in US English—compare "maniacally" or "forensically" with "eroticly" or "heroicly"; "forensicly" doesn't look "right" to any English speakers, but "erotically" doesn't look "right" to many Americans. Some (mostly US-based) prescriptive grammar pundits would say that the "-ly" not "-ally" form is "correct" in any case in which there is no "-ical" variant of the basic word, and vice versa; i.e. "maniacally", not "maniacly", is correct because "maniacal" is a word, while "agnosticly", not "agnostically", must be correct because "agnostical" is (arguably) not a real word. This logic is in doubt, since most if not all "-ical" constructions arguably are "real" words and most have certainly occurred more than once in "reputable" publications, and are also immediately understood by any educated reader of English even if they "look funny" to some, or do not appear in popular dictionaries. Additionally, there are numerous examples of words that have very widely-accepted extended forms that have skipped one or more intermediary forms, e.g. "disestablishmentarian" in the absence of "disestablishmentary". At any rate, while some US editors might consider "-ally" vs. "-ly" to be pleonastic in some cases, the vast majority of other English speakers would not, and many "-ally" words are not pleonastic to anyone, even in American English.
The most common definitely pleonastic morphological usage in English is "irregardless", which is very widely criticised as being a nonword. The standard usage is "regardless", which is already negative; adding the negative prefix ir- is worse than redundant, becoming oxymoronic as it logically reverses the meaning to "with regard to/for", which is certainly not what the speaker intended to convey. ("Irregardless" appears to derive from confusion between "regardless" and "irrespective", which have overlapping meanings.)
## Subtler redundancies
In some cases, the redundancy in meaning occurs at a syntactic level above the word, such as at the phrase level:
The redundancy of these two well-known statements is deliberate, for humorous effect. (See Yogiisms.) But one does hear educated people say "my predictions about the future of politics" for "my predictions about politics", which are equivalent in meaning. While predictions are necessarily about the future (at least in relation to the time the prediction was made), the nature of this future can be subtle (e.g., "I predict that he died a week ago"—the prediction is about future discovery or proof of the date of death, not about the death itself). Generally "the future" is assumed, making most constructions of this sort pleonastic. Yogi Berra's humorous quote above about not making predictions isn't really a pleonasm, but rather an ironic play on words.
Redundancy, and "useless" or "nonsensical" words (or phrases, or morphemes) can also be inherited by one language from the influence of another, and are not pleonasms in the more critical sense, but actual changes in grammatical construction considered to be required for "proper" usage in the language or dialect in question. Irish English, for example, is prone to a number of constructions that non-Irish speakers find strange and sometimes directly confusing or silly:
All of these constructions originate from the application of Irish Gaelic grammatical rules to the English dialect spoken, in varying particular forms, throughout the island.
Seemingly "useless" additions and substitutions must be contrasted with similar constructions that are used for stress, humour or other intentional purposes, such as:
both of which are likely derived from Hebrew and Yiddish influences (respectively) on modern English, especially East Coast US English.
Sometimes editors and grammatical stylists will use "pleonasm" to describe simple wordiness. This phenomenon is also called prolixity or logorrhea. Compare:
- "The sound of the loud music drowned out the sound of the burglary."
- "The loud music drowned out the sound of the burglary."
-r even:
- "The music drowned out the burglary."
The reader or hearer does not have to be told that loud music has a sound, and in a newspaper headline or other abbreviated prose can even be counted upon to infer that "the burglary" is a proxy for "the sound of the burglary" and that the music necessarily must have been loud to drown it out. Many are critical of the excessively abbreviated constructions of "headline-itis" or "newsspeak", so "loud " and "sound of the " in the above example should probably not be properly regarded as pleonastic or otherwise genuinely redundant, but simply as informative and clarifying.
Prolixity is also used simply to obfuscate, confuse or euphemise, and is not necessarily redundant/pleonastic in such constructions, though it often is. "Post-traumatic stress disorder" (shellshock) and "pre-owned vehicle" (used car) are both tumid euphemisms but are not redundant. Redundant forms, however, are especially common in business, political and even academic language that is intended to sound impressive (or to be vague so as to make it hard to determine what is actually being promised, or otherwise misleading), For example: "This quarter, we are presently focusing with determination on an all-new, innovative integrated methodology and framework for rapid expansion of customer-oriented external programs designed and developed to bring the company's consumer-first paradigm into the marketplace as quickly as possible."
In contrast to redundancy, an oxymoron results when two seemingly contradictory words are adjoined.
## Other forms
Redundancies sometimes take the form of foreign words whose meaning is repeated in the context:
- "We went to the 'Il Ristorante' restaurant."
- "The La Brea tar pits are fascinating."
- "Roast beef served with au jus."
These sentences use phrases which mean, respectively, "the the restaurant restaurant", and "the the tar tar". However, many times these redundancies are necessary — especially when the foreign words make up a proper noun as opposed to a common one. For example, "We went to Il Ristorante" is acceptable provided your audience can infer that it is a restaurant (if they understand Italian and English it might likely, if spoken rather than written, be misinterpreted as a generic reference and not a proper noun, leading the hearer to ask "Which ristorante do you mean?" Such confusions are common in richly bi-lingual areas like Montreal or the American Southwest when people mix phrases from two languages at once). But avoiding the redundancy of the Spanish phrase in the second example would only leave you with an awkward alternative: "La Brea pits are fascinating."
Most find it best to not even drop articles when using proper nouns made from foreign languages:
- "The movie is playing at the 'El Capitan' theater."
This is also similar to the treatment of definite and indefinite articles in titles of books, films, etc., where the article can — indeed "must" — be present where it would otherwise be "forbidden":
- "Stephen King's 'The Shining' is scary."(Normally, the article would be left off following a possessive.)
- "I'm having an 'An American Werewolf in London' movie night at my place."(Seemingly doubled article, which would be taken for a stutter or typographical error in other contexts.)
Some cross-linguistic redundancies, especially in placenames, occur because a word in one language became the title of a place in another (e.g. the Sahara Desert—"Sahara" is an English approximation of the word for "deserts" in Arabic). An extreme example is Torpenhow Hill in Cumbria, the name of which is composed of words that essentially mean "hill" in the language of each of the cultures that have lived in the area during recorded history, such that it could be translated as "Hillhillhill Hill". See the List of tautological place names for many more examples.
Acronyms can also form the basis for redundancies; this is known humorously as RAS Syndrome (for Redundant Acronym Syndrome Syndrome):
- "I forgot my PIN number for the ATM machine."
- "I upgraded the RAM memory of my computer."
- "She is infected with the HIV virus."
In all the examples listed above, the word after the acronym repeats a word represented in the acronym—respectively, "Personal Identification Number number", "Automated Teller Machine machine", "Random Access Memory memory", "Human Immunodeficiency Virus virus". (See RAS Syndrome for many more examples.) The expansion of an acronym like PIN or HIV may be well-known to English speakers, but the acronyms themselves have come to be treated as words, so little thought is given to what their expansion is (and "PIN" is also pronounced the same as the word "pin"; disambiguation is probably the source of "PIN number"; "SIN number" for "Social Insurance Number number" is a similar common phrase in Canada.) But redundant acronyms are more common with technical (e.g. computer) terms where well-informed speakers recognize the redundancy and consider it silly or ignorant, but mainstream users might not, since they may not be aware or certain of the full expansion of an acronym like "RAM".
Some redundancies are simply typographical. For instance, when a short inflexional word like "the" occurs at the end of a line, it is very common to accidentally repeat it at the beginning of the line, and large number of readers would not even notice it.
Carefully constructed expressions, especially in poetry and political language, but also some general usages in everyday speech, may appear to be redundant but are not. This is most common with cognate objects (a verb's object that is cognate with the verb):
- "She slept a deep sleep.
The words need not be etymologically related, but simply conceptually, to be considered an example of cognate object:
- "We wept tears of joy."
Such constructions are not actually redundant (unlike "She slept a sleep" or "We wept tears") because the object's modifiers provide additional information. A rarer, more constructed form is polyptoton, the stylistic repetition of the same word or words derived from the same root:
- "...he only thing we have to fear is fear itself."—Franklin D. Roosevelt, "First Inaugural Address", March 1933.
- "With eager feeding food doth choke the feeder."—William Shakespeare, Richard II (play), II, i, 37.
As with cognate objects, these constructions are not redundant because the repeated words or derivatives cannot be removed without removing meaning or even destroying the sentence, though in most cases they could be replaced with non-related synonyms at the cost of style (e.g., compare "The only thing we have to fear is terror".)
## Semantic pleonasm and context
In many cases of semantic pleonasm, the status of a word as pleonastic depends on context. The relevant context can be as local as a neighbouring word, or as global as the extent of a speaker's knowledge. In fact, many examples of redundant expressions aren't inherently redundant, but can be redundant if used one way, and aren't redundant if used another way. The "up" in "climb up" is not always redundant, as in the example "He climbed up and then fell down the mountain." Many other examples of pleonasm are redundant only if you take the speaker's knowledge into account. For example, most English speakers would agree that "tuna fish" is redundant because tuna is a kind of fish. However, given the knowledge that "tuna" can also refer a kind of edible prickly pear , the "fish" in "tuna fish" is no longer necessarily a pleonasm, but now disambiguates between the fish and the prickly pear. Conversely, to English speakers who know no Spanish, there is nothing redundant about "The La Brea tar pits" because the name "La Brea" is opaque: the speaker doesn't know that it's Spanish for "the tar". Similarly, even though scuba stands for "self-contained underwater breathing apparatus", a phrase like "the scuba gear" would probably not be considered pleonastic because "scuba" has been reanalyzed into English as a simple adjective. (Most do not even know that it is an acronym, and do not spell it SCUBA or S.C.U.B.A. See radar for another example.) | Pleonasm
Template:Cleanup
Template:TOCright
Pleonasm is the use of more words (or even word-parts) than necessary to express an idea clearly. The word comes originally from Greek Template:Polytonic ("excess"). A closely related, narrower concept (some would say a subset of pleonasm) is rhetorical tautology, in which essentially the same thing is said more than once in different words (e.g "black darkness", "cold ice", "burning fire"). Regardless, both are a form of redundancy. Pleonasm and tautology each refer to different forms of redundancy in speech and the written word.
# Pleonasm usage
Often, pleonasm is understood to mean a word or phrase which is useless, clichéd, or repetitive, but a pleonasm can also be simply an unremarkable use of idiom. It can even aid in achieving a particular linguistic effect, be it social, poetic, or literary. In other words, pleonasm sometimes serves the same function as rhetorical repetition — it reinforces a point, rendering writing clearer and easier to understand. Further, pleonasm can serve as a redundancy check: If a word is unknown, misunderstood, or misheard, or the medium of communication is poor — a wireless telephone connection or sloppy handwriting — pleonastic phrases can help ensure that the entire meaning gets across even if some of the words get lost.
## Idiomatic expressions
Some pleonastic phrases are part of a language's idiom, like "safe haven" and "tuna fish" in English. They are so common that their use is unremarkable, although in many cases the redundancy can be dropped with no loss of meaning.
Pleonastic phrases like "off of" are common in spoken or informal written American English, such as when used in a phrase like "keep the cat off of the couch". In a satellite-framed language like English, verb phrases containing particles that denote direction of motion are so frequent that even when such a particle is pleonastic, it seems natural to include it.
## Professional and scholarly use
Some pleonastic phrases, when used in professional or scholarly writing, may reflect a standardized usage that has evolved over time; or a precise meaning familiar to specialists, but not necessarily to those outside that discipline. One such example is legally operative language ("null and void", "terms and conditions", "each and all") often drafted into legal documents. Although such usage may be favoured in certain contexts, it may also be disfavoured when used gratuitously to portray false erudition, obfuscate, or otherwise introduce unnecessary verbiage. This is especially so in disciplines (such as the natural sciences) where such imprecision may introduce critical ambiguities.[1]
## Stylistic preference
In addition, pleonasms can serve purposes external to meaning. For example, a speaker who is too terse often is interpreted as lacking ease or grace, because, in spoken and signed language, sentences are spontaneously created without the benefit of editing. The restriction on the ability to plan often creates much redundancy. In written language, removing words not strictly necessary sometimes makes writing seem stilted or awkward, especially if the words are cut from an idiomatic expression.
On the other hand, as is the case with any literary or rhetorical effect, excessive use of pleonasm weakens writing and speech; too many words distract from the content. Writers wanting to conceal a thought or a purpose obscure their meaning with verbiage. William Strunk Jr. advocated concision in The Elements of Style, (1918):
Yet, one has only to look at Baroque, Mannerist, and Victorian sources for different opinions.
## Literary uses
- "This was the most unkindest cut of all."—William Shakespeare, Julius Caesar.
- "O LORD, how many are my foes! Many are rising against me;"—Psalm 3:1, New Revised Standard Version of the Bible. (The Psalms contain numerous similar examples.)
- "From that day mortal, and this happie State/ Shalt loose, expell'd from hence into a World/ Of woe and sorrow"—John Milton, Paradise Lost. (See also Shakespeare's "Sonnet 81".)
- "Beyond the garage were some decorative trees trimmed as carefully as poodle dogs."—Raymond Chandler, The Big Sleep. (When Chandler wrote this line, poodles may not have been as widely known as now. He may have chosen the redundancy to assure his simile would be understood.)
# Pleonasm types
There are two kinds of pleonasm: syntactic pleonasm and semantic pleonasm.
# Syntactic pleonasm
Syntactic pleonasm occurs when the grammar of a language makes certain function words optional. For example, consider the following English sentences:
In this construction, the conjunction that is optional when joining a sentence to a verb phrase with know. Both sentences are grammatically correct, but the word that is considered pleonastic in this case.
The same phenomenon occurs in Spanish with subject pronouns. Since Spanish is a null subject language, which allows subject pronouns to be deleted when understood, the following sentences mean the same:-
In this case, the pronoun yo ("I") is grammatically optional; both sentences mean "I love you" (however, they may not have the same tone or intention—this depends on pragmatics rather than grammar). Such differing but syntactically equivalent constructions, in many language, may also indicate a difference in register.
The process of deleting pronouns is called pro-dropping, and it also happens in many other languages, such as Portuguese, some Slavic languages, and Lao.
The pleonastic ne (ne pléonastique) expressing uncertainty in formal French works as follows:
Two more striking examples of French pleonastic construction are the word "aujourd'hui" translated as "today", but originally meaning "on the day of today", and the phrase "Qu'est-ce que c'est?" meaning "What's that?" or "What is it?", while literally it means "What is it that it is?".
When Robert South said, "It is a pleonasam [sic], a figure usual in Scripture, by a multiplicity of expressions to signify one notable thing," he was observing the Biblical Hebrew poetic propensity to repeat thoughts in different words, a result of the fact that written Biblical Hebrew was a comparatively early form of written language and was written using oral patterning, which has lots of pleonasms. In particular, very many verses of the Psalms are split into two halves, each of which says much the same thing in different words. The complex rules and forms of written language as distinct from spoken language were not as well developed as they are today when the books making up the Judeo-Christian Old Testament were written. [2][3] See also parallelism (rhetoric).
This same pleonastic style remains very common in modern poetry and songwriting (e.g., "Anne, with her father / is out in the boat / riding the water / riding the waves / on the sea", from Peter Gabriel's "Mercy Street").
# Semantic pleonasm
Template:OR
Semantic pleonasm is more a question of style and usage than grammar. Linguists usually call this redundancy to avoid confusion with syntactic pleonasm, a more important phenomenon for theoretical linguistics. It can take various forms, including:
- Overlap: One word's semantic component is subsumed by the other:
- Prolixity: A phrase may have words which add nothing, or nothing logical or relevant, to the meaning.
See List of redundant expressions for more examples.
An expression like "tuna fish", however, might elicit one of many possible responses, such as:
- It will simply be accepted as synonymous with "tuna".
- It will be perceived as redundant (and thus perhaps silly, illogical, ignorant, inefficient, dialectal, odd, and/or intentionally humorous).
- It will imply a distinction. A reader of "tuna fish" could properly wonder: "Is there a kind of tuna which is not a fish? There is, after all, a dolphin mammal and a dolphin fish." This assumption turns out to be correct, as a "tuna" can also mean a prickly pear [1]; and "tuner" is pronounced the same in some dialects of English.
- It will be perceived as a verbal clarification, since the word "tuna" is quite short, and may be misheard as "tune" followed by an aspiration, for example.
This is a good reason for careful speakers and writers to be aware of pleonasms, especially with cases such as "tuna fish", which is normally used only in some dialects of American English, and would sound strange in other variants of the language, and even odder in translation into other languages.
Note that not all constructions that are typically pleonasms are so in all cases, nor are all constructions derived from pleonasms themselves pleonastic:
Morphemes, not just words, can enter the realm of pleonasm: Some word-parts are simply optional in various languages and dialects. A familiar example to American English speakers would be the allegedly optional "-al-", probably most commonly seen in "publically" vs. "publicly"—both spellings are considered correct/acceptable in American English, and both pronounced the same, in this dialect, rendering the "publically" spelling pleonastic in US English; in other dialects it is "required", while it is quite conceivable that in another generation or so of American English it will be "forbidden". This treatment of words ending in "-ic", "-ac", etc., is quite inconsistent in US English—compare "maniacally" or "forensically" with "eroticly" or "heroicly"; "forensicly" doesn't look "right" to any English speakers, but "erotically" doesn't look "right" to many Americans. Some (mostly US-based) prescriptive grammar pundits would say that the "-ly" not "-ally" form is "correct" in any case in which there is no "-ical" variant of the basic word, and vice versa; i.e. "maniacally", not "maniacly", is correct because "maniacal" is a word, while "agnosticly", not "agnostically", must be correct because "agnostical" is (arguably) not a real word. This logic is in doubt, since most if not all "-ical" constructions arguably are "real" words and most have certainly occurred more than once in "reputable" publications, and are also immediately understood by any educated reader of English even if they "look funny" to some, or do not appear in popular dictionaries. Additionally, there are numerous examples of words that have very widely-accepted extended forms that have skipped one or more intermediary forms, e.g. "disestablishmentarian" in the absence of "disestablishmentary". At any rate, while some US editors might consider "-ally" vs. "-ly" to be pleonastic in some cases, the vast majority of other English speakers would not, and many "-ally" words are not pleonastic to anyone, even in American English.[citation needed]
The most common definitely pleonastic morphological usage in English is "irregardless", which is very widely criticised as being a nonword. The standard usage is "regardless", which is already negative; adding the negative prefix ir- is worse than redundant, becoming oxymoronic as it logically reverses the meaning to "with regard to/for", which is certainly not what the speaker intended to convey. ("Irregardless" appears to derive from confusion between "regardless" and "irrespective", which have overlapping meanings.)
## Subtler redundancies
In some cases, the redundancy in meaning occurs at a syntactic level above the word, such as at the phrase level:
The redundancy of these two well-known statements is deliberate, for humorous effect. (See Yogiisms.) But one does hear educated people say "my predictions about the future of politics" for "my predictions about politics", which are equivalent in meaning. While predictions are necessarily about the future (at least in relation to the time the prediction was made), the nature of this future can be subtle (e.g., "I predict that he died a week ago"—the prediction is about future discovery or proof of the date of death, not about the death itself). Generally "the future" is assumed, making most constructions of this sort pleonastic. Yogi Berra's humorous quote above about not making predictions isn't really a pleonasm, but rather an ironic play on words.
Redundancy, and "useless" or "nonsensical" words (or phrases, or morphemes) can also be inherited by one language from the influence of another, and are not pleonasms in the more critical sense, but actual changes in grammatical construction considered to be required for "proper" usage in the language or dialect in question. Irish English, for example, is prone to a number of constructions that non-Irish speakers find strange and sometimes directly confusing or silly:
All of these constructions originate from the application of Irish Gaelic grammatical rules to the English dialect spoken, in varying particular forms, throughout the island.
Seemingly "useless" additions and substitutions must be contrasted with similar constructions that are used for stress, humour or other intentional purposes, such as:
both of which are likely derived from Hebrew and Yiddish influences (respectively) on modern English, especially East Coast US English.
Sometimes editors and grammatical stylists will use "pleonasm" to describe simple wordiness. This phenomenon is also called prolixity or logorrhea. Compare:
- "The sound of the loud music drowned out the sound of the burglary."
- "The loud music drowned out the sound of the burglary."
or even:
- "The music drowned out the burglary."
The reader or hearer does not have to be told that loud music has a sound, and in a newspaper headline or other abbreviated prose can even be counted upon to infer that "the burglary" is a proxy for "the sound of the burglary" and that the music necessarily must have been loud to drown it out. Many are critical of the excessively abbreviated constructions of "headline-itis" or "newsspeak", so "loud [music]" and "sound of the [burglary]" in the above example should probably not be properly regarded as pleonastic or otherwise genuinely redundant, but simply as informative and clarifying.
Prolixity is also used simply to obfuscate, confuse or euphemise, and is not necessarily redundant/pleonastic in such constructions, though it often is. "Post-traumatic stress disorder" (shellshock) and "pre-owned vehicle" (used car) are both tumid euphemisms but are not redundant. Redundant forms, however, are especially common in business, political and even academic language that is intended to sound impressive (or to be vague so as to make it hard to determine what is actually being promised, or otherwise misleading), For example: "This quarter, we are presently focusing with determination on an all-new, innovative integrated methodology and framework for rapid expansion of customer-oriented external programs designed and developed to bring the company's consumer-first paradigm into the marketplace as quickly as possible."
In contrast to redundancy, an oxymoron results when two seemingly contradictory words are adjoined.
## Other forms
Redundancies sometimes take the form of foreign words whose meaning is repeated in the context:
- "We went to the 'Il Ristorante' restaurant."
- "The La Brea tar pits are fascinating."
- "Roast beef served with au jus."
These sentences use phrases which mean, respectively, "the the restaurant restaurant", and "the the tar tar". However, many times these redundancies are necessary — especially when the foreign words make up a proper noun as opposed to a common one. For example, "We went to Il Ristorante" is acceptable provided your audience can infer that it is a restaurant (if they understand Italian and English it might likely, if spoken rather than written, be misinterpreted as a generic reference and not a proper noun, leading the hearer to ask "Which ristorante do you mean?" Such confusions are common in richly bi-lingual areas like Montreal or the American Southwest when people mix phrases from two languages at once). But avoiding the redundancy of the Spanish phrase in the second example would only leave you with an awkward alternative: "La Brea pits are fascinating."
Most find it best to not even drop articles when using proper nouns made from foreign languages:
- "The movie is playing at the 'El Capitan' theater."
This is also similar to the treatment of definite and indefinite articles in titles of books, films, etc., where the article can — indeed "must" — be present where it would otherwise be "forbidden":
- "Stephen King's 'The Shining' is scary."(Normally, the article would be left off following a possessive.)
- "I'm having an 'An American Werewolf in London' movie night at my place."(Seemingly doubled article, which would be taken for a stutter or typographical error in other contexts.)
Some cross-linguistic redundancies, especially in placenames, occur because a word in one language became the title of a place in another (e.g. the Sahara Desert—"Sahara" is an English approximation of the word for "deserts" in Arabic). An extreme example is Torpenhow Hill in Cumbria, the name of which is composed of words that essentially mean "hill" in the language of each of the cultures that have lived in the area during recorded history, such that it could be translated as "Hillhillhill Hill". See the List of tautological place names for many more examples.
Acronyms can also form the basis for redundancies; this is known humorously as RAS Syndrome (for Redundant Acronym Syndrome Syndrome):
- "I forgot my PIN number for the ATM machine."
- "I upgraded the RAM memory of my computer."
- "She is infected with the HIV virus."
In all the examples listed above, the word after the acronym repeats a word represented in the acronym—respectively, "Personal Identification Number number", "Automated Teller Machine machine", "Random Access Memory memory", "Human Immunodeficiency Virus virus". (See RAS Syndrome for many more examples.) The expansion of an acronym like PIN or HIV may be well-known to English speakers, but the acronyms themselves have come to be treated as words, so little thought is given to what their expansion is (and "PIN" is also pronounced the same as the word "pin"; disambiguation is probably the source of "PIN number"; "SIN number" for "Social Insurance Number number" [sic] is a similar common phrase in Canada.) But redundant acronyms are more common with technical (e.g. computer) terms where well-informed speakers recognize the redundancy and consider it silly or ignorant, but mainstream users might not, since they may not be aware or certain of the full expansion of an acronym like "RAM".
Some redundancies are simply typographical. For instance, when a short inflexional word like "the" occurs at the end of a line, it is very common to accidentally repeat it at the beginning of the line, and large number of readers would not even notice it.
Carefully constructed expressions, especially in poetry and political language, but also some general usages in everyday speech, may appear to be redundant but are not. This is most common with cognate objects (a verb's object that is cognate with the verb):
- "She slept a deep sleep.
The words need not be etymologically related, but simply conceptually, to be considered an example of cognate object:
- "We wept tears of joy."
Such constructions are not actually redundant (unlike "She slept a sleep" or "We wept tears") because the object's modifiers provide additional information. A rarer, more constructed form is polyptoton, the stylistic repetition of the same word or words derived from the same root:
- "...[T]he only thing we have to fear is fear itself."—Franklin D. Roosevelt, "First Inaugural Address", March 1933.
- "With eager feeding[,] food doth choke the feeder."—William Shakespeare, Richard II (play), II, i, 37.
As with cognate objects, these constructions are not redundant because the repeated words or derivatives cannot be removed without removing meaning or even destroying the sentence, though in most cases they could be replaced with non-related synonyms at the cost of style (e.g., compare "The only thing we have to fear is terror".)
## Semantic pleonasm and context
Template:Cleanup-tone
In many cases of semantic pleonasm, the status of a word as pleonastic depends on context. The relevant context can be as local as a neighbouring word, or as global as the extent of a speaker's knowledge. In fact, many examples of redundant expressions aren't inherently redundant, but can be redundant if used one way, and aren't redundant if used another way. The "up" in "climb up" is not always redundant, as in the example "He climbed up and then fell down the mountain." Many other examples of pleonasm are redundant only if you take the speaker's knowledge into account. For example, most English speakers would agree that "tuna fish" is redundant because tuna is a kind of fish. However, given the knowledge that "tuna" can also refer a kind of edible prickly pear [2], the "fish" in "tuna fish" is no longer necessarily a pleonasm, but now disambiguates between the fish and the prickly pear. Conversely, to English speakers who know no Spanish, there is nothing redundant about "The La Brea tar pits" because the name "La Brea" is opaque: the speaker doesn't know that it's Spanish for "the tar". Similarly, even though scuba stands for "self-contained underwater breathing apparatus", a phrase like "the scuba gear" would probably not be considered pleonastic because "scuba" has been reanalyzed into English as a simple adjective. (Most do not even know that it is an acronym, and do not spell it SCUBA or S.C.U.B.A. See radar for another example.) | https://www.wikidoc.org/index.php/Pleonasm | |
b7b8a865c564fffd721dcd3e9eec11caff55c94e | wikidoc | Plum pox | Plum pox
Plum pox, also known as sharka, is the most devastating viral disease of stone fruit from the genus Prunus. The disease is caused by the plum pox virus (PPV), and the different strains may infect a variety of stone fruit species including peaches, apricots, plums, nectarine, almonds, and sweet and tart cherries. Wild and ornamental species of Prunus may also become infected by some strains of the virus.
The virus is transmitted by aphids and by the transfer of infected plant material to new locations. Plum pox poses no danger to consumers. But it can ruin the marketability of stone fruit by causing acidity and deformities. The only way to manage the disease is to destroy all infected trees, which can cause significant economic losses. A genetically modified plum resistant to plum pox virus has been developed but is not commercially available.
# Biology
The plum pox virus is a linear single stranded RNA virus. There are four strains of plum pox virus: PPV-D, PPV-M, PPV-EA, and PPV-C. PPV-M isolates are more aggressive in peach, are aphid vectored more efficiently, and spread more rapidly in an orchard. PPV-M has been reported to be seed transmitted, the other PPV strains are known not be transmitted through seeds. Both PPV strains M and D infest peach, plum, and apricot. PPV-C infects sweet and tart cherry naturally and is the only strain known to do so, it has infected other Prunus hosts experimentally.
# Pathology
Several aphid species can transmit plum pox within an orchard and over short distances (200-300 meters) to trees in nearby orchards. Unlike some other viruses, like barley yellow dwarf virus, PPV is not persistent in the aphid and is transferred from the mouthparts of the aphid between plants. Long distance spread usually occurs as a result of the movement of infected nursery stock or propagative materials. Once a plant is infected the virus is systemic and occurs in the cytoplasm of cells from all parts of the plant.
When a host tree is infected by plum pox, the infection eventually results in severely reduced fruit production, and the fruit that is produced is often misshapen and blemished. The presence of plum pox can also enhance the effects of other endemic viruses infecting various species of the genus Prunus, such as prune dwarf virus, Prunus necrotic (browning) ringspot virus, and apple chlorotic (yellowing) leaf spot virus, resulting in still greater economic losses.
In peach, infected trees may exhibit color-breaking symptoms in the blossoms. This appears as darker pink stripes on the flower petals and can be useful for early season surveys. Symptoms can be present in young leaves in the spring and /or on developing fruit. Some trees show no symptoms on leaves or fruit.
Not all infection in Prunus are characterized by a ring symptom on leaves. Several cultivars show yellowing line patterns and blotches, or necrotic ring symptoms on expanded leaves. Leaf distortion has also been observed. Infected fruit can develop yellow rings or blotches, or brown rings, and some plum and apricot fruit can be severely deformed and bumpy. The seed of many infected apricots and some plums show rings.
Many non-Prunus species, in at least nine plant families, have been infected artificially with one or more strains of the plum pox virus, and in some cases found naturally infected in the field. The manintance of the virus in non-Prunus species complicates disease management.
# Management
There is no cure or treatment for the disease once a tree becomes infected. Infected trees must be destroyed. Once the disease becomes established, control and prevention measures for plum pox include field surveys, use of certified nursery materials, control of aphids, and elimination of infected trees in nurseries and orchards.
Sources of resistance exist in Prunus, but are not common. A team of scientists from the United States and France has genetically engineered a plum pox-resistant plum called C5, and the resistance can be transferred through hybridization to other plum trees. The transgenic plum expresses a plum pox virus coat protein, the plant produces the coat protein mRNA and it is processed by a system called post transcriptional gene silencing (PTGS), which functions like the plants immune system and is mechanistically similar to RNAi. C5 provides a unique source of germplasm for future breeding programs worldwide. Similar success has not yet occurred in attempt to genetically modify other Prunus species, although these efforts are ongoing.
# Distribution
In the fall of 1999, plum pox strain PPV-D was detected in an Adams County, Pennsylvania orchard. This was the first time that plum pox had been found in North America. The infected areas in Pennsylvania have been quarantined to prevent the spread of the disease, and infected trees have been destroyed.
Since this time, as a result of random surveying done in 2000, detection has also occurred in Nova Scotia and in Southern Ontario, particularly in the Niagara Region. Like the United States infection, the Canadian Food Inspection Agency has put into effect quarantine zones throughout Southern Ontario in a bid to prevent the spread of PPV. The virus has yet to be found in other areas of Canada which contain susceptible trees despite intense surveying. The Canadian plum pox eradication initiative has involved large numbers of samples tested for the plum pox virus. Samples are tested through a technology known as enzyme linked immunosorbent assay (ELISA). The University of Guelph - Laboratory Services Division has performed well over 2,000,000 tests in the past 5 years in support of this initiative. | Plum pox
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Plum pox, also known as sharka, is the most devastating viral disease of stone fruit from the genus Prunus. The disease is caused by the plum pox virus (PPV), and the different strains may infect a variety of stone fruit species including peaches, apricots, plums, nectarine, almonds, and sweet and tart cherries. Wild and ornamental species of Prunus may also become infected by some strains of the virus.
The virus is transmitted by aphids and by the transfer of infected plant material to new locations. Plum pox poses no danger to consumers. But it can ruin the marketability of stone fruit by causing acidity and deformities. The only way to manage the disease is to destroy all infected trees, which can cause significant economic losses. A genetically modified plum resistant to plum pox virus has been developed but is not commercially available.
# Biology
The plum pox virus is a linear single stranded RNA virus.[1] There are four strains of plum pox virus: PPV-D, PPV-M, PPV-EA, and PPV-C. PPV-M isolates are more aggressive in peach, are aphid vectored more efficiently, and spread more rapidly in an orchard.[2] PPV-M has been reported to be seed transmitted, the other PPV strains are known not be transmitted through seeds. Both PPV strains M and D infest peach, plum, and apricot. PPV-C infects sweet and tart cherry naturally and is the only strain known to do so, it has infected other Prunus hosts experimentally.
# Pathology
Several aphid species can transmit plum pox within an orchard and over short distances (200-300 meters) to trees in nearby orchards. Unlike some other viruses, like barley yellow dwarf virus, PPV is not persistent in the aphid and is transferred from the mouthparts of the aphid between plants. Long distance spread usually occurs as a result of the movement of infected nursery stock or propagative materials. Once a plant is infected the virus is systemic and occurs in the cytoplasm of cells from all parts of the plant.
When a host tree is infected by plum pox, the infection eventually results in severely reduced fruit production, and the fruit that is produced is often misshapen and blemished. The presence of plum pox can also enhance the effects of other endemic viruses infecting various species of the genus Prunus, such as prune dwarf virus, Prunus necrotic (browning) ringspot virus, and apple chlorotic (yellowing) leaf spot virus, resulting in still greater economic losses.
In peach, infected trees may exhibit color-breaking symptoms in the blossoms. This appears as darker pink stripes on the flower petals and can be useful for early season surveys. Symptoms can be present in young leaves in the spring and /or on developing fruit. Some trees show no symptoms on leaves or fruit.
Not all infection in Prunus are characterized by a ring symptom on leaves. Several cultivars show yellowing line patterns and blotches, or necrotic ring symptoms on expanded leaves. Leaf distortion has also been observed. Infected fruit can develop yellow rings or blotches, or brown rings, and some plum and apricot fruit can be severely deformed and bumpy. The seed of many infected apricots and some plums show rings.
Many non-Prunus species, in at least nine plant families, have been infected artificially with one or more strains of the plum pox virus, and in some cases found naturally infected in the field. The manintance of the virus in non-Prunus species complicates disease management.
# Management
There is no cure or treatment for the disease once a tree becomes infected. Infected trees must be destroyed. Once the disease becomes established, control and prevention measures for plum pox include field surveys, use of certified nursery materials, control of aphids, and elimination of infected trees in nurseries and orchards.
Sources of resistance exist in Prunus, but are not common. A team of scientists from the United States and France has genetically engineered a plum pox-resistant plum called C5, and the resistance can be transferred through hybridization to other plum trees. The transgenic plum expresses a plum pox virus coat protein, the plant produces the coat protein mRNA and it is processed by a system called post transcriptional gene silencing (PTGS), which functions like the plants immune system and is mechanistically similar to RNAi.[3] C5 provides a unique source of germplasm for future breeding programs worldwide. Similar success has not yet occurred in attempt to genetically modify other Prunus species, although these efforts are ongoing.
# Distribution
In the fall of 1999, plum pox strain PPV-D was detected in an Adams County, Pennsylvania orchard. This was the first time that plum pox had been found in North America. The infected areas in Pennsylvania have been quarantined to prevent the spread of the disease, and infected trees have been destroyed.[2]
Since this time, as a result of random surveying done in 2000, detection has also occurred in Nova Scotia and in Southern Ontario, particularly in the Niagara Region. Like the United States infection, the Canadian Food Inspection Agency has put into effect quarantine zones throughout Southern Ontario in a bid to prevent the spread of PPV. The virus has yet to be found in other areas of Canada which contain susceptible trees despite intense surveying. The Canadian plum pox eradication initiative has involved large numbers of samples tested for the plum pox virus. Samples are tested through a technology known as enzyme linked immunosorbent assay (ELISA). The University of Guelph - Laboratory Services Division has performed well over 2,000,000 tests in the past 5 years in support of this initiative. | https://www.wikidoc.org/index.php/Plum_pox | |
92a136ea578c1c341ef1069e2453e4d77120b2e5 | wikidoc | Plumeria | Plumeria
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.
Plumeria (common name Frangipani; syn. Himatanthus Willd. ex Roem. & Schult.) is a small genus of 7-8 species native to tropical and subtropical Americas. The genus consists of mainly deciduous shrubs and trees. P. rubra (Common Frangipani, Red Frangipani), native to Mexico, Central America, and Venezuela, produces flowers ranging from yellow to pink depending on form or cultivar. From Mexico and Central America, Plumeria has spread to all tropical areas of the world, especially Hawaii, where it grows so abundantly that many people think that it is endemic to there.
# Plant
Plumeria is related to the Oleander, Nerium oleander, and both possess poisonous, milky sap, rather similar to that of Euphorbia. Each of the separate species of Plumeria bears differently shaped leaves and their form and growth habits are also distinct. The leaves of P. alba are quite narrow and corrugated, while leaves of P. pudica have an elongated oak shape and glossy, dark green color. P. pudica is one of the everblooming types with non-deciduous, evergreen leaves. Another species that retains leaves and flowers in winter is P. obtusa; though its common name is "Singapore", it is originally from Colombia. Frangipani can also be found in Eastern Africa, where they are sometimes referred to in Swahili love poems.
Plumeria flowers are most fragrant at night in order to lure sphinx moths to pollinate them. The flowers have no nectar, and simply dupe their pollinators. The moths inadvertently pollinate them by transferring pollen from flower to flower in their fruitless search for nectar.
"Plumeria" species are easily propagated by taking a cutting of leafless stem tips in Spring and allowing them to dry at the base before inserting them into soil. They are also propagated via tissue culture both from cuttings of freshly elongated stems and aseptically germinated seed.
# Etymology and common names
The genus, originally spelled Plumiera, is named in honor of the seventeenth-century French botanist Charles Plumier, who traveled to the New World documenting many plant and animal species. The common name "Frangipani" comes from an Italian noble family, a sixteenth-century marquess of which invented a plumeria-scented perfume.
In Mexico, the Nahuatl (Aztec language) name for this plant is "cacalloxochitl" which means "crow flower." It was used for many medicinal purposes such as salves and ointments.
Depending on location, many other common names exist: "Kembang Kamboja" in Indonesia, "Temple Tree" or "Champa" in India, "Kalachuchi" in the Philippines, "Araliya" or "Pansal Mal" in Sri Lanka, "Champa" in Laos, "Lantom" or "Leelaawadee" in Thai. Many English speakers also simply use the generic name "plumeria".
# In culture
They are now common naturalised plants in southern and southeastern Asia, and in local folk beliefs provide shelter to ghosts and demons. The scent of the Plumeria has been associated with a vampire in Malay folklore, the pontianak. They are associated with temples in both Hindu and Buddhist cultures, though Hindus do not use the flowers in their temple offerings.
In several Pacific islands, such as Tahiti, Fiji, Hawaii, Tonga and the Cook Islands Plumeria is used for making leis. In modern Polynesian culture, it can be worn by women to indicate their relationship status - over the right ear if seeking a relationship, and over the left if taken.
P. alba is the national flower of Nicaragua and Laos, where it is known under the local name "Sacuanjoche" (Nicaragua) and "Champa" (Laos).
In the book "A Varanda do Frangipani" by Mozambican author, Mia Couto the shedding of the tree's flowers serves to mark the passage of time, and the conclusion sees the protagonists submerging into the tree's roots as the ultimate solution to fix their shattered world.
In Bangladeshi culture most white flowers, and particularly plumeria (Bengali: চম্পা chômpa or চাঁপা chãpa), are associated with funerals and death.
# Literary occurrences
- 1819 - P. B. Shelley "The champak odours fail / Like sweet thoughts in a dream", line from "Indian Serenade"
- 1884 - In Huysmans's "À rebours" the persistent odor of frangipani troubles Jean des Esseintes.
- 1890 - In Oscar Wilde's "The Picture of Dorian Gray", the Lord Henry's wife's perfume leaves the scent of frangipani to linger in the room, likely referencing Huysmans.
- 1913 - Rabindranath Tagore story entitled 'The Champa Flower' from the collection Crescent Moon
- 1996 - "Under the Frangipani" by Mia Couto
- 2006 - American singer-songwriter John Vanderslice references the frangipani tree in the song "Kookaburra" on his 2007 release, Emerald City.
# Plumeria obtusa Gallery
- Fruit & flower
Fruit & flower
- Flowers
Flowers
- Bark
Bark
- Leaves
Leaves
- Flower
Flower | Plumeria
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.
Plumeria (common name Frangipani; syn. Himatanthus Willd. ex Roem. & Schult.) is a small genus of 7-8 species native to tropical and subtropical Americas. The genus consists of mainly deciduous shrubs and trees. P. rubra (Common Frangipani, Red Frangipani), native to Mexico, Central America, and Venezuela, produces flowers ranging from yellow to pink depending on form or cultivar. From Mexico and Central America, Plumeria has spread to all tropical areas of the world, especially Hawaii, where it grows so abundantly that many people think that it is endemic to there.
# Plant
Plumeria is related to the Oleander, Nerium oleander, and both possess poisonous, milky sap, rather similar to that of Euphorbia. Each of the separate species of Plumeria bears differently shaped leaves and their form and growth habits are also distinct. The leaves of P. alba are quite narrow and corrugated, while leaves of P. pudica have an elongated oak shape and glossy, dark green color. P. pudica is one of the everblooming types with non-deciduous, evergreen leaves. Another species that retains leaves and flowers in winter is P. obtusa; though its common name is "Singapore", it is originally from Colombia. Frangipani can also be found in Eastern Africa, where they are sometimes referred to in Swahili love poems.[1]
Plumeria flowers are most fragrant at night in order to lure sphinx moths to pollinate them. The flowers have no nectar, and simply dupe their pollinators. The moths inadvertently pollinate them by transferring pollen from flower to flower in their fruitless search for nectar.
"Plumeria" species are easily propagated by taking a cutting of leafless stem tips in Spring and allowing them to dry at the base before inserting them into soil. They are also propagated via tissue culture both from cuttings of freshly elongated stems and aseptically germinated seed.
# Etymology and common names
The genus, originally spelled Plumiera, is named in honor of the seventeenth-century French botanist Charles Plumier, who traveled to the New World documenting many plant and animal species. The common name "Frangipani" comes from an Italian noble family, a sixteenth-century marquess of which invented a plumeria-scented perfume.
In Mexico, the Nahuatl (Aztec language) name for this plant is "cacalloxochitl" which means "crow flower." It was used for many medicinal purposes such as salves and ointments.
Depending on location, many other common names exist: "Kembang Kamboja" in Indonesia, "Temple Tree" or "Champa" in India, "Kalachuchi" in the Philippines, "Araliya" or "Pansal Mal" in Sri Lanka, "Champa" in Laos, "Lantom" or "Leelaawadee" in Thai. Many English speakers also simply use the generic name "plumeria".
# In culture
They are now common naturalised plants in southern and southeastern Asia, and in local folk beliefs provide shelter to ghosts and demons. The scent of the Plumeria has been associated with a vampire in Malay folklore, the pontianak. They are associated with temples in both Hindu and Buddhist cultures, though Hindus do not use the flowers in their temple offerings.
In several Pacific islands, such as Tahiti, Fiji, Hawaii, Tonga and the Cook Islands Plumeria is used for making leis. In modern Polynesian culture, it can be worn by women to indicate their relationship status - over the right ear if seeking a relationship, and over the left if taken.
P. alba is the national flower of Nicaragua and Laos, where it is known under the local name "Sacuanjoche" (Nicaragua) and "Champa" (Laos).
In the book "A Varanda do Frangipani" by Mozambican author, Mia Couto[2] the shedding of the tree's flowers serves to mark the passage of time, and the conclusion sees the protagonists submerging into the tree's roots as the ultimate solution to fix their shattered world.
In Bangladeshi culture most white flowers, and particularly plumeria (Bengali: চম্পা chômpa or চাঁপা chãpa), are associated with funerals and death.
# Literary occurrences
- 1819 - P. B. Shelley "The champak odours fail / Like sweet thoughts in a dream", line from "Indian Serenade"
- 1884 - In Huysmans's "À rebours" the persistent odor of frangipani troubles Jean des Esseintes.
- 1890 - In Oscar Wilde's "The Picture of Dorian Gray", the Lord Henry's wife's perfume leaves the scent of frangipani to linger in the room, likely referencing Huysmans.
- 1913 - Rabindranath Tagore story entitled 'The Champa Flower' from the collection Crescent Moon[3]
- 1996 - "Under the Frangipani" by Mia Couto
- 2006 - American singer-songwriter John Vanderslice references the frangipani tree in the song "Kookaburra" on his 2007 release, Emerald City.
# Plumeria obtusa Gallery
- Fruit & flower
Fruit & flower
- Flowers
Flowers
- Bark
Bark
- Leaves
Leaves
- Flower
Flower | https://www.wikidoc.org/index.php/Plumeria | |
505e09c6ccba426fe9da8d975bd88b26b7dfc749 | wikidoc | Pokeweed | Pokeweed
For the Hawaiian fish salad, see Poke (food).
The pokeweeds, also known as poke, pokebush, pokeberry, pokeroot, polk salad, polk sallet, inkberry or ombú, comprise the genus Phytolacca, perennial plants native to North America, South America, East Asia and New Zealand. Pokeweed contains phytolaccatoxin and phytolaccigenin, which are poisonous to mammals. However, the berries are eaten by birds, which are not affected by the toxin because the small seeds with incredibly hard outer shells remain intact in the digestive system and are eliminated whole.
Pokeweeds are herbs growing from 1 to 10 ft. tall. They have single alternate leaves, pointed at the end, with crinkled edges. The stems are often pink or red. The flowers are greenish-white, in long clusters at the ends of the stems. They develop into dark purple berries.
Phytolacca dioica, the ombú, grows as a tree on the pampas of South America and is one of the few providers of shade on the open grassland. It is a symbol of Argentina and gaucho culture.
# Uses
Young pokeweed leaves can be boiled three times to reduce the toxin, discarding the water after each boiling. The result is known as poke salit, or Poke salad, and is occasionally available commercially. Many authorities advise against eating pokeweed even after thrice boiling, as traces of the toxin may still remain. For many decades, Poke salad has been a staple of southern U.S. cuisine, despite campaigns by doctors who believed pokeweed remained toxic even after being boiled. The lingering cultural significance of Poke salad can be seen in the 1969 hit song "Polk Salad Annie" by written and performed by Tony Joe White, famously covered by Elvis Presley and the El Orbits. Pokeberry juice is added to other juices for jelly by those who believe it can relieve the pain of arthritis.
Pokeweed is used as a homeopathic remedy to treat many ailments. It can be applied topically or taken internally. Topical treatments have been used for acne and other ailments. Internal treatments include tonsilitis, swollen glands and weight loss. Grated pokeroot was used by Native Americans as a poultice to treat inflamations and rashes of the breast.
Pokeweed berries yield a red ink or dye, which was once used by Native Americans to decorate their horses. The Declaration of Independence of the United States was written in fermented pokeberry juice (hence the common name 'inkberry'). Many letters written home during the Civil War were written in pokeberry ink; the writing in these surviving letters appears brown. The red juice has also been used to symbolize blood, as in the anti-slavery protest of Benjamin Lay. A beautiful rich brown dye can be made by soaking fabrics in fermenting berries in a hollowed-out pumpkin.
Some pokeweeds are also grown as ornamental plants, mainly for their attractive berries; a number of cultivars have been selected for larger fruit panicles.
Pokeweeds are used as food plants by the larvae of some Lepidoptera species including Giant Leopard Moth.
Toxic Principle
Saponins, believed to be the primary toxic constituents, are present in the berry juice and other parts.
Other toxic constituents have also been identified including the alkaloid phytolaccine (in small amounts) and the alkaloid phytolaccotoxin, as well as a glycoprotein.
If used as food, the water in which they are boiled must be thrown away.
Clinical signs
The eating of nonfatal quantities of poke, perhaps of the shoots, may cause retching or vomiting after two hours or more. These signs may be followed by dyspnea, perspiration, spasms, severe purging, prostration, tremors, watery diarrhea (often bloody) and, sometimes, convulsions. If a fatal quantity is eaten, perhaps including roots, the above signs are followed by paralysis of the respiratory organs and other narcotic effects, culminating in the death of the poisoned person.
Colic, diarrhea, respiratory failure.
Unsteadiness, inability to rise, wretching.
Jerking movements of the legs.
Subnormal temperature.
Same general signs plus a decrease in milk production.
# Notes and references
- ↑ Armstrong, Wayne. "Pokeweed: An Interesting American Vegetable". Retrieved 2007-07-21..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}
da:Kermesbær
pdc:Dindebeer
de:Kermesbeeren
hsb:Ameriska fytolaka
lt:Fitolaka | Pokeweed
For the Hawaiian fish salad, see Poke (food).
The pokeweeds, also known as poke, pokebush, pokeberry, pokeroot, polk salad, polk sallet, inkberry or ombú, comprise the genus Phytolacca, perennial plants native to North America, South America, East Asia and New Zealand. Pokeweed contains phytolaccatoxin and phytolaccigenin, which are poisonous to mammals. However, the berries are eaten by birds, which are not affected by the toxin because the small seeds with incredibly hard outer shells remain intact in the digestive system and are eliminated whole.
Pokeweeds are herbs growing from 1 to 10 ft. tall. They have single alternate leaves, pointed at the end, with crinkled edges. The stems are often pink or red. The flowers are greenish-white, in long clusters at the ends of the stems. They develop into dark purple berries.
Phytolacca dioica, the ombú, grows as a tree on the pampas of South America and is one of the few providers of shade on the open grassland. It is a symbol of Argentina and gaucho culture.
# Uses
Young pokeweed leaves can be boiled three times to reduce the toxin, discarding the water after each boiling. The result is known as poke salit, or Poke salad, and is occasionally available commercially.[1] Many authorities advise against eating pokeweed even after thrice boiling, as traces of the toxin may still remain. For many decades, Poke salad has been a staple of southern U.S. cuisine, despite campaigns by doctors who believed pokeweed remained toxic even after being boiled. The lingering cultural significance of Poke salad can be seen in the 1969 hit song "Polk Salad Annie" by written and performed by Tony Joe White, famously covered by Elvis Presley and the El Orbits. Pokeberry juice is added to other juices for jelly by those who believe it can relieve the pain of arthritis.
Pokeweed is used as a homeopathic remedy to treat many ailments. It can be applied topically or taken internally. Topical treatments have been used for acne and other ailments. Internal treatments include tonsilitis, swollen glands and weight loss. Grated pokeroot was used by Native Americans as a poultice to treat inflamations and rashes of the breast.
Pokeweed berries yield a red ink or dye, which was once used by Native Americans to decorate their horses. The Declaration of Independence of the United States was written in fermented pokeberry juice (hence the common name 'inkberry'). Many letters written home during the Civil War were written in pokeberry ink; the writing in these surviving letters appears brown. The red juice has also been used to symbolize blood, as in the anti-slavery protest of Benjamin Lay. A beautiful rich brown dye can be made by soaking fabrics in fermenting berries in a hollowed-out pumpkin.
Some pokeweeds are also grown as ornamental plants, mainly for their attractive berries; a number of cultivars have been selected for larger fruit panicles.
Pokeweeds are used as food plants by the larvae of some Lepidoptera species including Giant Leopard Moth.
Toxic Principle
Saponins, believed to be the primary toxic constituents, are present in the berry juice and other parts.
Other toxic constituents have also been identified including the alkaloid phytolaccine (in small amounts) and the alkaloid phytolaccotoxin, as well as a glycoprotein.
If used as food, the water in which they are boiled must be thrown away.
Clinical signs
The eating of nonfatal quantities of poke, perhaps of the shoots, may cause retching or vomiting after two hours or more. These signs may be followed by dyspnea, perspiration, spasms, severe purging, prostration, tremors, watery diarrhea (often bloody) and, sometimes, convulsions. If a fatal quantity is eaten, perhaps including roots, the above signs are followed by paralysis of the respiratory organs and other narcotic effects, culminating in the death of the poisoned person.
Colic, diarrhea, respiratory failure.
Unsteadiness, inability to rise, wretching.
Jerking movements of the legs.
Subnormal temperature.
Same general signs plus a decrease in milk production.
# Notes and references
- ↑ Armstrong, Wayne. "Pokeweed: An Interesting American Vegetable". Retrieved 2007-07-21..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}
da:Kermesbær
pdc:Dindebeer
de:Kermesbeeren
hsb:Ameriska fytolaka
lt:Fitolaka | https://www.wikidoc.org/index.php/Pokeweed | |
443b124a6102318fe2615b3f53825f6042f1d13d | wikidoc | PolyHeme | PolyHeme
# Overview
PolyHeme is a temporary oxygen-carrying blood substitute made from human hemoglobin that is currently in development for emergency treatment of trauma situations where large volumes of blood are lost, with emphasis on situations where fresh blood for transfusion is not readily available. It originally began as a military project following the Vietnam war and is currently being developed by Northfield Laboratories, Inc.
# Production
PolyHeme is a solution of human hemoglobin extracted from red blood cells that has been modified using a multi-step polymerization process. The purified hemoglobin is associated into tetramers and is incorporated into an electrolyte solution. The polymerization of the hemoglobin represents the critical advance in the development of artificial blood. Previous attempts using non-polymerized hemoglobin caused vasoconstriction. Also, filtration of free globin chains by the kidney causes renal failure. The company currently uses expired human blood from which the hemoglobin is extracted and purified. The hemoglobin molecule is the pyridoxylated to raise the P50. Subsequently, this hemoglobin is polymerized with glutaraldehyde.
# Benefits
PolyHeme is universally compatible with all blood types and so it doesn't require cross-matching or typing prior to infusion. In any tests completed to date, there have been no recorded transfusion reactions and it is manufactured from human red blood cells and has gone through steps to reduce the risk of viral infection. It has a shelf life of over twelve months. PolyHeme can be stored at room temperature, versus donated whole blood which requires refrigeration. This makes PolyHeme advantageous in emergency situations. Another advantage is its acceptance by patients seeking bloodless medical care. It does not have most attributes of whole blood, such as the ability to coagulate.
# Development and production
On May 23, 2006, Northfield Labs selected Jacobs Engineering Group Inc. to provide engineering services for a new biological manufacturing facility. The facility will consist of commercial manufacturing space in a facility adjacent to Northfield Laboratories' existing pilot plant operations in Mt. Prospect, Ill and will include production modules, laboratories, warehousing, utility support, and offices.
Additionally, on June 16, 2006, Northfield Labs announced that it had signed an agreement to purchase a 106,000 square foot property that it had been leasing to be used as the first planned commercial facility to manufacture PolyHeme. The Mt. Prospect, IL facility was purchased for $6.7 millions and is expected to be capable of producing at least 100,000 units of PolyHeme annually.
# Clinical trials and consent controversy
Polyheme finished a Phase III trauma trial in June 2006.
The testing was completed at more than 25 Level I trauma centers in the United States under a Food and Drug Administration special category (21CFR 50.24) in 1996 that allows its use without patient consent in special circumstances. PolyHeme was the 15th such experiment allowed by the FDA. Although Northfield Laboratories came under scrutiny for this trial, enrollment of the 720 patient trial was completed on July 31, 2006.
The controversy arose from the fact that the participants in this study were incapable of giving their consent due to the nature of their injuries. The only way to opt out from the study was by wearing a special bracelet prior to needing emergency care (the bracelet can be requested by calling 717-531-5829). Even though this practice is sanctioned by the FDA as necessary emergency research, patients’ rights groups protested the study.
Lists of the participating hospitals can be found at and .
# Petition for fast track
In a financial analysts and investors meeting on August 8, 2006 in New York, Northfield Labs revealed that it had just sent in an application to the FDA for Fast Track designation of PolyHeme and that by law, the FDA was supposed to provide a response within two months. If a Fast Track designation is approved, Northfield planned to request for Priority Review when it submit its Biologic License Application (BLA) sometime in the first half of the year 2007. Fast Track is a feature of the FDA Modernization Act of 1997 and is intended to facilitate the development and expedite the review of products intended for the treatment of serious or life-threatening conditions and which demonstrate the potential to address an unmet medical need for such a condition. It was also re-stated that the company expected to report top-line results of PolyHeme's Phase III study in the fall of 2006.
In a press release on October 10, 2006, it was released that Northfield Labs and the FDA had both agreed to defer the Fast Track designation until the availability of the top-line result in the fall. Fast Track designation was deferred because the FDA needs to know not just the product, but also the indication for which the product will be used. The indication was yet to be determined because the PolyHeme Phase III trial had two primary endpoints of superiority and non-inferiority. And until the release of the top-line result, whether either, both or none of the endpoints were met is unknown.
The Phase III trial was designed as an "active-control dual superiority-noninferiority trial comparing the survival of PolyHeme patients to those who received standard treatment (salt water plus blood)". On December 19, 2006, Northfield Labs released preliminary results of the trial, and the mortality data was disappointing: 13.2 percent of patients receiving PolyHeme died versus 9.6 percent among the control group. This news led to Northfield shares plummeting more than 50%. However, the company remains optimistic, noting that of the 712 randomized treatment patients, 20% of the PolyHeme group and 15% of the control group were protocol violations, leaving a valid total of 586 patients. Northfield is currently re-evaluating the study database to determine if any additional statistical errors are present. They expect to announce any release of the final results only after error corrections are complete. Additional safety data is also expected from the CRO in four to six weeks from the December 19 announcement. | PolyHeme
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
PolyHeme is a temporary oxygen-carrying blood substitute made from human hemoglobin that is currently in development for emergency treatment of trauma situations where large volumes of blood are lost, with emphasis on situations where fresh blood for transfusion is not readily available. It originally began as a military project following the Vietnam war and is currently being developed by Northfield Laboratories, Inc.
# Production
PolyHeme is a solution of human hemoglobin extracted from red blood cells that has been modified using a multi-step polymerization process. The purified hemoglobin is associated into tetramers and is incorporated into an electrolyte solution. The polymerization of the hemoglobin represents the critical advance in the development of artificial blood. Previous attempts using non-polymerized hemoglobin caused vasoconstriction. Also, filtration of free globin chains by the kidney causes renal failure. The company currently uses expired human blood from which the hemoglobin is extracted and purified. The hemoglobin molecule is the pyridoxylated to raise the P50. Subsequently, this hemoglobin is polymerized with glutaraldehyde.
# Benefits
PolyHeme is universally compatible with all blood types and so it doesn't require cross-matching or typing prior to infusion. In any tests completed to date, there have been no recorded transfusion reactions and it is manufactured from human red blood cells and has gone through steps to reduce the risk of viral infection. It has a shelf life of over twelve months. PolyHeme can be stored at room temperature, versus donated whole blood which requires refrigeration. This makes PolyHeme advantageous in emergency situations. Another advantage is its acceptance by patients seeking bloodless medical care. It does not have most attributes of whole blood, such as the ability to coagulate.
# Development and production
On May 23, 2006, Northfield Labs selected Jacobs Engineering Group Inc. to provide engineering services for a new biological manufacturing facility. The facility will consist of commercial manufacturing space in a facility adjacent to Northfield Laboratories' existing pilot plant operations in Mt. Prospect, Ill and will include production modules, laboratories, warehousing, utility support, and offices.
Additionally, on June 16, 2006, Northfield Labs announced that it had signed an agreement to purchase a 106,000 square foot property that it had been leasing to be used as the first planned commercial facility to manufacture PolyHeme. The Mt. Prospect, IL facility was purchased for $6.7 millions and is expected to be capable of producing at least 100,000 units of PolyHeme annually.
# Clinical trials and consent controversy
Polyheme finished a Phase III trauma trial in June 2006.
The testing was completed at more than 25 Level I trauma centers in the United States under a Food and Drug Administration special category (21CFR 50.24) in 1996 that allows its use without patient consent in special circumstances. PolyHeme was the 15th such experiment allowed by the FDA. Although Northfield Laboratories came under scrutiny for this trial, enrollment of the 720 patient trial was completed on July 31, 2006.
The controversy arose from the fact that the participants in this study were incapable of giving their consent due to the nature of their injuries. The only way to opt out from the study was by wearing a special bracelet prior to needing emergency care (the bracelet can be requested by calling 717-531-5829). Even though this practice is sanctioned by the FDA as necessary emergency research, patients’ rights groups protested the study.
Lists of the participating hospitals can be found at [2] and [3].
# Petition for fast track
In a financial analysts and investors meeting on August 8, 2006 in New York, Northfield Labs revealed that it had just sent in an application to the FDA for Fast Track designation of PolyHeme and that by law, the FDA was supposed to provide a response within two months. If a Fast Track designation is approved, Northfield planned to request for Priority Review when it submit its Biologic License Application (BLA) sometime in the first half of the year 2007. Fast Track is a feature of the FDA Modernization Act of 1997 and is intended to facilitate the development and expedite the review of products intended for the treatment of serious or life-threatening conditions and which demonstrate the potential to address an unmet medical need for such a condition. It was also re-stated that the company expected to report top-line results of PolyHeme's Phase III study in the fall of 2006.
In a press release on October 10, 2006, it was released that Northfield Labs and the FDA had both agreed to defer the Fast Track designation until the availability of the top-line result in the fall. Fast Track designation was deferred because the FDA needs to know not just the product, but also the indication for which the product will be used. The indication was yet to be determined because the PolyHeme Phase III trial had two primary endpoints of superiority and non-inferiority. And until the release of the top-line result, whether either, both or none of the endpoints were met is unknown.
The Phase III trial was designed as an "active-control dual superiority-noninferiority trial comparing the survival of PolyHeme patients to those who received standard treatment (salt water plus blood)". On December 19, 2006, Northfield Labs released preliminary results of the trial, and the mortality data was disappointing: 13.2 percent of patients receiving PolyHeme died versus 9.6 percent among the control group. This news led to Northfield shares plummeting more than 50%. However, the company remains optimistic, noting that of the 712 randomized treatment patients, 20% of the PolyHeme group and 15% of the control group were protocol violations, leaving a valid total of 586 patients. Northfield is currently re-evaluating the study database to determine if any additional statistical errors are present. They expect to announce any release of the final results only after error corrections are complete. Additional safety data is also expected from the CRO in four to six weeks from the December 19 announcement. | https://www.wikidoc.org/index.php/PolyHeme | |
eb56a5810900afdc397081372e448a5c79194a23 | wikidoc | Polypill | Polypill
# Polypills
In medicine, the term Polypill has been coined to refer to a medication which contains a combination of active ingredients.
In an important and controversial article in the BMJ in 2003, Wald and Law proposed the
concept of a polypill combining 6 medications that are already on the market and have been
used for decades in order to reduce cardiovascular disease. Wald and Law used an innovative analytic approach that combined the numerical results from several
high quality meta-analyses of the individual impact of these medications to produce an
estimate of the overall combined effect of the proposed polypill on morbidity and
mortality.
So, the "polypill" is both
- an idea for a physical pill - to increase adherence / compliance by reducing the number of pills that a person has to take, and
- a novel methodological approach - in a sense a numeric "meta-analysis of meta-analyses" to estimate the combined impact of several medications and / or interventions.
Since then, there have been many articles written proposing other sorts of "polypills",
and using methodology similar to Wald and Law's.
One of the most promising is a "polypill" for diabetes (and potentially for pre-diabetes).
(See : Kuehn B. M. 2006. ""Polypill" Could Slash Diabetes Risks" JAMA. 2006;296:377-380.)
## Wald and Law's "Polypill" Strategy to Reduce Cardiovascular disease by more than 80 %
In their paper A strategy to reduce cardiovascular disease by more than 80% (published in the British Medical Journal) on June 28, 2003, Wald and Law postulated that by using a combination of well known, cheap medications in one pill (the "Polypill") would be a particularly effective treatment against cardiovascular disease. They presented a statistical model which suggested widespread use of the polypill could reduce mortality due to heart disease and strokes by up to 80%. The treatment is potentially cheap, with few side effects (in perhaps 10-15% of recipients) and the research was based on data from many trials relating to the individual components.
To date there have, however, been no actual patient research on the real benefits of the combined medications compared to the inferred benefits - calculated from the overwhelming evidence in favor of the polypill's individual components. The concepts they present are well recognised: reducing blood pressure, cholesterol and taking a low dose of aspirin will help prevent heart disease and stroke. Tests of the Wald and Law polypill have been recommended in 2005. Additionally, "polypills" are currently available in India.
Any GP can currently prescribe the ALL the components of the polypill separately for her/his patients. Unfortunately, the ingredients of the polypill are off patent. Since this would make the polypill quite cheap (some estimates on the BMJ rapid responses were less than 70 pounds per year), there is little financial incentive for pharmaceutical companies to pay the high costs of a clinical trial. (Naturally, however, large insurers, or national healthcare systems, may have considerable financial incentive to pay for such trials).
Wald and Law has taken the unusual and novel perspective that everyone over the age of 55 should take a pill containing medications to manage these issues irrespective of individual risks. The idea is that if you reduce all blood pressures and cholesterols in all patients the population will benefit. Basically, the polypill could be used as a default medication
for all people over 55 (or for others with comparable risks).
Currently, individual cardiovascular risk can be calculated based on 50 year longitudinal study (and still going) on the population of Framingham, Massachusetts (the Framingham Heart Study). The polypill takes a population based approach to management. The concept of "normal" and treatment thresholds becomes less relevant when taking a population based approach to disease control.Traditionally, the approach has been to treat only if certain risk thresholds have been reached.
Paradoxically, even though an individual maybe not reach these traditional thresholds, benefit will still accrue by further reductions in blood pressure, cholesterol etc. This is because there is a sliding scale of risk; the concept of abnormal on one side of the line corresponding to high risk and requiring treatment, and normal on the other side, being low risk requiring no treatment is now under scrutiny.
Doctors will be treating population risk rather than individual risk factor thresholds as is current mainstream practice. So, if everyone was given the “Polypill” the average blood pressure and cholesterol levels within the population would fall, thus reducing overall population risk.
The "polypill" would contain 3 blood pressure medications at low dose:
- a diuretic, such as bendroflumethiazide,
- a beta-blocker such as atenolol,
- an ACE inhibitor such as enalapril.
This is combined with
- a statin such as simvastatin
- aspirin at a dose of 75mg
- folic acid
Folic acid has been shown to reduce level of homocysteine in the blood which is another risk factor for heart disease.
Further research is being planned and coordinated after an international forum recently discussed the concept of the “Polypill”.
## Polypill for diabetes and Syndrome X
Diabetes - particularly Type II diabetes is a major cause of morbidity and mortality.
Diabetes also contributes substantially to cardiovascular risk. Unfortunately, some
-f the ingredients in Wald and Law's original polypill may not be advisable for patients
with diabetes (for example : beta-blockers - which can lead to weight gain, and
thiazide diuretics). The polypill for diabetes includes :
- A Statin. To reduce LDL cholesterol and they also have recently been shown to have anti-inflamatory properties.
- An ACE inhibitor (for blood pressure control AND to protect the kidneys).
- Aspirin (antiplatelet and antiinflamatory properties), and
- Metformin - an excellent medication for diabetes that is also associated with weight loss.
Many people who are overweight are diabetic without knowing it. Many additional people
have pre diabetes and may benefit from active intervention. Overall, people who
have diabetes or prediabetes, high cholesterol and /or high blood pressure and are overweight
are considered to have metabolic syndrome X, and may benefit substantially from the Diabetes polypill.
Perhaps, as the polypill strategy becomes widely adopted, people over 55 with a "normal"
body mass index or waist circumference will take the Wald and Law polypill, and the obese or
substantially overweight will take the Diabetes / Syndrome X polypill.
## Cost Effectiveness
If Wald and Law's analysis is correct, major cost savings and productivity gains can be
-btained from a polypill approach. Similarly, the Diabetes / Syndrome X polypill is
estimated to save 100s of billions of dollars.
More importantly, the tremendous human cost of these devastating and underappreciated
chronic diseases can be substantially reduced. When a person has a stroke, it can
ruin his or her quality of life. It also places a major burden on carers.
Kidney failure and dialysis (common in end-stage diabetics) is also devastating.
A health care system or major insurer - like Kaiser Permanente - could do very well both
financially and on a human level - if they fully tested and introduced the polypills.
## Sources of resistance
### Medical expertise and simplicity of treatment
If a polypill strategy works for a large percentage of the patient population,
it may threaten some experts and specialists who might stand to lose financially
(although no doubt most of these experts would be delighted by the human benefits,
and would probably endorse it - despite any personal financial hardship that this might
cause them).
The polypill - being a simple "off-the-rack" default treatment - also reduces the
sense of control and exercise of expertise that comes from prescribing individually
tailored medication regimens. Unfortunately, individually tailored approaches may be
more expensive and difficult and time consuming to access.
### Lifestyle Modification and "punishing the sinners"
There are a large cohort of health professionals that advocate lifestyle modification.
It is true that if you stop smoking, exercise an hour or more a day, and eat a healthy
low fat diet, that over time you can dramatically reduce your cardiovascular risk.
Unfortunately, most people - in reality - find this far too difficult, unpleasant,
invasive and intrusive to adhere to, and therefore can not - in reality - achieve and
sustain these gains.
Furthermore, there is increasing evidence that even among individuals with healthly
lifestyles, that some medications - like statins - can even further reduce one's
cardiovascular risk.
It is - no doubt - best to remind patients about the benefits of lifestyle modifications
and encourage them to pursue them, but this does not justify delay of potentially highly
beneficial medications like the polypill. In practice, most people above 55 will not be able
to sustain sufficient lifestyle modifications, and will benefit from medications such as those
contained in the polypill.
In a sense, overly strong devotion to the lifestyle modification approach implies
that "sinners" (those who are unable or unwilling to dramatically alter their lifestyle
and habits) should expect to suffer for their non-compliance. This does not seem to
be an appropriate way to deal with our fellow human beings who - like ourselves - are
sometimes flawed and weak - but nevertheless deserve effective preventive care.
Naturally, individuals who prefer to first try a lifestyle modification approach should
be encouraged to do so. But they should also be reminded that many people do not succeed
and that effective medical treatment is available.
Cardiovascular disease and diabetes are often asymptomatic until substantial irreversible
damage has been done. This makes a dogmatic "lifestyle modification" approach particularly
dangerous because it may drive away patients from treatment.
## Satire
Wald and Law's approach has generated substantial controversy and criticism.
Some of the more original contributions in this regard have take the form of satire.
One such article - which is quite well written - proposes - with tongue in cheek -
a mixture of many different healthy food types. The authors have referred to this
as the polymeal.
References
Wald and Law. 2003. A strategy to reduce cardiovascular disease by more than 80% British Medical Journal on June 28, 2003.
Kuehn B. M. 2006. ""Polypill" Could Slash Diabetes Risks" JAMA. 2006;296:377-380. | Polypill
# Polypills
In medicine, the term Polypill has been coined to refer to a medication which contains a combination of active ingredients.
In an important and controversial article in the BMJ in 2003, Wald and Law proposed the
concept of a polypill combining 6 medications that are already on the market and have been
used for decades in order to reduce cardiovascular disease. Wald and Law used an innovative analytic approach that combined the numerical results from several
high quality meta-analyses of the individual impact of these medications to produce an
estimate of the overall combined effect of the proposed polypill on morbidity and
mortality.
So, the "polypill" is both
- an idea for a physical pill - to increase adherence / compliance by reducing the number of pills that a person has to take, and
- a novel methodological approach - in a sense a numeric "meta-analysis of meta-analyses" to estimate the combined impact of several medications and / or interventions.
Since then, there have been many articles written proposing other sorts of "polypills",
and using methodology similar to Wald and Law's.
One of the most promising is a "polypill" for diabetes (and potentially for pre-diabetes).
(See : Kuehn B. M. 2006. ""Polypill" Could Slash Diabetes Risks" JAMA. 2006;296:377-380.)
## Wald and Law's "Polypill" Strategy to Reduce Cardiovascular disease by more than 80 %
In their paper A strategy to reduce cardiovascular disease by more than 80% (published in the British Medical Journal) on June 28, 2003, Wald and Law postulated that by using a combination of well known, cheap medications in one pill (the "Polypill") would be a particularly effective treatment against cardiovascular disease. They presented a statistical model which suggested widespread use of the polypill could reduce mortality due to heart disease and strokes by up to 80%. The treatment is potentially cheap, with few side effects (in perhaps 10-15% of recipients) and the research was based on data from many trials relating to the individual components.
To date there have, however, been no actual patient research on the real benefits of the combined medications compared to the inferred benefits - calculated from the overwhelming evidence in favor of the polypill's individual components. The concepts they present are well recognised: reducing blood pressure, cholesterol and taking a low dose of aspirin will help prevent heart disease and stroke. Tests of the Wald and Law polypill have been recommended in 2005. Additionally, "polypills" are currently available in India.
Any GP can currently prescribe the ALL the components of the polypill separately for her/his patients. Unfortunately, the ingredients of the polypill are off patent. Since this would make the polypill quite cheap (some estimates on the BMJ rapid responses were less than 70 pounds per year), there is little financial incentive for pharmaceutical companies to pay the high costs of a clinical trial. (Naturally, however, large insurers, or national healthcare systems, may have considerable financial incentive to pay for such trials).
Wald and Law has taken the unusual and novel perspective that everyone over the age of 55 should take a pill containing medications to manage these issues irrespective of individual risks. The idea is that if you reduce all blood pressures and cholesterols in all patients the population will benefit. Basically, the polypill could be used as a default medication
for all people over 55 (or for others with comparable risks).
Currently, individual cardiovascular risk can be calculated based on 50 year longitudinal study (and still going) on the population of Framingham, Massachusetts (the Framingham Heart Study). The polypill takes a population based approach to management. The concept of "normal" and treatment thresholds becomes less relevant when taking a population based approach to disease control.Traditionally, the approach has been to treat only if certain risk thresholds have been reached.
Paradoxically, even though an individual maybe not reach these traditional thresholds, benefit will still accrue by further reductions in blood pressure, cholesterol etc. This is because there is a sliding scale of risk; the concept of abnormal on one side of the line corresponding to high risk and requiring treatment, and normal on the other side, being low risk requiring no treatment is now under scrutiny.
Doctors will be treating population risk rather than individual risk factor thresholds as is current mainstream practice. So, if everyone was given the “Polypill” the average blood pressure and cholesterol levels within the population would fall, thus reducing overall population risk.
The "polypill" would contain 3 blood pressure medications at low dose:
- a diuretic, such as bendroflumethiazide,
- a beta-blocker such as atenolol,
- an ACE inhibitor such as enalapril.
This is combined with
- a statin such as simvastatin
- aspirin at a dose of 75mg
- folic acid
Folic acid has been shown to reduce level of homocysteine in the blood which is another risk factor for heart disease.
Further research is being planned and coordinated after an international forum recently discussed the concept of the “Polypill”.
## Polypill for diabetes and Syndrome X
Diabetes - particularly Type II diabetes is a major cause of morbidity and mortality.
Diabetes also contributes substantially to cardiovascular risk. Unfortunately, some
of the ingredients in Wald and Law's original polypill may not be advisable for patients
with diabetes (for example : beta-blockers - which can lead to weight gain, and
thiazide diuretics). The polypill for diabetes includes :
- A Statin. To reduce LDL cholesterol and they also have recently been shown to have anti-inflamatory properties.
- An ACE inhibitor (for blood pressure control AND to protect the kidneys).
- Aspirin (antiplatelet and antiinflamatory properties), and
- Metformin - an excellent medication for diabetes that is also associated with weight loss.
Many people who are overweight are diabetic without knowing it. Many additional people
have pre diabetes and may benefit from active intervention. Overall, people who
have diabetes or prediabetes, high cholesterol and /or high blood pressure and are overweight
are considered to have metabolic syndrome X, and may benefit substantially from the Diabetes polypill.
Perhaps, as the polypill strategy becomes widely adopted, people over 55 with a "normal"
body mass index or waist circumference will take the Wald and Law polypill, and the obese or
substantially overweight will take the Diabetes / Syndrome X polypill.
## Cost Effectiveness
If Wald and Law's analysis is correct, major cost savings and productivity gains can be
obtained from a polypill approach. Similarly, the Diabetes / Syndrome X polypill is
estimated to save 100s of billions of dollars.
More importantly, the tremendous human cost of these devastating and underappreciated
chronic diseases can be substantially reduced. When a person has a stroke, it can
ruin his or her quality of life. It also places a major burden on carers.
Kidney failure and dialysis (common in end-stage diabetics) is also devastating.
A health care system or major insurer - like Kaiser Permanente - could do very well both
financially and on a human level - if they fully tested and introduced the polypills.
## Sources of resistance
### Medical expertise and simplicity of treatment
If a polypill strategy works for a large percentage of the patient population,
it may threaten some experts and specialists who might stand to lose financially
(although no doubt most of these experts would be delighted by the human benefits,
and would probably endorse it - despite any personal financial hardship that this might
cause them).
The polypill - being a simple "off-the-rack" default treatment - also reduces the
sense of control and exercise of expertise that comes from prescribing individually
tailored medication regimens. Unfortunately, individually tailored approaches may be
more expensive and difficult and time consuming to access.
### Lifestyle Modification and "punishing the sinners"
There are a large cohort of health professionals that advocate lifestyle modification.
It is true that if you stop smoking, exercise an hour or more a day, and eat a healthy
low fat diet, that over time you can dramatically reduce your cardiovascular risk.
Unfortunately, most people - in reality - find this far too difficult, unpleasant,
invasive and intrusive to adhere to, and therefore can not - in reality - achieve and
sustain these gains.
Furthermore, there is increasing evidence that even among individuals with healthly
lifestyles, that some medications - like statins - can even further reduce one's
cardiovascular risk.
It is - no doubt - best to remind patients about the benefits of lifestyle modifications
and encourage them to pursue them, but this does not justify delay of potentially highly
beneficial medications like the polypill. In practice, most people above 55 will not be able
to sustain sufficient lifestyle modifications, and will benefit from medications such as those
contained in the polypill.
In a sense, overly strong devotion to the lifestyle modification approach implies
that "sinners" (those who are unable or unwilling to dramatically alter their lifestyle
and habits) should expect to suffer for their non-compliance. This does not seem to
be an appropriate way to deal with our fellow human beings who - like ourselves - are
sometimes flawed and weak - but nevertheless deserve effective preventive care.
Naturally, individuals who prefer to first try a lifestyle modification approach should
be encouraged to do so. But they should also be reminded that many people do not succeed
and that effective medical treatment is available.
Cardiovascular disease and diabetes are often asymptomatic until substantial irreversible
damage has been done. This makes a dogmatic "lifestyle modification" approach particularly
dangerous because it may drive away patients from treatment.
## Satire
Wald and Law's approach has generated substantial controversy and criticism.
Some of the more original contributions in this regard have take the form of satire.
One such article - which is quite well written - proposes - with tongue in cheek -
a mixture of many different healthy food types. The authors have referred to this
as the polymeal.
References
Wald and Law. 2003. A strategy to reduce cardiovascular disease by more than 80% British Medical Journal on June 28, 2003.
Kuehn B. M. 2006. ""Polypill" Could Slash Diabetes Risks" JAMA. 2006;296:377-380. | https://www.wikidoc.org/index.php/Polypill | |
c1c7b39bd37c29880126e844f6bdac5701c05cf3 | wikidoc | Vagotomy | Vagotomy
A vagotomy is a surgical procedure that is performed only in humans. It is resection (removal of, or at least severing) of part of the vagus nerve.
The operation was popular up until the mid-1990s as a way of treating peptic ulcer disease, and preventing its recurrence. It was (incorrectly) thought that peptic ulcer disease was due to excess secretion of the acid environment in the stomach, or at least that peptic ulcer disease was made worse by hyperacidity. Vagotomy was a way to reduce the acidity of the stomach, by denervating the peptic cells that produce acid. This was done with the hope that it would treat or prevent peptic ulcers. It also had the effect of reducing or eliminating symptoms of gastro-esophageal reflux in those who suffered from it.
The incidence of vagotomy decreased following the discovery by Barry Marshall and Robin Warren that Helicobacter pylori is responsible for most peptic ulcers. The first-line treatment for peptic ulcer disease, if due to H. pylori, is "triple therapy": 2 antibiotics (clarithromycin and amoxicillin or metronidazole)and a proton pump inhibitor (e.g. omeprazole). However, in chronic ulceration or in gastric outlet obstruction there is still an important role for truncal vagotomy.
A plain vagotomy is a very destructive procedure, since all the parasympathetic supply from the stomach to the left side of the transverse colon relies on the vagus nerves. The gut will still function without vagus supply, but less well.
Vagotomy technique was therefore improved by restricting resection to only those branches that go to the stomach (selective vagotomy), and further by selecting only those branches that appear to supply peptic cells (highly selective vagotomy).
Humans have two vagus nerves, whose fibres decussate and intermingle around the stomach. Accordingly, a vagotomy operates on both nerves simultaneously and in practise there is no need or way to make a distinction between them. | Vagotomy
Template:Interventions infobox
A vagotomy is a surgical procedure that is performed only in humans. It is resection (removal of, or at least severing) of part of the vagus nerve.
The operation was popular up until the mid-1990s as a way of treating peptic ulcer disease, and preventing its recurrence. It was (incorrectly) thought that peptic ulcer disease was due to excess secretion of the acid environment in the stomach, or at least that peptic ulcer disease was made worse by hyperacidity. Vagotomy was a way to reduce the acidity of the stomach, by denervating the peptic cells that produce acid. This was done with the hope that it would treat or prevent peptic ulcers. It also had the effect of reducing or eliminating symptoms of gastro-esophageal reflux in those who suffered from it.
The incidence of vagotomy decreased following the discovery by Barry Marshall and Robin Warren that Helicobacter pylori is responsible for most peptic ulcers. The first-line treatment for peptic ulcer disease, if due to H. pylori, is "triple therapy": 2 antibiotics (clarithromycin and amoxicillin or metronidazole)and a proton pump inhibitor (e.g. omeprazole). However, in chronic ulceration or in gastric outlet obstruction there is still an important role for truncal vagotomy.
A plain vagotomy is a very destructive procedure, since all the parasympathetic supply from the stomach to the left side of the transverse colon relies on the vagus nerves. The gut will still function without vagus supply, but less well.
Vagotomy technique was therefore improved by restricting resection to only those branches that go to the stomach (selective vagotomy), and further by selecting only those branches that appear to supply peptic cells (highly selective vagotomy).
Humans have two vagus nerves, whose fibres decussate and intermingle around the stomach. Accordingly, a vagotomy operates on both nerves simultaneously and in practise there is no need or way to make a distinction between them.
# External links
- Vagotomy at the US National Library of Medicine Medical Subject Headings (MeSH)
- Template:Chorus
- Template:GPnotebook
- Overview and illustrations at surgeryencyclopedia.com
- Four types, at endoscopy-sages.com
- Overview at healthatoz.com
Template:Neurosurgical procedures
de:Vagotomie
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Post-vagotomy | |
49ad4d131443ab146e352d8670648f839bcd81f6 | wikidoc | Poultice | Poultice
A poultice, also called cataplasm, is a soft moist mass, often heated and medicated, that is spread on cloth over the skin to treat an aching, inflamed, or painful part of the body. It can also be a porous solid filled with solvent used to remove stains from porous stone such as marble or granite.
The word "poultice" comes from the Latin puls, pultes, meaning "porridge." Historically poultices were made from bread or other cereals, or lead, which is thought to have resulted in the fatal advancement of existing lead poisoning in Beethoven.
# Types of poultice
- 'Animalintex' is a brand name poultice made from an absorbent material
- Bran is also used as a poultice as it is so absorbent. It is packed into the wound and then covered with a piece of sacking or similar material, before being bandaged onto the foot or site of the wound.
- There are also many commercial poultices that are ready-made. Some of these may be labelled as "drawing salves".
# Inflammation treatment
A poultice is a common treatment used on horses to relieve inflammation. It is usually used on the lower legs, under a stable bandage, to focus treatment on the easily-injured tendons in the area. Poultices are sometimes applied as a precautionary measure after the horse has worked hard, such as after a cross-country run, to prevent heat and filling. They are also used to treat abscess wounds, where a build up of pus needs to be drawn out.
Poultices may also be heated and placed on an area where extra circulation is desired.
# Stain removal
Stone is a porous material which is susceptible to staining. Granite and marble are frequently used in residential construction of bathrooms and kitchens and are susceptible to a variety of stains.
From a chemical standpoint, a porous stone becomes stained when a solution containing a solute penetrates its surface and then evaporates leaving the solid solute behind within the stone. Alternatively, grease may penetrate the porous surface and remain within the stone without evaporating. In either case, the stone will become visibly "stained."
Poultices for removing stains are made from a malleable mass of a porous material (paper, whiting, diatomaceous earth, flour, limestone) filled with a solvent which can be applied to the surface of the stone. The solvent used (ammonia, acetone, alcohol, peroxide, etc.) depends on what substance caused the stain. As the solvent penetrates the surface of the porous stone containing the stain, it forms a single continuous solution between the stone and the poultice on the surface. The poultice is kept moist and covered to allow time for the solvent to sufficiently penetrate the stone and dissolve the staining material, be it grease or solute. The solute will then equilibrate by passive diffusion between the stone and the poultice. After an adequate time for this process to occur, the poultice is removed and with it the solution containing a portion of the dissolved solute or "stain." Multiple repetitions of the process will eventually decrease the concentration of the solute or "stain" within the stone until it is invisible or minimally visible. | Poultice
A poultice, also called cataplasm, is a soft moist mass, often heated and medicated, that is spread on cloth over the skin to treat an aching, inflamed, or painful part of the body. It can also be a porous solid filled with solvent used to remove stains from porous stone such as marble or granite.
The word "poultice" comes from the Latin puls, pultes, meaning "porridge." Historically poultices were made from bread or other cereals, or lead, which is thought to have resulted in the fatal advancement of existing lead poisoning in Beethoven.
# Types of poultice
- 'Animalintex' is a brand name poultice made from an absorbent material
- Bran is also used as a poultice as it is so absorbent. It is packed into the wound and then covered with a piece of sacking or similar material, before being bandaged onto the foot or site of the wound.
- There are also many commercial poultices that are ready-made. Some of these may be labelled as "drawing salves"[citation needed].
# Inflammation treatment
A poultice is a common treatment used on horses to relieve inflammation. It is usually used on the lower legs, under a stable bandage, to focus treatment on the easily-injured tendons in the area. Poultices are sometimes applied as a precautionary measure after the horse has worked hard, such as after a cross-country run, to prevent heat and filling. They are also used to treat abscess wounds, where a build up of pus needs to be drawn out.
Poultices may also be heated and placed on an area where extra circulation is desired.
# Stain removal
Stone is a porous material which is susceptible to staining. Granite and marble are frequently used in residential construction of bathrooms and kitchens and are susceptible to a variety of stains.
From a chemical standpoint, a porous stone becomes stained when a solution containing a solute penetrates its surface and then evaporates leaving the solid solute behind within the stone. Alternatively, grease may penetrate the porous surface and remain within the stone without evaporating. In either case, the stone will become visibly "stained."
Poultices for removing stains are made from a malleable mass of a porous material (paper, whiting, diatomaceous earth, flour[1], limestone[2]) filled with a solvent which can be applied to the surface of the stone. The solvent used (ammonia, acetone, alcohol, peroxide[1], etc.) depends on what substance caused the stain. As the solvent penetrates the surface of the porous stone containing the stain, it forms a single continuous solution between the stone and the poultice on the surface. The poultice is kept moist and covered to allow time for the solvent to sufficiently penetrate the stone and dissolve the staining material, be it grease or solute. The solute will then equilibrate by passive diffusion between the stone and the poultice. After an adequate time for this process to occur, the poultice is removed and with it the solution containing a portion of the dissolved solute or "stain." Multiple repetitions of the process will eventually decrease the concentration of the solute or "stain" within the stone until it is invisible or minimally visible. | https://www.wikidoc.org/index.php/Poultice | |
019b947f342740592fc0ba4c8ed700c2a23b8408 | wikidoc | Prazepam | Prazepam
# Overview
Prazepam is a benzodiazepine derivative drug developed by Warner-Lambert in the 1960s. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. Prazepam is a prodrug for desmethyldiazepam which is responsible for the therapeutic effects of prazepam.
Prazepam is marketed for anxiolytic use under various trade names: Centrac, Centrax, Demetrin, Lysanxia, Mono Demetrin, Pozapam, Prasepine, Prazene, Reapam and Trepidan.
# Indications
Prazepam is indicated for the short-term treatment of anxiety. After short-term therapy, the dose is usually gradually tapered-off to reduce or avoid any withdrawal or rebound effects. Desmethyldiazepam, an active metabolite, has a very long half-life of 29 to 224 hours, which contributes to the therapeutic effects of prazepam.
# Side effects
Side effects of prazepam are less profound than with other benzodiazepines. Excessive drowsiness and with longer-term use, drug dependence, are the most common side effects of prazepam. Side effects such as fatigue or "feeling spacey" can also occur but less commonly than with other benzodiazepines. Other side effects include feebleness, clumsiness or lethargic, clouded thinking and mental slowness.
# Tolerance, dependence and withdrawal
Tolerance and dependence can develop with long-term use of prazepam, and upon cessation or reduction in dosage, then a benzodiazepine withdrawal syndrome may occur with symptoms such as tremulousness, dysphoria, psychomotor agitation, tachycardia and sweating. In severe cases, hallucinations, psychosis and seizures can occur. Withdrawal-related psychosis is generally unresponsive to antipsychotic mediations. The risk and severity of the withdrawal syndrome increases the higher the dose and the longer prazepam is taken for. Tolerance, dependence and withdrawal problems may be less severe than with other benzodiazepines, such as diazepam. It may be because tolerance is slower to develop with prazepam than with other benzodiazepines. Abrupt or over-rapid discontinuation of prazepam after long-term use, even at low dosage, may result in a protracted withdrawal syndrome.
Benzodiazepines can induce serious problems of addiction, which is one of the main reasons for their use being restricted to short-term use. A survey in Senegal found that the majority of doctors believed that their training in this area was generally poor. Recommendations for national authorities to take urgent action regarding the rational use of benzodiazepines. Another study in Dakar found that almost one-fifth of doctors ignored prescription guidelines regarding short-term use of benzodiazepines, and almost three-quarters of doctors regarded their training and knowledge of benzodiazepines to be inadequate. More training regarding benzodiazepines has been recommended for doctors.
# Contraindications and special caution
Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.
# Mechanism of action
Prazepam exerts its therapeutic effects primarily via modulating the benzodiazepine receptor which in turn enhances GABA function in the brain. Prazepam like other benzodiazepines has anticonvulsant properties, but its anticonvulsant properties are not as potent as other benzodiazepines when tested in animal studies.
# Pharmacokinetics
Prazepam is metabolised into descyclopropylmethylprazepam (also known as desmethyldiazepam) and 3-hydroxyprazepam which is further metabolised into oxazepam. Prazepam is a prodrug for descyclopropylmethylprazepam/desmethyldiazepam (also known as norprazepam or nordiazepam) which is responsible for most of the therapeutic activity of prazepam rather than prazepam itself.
# Interactions
Prazepam may interact with cimetidine. Alcohol in combination with prazepam increases the adverse effects, particularly performance impairing side effects and drowsiness.
# Trade names
Prazepam is available under different trade names in the following countries; Austria: Demetrin, Belgium: Lysanxia, France: Lysanxia, Germany: Demetrin; Mono Demetrin, Greece: Centrac, Ireland: Centrax, Italy: Prazene; Trepidan, Macedonia: Demetrin, Prazepam, Netherlands: Reapam, Portugal: Demetrin, South Africa: Demetrin, Switzerland: Demetrin, Thailand: Pozapam; Prasepine.
# Overdose
The symptoms of an overdose of prazepam include sleepiness, agitation and ataxia. Hypotonia may also occur in severe cases. Overdoses in children typically result in more severe symptoms of overdose.
# Abuse potential
Prazepam like other benzodiazepines has abuse potential and can be habit forming. However, its abuse potential may be lower than other benzodiazepines because it has a slow onset of action.
# Toxicity
Animal studies have found prazepam taken during pregnancy results in delayed growth and reproductive abnormalities.
# Synthesis
Prazepam differs from diazepam in that it has a substituent on the nitrogen atom in the first position of the benzodiazepine system.
This drug is made according to a scheme very similar to that of diazepam. It is derived from the same initial 2-amino-5-chlorobenzophenone, which undergoes acylation by cyclopropancarboxylic acid chloride. The resulting 2-cyclopropylcarbonylamino-5-chlorobenzophenone is reduced by lithium aluminum hydride into 2-cyclopropylmethylamino-5-chlorobenzhydrol, and the resulting product is oxidized by manganese dioxide into 2-cyclopropylmethylamino-5-chlorobenzophenone. This is acylated by phthalimidoacetic acid chloride. The phthalimide protecting group in the resulting product is removed by treatment with hydrazine, during which an intramolecular reaction of imino formation occurs under the conditions of synthesis, leading to the formation of the desired product, prazepam.
In the second, simpler scheme, synthesis begins with 7-chloro-5-phenyl-2,3-dihydro-1H-
1,4-benzodiazepin-2-one, which is alkylated by cyclopropylmethylbromide in the presence of sodium hydride into prazepam.
- H.M. Wuest, Template:US Patent (1965).
- S. Inaba, T. Hirohashi, H. Yamamoto, Chem. Pharm. Bull., 17, 1263 (1969). | Prazepam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Prazepam is a benzodiazepine derivative drug developed by Warner-Lambert in the 1960s.[1] It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties.[2] Prazepam is a prodrug for desmethyldiazepam which is responsible for the therapeutic effects of prazepam.[3]
Prazepam is marketed for anxiolytic use under various trade names: Centrac, Centrax, Demetrin, Lysanxia, Mono Demetrin, Pozapam, Prasepine, Prazene, Reapam and Trepidan.
# Indications
Prazepam is indicated for the short-term treatment of anxiety. After short-term therapy, the dose is usually gradually tapered-off to reduce or avoid any withdrawal or rebound effects.[4][5] Desmethyldiazepam, an active metabolite, has a very long half-life of 29 to 224 hours, which contributes to the therapeutic effects of prazepam.[6][7]
# Side effects
Side effects of prazepam are less profound than with other benzodiazepines.[8] Excessive drowsiness and with longer-term use, drug dependence, are the most common side effects of prazepam.[9][10] Side effects such as fatigue or "feeling spacey" can also occur but less commonly than with other benzodiazepines. Other side effects include feebleness, clumsiness or lethargic, clouded thinking and mental slowness.[11][12][13]
# Tolerance, dependence and withdrawal
Tolerance and dependence can develop with long-term use of prazepam, and upon cessation or reduction in dosage, then a benzodiazepine withdrawal syndrome may occur with symptoms such as tremulousness, dysphoria, psychomotor agitation, tachycardia and sweating. In severe cases, hallucinations, psychosis and seizures can occur. Withdrawal-related psychosis is generally unresponsive to antipsychotic mediations. The risk and severity of the withdrawal syndrome increases the higher the dose and the longer prazepam is taken for.[14] Tolerance, dependence and withdrawal problems may be less severe than with other benzodiazepines, such as diazepam.[15] It may be because tolerance is slower to develop with prazepam than with other benzodiazepines.[16] Abrupt or over-rapid discontinuation of prazepam after long-term use, even at low dosage, may result in a protracted withdrawal syndrome.[17]
Benzodiazepines can induce serious problems of addiction, which is one of the main reasons for their use being restricted to short-term use. A survey in Senegal found that the majority of doctors believed that their training in this area was generally poor. Recommendations for national authorities to take urgent action regarding the rational use of benzodiazepines.[18] Another study in Dakar found that almost one-fifth of doctors ignored prescription guidelines regarding short-term use of benzodiazepines, and almost three-quarters of doctors regarded their training and knowledge of benzodiazepines to be inadequate. More training regarding benzodiazepines has been recommended for doctors.[19]
# Contraindications and special caution
Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.[20]
# Mechanism of action
Prazepam exerts its therapeutic effects primarily via modulating the benzodiazepine receptor which in turn enhances GABA function in the brain.[21] Prazepam like other benzodiazepines has anticonvulsant properties, but its anticonvulsant properties are not as potent as other benzodiazepines when tested in animal studies.[22][23][24][25]
# Pharmacokinetics
Prazepam is metabolised into descyclopropylmethylprazepam (also known as desmethyldiazepam) and 3-hydroxyprazepam which is further metabolised into oxazepam.[26][27][28][29][30] Prazepam is a prodrug for descyclopropylmethylprazepam/desmethyldiazepam (also known as norprazepam or nordiazepam) which is responsible for most of the therapeutic activity of prazepam rather than prazepam itself.[14][21][31][32]
# Interactions
Prazepam may interact with cimetidine.[33] Alcohol in combination with prazepam increases the adverse effects, particularly performance impairing side effects and drowsiness.[34]
# Trade names
Prazepam is available under different trade names in the following countries; Austria: Demetrin, Belgium: Lysanxia, France: Lysanxia, Germany: Demetrin; Mono Demetrin, Greece: Centrac, Ireland: Centrax, Italy: Prazene; Trepidan, Macedonia: Demetrin, Prazepam, Netherlands: Reapam, Portugal: Demetrin, South Africa: Demetrin, Switzerland: Demetrin, Thailand: Pozapam; Prasepine.[35]
# Overdose
The symptoms of an overdose of prazepam include sleepiness, agitation and ataxia. Hypotonia may also occur in severe cases. Overdoses in children typically result in more severe symptoms of overdose.[36]
# Abuse potential
Prazepam like other benzodiazepines has abuse potential and can be habit forming. However, its abuse potential may be lower than other benzodiazepines because it has a slow onset of action.[14][37]
# Toxicity
Animal studies have found prazepam taken during pregnancy results in delayed growth and reproductive abnormalities.[38][39][40]
# Synthesis
Prazepam differs from diazepam in that it has a substituent on the nitrogen atom in the first position of the benzodiazepine system.
This drug is made according to a scheme very similar to that of diazepam. It is derived from the same initial 2-amino-5-chlorobenzophenone, which undergoes acylation by cyclopropancarboxylic acid chloride. The resulting 2-cyclopropylcarbonylamino-5-chlorobenzophenone is reduced by lithium aluminum hydride into 2-cyclopropylmethylamino-5-chlorobenzhydrol, and the resulting product is oxidized by manganese dioxide into 2-cyclopropylmethylamino-5-chlorobenzophenone. This is acylated by phthalimidoacetic acid chloride. The phthalimide protecting group in the resulting product is removed by treatment with hydrazine, during which an intramolecular reaction of imino formation occurs under the conditions of synthesis, leading to the formation of the desired product, prazepam.
In the second, simpler scheme, synthesis begins with 7-chloro-5-phenyl-2,3-dihydro-1H-
1,4-benzodiazepin-2-one, which is alkylated by cyclopropylmethylbromide in the presence of sodium hydride into prazepam.
- H.M. Wuest, Template:US Patent (1965).
- S. Inaba, T. Hirohashi, H. Yamamoto, Chem. Pharm. Bull., 17, 1263 (1969). | https://www.wikidoc.org/index.php/Prazepam | |
ec2d1beaecf4a01c8eb0a384bd0c9c7700976e7b | wikidoc | Preotact | Preotact
Preotact® is a pharmaceutical form of parathyroid hormone (H05AA03) manufactured using a strain of Escherichia coli modified by recombinant DNA technology. Preotact is used in the treatment of osteoporosis in postmenopausal women at high risk of osteoporotic fractures. A significant reduction in the incidence of vertebral fractures has been demonstrated.
Preotact® is marketed in Europe by Nycomed. PreosTM is a registered trade mark owned by NPS Pharmaceuticals, Inc. The name PreosTM and the New Drug Application is pending FDA approval.
# Clinical indication/use
Preotact is approved by the European Medicines Agency (EMEA) for the treatment of osteoporosis in postmenopausal women at high risk of fractures. US approval is pending with the FDA.
# Administration
The recommended dose is 100 micrograms of Preotact administered once-daily as a subcutaneous injection into the abdomen, during 18 months (data support treatment up to 24 months). The injections are given using a specially designed injection device (Preotact(TM)Pen). The PreotactPen is specifically designed to allow osteoporosis patients to administer the injections, despite challenges of vision impairment and limited strength of hands and digits tributable to high age. Patients should receive supplemental calcium and vitamin D during treatment with parathyroid hormone.
Following treatment with Preotact, patients can be treated with a bisphosphonate to further increase bone mineral densisty
# Contraindications for use
Parathyroid hormone treatment should not be initiated in patients:
- with hypersensitivity to PTH or excipients
- who have received radiation therapy to the skeleton
- with pre-existing hypercalcemia and other disturbances in the metabolism of phosphate or calcium
- with metabolic bone diseases other than primary osteoporosis (including hyperparathyroidism and Paget's disease
- with unexplained elevations of bone-specific alkaline phosphatase
- with severe renal impairment
- with severe hepatic impairment
# Interactions
Parathyroid hormone is a natural peptide that is not metabolised in the liver. PTH is not protein bound and has a low volume of distribution, therefore no specific drug-drug interactions are suspected. From the knowledge of the mechanism of action, combined use of Preotact and cardiac glycosides may predispose patients to digitalis toxicity if hypercalcemia develops.
# Undesirable effects
Hypercalcemia and/or hypercalciuria reflect the known pharmacodynamic actions of PTH in the gastrointestinal tract, the kidney and the skeleton, and is therefore an expected undesirable effect. Nausea is another commonly reported adverse reaction to the use of PTH.
# Pharmacodynamic properties
## Mechanism of action
Preotact contains recombinant human parathyroid hormone which is identical to the full-length native 84-amino acid polypeptide.
Physiological actions of PTH include stimulation of bone formation by direct effects on bone forming cells (osteoblasts) indirectly increasing the intestinal absorption of calcium and increasing the tubular reabsorption of calcium and excretion of phosphate by the kidney.
## Pharmacodynamic effects
The skeletal effects of PTH depend upon the pattern of systemic exposure. Transient elevations in PTH levels after subcutaneous injection of Preotact stimulates new bone formation on trabecular and cortical bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity.
## Effects on serum calcium concentrations
PTH is the principal regulator of serum calcium hemostasis. In response to subcutaneous doses of Preotact (100 micrograms), serum total calcium levels increase gradually and reach peak concentration at approximately 6 to 8 hours after dosing. In general, serum calcium levels return to normal within 24 hours.
## Clinical efficacy
In an 18 month double-blind, placebo controlled study, the effects of Preotact on the fracture incidence in 2532 women with postmenopausal osteoporosis was studied. Approximately 19% of patients had a prevalent vertebral fracture at baseline and the mean lumbar T-score of -3.0 in both active and placebo arm.
Compared to the placbo group, there was a 61% relative risk reduction of a new vertebral fracture at month 18 for the women in the Preotact group.
To prevent one or more new vertebral fractures, 48 women had to be treated for a median of 18 months for the total population. For patients who were already fractured, the number needed to treat (NNT) was 21.
## Effect on bone mineral density (BMD)
In the same study mentioned above, Preotact increased BMD in the lumbar spine after 18 months treatment by 6.5% compared with a reduction by 0.3% in the placebo group. The difference was statistically significant. The increase of BMD in the hip was also statistically significant compared to placebo, but only around 1.0% at study endpoint. Continued treatment up to 24 months lead to a continued increase in BMD.
# Pharmacokinetics
## Absorption
Subcutaneous administration of PTH into the abdomen produces a rapid increase in plasma PTH levels which reaches peak at 1 to 2 hours after dosing. The mean half-life is approximately 1.5 hours. The absolute bioavailability of 100 micrograms of Preotact after subcutaneous administration in the abdomen is 55%.
## Distribution
The volume of distribution at steady-state following intravenous administration is approximately 5.4 liters. Intersubject variability is about 40%.
## Biotransformation
Parathyroid hormone is efficiently removed from the blood by a receptor-mediated process in the liver and is broken down into smaller peptide fragments. The fragments derived from the amino-terminus are further degraded within the cell while the fragments derived from the carboxy-terminus are released back into the blood and cleared by the kidney. These carboxy-terminal fragments are thought to play a role in the regulation of PTH activity. Under normal physiological conditions full-length PTH constitutes only 5-30% of the circulating forms of the molecule, while 70-95% is present as carboxy-terminal fragments. Following administration of Preotact, carboxy-terminal fragments make up about 60-90% of the circulating forms of the molecule. Intersubject variability in systemic clearance is about 15%.
## Elimination
PTH is metabolised in the liver and to a lesser extent in the kidney. It is not excreted from the body in its intact form. Circulating carboxy-terminal fragments are filtered by the kidney, but are subsequently broken down into even smaller fragments during tubular reuptake. No studies have so far been performed in patients with severe hepatic impairment. The pharmacokinetics of PTH in patients with severe renal insufficiency (creatinine clearance of less than 30 ml/min) has not been investigated either.
# Pharmaceutical particulars
Preotact is delivered in a two chamber, glass ampoule. One chamber contains the active substance in the form of a white powder (with excipients: mannitol, citric acid monohydrate, NaCl, NaOH, HCl). And the other contains the solvent; water for injection. The powder is mixed with the solvent when the ampoule is insterted into the injection device.
# Storage and shelf-life
The mixed solution is stable for 28 days when stored between 2 and 8°C. During this 28 day period the mixed solution may be stored for up to 7 days at room temperature, allowing the patient the freedom to travel.
Unmixed ampolues have a shelf-life of 30 months. The products should not be frozen and should be protected from light. | Preotact
Preotact® is a pharmaceutical form of parathyroid hormone (H05AA03) manufactured using a strain of Escherichia coli modified by recombinant DNA technology. Preotact is used in the treatment of osteoporosis in postmenopausal women at high risk of osteoporotic fractures. A significant reduction in the incidence of vertebral fractures has been demonstrated.
Preotact® is marketed in Europe by Nycomed. PreosTM is a registered trade mark owned by NPS Pharmaceuticals, Inc. The name PreosTM and the New Drug Application is pending FDA approval.
# Clinical indication/use
Preotact is approved by the European Medicines Agency (EMEA) for the treatment of osteoporosis in postmenopausal women at high risk of fractures. US approval is pending with the FDA.
# Administration
The recommended dose is 100 micrograms of Preotact administered once-daily as a subcutaneous injection into the abdomen, during 18 months (data support treatment up to 24 months). The injections are given using a specially designed injection device (Preotact(TM)Pen). The PreotactPen is specifically designed to allow osteoporosis patients to administer the injections, despite challenges of vision impairment and limited strength of hands and digits tributable to high age. Patients should receive supplemental calcium and vitamin D during treatment with parathyroid hormone.
Following treatment with Preotact, patients can be treated with a bisphosphonate to further increase bone mineral densisty
# Contraindications for use
Parathyroid hormone treatment should not be initiated in patients:
- with hypersensitivity to PTH or excipients
- who have received radiation therapy to the skeleton
- with pre-existing hypercalcemia and other disturbances in the metabolism of phosphate or calcium
- with metabolic bone diseases other than primary osteoporosis (including hyperparathyroidism and Paget's disease
- with unexplained elevations of bone-specific alkaline phosphatase
- with severe renal impairment
- with severe hepatic impairment
# Interactions
Parathyroid hormone is a natural peptide that is not metabolised in the liver. PTH is not protein bound and has a low volume of distribution, therefore no specific drug-drug interactions are suspected. From the knowledge of the mechanism of action, combined use of Preotact and cardiac glycosides may predispose patients to digitalis toxicity if hypercalcemia develops.
# Undesirable effects
Hypercalcemia and/or hypercalciuria reflect the known pharmacodynamic actions of PTH in the gastrointestinal tract, the kidney and the skeleton, and is therefore an expected undesirable effect. Nausea is another commonly reported adverse reaction to the use of PTH.
# Pharmacodynamic properties
## Mechanism of action
Preotact contains recombinant human parathyroid hormone which is identical to the full-length native 84-amino acid polypeptide.
Physiological actions of PTH include stimulation of bone formation by direct effects on bone forming cells (osteoblasts) indirectly increasing the intestinal absorption of calcium and increasing the tubular reabsorption of calcium and excretion of phosphate by the kidney.
## Pharmacodynamic effects
The skeletal effects of PTH depend upon the pattern of systemic exposure. Transient elevations in PTH levels after subcutaneous injection of Preotact stimulates new bone formation on trabecular and cortical bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity.
## Effects on serum calcium concentrations
PTH is the principal regulator of serum calcium hemostasis. In response to subcutaneous doses of Preotact (100 micrograms), serum total calcium levels increase gradually and reach peak concentration at approximately 6 to 8 hours after dosing. In general, serum calcium levels return to normal within 24 hours.
## Clinical efficacy
In an 18 month double-blind, placebo controlled study, the effects of Preotact on the fracture incidence in 2532 women with postmenopausal osteoporosis was studied. Approximately 19% of patients had a prevalent vertebral fracture at baseline and the mean lumbar T-score of -3.0 in both active and placebo arm.
Compared to the placbo group, there was a 61% relative risk reduction of a new vertebral fracture at month 18 for the women in the Preotact group.
To prevent one or more new vertebral fractures, 48 women had to be treated for a median of 18 months for the total population. For patients who were already fractured, the number needed to treat (NNT) was 21.
## Effect on bone mineral density (BMD)
In the same study mentioned above, Preotact increased BMD in the lumbar spine after 18 months treatment by 6.5% compared with a reduction by 0.3% in the placebo group. The difference was statistically significant. The increase of BMD in the hip was also statistically significant compared to placebo, but only around 1.0% at study endpoint. Continued treatment up to 24 months lead to a continued increase in BMD.
# Pharmacokinetics
## Absorption
Subcutaneous administration of PTH into the abdomen produces a rapid increase in plasma PTH levels which reaches peak at 1 to 2 hours after dosing. The mean half-life is approximately 1.5 hours. The absolute bioavailability of 100 micrograms of Preotact after subcutaneous administration in the abdomen is 55%.
## Distribution
The volume of distribution at steady-state following intravenous administration is approximately 5.4 liters. Intersubject variability is about 40%.
## Biotransformation
Parathyroid hormone is efficiently removed from the blood by a receptor-mediated process in the liver and is broken down into smaller peptide fragments. The fragments derived from the amino-terminus are further degraded within the cell while the fragments derived from the carboxy-terminus are released back into the blood and cleared by the kidney. These carboxy-terminal fragments are thought to play a role in the regulation of PTH activity. Under normal physiological conditions full-length PTH constitutes only 5-30% of the circulating forms of the molecule, while 70-95% is present as carboxy-terminal fragments. Following administration of Preotact, carboxy-terminal fragments make up about 60-90% of the circulating forms of the molecule. Intersubject variability in systemic clearance is about 15%.
## Elimination
PTH is metabolised in the liver and to a lesser extent in the kidney. It is not excreted from the body in its intact form. Circulating carboxy-terminal fragments are filtered by the kidney, but are subsequently broken down into even smaller fragments during tubular reuptake. No studies have so far been performed in patients with severe hepatic impairment. The pharmacokinetics of PTH in patients with severe renal insufficiency (creatinine clearance of less than 30 ml/min) has not been investigated either.
# Pharmaceutical particulars
Preotact is delivered in a two chamber, glass ampoule. One chamber contains the active substance in the form of a white powder (with excipients: mannitol, citric acid monohydrate, NaCl, NaOH, HCl). And the other contains the solvent; water for injection. The powder is mixed with the solvent when the ampoule is insterted into the injection device.
# Storage and shelf-life
The mixed solution is stable for 28 days when stored between 2 and 8°C. During this 28 day period the mixed solution may be stored for up to 7 days at room temperature, allowing the patient the freedom to travel.
Unmixed ampolues have a shelf-life of 30 months. The products should not be frozen and should be protected from light. | https://www.wikidoc.org/index.php/Preotact | |
300381957742e09af6fe78464ac47ffd29ede87f | wikidoc | Pressure | Pressure
Pressure (symbol: 'P') is the force per unit area applied on a surface in a direction perpendicular to that surface.
Gauge pressure is the pressure relative to the local atmospheric or ambient pressure.
# Definition
## Formula
Mathematically:
p = \frac{F}{A}\ \mbox{or}\ p = \frac{dF}{dA}
where:
Pressure is a scalar quantity, and has SI units of pascals; 1 Pa = 1 N/m2.
Pressure is transmitted to solid boundaries or across arbitrary sections of fluid normal to these boundaries or sections at every point. It is a fundamental parameter in thermodynamics and it is conjugate to volume.
## Units
The SI unit for pressure is the pascal (Pa), equal to one newton per square metre (N·m-2 or kg·m-1·s-2). This special name for the unit was added in 1971; before that, pressure in SI was expressed simply as N/m2.
Non-SI measures such as pound per square inch (psi) and bar are used in some parts of the world. The cgs unit of pressure is the barye (ba), equal to 1 dyn·cm-2. Pressure is sometimes expressed in grams-force/cm2, or as ] and the like without properly identifying the force units. But using the names kilogram, gram, kilogram-force, or gram-force (or their symbols) as units of force is expressly forbidden in SI. The technical atmosphere (symbol: at) is 1 kgf/cm2.
Some meteorologists prefer the hectopascal (hPa) for atmospheric air pressure, which is equivalent to the older unit millibar (mbar). Similar pressures are given in kilopascals (kPa) in most other fields, where the hecto prefix is rarely used. The unit inch of mercury (inHg, see below) is still used in the United States. Oceanographers usually measure underwater pressure in decibars (dbar) because an increase in pressure of 1 dbar is approximately equal to an increase in depth of 1 meter. Scuba divers often use a manometric rule of thumb: the pressure exerted by ten metres depth of water is approximately equal to one atmosphere.
The standard atmosphere (atm) is an established constant. It is approximately equal to typical air pressure at earth mean sea level and is defined as follows:
Because pressure is commonly measured by its ability to displace a column of liquid in a manometer, pressures are often expressed as a depth of a particular fluid (e.g., inches of water). The most common choices are mercury (Hg) and water; water is nontoxic and readily available, while mercury's high density allows for a shorter column (and so a smaller manometer) to measure a given pressure. The pressure exerted by a column of liquid of height h and density ρ is given by the hydrostatic pressure equation p = ρgh. Fluid density and local gravity can vary from one reading to another depending on local factors, so the height of a fluid column does not define pressure precisely. When millimeters of mercury or inches of mercury are quoted today, these units are not based on a physical column of mercury; rather, they have been given precise definitions that can be expressed in terms of SI units. The water-based units still depend on the density of water, a measured, rather than defined, quantity. These manometric units are still encountered in many fields. Blood pressure is measured in millimeters of mercury in most of the world, and lung pressures in centimeters of water are still common.
Presently or formerly popular pressure units include the following:
- atmosphere
- manometric units:
centimeter, inch, and millimeter of mercury (torr)
millimeter, centimeter, meter, inch, and foot of water
- centimeter, inch, and millimeter of mercury (torr)
- millimeter, centimeter, meter, inch, and foot of water
- imperial units:
kip, ton-force (short), ton-force (long), pound-force, ounce-force, and poundal per square inch
pound-force, ton-force (short), and ton-force (long)
- kip, ton-force (short), ton-force (long), pound-force, ounce-force, and poundal per square inch
- pound-force, ton-force (short), and ton-force (long)
- non-SI metric units:
bar, decibar, millibar
kilogram-force, or kilopond, per square centimetre (technical atmosphere)
gram-force and tonne-force (metric ton-force) per square centimetre
barye (dyne per square centimetre)
kilogram-force and tonne-force per square metre
sthene per square metre (pieze)
- bar, decibar, millibar
- kilogram-force, or kilopond, per square centimetre (technical atmosphere)
- gram-force and tonne-force (metric ton-force) per square centimetre
- barye (dyne per square centimetre)
- kilogram-force and tonne-force per square metre
- sthene per square metre (pieze)
## Examples
As an example of varying pressures, a finger can be pressed against a wall without making any lasting impression; however, the same finger pushing a thumbtack can easily damage the wall. Although the force applied to the surface is the same, the thumbtack applies more pressure because the point concentrates that force into a smaller area. Pressure is transmitted to solid boundaries or across arbitrary sections of fluid normal to these boundaries or sections at every point. Unlike stress, pressure is defined as a scalar quantity.
The gradient of pressure is called the force density.
For gases, pressure is sometimes measured not as an absolute pressure, but relative to atmospheric pressure; such measurements are called gauge pressure (also sometimes spelled gage pressure). An example of this is the air pressure in an automobile tire, which might be said to be "220 kPa", but is actually 220 kPa above atmospheric pressure. Since atmospheric pressure at sea level is about 100 kPa, the absolute pressure in the tire is therefore about 320 kPa. In technical work, this is written "a gauge pressure of 220 kPa". Where space is limited, such as on pressure gauges, name plates, graph labels, and table headings, the use of a modifier in parentheses, such as "kPa (gauge)" or "kPa (absolute)", is permitted. In non-SI technical work, a gauge pressure is sometimes written as "32 psig", though the other methods explained above that avoid attaching characters to the unit of pressure are preferred.
Gauge pressure is the relevant measure of pressure wherever one is interested in the stress on storage vessels and the plumbing components of fluidics systems. However, whenever equation-of-state properties, such as densities or changes in densities, must be calculated, pressures must be expressed in terms of their absolute values. For instance, if the atmospheric pressure is 100 kPa, a gas (such as helium) at 200 kPa (gauge) (300 kPa ) is 50 % more dense than the same gas at 100 kPa (gauge) (200 kPa ). Focusing on gauge values, one might erroneously conclude the first sample had twice the density of the second.
## Scalar nature
In a static gas, the gas as a whole does not appear to move. The individual molecules of the gas, however, are in constant random motion. Because we are dealing with an extremely large number of molecules and because the motion of the individual molecules is random in every direction, we do not detect any motion. If we enclose the gas within a container, we detect a pressure in the gas from the molecules colliding with the walls of our container. We can put the walls of our container anywhere inside the gas, and the force per unit area (the pressure) is the same. We can shrink the size of our "container" down to an infinitely small point, and the pressure has a single value at that point. Therefore, pressure is a scalar quantity, not a vector quantity. It has a magnitude but no direction associated with it. Pressure acts in all directions at a point inside a gas. At the surface of a gas, the pressure force acts perpendicular to the surface.
A closely related quantity is the stress tensor σ, which relates the vector force F to the vector area A via
\mathbf{F}=\mathbf{\sigma A}\,
This tensor may be divided up into a scalar part (pressure) and a traceless tensor part shear. The shear tensor gives the force in directions parallel to the surface, usually due to viscous or frictional forces. The stress tensor is sometimes called the pressure tensor, but in the following, the term "pressure" will refer only to the scalar pressure.
# Types
## Explosion or deflagration pressures
Explosion or deflagration pressures are the result of the ignition of explosible gases, mists, dust/air suspensions, in unconfined and confined spaces.
## Negative pressures
While pressures are generally positive, there are several situations in which a negative pressure may be encountered:
- When dealing in relative (gauge) pressures. For instance, an absolute pressure of 80 kPa may be described as a gauge pressure of -21 kPa (i.e., 21 kPa below an atmospheric pressure of 101 kPa).
- When attractive forces (e.g., Van der Waals forces) between the particles of a fluid exceed repulsive forces. Such scenarios are generally unstable since the particles will move closer together until repulsive forces balance attractive forces. Negative pressure exists in the transpiration pull of plants.
- The Casimir effect can create a small attractive force due to interactions with vacuum energy; this force is sometimes termed 'vacuum pressure' (not to be confused with the negative gauge pressure of a vacuum).
- Depending on how the orientation of a surface is chosen, the same distribution of forces may be described either as a positive pressure along one surface normal, or as a negative pressure acting along the opposite surface normal.
- In the cosmological constant.
## Hydrostatic pressure (head pressure)
Hydrostatic pressure is the pressure due to the weight of a fluid.
p = \rho g h\,
where:
See also Pascal's law.
## Stagnation pressure
Stagnation pressure is the pressure a fluid exerts when it is forced to stop moving. Consequently, although a fluid moving at higher speed will have a lower static pressure, it may have a higher stagnation pressure when forced to a standstill. Static pressure and stagnation pressure are related by the Mach number of the fluid. In addition, there can be differences in pressure due to differences in the elevation (height) of the fluid. See Bernoulli's equation (note: Bernoulli's equation only applies for incompressible flow).
The pressure of a moving fluid can be measured using a Pitot tube, or one of its variations such as a Kiel probe or Cobra probe, connected to a manometer. Depending on where the inlet holes are located on the probe, it can measure static pressure or stagnation pressure.
## Surface pressure
There is a two-dimensional analog of pressure -- the lateral force per unit length applied on a line perpendicular to the force.
Surface pressure is denoted by π and shares many similar properties with three-dimensional pressure. Properties of surface chemicals can be investigated by measuring pressure/area isotherms, as the two-dimensional analog of Boyle's law, πA = k, at constant temperature. | Pressure
Template:Otheruse
Pressure (symbol: 'P') is the force per unit area applied on a surface in a direction perpendicular to that surface.
Gauge pressure is the pressure relative to the local atmospheric or ambient pressure.
# Definition
## Formula
Template:Conjugate variables (thermodynamics)
Mathematically:
p = \frac{F}{A}\ \mbox{or}\ p = \frac{dF}{dA}
</math>
where:
Pressure is a scalar quantity, and has SI units of pascals; 1 Pa = 1 N/m2.
Pressure is transmitted to solid boundaries or across arbitrary sections of fluid normal to these boundaries or sections at every point. It is a fundamental parameter in thermodynamics and it is conjugate to volume.
## Units
The SI unit for pressure is the pascal (Pa), equal to one newton per square metre (N·m-2 or kg·m-1·s-2). This special name for the unit was added in 1971; before that, pressure in SI was expressed simply as N/m2.
Non-SI measures such as pound per square inch (psi) and bar are used in some parts of the world. The cgs unit of pressure is the barye (ba), equal to 1 dyn·cm-2. Pressure is sometimes expressed in grams-force/cm2, or as [[kg/cm2]] and the like without properly identifying the force units. But using the names kilogram, gram, kilogram-force, or gram-force (or their symbols) as units of force is expressly forbidden in SI. The technical atmosphere (symbol: at) is 1 kgf/cm2.
Some meteorologists prefer the hectopascal (hPa) for atmospheric air pressure, which is equivalent to the older unit millibar (mbar). Similar pressures are given in kilopascals (kPa) in most other fields, where the hecto prefix is rarely used. The unit inch of mercury (inHg, see below) is still used in the United States. Oceanographers usually measure underwater pressure in decibars (dbar) because an increase in pressure of 1 dbar is approximately equal to an increase in depth of 1 meter. Scuba divers often use a manometric rule of thumb: the pressure exerted by ten metres depth of water is approximately equal to one atmosphere.
The standard atmosphere (atm) is an established constant. It is approximately equal to typical air pressure at earth mean sea level and is defined as follows:
Because pressure is commonly measured by its ability to displace a column of liquid in a manometer, pressures are often expressed as a depth of a particular fluid (e.g., inches of water). The most common choices are mercury (Hg) and water; water is nontoxic and readily available, while mercury's high density allows for a shorter column (and so a smaller manometer) to measure a given pressure. The pressure exerted by a column of liquid of height h and density ρ is given by the hydrostatic pressure equation p = ρgh. Fluid density and local gravity can vary from one reading to another depending on local factors, so the height of a fluid column does not define pressure precisely. When millimeters of mercury or inches of mercury are quoted today, these units are not based on a physical column of mercury; rather, they have been given precise definitions that can be expressed in terms of SI units. The water-based units still depend on the density of water, a measured, rather than defined, quantity. These manometric units are still encountered in many fields. Blood pressure is measured in millimeters of mercury in most of the world, and lung pressures in centimeters of water are still common.
Presently or formerly popular pressure units include the following:
- atmosphere
- manometric units:
centimeter, inch, and millimeter of mercury (torr)
millimeter, centimeter, meter, inch, and foot of water
- centimeter, inch, and millimeter of mercury (torr)
- millimeter, centimeter, meter, inch, and foot of water
- imperial units:
kip, ton-force (short), ton-force (long), pound-force, ounce-force, and poundal per square inch
pound-force, ton-force (short), and ton-force (long)
- kip, ton-force (short), ton-force (long), pound-force, ounce-force, and poundal per square inch
- pound-force, ton-force (short), and ton-force (long)
- non-SI metric units:
bar, decibar, millibar
kilogram-force, or kilopond, per square centimetre (technical atmosphere)
gram-force and tonne-force (metric ton-force) per square centimetre
barye (dyne per square centimetre)
kilogram-force and tonne-force per square metre
sthene per square metre (pieze)
- bar, decibar, millibar
- kilogram-force, or kilopond, per square centimetre (technical atmosphere)
- gram-force and tonne-force (metric ton-force) per square centimetre
- barye (dyne per square centimetre)
- kilogram-force and tonne-force per square metre
- sthene per square metre (pieze)
Template:Pressure Units
## Examples
As an example of varying pressures, a finger can be pressed against a wall without making any lasting impression; however, the same finger pushing a thumbtack can easily damage the wall. Although the force applied to the surface is the same, the thumbtack applies more pressure because the point concentrates that force into a smaller area. Pressure is transmitted to solid boundaries or across arbitrary sections of fluid normal to these boundaries or sections at every point. Unlike stress, pressure is defined as a scalar quantity.
The gradient of pressure is called the force density.
For gases, pressure is sometimes measured not as an absolute pressure, but relative to atmospheric pressure; such measurements are called gauge pressure (also sometimes spelled gage pressure).[1] An example of this is the air pressure in an automobile tire, which might be said to be "220 kPa", but is actually 220 kPa above atmospheric pressure. Since atmospheric pressure at sea level is about 100 kPa, the absolute pressure in the tire is therefore about 320 kPa. In technical work, this is written "a gauge pressure of 220 kPa". Where space is limited, such as on pressure gauges, name plates, graph labels, and table headings, the use of a modifier in parentheses, such as "kPa (gauge)" or "kPa (absolute)", is permitted. In non-SI technical work, a gauge pressure is sometimes written as "32 psig", though the other methods explained above that avoid attaching characters to the unit of pressure are preferred.[2]
Gauge pressure is the relevant measure of pressure wherever one is interested in the stress on storage vessels and the plumbing components of fluidics systems. However, whenever equation-of-state properties, such as densities or changes in densities, must be calculated, pressures must be expressed in terms of their absolute values. For instance, if the atmospheric pressure is 100 kPa, a gas (such as helium) at 200 kPa (gauge) (300 kPa [absolute]) is 50 % more dense than the same gas at 100 kPa (gauge) (200 kPa [absolute]). Focusing on gauge values, one might erroneously conclude the first sample had twice the density of the second.
## Scalar nature
In a static gas, the gas as a whole does not appear to move. The individual molecules of the gas, however, are in constant random motion. Because we are dealing with an extremely large number of molecules and because the motion of the individual molecules is random in every direction, we do not detect any motion. If we enclose the gas within a container, we detect a pressure in the gas from the molecules colliding with the walls of our container. We can put the walls of our container anywhere inside the gas, and the force per unit area (the pressure) is the same. We can shrink the size of our "container" down to an infinitely small point, and the pressure has a single value at that point. Therefore, pressure is a scalar quantity, not a vector quantity. It has a magnitude but no direction associated with it. Pressure acts in all directions at a point inside a gas. At the surface of a gas, the pressure force acts perpendicular to the surface.
A closely related quantity is the stress tensor σ, which relates the vector force F to the vector area A via
\mathbf{F}=\mathbf{\sigma A}\,
</math>
This tensor may be divided up into a scalar part (pressure) and a traceless tensor part shear. The shear tensor gives the force in directions parallel to the surface, usually due to viscous or frictional forces. The stress tensor is sometimes called the pressure tensor, but in the following, the term "pressure" will refer only to the scalar pressure.
# Types
## Explosion or deflagration pressures
Explosion or deflagration pressures are the result of the ignition of explosible gases, mists, dust/air suspensions, in unconfined and confined spaces.
## Negative pressures
While pressures are generally positive, there are several situations in which a negative pressure may be encountered:
- When dealing in relative (gauge) pressures. For instance, an absolute pressure of 80 kPa may be described as a gauge pressure of -21 kPa (i.e., 21 kPa below an atmospheric pressure of 101 kPa).
- When attractive forces (e.g., Van der Waals forces) between the particles of a fluid exceed repulsive forces. Such scenarios are generally unstable since the particles will move closer together until repulsive forces balance attractive forces. Negative pressure exists in the transpiration pull of plants.
- The Casimir effect can create a small attractive force due to interactions with vacuum energy; this force is sometimes termed 'vacuum pressure' (not to be confused with the negative gauge pressure of a vacuum).
- Depending on how the orientation of a surface is chosen, the same distribution of forces may be described either as a positive pressure along one surface normal, or as a negative pressure acting along the opposite surface normal.
- In the cosmological constant.
## Hydrostatic pressure (head pressure)
Hydrostatic pressure is the pressure due to the weight of a fluid.
p = \rho g h\,
</math>
where:
See also Pascal's law.
## Stagnation pressure
Stagnation pressure is the pressure a fluid exerts when it is forced to stop moving. Consequently, although a fluid moving at higher speed will have a lower static pressure, it may have a higher stagnation pressure when forced to a standstill. Static pressure and stagnation pressure are related by the Mach number of the fluid. In addition, there can be differences in pressure due to differences in the elevation (height) of the fluid. See Bernoulli's equation (note: Bernoulli's equation only applies for incompressible flow).
The pressure of a moving fluid can be measured using a Pitot tube, or one of its variations such as a Kiel probe or Cobra probe, connected to a manometer. Depending on where the inlet holes are located on the probe, it can measure static pressure or stagnation pressure.
## Surface pressure
There is a two-dimensional analog of pressure -- the lateral force per unit length applied on a line perpendicular to the force.
Surface pressure is denoted by π and shares many similar properties with three-dimensional pressure. Properties of surface chemicals can be investigated by measuring pressure/area isotherms, as the two-dimensional analog of Boyle's law, πA = k, at constant temperature. | https://www.wikidoc.org/index.php/Pressure | |
9032bbe4c36437044aaec9a44a88deed36afd0e6 | wikidoc | Pro-Test | Pro-Test
Pro-Test is a British group that promotes and supports animal testing in medical research. It was founded on January 29, 2006 to counter SPEAK, an animal-rights campaign opposing the construction by Oxford University of a biomedical and animal-research facility, which SPEAK believes may include a primate-testing centre. Pro-Test held its first rally on February 25, 2006, attracting hundreds in support of the research facility and opposed by a smaller number of anti-lab demonstrators.
The group was founded by Laurie Pycroft from Swindon when he was 16. After forming the group, British newspapers described of Pycroft as a "sixth form drop-out," "bedroom blogger," and "campaigning hero." It is now run by a committee composed of three academics; Tipu Aziz, John Stein, and David Priestman; six Oxford graduate and undergraduate students; medical writer Alison Eden; and Pycroft.
Pro-Test says that it stands for "science, reasoned debate and, above all, the welfare of mankind. … We support only non-violent protest and we condemn those using violence or intimidation to further their goals. We strongly support animal testing as crucially necessary to further medical science." The Guardian has written that it is a "new public interest cause," seeking to "defend animal-testing to advance medical science."
# Background
The construction site of the Oxford research centre is located on South Parks Road behind a five-metre (15 ft) barrier. Construction work is carried out by workmen wearing balaclavas and using unmarked vehicles, after the first contractor, Walter Lilly, owned by Montpellier plc, pulled out in the face of threats. The facility is intended to become the "centre for all animal research at Oxford," according to Mark Matfield, former director of the Research Defence Society, resulting in "the closure of a number of existing animal facilities".
The formation of Pro-Test coincided with threats made by the Animal Liberation Front, against Oxford staff and students, on the Bite Back website. ALF spokesman, Robin Webb confirmed that "high-level student groups working against SPEAK protesters may be targeted."
Pycroft describes in his blog, hosted at the LiveJournal website, how he set up Pro-Test after visiting his girlfriend in Oxford on January 28, 2006 and watching a SPEAK demonstration from the window of a coffee shop. Pycroft, his girlfriend, and one other, staged a personal counter-demonstration.
After writing about the experience on his blog, Pycroft has said he was receiving 300 hits an hour within days, and after attracting interest from the media, Oxford students, and the pro-animal-testing movement, he decided to schedule a second demonstration to coincide with a SPEAK protest on February 25, 2006. According to The Times, "Pro-Test’s tactics mirror those of animal rights activists, with about 150 students using websites and chat forums to organise protests."
# February 2006 rally
According to police estimates, about 700 students, academics and members of the public took part in the February 25, 2006 protest in the centre of Oxford which passed without violent incident, marching at the same time as more than 150 SPEAK protestors demonstrated in various locations across the city.
A number of politicians and scientists addressed the Pro-Test demonstrators. These included Evan Harris, the Liberal Democrat science spokesperson and MP for Oxford West and Abingdon; the Radcliffe Hospital's neurosurgeon and Pro-Test committee member Professor Tipu Aziz, whose research into Parkinson's disease "involves the use of primates," and who recently spoke out in support of testing cosmetics on animals; Simon Festing of the Research Defence Society, a lobby group funded by the pharmaceutical industry and universities; and Pro-Test committee member Professor John Stein, an Oxford neurophysiologist who "induces Parkinson's disease in monkeys and then attaches electrodes to their brains to test therapies which may help human sufferers," according to The Guardian. In his speech to the crowd, Stein declared, "This is a historic day; we are drawing a line in the sand."
# June 2006 rally
Supporters of Pro-Test marched through Oxford on Saturday, 3 June, 2006. Their route led them through Radcliffe Square, the High Street and ended nearby the laboratory in the University's science area. Speakers included Prof. Colin Blakemore (the chief executive of the Medical Research Council), Dr Evan Harris MP, Alan Duncan MP (the Shadow Cabinet Trade and Industry Secretary), and Dr Ken Fleming.
# Other activities
Pro-Test have taken the case for animal research to Parliament, participating in a debate at The Associate Parliamentary Group for Animal Welfare (APGAW). The debate focused specifically upon whether the Oxford biomedical research lab should be built and involved both MPs and members of the public. The principal speakers were Iain Simpson, press officer for Pro-Test, and Dr. Jarrod Bailey of Europeans for Medical Progress.
Pro-Test handed out doughnuts and cakes to workers on the South Parks Road site on March 31, 2006 to show their support for their work.
Pro-Test fielded Pycroft for a debate at the Oxford Union on the motion "This house would not test on animals". Supporting the motion were Dr Gill Langley, Dr Andrew Knight, Uri Gellar and Alistair Currie. On the opposing side were Pycroft, Professor Colin Blakemore, Professor John Stein and Professor Lord Robert Winston. The motion was defeated, 273 to 48 of the Union members voting with the opposing side.
A cross-college student referendum propositioned by Pro-Test was held on November 16 2006. It proposed support for the Oxford lab's construction and animal testing in general, and found support from approximately 90% of voters.
On May 9, 2006, the BBC reported that Pro-Test had bought shares in GlaxoSmithKline (GSK), as a "gesture of solidarity" with the company and its investors. An animal rights group had earlier sent letters to individual shareholders threatening to reveal personal details unless their shares were sold. The letters explained GSK's investors were targeted because of the company's association with Huntingdon Life Sciences. Pro-Test announced that their share purchase was to demonstrate that "intimidation has no place in the UK".
British Prime Minister Tony Blair gave his support to Pro-Test and The People's Petition in an article for the Sunday Telegraph, citing "the Pro-Test demonstration in Oxford, which... deserves support" as an example of the change in public attitudes in the UK.
An unnamed Oxford academic told the BBC that "a war is looming over 'scientific freedom' and the 'future of progress'," and suggests that the Pro-Test campaign is part of a wider reaction against animal-rights activism.
The BBC programme Newsnight hosted a vivisection debate on the 24 July, 2006. Tipu Aziz, John Stein and Iain Simpson of Pro-Test featured in the debate, as did members of SPEAK and Europeans for Medical Progress. | Pro-Test
Template:Animal testing
Pro-Test is a British group that promotes and supports animal testing in medical research. It was founded on January 29, 2006 to counter SPEAK, an animal-rights campaign opposing the construction by Oxford University of a biomedical and animal-research facility,[1] which SPEAK believes may include a primate-testing centre.[2] Pro-Test held its first rally on February 25, 2006, attracting hundreds in support of the research facility and opposed by a smaller number of anti-lab demonstrators.[3]
The group was founded by Laurie Pycroft from Swindon when he was 16. After forming the group, British newspapers described of Pycroft as a "sixth form drop-out," "bedroom blogger,"[4] and "campaigning hero."[5] It is now run by a committee composed of three academics; Tipu Aziz, John Stein, and David Priestman; six Oxford graduate and undergraduate students; medical writer Alison Eden; and Pycroft. [6]
Pro-Test says that it stands for "science, reasoned debate and, above all, the welfare of mankind. … We support only non-violent protest and we condemn those using violence or intimidation to further their goals. We strongly support animal testing as crucially necessary to further medical science." [7] The Guardian has written that it is a "new public interest cause," seeking to "defend animal-testing to advance medical science."[8]
# Background
The construction site of the Oxford research centre is located on South Parks Road behind a five-metre (15 ft) barrier. Construction work is carried out by workmen wearing balaclavas and using unmarked vehicles, after the first contractor, Walter Lilly, owned by Montpellier plc, pulled out in the face of threats.[9] The facility is intended to become the "centre for all animal research at Oxford," according to Mark Matfield, former director of the Research Defence Society,[10] resulting in "the closure of a number of existing animal facilities". [11]
The formation of Pro-Test coincided with threats made by the Animal Liberation Front, against Oxford staff and students, on the Bite Back website. [12] ALF spokesman, Robin Webb confirmed that "high-level student groups working against SPEAK protesters may be targeted."[13]
Pycroft describes in his blog, hosted at the LiveJournal website, how he set up Pro-Test after visiting his girlfriend in Oxford on January 28, 2006 and watching a SPEAK demonstration from the window of a coffee shop.[14] [15] Pycroft, his girlfriend, and one other, staged a personal counter-demonstration.
After writing about the experience on his blog, Pycroft has said he was receiving 300 hits an hour within days, [16] and after attracting interest from the media, Oxford students, and the pro-animal-testing movement, he decided to schedule a second demonstration to coincide with a SPEAK protest on February 25, 2006. According to The Times, "Pro-Test’s tactics mirror those of animal rights activists, with about 150 students using websites and chat forums to organise protests."[17]
# February 2006 rally
According to police estimates[3], about 700 students, academics and members of the public took part in the February 25, 2006 protest in the centre of Oxford which passed without violent incident, [18] marching at the same time as more than 150 SPEAK protestors[19] demonstrated in various locations across the city.
A number of politicians and scientists addressed the Pro-Test demonstrators. These included Evan Harris, the Liberal Democrat science spokesperson and MP for Oxford West and Abingdon; the Radcliffe Hospital's neurosurgeon and Pro-Test committee member Professor Tipu Aziz, [6] whose research into Parkinson's disease "involves the use of primates," [9] and who recently spoke out in support of testing cosmetics on animals; [20] Simon Festing of the Research Defence Society, a lobby group funded by the pharmaceutical industry and universities; and Pro-Test committee member Professor John Stein, [6] an Oxford neurophysiologist who "induces Parkinson's disease in monkeys and then attaches electrodes to their brains to test therapies which may help human sufferers," according to The Guardian. [4] In his speech to the crowd, Stein declared, "This is a historic day; we are drawing a line in the sand." [21]
# June 2006 rally
Supporters of Pro-Test marched through Oxford on Saturday, 3 June, 2006. Their route led them through Radcliffe Square, the High Street and ended nearby the laboratory in the University's science area. Speakers included Prof. Colin Blakemore (the chief executive of the Medical Research Council), Dr Evan Harris MP, Alan Duncan MP (the Shadow Cabinet Trade and Industry Secretary), and Dr Ken Fleming.[citation needed] [1] [2]
# Other activities
Pro-Test have taken the case for animal research to Parliament, participating in a debate at The Associate Parliamentary Group for Animal Welfare (APGAW). The debate focused specifically upon whether the Oxford biomedical research lab should be built and involved both MPs and members of the public. The principal speakers were Iain Simpson, press officer for Pro-Test, and Dr. Jarrod Bailey of Europeans for Medical Progress.[22]
Pro-Test handed out doughnuts and cakes to workers on the South Parks Road site on March 31, 2006 to show their support for their work. [23]
Pro-Test fielded Pycroft for a debate at the Oxford Union on the motion "This house would not test on animals". Supporting the motion were Dr Gill Langley, Dr Andrew Knight, Uri Gellar and Alistair Currie. On the opposing side were Pycroft, Professor Colin Blakemore, Professor John Stein and Professor Lord Robert Winston. The motion was defeated, 273 to 48 of the Union members voting with the opposing side.
A cross-college student referendum propositioned by Pro-Test was held on November 16 2006. It proposed support for the Oxford lab's construction and animal testing in general, and found support from approximately 90% of voters. [3]
On May 9, 2006, the BBC reported that Pro-Test had bought shares in GlaxoSmithKline (GSK), as a "gesture of solidarity" with the company and its investors. An animal rights group had earlier sent letters to individual shareholders threatening to reveal personal details unless their shares were sold. The letters explained GSK's investors were targeted because of the company's association with Huntingdon Life Sciences. Pro-Test announced that their share purchase was to demonstrate that "intimidation has no place in the UK". [24]
British Prime Minister Tony Blair gave his support to Pro-Test and The People's Petition in an article for the Sunday Telegraph, citing "the Pro-Test demonstration in Oxford, which... deserves support" as an example of the change in public attitudes in the UK. [4] [5] [6]
An unnamed Oxford academic told the BBC that "a war is looming over 'scientific freedom' and the 'future of progress'," and suggests that the Pro-Test campaign is part of a wider reaction against animal-rights activism. [25]
The BBC programme Newsnight hosted a vivisection debate on the 24 July, 2006. Tipu Aziz, John Stein and Iain Simpson of Pro-Test featured in the debate, as did members of SPEAK and Europeans for Medical Progress. [26] | https://www.wikidoc.org/index.php/Pro-Test | |
632d22a4c078b070579b3c55fad8475bde02ef9b | wikidoc | ProSavin | ProSavin
ProSavin is an experimental drug believed to be of use in the treatment of Parkinson's Disease. It is administered to the striatum in the brain, inducing production of dopamine.
It is manufactured by Oxford BioMedica, who plan to start European Phase I and Phase II clinical trials in 2007. Animal trials have been a success, with dopamine levels restored without the side effects associated with other current treatments for Parkinson's.
# Mechanism of Action
Prosavin uses Oxford BioMedica's Lentivector delivery system to transfer three genes, aromatic amino acid dopa decarboxylase, tyrosine hydroxylase and GTP-cyclohydrolase 1, to the striatum in the brain, reprogramming transduced cells to secrete dopamine. | ProSavin
ProSavin is an experimental drug believed to be of use in the treatment of Parkinson's Disease. It is administered to the striatum in the brain, inducing production of dopamine.[1]
It is manufactured by Oxford BioMedica, who plan to start European Phase I and Phase II clinical trials in 2007. Animal trials have been a success, with dopamine levels restored without the side effects associated with other current treatments for Parkinson's.[2]
# Mechanism of Action
Prosavin uses Oxford BioMedica's Lentivector delivery system to transfer three genes, aromatic amino acid dopa decarboxylase, tyrosine hydroxylase and GTP-cyclohydrolase 1, to the striatum in the brain, reprogramming transduced cells to secrete dopamine.[3] | https://www.wikidoc.org/index.php/ProSavin | |
21b9a994a93e4c9170ff6caad8c2f2bf86b650cf | wikidoc | Prodrome | Prodrome
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
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# Overview
A prodrome is an early non-specific symptom (or set of symptoms) indicating the start of a disease before specific symptoms occur. For example fever, malaise, headache and anorexia (lack of desire to eat) are part of the prodrome for mumps or a variety of infective disorders. A prodrome can be the precursor to the onset of a chronic neurological disorder such as migraine or epilepsy, where prodrome symptoms include scotoma, disorientation, aphasia, or photosensitivity.
It also refers to the initial in vivo round of viral replication.
Prodromal labour, also called "false labour," is the early signs before labour starts. See Braxton Hicks. | Prodrome
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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# Overview
A prodrome is an early non-specific symptom (or set of symptoms) indicating the start of a disease before specific symptoms occur. For example fever, malaise, headache and anorexia (lack of desire to eat) are part of the prodrome for mumps or a variety of infective disorders. A prodrome can be the precursor to the onset of a chronic neurological disorder such as migraine or epilepsy, where prodrome symptoms include scotoma, disorientation, aphasia, or photosensitivity.
It also refers to the initial in vivo round of viral replication.
Prodromal labour, also called "false labour," is the early signs before labour starts. See Braxton Hicks.
Template:Skin and subcutaneous tissue symptoms and signs
Template:Nervous and musculoskeletal system symptoms and signs
Template:Urinary system symptoms and signs
Template:Cognition, perception, emotional state and behaviour symptoms and signs
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Template:General symptoms and signs
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6a6e1eedcd8e5e8c997870bd046a8d57515f9588 | wikidoc | Progerin | Progerin
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Progerin is a truncated version of lamin A protein involved in Hutchinson-Gilford progeria syndrome. Progerin is most often generated by a mutation (C1824T) in the lamin A gene, LMNA. This mutation activates a cryptic splice site and gives rise to a form of lamin A with a deletion of 50 amino acids. Approximately
80% of Hutchinson-Gilford progeria syndrome cases carry a single copy of the most common mutation, a silent point mutation (G608G) within exon 11 of LMNA gene.
Lamin A constitutes a major structural component of the lamina, a scaffold of proteins found inside the nuclear membrane of a cell; progerin does not properly integrate into the lamina, which disrupts the scaffold structure and leads to significant disfigurement of the nucleus, characterized by a lobular shape. Researchers have shown that progerin activates genes that regulate stem cell differentiation via the Notch signaling pathway.
Researchers are exploring farnesyltransferase inhibitors as a potential pharmacological therapy against the negative effects of progerin on nuclear morphology.
Progerin, which has been linked to normal aging, is produced in healthy indivduals via "sporadic use of the cryptic splice site". | Progerin
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.
Progerin is a truncated version of lamin A protein involved in Hutchinson-Gilford progeria syndrome. Progerin is most often generated by a mutation (C1824T) in the lamin A gene, LMNA. This mutation activates a cryptic splice site and gives rise to a form of lamin A with a deletion of 50 amino acids.[1] Approximately
80% of Hutchinson-Gilford progeria syndrome cases carry a single copy of the most common mutation, a silent point mutation (G608G) within exon 11 of LMNA gene.[2]
Lamin A constitutes a major structural component of the lamina, a scaffold of proteins found inside the nuclear membrane of a cell; progerin does not properly integrate into the lamina, which disrupts the scaffold structure and leads to significant disfigurement of the nucleus, characterized by a lobular shape.[3] Researchers have shown that progerin activates genes that regulate stem cell differentiation via the Notch signaling pathway.[4]
Researchers are exploring farnesyltransferase inhibitors as a potential pharmacological therapy against the negative effects of progerin on nuclear morphology.[3]
Progerin, which has been linked to normal aging, is produced in healthy indivduals via "sporadic use of the cryptic splice site".[4][5] | https://www.wikidoc.org/index.php/Progerin | |
a4b538c623195924b2b7c122004730f652f84da9 | wikidoc | Promoter | Promoter
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# Overview
In biology, a promoter is a regulatory region of DNA generally located upstream (towards the 5' region of the anti-sense strand) of a gene that generally promotes transcription of the gene.
The promoter contains specific DNA sequences, response elements, that are recognized by proteins known as transcription factors. These factors bind to the promoter sequences, recruiting RNA polymerase, the enzyme that synthesizes the RNA from the coding region of the gene.
- In prokaryotes, the promoter is recognized by RNA polymerase and an associated sigma factor, which in turn are brought to the promoter DNA by an activator protein binding to its own DNA sequence nearby.
- In eukaryotes, the process is more complicated, and at least seven different factors are necessary for the binding of an RNA polymerase II to the promoter.
Promoters represent critical elements that can work in concert with other regulatory regions (enhancers, silencers, boundary elements/insulators) to direct the level of transcription of a given gene.
It is worth noting that promoters are not DNA specific, and can in fact locate upstream towards the 3' end of an RNA genome, e.g. Respiratory Syncytial Virus (RSV).
# Identification of relative location
As promoters are typically immediately adjacent to the gene in question, positions in the promoter are designated relative to the transcriptional start site, where transcription of RNA begins for a particular gene (i.e., positions upstream are negative numbers counting back from -1, for example -100 is a position 100 base pairs upstream).
# Promoter elements
- Core promoter - the minimal portion of the promoter required to properly initiate transcription
Transcription Start Site (TSS)
Approximately -34
A binding site for RNA polymerase
RNA polymerase I: transcribes genes encoding ribosomal RNA
RNA polymerase II: transcribes genes encoding messenger RNA and certain small nuclear RNAs
RNA polymerase III: transcribes genes encoding tRNAs and other small RNAs
General transcription factor binding sites
- Transcription Start Site (TSS)
- Approximately -34
- A binding site for RNA polymerase
RNA polymerase I: transcribes genes encoding ribosomal RNA
RNA polymerase II: transcribes genes encoding messenger RNA and certain small nuclear RNAs
RNA polymerase III: transcribes genes encoding tRNAs and other small RNAs
- RNA polymerase I: transcribes genes encoding ribosomal RNA
- RNA polymerase II: transcribes genes encoding messenger RNA and certain small nuclear RNAs
- RNA polymerase III: transcribes genes encoding tRNAs and other small RNAs
- General transcription factor binding sites
- Proximal promoter - the proximal sequence upstream of the gene that tends to contain primary regulatory elements
Approximately -250
Specific transcription factor binding sites
- Approximately -250
- Specific transcription factor binding sites
- Distal promoter - the distal sequence upstream of the gene that may contain additional regulatory elements, often with a weaker influence than the proximal promoter
Anything further upstream (but not an enhancer or other regulatory region whose influence is positional/orientation independent)
Specific transcription factor binding sites
- Anything further upstream (but not an enhancer or other regulatory region whose influence is positional/orientation independent)
- Specific transcription factor binding sites
## Prokaryotic promoters
In prokaryotes, the promoter consists of two short sequences at -10 and -35 positions upstream from the transcription start site. Sigma factors not only help in enhancing RNAP binding to the promoter but helps RNAP target which genes to transcribe.
- The sequence at -10 is called the Pribnow box, or the -10 element, and usually consists of the six nucleotides TATAAT. The Pribnow box is absolutely essential to start transcription in prokaryotes.
- The other sequence at -35 (the -35 element) usually consists of the six nucleotides TTGACA. Its presence allows a very high transcription rate.
- Both of the above consensus sequences, while conserved on average, are not found intact in most promoters. On average only 3 of the 6 base pairs in each consensus sequence is found in any given promoter. No promoter has been identified to date that has intact consensus sequences at both the -10 and -35; it is thought that this would lead to such tight binding by the sigma factor that the polymerase would be unable to initiate productive transcription.
- Some promoters contain a UP element (consensus sequence 5’-TGNTATAAT-3')upstream of the -35 element; the presence of the -35 element appears to be unimportant for transcription from the UP element-containing promoters.
It should be noted that the above promoter sequences are only recognized by the sigma-70 protein that interacts with the prokaryotic RNA polymerase. Complexes of prokaryotic RNA polymerase with other sigma factors recognize totally different core promoter sequences.
### Probability of occurrence of each nucleotide
## Eukaryotic promoters
Eukaryotic promoters are extremely diverse and are difficult to characterize. They typically lie upstream of the gene and can have regulatory elements several kilobases away from the transcriptional start site. In eukaryotes, the transcriptional complex can cause the DNA to bend back on itself, which allows for placement of regulatory sequences far from the actual site of transcription. Many eukaryotic promoters, but by no means all, contain a TATA box (sequence TATAAA), which in turn binds a TATA binding protein which assists in the formation of the RNA polymerase transcriptional complex. The TATA box typically lies very close to the transcriptional start site (often within 50 bases).
Eukaryotic promoter regulatory sequences typically bind proteins called transcription factors which are involved in the formation of the transcriptional complex. An example is the E-box (sequence CACGTG), which binds transcription factors in the basic-helix-loop-helix (bHLH) family (e.g. BMAL1-Clock, cMyc).
# Detection of promoters
A wide variety of algorithms have been developed to facilitate detection of promoters in genomic sequence, and promoter prediction is a common element of many gene prediction methods.
# Evolutionary change
A major question in evolutionary biology is how important tinkering with promoter sequences is to evolutionary change, for example, the changes that have occurred in the human lineage after separating from chimps.
Some evolutionary biologists, for example Allan Wilson, have proposed that evolution in promoter or regulatory regions may be more important than changes in coding sequences over such time frames.
# Binding
The binding of a promoter sequence (P) to a sigma factor-RNAP complex (R) is a two-step process:
- R+P ↔ RP(closed). K = 107
- RP(closed) → RP(open). K = 10−2
# Diseases associated with aberrant promoter function
Though OMIM is a major resource for gathering information on the relationship between mutations and natural variation in gene sequence and susceptibility to hundreds of diseases, it requires a sophisticated search strategy to extract those diseases that are associated with defects in transcriptional control where the promoter is believed to have direct involvement.
This is a list of diseases that evidence suggests have some involvement of promoter malfunction, either through direct mutation of a promoter sequence or mutation in a transcription factor or transcriptional co-activator.
Keep in mind that most diseases are heterogeneous in etiology, meaning that one "disease" is often many different diseases at the molecular level, though the symptoms exhibited and the response to treatment might be identical. How diseases respond differently to treatment as a result of differences in the underlying molecular origins is partially addressed by the discipline of pharmacogenomics.
Not listed here are the many kinds of cancers that involve aberrant changes in transcriptional regulation owing to the creation of chimeric genes through pathological chromosomal translocation.
# Canonical sequences and wild-type
The usage of canonical sequence for a promoter is often problematic, and can lead to misunderstandings about promoter sequences. Canonical implies perfect, in some sense.
In the case of a transcription factor binding site, then there may be a single sequence which binds the protein most strongly under specified cellular conditions. This might be called canonical.
However, natural selection may favor less energetic binding as a way of regulating transcriptional output. In this case, we may call the most common sequence in a population, the wild-type sequence. It may not even be the most advantageous sequence to have under prevailing conditions.
Recent evidence also indicates that several genes (including the proto-oncogene c-myc) have G-quadruplex motifs as potential regulatory signals.
# Diseases associated with promoter elements
- Asthma
- Beta thalassemia
- Rubinstein-Taybi syndrome | Promoter
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
In biology, a promoter is a regulatory region of DNA generally located upstream (towards the 5' region of the anti-sense strand) of a gene that generally promotes transcription of the gene.
The promoter contains specific DNA sequences, response elements, that are recognized by proteins known as transcription factors. These factors bind to the promoter sequences, recruiting RNA polymerase, the enzyme that synthesizes the RNA from the coding region of the gene.
- In prokaryotes, the promoter is recognized by RNA polymerase and an associated sigma factor, which in turn are brought to the promoter DNA by an activator protein binding to its own DNA sequence nearby.
- In eukaryotes, the process is more complicated, and at least seven different factors are necessary for the binding of an RNA polymerase II to the promoter.
Promoters represent critical elements that can work in concert with other regulatory regions (enhancers, silencers, boundary elements/insulators) to direct the level of transcription of a given gene.
It is worth noting that promoters are not DNA specific, and can in fact locate upstream towards the 3' end of an RNA genome, e.g. Respiratory Syncytial Virus (RSV).
# Identification of relative location
As promoters are typically immediately adjacent to the gene in question, positions in the promoter are designated relative to the transcriptional start site, where transcription of RNA begins for a particular gene (i.e., positions upstream are negative numbers counting back from -1, for example -100 is a position 100 base pairs upstream).
# Promoter elements
- Core promoter - the minimal portion of the promoter required to properly initiate transcription
Transcription Start Site (TSS)
Approximately -34
A binding site for RNA polymerase
RNA polymerase I: transcribes genes encoding ribosomal RNA
RNA polymerase II: transcribes genes encoding messenger RNA and certain small nuclear RNAs
RNA polymerase III: transcribes genes encoding tRNAs and other small RNAs
General transcription factor binding sites
- Transcription Start Site (TSS)
- Approximately -34
- A binding site for RNA polymerase
RNA polymerase I: transcribes genes encoding ribosomal RNA
RNA polymerase II: transcribes genes encoding messenger RNA and certain small nuclear RNAs
RNA polymerase III: transcribes genes encoding tRNAs and other small RNAs
- RNA polymerase I: transcribes genes encoding ribosomal RNA
- RNA polymerase II: transcribes genes encoding messenger RNA and certain small nuclear RNAs
- RNA polymerase III: transcribes genes encoding tRNAs and other small RNAs
- General transcription factor binding sites
- Proximal promoter - the proximal sequence upstream of the gene that tends to contain primary regulatory elements
Approximately -250
Specific transcription factor binding sites
- Approximately -250
- Specific transcription factor binding sites
- Distal promoter - the distal sequence upstream of the gene that may contain additional regulatory elements, often with a weaker influence than the proximal promoter
Anything further upstream (but not an enhancer or other regulatory region whose influence is positional/orientation independent)
Specific transcription factor binding sites
- Anything further upstream (but not an enhancer or other regulatory region whose influence is positional/orientation independent)
- Specific transcription factor binding sites
## Prokaryotic promoters
In prokaryotes, the promoter consists of two short sequences at -10 and -35 positions upstream from the transcription start site. Sigma factors not only help in enhancing RNAP binding to the promoter but helps RNAP target which genes to transcribe.
- The sequence at -10 is called the Pribnow box, or the -10 element, and usually consists of the six nucleotides TATAAT. The Pribnow box is absolutely essential to start transcription in prokaryotes.
- The other sequence at -35 (the -35 element) usually consists of the six nucleotides TTGACA. Its presence allows a very high transcription rate.
- Both of the above consensus sequences, while conserved on average, are not found intact in most promoters. On average only 3 of the 6 base pairs in each consensus sequence is found in any given promoter. No promoter has been identified to date that has intact consensus sequences at both the -10 and -35; it is thought that this would lead to such tight binding by the sigma factor that the polymerase would be unable to initiate productive transcription.
- Some promoters contain a UP element (consensus sequence 5’-TGNTATAAT-3')upstream of the -35 element; the presence of the -35 element appears to be unimportant for transcription from the UP element-containing promoters.
It should be noted that the above promoter sequences are only recognized by the sigma-70 protein that interacts with the prokaryotic RNA polymerase. Complexes of prokaryotic RNA polymerase with other sigma factors recognize totally different core promoter sequences.
### Probability of occurrence of each nucleotide
## Eukaryotic promoters
Eukaryotic promoters are extremely diverse and are difficult to characterize. They typically lie upstream of the gene and can have regulatory elements several kilobases away from the transcriptional start site. In eukaryotes, the transcriptional complex can cause the DNA to bend back on itself, which allows for placement of regulatory sequences far from the actual site of transcription. Many eukaryotic promoters, but by no means all, contain a TATA box (sequence TATAAA), which in turn binds a TATA binding protein which assists in the formation of the RNA polymerase transcriptional complex.[1] The TATA box typically lies very close to the transcriptional start site (often within 50 bases).
Eukaryotic promoter regulatory sequences typically bind proteins called transcription factors which are involved in the formation of the transcriptional complex. An example is the E-box (sequence CACGTG), which binds transcription factors in the basic-helix-loop-helix (bHLH) family (e.g. BMAL1-Clock, cMyc).[2]
# Detection of promoters
A wide variety of algorithms have been developed to facilitate detection of promoters in genomic sequence, and promoter prediction is a common element of many gene prediction methods.
# Evolutionary change
A major question in evolutionary biology is how important tinkering with promoter sequences is to evolutionary change, for example, the changes that have occurred in the human lineage after separating from chimps.
Some evolutionary biologists, for example Allan Wilson, have proposed that evolution in promoter or regulatory regions may be more important than changes in coding sequences over such time frames.
# Binding
The binding of a promoter sequence (P) to a sigma factor-RNAP complex (R) is a two-step process:
- R+P ↔ RP(closed). K = 107
- RP(closed) → RP(open). K = 10−2
# Diseases associated with aberrant promoter function
Though OMIM is a major resource for gathering information on the relationship between mutations and natural variation in gene sequence and susceptibility to hundreds of diseases, it requires a sophisticated search strategy to extract those diseases that are associated with defects in transcriptional control where the promoter is believed to have direct involvement.
This is a list of diseases that evidence suggests have some involvement of promoter malfunction, either through direct mutation of a promoter sequence or mutation in a transcription factor or transcriptional co-activator.
Keep in mind that most diseases are heterogeneous in etiology, meaning that one "disease" is often many different diseases at the molecular level, though the symptoms exhibited and the response to treatment might be identical. How diseases respond differently to treatment as a result of differences in the underlying molecular origins is partially addressed by the discipline of pharmacogenomics.
Not listed here are the many kinds of cancers that involve aberrant changes in transcriptional regulation owing to the creation of chimeric genes through pathological chromosomal translocation.
# Canonical sequences and wild-type
The usage of canonical sequence for a promoter is often problematic, and can lead to misunderstandings about promoter sequences. Canonical implies perfect, in some sense.
In the case of a transcription factor binding site, then there may be a single sequence which binds the protein most strongly under specified cellular conditions. This might be called canonical.
However, natural selection may favor less energetic binding as a way of regulating transcriptional output. In this case, we may call the most common sequence in a population, the wild-type sequence. It may not even be the most advantageous sequence to have under prevailing conditions.
Recent evidence also indicates that several genes (including the proto-oncogene c-myc) have G-quadruplex motifs as potential regulatory signals.
# Diseases associated with promoter elements
- Asthma[3][4]
- Beta thalassemia[5]
- Rubinstein-Taybi syndrome[6] | https://www.wikidoc.org/index.php/Promoter | |
1ada52c3d4155c8c69f59579b605b73312fd7b2d | wikidoc | Prophage | Prophage
A prophage is a phage genome inserted as part of the linear structure of the DNA chromosome of a bacterium. A temperate phage integrated into the host chromosome or existing as an extrachromosomal plasmid. This is a latent form of a bacteriophage in which the viral genes are incorporated into the bacterial chromosomes without causing disruption of the bacterial cell.
Upon detection of host cell damage, the prophage is excised from the bacterial chromosome in a process called prophage induction. After induction, viral replication begins via the lytic cycle. Prophages are important agents of horizontal gene transfer, and are considered to be part of the mobilome.
# Prophages and Their Contribution to Host Cell Phenotype
In many bacterial species, prophages figure prominently in the biology of these cells, often conferring key phenotypes that can convert a non-pathogenic strain into a pathogen. The source of these phenotypic changes can be through prophage-encoded toxins, bacterial cell surface alterations, or resistance to the human immune system. Further, prophage integration into the host genome can inactivate or alter the expression of host genes. In addition to these direct genetic alterations associated with the addition or inactivation of genes, prophages can also alter the phenotype of bacteria at the population level by facilitating the spread of favorable genes through transduction.
# Prophage Induction of Phage λ
The gene regulatory circuitry of phage λ is among the best-understood circuits at the mechanistic level. This circuitry involves several interesting regulatory behaviors. An infected cell undergoes a decision between two alternative pathways, the lytic and lysogenic pathways. If the latter is followed, the lysogenic state is established and maintained. While this state is highly stable, it can switch to the lytic pathway in the process of prophage induction, which occurs when the host SOS response is triggered by DNA damage. | Prophage
A prophage is a phage genome inserted as part of the linear structure of the DNA chromosome of a bacterium. A temperate phage integrated into the host chromosome or existing as an extrachromosomal plasmid. This is a latent form of a bacteriophage in which the viral genes are incorporated into the bacterial chromosomes without causing disruption of the bacterial cell.
Upon detection of host cell damage, the prophage is excised from the bacterial chromosome in a process called prophage induction. After induction, viral replication begins via the lytic cycle. Prophages are important agents of horizontal gene transfer, and are considered to be part of the mobilome.
# Prophages and Their Contribution to Host Cell Phenotype
In many bacterial species, prophages figure prominently in the biology of these cells, often conferring key phenotypes that can convert a non-pathogenic strain into a pathogen. The source of these phenotypic changes can be through prophage-encoded toxins, bacterial cell surface alterations, or resistance to the human immune system. Further, prophage integration into the host genome can inactivate or alter the expression of host genes. In addition to these direct genetic alterations associated with the addition or inactivation of genes, prophages can also alter the phenotype of bacteria at the population level by facilitating the spread of favorable genes through transduction. [1]
# Prophage Induction of Phage λ
The gene regulatory circuitry of phage λ is among the best-understood circuits at the mechanistic level. This circuitry involves several interesting regulatory behaviors. An infected cell undergoes a decision between two alternative pathways, the lytic and lysogenic pathways. If the latter is followed, the lysogenic state is established and maintained. While this state is highly stable, it can switch to the lytic pathway in the process of prophage induction, which occurs when the host SOS response is triggered by DNA damage.[1] | https://www.wikidoc.org/index.php/Prophage | |
75604568d902ee33f697424d37029eff97a01bd1 | wikidoc | Prosopis | Prosopis
Prosopis is a genus of about 45 species of leguminous spiny trees and shrubs found in subtropical and tropical regions of the Americas, Africa and southwest Asia. They often thrive in arid soil and are resistant to droughts, on occasion developing extremely deep root systems. Their wood is usually hard, dense and durable. Their fruits are pods and may contain large amounts of sugar.
# Species
Some of the species in this genus are:
- Mesquite species (southern United States, Mexico):
Prosopis glandulosa (Honey Mesquite)
Prosopis pallida
Prosopis pubescens (Screwbean Mesquite)
Prosopis reptans (Tornillo)
Prosopis strombulifera (Creeping Mesquite)
Prosopis velutina (Velvet Mesquite)
- Prosopis glandulosa (Honey Mesquite)
- Prosopis pallida
- Prosopis pubescens (Screwbean Mesquite)
- Prosopis reptans (Tornillo)
- Prosopis strombulifera (Creeping Mesquite)
- Prosopis velutina (Velvet Mesquite)
- South American species (algarrobos of the Gran Chaco and others):
Prosopis affinis (Ñandubay)
Prosopis alba (Algarrobo blanco)
Prosopis alba var. panta (Algarrobo panta)
Prosopis caldenia (Caldén)
Prosopis chilensis (Algarrobo chileno)
Prosopis fiebrigii
Prosopis flexuosa (Alpataco)
Prosopis hassleri
Prosopis juliflora
Prosopis kuntzei (Itín)
Prosopis nigra (Algarrobo negro)
Prosopis rojasiana
Prosopis ruscifolia (Vinal)
- Prosopis affinis (Ñandubay)
- Prosopis alba (Algarrobo blanco)
Prosopis alba var. panta (Algarrobo panta)
- Prosopis alba var. panta (Algarrobo panta)
- Prosopis caldenia (Caldén)
- Prosopis chilensis (Algarrobo chileno)
- Prosopis fiebrigii
- Prosopis flexuosa (Alpataco)
- Prosopis hassleri
- Prosopis juliflora
- Prosopis kuntzei (Itín)
- Prosopis nigra (Algarrobo negro)
- Prosopis rojasiana
- Prosopis ruscifolia (Vinal)
- African species
Prosopis africana
- Prosopis africana
- Asian species (India (mainly Rajasthan), Syria, Iraq):
Prosopis cineraria (Khejri, Jand, Sangri, Kandi)
- Prosopis cineraria (Khejri, Jand, Sangri, Kandi)
- Uncategorized species
# Phytochemistry
Prosopis has been found to contain 5-hydroxytryptamine, apigenin, isorhamnetin-3-diglucoside, l-arabinose, quercetin, tannin and tryptamine.
# Photos
- Prosopis affinis
Prosopis affinis
- Prosopis alba
Prosopis alba
- Prosopis caldenia
Prosopis caldenia
- Prosopis cineraria
Prosopis cineraria
- Prosopis glandulosa
Prosopis glandulosa
- Prosopis juliflora
Prosopis juliflora
- Prosopis kuntzei
Prosopis kuntzei
- Prosopis nigra
Prosopis nigra
- Prosopis pallida
Prosopis pallida
- Prosopis pubescens
Prosopis pubescens | Prosopis
Prosopis is a genus of about 45 species of leguminous spiny trees and shrubs found in subtropical and tropical regions of the Americas, Africa and southwest Asia. They often thrive in arid soil and are resistant to droughts, on occasion developing extremely deep root systems. Their wood is usually hard, dense and durable. Their fruits are pods and may contain large amounts of sugar.
# Species
Some of the species in this genus are:
- Mesquite species (southern United States, Mexico):
Prosopis glandulosa (Honey Mesquite)
Prosopis pallida
Prosopis pubescens (Screwbean Mesquite)
Prosopis reptans (Tornillo)
Prosopis strombulifera (Creeping Mesquite)
Prosopis velutina (Velvet Mesquite)
- Prosopis glandulosa (Honey Mesquite)
- Prosopis pallida
- Prosopis pubescens (Screwbean Mesquite)
- Prosopis reptans (Tornillo)
- Prosopis strombulifera (Creeping Mesquite)
- Prosopis velutina (Velvet Mesquite)
- South American species (algarrobos of the Gran Chaco and others):
Prosopis affinis (Ñandubay)
Prosopis alba (Algarrobo blanco)
Prosopis alba var. panta (Algarrobo panta)
Prosopis caldenia (Caldén)
Prosopis chilensis (Algarrobo chileno)
Prosopis fiebrigii
Prosopis flexuosa (Alpataco)
Prosopis hassleri
Prosopis juliflora
Prosopis kuntzei (Itín)
Prosopis nigra (Algarrobo negro)
Prosopis rojasiana
Prosopis ruscifolia (Vinal)
- Prosopis affinis (Ñandubay)
- Prosopis alba (Algarrobo blanco)
Prosopis alba var. panta (Algarrobo panta)
- Prosopis alba var. panta (Algarrobo panta)
- Prosopis caldenia (Caldén)
- Prosopis chilensis (Algarrobo chileno)
- Prosopis fiebrigii
- Prosopis flexuosa (Alpataco)
- Prosopis hassleri
- Prosopis juliflora
- Prosopis kuntzei (Itín)
- Prosopis nigra (Algarrobo negro)
- Prosopis rojasiana
- Prosopis ruscifolia (Vinal)
- African species
Prosopis africana
- Prosopis africana
- Asian species (India (mainly Rajasthan), Syria, Iraq):
Prosopis cineraria (Khejri, Jand, Sangri, Kandi)
- Prosopis cineraria (Khejri, Jand, Sangri, Kandi)
- Uncategorized species
# Phytochemistry
Prosopis has been found to contain 5-hydroxytryptamine, apigenin, isorhamnetin-3-diglucoside, l-arabinose, quercetin, tannin and tryptamine.[1]
# Photos
- Prosopis affinis
Prosopis affinis
- Prosopis alba
Prosopis alba
- Prosopis caldenia
Prosopis caldenia
- Prosopis cineraria
Prosopis cineraria
- Prosopis glandulosa
Prosopis glandulosa
- Prosopis juliflora
Prosopis juliflora
- Prosopis kuntzei
Prosopis kuntzei
- Prosopis nigra
Prosopis nigra
- Prosopis pallida
Prosopis pallida
- Prosopis pubescens
Prosopis pubescens | https://www.wikidoc.org/index.php/Prosopis | |
78dc26321cf86257a12a322a8517f6016a7536ed | wikidoc | Psoralen | Psoralen
# Overview
Psoralen (also called psoralene) is the parent compound in a family of natural products known as furocoumarins. It is structurally related to coumarin by the addition of a fused furan ring, and may be considered as a derivative of umbelliferone. Psoralen occurs naturally in the seeds of Psoralea corylifolia, as well as in the common fig, celery, parsley and West Indian satinwood. It is widely used in PUVA (= psoralen + UVA) treatment for psoriasis, eczema, vitiligo, and cutaneous T-cell lymphoma. Many furocoumarins are extremely toxic to fish, and some are deposited in streams in Indonesia to catch fish.
# Uses
Psoralen is a mutagen, and is used for this purpose in molecular biology research. Psoralen intercalates into the DNA and, on exposure to ultraviolet (UVA) radiation, can form covalent interstrand cross-links (ICL) with thymines preferentially at 5'-TpA sites in the genome, inducing apoptosis. Psoralen plus UVA (PUVA) therapy has shown considerable clinical efficacy. Unfortunately, a side effect of PUVA treatment is a higher risk of skin cancer.
An important use of psoralen is in PUVA treatment for skin problems such as psoriasis and (to a lesser extent) eczema and vitiligo. This takes advantage of the high UV absorbance of psoralen. The psoralen is applied first to sensitise the skin, then UVA light is applied to clean up the skin problem. Psoralen has also been recommended for treating alopecia. Psoralens are also used in photopheresis, where they are mixed with the extracted leukocytes before UV radiation is applied.
Despite the photocarcinogenic properties of psoralen, It had been used as a tanning activator in sunscreens until 1996.
Psoralens are used in tanning accelerators, but users should keep in mind that psoralen increases the skin’s sensitivity to light.
Some patients have had severe skin loss after sunbathing with psoralen-containing tanning activators.
Patients with lighter skin colour suffer four times as much from the melanoma-generating properties of psoralens than those with darker skin
The synthetic amino-psoralen, amotosalen HCl, has been developed for the inactivation of infectious pathogens (bacteria, viruses, protozoa) in platelet and plasma blood components prepared for transfusion support of patients. The technology is currently in routine use in certain European blood centers.
# Chemistry
One isomer of psoralen is angelicin, and most furocoumarins can be regarded as derivatives of psoralen or angelicin. Some important psoralen derivatives are Imperatorin, xanthotoxin, bergapten and nodekenetin.
Another important feature of this class of compounds is their ability to generate singlet oxygen.
## Structure
The structure of psoralen was originally deduced by identifying the products of its degradation reactions. It exhibits the normal reactions of the lactone of coumarin, such as ring opening by alkali to give a coumarinic acid or coumaric acid derivative. Potassium permanganate causes oxidation of the furan ring, while other methods of oxidation produce furan-2,3-carboxylic acid.
## Synthesis
Psoralen synthesis is difficult, due the fact that umbelliferone undergoes substitution at the 8-position rather than at the desired 6 position. Benzofuran reacts preferentially in the furan ring rather than in the benzene ring. However, the 7-hydroxy derivative of 2,3-dihydrobenzofuran (also called coumaran) does undergo substitution at the desired 6-position allowing the following synthesis of the coumarin system via a Gattermann-Koch reaction followed by a Perkin condensation using acetic anhydride. The synthesis is then completed by dehydrogenation of the five-membered ring to produce the furan ring.
# Biosynthesis
Psoralen originates from coumarins in the shikimate pathway; its biosynthesis is shown in the figure below. The aromatic ring in 6 is activated at positions ortho to the hydroxyl group, and is alkylated by 5, an alkylating agent. The dimethylallyl group in 7 then undergoes cyclization with the phenol group to give 8. This transformation is catalysed by a cytochome P-450-dependent monooxygenase17 (psoralen 5-monooxygenase), and cofactors (NADPH) and molecular oxygen.
A biosynthetic pathway in which psoralen is formed is shown in the figure below. A second P-450-dependent monooxygenase enzyme (psoralen synthase) then cleaves off 10 (in the form of 11) from 8 to give 1. This pathway does not involve any hydroxylated intermediate, and cleavage is postulated to be initiated by a radical reaction.
# Plant sources
Ficus carica (fig) is probably the most abundant source of psoralens. They are also found in small quantities in Ammi visnaga (bisnaga), Pastinaca sativa (parsnip), Petroselinum crispum (parsley), Levisticum officinale (lovage), Foeniculum vulgare (fruit, i.e., fennel seeds), Daucus carota (carrot), Psoralea corylifolia (babchi), and Apium graveolens (celery). | Psoralen
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Psoralen (also called psoralene) is the parent compound in a family of natural products known as furocoumarins. It is structurally related to coumarin by the addition of a fused furan ring, and may be considered as a derivative of umbelliferone. Psoralen occurs naturally in the seeds of Psoralea corylifolia, as well as in the common fig, celery, parsley and West Indian satinwood. It is widely used in PUVA (= psoralen + UVA) treatment for psoriasis, eczema, vitiligo, and cutaneous T-cell lymphoma. Many furocoumarins are extremely toxic to fish, and some are deposited in streams in Indonesia to catch fish.
# Uses
Psoralen is a mutagen, and is used for this purpose in molecular biology research. Psoralen intercalates into the DNA and, on exposure to ultraviolet (UVA) radiation, can form covalent interstrand cross-links (ICL) with thymines preferentially at 5'-TpA sites in the genome, inducing apoptosis. Psoralen plus UVA (PUVA) therapy has shown considerable clinical efficacy.[1] Unfortunately, a side effect of PUVA treatment is a higher risk of skin cancer.[2]
An important use of psoralen is in PUVA treatment for skin problems such as psoriasis and (to a lesser extent) eczema and vitiligo. This takes advantage of the high UV absorbance of psoralen. The psoralen is applied first to sensitise the skin, then UVA light is applied to clean up the skin problem. Psoralen has also been recommended for treating alopecia.[citation needed] Psoralens are also used in photopheresis, where they are mixed with the extracted leukocytes before UV radiation is applied.
Despite the photocarcinogenic properties of psoralen,[3][4] It had been used as a tanning activator in sunscreens until 1996.[5]
Psoralens are used in tanning accelerators, but users should keep in mind that psoralen increases the skin’s sensitivity to light.
Some patients have had severe skin loss after sunbathing with psoralen-containing tanning activators.[6]
Patients with lighter skin colour suffer four times as much from the melanoma-generating properties of psoralens than those with darker skin[5]
The synthetic amino-psoralen, amotosalen HCl, has been developed for the inactivation of infectious pathogens (bacteria, viruses, protozoa) in platelet and plasma blood components prepared for transfusion support of patients. The technology is currently in routine use in certain European blood centers.[7][8]
# Chemistry
One isomer of psoralen is angelicin, and most furocoumarins can be regarded as derivatives of psoralen or angelicin. Some important psoralen derivatives are Imperatorin, xanthotoxin, bergapten and nodekenetin.
Another important feature of this class of compounds is their ability to generate singlet oxygen.
## Structure
The structure of psoralen was originally deduced by identifying the products of its degradation reactions. It exhibits the normal reactions of the lactone of coumarin, such as ring opening by alkali to give a coumarinic acid or coumaric acid derivative. Potassium permanganate causes oxidation of the furan ring, while other methods of oxidation produce furan-2,3-carboxylic acid.
## Synthesis
Psoralen synthesis is difficult, due the fact that umbelliferone undergoes substitution at the 8-position rather than at the desired 6 position. Benzofuran reacts preferentially in the furan ring rather than in the benzene ring. However, the 7-hydroxy derivative of 2,3-dihydrobenzofuran (also called coumaran) does undergo substitution at the desired 6-position allowing the following synthesis of the coumarin system via a Gattermann-Koch reaction followed by a Perkin condensation using acetic anhydride. The synthesis is then completed by dehydrogenation of the five-membered ring to produce the furan ring.
# Biosynthesis
Psoralen originates from coumarins in the shikimate pathway; its biosynthesis is shown in the figure below. The aromatic ring in 6 is activated at positions ortho to the hydroxyl group, and is alkylated by 5, an alkylating agent. The dimethylallyl group in 7 then undergoes cyclization with the phenol group to give 8. This transformation is catalysed by a cytochome P-450-dependent monooxygenase17 (psoralen 5-monooxygenase), and cofactors (NADPH) and molecular oxygen.[9]
A biosynthetic pathway in which psoralen is formed is shown in the figure below. A second P-450-dependent monooxygenase enzyme (psoralen synthase) then cleaves off 10 (in the form of 11) from 8 to give 1. This pathway does not involve any hydroxylated intermediate, and cleavage is postulated to be initiated by a radical reaction.[9]
# Plant sources
Ficus carica (fig) is probably the most abundant source of psoralens. They are also found in small quantities in Ammi visnaga (bisnaga), Pastinaca sativa (parsnip), Petroselinum crispum (parsley), Levisticum officinale (lovage), Foeniculum vulgare (fruit, i.e., fennel seeds), Daucus carota (carrot), Psoralea corylifolia (babchi), and Apium graveolens (celery).[10] | https://www.wikidoc.org/index.php/Psoralen | |
d8fe12ea9182b9ae4c6c8c85e63f02c0978b5848 | wikidoc | Pulpitis | Pulpitis
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.
Pulpitis is an inflammation of the dental pulp.
# Causes of Pulpitis
- Caries that penetrate though the tooth enamel, the dentin, and into the pulp
- Repeated dental procedures or tooth trauma
Regardless of the cause of pulpitis the inflammation can be associated with a bacterial infection. As in the case of a carie that penetrates the pulp cavity the tooth is no longer sealed to infectious pathogens, where as when the blood supply is cut off to the pulp, bacteria have an opportunity to over take the pulp.
When the pulp becomes inflamed pressure begins to build up in the pulp cavity exerting pressure on the nerve of the tooth and the surrounding tissues. Pressure from inflammation can cause mild to extreme pain, depending upon the severity of the inflammation. Often, pulpitis can create so much pressure on the tooth nerve the individual will have trouble locating the source of the pain, confusing it with neighbouring teeth. Inflammation in the tooth provides a difficult environment for reducing the inflammation in the pulp cavity. Unlike other parts of the body where pressure can dissipate through the surrounding soft tissues and where lymph can reach, the pulp cavity is very different. The dentin surrounding the pulp is hard and does not give under the pressure of the inflammation so the pressure has very little chance of dissipating before pulp necrosis occurs. The pulp cavity inherently provides the body with an immune system response challenge, which makes it very unlikely that the bacterial infection can be eliminated. The pain will usually stop once the pulp has died, however the infection can spread to the ancillary anatomy.
# Differential Diagnosis of Pulpitis
# Treatment
Once the pulp has become inflamed the tooth can be diagnostically divided into two categories.
- reversible pulpitis
- irreversible pulpitis
## Reversible pulpitis
Once the irritant is removed the pulp remains vital and is not unduely affected by the changes.
## Irreversible pulpitis
The pulp is irreversibly damaged and necrosis will follow. Pain may not subside after removal of the irritant. Pain may be sharp or dull and throbbing. If there is any drainage then severity of pain is reduced
The tooth may be endodontically treated where by the pulp is removed and replaced by gutta percha. An alternative is extraction of the tooth. This may be required if there is insufficient coronal tissue remaining for restoration once root canal therapy has been completed.
zh-min-nan:Khí-chhoé-iām
de:Pulpitis
it:Pulpite
lt:Pulpitas
nl:Kiespijn | Pulpitis
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.
Pulpitis is an inflammation of the dental pulp.
# Causes of Pulpitis
- Caries that penetrate though the tooth enamel, the dentin, and into the pulp
- Repeated dental procedures or tooth trauma
Regardless of the cause of pulpitis the inflammation can be associated with a bacterial infection. As in the case of a carie that penetrates the pulp cavity the tooth is no longer sealed to infectious pathogens, where as when the blood supply is cut off to the pulp, bacteria have an opportunity to over take the pulp.
When the pulp becomes inflamed pressure begins to build up in the pulp cavity exerting pressure on the nerve of the tooth and the surrounding tissues. Pressure from inflammation can cause mild to extreme pain, depending upon the severity of the inflammation. Often, pulpitis can create so much pressure on the tooth nerve the individual will have trouble locating the source of the pain, confusing it with neighbouring teeth. Inflammation in the tooth provides a difficult environment for reducing the inflammation in the pulp cavity. Unlike other parts of the body where pressure can dissipate through the surrounding soft tissues and where lymph can reach, the pulp cavity is very different. The dentin surrounding the pulp is hard and does not give under the pressure of the inflammation so the pressure has very little chance of dissipating before pulp necrosis occurs. The pulp cavity inherently provides the body with an immune system response challenge, which makes it very unlikely that the bacterial infection can be eliminated. The pain will usually stop once the pulp has died, however the infection can spread to the ancillary anatomy.
# Differential Diagnosis of Pulpitis
# Treatment
Once the pulp has become inflamed the tooth can be diagnostically divided into two categories.
- reversible pulpitis
- irreversible pulpitis
## Reversible pulpitis
Once the irritant is removed the pulp remains vital and is not unduely affected by the changes.
## Irreversible pulpitis
The pulp is irreversibly damaged and necrosis will follow. Pain may not subside after removal of the irritant. Pain may be sharp or dull and throbbing. If there is any drainage then severity of pain is reduced
The tooth may be endodontically treated where by the pulp is removed and replaced by gutta percha. An alternative is extraction of the tooth. This may be required if there is insufficient coronal tissue remaining for restoration once root canal therapy has been completed.
Template:Oral pathology
zh-min-nan:Khí-chhoé-iām
de:Pulpitis
it:Pulpite
lt:Pulpitas
nl:Kiespijn
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Pulpitis | |
ecdee7a1e22aedfd2e9d414a36e5e29b1825f66f | wikidoc | Pungency | Pungency
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
Pungency is a sharp and biting sensory impression. Regarding chili peppers, it refers to a scientific equivalent of the Scoville scale of measuring spicyness.
# Mechanism
The pungent feeling caused by capsaicin, piperine, and allicin is caused by activation of the heat and acidity sensing TRPC ion channel TRPC1 on nociceptors (pain sensing nerve cells). | Pungency
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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# Overview
Pungency is a sharp and biting sensory impression. Regarding chili peppers, it refers to a scientific equivalent of the Scoville scale of measuring spicyness.
# Mechanism
The pungent feeling caused by capsaicin, piperine, and allicin is caused by activation of the heat and acidity sensing TRPC ion channel TRPC1 on nociceptors (pain sensing nerve cells). | https://www.wikidoc.org/index.php/Pungency | |
112126b5621719cc51334172ecf0b4d416650e3c | wikidoc | Q-Q plot | Q-Q plot
In statistics, a Q-Q plot ("Q" stands for quantile) is a graphical method for diagnosing differences, between the probability distribution of a statistical population from which a random sample has been taken and a comparison distribution. An example of the kind of differences that can be tested for is non-normality of the population distribution.
For a sample of size n, one plots n points, with the (n+1)-quantiles of the comparison distribution (e.g. the normal distribution) on the horizontal axis (for k = 1, ..., n), and the order statistics of the sample on the vertical axis. If the population distribution is the same as the comparison distribution this approximates a straight line, especially near the center. In the case of substantial deviations from linearity, the statistician rejects the null hypothesis of sameness.
# Plotting positions
For the quantiles of the comparison distribution typically the formula k/(n + 1) is used.
Several different formulas have been used or proposed as symmetrical plotting positions. Such formulas have the form (k − a)/(n + 1 − 2a) for some value of a in the range from 0 to 1/2. The above expression k/(n + 1) is one example of these, for a = 0. Other expressions include:
- (k − 1/3)/(n + 1/3)
- (k − 0.3175)/(n + 0.365)
- (k − 0.326)/(n + 0.348)
- (k − 0.375)/(n + 0.25)
- (k − 0.44)/(n + 0.12)
For large sample size, n, there is little difference between these various expressions.
# Relation with rankit plots
Q-Q plots are similar to rankit plots, also called normal probability plots. The difference is that in normal probability plots, instead of using the quantile of the normal distribution as the x-axis, one uses the expected value of the kth order statistic from a normal distribution with expectation 0 and variance 1. Only when n is small is there a substantial difference between a Q-Q plot and a normal probability plot. | Q-Q plot
In statistics, a Q-Q plot ("Q" stands for quantile) is a graphical method for diagnosing differences, between the probability distribution of a statistical population from which a random sample has been taken and a comparison distribution. An example of the kind of differences that can be tested for is non-normality of the population distribution.
For a sample of size n, one plots n points, with the (n+1)-quantiles of the comparison distribution (e.g. the normal distribution) on the horizontal axis (for k = 1, ..., n), and the order statistics of the sample on the vertical axis. If the population distribution is the same as the comparison distribution this approximates a straight line, especially near the center. In the case of substantial deviations from linearity, the statistician rejects the null hypothesis of sameness.
# Plotting positions
For the quantiles of the comparison distribution typically the formula k/(n + 1) is used.
Several different formulas have been used or proposed as symmetrical plotting positions. Such formulas have the form (k − a)/(n + 1 − 2a) for some value of a in the range from 0 to 1/2. The above expression k/(n + 1) is one example of these, for a = 0. Other expressions include:
- (k − 1/3)/(n + 1/3) [1]
- (k − 0.3175)/(n + 0.365) [2]
- (k − 0.326)/(n + 0.348) [3]
- (k − 0.375)/(n + 0.25)[4]
- (k − 0.44)/(n + 0.12)[5]
For large sample size, n, there is little difference between these various expressions.
# Relation with rankit plots
Q-Q plots are similar to rankit plots, also called normal probability plots. The difference is that in normal probability plots, instead of using the quantile of the normal distribution as the x-axis, one uses the expected value of the kth order statistic from a normal distribution with expectation 0 and variance 1. Only when n is small is there a substantial difference between a Q-Q plot and a normal probability plot. | https://www.wikidoc.org/index.php/Q-Q_plot | |
8f6d6f05372fe5ea33bbe929f726f2c700af00c2 | wikidoc | QH-II-66 | QH-II-66
QH-II-66 (QH-ii-066) is a sedative drug which is a benzodiazepine derivative. It produces some of the same effects as other benzodiazepines, but is much more selective than most other drugs of this class and so produces somewhat less sedation and ataxia than other related drugs such as diazepam and triazolam, although it still retains anticonvulsant effects.
QH-ii-066 is a highly subtype-selective GABAA agonist which was designed to bind selectively to the α5 subtype of GABAA receptors.
The α5 subtype (and to a lesser extent the α1 subtype) of GABAA are two of the most important targets in the brain that produce the effects of alcohol, and so one of the purposes for which QH-ii-066 was developed was to reproduce the GABAergic effects of alcohol separately from its other actions.
QH-ii-066 replicates some of the effects of alcohol, such as sedation and ataxia, but does not increase appetite, as this effect seems to be produced by the α1 subtype of GABAA rather than α5. It is also interesting to note that the inverse agonist Ro15-4513, which blocks the α4 subtype of GABAA, reverses the effects of alcohol, suggesting that this subtype is also important in producing the subjective effects of alcohol intoxication. | QH-II-66
QH-II-66 (QH-ii-066) is a sedative drug which is a benzodiazepine derivative.[1] It produces some of the same effects as other benzodiazepines, but is much more selective than most other drugs of this class and so produces somewhat less sedation and ataxia than other related drugs such as diazepam and triazolam, although it still retains anticonvulsant effects.[2]
QH-ii-066 is a highly subtype-selective GABAA agonist which was designed to bind selectively to the α5 subtype of GABAA receptors.[3]
The α5 subtype (and to a lesser extent the α1 subtype) of GABAA are two of the most important targets in the brain that produce the effects of alcohol,[4] and so one of the purposes for which QH-ii-066 was developed was to reproduce the GABAergic effects of alcohol separately from its other actions.[5]
QH-ii-066 replicates some of the effects of alcohol, such as sedation and ataxia, but does not increase appetite, as this effect seems to be produced by the α1 subtype of GABAA rather than α5.[6] It is also interesting to note that the inverse agonist Ro15-4513, which blocks the α4 subtype of GABAA, reverses the effects of alcohol, suggesting that this subtype is also important in producing the subjective effects of alcohol intoxication.[7] | https://www.wikidoc.org/index.php/QH-II-66 | |
231ac6b204f57baf091fa6477ebd9e4c330ced8b | wikidoc | Quackery | Quackery
Quackery is a derogatory term used to describe questionable medical practices. According to Random House Dictionary, a "quack" is considered a "fraudulent or ignorant pretender to medical skill" or "a person who pretends, professionally or publicly, to have skill, knowledge, or qualifications he or she does not possess; a charlatan." It is defined as the "medical practice and advice based on observation and experience in ignorance of scientific findings. The dishonesty of a charlatan."
The word "quack" derives from "quacksalver," an archaic word originally of Dutch origin (spelled kwakzalver in contemporary Dutch), meaning "boaster who applies a salve." The correct meaning of the German word "quacksalber" is "questionable salesperson (literal translation: quack salver)." In the Middle Ages the word quack itself meant "shouting". The quacksalvers sold their wares on the market shouting in a loud voice."
"Health fraud" is often used as a synonym for quackery, but this use can be problematic, since quackery can exist without fraud, a word which always implies deliberate deception.
# The quacksalver
Unproven, usually ineffective, and sometimes dangerous medicines and treatments have been peddled throughout human history. Theatrical performances were sometimes mixed with purported medicine to enhance credibility.
Quack medicines often had no effective ingredients, while others, such as morphine and the like, made the patient feel better without curative properties. Some did have medicinal effects; for example mercury, silver and arsenic compounds may have helped some infections, willow bark contained salicylic acid (aspirin), quinine from bark was an effective treatment for malaria. Knowledge of appropriate use and dosage was poor.
# History of quackery in the United States
With little understanding of the causes and mechanisms of illnesses, widely marketed "cures" (as opposed to locally produced and locally used remedies), often referred to as patent medicines, first came to prominence during the 17th and 18th centuries in Britain and the British colonies, including those in North America. Daffy's Elixir and Turlington's Balsam were among the first products to make use of branding (for example, by the use of highly distinctive containers) and mass marketing, in order to create and maintain markets. A similar process occurred in other countries of Europe around the same time, for example with the marketing of Eau de Cologne as a cure-all medicine by Johann Maria Farina and his imitators.
The later years of the 18th century saw an increase in the number of internationally marketed quack medicines, the majority of which were British in origin, and which were exported throughout the British Empire as well as the (by then independent) United States. So popularly successful were these treatments that by 1830 British parliamentary records list over 1,300 different "proprietary medicines", the majority of which can be described as "quack" cures today.
British patent medicines started to lose their dominance in the United States when they were denied access to the American market during the American Revolution, and lost further ground for the same reason during the War of 1812. From the early 19th century "home-grown" American brands started to fill the gap, reaching their peak in the years after the American Civil War. British medicines never regained their previous dominance in North America, and the subsequent era of mass marketing of American patent medicines is usually considered to have been a "golden age" of quackery in the United States. This was mirrored by similar growth in marketing of quack medicines elsewhere in the world.
In the United States, false medicines in this era were often denoted by the slang term snake oil, a reference to sales pitches for the false medicines which used claims that their exotic ingredients were responsible for the supposed results or benefits. Those who sold them were called "snake oil peddlers", and usually sold their medicines with a fervent pitch similar to a fire and brimstone religious sermon. They often accompanied other theatrical and entertainment productions that travelled as a road show from town to town, leaving quickly before the falseness of their medicine could be discovered. Not all quacks were restricted to such small-time businesses however, and a number, especially in the United States, became enormously wealthy through national and international sales of their products.
One among many examples is that of William Radam, a German immigrant to the USA who, in the 1880s, started to sell his "Microbe Killer" throughout the United States and, soon afterwards, in Britain and throughout the British colonies. His concoction was widely advertised as being able to "Cure All Diseases" (W. Radam, 1890) and this phrase was even embossed on the glass bottles the medicine was sold in. In fact, Radam's medicine was a therapeutically useless (and in large quantities actively poisonous) dilute solution of sulphuric acid, coloured with a little red wine. Radam's publicity material, particularly his books (see for example Radam, 1890), provide an insight into the role that pseudo-science played in the development and marketing of "quack" medicines towards the end of the 19th century.
Similar advertising claims to those of Radam can be found throughout the 18th, 19th and 20th centuries. "Dr." Sibley, an English patent medicine seller of the late 18th and early 19th centuries, even went so far as to claim that his Reanimating Solar Tincture would, as the name implies, "restore life in the event of sudden death". Another English quack, "Dr. Solomon" claimed that his Cordial Balm of Gilead cured almost anything, but was particularly effective against all venereal complaints, from gonorrhoea to onanism. Although it was basically just brandy flavoured with herbs, it retailed widely at 33 shillings a bottle in the period of the Napoleonic wars, the equivalent of over $100 per bottle today.
Not all patent medicines were without merit. Turlingtons Balsam of Life, first marketed in the mid-18th century, did have genuinely beneficial properties. This medicine continued to be sold under the original name into the early 20th century, and can still be found in the British and American Pharmacopoeias as "Compound tincture of benzoin". It can be argued that for some of these medicines this is an example of the infinite monkey theorem in action.
The end of the road for the quack medicines now considered grossly fraudulent in the nations of North America and Europe came in the early 20th century. February 21, 1906 saw the passage into law of the Pure Food and Drug Act in the United States. This was the result of decades of campaigning by both government departments and the medical establishment, supported by a number of publishers and journalists (one of the most effective of whom was Samuel Hopkins Adams, whose series "The Great American Fraud" was published in Colliers Weekly starting in late 1905). This American Act was followed three years later by similar legislation in Britain, and in other European nations. Between them, these laws began to remove the more outrageously dangerous contents from patent and proprietary medicines, and to force quack medicine proprietors to stop making some of their more blatantly dishonest claims.
# Quackery in contemporary culture
Considered by many an archaic term, quackery is most often used to denote the peddling of the "cure-alls" described above. Quackery continues even today; it can be found in any culture and in every medical tradition. Unlike other advertising mediums, rapid advancements in communication through the Internet have opened doors for an unregulated market of quack cures and marketing campaigns rivaling the early 1900s. Most people with an e-mail account have experienced the marketing tactics of spamming — touting the newest current trend for miraculous remedies for "weight-loss" and "sexual enhancement," as well as outlets for unprescribed medicines of unknown quality.
For those in the practice of any medicine, to allege quackery is to level a serious objection to a particular form of practice. Most developed countries have a governmental agency, such as the Food and Drug Administration (FDA) in the US, whose purpose is to monitor and regulate the safety of medications as well as the claims made by the manufacturers of these new and existing products, including drugs and nutritional supplements or vitamins. To better address less regulated products, in 2000, US President Clinton signed Executive Order 13147 that created the White House Commission on Complementary and Alternative Medicine. In 2002, the commission's final report made several suggestions regarding education, research, implementation, and reimbursement as ways to evaluate the risks and benefits of each. As a direct result, more public dollars have been allocated for research into some of these methods. According to Norcross et al (2006) several authors have attempted to identify quack psychotherapies; (e.g., Carroll, 2003; Della Sala, 1999; Eisner, 2000; Lilienfeld, Lynn, & Rohr 2003; Singer and Lalich 1996). The evidence based practice (EBP) movement in mental health emphasises the consensus in psychology that psychological practice should rely on empirical research. There are also "anti-quackery" web sites that consumers can access to help evaluate particular claims as well.
# Reasons quackery persists
There are several reasons quackery continues to be a part of healthcare:
- Ignorance: An uneducated consumer is more likely to fall victim to implausible treatments.
- The placebo effect: Medicines or treatments known to have no effect on a disease can still affect a people's perception of their illness. People report reduced pain, increased well-being, improvement, or even total alleviation of symptoms. Both the practitioner and consumer can draw the wrong conclusion that the treatment was effective.
- The regression fallacy: Certain "self-limiting conditions", such as warts and the common cold, almost always improve, in the latter case in a rather predictable amount of time. A patient may associate the usage of treatments with recovering, when recovery was inevitable.
- Post hoc ergo propter hoc fallacy: One recovers after taking a specific medicine or treatment, and therefore it is assumed the recovery is caused by the medicine or treatment. In reality, however, it is not necessarily caused by the specific medicine or treatment.
- Distrust of conventional medicine: Many people have a distrust of conventional medicines, government regulatory organizations, or major drug corporations.
- Fear: The perception that a great variety of pharmaceutical medications and medicinal herbs can have very distressing side effects, and many people fear surgery and its consequences, so they may opt to shy away from these treatments.
- Price: There are some people who simply cannot afford conventional treatment, and seek out a cheaper alternative.
- Desperation: People with a serious or terminal disease, or who have been told by their practitioner that their condition is "untreatable," may react by seeking out treatment, disregarding the lack of scientific proof for its effectiveness, or even the existence of evidence that the method is ineffective or even dangerous.
- Pride: Once a person has endorsed or defended a cure, or invested time and money in it, they may be reluctant to admit its ineffectiveness, and therefore recommend the cure that did not work for them to others.
- Fraud: Manufacturers, fully aware of the ineffectiveness of their medicine, may intentionally produce fraudulent scientific studies and medical test results, thereby confusing practitioners and consumers as to the effectiveness of the medical treatment.
- Anti-elitism: Quacks often portray themselves as members of the "common people" who care about those in need. The medical establishment is cast as an insular elite that cares more about financial gain than healing the sick. In this case the quack's lack of medical certification is a valuable asset.
# Notable historical persons accused of quackery
- Albert Abrams (1863–1924) was a quack and a fraud, posing as a doctor in San Francisco, whose tool for gaining profit from the gullible was a variety of "electricity therapy" he called ERA, or Electronic Reactions of Abrams.
- John R. Brinkley (1885–1942), (later John Richard Brinkley), was both a controversial medical doctor who experimented with goat glands as a means of curing male impotence and a radio pioneer who created the age of Mexican border blasters.
- Ruth Drown (1891–1965) built a radionic device constituted of several adjustable resistors connected in series. An extremity was connected to ground, the other extremity was connected to a metallic plate having on it a specimen of the patient.
- Samuel Hahnemann (1755–1843), founder of homeopathy. Hahnemann believed that all diseases were caused by psora (itch), and that illnesses could be treated by extreme dilutions of substances that — in a healthy person — produced similar symptoms to the illness suffered.
- Harry Hoxsey (1901–1974), founder of Hoxsey Therapy, was a vaudevillian with no medical or scientific education who marketed a mixture of herbs as a purported cure for cancer in the 1920's.
- L. Ron Hubbard (1911–1986), was the founder of the Church of Scientology. He was an American science fiction writer, former United States Navy officer and creator of Dianetics.
- John Harvey Kellogg (1852–1943) was an American medical doctor in Battle Creek, Michigan who ran a sanitarium using holistic methods, with a particular focus on nutrition, enemas and exercise. Kellogg was an advocate of vegetarianism, and is best known for the invention of the corn flake breakfast cereal with his brother, Will Keith Kellogg.
- Franz Anton Mesmer (1734–1815) discovered what he called magnétisme animal (animal magnetism) and others often called mesmerism. The evolution of Mesmer's ideas and practices led James Braid (1795–1860) to develop hypnosis in 1842.
- Daniel David Palmer (1845–1913), also known as DD Palmer, was the founder of Chiropractic. He was a spiritualist and practitioner of magnetic healing beginning in the mid-1880s in Burlington and Davenport, Iowa.
- Louis Pasteur (1822 – 1895) was a French chemist best known for his remarkable breakthroughs in microbiology. His experiments confirmed the germ theory of disease, also reducing mortality from puerperal fever (childbed), and he created the first vaccine for rabies. He is best known to the general public for showing how to stop milk and wine from going sour - this process came to be called pasteurization. He is regarded as one of the three main founders of microbiology, together with Ferdinand Cohn and Robert Koch. His hypotheses initially met with much hostility, and he was accused of quackery on multiple occasions.
- Ignaz Semmelweis (1818 - 1865), was an Austrian-Hungarian who discovered that the incidence of puerperal fever could be drastically cut by use of hand washing standards in obstetrical clinics. His unconventional ideas and methods led to him being banned from some hospitals. Puerperal fever (or childbed fever) was common in mid-19th-century hospitals and often fatal, with mortality at 10%-35%.
- Dr. C. J. Thacher was a practitioner of magnet therapy. In the 1920s his "Chicago Magnetic Company" promised "health without the use of medicine." He was dubbed the "King of the magnetic quacks" by Collier's Magazine.
- Royal Rife Invented the "Rife machine", a machine produces Radio waves at a frequency of 10-100mhz, and claimed that it was able to cure cancer.
# Quackery in popular media
- In Metal Gear Solid 3, Para-medic's nickname is Quack, which Snake finds out after Asking Para-Medic about her reputation.
- In one episode of Scrubs, the Janitor doctors a picture of Dr. Cox to show him with a duck's bill, "because you're a 'quack.'"
- The 1977 Walt Disney film Pete's Dragon features a quack doctor named Dr. Terminus (Jim Dale) as its main villain. He brings his traveling medicine show to town and tries to capture Elliott the dragon and use his parts to sell phony medicines.
- Dr. Nick Riviera on The Simpsons is a quack physician. He claims to be as good as Dr. Hibbert, however, is obviously not. This is represented when he tries to perform a Bypass surgery on Homer and does not know where to make the incision, among other things. | Quackery
Quackery is a derogatory term used to describe questionable medical practices. According to Random House Dictionary, a "quack" is considered a "fraudulent or ignorant pretender to medical skill" or "a person who pretends, professionally or publicly, to have skill, knowledge, or qualifications he or she does not possess; a charlatan."[1] It is defined as the "medical practice and advice based on observation and experience in ignorance of scientific findings. The dishonesty of a charlatan."[2]
The word "quack" derives from "quacksalver," an archaic word originally of Dutch origin (spelled kwakzalver in contemporary Dutch), meaning "boaster who applies a salve."[3] The correct meaning of the German word "quacksalber" is "questionable salesperson (literal translation: quack salver)." In the Middle Ages the word quack itself meant "shouting". The quacksalvers sold their wares on the market shouting in a loud voice."[4]
"Health fraud" is often used as a synonym for quackery, but this use can be problematic, since quackery can exist without fraud, a word which always implies deliberate deception.[5]
# The quacksalver
Unproven, usually ineffective, and sometimes dangerous medicines and treatments have been peddled throughout human history. Theatrical performances were sometimes mixed with purported medicine to enhance credibility.
Quack medicines often had no effective ingredients, while others, such as morphine and the like, made the patient feel better without curative properties. Some did have medicinal effects; for example mercury, silver and arsenic compounds may have helped some infections, willow bark contained salicylic acid (aspirin), quinine from bark was an effective treatment for malaria. Knowledge of appropriate use and dosage was poor.
# History of quackery in the United States
With little understanding of the causes and mechanisms of illnesses, widely marketed "cures" (as opposed to locally produced and locally used remedies), often referred to as patent medicines, first came to prominence during the 17th and 18th centuries in Britain and the British colonies, including those in North America. Daffy's Elixir and Turlington's Balsam were among the first products to make use of branding (for example, by the use of highly distinctive containers) and mass marketing, in order to create and maintain markets.[6] A similar process occurred in other countries of Europe around the same time, for example with the marketing of Eau de Cologne as a cure-all medicine by Johann Maria Farina and his imitators.
The later years of the 18th century saw an increase in the number of internationally marketed quack medicines, the majority of which were British in origin,[7] and which were exported throughout the British Empire as well as the (by then independent) United States. So popularly successful were these treatments that by 1830 British parliamentary records list over 1,300 different "proprietary medicines",[8] the majority of which can be described as "quack" cures today.
British patent medicines started to lose their dominance in the United States when they were denied access to the American market during the American Revolution, and lost further ground for the same reason during the War of 1812. From the early 19th century "home-grown" American brands started to fill the gap, reaching their peak in the years after the American Civil War.[7][9] British medicines never regained their previous dominance in North America, and the subsequent era of mass marketing of American patent medicines is usually considered to have been a "golden age" of quackery in the United States. This was mirrored by similar growth in marketing of quack medicines elsewhere in the world.
In the United States, false medicines in this era were often denoted by the slang term snake oil, a reference to sales pitches for the false medicines which used claims that their exotic ingredients were responsible for the supposed results or benefits. Those who sold them were called "snake oil peddlers", and usually sold their medicines with a fervent pitch similar to a fire and brimstone religious sermon. They often accompanied other theatrical and entertainment productions that travelled as a road show from town to town, leaving quickly before the falseness of their medicine could be discovered. Not all quacks were restricted to such small-time businesses however, and a number, especially in the United States, became enormously wealthy through national and international sales of their products.
One among many examples is that of William Radam, a German immigrant to the USA who, in the 1880s, started to sell his "Microbe Killer" throughout the United States and, soon afterwards, in Britain and throughout the British colonies. His concoction was widely advertised as being able to "Cure All Diseases" (W. Radam, 1890) and this phrase was even embossed on the glass bottles the medicine was sold in. In fact, Radam's medicine was a therapeutically useless (and in large quantities actively poisonous) dilute solution of sulphuric acid, coloured with a little red wine.[9] Radam's publicity material, particularly his books (see for example Radam, 1890), provide an insight into the role that pseudo-science played in the development and marketing of "quack" medicines towards the end of the 19th century.
Similar advertising claims to those of Radam can be found throughout the 18th, 19th and 20th centuries. "Dr." Sibley, an English patent medicine seller of the late 18th and early 19th centuries, even went so far as to claim that his Reanimating Solar Tincture would, as the name implies, "restore life in the event of sudden death". Another English quack, "Dr. Solomon" claimed that his Cordial Balm of Gilead cured almost anything, but was particularly effective against all venereal complaints, from gonorrhoea to onanism. Although it was basically just brandy flavoured with herbs, it retailed widely at 33 shillings a bottle in the period of the Napoleonic wars, the equivalent of over $100 per bottle today.
Not all patent medicines were without merit. Turlingtons Balsam of Life, first marketed in the mid-18th century, did have genuinely beneficial properties. This medicine continued to be sold under the original name into the early 20th century, and can still be found in the British and American Pharmacopoeias as "Compound tincture of benzoin". It can be argued that for some of these medicines this is an example of the infinite monkey theorem in action.
The end of the road for the quack medicines now considered grossly fraudulent in the nations of North America and Europe came in the early 20th century. February 21, 1906 saw the passage into law of the Pure Food and Drug Act in the United States. This was the result of decades of campaigning by both government departments and the medical establishment, supported by a number of publishers and journalists (one of the most effective of whom was Samuel Hopkins Adams, whose series "The Great American Fraud" was published in Colliers Weekly starting in late 1905). This American Act was followed three years later by similar legislation in Britain, and in other European nations. Between them, these laws began to remove the more outrageously dangerous contents from patent and proprietary medicines, and to force quack medicine proprietors to stop making some of their more blatantly dishonest claims.
# Quackery in contemporary culture
Considered by many an archaic term, quackery is most often used to denote the peddling of the "cure-alls" described above. Quackery continues even today; it can be found in any culture and in every medical tradition. Unlike other advertising mediums, rapid advancements in communication through the Internet have opened doors for an unregulated market of quack cures and marketing campaigns rivaling the early 1900s. Most people with an e-mail account have experienced the marketing tactics of spamming — touting the newest current trend for miraculous remedies for "weight-loss" and "sexual enhancement," as well as outlets for unprescribed medicines of unknown quality.
For those in the practice of any medicine, to allege quackery is to level a serious objection to a particular form of practice. Most developed countries have a governmental agency, such as the Food and Drug Administration (FDA) in the US, whose purpose is to monitor and regulate the safety of medications as well as the claims made by the manufacturers of these new and existing products, including drugs and nutritional supplements or vitamins. To better address less regulated products, in 2000, US President Clinton signed Executive Order 13147 that created the White House Commission on Complementary and Alternative Medicine. In 2002, the commission's final report made several suggestions regarding education, research, implementation, and reimbursement as ways to evaluate the risks and benefits of each. As a direct result, more public dollars have been allocated for research into some of these methods. According to Norcross et al (2006) several authors have attempted to identify quack psychotherapies; (e.g., Carroll, 2003; Della Sala, 1999; Eisner, 2000; Lilienfeld, Lynn, & Rohr 2003; Singer and Lalich 1996). The evidence based practice (EBP) movement in mental health emphasises the consensus in psychology that psychological practice should rely on empirical research. There are also "anti-quackery" web sites that consumers can access to help evaluate particular claims as well.
# Reasons quackery persists
There are several reasons quackery continues to be a part of healthcare:
- Ignorance: An uneducated consumer is more likely to fall victim to implausible treatments.
- The placebo effect: Medicines or treatments known to have no effect on a disease can still affect a people's perception of their illness. People report reduced pain, increased well-being, improvement, or even total alleviation of symptoms. Both the practitioner and consumer can draw the wrong conclusion that the treatment was effective.
- The regression fallacy: Certain "self-limiting conditions", such as warts and the common cold, almost always improve, in the latter case in a rather predictable amount of time. A patient may associate the usage of treatments with recovering, when recovery was inevitable.
- Post hoc ergo propter hoc fallacy: One recovers after taking a specific medicine or treatment, and therefore it is assumed the recovery is caused by the medicine or treatment. In reality, however, it is not necessarily caused by the specific medicine or treatment.
- Distrust of conventional medicine: Many people have a distrust of conventional medicines, government regulatory organizations, or major drug corporations.
- Fear: The perception that a great variety of pharmaceutical medications and medicinal herbs can have very distressing side effects, and many people fear surgery and its consequences, so they may opt to shy away from these treatments.
- Price: There are some people who simply cannot afford conventional treatment, and seek out a cheaper alternative.
- Desperation: People with a serious or terminal disease, or who have been told by their practitioner that their condition is "untreatable," may react by seeking out treatment, disregarding the lack of scientific proof for its effectiveness, or even the existence of evidence that the method is ineffective or even dangerous.
- Pride: Once a person has endorsed or defended a cure, or invested time and money in it, they may be reluctant to admit its ineffectiveness, and therefore recommend the cure that did not work for them to others.
- Fraud: Manufacturers, fully aware of the ineffectiveness of their medicine, may intentionally produce fraudulent scientific studies and medical test results, thereby confusing practitioners and consumers as to the effectiveness of the medical treatment.
- Anti-elitism: Quacks often portray themselves as members of the "common people" who care about those in need. The medical establishment is cast as an insular elite that cares more about financial gain than healing the sick. In this case the quack's lack of medical certification is a valuable asset.
# Notable historical persons accused of quackery
- Albert Abrams (1863–1924) was a quack and a fraud, posing as a doctor in San Francisco, whose tool for gaining profit from the gullible was a variety of "electricity therapy" he called ERA, or Electronic Reactions of Abrams.[10]
- John R. Brinkley (1885–1942), (later John Richard Brinkley), was both a controversial medical doctor who experimented with goat glands as a means of curing male impotence and a radio pioneer who created the age of Mexican border blasters.[11]
- Ruth Drown (1891–1965) built a radionic device constituted of several adjustable resistors connected in series. An extremity was connected to ground, the other extremity was connected to a metallic plate having on it a specimen of the patient.[12][13]
- Samuel Hahnemann (1755–1843), founder of homeopathy. Hahnemann believed that all diseases were caused by psora (itch), and that illnesses could be treated by extreme dilutions of substances that — in a healthy person — produced similar symptoms to the illness suffered.[14][15]
- Harry Hoxsey (1901–1974), founder of Hoxsey Therapy, was a vaudevillian with no medical or scientific education who marketed a mixture of herbs as a purported cure for cancer in the 1920's.[16]
- L. Ron Hubbard (1911–1986), was the founder of the Church of Scientology. He was an American science fiction writer, former United States Navy officer and creator of Dianetics.[17][18][19]
- John Harvey Kellogg (1852–1943) was an American medical doctor in Battle Creek, Michigan who ran a sanitarium using holistic methods, with a particular focus on nutrition, enemas and exercise. Kellogg was an advocate of vegetarianism, and is best known for the invention of the corn flake breakfast cereal with his brother, Will Keith Kellogg.[20]
- Franz Anton Mesmer (1734–1815) discovered what he called magnétisme animal (animal magnetism) and others often called mesmerism. The evolution of Mesmer's ideas and practices led James Braid (1795–1860) to develop hypnosis in 1842.[21][22][23]
- Daniel David Palmer (1845–1913), also known as DD Palmer, was the founder of Chiropractic. He was a spiritualist and practitioner of magnetic healing beginning in the mid-1880s in Burlington and Davenport, Iowa.[24][25]
- Louis Pasteur (1822 – 1895) was a French chemist best known for his remarkable breakthroughs in microbiology. His experiments confirmed the germ theory of disease, also reducing mortality from puerperal fever (childbed), and he created the first vaccine for rabies. He is best known to the general public for showing how to stop milk and wine from going sour - this process came to be called pasteurization. He is regarded as one of the three main founders of microbiology, together with Ferdinand Cohn and Robert Koch. His hypotheses initially met with much hostility, and he was accused of quackery on multiple occasions.[26][27]
- Ignaz Semmelweis (1818 - 1865), was an Austrian-Hungarian who discovered that the incidence of puerperal fever could be drastically cut by use of hand washing standards in obstetrical clinics. His unconventional ideas and methods led to him being banned from some hospitals.[28] Puerperal fever (or childbed fever) was common in mid-19th-century hospitals and often fatal, with mortality at 10%-35%.
- Dr. C. J. Thacher was a practitioner of magnet therapy. In the 1920s his "Chicago Magnetic Company" promised "health without the use of medicine." He was dubbed the "King of the magnetic quacks" by Collier's Magazine.[29]
- Royal Rife Invented the "Rife machine", a machine produces Radio waves at a frequency of 10-100mhz, and claimed that it was able to cure cancer[1].
# Quackery in popular media
Template:Trivia
- In Metal Gear Solid 3, Para-medic's nickname is Quack, which Snake finds out after Asking Para-Medic about her reputation.
- In one episode of Scrubs, the Janitor doctors a picture of Dr. Cox to show him with a duck's bill, "because you're a 'quack.'"
- The 1977 Walt Disney film Pete's Dragon features a quack doctor named Dr. Terminus (Jim Dale) as its main villain. He brings his traveling medicine show to town and tries to capture Elliott the dragon and use his parts to sell phony medicines.
- Dr. Nick Riviera on The Simpsons is a quack physician. He claims to be as good as Dr. Hibbert, however, is obviously not. This is represented when he tries to perform a Bypass surgery on Homer and does not know where to make the incision, among other things. | https://www.wikidoc.org/index.php/Quackery | |
a187140968d52ea9136a5d6677cadadb49c27d9b | wikidoc | RNASEH2A | RNASEH2A
Ribonuclease H2 subunit A, also known as RNase H2 subunit A, is an enzyme that in humans is encoded by the RNASEH2A gene.
# Function
The protein encoded by this gene is a component of the heterotrimeric type II ribonuclease H enzyme (RNaseH2). The other two subunits are the non-catalytic RNASEH2B and RNASEH2C. RNaseH2 is the major source of ribonuclease H activity in mammalian cells and endonucleolytically cleaves ribonucleotides. It is predicted to remove Okazaki fragment RNA primers during lagging strand DNA synthesis and to excise single ribonucleotides from DNA-DNA duplexes.
# Clinical significance
Mutations in this gene cause Aicardi-Goutieres syndrome (AGS), an autosomal recessive neurological disorder characterized by progressive microcephaly and psychomotor retardation, intracranial calcifications, elevated levels of interferon-alpha and white blood cells in the cerebrospinal fluid. | RNASEH2A
Ribonuclease H2 subunit A, also known as RNase H2 subunit A, is an enzyme that in humans is encoded by the RNASEH2A gene.[1]
# Function
The protein encoded by this gene is a component of the heterotrimeric type II ribonuclease H enzyme (RNaseH2). The other two subunits are the non-catalytic RNASEH2B and RNASEH2C. RNaseH2 is the major source of ribonuclease H activity in mammalian cells and endonucleolytically cleaves ribonucleotides. It is predicted to remove Okazaki fragment RNA primers during lagging strand DNA synthesis and to excise single ribonucleotides from DNA-DNA duplexes.[1]
# Clinical significance
Mutations in this gene cause Aicardi-Goutieres syndrome (AGS), an autosomal recessive neurological disorder characterized by progressive microcephaly and psychomotor retardation, intracranial calcifications, elevated levels of interferon-alpha and white blood cells in the cerebrospinal fluid.[1] | https://www.wikidoc.org/index.php/RNASEH2A | |
061c825de7676f1842ce8e35357c32873183fd70 | wikidoc | RNASEH2B | RNASEH2B
Ribonuclease H2, subunit B is a protein that in humans is encoded by the RNASEH2B gene. RNase H2 is composed of a single catalytic subunit (A) and two non-catalytic subunits (B and C), and degrades the RNA of RNA:DNA hybrids. The non-catalytic B subunit of RNase H2 is thought to play a role in DNA replication.
Mutations in this gene are a cause of Aicardi-Goutieres syndrome type 2 (AGS2).
# Model organisms
Model organisms have been used in the study of RNASEH2B function. A conditional knockout mouse line, called Rnaseh2btm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on mutant mice and three significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and an increased susceptibility to bacterial infection was observed in female animals.
# Related Studies
In a study of Reijns et al. 2012, it was made targeted mutagenesis of the mouse Rnaseh2b gene to gain insight into the in vivo role of the mammalian RNase H2 enzyme, because the ablation of Rnaseh2b in mice leads to early embryonic lethality.
Their hypothesis was that the growth arrest was a consequence of a p53-dependent DNA damage response associated with the accumulation of single RN in genomic DNA.
They discuss the following facts:
1. Ribonucleotide accumulate in RNaseH2 null cells as a consequence of incorporation by DNA polymerases: The authors show that the ribonucleotide incorporation also occurs in metazoans, these lesions are harmful to mammalian cells, and their removal is required for mouse embryonic development. They also characterize alkali-sensitive sites: Lesions are single or diRN covalently incorporated into genomic DNA, at a frequency of approx. 1.000.000 sites per cell, making it the most common endogenous base lesion in the mammalian genome. These lesions are best explained by misincorporation by the major replicative polymerases.
2. RNase H2 is a genome surveillance enzyme required for ribonucleotide removal: They found that ribonucleotide accumulation in genomic DNA of RNaseH2null mice implicates the RNaseH2 complex in the maintenance of genome integrity. These ribonucleotide changes are likely to be harmful, as their ribose 2’-hydroxyl group increases susceptibility of the adjacent phosphodiester bond to hydrolysis. Actually, they report that the ribonucleotides are being incorporated 1 every ~7.600 nt in null cells = 1.300.000 lesions per cell. This have the same order of magnitude predicted from in vitro incorporation rates by eukaryotic replicative polymerases.
3. Misincorporated ribonucleotide induce DNA damage: It is not that the ribonucleotides do not prevent replication; actually, polDNA can tolerate templates with ribonucleotides, having normal early embryogenesis. The problem appears with excessive numbers of ribonucleotides. DNA damage response signaling activated maybe by incorporation of ribonucleotides in difficult to replicate regions or near other detrimental lesions. They also found chromosomal rearrangements: DNA breaks may origin by replication fork collapse or hydrolysis of RN on opposing DNA strands. Also, the marked activation of DNA damage signaling in embryo may produce a p53-mediated inhibition of proliferation that might contribute to the lethality of null embryos.
4. Ribonucleotide incorporation in health and disease: Past studies reported only two contexts where there’s stable incorporation of ribonucleotides: 1) diRibonucleotides in S. pombe may be a signal to initiate homologous recombination. 2) Ribonucleotides in mtDNA (Mouse and HeLa cells). Low levels of ribonucleotides incorporation in the nuclear genome may be tolerated. Actually, aberrant nucleic acid substrates, generated by repair pathways non-RNaseH2 dependent (due to reduced RNaseH2 activity in Aicardi-Goutières Syndrome) are thought to drive innate immune response. Alternatively, ribonucleotides might induce DNA-damage response signaling that by itself may stimulates interferon production.
In summary, this study highlights the fact that the ribonucleotides can be highly deleterious to the mammalian cell, causing genome instability, and that the RNaseH2 is a critical enzyme for ensuring integrity of genomic DNA. It also calls for attention and interest about the pathway(s) that remove ribonucleotides from genomic DNA, site and nature of ribonucleotides -induced DNA damage, and distribution of ribonucleotides in the genome. Knowing this, it may gain understanding about the pathological and physiological roles of RN in genomic DNA, of significance to both nucleic acid-driven autoimmunity and carcinogenesis. | RNASEH2B
Ribonuclease H2, subunit B is a protein that in humans is encoded by the RNASEH2B gene.[1] RNase H2 is composed of a single catalytic subunit (A) and two non-catalytic subunits (B and C), and degrades the RNA of RNA:DNA hybrids. The non-catalytic B subunit of RNase H2 is thought to play a role in DNA replication.[1]
Mutations in this gene are a cause of Aicardi-Goutieres syndrome type 2 (AGS2).[1][2]
# Model organisms
Model organisms have been used in the study of RNASEH2B function. A conditional knockout mouse line, called Rnaseh2btm1a(EUCOMM)Wtsi[7][8] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[9][10][11]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[5][12] Twenty four tests were carried out on mutant mice and three significant abnormalities were observed.[5] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and an increased susceptibility to bacterial infection was observed in female animals.[5]
# Related Studies
In a study of Reijns et al. 2012,[13] it was made targeted mutagenesis of the mouse Rnaseh2b gene to gain insight into the in vivo role of the mammalian RNase H2 enzyme, because the ablation of Rnaseh2b in mice leads to early embryonic lethality.
Their hypothesis was that the growth arrest was a consequence of a p53-dependent DNA damage response associated with the accumulation of single RN in genomic DNA.
They discuss the following facts:
1. Ribonucleotide accumulate in RNaseH2 null cells as a consequence of incorporation by DNA polymerases: The authors show that the ribonucleotide incorporation also occurs in metazoans, these lesions are harmful to mammalian cells, and their removal is required for mouse embryonic development. They also characterize alkali-sensitive sites: Lesions are single or diRN covalently incorporated into genomic DNA, at a frequency of approx. 1.000.000 sites per cell, making it the most common endogenous base lesion in the mammalian genome. These lesions are best explained by misincorporation by the major replicative polymerases.
2. RNase H2 is a genome surveillance enzyme required for ribonucleotide removal: They found that ribonucleotide accumulation in genomic DNA of RNaseH2null mice implicates the RNaseH2 complex in the maintenance of genome integrity. These ribonucleotide changes are likely to be harmful, as their ribose 2’-hydroxyl group increases susceptibility of the adjacent phosphodiester bond to hydrolysis. Actually, they report that the ribonucleotides are being incorporated 1 every ~7.600 nt in null cells = 1.300.000 lesions per cell. This have the same order of magnitude predicted from in vitro incorporation rates by eukaryotic replicative polymerases.
3. Misincorporated ribonucleotide induce DNA damage: It is not that the ribonucleotides do not prevent replication; actually, polDNA can tolerate templates with ribonucleotides, having normal early embryogenesis. The problem appears with excessive numbers of ribonucleotides. DNA damage response signaling activated maybe by incorporation of ribonucleotides in difficult to replicate regions or near other detrimental lesions. They also found chromosomal rearrangements: DNA breaks may origin by replication fork collapse or hydrolysis of RN on opposing DNA strands. Also, the marked activation of DNA damage signaling in embryo may produce a p53-mediated inhibition of proliferation that might contribute to the lethality of null embryos.
4. Ribonucleotide incorporation in health and disease: Past studies reported only two contexts where there’s stable incorporation of ribonucleotides: 1) diRibonucleotides in S. pombe may be a signal to initiate homologous recombination. 2) Ribonucleotides in mtDNA (Mouse and HeLa cells). Low levels of ribonucleotides incorporation in the nuclear genome may be tolerated. Actually, aberrant nucleic acid substrates, generated by repair pathways non-RNaseH2 dependent (due to reduced RNaseH2 activity in Aicardi-Goutières Syndrome) are thought to drive innate immune response. Alternatively, ribonucleotides might induce DNA-damage response signaling that by itself may stimulates interferon production.
In summary, this study highlights the fact that the ribonucleotides can be highly deleterious to the mammalian cell, causing genome instability, and that the RNaseH2 is a critical enzyme for ensuring integrity of genomic DNA. It also calls for attention and interest about the pathway(s) that remove ribonucleotides from genomic DNA, site and nature of ribonucleotides -induced DNA damage, and distribution of ribonucleotides in the genome. Knowing this, it may gain understanding about the pathological and physiological roles of RN in genomic DNA, of significance to both nucleic acid-driven autoimmunity and carcinogenesis. | https://www.wikidoc.org/index.php/RNASEH2B | |
2ac510df557135066dcc7f27377d1547ba09ab27 | wikidoc | RNASEH2C | RNASEH2C
Ribonuclease H2 subunit C is a protein that in humans is encoded by the RNASEH2C gene.
RNase H2 is composed of a single catalytic subunit (A) and two non-catalytic subunits (B and C), and degrades the RNA of RNA:DNA hybrids.
Mutations in this gene are a cause of Aicardi-Goutieres syndrome type 3 (AGS3).
# Function
This gene encodes a ribonuclease H subunit that can cleave ribonucleotides from RNA:DNA duplexes. Mutations in this gene cause Aicardi-Goutieres syndrome-3, a disease that causes severe neurologic dysfunction. A pseudogene for this gene has been identified on chromosome Y, near the sex determining region Y (SRY) gene. | RNASEH2C
Ribonuclease H2 subunit C is a protein that in humans is encoded by the RNASEH2C gene.
[1] RNase H2 is composed of a single catalytic subunit (A) and two non-catalytic subunits (B and C), and degrades the RNA of RNA:DNA hybrids.
Mutations in this gene are a cause of Aicardi-Goutieres syndrome type 3 (AGS3).[1][2]
# Function
This gene encodes a ribonuclease H subunit that can cleave ribonucleotides from RNA:DNA duplexes. Mutations in this gene cause Aicardi-Goutieres syndrome-3, a disease that causes severe neurologic dysfunction. A pseudogene for this gene has been identified on chromosome Y, near the sex determining region Y (SRY) gene. | https://www.wikidoc.org/index.php/RNASEH2C | |
4fb4ee058981b92560679fb768439fee21308e05 | wikidoc | Ribozyme | Ribozyme
# Overview
A ribozyme (from ribonucleic acid enzyme, also called RNA enzyme or catalytic RNA) is an RNA molecule that catalyzes a chemical reaction. Many natural ribozymes catalyze either the hydrolysis of one of their own phosphodiester bonds, or the hydrolysis of bonds in other RNAs, but they have also been found to catalyze the aminotransferase activity of the ribosome.
Investigators studying the origin of life have produced ribozymes in the laboratory that are capable of catalyzing their own synthesis under very specific conditions, such as an RNA polymerase ribozyme. Mutagenesis and selection has been performed resulting in isolation of improved variants of the "Round-18" polymerase ribozyme from 2001. "B6.61" is able to add up to 20 nucleotides to a primer template in 24 hours, until it decomposes by hydrolysis of its phosphodiester bonds.
# Discovery
Before the discovery of ribozymes, enzymes, which are defined as catalytic proteins, were the only known biological catalysts. In 1967, Carl Woese, Francis Crick, and Leslie Orgel were the first to suggest that RNA could act as a catalyst based upon findings that it can form complex secondary structures. The first ribozymes were discovered in the 1980s by Thomas R. Cech, who was studying RNA splicing in the ciliated protozoan Tetrahymena thermophila and Sidney Altman, who was working on the bacterial RNase P complex. The ribozymes were found in the intron of an RNA transcript, which removed itself from the transcript and in the RNA component of the RNase P complex, which is involved in the maturation of pre-tRNAs. In 1989, Thomas R. Cech and Sidney Altman won the Nobel Prize in chemistry for their "discovery of catalytic properties of RNA." The term ribozyme was first introduced by Kelly Kruger et al. in 1982 in a paper published in Cell.
# Activity
Although most ribozymes are quite rare in the cell, their roles are sometimes essential to life. For example, the functional part of the ribosome, the molecular machine that translates RNA into proteins, is fundamentally a ribozyme. Ribozymes often have divalent metal ions such as Mg2+ as cofactors.
RNA can also act as a hereditary molecule, which encouraged Walter Gilbert to propose that in the past, the cell used RNA as both the genetic material and the structural and catalytic molecule, rather than dividing these functions between DNA and protein as they are today. This hypothesis became known as the "RNA world hypothesis" of the origin of life.
If ribozymes were the first molecular machines used by early life, then today's remaining ribozymes -- such as the ribosome machinery -- could be considered living fossils of a life based primarily on nucleic acids.
A recent test-tube study of prion folding suggests that an RNA may catalyze the pathological protein conformation in the manner of a chaperone enzyme.
# Known ribozymes
Naturally occurring ribozymes include:
- Peptidyl transferase 23S rRNA
- RNase P
- Group I and Group II introns
- GIR1 branching ribozyme
- Leadzyme - Although initially created in vitro, natural examples have been found
- Hairpin ribozyme
- Hammerhead ribozyme
- HDV ribozyme
- Mammalian CPEB3 ribozyme
- VS ribozyme
- glmS ribozyme
- CoTC ribozyme
# Artificial ribozymes
Since the discovery of ribozymes that exist in living organisms, there has been interest in the study of new synthetic ribozymes made in the laboratory. For example, artificially-produced self-cleaving RNAs that have good enzymatic activity have been produced. Tang and Breaker isolated self-cleaving RNAs by in vitro selection of RNAs originating from random-sequence RNAs. Some of the synthetic ribozymes that were produced had novel structures, while some were similar to the naturally occurring hammerhead ribozyme.
The techniques used to discover artificial ribozymes involve Darwinian evolution. This approach takes advantage of RNA's dual nature as both a catalyst and an informational polymer, making it easy for an investigator to produce vast populations of RNA catalysts using polymerase enzymes. The ribozymes are mutated by reverse transcibing them with reverse transcriptase into various cDNA and amplified with mutagenic PCR. The selection parameters in these experiments often differ. One approach for selecting a ligase ribozyme involves using biotin tags, which are covalently linked to the substrate. If a molecule possesses the desired ligase activity, a streptavidin matrix can be used to recover the active molecules. | Ribozyme
# Overview
A ribozyme (from ribonucleic acid enzyme, also called RNA enzyme or catalytic RNA) is an RNA molecule that catalyzes a chemical reaction. Many natural ribozymes catalyze either the hydrolysis of one of their own phosphodiester bonds, or the hydrolysis of bonds in other RNAs, but they have also been found to catalyze the aminotransferase activity of the ribosome.
Investigators studying the origin of life have produced ribozymes in the laboratory that are capable of catalyzing their own synthesis under very specific conditions, such as an RNA polymerase ribozyme.[1] Mutagenesis and selection has been performed resulting in isolation of improved variants of the "Round-18" polymerase ribozyme from 2001. "B6.61" is able to add up to 20 nucleotides to a primer template in 24 hours, until it decomposes by hydrolysis of its phosphodiester bonds.[2]
# Discovery
Before the discovery of ribozymes, enzymes, which are defined as catalytic proteins,[3] were the only known biological catalysts. In 1967, Carl Woese, Francis Crick, and Leslie Orgel were the first to suggest that RNA could act as a catalyst based upon findings that it can form complex secondary structures.[4] The first ribozymes were discovered in the 1980s by Thomas R. Cech, who was studying RNA splicing in the ciliated protozoan Tetrahymena thermophila and Sidney Altman, who was working on the bacterial RNase P complex. The ribozymes were found in the intron of an RNA transcript, which removed itself from the transcript and in the RNA component of the RNase P complex, which is involved in the maturation of pre-tRNAs. In 1989, Thomas R. Cech and Sidney Altman won the Nobel Prize in chemistry for their "discovery of catalytic properties of RNA."[5] The term ribozyme was first introduced by Kelly Kruger et al. in 1982 in a paper published in Cell.
# Activity
Although most ribozymes are quite rare in the cell, their roles are sometimes essential to life. For example, the functional part of the ribosome, the molecular machine that translates RNA into proteins, is fundamentally a ribozyme. Ribozymes often have divalent metal ions such as Mg2+ as cofactors.
RNA can also act as a hereditary molecule, which encouraged Walter Gilbert to propose that in the past, the cell used RNA as both the genetic material and the structural and catalytic molecule, rather than dividing these functions between DNA and protein as they are today. This hypothesis became known as the "RNA world hypothesis" of the origin of life.
If ribozymes were the first molecular machines used by early life, then today's remaining ribozymes -- such as the ribosome machinery -- could be considered living fossils of a life based primarily on nucleic acids.
A recent test-tube study of prion folding suggests that an RNA may catalyze the pathological protein conformation in the manner of a chaperone enzyme.[6]
# Known ribozymes
Naturally occurring ribozymes include:
- Peptidyl transferase 23S rRNA
- RNase P
- Group I and Group II introns
- GIR1 branching ribozyme[7]
- Leadzyme - Although initially created in vitro, natural examples have been found
- Hairpin ribozyme
- Hammerhead ribozyme
- HDV ribozyme
- Mammalian CPEB3 ribozyme
- VS ribozyme
- glmS ribozyme
- CoTC ribozyme
# Artificial ribozymes
Since the discovery of ribozymes that exist in living organisms, there has been interest in the study of new synthetic ribozymes made in the laboratory. For example, artificially-produced self-cleaving RNAs that have good enzymatic activity have been produced. Tang and Breaker[8] isolated self-cleaving RNAs by in vitro selection of RNAs originating from random-sequence RNAs. Some of the synthetic ribozymes that were produced had novel structures, while some were similar to the naturally occurring hammerhead ribozyme.
The techniques used to discover artificial ribozymes involve Darwinian evolution. This approach takes advantage of RNA's dual nature as both a catalyst and an informational polymer, making it easy for an investigator to produce vast populations of RNA catalysts using polymerase enzymes. The ribozymes are mutated by reverse transcibing them with reverse transcriptase into various cDNA and amplified with mutagenic PCR. The selection parameters in these experiments often differ. One approach for selecting a ligase ribozyme involves using biotin tags, which are covalently linked to the substrate. If a molecule possesses the desired ligase activity, a streptavidin matrix can be used to recover the active molecules. | https://www.wikidoc.org/index.php/RNA_Biocatalysis | |
b11ef2214ac3c10bfd16158cec8087fc438a648d | wikidoc | RUB A535 | RUB A535
RUB A535 (also known as Antiphlogistine) is a topical analgesic introduced in 1919 and manufactured by Church and Dwight in Canada. While relatively unknown outside of Canada (it isn't sold in the US), it is indeed a very popular product for the treatment of tough muscle pain, arthritic pains, rheumatic pains, bursitis, lumbago, etc. Church and Dwight claims on their website that nearly all the research, development and production of RUB A535 was and still is done in Canada. Patients who are allergic to salicylates (ASA based drugs, such as Aspirin ), or who are taking anticoagulant medications should avoid the use of the product.
Currently, RUB A535 has been released in a variety of products:
Originally, it was produced in a particular white cream, carrying a rather offensive medical odour.
Recently, the name was also given to a line of dual action back patches that change temperature (known as Hot-Cold patches).
Also, an improved cream was also developed, claiming to be odourless, differing from their normal cream, which carries the same smell as most topical anagesics.
ADDITIONAL REFERENCES:
RUB A535 is sometimes referred to by the shorter expression "A535". As the product is particularly Canadian, this usage may be only somewhat local. Meanwhile, for French-speaking consumers in Canada, the name Antiphlogistine is used instead.
According to entries in the SlangDictionary.com, RUB A535 is used in a sexual encounter known as a "Spicey Stranger" or "Fire and Ice". In both applications, the product is applied and rubbed into either the penis or scrotum of the individual to produce a warm or burning sensation. In "Fire and Ice", an ice cube is first used to "freeze" or stimulate the genitals first, and then RUB A535 is applied afterwards to "warm up" the sex organs.
This application has not been confirmed.
A similar usage in the USA might involve the use of "Ben-Gay" on the genitals, a practice that is reverved as extremely uncomforatble in the straight athletic community and locker rooms in the USA.
# Links
- The RUB A535 webpage on Church and Dwight's. | RUB A535
RUB A535 (also known as Antiphlogistine) is a topical analgesic introduced in 1919 and manufactured by Church and Dwight in Canada. While relatively unknown outside of Canada (it isn't sold in the US), it is indeed a very popular product for the treatment of tough muscle pain, arthritic pains, rheumatic pains, bursitis, lumbago, etc. Church and Dwight claims on their website that nearly all the research, development and production of RUB A535 was and still is done in Canada. Patients who are allergic to salicylates (ASA based drugs, such as Aspirin ), or who are taking anticoagulant medications should avoid the use of the product.
Currently, RUB A535 has been released in a variety of products:
Originally, it was produced in a particular white cream, carrying a rather offensive medical odour.
Recently, the name was also given to a line of dual action back patches that change temperature (known as Hot-Cold patches).
Also, an improved cream was also developed, claiming to be odourless, differing from their normal cream, which carries the same smell as most topical anagesics.
ADDITIONAL REFERENCES:
RUB A535 is sometimes referred to by the shorter expression "A535". As the product is particularly Canadian, this usage may be only somewhat local. Meanwhile, for French-speaking consumers in Canada, the name Antiphlogistine is used instead.
According to entries in the SlangDictionary.com, RUB A535 is used in a sexual encounter known as a "Spicey Stranger" or "Fire and Ice". In both applications, the product is applied and rubbed into either the penis or scrotum of the individual to produce a warm or burning sensation. In "Fire and Ice", an ice cube is first used to "freeze" or stimulate the genitals first, and then RUB A535 is applied afterwards to "warm up" the sex organs.
This application has not been confirmed.
A similar usage in the USA might involve the use of "Ben-Gay" on the genitals, a practice that is reverved as extremely uncomforatble in the straight athletic community and locker rooms in the USA.
# Links
- The RUB A535 webpage on Church and Dwight's.
Template:Pharma-stub
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/RUB_A535 | |
597066689fb93def39c4adf475b035bdc251d359 | wikidoc | Racemate | Racemate
In chemistry, a racemic mixture, or racemate, is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was 'racemic acid', which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.
# Properties
A racemate is optically inactive: because the two isomers rotate plane-polarized light in opposite directions they cancel out, therefore a racemic mixture does not rotate plane-polarized light.
In contrast to the two separate enantiomers, which generally have identical physical properties, a racemate often has different properties compared to either one of the pure enantiomers. Different melting points and solubilities are very common, but different boiling points are also possible.
Pharmaceuticals may be available as a racemate or as pure enantiomer, which might have different potencies.
# Crystallization
There are three ways a racemate can crystallize, this is important for the resolution of a racemate by crystallisation. Precise ways to distinguish between these crystal forms were summarised already in 1899 by H. W. B. Roozeboom.
- Conglomerate (sometimes racemic mixture or racemic conglomerate)
- Racemic compound (sometimes true racemate)
- Pseudoracemate (sometimes racemic solid solution)
- Quasiracemate.
# Resolution
The separation of a racemate into its components, the pure enantiomers, is called a chiral resolution. There are various methods, including crystallization, chromatography and the use of enzymes. The first successful resolution of a racemate was performed by Louis Pasteur, who manually separated the crystals of a conglomerate.
# Synthesis
Without a chiral influence (for example a chiral catalyst, solvent or starting material), a chemical reaction that makes a chiral product will always yield a racemate. That can make the synthesis of a racemate cheaper and easier than making the pure enantiomer, because it does not require special conditions. This fact also leads to the question how biological homochirality evolved on a presumably racemic primordial earth.
The reagents of, and the reactions that produce, racemic mixtures are said to be "not stereospecific" or "not stereoselective", for their indecision in a particular stereoisomerism.
# Racemic pharmaceuticals
Some drug molecules are chiral and the enantiomers have different effects on biological entities. They can be sold as one enantiomer or as a racemic mixture. Examples include Thalidomide, Ibuprofen, and Salbutamol. Adderall is a mixture of several different enantiomers. A single amphetamine dose combines the neutral sulfate salts of dextroamphetamine and amphetamine, with the dextro isomer of amphetamine saccharate and d, l-amphetamine aspartate monohydrate.
In some cases (e.g. Ibuprofen and Thalidomide) the enantiomers are interconverted in vivo. This means that preparing a pure enantiomer for medication is largely pointless.
In cases like Salbutamol and Thalidomide the inactive isomer may be harmful.
Methamphetamine is available by prescription under the brand name Desoxyn. The active component of Desoxyn is dextro-methamphetamine hydrochloride. This is the right-hand isomer of methamphetamine. The left-handed isomer of methamphetamine, levo-methamphetamine, is less centrally acting and more peripherally acting; therefore a racemic mixture of dextro/levo-methamphetamine isn't used in current medical practice. In the past, due to different levels of restrictions on precursor chemicals and lack of knowledge by those preparing the final product, racemic methamphetamine was produced and sold on the black market. Newer techniques typically use asymmetric synthesis methods and yield a majority of d-methamphetamine and relatively little l-methamphetamine. | Racemate
In chemistry, a racemic mixture, or racemate, is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was 'racemic acid', which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.
# Properties
A racemate is optically inactive: because the two isomers rotate plane-polarized light in opposite directions they cancel out, therefore a racemic mixture does not rotate plane-polarized light.
In contrast to the two separate enantiomers, which generally have identical physical properties, a racemate often has different properties compared to either one of the pure enantiomers. Different melting points and solubilities are very common, but different boiling points are also possible.
Pharmaceuticals may be available as a racemate or as pure enantiomer, which might have different potencies.
# Crystallization
There are three ways a racemate can crystallize, this is important for the resolution of a racemate by crystallisation. Precise ways to distinguish between these crystal forms were summarised already in 1899 by H. W. B. Roozeboom.
- Conglomerate (sometimes racemic mixture or racemic conglomerate)
- Racemic compound (sometimes true racemate)
- Pseudoracemate (sometimes racemic solid solution)
- Quasiracemate.
# Resolution
The separation of a racemate into its components, the pure enantiomers, is called a chiral resolution. There are various methods, including crystallization, chromatography and the use of enzymes. The first successful resolution of a racemate was performed by Louis Pasteur, who manually separated the crystals of a conglomerate.
# Synthesis
Without a chiral influence (for example a chiral catalyst, solvent or starting material), a chemical reaction that makes a chiral product will always yield a racemate. That can make the synthesis of a racemate cheaper and easier than making the pure enantiomer, because it does not require special conditions. This fact also leads to the question how biological homochirality evolved on a presumably racemic primordial earth.
The reagents of, and the reactions that produce, racemic mixtures are said to be "not stereospecific" or "not stereoselective", for their indecision in a particular stereoisomerism.
# Racemic pharmaceuticals
Some drug molecules are chiral and the enantiomers have different effects on biological entities. They can be sold as one enantiomer or as a racemic mixture. Examples include Thalidomide, Ibuprofen, and Salbutamol. Adderall is a mixture of several different enantiomers. A single amphetamine dose combines the neutral sulfate salts of dextroamphetamine and amphetamine, with the dextro isomer of amphetamine saccharate and d, l-amphetamine aspartate monohydrate.
In some cases (e.g. Ibuprofen and Thalidomide) the enantiomers are interconverted in vivo. This means that preparing a pure enantiomer for medication is largely pointless.
In cases like Salbutamol and Thalidomide the inactive isomer may be harmful.
Methamphetamine is available by prescription under the brand name Desoxyn. The active component of Desoxyn is dextro-methamphetamine hydrochloride. This is the right-hand isomer of methamphetamine. The left-handed isomer of methamphetamine, levo-methamphetamine, is less centrally acting and more peripherally acting; therefore a racemic mixture of dextro/levo-methamphetamine isn't used in current medical practice. In the past, due to different levels of restrictions on precursor chemicals and lack of knowledge by those preparing the final product, racemic methamphetamine was produced and sold on the black market. Newer techniques typically use asymmetric synthesis methods and yield a majority of d-methamphetamine and relatively little l-methamphetamine. | https://www.wikidoc.org/index.php/Racemate | |
8fa2b54946fad481d76577c37367f58883681d38 | wikidoc | Ramipril | Ramipril
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# Black Box Warning
# Overview
Ramipril is an Angiotensin converting enzyme inhibitor that is FDA approved for the treatment of hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension, asthenia, dizziness, headache, cough and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information (not receiving diuretic)
- Initial dose : Ramipril 2.5 mg PO qd should be used.Adjust dose according to blood pressure response.
- Maintenance dose: Ramipril 2.5-20 mg PO qd or bid
- In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients, consider an increase in dosage or twice daily administration. If blood pressure is not controlled with ALTACE alone, a diuretic can be added.
- Reduction in Myocardial Infarction, Stroke ,and Death from Cardiovascular Causes
- Dosage for 1st week: 2.5 mg PO qd
- Dosage for the next 3 weeks: 5 mg PO qd
- Maintaining dosage: 10 mg PO qd (if tolerated)
- If the patient is hypertensive or recently post-myocardial infarction, ALTACE can also be given as a divided dose.
- Dosing Information
- Initial dose for the 1st week : 2.5 mg PO bid
- For patients become hypotensive: switched to 1.25 mg PO bid
- Dosage from the 2nd dosage: 5 mg PO bid, with dosage increases being about 3 weeks apart.
- After the initial dose of ALTACE, observe the patient under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour. If possible, reduce the dose of any concomitant diuretic as this may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of ALTACE does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension (see Warnings and Precautions, Drug Interactions).
- Renal Impairment
- Indication for adjustment: In patients with estimated creatinine clearance ≤40 mL/min. (Usual dosage maybe safe in patients with creatinine clearance >40 mL/min )
- Adjustmented dosage: 25% of the usual dose is expected to produce full therapeutic levels.
- Hypertension
- Indication for adjustment: For patients with hypertension and renal impairment.
- Adjusted dosage: 1.25 mg PO bid, max: 2.5 mg PO bid (depending on clinical response and tolerability).
- Volume Depletion or Renal Artery Stenosis
- Initiate dosage: 1.25 mg PO qd. Adjust dosage according to blood pressure response.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
### Heart Failure
- Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA)
- Class of Recommendation: Class IIa
- Strength of Evidence: Level A
- Dosing Information/Recommendation
- Initial dosage: 2.5 mg PO bid
- Maintaining dosage: 5 mg PO bid (if tolerated)
### Non–Guideline-Supported Use
- Dosing information
- 10 mg/day
- 5 mg/day or more
- 1.25 mg/day
- Dosing information
- 1.25 mg
- Dosing information
- 2.5 mg/day
- 5 mg
- 1.25 mg or 5 mg
- 5 mg
- Dosing information
- 10 mg/day
- 5 mg
- 2.5-5 mg PO qd
- 1.25-5 mg PO qd
- 10 mg/day
- Dosing information
- 5 mg PO qd
- Dosing information
- 10 mg PO qd
### Peripheral arterial occlusive disease=
- Dosing information
- 10 mg PO qd
- Dosing information
- 20 mg PO qd
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
safety and efficacy not established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about guideline-supported off-label use
### Non–Guideline-Supported Use
- There is limited information about Off-Label Non–Guideline-Supported Use of Ramipril tablet in pediatric patients.
# Contraindications
- Altace is contraindicated in patients who are hypersensitive to this product or any other ACE inhibitor (e.g., a patient who has experienced angioedema during therapy with any other ACE inhibitor).
- Do not co-administer aliskiren with Altace in patients with diabetes
# Warnings
### Anaphylactoid and Possibly Related Reactions
- Presumably because drugs that act directly on the renin-angiotensin-aldosterone system (e.g., ACE inhibitors) affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving these drugs (including Altace) may be subject to a variety of adverse reactions, some of them serious.
### Angioedema
- Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor.
- Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, discontinue treatment with Altace and institute appropriate therapy immediately. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, administer appropriate therapy (e.g., subcutaneous epinephrine solution 1:1000 ) promptly.
- In considering the use of Altace, note that in controlled clinical trials ACE inhibitors cause a higher rate of angioedema in Black patients than in non-Black patients.
- In a large U.S. post-marketing study, angioedema (defined as reports of angio, face, larynx, tongue, or throat edema) was reported in 3/1523 (0.20%) Black patients and in 8/8680 (0.09%) non-Black patients. These rates were not different statistically.
- Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema
- Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Include intestinal angioedema in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
### Anaphylactoid Reactions During Desensitization
- Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
### Anaphylactoid Reactions During Membrane Exposure
- Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
### Hepatic Failure and Impaired Liver Function
- Rarely, ACE inhibitors, including Altace, have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Discontinue Altace if patient develops jaundice or marked elevations of hepatic enzymes.
- As ramipril is primarily metabolized by hepatic esterases to its active moiety, ramiprilat, patients with impaired liver function could develop markedly elevated plasma levels of ramipril. No formal pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function.
### Renal Impairment
- As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including Altace, may be associated with oliguria or progressive azotemia and rarely with acute renal failure or death.
- In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another ACE inhibitor suggests that these increases would be reversible upon discontinuation of Altace and/or diuretic therapy. In such patients, monitor renal function during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when Altace has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of Altace and/or discontinuation of the diuretic may be required.
### Neutropenia and Agranulocytosis
- In rare instances, treatment with ACE inhibitors may be associated with mild reductions in red blood cell count and hemoglobin content, blood cell or platelet counts. In isolated cases, agranulocytosis, pancytopenia, and bone marrow depression may occur. Hematological reactions to ACE inhibitors are more likely to occur in patients with collagen-vascular disease (e.g., systemic lupus erythematosus, scleroderma) and renal impairment. Consider monitoring white blood cell counts in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function.
### Hypotension
## General Considerations
- Altace can cause symptomatic hypotension, after either the initial dose or a later dose when the dosage has been increased. Like other ACE inhibitors, Altace, has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume- and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Correct volume- and salt-depletion before initiating therapy with Altace.
- If excessive hypotension occurs, place the patient in a supine position and, if necessary, treat with intravenous infusion of physiological saline. Altace treatment usually can be continued following restoration of blood pressure and volume.
### Heart Failure Post-Myocardial Infarction
- In patients with heart failure post-myocardial infarction who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of Altace. If the initial dose of 2.5 mg Altace cannot be tolerated, use an initial dose of 1.25 mg Altace to avoid excessive hypotension. Consider reducing the dose of concomitant diuretic to decrease the incidence of hypotension.
### Congestive Heart Failure
- In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and rarely, with acute renal failure and death. In such patients, initiate Altace therapy under close medical supervision and follow patients closely for the first 2 weeks of treatment and whenever the dose of Altace or diuretic is increased.
### Surgery and Anesthesia
- In patients undergoing surgery or during anesthesia with agents that produce hypotension, ramipril may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.
### Fetal Toxicity
### Pregnancy Category D
- Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Altace as soon as possible.
### Dual Blockade of the Renin-Angiotensin-Aldosterone System
- Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on Altace and other agents that affect the RAS.
### Telmisartan
- The ONTARGET trial enrolled 25,620 patients >55 years old with atherosclerotic disease or diabetes with end-organ damage, randomized them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months. Patients receiving the combination of telmisartan and ramipril did not obtain any benefit in the composite endpoint of cardiovascular death, MI, stroke and heart failure hospitalization compared to monotherapy, but experienced an increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, or dialysis) compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of telmisartan and ramipril is not recommended.
### Aliskiren
- Do not co-administer aliskiren with Altace in patients with diabetes. Avoid concomitant use of aliskiren with Altace in patients with renal impairment (GFR <60 mL/min/1.73 m2). (see Drug Interactions)
### Hyperkalemia
- In clinical trials with Altace, hyperkalemia (serum potassium >5.7 mEq/L) occurred in approximately 1% of hypertensive patients receiving Altace. In most cases, these were isolated values, which resolved despite continued therapy. None of these patients were discontinued from the trials because of hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with Altace.
### Cough
- Presumably caused by inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. Consider the possibility of angiotensin converting enzyme inhibitor induced-cough in the differential diagnosis of cough.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, the 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.
### Hypertension
- Altace has been evaluated for safety in over 4000 patients with hypertension; of these, 1230 patients were studied in U.S. controlled trials, and 1107 were studied in foreign controlled trials. Almost 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was similar in Altace and placebo patients.
- The most frequent clinical side effects (possibly or probably related to study drug) reported by patients receiving Altace in placebo-controlled trials were headache (5.4%), dizziness (2.2%), and fatigue or asthenia (2.0%), but only the last one was more common in Altace patients than in patients given placebo. Generally the side effects were mild and transient, and there was no relation to total dosage within the range of 1.25 mg–20 mg. Discontinuation of therapy because of a side effect was required in approximately 3% of U.S. patients treated with Altace. The most common reasons for discontinuation were cough (1.0%), dizziness (0.5%), and impotence (0.4%).
- Of observed side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with Altace, only asthenia (fatigue) was more common on Altace than placebo (2% vs. 1%, respectively).
- In placebo-controlled trials, there was also an excess of upper respiratory infection and flu syndrome in the Altace group, not attributed at that time to ramipril. As these studies were carried out before the relationship of cough to ACE inhibitors was recognized, some of these events may represent ramipril-induced cough. In a later 1-year study, increased cough was seen in almost 12% of Altace patients, with about 4% of patients requiring discontinuation of treatment.
### Reduction in the Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
- Safety data in the Heart Outcomes Prevention Evaluation (HOPE) study were collected as reasons for discontinuation or temporary interruption of treatment. The incidence of cough was similar to that seen in the Acute Infarction Ramipril Efficacy (AIRE) trial. The rate of angioedema was the same as in previous clinical trials.
### Heart Failure Post-Myocardial Infarction
- Adverse reactions (except laboratory abnormalities) considered possibly/probably related to study drug that occurred in more than 1% of patients and more frequently on Altace are shown below. The incidences are from the AIRE study. The follow-up time was between 6 and 46 months for this study.
### Other Adverse Reactions
- Other adverse reactions reported in controlled clinical trials (in less than 1% of Altace patients), or rarer events seen in post-marketing experience, include the following (in some, a causal relationship to drug is uncertain)
### Body as a whole
### Cardiovascular
- Symptomatic hypotension (reported in 0.5% of patients in U.S. trials) syncope, and palpitations.
### Hematologic
- Pancytopenia, hemolytic anemia, and thrombocytopenia.
- Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%, respectively) were rare, occurring in 0.4% of patients receiving Altace alone and in 1.5% of patients receiving Altace plus a diuretic.
### Renal
- Acute renal failure. Some hypertensive patients with no apparent pre-existing renal disease have developed minor, usually transient, increases in blood urea nitrogen and serum creatinine when taking Altace, particularly when Altace was given concomitantly with a diuretic.
### Angioneurotic edema
- Angioneurotic edema has been reported in 0.3% of patients in U.S. clinical trials of Altace.
### Gastrointestinal
- Hepatic failure, hepatitis, jaundice, pancreatitis, abdominal pain (sometimes with enzyme changes suggesting pancreatitis), anorexia, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, gastroenteritis, increased salivation, and taste disturbance.
### Dermatologic
- Apparent hypersensitivity reactions (manifested by urticaria, pruritus, or rash, with or without fever), photosensitivity, purpura, onycholysis, pemphigus, pemphigoid, erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome.
### Neurologic and Psychiatric
- Anxiety, amnesia, convulsions, depression, hearing loss, insomnia, nervousness, neuralgia, neuropathy, paresthesia, somnolence, tinnitus, tremor, vertigo, and vision disturbances.
### Miscellaneous
- As with other ACE inhibitors, a symptom complex has been reported which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, photosensitivity, rash and other dermatologic manifestations. Additionally, as with other ACE inhibitors, eosinophilic pneumonitis has been reported.
### Diuretics
- Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Altace. The possibility of hypotensive effects with Altace can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Altace. If this is not possible, reduce the starting dose.
- Altace can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the patient's serum potassium frequently.
### Other Antihypertensive Agents
- Limited experience in controlled and uncontrolled trials combining Altace with a calcium channel blocker, a loop diuretic, or triple therapy (beta-blocker, vasodilator, and a diuretic) indicate no unusual drug-drug interactions. Other ACE inhibitors have had less than additive effects with beta adrenergic blockers, presumably because both drug classes lower blood pressure by inhibiting parts of the renin-angiotensin-aldosterone system.
- The combination of ramipril and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart rate).
- In a large-scale, long-term clinical efficacy study, the combination of telmisartan and ramipril resulted in an increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, dialysis) compared with groups receiving either drug alone. Therefore, concomitant use of telmisartan and ramipril is not recommended.
### Lithium
- Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium; therefore, frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.
### Gold
- Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including Altace.
### Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
- In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including ramipril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving ramipril and NSAID therapy.
- The antihypertensive effect of ACE inhibitors, including ramipril, may be attenuated by NSAIDs.
### Aliskiren
- Do not co-administer aliskiren with Altace in patients with diabetes. Avoid concomitant use of aliskiren with Altace in patients with renal impairment (GFR <60 mL/min/1.73 m2).
### mTOR Inhibitors
- Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema.
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility.
- No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the recommended human dose.
### Other
- Neither ramipril nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin. The co-administration of ramipril and warfarin did not adversely affect the anticoagulation effects of the latter drug. Additionally, co-administration of ramipril with phenprocoumon did not affect minimum phenprocoumon levels or interfere with the patients' state of anticoagulation.
## Postmarketing Experience
In addition to adverse reactions reported from clinical trials, there have been rare reports of hypoglycemia reported during ALTACE therapy when given to patients concomitantly taking oral hypoglycemic agents or insulin. The causal relationship is unknown.
## Clinical Laboratory Test Findings
Creatinine and Blood Urea Nitrogen: Increases in creatinine levels occurred in 1.2% of patients receiving ALTACE alone, and in 1.5% of patients receiving ALTACE and a diuretic. Increases in blood urea nitrogen levels occurred in 0.5% of patients receiving ALTACE alone and in 3% of patients receiving ALTACE with a diuretic. None of these increases required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis (see Drug Interactions). As ramipril decreases aldosterone secretion, elevation of serum potassium can occur. Use potassium supplements and potassium sparing diuretics with caution, and monitor the patient's serum potassium frequently (see Drug Interactions).
Hemoglobin and Hematocrit: Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%, respectively) were rare, occurring in 0.4% of patients receiving ALTACE alone and in 1.5% of patients receiving ALTACE plus a diuretic. No US patients discontinued treatment because of decreases in hemoglobin or hematocrit.
Other (causal relationships unknown): Clinically important changes in standard laboratory tests were rarely associated with ALTACE administration. Elevations of liver enzymes, serum bilirubin, uric acid, and blood glucose have been reported, as have cases of hyponatremia and scattered incidents of leucopenia, eosinophilia, and proteinuria. In US trials, less than 0.2% of patients discontinued treatment for laboratory abnormalities; all of these were cases of proteinuria or abnormal liver-function tests.
# Drug Interactions
### Diuretics
- Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Altace. The possibility of hypotensive effects with Altace can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Altace. If this is not possible, reduce the starting dose.
- Altace can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the patient's serum potassium frequently.
### Other Antihypertensive Agents
- Limited experience in controlled and uncontrolled trials combining Altace with a calcium channel blocker, a loop diuretic, or triple therapy (beta-blocker, vasodilator, and a diuretic) indicate no unusual drug-drug interactions. Other ACE inhibitors have had less than additive effects with beta adrenergic blockers, presumably because both drug classes lower blood pressure by inhibiting parts of the renin-angiotensin-aldosterone system.
- The combination of ramipril and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart rate).
- In a large-scale, long-term clinical efficacy study, the combination of telmisartan and ramipril resulted in an increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, dialysis) compared with groups receiving either drug alone. Therefore, concomitant use of telmisartan and ramipril is not recommended.
### Lithium
- Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium; therefore, frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.
### Gold
- Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including Altace.
### Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
- In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including ramipril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving ramipril and NSAID therapy.
- The antihypertensive effect of ACE inhibitors, including ramipril, may be attenuated by NSAIDs.
### Aliskiren
- Do not co-administer aliskiren with Altace in patients with diabetes. Avoid concomitant use of aliskiren with Altace in patients with renal impairment.
### mTOR Inhibitors
- Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema.
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility.
- No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the recommended human dose.
### Other
- Neither ramipril nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin. The co-administration of ramipril and warfarin did not adversely affect the anticoagulation effects of the latter drug. Additionally, co-administration of ramipril with phenprocoumon did not affect minimum phenprocoumon levels or interfere with the patients' state of anticoagulation.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Altace as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
- In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Altace unless it is considered life-saving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Altace for hypotension, oliguria, and hyperkalemia.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ramipril in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ramipril during labor and delivery.
### Nursing Mothers
- Ingestion of a single 10 mg oral dose of Altace resulted in undetectable amounts of ramipril and its metabolites in breast milk. However, because multiple doses may produce low milk concentrations that are not predictable from a single dose, do not use Altace in nursing mothers.
### Pediatric Use
- Safety and efficacy not established in pediatric patients
### Geriatic Use
- Of the total number of patients who received Altace in U.S. clinical studies of Altace, 11.0% were ≥65 years of age while 0.2% were ≥75 years of age. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.
- One pharmacokinetic study conducted in hospitalized elderly patients indicated that peak ramiprilat levels and area under the plasma concentration-time curve (AUC) for ramiprilat are higher in older patients.
### Gender
There is no FDA guidance on the use of Ramipril with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ramipril with respect to specific racial populations.
### Renal Impairment
- Establish baseline renal function in patients initiating Altace. Usual regimens of therapy with Altace may be followed in patients with estimated creatinine clearance >40 mL/min. However, in patients with worse impairment, 25% of the usual dose of ramipril is expected to produce full therapeutic levels of ramiprilat.
- A single-dose pharmacokinetic study was conducted in hypertensive patients with varying degrees of renal impairment who received a single 10 mg dose of ramipril. Patients were stratified into four groups based on initial estimates of creatinine clearance: normal (>80 mL/min), mild impairment (40–80 mL/min), moderate impairment (15–40 mL/min), and severe impairment (<15 mL/min). On average, the AUC0–24h for ramiprilat was approximately 1.7-fold higher, 3.0-fold higher, and 3.2-fold higher in the groups with mild, moderate, and severe renal impairment, respectively, compared to the group with normal renal function. Overall, the results suggest that the starting dose of ramipril should be adjusted downward in patients with moderate-to-severe renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ramipril in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ramipril in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ramipril in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- General Dosing Information
- Generally, swallow ALTACE capsules whole. The ALTACE capsule can also be opened and the contents sprinkled on a small amount (about 4 oz.) of applesauce or mixed in 4 oz. (120 mL) of water or apple juice. To be sure that ramipril is not lost when such a mixture is used, consume the mixture in its entirety. The described mixtures can be pre-prepared and stored for up to 24 hours at room temperature or up to 48 hours under refrigeration.
Concomitant administration of ALTACE with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can lead to increases of serum potassium (see Warnings and Precautions).
### Monitoring
FDA Package Insert for Ramipril contains no information regarding Monitoring.
# IV Compatibility
FDA Package Insert for Ramipril contains no information regarding IV Compatibility.
# Overdosage
Single oral doses of ramipril in rats and mice of 10 g/kg–11 g/kg resulted in significant lethality. In dogs, oral doses as high as 1 g/kg induced only mild gastrointestinal distress. Limited data on human overdosage are available. The most likely clinical manifestations would be symptoms attributable to hypotension.
Laboratory determinations of serum levels of ramipril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of ramipril overdose.
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of ramipril and its metabolites. Similarly, it is not known which, if any, of these substances can be effectively removed from the body by hemodialysis.
Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of ramipril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of ramipril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat ramipril overdose by infusion of normal saline solution.
# Pharmacology
## Mechanism of Action
- Ramipril and ramiprilat inhibit ACE in human subjects and animals. Angiotensin converting enzyme is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with Altace alone for up to 56 weeks, approximately 4% of patients during the trial had an abnormally high serum potassium and an increase from baseline greater than 0.75 mEq/L, and none of the patients had an abnormally low potassium and a decrease from baseline greater than 0.75 mEq/L. In the same study, approximately 2% of patients treated with Altace and hydrochlorothiazide for up to 56 weeks had abnormally high potassium values and an increase from baseline of 0.75 mEq/L or greater; and approximately 2% had abnormally low values and decreases from baseline of 0.75 mEq/L or greater (see Warnings and Precautions). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
- The effect of ramipril on hypertension appears to result at least in part from inhibition of both tissue and circulating ACE activity, thereby reducing angiotensin II formation in tissue and plasma.
- Angiotensin converting enzyme is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasopressor peptide, play a role in the therapeutic effects of Altace remains to be elucidated.
- While the mechanism through which Altace lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, Altace has an antihypertensive effect even in patients with low-renin hypertension. Although Altace was antihypertensive in all races studied, Black hypertensive patients (usually a low-renin hypertensive population) had a blood pressure lowering response to monotherapy, albeit a smaller average response, than non-Black patients.
## Structure
Ramipril is a 2-aza-bicyclo -octane-3-carboxylic acid derivative. It is a white, crystalline substance soluble in polar organic solvents and buffered aqueous solutions. Ramipril melts between 105°–112°C.
The CAS Registry Number is 87333-19-5. Ramipril's chemical name is (2S,3aS,6aS)-1 alanyl] octahydrocyclopenta pyrrole-2-carboxylic acid, 1-ethyl ester.
The inactive ingredients present are pregelatinized starch NF, gelatin, and titanium dioxide. The 1.25 mg capsule shell contains yellow iron oxide, the 2.5 mg capsule shell contains D&C yellow #10 and FD&C red #40, the 5 mg capsule shell contains FD&C blue #1 and FD&C red #40, and the 10 mg capsule shell contains FD&C blue #1.
The structural formula for ramipril is:
Its empirical formula is C23H32N2O5 and its molecular weight is 416.5.
Ramiprilat, the diacid metabolite of ramipril, is a non-sulfhydryl ACE inhibitor. Ramipril is converted to ramiprilat by hepatic cleavage of the ester group.
## Pharmacodynamics
- Single doses of ramipril of 2.5 mg–20 mg produce approximately 60%–80% inhibition of ACE activity 4 hours after dosing with approximately 40%–60% inhibition after 24 hours. Multiple oral doses of ramipril of 2.0 mg or more cause plasma ACE activity to fall by more than 90% 4 hours after dosing, with over 80% inhibition of ACE activity remaining 24 hours after dosing. The more prolonged effect of even small multiple doses presumably reflects saturation of ACE binding sites by ramiprilat and relatively slow release from those sites.
## Pharmacokinetics
- Following oral administration of Altace, peak plasma concentrations (Cmax) of ramipril are reached within 1 hour. The extent of absorption is at least 50%–60%, and is not significantly influenced by the presence of food in the gastrointestinal tract, although the rate of absorption is reduced.
- In a trial in which subjects received Altace capsules or the contents of identical capsules dissolved in water, dissolved in apple juice, or suspended in applesauce, serum ramiprilat levels were essentially unrelated to the use or non-use of the concomitant liquid or food.
- Cleavage of the ester group (primarily in the liver) converts ramipril to its active diacid metabolite, ramiprilat. Peak plasma concentrations of ramiprilat are reached 2–4 hours after drug intake. The serum protein binding of ramipril is about 73% and that of ramiprilat about 56%; in vitro, these percentages are independent of concentration over the range of 0.01 µg/mL–10 µg/mL.
- Ramipril is almost completely metabolized to ramiprilat, which has about 6 times the ACE inhibitory activity of ramipril, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which are inactive.
- Plasma concentrations of ramipril and ramiprilat increase with increased dose, but are not strictly dose-proportional. The 24-hour AUC for ramiprilat, however, is dose-proportional over the 2.5 mg–20 mg dose range. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when 5 mg of oral ramipril was compared with the same dose of ramipril given intravenously.
- After once-daily dosing, steady-state plasma concentrations of ramiprilat are reached by the fourth dose. Steady-state concentrations of ramiprilat are somewhat higher than those seen after the first dose of Altace, especially at low doses (2.5 mg), but the difference is clinically insignificant.
- Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination phase, terminal elimination phase). The initial rapid decline, which represents distribution of the drug into a large peripheral compartment and subsequent binding to both plasma and tissue ACE, has a half-life of 2–4 hours. Because of its potent binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent elimination phase corresponds to the clearance of free ramiprilat and has a half-life of 9–18 hours. The terminal elimination phase has a prolonged half-life (>50 hours) and probably represents the binding/dissociation kinetics of the ramiprilat/ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of Altace 5 mg–10 mg, the half-life of ramiprilat concentrations within the therapeutic range was 13–17 hours.
- In patients with creatinine clearance <40 mL/min/1.73 m2, peak levels of ramiprilat are approximately doubled, and trough levels may be as much as quintupled. In multiple-dose regimens, the total exposure to ramiprilat (AUC) in these patients is 3–4 times as large as it is in patients with normal renal function who receive similar doses.
- In patients with impaired liver function, the metabolism of ramipril to ramiprilat appears to be slowed, possibly because of diminished activity of hepatic esterases, and plasma ramipril levels in these patients are increased about 3-fold. Peak concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function, and the effect of a given dose on plasma ACE activity does not vary with hepatic function.
- After oral administration of ramipril, about 60% of the parent drug and its metabolites are eliminated in the urine, and about 40% is found in the feces. Drug recovered in the feces may represent both biliary excretion of metabolites and/or unabsorbed drug, however the proportion of a dose eliminated by the bile has not been determined. Less than 2% of the administered dose is recovered in urine as unchanged ramipril.
- The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function. Compared to normal subjects, patients with creatinine clearance <40 mL/min/1.73 m2 had higher peak and trough ramiprilat levels and slightly longer times to peak concentrations.
## Nonclinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility.
No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the recommended human dose.
# Clinical Studies
### Hypertension
- Altace has been compared with other ACE inhibitors, beta-blockers, and thiazide diuretics as monotherapy for hypertension. It was approximately as effective as other ACE inhibitors and as atenolol.
- Administration of Altace to patients with mild to moderate hypertension results in a reduction of both supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted. Use of Altace in combination with thiazide diuretics gives a blood pressure lowering effect greater than that seen with either agent alone.
- In single-dose studies, doses of 5 mg–20 mg of Altace lowered blood pressure within 1–2 hours, with peak reductions achieved 3–6 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In longer term (4–12 weeks) controlled studies, once-daily doses of 2.5 mg–10 mg were similar in their effect, lowering supine or standing systolic and diastolic blood pressures 24 hours after dosing by about 6/4 mmHg more than placebo. In comparisons of peak vs. trough effect, the trough effect represented about 50–60% of the peak response. In a titration study comparing divided (bid) vs. qd treatment, the divided regimen was superior, indicating that for some patients, the antihypertensive effect with once-daily dosing is not adequately maintained.
- In most trials, the antihypertensive effect of Altace increased during the first several weeks of repeated measurements. The antihypertensive effect of Altace has been shown to continue during long-term therapy for at least 2 years. Abrupt withdrawal of Altace has not resulted in a rapid increase in blood pressure. Altace has been compared with other ACE inhibitors, beta-blockers, and thiazide diuretics. Altace was approximately as effective as other ACE inhibitors and as atenolol. In both Caucasians and Blacks, hydrochlorothiazide (25 or 50 mg) was significantly more effective than ramipril.
- Altace was less effective in blacks than in Caucasians. The effectiveness of Altace was not influenced by age, sex, or weight.
- In a baseline controlled study of 10 patients with mild essential hypertension, blood pressure reduction was accompanied by a 15% increase in renal blood flow. In healthy volunteers, glomerular filtration rate was unchanged.
### Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
- The HOPE study was a large, multicenter, randomized, double-blind, placebo-controlled, 2 × 2 factorial design study conducted in 9541 patients (4645 on Altace) who were 55 years or older and considered at high risk of developing a major cardiovascular event because of a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that was accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or documented microalbuminuria). Patients were either normotensive or under treatment with other antihypertensive agents. Patients were excluded if they had clinical heart failure or were known to have a low ejection fraction (<0.40). This study was designed to examine the long-term (mean of 5 years) effects of Altace (10 mg orally once daily) on the combined endpoint of myocardial infarction, stroke, or death from cardiovascular causes.
- The HOPE study results showed that Altace (10 mg/day) significantly reduced the rate of myocardial infarction, stroke, or death from cardiovascular causes (826/4652 vs. 651/4645, relative risk 0.78), as well as the rates of the 3 components of the combined endpoint. The relative risk of the composite outcomes in the Altace group as compared to the placebo group was 0.78% (95% confidence interval, 0.70–0.86). The effect was evident after about 1 year of treatment.
- Altace was effective in different demographic subgroups (i.e., gender, age), subgroups defined by underlying disease (e.g., cardiovascular disease, hypertension), and subgroups defined by concomitant medication. There were insufficient data to determine whether or not Altace was equally effective in ethnic subgroups.
- This study was designed with a prespecified substudy in diabetics with at least one other cardiovascular risk factor. Effects of Altace on the combined endpoint and its components were similar in diabetics (N=3577) to those in the overall study population.
- Cerebrovascular disease was defined as stroke or transient ischemic attacks. The size of each symbol is proportional to the number of patients in each group. The dashed line indicates overall relative risk.
- The benefits of Altace were observed among patients who were taking aspirin or other anti-platelet agents, beta-blockers, and lipid-lowering agents as well as diuretics and calcium channel blockers.
### Heart Failure Post-Myocardial Infarction
- Altace was studied in the AIRE trial. This was a multinational (mainly European) 161-center, 2006-patient, double-blind, randomized, parallel-group study comparing Altace to placebo in stable patients, 2–9 days after an acute myocardial infarction, who had shown clinical signs of congestive heart failure at any time after the myocardial infarction. Patients in severe (NYHA class IV) heart failure, patients with unstable angina, patients with heart failure of congenital or valvular etiology, and patients with contraindications to ACE inhibitors were all excluded. The majority of patients had received thrombolytic therapy at the time of the index infarction, and the average time between infarction and initiation of treatment was 5 days.
- Patients randomized to Altace treatment were given an initial dose of 2.5 mg twice daily. If the initial regimen caused undue hypotension, the dose was reduced to 1.25 mg, but in either event doses were titrated upward (as tolerated) to a target regimen (achieved in 77% of patients randomized to Altace) of 5 mg twice daily. Patients were then followed for an average of 15 months, with the range of follow-up between 6 and 46 months.
- The use of Altace was associated with a 27% reduction (p=0.002) in the risk of death from any cause; about 90% of the deaths that occurred were cardiovascular, mainly sudden death. The risks of progression to severe heart failure and of congestive heart failure-related hospitalization were also reduced, by 23% (p=0.017) and 26% (p=0.011), respectively. The benefits of Altace therapy were seen in both genders, and they were not affected by the exact timing of the initiation of therapy, but older patients may have had a greater benefit than those under 65. The benefits were seen in patients on (and not on) various concomitant medications. At the time of randomization these included aspirin (about 80% of patients), diuretics (about 60%), organic nitrates (about 55%), beta-blockers (about 20%), calcium channel blockers (about 15%), and digoxin (about 12%).
# How Supplied
Altace is available in 1.25 mg, 2.5 mg, 5 mg, and 10 mg hard gelatin capsules.
## Storage
Store at controlled room temperature (59°–86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Angioedema
- Angioedema, including laryngeal edema, can occur rarely with treatment with ACE inhibitors, especially following the first dose. Advise patients to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician.
- Neutropenia
- Advise patients to report promptly any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia.
- Symptomatic Hypotension
- Inform patients that light-headedness can occur, especially during the first days of therapy, and it should be reported. Advise patients to discontinue ALTACE if syncope (fainting) occurs, and to follow up with their health care providers.
Inform patients that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting while taking ALTACE can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.
- Pregnancy
- Female patients of childbearing age should be told about the consequences of exposure to Altace during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
- Hyperkalemia
- Advise patients not to use salt substitutes containing potassium without consulting their physician.
# Precautions with Alcohol
Alcohol-Ramipril tablet 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 Ramipril Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Ramipril Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ramipril
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2], Amr Marawan, M.D. [3]
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# Black Box Warning
# Overview
Ramipril is an Angiotensin converting enzyme inhibitor that is FDA approved for the treatment of hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension, asthenia, dizziness, headache, cough and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information (not receiving diuretic)
- Initial dose : Ramipril 2.5 mg PO qd should be used.Adjust dose according to blood pressure response.
- Maintenance dose: Ramipril 2.5-20 mg PO qd or bid
- In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients, consider an increase in dosage or twice daily administration. If blood pressure is not controlled with ALTACE alone, a diuretic can be added.
- Reduction in Myocardial Infarction, Stroke ,and Death from Cardiovascular Causes
- Dosage for 1st week: 2.5 mg PO qd
- Dosage for the next 3 weeks: 5 mg PO qd
- Maintaining dosage: 10 mg PO qd (if tolerated)
- If the patient is hypertensive or recently post-myocardial infarction, ALTACE can also be given as a divided dose.
- Dosing Information
- Initial dose for the 1st week : 2.5 mg PO bid
- For patients become hypotensive: switched to 1.25 mg PO bid
- Dosage from the 2nd dosage: 5 mg PO bid, with dosage increases being about 3 weeks apart.
- After the initial dose of ALTACE, observe the patient under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour. If possible, reduce the dose of any concomitant diuretic as this may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of ALTACE does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension (see Warnings and Precautions, Drug Interactions).
- Renal Impairment
- Indication for adjustment: In patients with estimated creatinine clearance ≤40 mL/min. (Usual dosage maybe safe in patients with creatinine clearance >40 mL/min )
- Adjustmented dosage: 25% of the usual dose is expected to produce full therapeutic levels.
- Hypertension
- Indication for adjustment: For patients with hypertension and renal impairment.
- Adjusted dosage: 1.25 mg PO bid, max: 2.5 mg PO bid (depending on clinical response and tolerability).
- Volume Depletion or Renal Artery Stenosis
- Initiate dosage: 1.25 mg PO qd. Adjust dosage according to blood pressure response.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
### Heart Failure
- Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA)
- Class of Recommendation: Class IIa
- Strength of Evidence: Level A
- Dosing Information/Recommendation
- Initial dosage: 2.5 mg PO bid
- Maintaining dosage: 5 mg PO bid (if tolerated)
### Non–Guideline-Supported Use
- Dosing information
- 10 mg/day [1]
- 5 mg/day or more [2]
- 1.25 mg/day[3]
- Dosing information
- 1.25 mg[4]
- Dosing information
- 2.5 mg/day[5]
- 5 mg[6]
- 1.25 mg or 5 mg[7]
- 5 mg[8]
- Dosing information
- 10 mg/day[1]
- 5 mg [9]
- 2.5-5 mg PO qd [10]
- 1.25-5 mg PO qd[11]
- 10 mg/day[1]
- Dosing information
- 5 mg PO qd[12]
- Dosing information
- 10 mg PO qd[13]
### Peripheral arterial occlusive disease=
- Dosing information
- 10 mg PO qd[14]
- Dosing information
- 20 mg PO qd[15]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
safety and efficacy not established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about guideline-supported off-label use
### Non–Guideline-Supported Use
- There is limited information about Off-Label Non–Guideline-Supported Use of Ramipril tablet in pediatric patients.
# Contraindications
- Altace is contraindicated in patients who are hypersensitive to this product or any other ACE inhibitor (e.g., a patient who has experienced angioedema during therapy with any other ACE inhibitor).
- Do not co-administer aliskiren with Altace in patients with diabetes
# Warnings
### Anaphylactoid and Possibly Related Reactions
- Presumably because drugs that act directly on the renin-angiotensin-aldosterone system (e.g., ACE inhibitors) affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving these drugs (including Altace) may be subject to a variety of adverse reactions, some of them serious.
### Angioedema
- Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor.
- Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, discontinue treatment with Altace and institute appropriate therapy immediately. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, administer appropriate therapy (e.g., subcutaneous epinephrine solution 1:1000 [0.3 mL to 0.5 mL]) promptly.
- In considering the use of Altace, note that in controlled clinical trials ACE inhibitors cause a higher rate of angioedema in Black patients than in non-Black patients.
- In a large U.S. post-marketing study, angioedema (defined as reports of angio, face, larynx, tongue, or throat edema) was reported in 3/1523 (0.20%) Black patients and in 8/8680 (0.09%) non-Black patients. These rates were not different statistically.
- Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema
- Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Include intestinal angioedema in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
### Anaphylactoid Reactions During Desensitization
- Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
### Anaphylactoid Reactions During Membrane Exposure
- Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
### Hepatic Failure and Impaired Liver Function
- Rarely, ACE inhibitors, including Altace, have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Discontinue Altace if patient develops jaundice or marked elevations of hepatic enzymes.
- As ramipril is primarily metabolized by hepatic esterases to its active moiety, ramiprilat, patients with impaired liver function could develop markedly elevated plasma levels of ramipril. No formal pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function.
### Renal Impairment
- As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including Altace, may be associated with oliguria or progressive azotemia and rarely with acute renal failure or death.
- In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another ACE inhibitor suggests that these increases would be reversible upon discontinuation of Altace and/or diuretic therapy. In such patients, monitor renal function during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when Altace has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of Altace and/or discontinuation of the diuretic may be required.
### Neutropenia and Agranulocytosis
- In rare instances, treatment with ACE inhibitors may be associated with mild reductions in red blood cell count and hemoglobin content, blood cell or platelet counts. In isolated cases, agranulocytosis, pancytopenia, and bone marrow depression may occur. Hematological reactions to ACE inhibitors are more likely to occur in patients with collagen-vascular disease (e.g., systemic lupus erythematosus, scleroderma) and renal impairment. Consider monitoring white blood cell counts in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function.
### Hypotension
## General Considerations
- Altace can cause symptomatic hypotension, after either the initial dose or a later dose when the dosage has been increased. Like other ACE inhibitors, Altace, has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume- and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Correct volume- and salt-depletion before initiating therapy with Altace.
- If excessive hypotension occurs, place the patient in a supine position and, if necessary, treat with intravenous infusion of physiological saline. Altace treatment usually can be continued following restoration of blood pressure and volume.
### Heart Failure Post-Myocardial Infarction
- In patients with heart failure post-myocardial infarction who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of Altace. If the initial dose of 2.5 mg Altace cannot be tolerated, use an initial dose of 1.25 mg Altace to avoid excessive hypotension. Consider reducing the dose of concomitant diuretic to decrease the incidence of hypotension.
### Congestive Heart Failure
- In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and rarely, with acute renal failure and death. In such patients, initiate Altace therapy under close medical supervision and follow patients closely for the first 2 weeks of treatment and whenever the dose of Altace or diuretic is increased.
### Surgery and Anesthesia
- In patients undergoing surgery or during anesthesia with agents that produce hypotension, ramipril may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.
### Fetal Toxicity
### Pregnancy Category D
- Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Altace as soon as possible.
### Dual Blockade of the Renin-Angiotensin-Aldosterone System
- Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on Altace and other agents that affect the RAS.
### Telmisartan
- The ONTARGET trial enrolled 25,620 patients >55 years old with atherosclerotic disease or diabetes with end-organ damage, randomized them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months. Patients receiving the combination of telmisartan and ramipril did not obtain any benefit in the composite endpoint of cardiovascular death, MI, stroke and heart failure hospitalization compared to monotherapy, but experienced an increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, or dialysis) compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of telmisartan and ramipril is not recommended.
### Aliskiren
- Do not co-administer aliskiren with Altace in patients with diabetes. Avoid concomitant use of aliskiren with Altace in patients with renal impairment (GFR <60 mL/min/1.73 m2). (see Drug Interactions)
### Hyperkalemia
- In clinical trials with Altace, hyperkalemia (serum potassium >5.7 mEq/L) occurred in approximately 1% of hypertensive patients receiving Altace. In most cases, these were isolated values, which resolved despite continued therapy. None of these patients were discontinued from the trials because of hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with Altace.
### Cough
- Presumably caused by inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. Consider the possibility of angiotensin converting enzyme inhibitor induced-cough in the differential diagnosis of cough.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, the 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.
### Hypertension
- Altace has been evaluated for safety in over 4000 patients with hypertension; of these, 1230 patients were studied in U.S. controlled trials, and 1107 were studied in foreign controlled trials. Almost 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was similar in Altace and placebo patients.
- The most frequent clinical side effects (possibly or probably related to study drug) reported by patients receiving Altace in placebo-controlled trials were headache (5.4%), dizziness (2.2%), and fatigue or asthenia (2.0%), but only the last one was more common in Altace patients than in patients given placebo. Generally the side effects were mild and transient, and there was no relation to total dosage within the range of 1.25 mg–20 mg. Discontinuation of therapy because of a side effect was required in approximately 3% of U.S. patients treated with Altace. The most common reasons for discontinuation were cough (1.0%), dizziness (0.5%), and impotence (0.4%).
- Of observed side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with Altace, only asthenia (fatigue) was more common on Altace than placebo (2% vs. 1%, respectively).
- In placebo-controlled trials, there was also an excess of upper respiratory infection and flu syndrome in the Altace group, not attributed at that time to ramipril. As these studies were carried out before the relationship of cough to ACE inhibitors was recognized, some of these events may represent ramipril-induced cough. In a later 1-year study, increased cough was seen in almost 12% of Altace patients, with about 4% of patients requiring discontinuation of treatment.
### Reduction in the Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
- Safety data in the Heart Outcomes Prevention Evaluation (HOPE) study were collected as reasons for discontinuation or temporary interruption of treatment. The incidence of cough was similar to that seen in the Acute Infarction Ramipril Efficacy (AIRE) trial. The rate of angioedema was the same as in previous clinical trials.
### Heart Failure Post-Myocardial Infarction
- Adverse reactions (except laboratory abnormalities) considered possibly/probably related to study drug that occurred in more than 1% of patients and more frequently on Altace are shown below. The incidences are from the AIRE study. The follow-up time was between 6 and 46 months for this study.
### Other Adverse Reactions
- Other adverse reactions reported in controlled clinical trials (in less than 1% of Altace patients), or rarer events seen in post-marketing experience, include the following (in some, a causal relationship to drug is uncertain)
### Body as a whole
### Cardiovascular
- Symptomatic hypotension (reported in 0.5% of patients in U.S. trials) syncope, and palpitations.
### Hematologic
- Pancytopenia, hemolytic anemia, and thrombocytopenia.
- Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%, respectively) were rare, occurring in 0.4% of patients receiving Altace alone and in 1.5% of patients receiving Altace plus a diuretic.
### Renal
- Acute renal failure. Some hypertensive patients with no apparent pre-existing renal disease have developed minor, usually transient, increases in blood urea nitrogen and serum creatinine when taking Altace, particularly when Altace was given concomitantly with a diuretic.
### Angioneurotic edema
- Angioneurotic edema has been reported in 0.3% of patients in U.S. clinical trials of Altace.
### Gastrointestinal
- Hepatic failure, hepatitis, jaundice, pancreatitis, abdominal pain (sometimes with enzyme changes suggesting pancreatitis), anorexia, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, gastroenteritis, increased salivation, and taste disturbance.
### Dermatologic
- Apparent hypersensitivity reactions (manifested by urticaria, pruritus, or rash, with or without fever), photosensitivity, purpura, onycholysis, pemphigus, pemphigoid, erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome.
### Neurologic and Psychiatric
- Anxiety, amnesia, convulsions, depression, hearing loss, insomnia, nervousness, neuralgia, neuropathy, paresthesia, somnolence, tinnitus, tremor, vertigo, and vision disturbances.
### Miscellaneous
- As with other ACE inhibitors, a symptom complex has been reported which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, photosensitivity, rash and other dermatologic manifestations. Additionally, as with other ACE inhibitors, eosinophilic pneumonitis has been reported.
### Diuretics
- Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Altace. The possibility of hypotensive effects with Altace can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Altace. If this is not possible, reduce the starting dose.
- Altace can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the patient's serum potassium frequently.
### Other Antihypertensive Agents
- Limited experience in controlled and uncontrolled trials combining Altace with a calcium channel blocker, a loop diuretic, or triple therapy (beta-blocker, vasodilator, and a diuretic) indicate no unusual drug-drug interactions. Other ACE inhibitors have had less than additive effects with beta adrenergic blockers, presumably because both drug classes lower blood pressure by inhibiting parts of the renin-angiotensin-aldosterone system.
- The combination of ramipril and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart rate).
- In a large-scale, long-term clinical efficacy study, the combination of telmisartan and ramipril resulted in an increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, dialysis) compared with groups receiving either drug alone. Therefore, concomitant use of telmisartan and ramipril is not recommended.
### Lithium
- Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium; therefore, frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.
### Gold
- Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including Altace.
### Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
- In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including ramipril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving ramipril and NSAID therapy.
- The antihypertensive effect of ACE inhibitors, including ramipril, may be attenuated by NSAIDs.
### Aliskiren
- Do not co-administer aliskiren with Altace in patients with diabetes. Avoid concomitant use of aliskiren with Altace in patients with renal impairment (GFR <60 mL/min/1.73 m2).
### mTOR Inhibitors
- Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema.
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility.
- No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the recommended human dose.
### Other
- Neither ramipril nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin. The co-administration of ramipril and warfarin did not adversely affect the anticoagulation effects of the latter drug. Additionally, co-administration of ramipril with phenprocoumon did not affect minimum phenprocoumon levels or interfere with the patients' state of anticoagulation.
## Postmarketing Experience
In addition to adverse reactions reported from clinical trials, there have been rare reports of hypoglycemia reported during ALTACE therapy when given to patients concomitantly taking oral hypoglycemic agents or insulin. The causal relationship is unknown.
## Clinical Laboratory Test Findings
Creatinine and Blood Urea Nitrogen: Increases in creatinine levels occurred in 1.2% of patients receiving ALTACE alone, and in 1.5% of patients receiving ALTACE and a diuretic. Increases in blood urea nitrogen levels occurred in 0.5% of patients receiving ALTACE alone and in 3% of patients receiving ALTACE with a diuretic. None of these increases required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis (see Drug Interactions). As ramipril decreases aldosterone secretion, elevation of serum potassium can occur. Use potassium supplements and potassium sparing diuretics with caution, and monitor the patient's serum potassium frequently (see Drug Interactions).
Hemoglobin and Hematocrit: Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%, respectively) were rare, occurring in 0.4% of patients receiving ALTACE alone and in 1.5% of patients receiving ALTACE plus a diuretic. No US patients discontinued treatment because of decreases in hemoglobin or hematocrit.
Other (causal relationships unknown): Clinically important changes in standard laboratory tests were rarely associated with ALTACE administration. Elevations of liver enzymes, serum bilirubin, uric acid, and blood glucose have been reported, as have cases of hyponatremia and scattered incidents of leucopenia, eosinophilia, and proteinuria. In US trials, less than 0.2% of patients discontinued treatment for laboratory abnormalities; all of these were cases of proteinuria or abnormal liver-function tests.
# Drug Interactions
### Diuretics
- Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Altace. The possibility of hypotensive effects with Altace can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Altace. If this is not possible, reduce the starting dose.
- Altace can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the patient's serum potassium frequently.
### Other Antihypertensive Agents
- Limited experience in controlled and uncontrolled trials combining Altace with a calcium channel blocker, a loop diuretic, or triple therapy (beta-blocker, vasodilator, and a diuretic) indicate no unusual drug-drug interactions. Other ACE inhibitors have had less than additive effects with beta adrenergic blockers, presumably because both drug classes lower blood pressure by inhibiting parts of the renin-angiotensin-aldosterone system.
- The combination of ramipril and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart rate).
- In a large-scale, long-term clinical efficacy study, the combination of telmisartan and ramipril resulted in an increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, dialysis) compared with groups receiving either drug alone. Therefore, concomitant use of telmisartan and ramipril is not recommended.
### Lithium
- Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium; therefore, frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.
### Gold
- Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including Altace.
### Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
- In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including ramipril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving ramipril and NSAID therapy.
- The antihypertensive effect of ACE inhibitors, including ramipril, may be attenuated by NSAIDs.
### Aliskiren
- Do not co-administer aliskiren with Altace in patients with diabetes. Avoid concomitant use of aliskiren with Altace in patients with renal impairment.
### mTOR Inhibitors
- Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema.
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility.
- No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the recommended human dose.
### Other
- Neither ramipril nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin. The co-administration of ramipril and warfarin did not adversely affect the anticoagulation effects of the latter drug. Additionally, co-administration of ramipril with phenprocoumon did not affect minimum phenprocoumon levels or interfere with the patients' state of anticoagulation.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Altace as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
- In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Altace unless it is considered life-saving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Altace for hypotension, oliguria, and hyperkalemia.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ramipril in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ramipril during labor and delivery.
### Nursing Mothers
- Ingestion of a single 10 mg oral dose of Altace resulted in undetectable amounts of ramipril and its metabolites in breast milk. However, because multiple doses may produce low milk concentrations that are not predictable from a single dose, do not use Altace in nursing mothers.
### Pediatric Use
- Safety and efficacy not established in pediatric patients
### Geriatic Use
- Of the total number of patients who received Altace in U.S. clinical studies of Altace, 11.0% were ≥65 years of age while 0.2% were ≥75 years of age. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.
- One pharmacokinetic study conducted in hospitalized elderly patients indicated that peak ramiprilat levels and area under the plasma concentration-time curve (AUC) for ramiprilat are higher in older patients.
### Gender
There is no FDA guidance on the use of Ramipril with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ramipril with respect to specific racial populations.
### Renal Impairment
- Establish baseline renal function in patients initiating Altace. Usual regimens of therapy with Altace may be followed in patients with estimated creatinine clearance >40 mL/min. However, in patients with worse impairment, 25% of the usual dose of ramipril is expected to produce full therapeutic levels of ramiprilat.
- A single-dose pharmacokinetic study was conducted in hypertensive patients with varying degrees of renal impairment who received a single 10 mg dose of ramipril. Patients were stratified into four groups based on initial estimates of creatinine clearance: normal (>80 mL/min), mild impairment (40–80 mL/min), moderate impairment (15–40 mL/min), and severe impairment (<15 mL/min). On average, the AUC0–24h for ramiprilat was approximately 1.7-fold higher, 3.0-fold higher, and 3.2-fold higher in the groups with mild, moderate, and severe renal impairment, respectively, compared to the group with normal renal function. Overall, the results suggest that the starting dose of ramipril should be adjusted downward in patients with moderate-to-severe renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ramipril in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ramipril in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ramipril in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- General Dosing Information
- Generally, swallow ALTACE capsules whole. The ALTACE capsule can also be opened and the contents sprinkled on a small amount (about 4 oz.) of applesauce or mixed in 4 oz. (120 mL) of water or apple juice. To be sure that ramipril is not lost when such a mixture is used, consume the mixture in its entirety. The described mixtures can be pre-prepared and stored for up to 24 hours at room temperature or up to 48 hours under refrigeration.
Concomitant administration of ALTACE with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can lead to increases of serum potassium (see Warnings and Precautions).
### Monitoring
FDA Package Insert for Ramipril contains no information regarding Monitoring.
# IV Compatibility
FDA Package Insert for Ramipril contains no information regarding IV Compatibility.
# Overdosage
Single oral doses of ramipril in rats and mice of 10 g/kg–11 g/kg resulted in significant lethality. In dogs, oral doses as high as 1 g/kg induced only mild gastrointestinal distress. Limited data on human overdosage are available. The most likely clinical manifestations would be symptoms attributable to hypotension.
Laboratory determinations of serum levels of ramipril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of ramipril overdose.
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of ramipril and its metabolites. Similarly, it is not known which, if any, of these substances can be effectively removed from the body by hemodialysis.
Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of ramipril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of ramipril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat ramipril overdose by infusion of normal saline solution.
# Pharmacology
## Mechanism of Action
- Ramipril and ramiprilat inhibit ACE in human subjects and animals. Angiotensin converting enzyme is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with Altace alone for up to 56 weeks, approximately 4% of patients during the trial had an abnormally high serum potassium and an increase from baseline greater than 0.75 mEq/L, and none of the patients had an abnormally low potassium and a decrease from baseline greater than 0.75 mEq/L. In the same study, approximately 2% of patients treated with Altace and hydrochlorothiazide for up to 56 weeks had abnormally high potassium values and an increase from baseline of 0.75 mEq/L or greater; and approximately 2% had abnormally low values and decreases from baseline of 0.75 mEq/L or greater (see Warnings and Precautions). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
- The effect of ramipril on hypertension appears to result at least in part from inhibition of both tissue and circulating ACE activity, thereby reducing angiotensin II formation in tissue and plasma.
- Angiotensin converting enzyme is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasopressor peptide, play a role in the therapeutic effects of Altace remains to be elucidated.
- While the mechanism through which Altace lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, Altace has an antihypertensive effect even in patients with low-renin hypertension. Although Altace was antihypertensive in all races studied, Black hypertensive patients (usually a low-renin hypertensive population) had a blood pressure lowering response to monotherapy, albeit a smaller average response, than non-Black patients.
## Structure
Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative. It is a white, crystalline substance soluble in polar organic solvents and buffered aqueous solutions. Ramipril melts between 105°–112°C.
The CAS Registry Number is 87333-19-5. Ramipril's chemical name is (2S,3aS,6aS)-1[(S)-N-[(S)-1-Carboxy-3-phenylpropyl] alanyl] octahydrocyclopenta [b]pyrrole-2-carboxylic acid, 1-ethyl ester.
The inactive ingredients present are pregelatinized starch NF, gelatin, and titanium dioxide. The 1.25 mg capsule shell contains yellow iron oxide, the 2.5 mg capsule shell contains D&C yellow #10 and FD&C red #40, the 5 mg capsule shell contains FD&C blue #1 and FD&C red #40, and the 10 mg capsule shell contains FD&C blue #1.
The structural formula for ramipril is:
Its empirical formula is C23H32N2O5 and its molecular weight is 416.5.
Ramiprilat, the diacid metabolite of ramipril, is a non-sulfhydryl ACE inhibitor. Ramipril is converted to ramiprilat by hepatic cleavage of the ester group.
## Pharmacodynamics
- Single doses of ramipril of 2.5 mg–20 mg produce approximately 60%–80% inhibition of ACE activity 4 hours after dosing with approximately 40%–60% inhibition after 24 hours. Multiple oral doses of ramipril of 2.0 mg or more cause plasma ACE activity to fall by more than 90% 4 hours after dosing, with over 80% inhibition of ACE activity remaining 24 hours after dosing. The more prolonged effect of even small multiple doses presumably reflects saturation of ACE binding sites by ramiprilat and relatively slow release from those sites.
## Pharmacokinetics
- Following oral administration of Altace, peak plasma concentrations (Cmax) of ramipril are reached within 1 hour. The extent of absorption is at least 50%–60%, and is not significantly influenced by the presence of food in the gastrointestinal tract, although the rate of absorption is reduced.
- In a trial in which subjects received Altace capsules or the contents of identical capsules dissolved in water, dissolved in apple juice, or suspended in applesauce, serum ramiprilat levels were essentially unrelated to the use or non-use of the concomitant liquid or food.
- Cleavage of the ester group (primarily in the liver) converts ramipril to its active diacid metabolite, ramiprilat. Peak plasma concentrations of ramiprilat are reached 2–4 hours after drug intake. The serum protein binding of ramipril is about 73% and that of ramiprilat about 56%; in vitro, these percentages are independent of concentration over the range of 0.01 µg/mL–10 µg/mL.
- Ramipril is almost completely metabolized to ramiprilat, which has about 6 times the ACE inhibitory activity of ramipril, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which are inactive.
- Plasma concentrations of ramipril and ramiprilat increase with increased dose, but are not strictly dose-proportional. The 24-hour AUC for ramiprilat, however, is dose-proportional over the 2.5 mg–20 mg dose range. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when 5 mg of oral ramipril was compared with the same dose of ramipril given intravenously.
- After once-daily dosing, steady-state plasma concentrations of ramiprilat are reached by the fourth dose. Steady-state concentrations of ramiprilat are somewhat higher than those seen after the first dose of Altace, especially at low doses (2.5 mg), but the difference is clinically insignificant.
- Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination phase, terminal elimination phase). The initial rapid decline, which represents distribution of the drug into a large peripheral compartment and subsequent binding to both plasma and tissue ACE, has a half-life of 2–4 hours. Because of its potent binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent elimination phase corresponds to the clearance of free ramiprilat and has a half-life of 9–18 hours. The terminal elimination phase has a prolonged half-life (>50 hours) and probably represents the binding/dissociation kinetics of the ramiprilat/ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of Altace 5 mg–10 mg, the half-life of ramiprilat concentrations within the therapeutic range was 13–17 hours.
- In patients with creatinine clearance <40 mL/min/1.73 m2, peak levels of ramiprilat are approximately doubled, and trough levels may be as much as quintupled. In multiple-dose regimens, the total exposure to ramiprilat (AUC) in these patients is 3–4 times as large as it is in patients with normal renal function who receive similar doses.
- In patients with impaired liver function, the metabolism of ramipril to ramiprilat appears to be slowed, possibly because of diminished activity of hepatic esterases, and plasma ramipril levels in these patients are increased about 3-fold. Peak concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function, and the effect of a given dose on plasma ACE activity does not vary with hepatic function.
- After oral administration of ramipril, about 60% of the parent drug and its metabolites are eliminated in the urine, and about 40% is found in the feces. Drug recovered in the feces may represent both biliary excretion of metabolites and/or unabsorbed drug, however the proportion of a dose eliminated by the bile has not been determined. Less than 2% of the administered dose is recovered in urine as unchanged ramipril.
- The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function. Compared to normal subjects, patients with creatinine clearance <40 mL/min/1.73 m2 had higher peak and trough ramiprilat levels and slightly longer times to peak concentrations.
## Nonclinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility.
No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the recommended human dose.
# Clinical Studies
### Hypertension
- Altace has been compared with other ACE inhibitors, beta-blockers, and thiazide diuretics as monotherapy for hypertension. It was approximately as effective as other ACE inhibitors and as atenolol.
- Administration of Altace to patients with mild to moderate hypertension results in a reduction of both supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted. Use of Altace in combination with thiazide diuretics gives a blood pressure lowering effect greater than that seen with either agent alone.
- In single-dose studies, doses of 5 mg–20 mg of Altace lowered blood pressure within 1–2 hours, with peak reductions achieved 3–6 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In longer term (4–12 weeks) controlled studies, once-daily doses of 2.5 mg–10 mg were similar in their effect, lowering supine or standing systolic and diastolic blood pressures 24 hours after dosing by about 6/4 mmHg more than placebo. In comparisons of peak vs. trough effect, the trough effect represented about 50–60% of the peak response. In a titration study comparing divided (bid) vs. qd treatment, the divided regimen was superior, indicating that for some patients, the antihypertensive effect with once-daily dosing is not adequately maintained.
- In most trials, the antihypertensive effect of Altace increased during the first several weeks of repeated measurements. The antihypertensive effect of Altace has been shown to continue during long-term therapy for at least 2 years. Abrupt withdrawal of Altace has not resulted in a rapid increase in blood pressure. Altace has been compared with other ACE inhibitors, beta-blockers, and thiazide diuretics. Altace was approximately as effective as other ACE inhibitors and as atenolol. In both Caucasians and Blacks, hydrochlorothiazide (25 or 50 mg) was significantly more effective than ramipril.
- Altace was less effective in blacks than in Caucasians. The effectiveness of Altace was not influenced by age, sex, or weight.
- In a baseline controlled study of 10 patients with mild essential hypertension, blood pressure reduction was accompanied by a 15% increase in renal blood flow. In healthy volunteers, glomerular filtration rate was unchanged.
### Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
- The HOPE study was a large, multicenter, randomized, double-blind, placebo-controlled, 2 × 2 factorial design study conducted in 9541 patients (4645 on Altace) who were 55 years or older and considered at high risk of developing a major cardiovascular event because of a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that was accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or documented microalbuminuria). Patients were either normotensive or under treatment with other antihypertensive agents. Patients were excluded if they had clinical heart failure or were known to have a low ejection fraction (<0.40). This study was designed to examine the long-term (mean of 5 years) effects of Altace (10 mg orally once daily) on the combined endpoint of myocardial infarction, stroke, or death from cardiovascular causes.
- The HOPE study results showed that Altace (10 mg/day) significantly reduced the rate of myocardial infarction, stroke, or death from cardiovascular causes (826/4652 vs. 651/4645, relative risk 0.78), as well as the rates of the 3 components of the combined endpoint. The relative risk of the composite outcomes in the Altace group as compared to the placebo group was 0.78% (95% confidence interval, 0.70–0.86). The effect was evident after about 1 year of treatment.
- Altace was effective in different demographic subgroups (i.e., gender, age), subgroups defined by underlying disease (e.g., cardiovascular disease, hypertension), and subgroups defined by concomitant medication. There were insufficient data to determine whether or not Altace was equally effective in ethnic subgroups.
- This study was designed with a prespecified substudy in diabetics with at least one other cardiovascular risk factor. Effects of Altace on the combined endpoint and its components were similar in diabetics (N=3577) to those in the overall study population.
- Cerebrovascular disease was defined as stroke or transient ischemic attacks. The size of each symbol is proportional to the number of patients in each group. The dashed line indicates overall relative risk.
- The benefits of Altace were observed among patients who were taking aspirin or other anti-platelet agents, beta-blockers, and lipid-lowering agents as well as diuretics and calcium channel blockers.
### Heart Failure Post-Myocardial Infarction
- Altace was studied in the AIRE trial. This was a multinational (mainly European) 161-center, 2006-patient, double-blind, randomized, parallel-group study comparing Altace to placebo in stable patients, 2–9 days after an acute myocardial infarction, who had shown clinical signs of congestive heart failure at any time after the myocardial infarction. Patients in severe (NYHA class IV) heart failure, patients with unstable angina, patients with heart failure of congenital or valvular etiology, and patients with contraindications to ACE inhibitors were all excluded. The majority of patients had received thrombolytic therapy at the time of the index infarction, and the average time between infarction and initiation of treatment was 5 days.
- Patients randomized to Altace treatment were given an initial dose of 2.5 mg twice daily. If the initial regimen caused undue hypotension, the dose was reduced to 1.25 mg, but in either event doses were titrated upward (as tolerated) to a target regimen (achieved in 77% of patients randomized to Altace) of 5 mg twice daily. Patients were then followed for an average of 15 months, with the range of follow-up between 6 and 46 months.
- The use of Altace was associated with a 27% reduction (p=0.002) in the risk of death from any cause; about 90% of the deaths that occurred were cardiovascular, mainly sudden death. The risks of progression to severe heart failure and of congestive heart failure-related hospitalization were also reduced, by 23% (p=0.017) and 26% (p=0.011), respectively. The benefits of Altace therapy were seen in both genders, and they were not affected by the exact timing of the initiation of therapy, but older patients may have had a greater benefit than those under 65. The benefits were seen in patients on (and not on) various concomitant medications. At the time of randomization these included aspirin (about 80% of patients), diuretics (about 60%), organic nitrates (about 55%), beta-blockers (about 20%), calcium channel blockers (about 15%), and digoxin (about 12%).
# How Supplied
Altace is available in 1.25 mg, 2.5 mg, 5 mg, and 10 mg hard gelatin capsules.
## Storage
Store at controlled room temperature (59°–86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Angioedema
- Angioedema, including laryngeal edema, can occur rarely with treatment with ACE inhibitors, especially following the first dose. Advise patients to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician.
- Neutropenia
- Advise patients to report promptly any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia.
- Symptomatic Hypotension
- Inform patients that light-headedness can occur, especially during the first days of therapy, and it should be reported. Advise patients to discontinue ALTACE if syncope (fainting) occurs, and to follow up with their health care providers.
Inform patients that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting while taking ALTACE can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.
- Pregnancy
- Female patients of childbearing age should be told about the consequences of exposure to Altace during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
- Hyperkalemia
- Advise patients not to use salt substitutes containing potassium without consulting their physician.
# Precautions with Alcohol
Alcohol-Ramipril tablet 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 Ramipril Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Ramipril Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ramace | |
c80b8aa7e9ffa3a0b5bd1f74b6efbf1d4e2dca6f | wikidoc | Rapeseed | Rapeseed
Rapeseed (Brassica napus), also known as Rape, Oilseed Rape, Rapa, Rapaseed and (one particular cultivar) Canola, is a bright yellow flowering member of the family Brassicaceae (mustard or cabbage family). The name is derived through Old English from a term for turnip, rapum (see Brassica napobrassica, which may be considered a variety of Brassica napus). Some botanists include the closely related Brassica campestris within B. napus. (See Triangle of U)
# Cultivation and uses
Rapeseed is grown for the production of animal feed, vegetable oil for human consumption, and biodiesel; leading producers include the European Union, Canada, the United States, Australia, China and India. In India, it is grown on 13% of cropped land. According to the United States Department of Agriculture, rapeseed was the third leading source of vegetable oil in the world in 2000, after soybean and oil palm, and also the world's second leading source of protein meal, although only one-fifth of the production of the leading soybean meal. World production is growing rapidly, with FAO reporting that 36 million tonnes of rapeseed was produced in the 2003-4 season, and 46 million tonnes in 2004-5. In Europe, rapeseed is primarily cultivated for animal feed (due to its very high lipid and medium protein content), and is a leading option for Europeans to avoid importation of GMO products.
Natural rapeseed oil contains erucic acid, which is mildly toxic to humans in large doses but is used as a food additive in smaller doses. Canola, originally a syncopated form of the abbreviation "Can.O., L-A." (Canadian Oilseed, Low-Acid) that was used by the Manitoba government to label the seed during its experimental stages, is now a tradename for low erucic acid rapeseed that is sometimes mis-applied to other varieties.
The rapeseed is the valuable, harvested component of the crop. The crop is also grown as a winter-cover crop. It provides good coverage of the soil in winter, and limits nitrogen run-off. The plant is ploughed back in the soil or used as bedding. On some ecological or organic operations, livestock such as sheep or cattle are allowed to graze on the plants.
Processing of rapeseed for oil production provides rapeseed animal meal as a by-product. The by-product is a high-protein animal feed, competitive with soya. The feed is mostly employed for cattle feeding, but also for pigs and chickens (though less valuable for these). The meal has a very low content of the glucosinolates responsible for metabolism disruption in cattle and pigs. Rapeseed "oil cake" is also used as a fertilizer in China, and may be used for ornamentals, such as Bonsai, as well.
Rapeseed leaves and stems are also edible, similar to those of the related bok choy or kale. Some varieties of rapeseed (called 油菜, yóu cài, lit. "oil vegetable" in Chinese; yu choy in Cantonese; and 菜の花, nanohana in Japanese) are sold as greens, primarily in Asian groceries.
Rapeseed is a heavy nectar producer, and honeybees produce a light colored, but peppery honey from it. It must be extracted immediately after processing is finished, as it will quickly granulate in the honeycomb and will be impossible to extract. The honey is usually blended with milder honeys, if used for table use, or sold as bakery grade. Rapeseed growers contract with beekeepers for the pollination of the crop.
# Nutritional value
Canola oil (or rapeseed oil) contains both omega-6 and omega-3 fatty acids in a ratio of 2:1 and is second only to flax oil in omega-3 fatty acid. It is one of the most heart-healthy oils and has been reported to reduce cholesterol levels, lower serum tryglyceride levels, and keep platelets from sticking together.
Some UK farmers (such as Hillfarm Oils) & Farrington Oils) have started to produce cold-pressed rapeseed oil as a versatile cooking oil and dressing, similar in use to olive oil.
ll
# Biodiesel
Rapeseed oil is used in the manufacture of biodiesel for powering motor vehicles. Biodiesel may be used in pure form in newer engines without engine damage, and is frequently combined with standard diesel in ratios varying from 2% to 20% biodiesel. Formerly, due to the costs of growing, crushing, and refining rapeseed biodiesel, rapeseed derived biodiesel cost more to produce than standard diesel fuel. Prices of rapeseed oil are at very high levels presently (start November 05) due to increased demand on rapeseed oil for this purpose. Rapeseed oil is the preferred oil stock for biodiesel production in most of Europe, partly because rapeseed produces more oil per unit of land area as compared to other oil sources, such as soy beans.
# Rapeseed and health
Rapeseed has been linked with adverse effects in asthma and hay fever sufferers. Some suggest that oilseed pollen is the cause of increased breathing difficulties. This is unlikely however, as rapeseed is an entomophilous crop, with pollen transfer primarily by insects. Others suggest that it is the inhalation of oilseed rape dust that causes this, and that allergies to the pollen are relatively rare. There may also be another effect at work; since rapeseed in flower has a distinctive and pungent smell, hay fever sufferers may wrongly jump to the conclusion that it is the rapeseed that is to blame simply because they can smell it. An alternative explanation may be that it is simply the sheer volume of rapeseed pollen in the air around farmland which triggers an allergic reaction in hayfever sufferers on inhalation, or following prolonged exposure to high levels.
# Controversy
The Monsanto Company has genetically engineered new cultivars of rapeseed that are resistant to the effects of its herbicide Roundup. They have been vigorously prosecuting farmers found to have the Roundup Ready gene in Canola in their fields without paying a license fee. These farmers have claimed the Roundup Ready gene was blown into their fields and crossed with unaltered Canola. Other farmers claim that after spraying Roundup in non-Canola fields to kill weeds before planting, Roundup Ready volunteers are left behind, causing extra expense to rid their fields of the weeds.
In a closely followed legal battle, the Supreme Court of Canada found in favor of Monsanto's patent infringement claim for illegal growing of Roundup Ready in its 2004 ruling on Monsanto Canada Inc. v. Schmeiser. The case garnered international controversy as a court-sanctioned legitimation for the global patent protection of genetically modified crops.
# Production
Worldwide production of rapeseed (including canola) rose to 46.4 million metric tons in 2005, the highest recorded total (source: FAO).
# Pests and diseases affecting rapeseed
## Animal pests
- Harlequin bug (Murgantia histrionica)
- Flea beetles (Phyllotreta sp.),
- Diamondback moths (Plutella xylostella),
- Bertha armyworms (Mamestra configurata),
- Root maggots (Delia sp.)
- Grasshoppers
- Lygus bugs (Lygus)
- Bronzed field beetle larvae
- Snails and slugs
## Diseases
- Beet Western Yellows virus
- Blackleg, caused by the fungus Leptosphaeria maculans
- Clubroot, caused by protist Plasmodiophora brassicae
- Sclerotinia white stem rot
White rust diease (Albugo candida)
# Genome sequencing and genetics
The 'A' genome component of the amphidiploid Rapeseed species B. napus is currently being sequenced by an international consortium. | Rapeseed
Rapeseed (Brassica napus), also known as Rape, Oilseed Rape, Rapa, Rapaseed and (one particular cultivar) Canola, is a bright yellow flowering member of the family Brassicaceae (mustard or cabbage family). The name is derived through Old English from a term for turnip, rapum (see Brassica napobrassica, which may be considered a variety of Brassica napus). Some botanists include the closely related Brassica campestris within B. napus. (See Triangle of U)
# Cultivation and uses
Rapeseed is grown for the production of animal feed, vegetable oil for human consumption, and biodiesel; leading producers include the European Union, Canada, the United States, Australia, China and India. In India, it is grown on 13% of cropped land. According to the United States Department of Agriculture, rapeseed was the third leading source of vegetable oil in the world in 2000, after soybean and oil palm, and also the world's second leading source of protein meal, although only one-fifth of the production of the leading soybean meal. World production is growing rapidly, with FAO reporting that 36 million tonnes of rapeseed was produced in the 2003-4 season, and 46 million tonnes in 2004-5. In Europe, rapeseed is primarily cultivated for animal feed[citation needed] (due to its very high lipid and medium protein content[citation needed]), and is a leading option for Europeans to avoid importation of GMO products[citation needed].
Natural rapeseed oil contains erucic acid, which is mildly toxic to humans in large doses but is used as a food additive in smaller doses. Canola, originally a syncopated form of the abbreviation "Can.O., L-A." (Canadian Oilseed, Low-Acid) that was used by the Manitoba government to label the seed during its experimental stages, is now a tradename for low erucic acid rapeseed that is sometimes mis-applied to other varieties[citation needed].
The rapeseed is the valuable, harvested component of the crop. The crop is also grown as a winter-cover crop. It provides good coverage of the soil in winter, and limits nitrogen run-off. The plant is ploughed back in the soil or used as bedding. On some ecological or organic operations, livestock such as sheep or cattle are allowed to graze on the plants.
Processing of rapeseed for oil production provides rapeseed animal meal as a by-product. The by-product is a high-protein animal feed, competitive with soya[citation needed]. The feed is mostly employed for cattle feeding, but also for pigs and chickens (though less valuable for these). The meal has a very low content of the glucosinolates responsible for metabolism disruption in cattle and pigs[citation needed]. Rapeseed "oil cake" is also used as a fertilizer in China, and may be used for ornamentals, such as Bonsai, as well.
Rapeseed leaves and stems are also edible, similar to those of the related bok choy or kale. Some varieties of rapeseed (called 油菜, yóu cài, lit. "oil vegetable" in Chinese; yu choy in Cantonese; and 菜の花, nanohana in Japanese) are sold as greens, primarily in Asian groceries.
Rapeseed is a heavy nectar producer, and honeybees produce a light colored, but peppery honey from it. It must be extracted immediately after processing is finished, as it will quickly granulate in the honeycomb and will be impossible to extract. The honey is usually blended with milder honeys, if used for table use, or sold as bakery grade. Rapeseed growers contract with beekeepers for the pollination of the crop.
# Nutritional value
Canola oil (or rapeseed oil) contains both omega-6 and omega-3 fatty acids in a ratio of 2:1 and is second only to flax oil in omega-3 fatty acid. It is one of the most heart-healthy oils and has been reported to reduce cholesterol levels, lower serum tryglyceride levels, and keep platelets from sticking together.
Some UK farmers (such as Hillfarm Oils[1]) & Farrington Oils[2]) have started to produce cold-pressed rapeseed oil as a versatile cooking oil and dressing, similar in use to olive oil.
ll
# Biodiesel
Rapeseed oil is used in the manufacture of biodiesel for powering motor vehicles. Biodiesel may be used in pure form in newer engines without engine damage, and is frequently combined with standard diesel in ratios varying from 2% to 20% biodiesel. Formerly, due to the costs of growing, crushing, and refining rapeseed biodiesel, rapeseed derived biodiesel cost more to produce than standard diesel fuel. Prices of rapeseed oil are at very high levels presently (start November 05) due to increased demand on rapeseed oil for this purpose. Rapeseed oil is the preferred oil stock for biodiesel production in most of Europe, partly because rapeseed produces more oil per unit of land area as compared to other oil sources, such as soy beans.
# Rapeseed and health
Rapeseed has been linked with adverse effects in asthma and hay fever sufferers.[citation needed] Some suggest that oilseed pollen is the cause of increased breathing difficulties.[citation needed] This is unlikely however[citation needed], as rapeseed is an entomophilous crop, with pollen transfer primarily by insects. Others suggest that it is the inhalation of oilseed rape dust that causes this[1], and that allergies to the pollen are relatively rare.[citation needed] There may also be another effect at work; since rapeseed in flower has a distinctive and pungent smell, hay fever sufferers may wrongly jump to the conclusion that it is the rapeseed that is to blame simply because they can smell it.[citation needed] An alternative explanation may be that it is simply the sheer volume of rapeseed pollen in the air around farmland which triggers an allergic reaction in hayfever sufferers on inhalation, or following prolonged exposure to high levels.
# Controversy
The Monsanto Company has genetically engineered new cultivars of rapeseed that are resistant to the effects of its herbicide Roundup. They have been vigorously prosecuting farmers found to have the Roundup Ready gene in Canola in their fields without paying a license fee[citation needed]. These farmers have claimed the Roundup Ready gene was blown into their fields and crossed with unaltered Canola[citation needed]. Other farmers claim that after spraying Roundup in non-Canola fields to kill weeds before planting, Roundup Ready volunteers are left behind, causing extra expense to rid their fields of the weeds[citation needed].
In a closely followed legal battle, the Supreme Court of Canada found in favor of Monsanto's patent infringement claim for illegal growing of Roundup Ready in its 2004 ruling on Monsanto Canada Inc. v. Schmeiser. The case garnered international controversy as a court-sanctioned legitimation for the global patent protection of genetically modified crops[citation needed].
# Production
Worldwide production of rapeseed (including canola) rose to 46.4 million metric tons in 2005, the highest recorded total (source: FAO).
# Pests and diseases affecting rapeseed
## Animal pests
- Harlequin bug (Murgantia histrionica)
- Flea beetles (Phyllotreta sp.),
- Diamondback moths (Plutella xylostella),
- Bertha armyworms (Mamestra configurata),
- Root maggots (Delia sp.)
- Grasshoppers
- Lygus bugs (Lygus)
- Bronzed field beetle larvae
- Snails and slugs
## Diseases
- Beet Western Yellows virus
- Blackleg, caused by the fungus Leptosphaeria maculans
- Clubroot, caused by protist Plasmodiophora brassicae
- Sclerotinia white stem rot
White rust diease (Albugo candida)
# Genome sequencing and genetics
The 'A' genome component of the amphidiploid Rapeseed species B. napus is currently being sequenced by an international consortium.
[2] | https://www.wikidoc.org/index.php/Rapeseed | |
44261a016673682fcbe4668e852e575d9812e119 | wikidoc | Raw milk | Raw milk
Raw milk is milk that has not been pasteurized before consumption.
# History
Humans consumed raw milk before factory farming methods coinciding with the industrial revolution, when large populations congregated into urban areas detached from the agricultural lifestyle to which they were accustomed. Up until that point, individuals and families owned their own goats, cows and other livestock and milked them on a daily basis.
## Health issues
The consumption of raw milk has been empirically linked to undulant fever, dysentery, salmonellosis, and tuberculosis, which are diseases that were eliminated by pasteurization. While pasteurization reduces the content of some vitamins, such as Vitamin C, these nutrients are not present in milk in large quantities to be begin with. .
Proponents of raw milk claim that it is healthy, contains proteins, beneficial bacteria, enzymes and hormones..
# Legal status
## Worldwide
Commercial distribution of packaged raw milk is prohibited in many countries. However, 28 US states allow sales of raw milk, and in other parts of the world, raw milk can often be bought directly from the farmer. In England, about 200 producers sell raw, or "green top" milk direct to consumers, either at the farm or through a delivery service. Raw milk is sometimes distributed through a share program, wherein the consumer owns a share in the dairy animal or the herd, and can be considered to be consuming milk from their own animal. In the United States, Arizona, California, Connecticut, and Washington allow raw milk sales in retail stores with appropriate warning labelling.
## In Middle East
Human consumption of raw camel milk is very popular in the Middle East, especially in rural areas. In many large cities there are people who sell raw milk, although some large cities are illegalizing that due to hygiene issues.
## In Africa
Although milk consumption is fairly low compared to the rest of the world, in tribes where milk consumption is popular, such as the Maasai tribe, milk drunk is typically unpasteurized.
## In Europe
Milk is typically consumed unpasteurized in rural areas of Europe, and raw milk can typically be found in small amounts at stores in large cities.
## In Asia
In rural areas of Asia where milk consumption is popular, milk is typically unpasteurized. In large cities of Asia, raw milk, especially from water buffalo, is typical. In most countries of Asia, laws prohibiting raw milk are nonexistent or rarely enforced.
## In Australia
Raw milk for drinking purposes is illegal in all states and territories, as is all raw cheese. This has been circumvented somewhat by selling Raw milk as 'bath milk'. An exception to the cheese rule has been made recently for two Roquefort cheeses. There is some indication of share owning cows, allowing the "owners" to consume the raw milk, but also evidence that the government is trying to close this loop hole.
## In Canada
The sale of raw milk directly to consumers is prohibited in Canada under the Food and Drug Regulations since 1991.
Section B.08.002.2 (1)
However, like the United States, Canada permits the sale of raw milk cheeses that are aged for at least 60 days.
## In the United States
Most states impose restrictions on raw milk suppliers due to concerns about safety. Every state but Pennsylvania, California, New York, and Maryland has passed the Pasteurized Milk Ordinance originally proposed by the United States Public Health Service in 1924. The most recent version is called the 2003 Grade "A" Pasteurized Milk Ordinance. All 50 states permit the sale of raw milk cheeses that are aged for at least 60 days.
Raw milk may be sold from the farm in 28 states under varying restrictions. In California, Connecticut, Maine, Pennsylvania, South Carolina and New Mexico it may be sold in stores. Washington State allows raw milk to be sold with restrictions. Some states allow raw milk to be sold "for animal consumption" only.
Although it is illegal in Indiana, Colorado, Michigan and Ohio for a dairy to sell raw milk, consumers are able to lease part of a cow (a "cow share") or part of a herd (a "herd share") to obtain raw milk. In Michigan, for example, "milk groups" have been formed in which suburban families take turns travelling to a distant dairy farm to obtain the week's raw milk for all the members of the group.
The FDA reports that, in 2002, consuming raw milk and raw milk products caused 200 Americans to become ill in any manner . In comparison, a 1999 CDC report showed that consuming undercooked fish and shellfish causes approximately 8,000 cases of Vibrio illness annually,Template:POV-statement in addition to all cases of salmonella poisoning, Yersiniosis, Listeriosis, Hepatitis, Gastroenteritis, Diphyllobothriasis, and Nanophyetiasis.
# Debate in the United States
Although agencies such as the Centers for Disease Control (CDC), the Food and Drug Administration (FDA) and numerous other world-wide regulatory agencies say that pathogens from raw milk make it unsafe to consume, certain organizations such as the Weston A. Price Foundation in its "Real Milk" campaign say that raw milk has health benefits that get lost in the pasteurization process, and that it can be produced hygienically. | Raw milk
Raw milk is milk that has not been pasteurized before consumption.
# History
Humans consumed raw milk before factory farming methods coinciding with the industrial revolution, when large populations congregated into urban areas detached from the agricultural lifestyle to which they were accustomed. Up until that point, individuals and families owned their own goats, cows and other livestock and milked them on a daily basis.
## Health issues
The consumption of raw milk has been empirically linked to undulant fever, dysentery, salmonellosis, and tuberculosis, which are diseases that were eliminated by pasteurization. While pasteurization reduces the content of some vitamins, such as Vitamin C, these nutrients are not present in milk in large quantities to be begin with. [1].
Proponents of raw milk claim that it is healthy, contains proteins, beneficial bacteria, enzymes and hormones.[2].
# Legal status
## Worldwide
Commercial distribution of packaged raw milk is prohibited in many countries. However, 28 US states allow sales of raw milk, and in other parts of the world, raw milk can often be bought directly from the farmer. In England, about 200 producers sell raw, or "green top" milk direct to consumers, either at the farm or through a delivery service. Raw milk is sometimes distributed through a share program, wherein the consumer owns a share in the dairy animal or the herd, and can be considered to be consuming milk from their own animal. In the United States, Arizona, California, Connecticut, and Washington allow raw milk sales in retail stores with appropriate warning labelling.
## In Middle East
Human consumption of raw camel milk is very popular in the Middle East, especially in rural areas. In many large cities there are people who sell raw milk, although some large cities are illegalizing that due to hygiene issues.
## In Africa
Although milk consumption is fairly low compared to the rest of the world, in tribes where milk consumption is popular, such as the Maasai tribe, milk drunk is typically unpasteurized.
## In Europe
Milk is typically consumed unpasteurized in rural areas of Europe, and raw milk can typically be found in small amounts at stores in large cities.
## In Asia
In rural areas of Asia where milk consumption is popular, milk is typically unpasteurized. In large cities of Asia, raw milk, especially from water buffalo, is typical. In most countries of Asia, laws prohibiting raw milk are nonexistent or rarely enforced.
## In Australia
Raw milk for drinking purposes is illegal in all states and territories, as is all raw cheese. This has been circumvented somewhat by selling Raw milk as 'bath milk'. An exception to the cheese rule has been made recently for two Roquefort cheeses. There is some indication of share owning cows, allowing the "owners" to consume the raw milk, but also evidence that the government is trying to close this loop hole.[3][4]
## In Canada
The sale of raw milk directly to consumers is prohibited in Canada[5] under the Food and Drug Regulations since 1991.
Section B.08.002.2 (1)
However, like the United States, Canada permits the sale of raw milk cheeses that are aged for at least 60 days.
## In the United States
Most states impose restrictions on raw milk suppliers due to concerns about safety. Every state but Pennsylvania, California, New York, and Maryland has passed the Pasteurized Milk Ordinance originally proposed by the United States Public Health Service in 1924. The most recent version is called the 2003 Grade "A" Pasteurized Milk Ordinance.[7][8] All 50 states permit the sale of raw milk cheeses that are aged for at least 60 days.
Raw milk may be sold from the farm in 28 states under varying restrictions. In California, Connecticut, Maine, Pennsylvania, South Carolina and New Mexico it may be sold in stores. Washington State allows raw milk to be sold with restrictions.[9] Some states allow raw milk to be sold "for animal consumption" only.
Although it is illegal in Indiana, Colorado, Michigan[10] and Ohio for a dairy to sell raw milk, consumers are able to lease part of a cow (a "cow share") or part of a herd (a "herd share") to obtain raw milk. In Michigan, for example, "milk groups" have been formed in which suburban families take turns travelling to a distant dairy farm to obtain the week's raw milk for all the members of the group.
The FDA reports that, in 2002, consuming raw milk and raw milk products caused 200 Americans to become ill in any manner [11]. In comparison, a 1999 CDC report showed that consuming undercooked fish and shellfish causes approximately 8,000 cases of Vibrio illness annually,[12]Template:POV-statement in addition to all cases of salmonella poisoning, Yersiniosis, Listeriosis, Hepatitis, Gastroenteritis, Diphyllobothriasis, and Nanophyetiasis.[13]
# Debate in the United States
Although agencies such as the Centers for Disease Control (CDC), the Food and Drug Administration (FDA) and numerous other world-wide regulatory agencies say that pathogens from raw milk make it unsafe to consume,[14] certain organizations such as the Weston A. Price Foundation in its "Real Milk" campaign say that raw milk has health benefits that get lost in the pasteurization process, and that it can be produced hygienically. [15] | https://www.wikidoc.org/index.php/Raw_milk | |
d9c0a06760823ea6fe2b3e3596b484735b11b95e | wikidoc | Reuptake | Reuptake
Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse.
Reuptake is necessary for normal synaptic physiology because it allows for the recycling of neurotransmitters and regulates the level of neurotransmitter present in the synapse and controls how long a signal resulting from neurotransmitter release lasts. Because neurotransmitters are too large and hydrophilic to diffuse through the membrane, specific transport proteins are necessary for the reabsorption of neurotransmitters. Much research, both biochemical and structural, has been performed to obtain clues about the mechanism of reuptake.
# Protein structure
The first primary sequence of a reuptake protein was published in 1990. The technique for protein determination is contingent upon the purification, sequencing, and cloning of the transporter protein in question. After separate investigations had sequenced the DNA that coded for both GABA transporter and norepinephrine transporter, it could be seen that there were many similarities between the two DNA sequences. Further exploration in the field of reuptake proteins found that many of the transporters associated with important neurotransmitters within the body were also very similar in sequence to the GABA and norepinephrine transporters. The members of this new family include dopamine, norepinephrine, serotonin, and GABA. They were given the name Classical Na+/Cl- dependent transporters. Sodium and Chloride ion dependence will be discussed later in the mechanism of action. Using the commonalities among sequences and hydropathy plot analyses, it was determined that there are 12 hydrophobic membrane spanning structural units in the ‘Classical’ transporter family. In addition to this, the Na and Cl termini exist in the intracellular space. These proteins also all have an extended fourth extracellular loop. There is an extracellular cavity in the protein, into which protrudes a helix hairpin formed by extracellular loop EL4 . After using further more advanced scanning techniques, Masson et al. proposed that transmembrane unit 1 (closest to the Na-terminus) exists in the membrane as a pore loop. In other words, unit 1 would not exist in a transmembrane fashion but rather as a loop existing solely in the membrane. This model has been used before to explain mechanisms for ion selectivity filters, although the purpose of this pore loop is not readily apparent. This pore loop observation is consistent across all of the classical family of transporter proteins, suggesting that it is important for some function shared among them. Later experiments indicated that a tyrosine amino acid is highly conserved across transport proteins, and was shown to be essential for substrate binding and transport. Other important features include function specific positions in the transmembrane section 1, where an aspartate differentiates between monoamine substrates and a glycine differentiates between amino acid substrates. It has also been shown that a negatively charged residue in the extracellular loop 5 and the transmembrane domain 10 may form an external gate.
Yamashita et al. chose to examine a bacterial homologue (LeuT: Leucine transporter) of these classical transporters from the bacterium Aquifex aeolicus. Protein structure of LeuT was determined via crystallization. They chose to crystallize the system with leucine and its respective 2 sodium ions in order to visualize the pore and binding sites. The crystal was scanned via multi-wavelength anomalous dispersion. Using this technique, they were able to replicate the findings in the classical transporters, but they determined that the folding and final structure were unique. They found that the transmembrane domains 1 and 6 contain unwound segments in the middle of the membrane. Along with this, transmembrane domains 3 and 8 and the areas surrounding the unwound sections of 1 and 6 form the substrate and sodium ion binding sites. They observed pseudo-symmetry among the LeuT protein, seen best when observing transmembrane domains 1-5 against 6-10.
# Mechanism of action
The classic transporter proteins use symport to transport neurotransmitter across the membrane of the presynaptic neuron. The classical transporters, which are sodium and chloride ion dependent, take advantage of the large sodium gradients across the membrane. The neurotransmitter in question will bind to sodium ions, where the sodium ion will flow down its concentration gradient as well as electrical gradient. These forces will pull the neurotransmitter into the cell, against its own gradients. The chloride ion also contributes by flowing down its concentration gradient, but it flows against the electrical gradient, greatly reducing its efficiency as a symport ion. The role of the chloride ion in the symport mechanism is not exactly known, but has been implicated to be useful for counterbalancing the charge of the sodium symport ions. Because the neurotransmitter binds to sodium ions, their respective binding sites are very close in proximity. In the LeuT protein, the binding sites would be across transmembrane domains 3 and 8, and specifically the unwound sections of 1 and 6. These binding sites are made up of hydrogen and ionic bonding between the substrate and the transport protein. The primary sodium binding sites are Na1 and Na2, which exist in the transmembrane domains 1 (TM1) and 6 (TM6) in the unwound regions. In the LeuT example, 2 sodium ions bind to the substrate leucine. These 2 sodium ions work to pull leucine into the cell, but also by stabilizing the core of LeuT. Sodium ion 1 (binds to Na1) is octahedrally coordinated by the leucine carboxy oxygen, the carbonyl oxygens of Ala22 (transmembrane domain 1), Thr254 (TM6), side-chain carbonyl oxygens of Asn27 (TM1) and Asn286 (TM7), and the hydroxyl oxygen of Thr254 (TM6). The second sodium ion (binds to Na2) is trigonal bi-pyramidally coordinated by means of the carbonyl oxygens of Gly20 and Val23 (TM1), Ala351 (TM8), and the hydroxyl oxygens from Thr354 and Ser355 (TM8).
After sodium ion coordination has taken place, some conformational change must occur. In an isolated system of TM3, TM8, TM1, and TM6, the unwound sections of 1 and 6 act like a joint and pivot the entire transmembrane domain relative to the rest of the protein and TM3 and TM8. The summation of actions mimics a half revolving door. Both TM3 and TM8 remain stationary and TM1 and TM6 swing about it.
The resulting system has affinity for both the substrate and sodium ions at both the intracellular level and the extracellular level. As the system progresses, the extracellular openings are blocked off by a gate. Because of the sodium gradient, it is unlikely that much substrate transfer occurs from the intracellular level to the extracellular level. The LeuT transporter protein is a homologue of the human classical transport proteins, and thus the proposed mechanism of action can be assumed to be largely similar to the human model.
# Mechanism of reuptake inhibition
The main objective of a reuptake inhibitor is to substantially decrease the rate by which neurotransmitters are reabsorbed into the presynaptic neuron, leaving a net gain in the concentration of neurotransmitter in the synapse. This increases the probability and frequency of neurotransmitter binding to postsynaptic neurotransmitter receptors. Depending on the neurological system in question, a reuptake inhibitor can have drastic effects on cognition and behavior. Zhou et al. examined how tricyclic antidepressants act upon a reuptake protein in order to inhibit reuptake of the appropriate neurotransmitters. They chose to examine the LeuT system as it was previously crystallized by Yamashita et al. in 2005. They also chose to examine LeuT because it is a homologue of the transport proteins of concern when considering depression. They examined this relationship between tricyclic antidepressants and the LeuT system by crystallizing the two together, along with leucine and the respective 2 sodium ions. They found that the leucine and the sodium ions bound exactly as previously determined by Yamashita et al. They also observed that the tricyclic antidepressant (desipramine) followed leucine into the pore. Desipramine effectively sits on top of leucine in LeuT and they both bind to the same protein residue. The tail of desipramine extends into the extracellular space. Most of the LeuT structure does not change, but the EL4 hairpin does form around desipramine as if it were locking it in place in the LeuT pore. Desipramine also acts by binding to the extracellular gate and forming a salt bridge between TM1 and TM10. This action prevents TM1 from pivoting, which prevents leucine from ever being exposed to the intracellular side of LeuT. Desipramine works as a reuptake inhibitor by effectively blocking and crowding up the pore of LeuT, which physically prevents its normal course of action.
# Human systems
Horschitz et al. examined reuptake inhibitor selectivity among the rat serotonin reuptake protein (SERT) expressed in human embryonic kidney cells (HEK-SERT). They presented SERT with varying doses of either citalopram (SSRI, selective serotonin reuptake inhibitor) or desipramine (an inhibitor of norepinephrine reuptake protein, NET). By examining the dose-response curves (using a normal medium as control), they were able to quantify that citalopram acted on SERT as an SSRI, and that desipramine had no effect on SERT. In a separate experiment, Horschitz et al. exposed HEK-SERT with citalopram on a long-term basis. They noticed that long-term exposure led to a down-regulation of binding sites. These results suggest some mechanism for long-term changes in the pre-synaptic neuron after drug therapy. Horschitz et al. found that after removing citalopram from the system, normal levels of SERT binding site expression returned.
Depression has been suggested to be a result of a decrease of serotonin found in the synapse. This theory has been supported by the successful reduction of depressive symptoms after administration of tri-cyclic antidepressants (such as desipramine) and SSRI’s. Tri-cyclic antidepressants inhibit the reuptake of both serotonin and norepinephrine by acting upon both the SERT and NET. SSRIs selectively inhibit the reuptake of serotonin by acting upon SERT. The net result is an increased amount of serotonin in the synapse, thus increasing the probability that serotonin will interact with a serotonin receptor of the postsynaptic neuron. There are additional mechanisms by which serotonin autoreceptor desensitization must occur, but the net result is the same. This increases serotonin signaling, which then acts to elevate mood and thus relieve depressive symptoms.
The net effect of amphetamine (AMPH) use is an increase of dopamine in the synapse. It has been shown that AMPH acts upon the dopamine reuptake protein (DAT) in a reverse fashion. In DAT knockout mice, dopamine levels in the synapse (as measured by microdialysis) were no different when they were exposed to AMPH relative to baseline levels. In normal mice, levels of dopamine in the synapse rose to ten times normal levels after exposure to AMPH.
# Neuroprotective role
Astrocytes seem to utilize reuptake mechanisms for a neuroprotective role. Astrocytes use GLT-1 to remove glutamate from the synapse. GLT-1 knockout mice were more prone to lethal and spontaneous seizures and acute brain injuries among the cortex. These effects could be linked to increased concentrations of glutamate in the brains of GLT-1 knockout mice, analyzed post-mortem.. | Reuptake
Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse.
Reuptake is necessary for normal synaptic physiology because it allows for the recycling of neurotransmitters and regulates the level of neurotransmitter present in the synapse and controls how long a signal resulting from neurotransmitter release lasts. Because neurotransmitters are too large and hydrophilic to diffuse through the membrane, specific transport proteins are necessary for the reabsorption of neurotransmitters. Much research, both biochemical and structural, has been performed to obtain clues about the mechanism of reuptake.
# Protein structure
The first primary sequence of a reuptake protein was published in 1990. The technique for protein determination is contingent upon the purification, sequencing, and cloning of the transporter protein in question. After separate investigations had sequenced the DNA that coded for both GABA transporter and norepinephrine transporter, it could be seen that there were many similarities between the two DNA sequences. Further exploration in the field of reuptake proteins found that many of the transporters associated with important neurotransmitters within the body were also very similar in sequence to the GABA and norepinephrine transporters. The members of this new family include dopamine, norepinephrine, serotonin, and GABA. They were given the name Classical Na+/Cl- dependent transporters. Sodium and Chloride ion dependence will be discussed later in the mechanism of action. Using the commonalities among sequences and hydropathy plot analyses, it was determined that there are 12 hydrophobic membrane spanning structural units in the ‘Classical’ transporter family.[1] In addition to this, the Na and Cl termini exist in the intracellular space. These proteins also all have an extended fourth extracellular loop. There is an extracellular cavity in the protein, into which protrudes a helix hairpin formed by extracellular loop EL4 [2]. After using further more advanced scanning techniques, Masson et al.[1] proposed that transmembrane unit 1 (closest to the Na-terminus) exists in the membrane as a pore loop. In other words, unit 1 would not exist in a transmembrane fashion but rather as a loop existing solely in the membrane. This model has been used before to explain mechanisms for ion selectivity filters, although the purpose of this pore loop is not readily apparent[1]. This pore loop observation is consistent across all of the classical family of transporter proteins, suggesting that it is important for some function shared among them. Later experiments indicated that a tyrosine amino acid is highly conserved across transport proteins, and was shown to be essential for substrate binding and transport. Other important features include function specific positions in the transmembrane section 1, where an aspartate differentiates between monoamine substrates and a glycine differentiates between amino acid substrates. It has also been shown that a negatively charged residue in the extracellular loop 5 and the transmembrane domain 10 may form an external gate.[3]
Yamashita et al.[3] chose to examine a bacterial homologue (LeuT: Leucine transporter) of these classical transporters from the bacterium Aquifex aeolicus. Protein structure of LeuT was determined via crystallization. They chose to crystallize the system with leucine and its respective 2 sodium ions in order to visualize the pore and binding sites. The crystal was scanned via multi-wavelength anomalous dispersion. Using this technique, they were able to replicate the findings in the classical transporters, but they determined that the folding and final structure were unique. They found that the transmembrane domains 1 and 6 contain unwound segments in the middle of the membrane. Along with this, transmembrane domains 3 and 8 and the areas surrounding the unwound sections of 1 and 6 form the substrate and sodium ion binding sites. They observed pseudo-symmetry among the LeuT protein, seen best when observing transmembrane domains 1-5 against 6-10.
# Mechanism of action
The classic transporter proteins use symport to transport neurotransmitter across the membrane of the presynaptic neuron. The classical transporters, which are sodium and chloride ion dependent, take advantage of the large sodium gradients across the membrane. The neurotransmitter in question will bind to sodium ions, where the sodium ion will flow down its concentration gradient as well as electrical gradient. These forces will pull the neurotransmitter into the cell, against its own gradients. The chloride ion also contributes by flowing down its concentration gradient, but it flows against the electrical gradient, greatly reducing its efficiency as a symport ion. The role of the chloride ion in the symport mechanism is not exactly known, but has been implicated to be useful for counterbalancing the charge of the sodium symport ions.[4] Because the neurotransmitter binds to sodium ions, their respective binding sites are very close in proximity. In the LeuT protein, the binding sites would be across transmembrane domains 3 and 8, and specifically the unwound sections of 1 and 6. These binding sites are made up of hydrogen and ionic bonding between the substrate and the transport protein. The primary sodium binding sites are Na1 and Na2, which exist in the transmembrane domains 1 (TM1) and 6 (TM6) in the unwound regions. In the LeuT example, 2 sodium ions bind to the substrate leucine. These 2 sodium ions work to pull leucine into the cell, but also by stabilizing the core of LeuT.[3] Sodium ion 1 (binds to Na1) is octahedrally coordinated by the leucine carboxy oxygen, the carbonyl oxygens of Ala22 (transmembrane domain 1), Thr254 (TM6), side-chain carbonyl oxygens of Asn27 (TM1) and Asn286 (TM7), and the hydroxyl oxygen of Thr254 (TM6). The second sodium ion (binds to Na2) is trigonal bi-pyramidally coordinated by means of the carbonyl oxygens of Gly20 and Val23 (TM1), Ala351 (TM8), and the hydroxyl oxygens from Thr354 and Ser355 (TM8).[3]
After sodium ion coordination has taken place, some conformational change must occur. In an isolated system of TM3, TM8, TM1, and TM6, the unwound sections of 1 and 6 act like a joint and pivot the entire transmembrane domain relative to the rest of the protein and TM3 and TM8. The summation of actions mimics a half revolving door. Both TM3 and TM8 remain stationary and TM1 and TM6 swing about it.
The resulting system has affinity for both the substrate and sodium ions at both the intracellular level and the extracellular level. As the system progresses, the extracellular openings are blocked off by a gate.[2] Because of the sodium gradient, it is unlikely that much substrate transfer occurs from the intracellular level to the extracellular level. The LeuT transporter protein is a homologue of the human classical transport proteins, and thus the proposed mechanism of action can be assumed to be largely similar to the human model.
# Mechanism of reuptake inhibition
The main objective of a reuptake inhibitor is to substantially decrease the rate by which neurotransmitters are reabsorbed into the presynaptic neuron, leaving a net gain in the concentration of neurotransmitter in the synapse. This increases the probability and frequency of neurotransmitter binding to postsynaptic neurotransmitter receptors. Depending on the neurological system in question, a reuptake inhibitor can have drastic effects on cognition and behavior. Zhou et al.[2] examined how tricyclic antidepressants act upon a reuptake protein in order to inhibit reuptake of the appropriate neurotransmitters. They chose to examine the LeuT system as it was previously crystallized by Yamashita et al. in 2005. They also chose to examine LeuT because it is a homologue of the transport proteins of concern when considering depression. They examined this relationship between tricyclic antidepressants and the LeuT system by crystallizing the two together, along with leucine and the respective 2 sodium ions. They found that the leucine and the sodium ions bound exactly as previously determined by Yamashita et al. They also observed that the tricyclic antidepressant (desipramine) followed leucine into the pore. Desipramine effectively sits on top of leucine in LeuT and they both bind to the same protein residue. The tail of desipramine extends into the extracellular space. Most of the LeuT structure does not change, but the EL4 hairpin does form around desipramine as if it were locking it in place in the LeuT pore.[2] Desipramine also acts by binding to the extracellular gate and forming a salt bridge between TM1 and TM10. This action prevents TM1 from pivoting, which prevents leucine from ever being exposed to the intracellular side of LeuT. Desipramine works as a reuptake inhibitor by effectively blocking and crowding up the pore of LeuT, which physically prevents its normal course of action.
# Human systems
Horschitz et al.[5] examined reuptake inhibitor selectivity among the rat serotonin reuptake protein (SERT) expressed in human embryonic kidney cells (HEK-SERT). They presented SERT with varying doses of either citalopram (SSRI, selective serotonin reuptake inhibitor) or desipramine (an inhibitor of norepinephrine reuptake protein, NET). By examining the dose-response curves (using a normal medium as control), they were able to quantify that citalopram acted on SERT as an SSRI, and that desipramine had no effect on SERT. In a separate experiment, Horschitz et al. exposed HEK-SERT with citalopram on a long-term basis. They noticed that long-term exposure led to a down-regulation of binding sites. These results suggest some mechanism for long-term changes in the pre-synaptic neuron after drug therapy. Horschitz et al. found that after removing citalopram from the system, normal levels of SERT binding site expression returned.[5]
Depression has been suggested to be a result of a decrease of serotonin found in the synapse. This theory has been supported by the successful reduction of depressive symptoms after administration of tri-cyclic antidepressants (such as desipramine) and SSRI’s. Tri-cyclic antidepressants inhibit the reuptake of both serotonin and norepinephrine by acting upon both the SERT and NET. SSRIs selectively inhibit the reuptake of serotonin by acting upon SERT. The net result is an increased amount of serotonin in the synapse, thus increasing the probability that serotonin will interact with a serotonin receptor of the postsynaptic neuron. There are additional mechanisms by which serotonin autoreceptor desensitization must occur, but the net result is the same.[6] This increases serotonin signaling, which then acts to elevate mood and thus relieve depressive symptoms.
The net effect of amphetamine (AMPH) use is an increase of dopamine in the synapse. It has been shown that AMPH acts upon the dopamine reuptake protein (DAT) in a reverse fashion. In DAT knockout mice, dopamine levels in the synapse (as measured by microdialysis) were no different when they were exposed to AMPH relative to baseline levels. In normal mice, levels of dopamine in the synapse rose to ten times normal levels after exposure to AMPH.[7]
# Neuroprotective role
Astrocytes seem to utilize reuptake mechanisms for a neuroprotective role. Astrocytes use GLT-1 to remove glutamate from the synapse. GLT-1 knockout mice were more prone to lethal and spontaneous seizures and acute brain injuries among the cortex. These effects could be linked to increased concentrations of glutamate in the brains of GLT-1 knockout mice, analyzed post-mortem.[8]. | https://www.wikidoc.org/index.php/Re-uptake |
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